[Federal Register Volume 81, Number 156 (Friday, August 12, 2016)]
[Proposed Rules]
[Pages 53688-53766]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-17954]



[[Page 53687]]

Vol. 81

Friday,

No. 156

August 12, 2016

Part IV





 Department of Justice





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 Drug Enforcement Administation





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21 CFR Chapter II and Part 1301





Denial of Petition To Initiate Proceedings To Reschedule Marijuana; 
Proposed Rules and Applications To Become Registered Under the 
Controlled Substances Act To Manufacture Marijuana To Supply 
Researchers in the United States; Policy Statement

  Federal Register / Vol. 81 , No. 156 / Friday, August 12, 2016 / 
Proposed Rules  

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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Chapter II

[Docket No. DEA-426]


Denial of Petition To Initiate Proceedings To Reschedule 
Marijuana

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Denial of petition to initiate proceedings to reschedule 
marijuana.

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SUMMARY: By letter dated July 19, 2016 the Drug Enforcement 
Administration (DEA) denied a petition to initiate rulemaking 
proceedings to reschedule marijuana. Because the DEA believes that this 
matter is of particular interest to members of the public, the agency 
is publishing below the letter sent to the petitioner which denied the 
petition, along with the supporting documentation that was attached to 
the letter.

DATES: August 12, 2016.

FOR FURTHER INFORMATION CONTACT: Michael J. Lewis, Office of Diversion 
Control, Drug Enforcement Administration; Mailing Address: 8701 
Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 598-
6812.

SUPPLEMENTARY INFORMATION: 

July 19, 2016

    Dear Ms. Raimondo and Mr. Inslee:
    On November 30, 2011, your predecessors, The Honorable Lincoln 
D. Chafee and The Honorable Christine O. Gregoire, petitioned the 
Drug Enforcement Administration (DEA) to initiate rulemaking 
proceedings under the rescheduling provisions of the Controlled 
Substances Act (CSA). Specifically, your predecessors petitioned the 
DEA to have marijuana and ``related items'' removed from Schedule I 
of the CSA and rescheduled as medical cannabis in Schedule II.
    Your predecessors requested that the DEA remove marijuana and 
related items from Schedule I based on their assertion that:
    (1) Cannabis has accepted medical use in the United States;
    (2) Cannabis is safe for use under medical supervision;
    (3) Cannabis for medical purposes has a relatively low potential 
for abuse, especially in comparison with other Schedule II drugs.
    In accordance with the CSA rescheduling provisions, after 
gathering the necessary data, the DEA requested a scientific and 
medical evaluation and scheduling recommendation from the Department 
of Health and Human Services (HHS). The HHS concluded that marijuana 
has a high potential for abuse, has no accepted medical use in the 
United States, and lacks an acceptable level of safety for use even 
under medical supervision. Therefore, the HHS recommended that 
marijuana remain in Schedule I. The scientific and medical 
evaluation and scheduling recommendation that the HHS submitted to 
the DEA is enclosed with this letter.
    Based on the HHS evaluation and all other relevant data, the DEA 
has concluded that there is no substantial evidence that marijuana 
should be removed from Schedule I. A document prepared by the DEA 
addressing these materials in detail also is enclosed. In short, 
marijuana continues to meet the criteria for Schedule I control 
under the CSA because:
    (1) Marijuana has a high potential for abuse. The HHS evaluation 
and the additional data gathered by the DEA show that marijuana has 
a high potential for abuse.
    (2) Marijuana has no currently accepted medical use in treatment 
in the United States. Based on the established five-part test for 
making such determination, marijuana has no ``currently accepted 
medical use'' because: As detailed in the HHS evaluation, the drug's 
chemistry is not known and reproducible; there are no adequate 
safety studies; there are no adequate and well-controlled studies 
proving efficacy; the drug is not accepted by qualified experts; and 
the scientific evidence is not widely available.
    (3) Marijuana lacks accepted safety for use under medical 
supervision. At present, there are no marijuana products approved by 
the U.S. Food and Drug Administration (FDA), nor is marijuana under 
a New Drug Application (NDA) evaluation at the FDA for any 
indication. The HHS evaluation states that marijuana does not have a 
currently accepted medical use in treatment in the United States or 
a currently accepted medical use with severe restrictions. At this 
time, the known risks of marijuana use have not been shown to be 
outweighed by specific benefits in well-controlled clinical trials 
that scientifically evaluate safety and efficacy.
    The statutory mandate of Title 21 United States Code, Section 
812(b) (21 U.S.C. 812(b)) is dispositive. Congress established only 
one schedule, Schedule I, for drugs of abuse with ``no currently 
accepted medical use in treatment in the United States'' and ``lack 
of accepted safety for use . . . under medical supervision.'' 21 
U.S.C. 812(b).
    Although the HHS evaluation and all other relevant data lead to 
the conclusion that marijuana must remain in schedule I, it should 
also be noted that, in view of United States obligations under 
international drug control treaties, marijuana cannot be placed in a 
schedule less restrictive than schedule II. This is explained in 
detail in accompanying document titled ``Preliminary Note Regarding 
Treaty Considerations.''
    Accordingly, and as set forth in detail in the accompanying HHS 
and DEA documents, there is no statutory basis under the CSA for the 
DEA to grant your predecessors' petition to initiate rulemaking 
proceedings to reschedule marijuana. The petition is, therefore, 
hereby denied.

Sincerely,

Chuck Rosenberg,

Acting Administrator.

Attachments:

Preliminary Note Regarding Treaty Considerations

    Cover Letter from HHS to DEA Summarizing the Scientific and 
Medical Evaluation and Scheduling Recommendation for Marijuana.
    U.S. Department of Health and Human Services (HHS)--Basis for 
the Recommendation for Maintaining Marijuana in Schedule I of the 
Controlled Substances Act
    U.S. Department of Justice--Drug Enforcement Administration 
(DEA), Schedule of Controlled Substances: Maintaining Marijuana in 
Schedule I of the Controlled Substances Act, Background, Data, and 
Analysis: Eight Factors Determinative of Control and Findings 
Pursuant to 21 U.S.C. 812(b)

    Dated: July 19, 2016.
Chuck Rosenberg,
Acting Administrator, Preliminary Note Regarding Treaty Considerations.

    As the Controlled Substances Act (CSA) recognizes, the United 
States is a party to the Single Convention on Narcotic Drugs, 1961 
(referred to here as the Single Convention or the treaty). 21 U.S.C. 
801(7). Parties to the Single Convention are obligated to maintain 
various control provisions related to the drugs that are covered by the 
treaty. Many of the provisions of the CSA were enacted by Congress for 
the specific purpose of ensuring U.S. compliance with the treaty. Among 
these is a scheduling provision, 21 U.S.C. 811(d)(1). Section 811(d)(1) 
provides that, where a drug is subject to control under the Single 
Convention, the DEA Administrator (by delegation from the Attorney 
General) must ``issue an order controlling such drug under the schedule 
he deems most appropriate to carry out such [treaty] obligations, 
without regard to the findings required by [21 U.S.C. 811(a) or 812(b)] 
and without regard to the procedures prescribed by [21 U.S.C. 811(a) 
and (b)].''
    Marijuana is a drug listed in the Single Convention. The Single 
Convention uses the term ``cannabis'' to refer to marijuana.\1\ Thus, 
the DEA

[[Page 53689]]

Administrator is obligated under section 811(d) to control marijuana in 
the schedule that he deems most appropriate to carry out the U.S. 
obligations under the Single Convention. It has been established in 
prior marijuana rescheduling proceedings that placement of marijuana in 
either schedule I or schedule II of the CSA is ``necessary as well as 
sufficient to satisfy our international obligations'' under the Single 
Convention. NORML v. DEA, 559 F.2d 735, 751 (D.C. Cir. 1977). As the 
United States Court of Appeals for the DC Circuit has stated, ``several 
requirements imposed by the Single Convention would not be met if 
cannabis and cannabis resin were placed in CSA schedule III, IV, or 
V.'' \2\ Id. Therefore, in accordance with section 811(d)(1), DEA must 
place marijuana in either schedule I or schedule II.
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    \1\ Under the Single Convention, ``cannabis plant' means any 
plant of the genus Cannabis.'' Article 1(c). The Single Convention 
defines ``cannabis'' to include ``the flowering or fruiting tops of 
the cannabis plant (excluding the seeds and leaves when not 
accompanied by the tops) from which the resin has not been 
extracted, by whatever name they may be designated.'' Article 1(b). 
This definition of ``cannabis'' under the Single Convention is 
slightly less inclusive than the CSA definition of ``marihuana,'' 
which includes all parts of the cannabis plant except for the mature 
stalks, sterilized seeds, oil from the seeds, and certain 
derivatives thereof. See 21 U.S.C. 802(16). Cannabis and cannabis 
resin are included in the list of drugs in Schedule I and Schedule 
IV of the Single Convention. In contrast to the CSA, the drugs 
listed in Schedule IV of the Single Convention are also listed in 
Schedule I of the Single Convention and are subject to the same 
controls as Schedule I drugs as well as additional controls. Article 
2, par. 5
    \2\ The Court further stated: ``For example, [article 31 
paragraph 4 of the Single Convention] requires import and export 
permits that would not be obtained if the substances were placed in 
CSA schedules III through V. In addition, the quota and 
[recordkeeping] requirements of Articles 19 through 21 of the Single 
Convention would be satisfied only by placing the substances in CSA 
schedule I or II.'' Id. n. 71 (internal citations omitted).
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    Because schedules I and II are the only possible schedules in which 
marijuana may be placed, for purposes of evaluating this scheduling 
petition, it is essential to understand the differences between the 
criteria for placement of a substance in schedule I and those for 
placement in schedule II. These criteria are set forth in 21 U.S.C. 
812(b)(1) and (b)(2), respectively. As indicated therein, substances in 
both schedule I and schedule II share the characteristic of ``a high 
potential for abuse.'' Where the distinction lies is that schedule I 
drugs have ``no currently accepted medical use in treatment in the 
United States'' and ``a lack of accepted safety for use of the drug . . 
. under medical supervision,'' while schedule II drugs do have ``a 
currently accepted medical use in treatment in the United States.'' \3\
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    \3\ As DEA has stated in evaluating prior marijuana rescheduling 
petitions, ``Congress established only one schedule, schedule I, for 
drugs of abuse with `no currently accepted medical use in treatment 
in the United States'and `lack of accepted safety for use . . . 
under medical supervision.' 21 U.S.C. 812(b).'' 76 FR 40552 (2011); 
66 FR 20038 (2001).
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    Accordingly, in view of section 811(d)(1), this scheduling petition 
turns on whether marijuana has a currently accepted medical use in 
treatment in the United States. If it does not, DEA must, pursuant to 
section 811(d), deny the petition and keep marijuana in schedule I.
    As indicated, where section 811(d)(1) applies to a drug that is the 
subject of a rescheduling petition, the DEA Administrator must issue an 
order controlling the drug under the schedule he deems most appropriate 
to carry out United States obligations under the Single Convention, 
without regard to the findings required by sections 811(a) or 812(b) 
and without regard to the procedures prescribed by sections 811(a) and 
(b). Thus, since the only determinative issue in evaluating the present 
scheduling petition is whether marijuana has a currently accepted 
medical use in treatment in the United States, DEA need not consider 
the findings of sections 811(a) or 812(b) that have no bearing on that 
determination, and DEA likewise need not follow the procedures 
prescribed by sections 811(a) and (b) with respect to such irrelevant 
findings. Specifically, DEA need not evaluate the relative abuse 
potential of marijuana or the relative extent to which abuse of 
marijuana may lead to physical or psychological dependence.
    As explained below, the medical and scientific evaluation and 
scheduling recommendation issued by the Secretary of Health and Human 
Services concludes that marijuana has no currently accepted medical use 
in treatment in the United States, and the DEA Administrator likewise 
so concludes. For the reasons just indicated, no further analysis 
beyond this consideration is required. Nonetheless, because of the 
widespread public interest in understanding all the facts relating to 
the harms associated with marijuana, DEA is publishing here the entire 
medical and scientific analysis and scheduling evaluation issued by the 
Secretary, as well as DEA's additional analysis.

Department of Health and Human Services, Office of the Secretary 
Assistant Secretary for Health, Office of Public Health and Science, 
Washington, DC 20201.

June 25, 2015.

The Honorable Chuck Rosenberg

Acting Administrator, Drug Enforcement Administration, U.S. 
Department of Justice, 8701 Morrissette Drive, Springfield, VA 
22152.

    Dear Mr. Rosenberg:
    Pursuant to the Controlled Substances Act (CSA, 21 U.S.C. Sec.  
811(b), (c), and (f)), the Department of Health and Human Services 
(HHS) is recommending that marijuana continue to be maintained in 
Schedule I of the CSA.
    The Food and Drug Administration (FDA) has considered the abuse 
potential and dependence-producing characteristics of marijuana.
    Marijuana meets the three criteria for placing a substance in 
Schedule I of the CSA under 21 U.S.C. 812(b)(1). As discussed in the 
enclosed analyses, marijuana has a high potential for abuse, no 
currently accepted medical use in treatment in the United States, 
and a lack of accepted safety for use under medical supervision. 
Accordingly, HHS recommends that marijuana be maintained in Schedule 
I of the CSA. Enclosed are two documents prepared by FDA's 
Controlled Substance Staff (in response to petitions filed in 2009 
by Mr. Bryan Krumm and in 2011 by Governors Lincoln D. Chafee and 
Christine O. Gregoire) that form the basis for the recommendation. 
Pursuant to the requests in the petitions, FDA broadly evaluated 
marijuana, and did not focus its evaluation on particular strains of 
marijuana or components or derivatives of marijuana.
    FDA's Center for Drug Evaluation and Research's current review 
of the available evidence and the published clinical studies on 
marijuana demonstrated that since our 2006 scientific and medical 
evaluation and scheduling recommendation responding to a previous 
DEA petition, research with marijuana has progressed. However, the 
available evidence is not sufficient to determine that marijuana has 
an accepted medical use. Therefore, more research is needed into 
marijuana's effects, including potential medical uses for marijuana 
and its derivatives. Based on the current review, we identified 
several methodological challenges in the marijuana studies published 
in the literature. We recommend they be addressed in future clinical 
studies with marijuana to ensure that valid scientific data are 
generated in studies evaluating marijuana's safety and efficacy for 
therapeutic use. For example, we recommend that studies need to 
focus on consistent administration and reproducible dosing of 
marijuana, potentially through the use of administration methods 
other than smoking. A summary of our review of the published 
literature on the clinical uses of marijuana, including 
recommendations for future studies, is attached to this document.
    FDA and the National Institutes of Health's National Institute 
on Drug Abuse (NIDA) also believe that work continues to be needed 
to ensure support by the federal government for the efficient 
conduct of clinical research using marijuana. Concerns have been 
raised about whether the existing federal regulatory system is 
flexible enough to respond to increased interest in research into 
the potential therapeutic uses of marijuana and marijuana-derived 
drugs. HHS welcomes an opportunity to continue to explore these 
concerns with DEA.
    Should you have any questions regarding theses recommendations, 
please contact Corinne P. Moody, Science Policy Analyst, Controlled 
Substances Staff, Center for Drug Evaluation and Research, FDA, at 
(301) 796-3152.

Sincerely yours,

Karen B. DeSalvo, MD, MPH, MSc

Acting Assistant Secretary for Health.

Enclosure: Basis for the Recommendation for Maintaining Marijuana in 
Schedule I of the Controlled Substances Act

[[Page 53690]]

Basis for the Recommendation for Maintaining Marijuana in Schedule I of 
the Controlled Substances Act

    On November 30, 2011, Governors Lincoln D. Chafee of Rhode Island 
and Christine O. Gregoire of Washington submitted a petition to the 
Drug Enforcement Administration (DEA) requesting that proceeding be 
initiated to repeal the rules and regulations that place marijuana \4\ 
in Schedule I of the Controlled Substances Act (CSA). The petition 
contends that cannabis has an accepted medical use in the United 
States, is safe for use under medical supervision, and has a relatively 
low abuse potential compared to other Schedule II drugs. The petition 
requests that marijuana and ``related items'' be rescheduled in 
Schedule II of the CSA. In June 2013, the DEA Administrator requested 
that the U.S. Department of Health and Human Services (HHS) provide a 
scientific and medical evaluation of the available information and a 
scheduling recommendation for marijuana, in accordance with the 
provisions of 21 U.S.C. 811(b).
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    \4\ Note that ``marihuana'' is the spelling originally used in 
the Controlled Substances Act (CSA). This document uses the spelling 
that is more common in current usage, ``marijuana.''
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    In accordance with 21 U.S.C. 811(b), DEA has gathered information 
related to the control of marijuana (Cannabis sativa) \5\ under the 
CSA. Pursuant to 21 U.S.C. 811(b), the Secretary of HHS is required to 
consider in a scientific and medical evaluation eight factors 
determinative of control under the CSA. Following consideration of the 
eight factors, if it is appropriate, the Secretary must make three 
findings to recommend scheduling a substance in the CSA. The findings 
relate to a substance's abuse potential, legitimate medical use, and 
safety or dependence liability.
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    \5\ The CSA defines marijuana as the following:
    All parts of the plant Cannabis Sativa L., whether growing or 
not; the seeds thereof; the resin extracted from any part of such 
plant; and every compound, manufacture, salt, derivative, mixture, 
or preparation of such plant, its seeds or resin. Such term does not 
include the mature stalks of such plant, fiber produced from such 
stalks, oil or cake made from the seeds of such plant, any other 
compound, manufacture, salt, derivative, mixture, or preparation of 
such mature stalks (except the resin extracted therefrom), fiber, 
oil, or cake, or the sterilized seed of such plant which is 
incapable of germination (21 U.S.C. 802(16)).
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    Administrative responsibilities for evaluating a substance for 
control under the CSA are performed by the Food and Drug Administration 
(FDA), with the concurrence of the National Institute on Drug Abuse 
(NIDA), as described in the Memorandum of Understanding (MOU) of March 
8, 1985 (50 FR 9518-20).
    In this document, FDA recommends the continued control of marijuana 
in Schedule I of the CSA. Pursuant to 21 U.S.C. 811(c), the eight 
factors pertaining to the scheduling of marijuana are considered below.

1. Its Actual or Relative Potential for Abuse

    Under the first factor the Secretary must consider marijuana's 
actual or relative potential for abuse. The CSA does not define the 
term ``abuse.'' However, the CSA's legislative history suggests the 
following in determining whether a particular drug or substance has a 
potential for abuse: \6\
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    \6\ Comprehensive Drug Abuse Prevention and Control Act of 1970, 
H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970) reprinted in 
U.S.C.C.A.N. 4566, 4603.
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    a. There is evidence that individuals are taking the drug or drugs 
containing such a substance in amounts sufficient to create a hazard to 
their health or to the safety of other individuals or to the community.
    b. There is a significant diversion of the drug or drugs containing 
such a substance from legitimate drug channels.
    c. Individuals are taking the drug or drugs containing such a 
substance on their own initiative rather than on the basis of medical 
advice from a practitioner licensed by law to administer such drugs in 
the course of his professional practice.
    d. The drug or drugs containing such a substance are new drugs so 
related in their action to a drug or drugs already listed as having a 
potential for abuse to make it likely that the drug will have the same 
potentiality for abuse as such drugs, thus making it reasonable to 
assume that there may be significant diversions from legitimate 
channels, significant use contrary to or without medical advice, or 
that it has a substantial capability of creating hazards to the health 
of the user or to the safety of the community.
    In the development of this scientific and medical evaluation for 
the purpose of scheduling, the Secretary analyzed considerable data 
related to the substance's abuse potential. The data include a 
discussion of the prevalence and frequency of use, the amount of the 
substance available for illicit use, the ease of obtaining or 
manufacturing the substance, the reputation or status of the substance 
``on the street,'' and evidence relevant to at-risk populations. 
Importantly, the petitioners define marijuana as including all Cannabis 
cultivated strains. Different marijuana samples derived from various 
cultivated strains may have very different chemical constituents, thus 
the analysis is based on what is known about the range of these 
constituents across all cultivated strains.
    Determining the abuse potential of a substance is complex with many 
dimensions, and no single test or assessment provides a complete 
characterization. Thus, no single measure of abuse potential is ideal. 
Scientifically, a comprehensive evaluation of the relative abuse 
potential of a substance can include consideration of the following 
elements: Receptor binding affinity, preclinical pharmacology, 
reinforcing effects, discriminative stimulus effects, dependence 
producing potential, pharmacokinetics, route of administration, 
toxicity, data on actual abuse, clinical abuse potential studies, and 
public health risks. Importantly, abuse can exist independently from 
tolerance or physical dependence because individuals may abuse drugs in 
doses or patterns that do not induce these phenomena. Additionally 
evidence of clandestine population and illicit trafficking of a 
substance can shed light on both the demand for a substance as well as 
the ease of obtaining a substance. Animal and human laboratory data and 
epidemiological data are all used in determining a substance's abuse 
potential. Moreover, epidemiological data can indicate actual abuse.
    The petitioners compare the effects of marijuana to currently 
controlled Schedule II substances and make repeated claims about their 
comparative effects. Comparisons between marijuana and the diverse 
array of Schedule II substances is difficult, because of the 
pharmacologically dissimilar actions of substances of Schedule II of 
the CSA. For example, Schedule II substances include stimulant-like 
drugs (e.g., cocaine, methylphenidate, and amphetamine), opioids (e.g., 
oxycodone, fentanyl), sedatives (e.g., pentobarbital, amobarbital), 
dissociative anesthetics (e.g., PCP), and naturally occurring plant 
components (e.g., coca leaves and poppy straw). The mechanism(s) of 
action of the above Schedule II substances are wholly different from 
one another, and they are different from tetrahydrocannabinol (THC) and 
marijuana as well. For example, Schedule II stimulants typically 
function by increasing monoaminergic tone via an increase in dopamine 
and norepinephrine (Schmitt et al., 2013). In contrast, opioid 
analgesics function via mu-opioid receptor agonist effects. These 
differing mechanism(s) of action result in vastly different behavioral 
and adverse effect profiles, making comparisons across the range of

[[Page 53691]]

pharmacologically diverse C-II substances inappropriate.
    In addition, many substances scheduled under the CSA are reviewed 
and evaluated within the context of commercial drug development, using 
data submitted in the form of a new drug application (NDA). A new 
analgesic drug might be compared to a currently scheduled analgesic 
drug as part of the assessment of its relative abuse potential. 
However, because the petitioners have not identified a specific 
indication for the use of marijuana, identifying an appropriate 
comparator based on indication cannot be done.
    a. There is evidence that individuals are taking the substance in 
amounts sufficient to create a hazard to their health or to the safety 
of other individuals or to the community.
    Evidence shows that some individuals are taking marijuana in 
amounts sufficient to create a hazard to their health and to the safety 
of other individuals and the community. A large number of individuals 
use marijuana. HHS provides data on the extent of marijuana abuse 
through NIDA and the Substance Abuse and Mental Health Services 
Administration (SAMHSA). According to the most recent data from 
SAMHSA's 2012 National Survey on Drug Use and Health (NSDUH), which 
estimates the number of individuals who have used a substance within a 
month prior to the study (described as ``current use''), marijuana is 
the most commonly used illicit drug among Americans aged 12 years and 
older, with an estimated 18.9 million Americans having used marijuana 
within the month prior to the 2012 NSDUH. Compared to 2004, when an 
estimated 14.6 million individuals reported using marijuana within the 
month prior to the study, the estimated rates in 2012 show an increase 
of approximately 4.3 million individuals. The 2013 Monitoring the 
Future (MTF) survey of 8th, 10th, and 12th grade students also 
indicates that marijuana is the most widely used illicit substance in 
this age group. Specifically, current month use was at 7.0 percent of 
8th graders, 18.0 percent of 10th, graders and 22.7 percent of 12th 
graders. Additionally, the 2011 Treatment Episode Data Set (TEDS) 
reported that primary marijuana abuse accounted for 18.1 percent of 
non-private substance-abuse treatment facility admissions, with 24.3 
percent of those admitted reporting daily use. However, of these 
admissions for primary marijuana abuse, the criminal justice system 
referred 51.6 percent to treatment. SAMHSA's Drug Abuse Warning Network 
(DAWN) was a national probability survey of U.S. hospitals with 
emergency departments (EDs) and was designed to obtain information on 
ED visits in which marijuana was mentioned, accounting for 36.4 percent 
of illicit drug related ED visits. There are some limitations related 
to DAWN data on ED visits, which are discussed in detail in Factor 4, 
``Its History and Current Pattern of Abuse;'' Factor 5, ``The Scope, 
Duration, and Significance of Abuse;'' and Factor 6, ``What, if any, 
Risk There is to the Public Health.'' These factors contain detailed 
discussions of these data.
    A number of risks can occur with both acute and chronic use of 
marijuana. Detailed discussions of the risks are addressed in Factor 2, 
``Scientific Evidence of its Pharmacological Effect, if Known,'' and 
Factor 6, ``What, if any, Risk There is to the Public Health.''
    b. There is significant diversion of the substance from legitimate 
drug channels.
    There is a lack of evidence of significant diversion of marijuana 
from legitimate drug channels, but this is likely due to the fact that 
marijuana is more widely available from illicit sources rather than 
through legitimate channels. Marijuana is not an FDA-approved drug 
product, as an NDA or biologics license application (BLA) has not been 
approved for marketing in the United States. Numerous states and the 
District of Columbia have state-level medical marijuana laws that allow 
for marijuana use within that state. These state-level drug channels do 
not have sufficient collection of data related to medical treatment, 
including efficacy and safety.
    Marijuana is used by researchers for nonclinical research as well 
as clinical research under investigational new drug (IND) applications; 
this represents the only legitimate drug channel in the United States. 
However, marijuana used for research represents a very small 
contribution of the total amount of marijuana available in the United 
States, and thus provides limited information about diversion. In 
addition, the lack of significant diversion of investigation supplies 
is likely because of the widespread availability of illicit marijuana 
of equal or greater amounts of delta\9\-THC. The data originating from 
the DEA on seizure statistics demonstrate the magnitude of the 
availability for illicit marijuana. DEA's System to Retrieve 
Information from Drug Evidence (STRIDE) provides information on total 
domestic drug seizures. STRIDE reports a total domestic seizure of 
573,195 kg of marijuana in 2011, the most recent year with complete 
data that is currently publically available (DEA Domestic Drug 
Seizures, n.d.).
    c. Individuals are taking the substance on their own initiative 
rather than on the basis of medical advice from a practitioner licensed 
by law to administer such substances.
    Because the FDA has not approved an NDA or BLA for a marijuana drug 
product for any therapeutic indication, the only way an individual can 
take marijuana on the basis of medical advice through legitimate 
channels at the federal level is by participating in research under an 
IND application. That said, numerous states and the District of 
Columbia have passed state-level medical marijuana laws allowing for 
individuals to use marijuana under certain circumstances. However, data 
are not yet available to determine the number of individuals using 
marijuana under these state-level medical marijuana laws. Regardless, 
according to the 2012 NSDUH data, 18.9 million American adults 
currently use marijuana (SAMHSA, 2013). Based on the large number of 
individuals reporting current use of marijuana and the lack of an FDA-
approved drug product in the United States, one can assume that it is 
likely that the majority of individuals using marijuana do so on their 
own initiative rather than on the basis of medical advice from a 
licensed practitioner.
    d. The substance is so related in its action to a substance already 
listed as having a potential for abuse to make it likely that it will 
have the same potential for abuse as such substance, thus making it 
reasonable to assume that there may be significant diversions from 
legitimate channels, significant use contrary to or without medical 
advice, or that it has a substantial capability of creating hazards to 
the health of the user or to the safety of the community.
    FDA has approved two drug products containing cannabinoid compounds 
that are structurally related to the active components in marijuana. 
These two marketed products are controlled under the CSA. Once a 
specific drug product containing cannabinoids becomes approved, that 
specific drug product may be moved from Schedule I to a different 
Schedule (II-V) under the CSA. Firstly, Marinol--generically known as 
dronabinol--is a Schedule III drug product containing synthetic 
delta\9\-THC. Marinol, which is formulated in sesame oil in soft 
gelatin capsules, was first placed in Schedule II under the CSA 
following its approval by the FDA. Marinol was later rescheduled to 
Schedule III under the CSA because of low numbers of reports of abuse 
relative to marijuana. Dronabinol is

[[Page 53692]]

listed in Schedule I under the CSA. FDA approved Marinol in 1985 for 
the treatment of nausea and vomiting associated with cancer 
chemotherapy in patients who failed to respond adequately to 
conventional anti-emetic treatments. In 1992, FDA approved Marional for 
anorexia associated with weight loss in patients with acquired 
immunodeficiency syndrome (AIDS). Secondly, in 1985, FDA approved 
Cesamet, a drug product containing the Schedule II substance nabilone, 
for the treatment of nausea and vomiting associated with cancer 
chemotherapy. Besides the two cannabinoid-containing drug products FDA 
approved for marketing, other naturally occurring cannabinoids and 
their derivatives (from Cannabis) and their synthetic equivalents with 
similar chemical structure and pharmacological activity are included in 
the CSA as Schedule I substances.

2. Scientific Evidence of Its Pharmacological Effects, if Known

    Under the second factor, the Secretary must consider the scientific 
evidence of marijuana's pharmacological effects. Abundant scientific 
data are available on the neurochemistry, toxicology, and pharmacology 
of marijuana. This section includes a scientific evaluation of 
marijuana's neurochemistry; pharmacology; and human and animal 
behavioral, central nervous system, cognitive, cardiovascular, 
autonomic, endocrinological, and immunological system effects. The 
overview presented below relies upon the most current research 
literature on cannabinoids.

Neurochemistry and Pharmacology of Marijuana

    Marijuana is a plant that contains numerous natural constituents, 
such as cannabinoids, that have a variety of pharmacological actions. 
The petition defines marijuana as including all Cannabis cultivated 
strains. Different marijuana samples derived from various cultivated 
strains may have very different chemical constituents including 
delta\9\-THC and other cannabinoids (Appendino et al., 2011). As a 
consequence, marijuana products from different strains will have 
different biological and pharmacological profiles.
    According to ElSohly and Slade (2005) and Appendino et al. (2011), 
marijuana contains approximately 525 identified natural constituents, 
including approximately 100 compounds classified as cannabinoids. 
Cannabinoids primarily exist in Cannabis, and published data suggests 
that most major cannabinoid compounds occurring naturally have been 
identified chemically. New and minor cannabinoids and other new 
compounds are continuously being characterized (Pollastro et al., 
2011). So far, only two cannabinoids (cannabigerol and its 
corresponding acid) have been obtained from a non-Cannabis source. A 
South African Helichrysum (H. umbraculigerum) accumulates these 
compounds (Appendino et al., 2011). The chemistry of marijuana is 
described in more detail in Factor 3, ``The State of Current Scientific 
Knowledge Regarding the Drug or Other Substance.''
    The site of cannabinoid action is at the cannabinoid receptors. 
Cloning of cannabinoid receptors, first from rat brain tissue (Matsuda 
et al., 1990) and then from human brain tissue (Gerard et al., 1991), 
has verified the site of action. Two cannabinoid receptors, 
CB1 and CB2, were characterized (Battista et al., 
2012; Piomelli, 2005). Evidence of a third cannabinoid receptor exists, 
but it has not been identified (Battista et al., 2012).
    The cannabinoid receptors, CB1 and CB2, 
belong to the family of G-protein-coupled receptors, and present a 
typical seven transmembrane-spanning domain structure. Cannabinoid 
receptors link to an inhibitory G-protein (Gi), such that 
adenylate cyclase activity is inhibited when a ligand binds to the 
receptor. This, in turn, prevents the conversion of ATP to the second 
messenger, cyclic AMP (cAMP). Examples of inhibitory coupled receptors 
include opioid, muscarinic cholinergic, alpha2-
adrenoreceptors, dopamine (D2), and serotonin (5-
HT1).
    Cannabinoid receptor activation inhibits N- and P/Q-type calcium 
channels and activates inwardly rectifying potassium channels (Mackie 
et al., 1995; Twitchell et al., 1997). N-type calcium channel 
inhibition decreases neurotransmitter release from several tissues. 
Thus, calcium channel inhibition may be the mechanism by which 
cannabinoids inhibit acetylcholine, norepinephrine, and glutamate 
release from specific areas of the brain. These effects may represent a 
potential cellular mechanism underlying cannabinoids' antinociceptive 
and psychoactive effects (Ameri, 1999).
    CB1 receptors are found primarily in the central nervous 
system, but are also present in peripheral tissues. CB1 
receptors are located mainly in the basal ganglia, hippocampus, and 
cerebellum of the brain (Howlett et al., 2004). The localization of 
these receptors may explain cannabinoid interference with movement 
coordination and effects on memory and cognition. Additionally, 
CB1 receptors are found in the immune system and numerous 
other peripheral tissues (Petrocellis and Di Marzo, 2009). However, the 
concentration of CB1 receptors is considerably lower in 
peripheral tissues than in the central nervous system (Herkenharn et 
al., 1990 and 1992).
    CB2 receptors are found primarily in the immune system, 
but are also present in the central nervous system and other peripheral 
tissues. In the immune system, CB2 receptors are found 
predominantly in B lymphocytes and natural killer cells (Bouaboula et 
al., 1993). CB2 receptors may mediate cannabinoids' 
immunological effects (Galiegue et al., 1995). Additionally, 
CB2 receptors have been localized in the brain, primarily in 
the cerebellum and hippocampus (Gong et al., 2006). The distribution of 
CB2 receptors throughout the body is less extensive than the 
distribution of CB1 receptors (Petrocellis and Di Marzo, 
2009). However, both CB1 and CB2 receptors are 
present in numerous tissues of the body.
    Cannabinoid receptors have endogenous ligands. In 1992 and 1995, 
two endogenous cannabinoid receptor agonists, anandamide and 
arachidonyl glycerol (2-AG), respectively, were identified (Di Marzo, 
2006). Anandamide is a low efficacy agonist (Breivogel and Childers, 
2000) and 2-AG is a high efficacy agonist (Gonsiorek et al., 2000). 
Cannabinoid endogenous ligands are present in central as well as 
peripheral tissues. A combination of uptake and hydrolysis terminate 
the action of the endogenous ligands. The endogenous cannabinoid system 
is a locally active signaling system that, to help restore homeostasis, 
is activated ``on demand'' in response to changes to the local 
homeostasis (Petrocellis and Di Marzo, 2009). The endogenous 
cannabinoid system, including the endogenous cannabinoids and the 
cannabinoid receptors, demonstrate substantial plasticity in response 
to several physiological and pathological stimuli (Petrocellis and Di 
Marzo, 2009). This plasticity is particularly evident in the central 
nervous system.
    Delta\9\-THC and cannabidiol (CBD) are two abundant cannabinoids 
present in marijuana. Marijuana's major psychoactive cannabinoid is 
delta\9\-THC (Wachtel et al., 2002). In 1964, Gaoni and Mechoularn 
first described delta\9\-THC's structure and function. In 1963, 
Mechoularn and Shvo first described CBD's structure. The 
pharmacological actions of CBD have not been fully studied in humans.
    Delta\9\-THC and CBD have varying affinity and effects at the 
cannabinoid receptors. Delta\9\-THC displays similar

[[Page 53693]]

affinity for CB1 and CB2 receptors, but behaves 
as a weak agonist for CB2 receptors. The identification of 
synthetic cannabinoid ligands that selectively bind to CB2 
receptors but do not have the typical delta\9\-THC-like psychoactive 
properties suggests that the activation of CB1-receptors 
mediates cannabinoids' psychotropic effects (Hanus et al., 1999). CBD 
has low affinity for both CB1 and CB2 receptors 
(Mechoulam et al., 2007). According to Mechoulam et al. (2007), CBD has 
antagonistic effects at CB1 receptors and some inverse 
agonistic properties at CB2 receptors. When cannabinoids are 
given subacutely to rats, CB1 receptors down-regulate and 
the binding of the second messenger system coupled to CB1 
receptors, GTPgarnmaS, decreases (Breivogel et al., 2001).
Animal Behavioral Effects
Self-Administration
    Self-administration is a method that assesses the ability of a drug 
to produce rewarding effects. The presence of rewarding effects 
increases the likelihood of behavioral responses to obtain additional 
drug. Animal self-administration of a drug is often useful in 
predicting rewarding effects in humans, and is indicative of abuse 
liability. A good correlation is often observed between those drugs 
that rhesus monkeys self-administer and those drugs that humans abuse 
(Balster and Bigelow, 2003). Initially, researchers could not establish 
self-administration of cannabinoids, including delta\9\-THC, in animal 
models. However, self-administration of delta\9\ -THC can now be 
established in a variety of animal models under specific training 
paradigms (Justinova et al., 2003, 2004, 2005).
    Squirrel monkeys, with and without prior exposure to other drugs of 
abuse, self-administer delta\9\-THC under specific conditions. For 
instance, Tanda et al. (2000) observed that when squirrel monkeys are 
initially trained to self-administer intravenous cocaine, they will 
continue to bar-press delta\9\-THC at the same rate as they would with 
cocaine. The doses were notably comparable to those doses used by 
humans who smoke marijuana. SR141716, a CB1 cannabinoid 
receptor agonist-antagonist, can block this rewarding effect. Other 
studies show that na[iuml]ve squirrel monkeys can be successfully 
trained to self-administer delta\9\-THC intravenously (Justinova et 
al., 2003). The maximal responding rate is 4 [mu]g/kg per injection, 
which is 2-3 times greater than observed in previous studies using 
cocaine-experienced monkeys. Naltrexone, a mu-opioid antagonist, 
partially antagonizes these rewarding effects of delta\9\-THC 
(Justinova et al., 2004).
    Additionally, data demonstrate that under specific conditions, 
rodents self-administer cannabinoids. Rats will self-administer 
delta\9\-THC when applied intracerebroventricularly (i.c.v.), but only 
at the lowest doses tested (0.01-0.02 [mu]g/infusion) (Braida et al., 
2004). SR141716 and the opioid antagonist naloxone can antagonize this 
effect. However, most studies involve rodents self-administrating the 
synthetic cannabinoid WIN 55212, a CB1 receptor agonist with 
a non-cannabinoid structure (Deiana et al., 2007; Fattore et al., 2007; 
Martellotta et al., 1998; Mendizabal et al., 2006).
    Aversive effects, rather than reinforcing effects, occur in rats 
that received high doses of WIN 55212 (Chaperon et al., 1998) or 
delta\9\-THC (Sanudo-Pena et al., 1997), indicating a possible critical 
dose-dependent effect. In both studies, SR141716 reversed these 
aversive effects.
Conditioned Place Preference
    Conditioned place preference (CPP) is a less rigorous method than 
self-administration for determining whether or not a drug has rewarding 
properties. In this behavioral test, animals spend time in two distinct 
environments: one where they previously received a drug and one where 
they received a placebo. If the drug is reinforcing, animals will 
choose to spend more time in the environment paired with the drug, 
rather than with the placebo, when presented with both options 
s.imultaneously.
    Animals show CPP to delta\9\-THC, but only at the lowest doses 
tested (0.075-1.0 mg/kg, intraperitoneal (i.p.)) (Braida et al., 2004). 
SR141716 and naloxone antagonize this effect (Braida et al., 2004). As 
a partial agonist, SR141716 can induce CPP at doses of 0.25, 0.5, 2 and 
3 mg/kg (Cheer et al., 2000). In knockout mice, those without [mu]-
opioid receptors do not develop CPP to delta\9\-THC (Ghozland et al., 
2002).
Drug Discrimination Studies
    Drug discrimination is a method where animals indicate whether a 
test drug produces physical or psychic perceptions similar to those 
produced by a known drug of abuse. In this test, an animal learns to 
press one bar when it receives the known drug of abuse and another bar 
when it receives placebo. To determine whether the test drug is like 
the known drug of abuse, a challenge session with the test drug 
demonstrates which of the two bars the animal presses more often.
    In addition to humans (Lile et al., 2009; Lile et al., 2011), it 
has been noted that animals, including monkeys (McMahon, 2009), mice 
(McMahon et al., 2008), and rats (Gold et al., 1992), are able to 
discriminate cannabinoids from other drugs or placebo. Moreover, the 
major active metabolite of delta\9\-THC, 11-hydroxy-delta\9\-THC, also 
generalizes (following oral administration) to the stimulus cues 
elicited by delta\9\-THC (Browne and Weissman, 1981). Twenty-two other 
cannabinoids found in marijuana also fully substitute for delta\9\-THC. 
However, CBD does not substitute for delta\9\-THC in rats (Vann et al., 
2008).
    Discriminative stimulus effects of delta\9\-THC are 
pharmacologically specific for marijuana containing cannabinoids 
(Balster and Prescott, 1992; Browne and Weissman, 1981; Wiley et al., 
1993, 1995). The discriminative stimulus effects of the cannabinoid 
group appear to provide unique effects because stimulants, 
hallucinogens, opioids, benzodiazepines, barbiturates, NMDA 
antagonists, and antipsychotics do not fully substitute for delta\9\-
THC.

Central Nervous System Effects

Human Physiological and Psychological Effects
Psychoactive Effects
    Below is a list of the common subjective responses to cannabinoids 
(Adams and Martin, 1996; Gonzalez, 2007; Hollister 1986, 1988; 
Institute of Medicine, 1982). According to Maldonado (2002), these 
responses to marijuana are pleasurable to many humans and are often 
associated with drug-seeking and drug-taking. High levels of positive 
psychoactive effects are associated with increased marijuana use, 
abuse, and dependence (Scherrer et al., 2009; Zeiger et al., 2010).
    (1) Disinhibition, relaxation, increased sociability, and 
talkativeness.
    (2) Increased merriment and appetite, and even exhilaration at high 
doses.
    (3) Enhanced sensory perception, which can generate an increased 
appreciation of music, art, and touch.
    (4) Heightened imagination, which can lead to a subjective sense of 
increased creativity.
    (5) Initial dizziness, nausea, tachycardia, facial flushing, dry 
mouth, and tremor.
    (6) Disorganized thinking, inability to converse logically, time 
distortions, and short-term memory impairment.
    (7) Ataxia and impaired judgment, which can impede driving ability 
or

[[Page 53694]]

lead to an increase in risk-tasking behavior.
    (8) Illusions, delusions, and hallucinations that intensify with 
higher doses.
    (9) Emotional lability, incongruity of affect, dysphoria, 
agitation, paranoia, confusion, drowsiness, and panic attacks, which 
are more common in inexperienced or high-dosed users.
    As with many psychoactive drugs, a person's medical, psychiatric, 
and drug-taking history can influence the individual's response to 
marijuana. Dose preferences to marijuana occur in that marijuana users 
prefer higher concentrations of the principal psychoactive substance 
(1.95 percent delta\9\-THC) over lower concentrations (0.63 percent 
delta\9\-THC) (Chait and Burke, 1994). Nonetheless, frequent marijuana 
users (>100 times of use) were able to identify a drug effect from low-
dose delta\9\-THC better than occasional users (<10 times of use) while 
also experiencing fewer sedative effects from marijuana (Kirk and de 
Wit, 1999).
    The petitioners contend that many of marijuana's naturally 
occurring cannabinoids mitigate the psychoactive effects of delta\9\-
THC, and therefore that marijuana lacks sufficient abuse potential to 
warrant Schedule I placement, because Marinol, which is in Schedule 
III, contains only delta\9\-THC. This theory has not been demonstrated 
in controlled studies. Moreover, the concept of abuse potential 
encompasses all properties of a substance, including its chemistry, 
pharmacology, and pharmacokinetics, as well as usage patterns and 
diversion history. The abuse potential of a substance is associated 
with the repeated or sporadic use of a substance in nonmedical 
situations for the psychoactive effects the substance produces. These 
psychoactive effects include euphoria, perceptual and other cognitive 
distortions, hallucinations, and mood changes. However, as stated 
above, the abuse potential not only includes the psychoactive effects, 
but also includes other aspects related to a substance.
    DEA's final published rule entitled ``Rescheduling of the Food and 
Drug Administration Approved Product Containing Synthetic Dronabinol 
[(-)-delta\9\-(trans)-Tetrahydrocannabinol] in Sesame Oil and 
Encapsulated in Soft Gelatin Capsules From Schedule II to Schedule 
III'' (64 FR 35928, July 2, 1999) rescheduled Marinol from Schedule II 
to Schedule III. The HHS assessment of the abuse potential and 
subsequent scheduling recommendation compared Marinol to marijuana on 
different aspects related to abuse potential. Major differences in 
formulation, availability, and usage between marijuana and the drug 
product, Marinol, contribute to their differing abuse potentials.
    Hollister and Gillespie (1973) estimated that delta\9\-THC by 
smoking is 2.6 to 3 times more potent than delta\9\-THC ingested 
orally. The intense psychoactive drug effect achieved, rapidly by 
smoking is generally considered to produce the effect desired by the 
abuser. This effect explains why abusers often prefer to administer 
certain drugs by inhalation, intravenously, or intranasally rather than 
orally. Such is the case with cocaine, opium, heroin, phencyclidine, 
methamphetamine, and delta\9\-THC from marijuana (0.1-9.5 percent 
delta\9\-THC range) or hashish (10-30 percent delta\9\-THC range) 
(Wesson and Washburn, 1990). Thus, the delayed onset and longer 
duration of action for Marinol may be contributing factors limiting the 
abuse or appeal of Marinol as a drug of abuse relative to marijuana.
    The formulation of Marinol is a factor that contributes to 
differential scheduling of Marinol and marijuana. For example, 
extraction and purification of dronabinol from the encapsulated sesame 
oil mixture of Marinol is highly complex and difficult. Additionally, 
the presence of sesame oil mixture in the formulation may preclude the 
smoking of Marinol-laced cigarettes.
    Additionally, there is a dramatic difference between actual abuse 
and illicit trafficking of Marinol and marijuana. Despite Marinol's 
availability in the United States, there have been no significant 
reports of abuse, diversion, or public health problems due to Marinol. 
By comparison, 18.9 million American adults report currently using 
marijuana (SAMHSA, 2013).
    In addition, FDA's approval of an NDA for Marinol allowed for 
Marinol to be rescheduled to Schedule II, and subsequently to Schedule 
III of the CSA. In conclusion, marijuana and Marinol differ on a wide 
variety of factors that contribute to each substance's abuse potential. 
These differences are major reasons distinguishing the higher abuse 
potential for marijuana and the different scheduling determinations of 
marijuana and Marinol.
    In terms of the petitioners' claim that different cannabinoids 
present in marijuana mitigate the psychoactive effects of delta\9\-THC, 
only three of the cannabinoids present in marijuana were simultaneously 
administered with delta\9\-THC to examine how the combinations of these 
cannabinoids such as CBD, cannabichromene (CBC) and cannabinol (CBN) 
influence delta\9\-THC's psychoactive effects. Dalton et al. (1976) 
observed that smoked administration of placebo marijuana cigarettes 
containing injections of 0.15 mg/kg CBD combined with 0.025mg/kg of 
delta\9\-THC, in a 7:1 ratio of CBD to delta\9\-THC, significantly 
decreased ratings of acute subjective effects and ``high'' when 
compared to smoking delta\9\-THC alone. In contrast, Ilan et al. (2005) 
calculated the naturally occurring concentrations of CBC and CBD in a 
batch of marijuana cigarettes with either 1.8 percent or 3.6 percent 
delta\9\-THC concentration by weight. For each strength of delta\9\-THC 
in marijuana cigarettes, the concentrations of CBC and CBD were 
classified in groups of either low or high. The study varied the amount 
of CBC and CBD within each strength of delta\9\-THC marijuana 
cigarettes, with administrations consisting of either low CBC (between 
0.1-0.2 percent CBC concentration by weight) and low CBD (between 0.1-
0.4 percent CBD concentration by weight), high CBC (>0.5 percent CBC 
concentration by weight) and low CBD, or low CBC and high CBD (>1.0 
percent CBD concentration by weight). Overall, all combinations scored 
significantly greater than placebo on ratings of subjective effects, 
and there was no significant difference between any combinations.
    The oral administration of a combination of either 15, 30, or 60 mg 
CBD with 30 mg delta\9\-THC dissolved in liquid (in a ratio of at least 
1:2 CBD to delta\9\-THC) reduced the subjective effects produced by 
delta\9\-THC alone (Karniol et al., 1974). Additionally, orally 
administering a liquid mixture combining 1 mg/kg CBD with 0.5 mg/kg of 
delta\9\-THC (ratio of 2:1 CBD to delta\9\-THC) decreased scores of 
anxiety and marijuana drug effect on the Addiction Research Center 
Inventory (ARCI) compared to delta\9\-THC alone (Zuardi et al.,1982). 
Lastly, oral administration of either 12.5, 25, or 50 mg CBN combined 
with 25 mg delta\9\-THC dissolved in liquid (ratio of at least 1:2 CBN 
to delta\9\-THC) significantly increased subjective ratings of 
``drugged,'' ``drowsy,'' ``dizzy,'' and ``drunk,'' compared to 
delta\9\-THC alone (Karniol et al., 1975).
    Even though some studies suggest that CBD may decrease some of 
delta\9\-THC's psychoactive effects, the ratios of CBD to delta\9\-THC 
administered in these studies are not present in marijuana used by most 
people. For example, in one study, researchers used smoked marijuana 
with ratios of CBD to delta\9\-THC naturally present in marijuana

[[Page 53695]]

plant material and they found out that varying the amount of CBD 
actually had no effect on delta\9\-THC's psychoactive effects (Ilan et 
al., 2005). Because most marijuana currently available on the street 
has high amounts of delta\9\-THC with low amounts of CBD and other 
cannabinoids, most individuals use marijuana with low levels of CBD 
present (Mehmedic et al., 2010). Thus, any possible mitigation of 
delta\9\-THC's psychoactive effects by CBD will not occur for most 
marijuana users. In contrast, one study indicated that another 
cannabinoid present in marijuana, CBN, may enhance delta\9\-THC's 
psychoactive effects (Karniol et al., 1975).
Behavioral Impairment
    Marijuana induces various psychoactive effects that can lead to 
behavioral impairment. Marijuana's acute effects can significantly 
interfere with a person's ability to learn in the classroom or to 
operate motor vehicles. Acute administration of smoked marijuana 
impairs performance on learning, associative processes, and psychomotor 
behavioral tests (Block et al., 1992). Ramaekers et al. (2006a) showed 
that acute administration of 250 [mu]g/kg and 500 [mu]g/kg of delta\9\-
THC in smoked marijuana dose-dependently impairs cognition and motor 
control, including motor impulsivity and tracking impairments 
(Ramaekers et al., 2006b). Similarly, administration of 290 [mu]g/kg 
delta\9\-THC in a smoked marijuana cigarette resulted in impaired 
perceptual motor speed and accuracy: Two skills which are critical to 
driving ability (Kurzthaler et al., 1999). Lastly, administration of 
3.95 percent delta\9\-THC in a smoked marijuana cigarette not only 
increased disequilibrium measures, but also increased the latency in a 
task of simulated vehicle braking at a rate comparable to an increase 
in stopping distance of five feet at 60 mph (Liguori et al., 1998). 
However, acute administration of marijuana containing 2.1 percent 
delta\9\-THC does not produce ``hangover effects'' (Chait, 1990).
    In addition to measuring the acute effects immediately following 
marijuana administration, researchers have conducted studies to 
determine how long behavioral impairments last after abstinence. Some 
of marijuana's acute effects may not fully resolve until at least one 
day after the acute psychoactive effects have subsided. Heishman et al. 
(1990) showed that impairment on memory tasks persists for 24 hours 
after smoking marijuana cigarettes containing 2.57 percent delta\9\-
THC. However, Fant et al. (1998) showed that the morning after exposure 
to 1.8 percent or 3.6 percent smoked delta\9\-THC, subjects had minimal 
residual alterations in subjective or performance measures.
    A number of factors may influence marijuana's behavioral effects 
including the duration of use (chronic or short term), frequency of use 
(daily, weekly, or occasionally), and amount of use (heavy or 
moderate). Researchers also have examined how long behavioral 
impairments last following chronic marijuana use. These studies used 
self-reported histories of past duration, frequency, and amount of past 
marijuana use, and administered a variety of performance and cognitive 
measures at different time points following marijuana abstinence. In 
chronic marijuana users, behavioral impairments may persist for up to 
28 days of abstinence. Solowij et al. (2002) demonstrated that after 17 
hours of abstinence, 51 adult heavy chronic marijuana users performed 
worse on memory and attention tasks than 33 non-using controls or 51 
heavy, short-term users. Another study noted that heavy, frequent 
marijuana users, abstinent for at least 24 hours, performed 
significantly worse than the controls on verbal memory and psychomotor 
speed tests (Messinis et al., 2006). Additionally, after at least 1 
week of abstinence, young adult frequent marijuana users, aged 18-28, 
showed deficits in psychomotor speed, sustained attention, and 
cognitive inhibition (Lisdahl and Price, 2012). Adult heavy, chronic 
marijuana users showed deficits on memory tests after 7 days of 
supervised abstinence (Pope et al., 2002). However, when these same 
individuals were again tested after 28 days of abstinence, they did not 
show significant memory deficits. The authors concluded, ``cannabis-
associated cognitive deficits are reversible and related to recent 
cannabis exposure, rather than irreversible and related to cumulative 
lifetime use.'' \7\ However, other researchers reported 
neuropsychological deficits in memory, executive functioning, 
psychomotor speed and manual dexterity in heavy marijuana users 
abstinent for 28 days (Bolla et al., 2002). Furthermore, a follow-up 
study of heavy marijuana users noted decision-making deficits after 25 
days of supervised abstinence. (Bolla et al., 2005). However, moderate 
marijuana users did not show decision-making deficits after 25 days of 
abstinence, suggesting the amount of marijuana use may impact the 
duration of residual impairment.
---------------------------------------------------------------------------

    \7\ In this quotation the term Cannabis is used interchangeably 
for marijuana.
---------------------------------------------------------------------------

    The effects of chronic marijuana use do not seem to persist after 
more than 1 to 3 months of abstinence. After 3 months of abstinence, 
any deficits observed in IQ, immediate memory, delayed memory, and 
information-processing speeds following heavy marijuana use compared to 
pre-drug use scores were no longer apparent (Fried et al., 2005). 
Marijuana did not appear to have lasting effects on performance of a 
comprehensive neuropsychological battery when 54 monozygotic male twins 
(one of whom used marijuana, one of whom did not) were compared 1-20 
years after cessation of marijuana use (Lyons et al., 2004). Similarly, 
following abstinence for a year or more, both light and heavy adult 
marijuana users did not show deficits on scores of verbal memory 
compared to non-using controls (Tait et al., 2011). According to a 
recent meta-analysis looking at non-acute and long-lasting effects of 
marijuana use on neurocognitive performance, any deficits seen within 
the first month following abstinence are generally not present after 
about 1 month of abstinence (Schreiner and Dunn, 2012).
    Another aspect that may be a critical factor in the intensity and 
persistence of impairment resulting from chronic marijuana use is the 
age of first use. Individuals with a diagnosis of marijuana misuse or 
dependence who were seeking treatment for substance use, who initiated 
marijuana use before the age of 15 years, showed deficits in 
performance on tasks assessing sustained attention, impulse control, 
and general executive functioning compared to non-using controls. These 
deficits were not seen in individuals who initiated marijuana use after 
the age of 15 years (Fontes et al., 2011). Similarly, heavy, chronic 
marijuana users who began using marijuana before the age of 16 years 
had greater decrements in executive functioning tasks than heavy, 
chronic marijuana users who started using after the age of 16 years and 
non-using controls (Gruber et al., 2012). Additionally, in a 
prospective longitudinal birth cohort study of 1,037 individuals, 
marijuana dependence or chronic marijuana use was associated with a 
decrease in IQ and general neuropsychological performance compared to 
pre-marijuana exposure levels in adolescent onset users (Meier et al., 
2012). The decline in adolescent-onset user's IQ persisted even after 
reduction or abstinence of marijuana use for at least 1 year. In 
contrast, the adult-onset chronic marijuana users showed no significant 
changes in IQ compared to pre-exposure

[[Page 53696]]

levels whether they were current users or abstinent for at least 1 year 
(Meier et al., 2012).
    In addition to the age of onset of use, some evidence suggests that 
the amount of marijuana used may relate to the intensity of 
impairments. In the above study by Gruber et al. (2012), where early-
onset users had greater deficits than late-onset users, the early-onset 
users reported using marijuana twice as often and using three times as 
much marijuana per week than the late-onset users. Meier et al. (2012) 
showed that the deficits in IQ seen in adolescent-onset users increased 
with the amount of marijuana used. Moreover, when comparing scores for 
measures of IQ, immediate memory, delayed memory, and information-
processing speeds to pre-drug-use levels, the current, heavy, chronic 
marijuana users showed deficits in all three measures while current, 
occasional marijuana users did not (Fried et al., 2005).
Behavioral Effects of Prenatal Exposure
    Studies with children at different stages of development are used 
to examine the impact of prenatal marijuana exposure on performance in 
a series of cognitive tasks. However, many pregnant women who reported 
marijuana use were more likely to also report use of alcohol, tobacco, 
and cocaine (Goldschmidt et al., 2008). Thus, with potential exposure 
to multiple drugs, it is difficult to determine the specific impact of 
prenatal marijuana exposure.
    Most studies assessing the behavioral effects of prenatal marijuana 
exposure included women who, in addition to using marijuana, also 
reported using alcohol and tobacco. However, some evidence suggests an 
association between heavy prenatal marijuana exposure and deficits in 
some cognitive domains. In both 4-year-old and 6-year-old children, 
heavy prenatal marijuana use is negatively associated with performance 
on tasks assessing memory, verbal reasoning, and quantitative reasoning 
(Fried and Watkinson, 1987; Goldschmidt et al., 2008). Additionally, 
heavy prenatal marijuana use is associated with deficits in measures of 
sustained attention in children at the ages of 6 years and 13-16 years 
(Fried et al., 1992; Fried, 2002). In 9- to 12-year-old children, 
prenatal marijuana exposure is negatively associated with executive 
functioning tasks that require impulse control, visual analysis, and 
hypothesis (Fried et al., 1998).
Association of Marijuana Use With Psychosis
    This analysis evaluates only the evidence for a direct link between 
prior marijuana use and the subsequent development of psychosis. Thus, 
this discussion does not consider issues such as whether marijuana's 
transient effects are similar to psychotic symptoms in healthy 
individuals or exacerbate psychotic symptoms in individuals already 
diagnosed with schizophrenia.
    Extensive research has been conducted to investigate whether 
exposure to marijuana is associated with the development of 
schizophrenia or other psychoses. Although many studies are small and 
inferential, other studies in the literature use hundreds to thousands 
of subjects. At present, the available data do not suggest a causative 
link between marijuana use and the development of psychosis (Minozzi et 
al., 2010). Numerous large, longitudinal studies show that subjects who 
used marijuana do not have a greater incidence of psychotic diagnoses 
compared to those who do not use marijuana (Fergusson et al., 2005; 
Kuepper et al., 2011; Van Os et al., 2002).
    When analyzing the available evidence of the connection between 
psychosis and marijuana, it is critical to determine whether the 
subjects in the studies are patients who are already diagnosed with 
psychosis or individuals who demonstrate a limited number of symptoms 
associated with psychosis without qualifying for a diagnosis of the 
disorder. For example, instead of using a diagnosis of psychosis, some 
researchers relied on non-standard methods of representing symptoms of 
psychosis including ``schizophrenic cluster'' (Maremmani et al., 2004), 
``subclinical psychotic symptoms'' (Van Gastel et al., 2012), ``pre-
psychotic clinical high risk'' (Van der Meer et al., 2012), and 
symptoms related to ``psychosis vulnerability'' (Griffith-Lendering et 
al., 2012). These groupings do not conform to the criteria in the 
Diagnostic and Statistical Manual (DSM-5) or the International 
Classification of Diseases (ICD-10) for a diagnosis of psychosis. Thus, 
these groupings are not appropriate for use in evaluating marijuana's 
impact on the development of actual psychosis. Accordingly, this 
analysis includes only those studies that use subjects diagnosed with a 
psychotic disorder.
    In the largest study evaluating the link between psychosis and drug 
use, 274 of the approximately 45,500 Swedish conscripts in the study 
population (<0.01 percent) received a diagnosis of schizophrenia within 
the 14-year period following military induction from 1969 to 1983 
(Andreasson et al., 1987). Of the conscripts diagnosed with psychosis, 
7.7 percent (21 of the 274 conscripts with psychosis) had used 
marijuana more than 50 times at induction, while 72 percent (197 of the 
274 conscripts with psychosis) had never used marijuana. Although high 
marijuana use increased the relative risk for schizophrenia to 6.0, the 
authors note that substantial marijuana use history ``accounts for only 
a minority of all cases'' of psychosis (Andreasson et al., 1987). 
Instead, the best predictor for whether a conscript would develop 
psychosis was a non-psychotic psychiatric diagnosis upon induction. The 
authors concluded that marijuana use increased the risk for psychosis 
only among individuals predisposed to develop the disorder. In 
addition, a 35-year follow up to this study reported very similar 
results (Manrique-Garcia et al., 2012). In this follow up study, 354 
conscripts developed schizophrenia; of these 354 conscripts, 32 used 
marijuana more than 50 times at induction (9 percent, an odds ratio of 
6.3), while 255 had never used marijuana (72 percent).
    Additionally, the conclusion that the impact of marijuana may 
manifest only in individuals likely to develop psychotic disorders has 
been shown in many other types of studies. For example, although 
evidence shows that marijuana use may precede the presentation of 
symptoms in individuals later diagnosed with psychosis (Schimmelmann et 
al., 2011), most reports conclude that prodromal symptoms of 
schizophrenia appear prior to marijuana use (Schiffman et al., 2005). 
Similarly, a review of the gene-environment interaction model for 
marijuana and psychosis concluded that some evidence supports marijuana 
use as a factor that may influence the development of psychosis, but 
only in those individuals with psychotic liability (Pelayo-Teran et 
al., 2012).
    A similar conclusion was drawn when the prevalence of schizophrenia 
was modeled against marijuana use across eight birth cohorts in 
Australia in individuals born between the years 1940 to 1979 
(Degenhardt et al., 2003). Although marijuana use increased over time 
in adults born during the four-decade period, there was not a 
corresponding increase in diagnoses for psychosis in these individuals. 
The authors conclude that marijuana may precipitate schizophrenic 
disorders only in those individuals who are vulnerable to developing 
psychosis. Thus, marijuana per se does not appear to

[[Page 53697]]

induce schizophrenia in the majority of individuals who have tried or 
continue to use marijuana. However, in individuals with a genetic 
vulnerability for psychosis, marijuana use may influence the 
development of psychosis.

Cardiovascular and Autonomic Effects

    Single smoked or oral doses of delta\9\-THC produce tachycardia and 
may increase blood pressure (Capriotti et al., 1988; Benowitz and 
Jones, 1975). Some evidence associates the tachycardia produced by 
delta\9\-THC with excitation of the sympathetic and depression of the 
parasympathetic nervous systems (Malinowska et al., 2012). During 
chronic marijuana ingestion, a tolerance to tachycardia develops 
(Malinowska et al., 2012).
    However, prolonged delta\9\-THC ingestion produces bradycardia and 
hypotension (Benowitz and Jones, 1975). Plant-derived cannabinoids and 
endocannabinoids elicit hypotension and bradycardia via activation of 
peripherally-located CB1 receptors (Wagner et al., 1998). Specifically, 
the mechanism of this effect is through presynaptic CB1 receptor-
mediated inhibition of norepinephrine release from peripheral 
sympathetic nerve terminals, with possible additional direct 
vasodilation via activation of vascular cannabinoid receptors (Pacher 
et al., 2006). In humans, tolerance can develop to orthostatic 
hypotension (Jones, 2002; Sidney, 2002) possibly related to plasma 
volume expansion, but tolerance does not develop to the supine 
hypotensive effects (Benowitz and Jones, 1975). Additionally, 
electrocardiographic changes are minimal, even after large cumulative 
doses of delta\9\-THC are administered. (Benowitz and Jones, 1975).
    Marijuana smoking by individuals, particularly those with some 
degree of coronary artery or cerebrovascular disease, poses risks such 
as increased cardiac work, catecholamines and carboxyhemoglobin, 
myocardial infarction, and postural hypotension (Benowitz and Jones, 
1981; Hollister, 1988; Mittleman et al., 2001; Malinowska et al., 
2012).

Respiratory Effects

    After acute exposure to marijuana, transient bronchodilation is the 
most typical respiratory effect (Gong et al., 1984). A recent 20-year 
longitudinal study with over 5,000 individuals collected information on 
the amount of marijuana use and pulmonary function data at years 0, 2, 
5, 10, and 20 (Pletcher et al., 2012). Among the more than 5,000 
individuals who participated in the study, almost 800 of them reported 
current marijuana use but not tobacco use at the time of assessment. 
Pletcher et al. (2012) found that the occasional use of marijuana is 
not associated with decreased pulmonary function. However, some 
preliminary evidence suggests that heavy marijuana use may be 
associated with negative pulmonary effects (Pletcher et al., 2012). 
Long-term use of marijuana can lead to chronic cough and increased 
sputum, as well as an increased frequency of chronic bronchitis and 
pharyngitis. In addition, pulmonary function tests reveal that large-
airway obstruction can occur with chronic marijuana smoking, as can 
cellular inflammatory histopathological abnormalities in bronchial 
epithelium (Adams and Martin 1996; Hollister 1986).
    Evidence regarding marijuana smoking leading to cancer is 
inconsistent, as some studies suggest a positive correlation while 
others do not (Lee and Hancox, 2011; Tashkin, 2005). Several lung 
cancer cases have been reported in young marijuana users with no 
tobacco smoking history or other significant risk factors (Fung et al., 
1999). Marijuana use may dose-dependently interact with mutagenic 
sensitivity, cigarette smoking, and alcohol use to increase the risk of 
head and neck cancer (Zhang et al., 1999). However, in a large study 
with 1,650 subjects, a positive association was not found between 
marijuana and lung cancer (Tashkin et al., 2006). This finding remained 
true, regardless of the extent of marijuana use, when controlling for 
tobacco use and other potential confounding variables. Overall, new 
evidence suggests that the effects of marijuana smoking on respiratory 
function and carcinogenicity differ from those of tobacco smoking (Lee 
and Hancox, 2011).

Endocrine System

    Experimental marijuana administration to humans does not 
consistently alter many endocrine parameters. In an early study, male 
subjects who experimentally received smoked marijuana showed a 
significant depression in luteinizing hormone and a significant 
increase in cortisol (Cone et al., 1986). However, two later studies 
showed no changes in hormones. Male subjects experimentally exposed to 
smoked delta\9\-THC (18 mg/marijuana cigarette) or oral delta\9\-THC 
(10 mg three times per day for 3 days and on the morning of the fourth 
day) showed no changes in plasma adrenocorticotropic hormone (ACTH), 
cortisol, prolactin, luteinizing hormone, or testosterone levels (Dax 
et al., 1989). Similarly, a study with 93 men and 56 women showed that 
chronic marijuana use did not significantly alter concentrations of 
testosterone, luteinizing hormone, follicle stimulating hormone, 
prolactin, or cortisol (Block et al., 1991). Additionally, chronic 
marijuana use did not affect serum levels of thyrotropin, thyroxine, 
and triiodothyronine (Bonnet, 2013). However, in a double-blind, 
placebo-controlled, randomized clinical trial of HIV-positive men, 
smoking marijuana dose-dependently increased plasma levels of ghrelin 
and leptin, and decreased plasma levels of peptide YY (Riggs et al., 
2012).
    The effects of marijuana on female reproductive system 
functionality differ between humans and animals. In monkeys, delta\9\-
THC administration suppressed ovulation (Asch et al., 1981) and reduced 
progesterone levels (Almirez et al., 1983). However, in women, smoked 
marijuana did not alter hormone levels or the menstrual cycle 
(Mendelson and Mello, 1984). Brown and Dobs (2002) suggest that the 
development of tolerance in humans may be the cause of the 
discrepancies between animal and human hormonal response to 
cannabinoids.
    The presence of in vitro delta\9\-THC reduces binding of the 
corticosteroid, dexamethasone, in hippocampal tissue from 
adrenalectomized rats, suggesting an interaction with the 
glucocorticoid receptor (Eldridge et al., 1991). Although acute 
delta\9\-THC presence releases corticosterone, tolerance develops in 
rats with chronic administration (Eldridge et al., 1991).
    Some studies support a possible association between frequent, long-
term marijuana use and increased risk of testicular germ cell tumors 
(Trabert et al., 2011). On the other hand, recent data suggest that 
cannabinoid agonists may have therapeutic value in the treatment of 
prostate cancer, a type of carcinoma in which growth is stimulated by 
androgens. Research with prostate cancer cells shows that the mixed 
CB1/CB2 agonist, WIN-55212-2, induces apoptosis 
in prostate cancer cells, as well as decreases the expression of 
androgen receptors and prostate-specific antigens (Sarfaraz et al., 
2005).

Immune System

    Cannabinoids affect the immune system in many different ways. 
Synthetic, natural, and endogenous cannabinoids often cause different 
effects in a dose-dependent biphasic manner (Croxford and Yamamura, 
2005; Tanasescu and Constantinescu, 2010).
    Studies in humans and animals give conflicting results about 
cannabinoid

[[Page 53698]]

effects on immune functioning in subjects with compromised immune 
systems. Abrams et al. (2003) investigated marijuana's effect on 
immunological functioning in 62 AIDS patients taking protease 
inhibitors. Subjects received one of the following three times a day: A 
smoked marijuana cigarette containing 3.95 percent delta\9\-THC, an 
oral tablet containing delta\9\-THC (2.5 mg oral dronabinol), or an 
oral placebo. The results showed no changes in CD4+ and CD8+ cell 
counts, HIV RNA levels, or protease inhibitor levels between groups. 
Thus, the use of cannabinoids showed no short-term adverse virologic 
effects in individuals with compromised immune systems. However, these 
human data contrast with data generated in immunodeficient mice, which 
demonstrated that exposure to delta\9\-THC in vivo suppresses immune 
function, increases HIV co-receptor expression, and acts as a cofactor 
to enhance HIV replication (Roth et al., 2005).

3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance

    Under the third factor, the Secretary must consider the state of 
current scientific knowledge regarding marijuana. Thus, this section 
discusses the chemistry, human pharmacokinetics, and medical uses of 
marijuana.

Chemistry

    Marijuana is one of the common names of Cannabis sativa L. in the 
family Cannabaceae.
    Cannabis is one of the oldest cultivated crops, providing a source 
of fiber, food, oil, and drug. Botanists still debate whether Cannabis 
should be considered as a single (The Plant List, 2010) or three 
species, i.e., C. sativa, C. indica, and C. ruderalis (Hillig, 2005). 
Specifically, marijuana is developed as sativa and indica cultivated 
varieties (strains) or various hybrids.
    The petition defines marijuana as including all Cannabis cultivated 
strains. Different marijuana samples derived from various cultivated 
strains may have very different chemical constituents including 
delta\9\ -THC and other cannabinoids (Appendino et al., 2011). As a 
consequence, marijuana products from different strains will have 
different safety, biological, pharmacological, and toxicological 
profiles. Thus, all Cannabis strains cannot be considered together 
because of the varying chemical constituents between strains.
    Marijuana contains numerous naturally occurring constituents 
including cannabinoids. Overall, various Cannabis strains contain more 
than 525 identified natural constituents. Among those constituents, the 
most important ones are the 21 (or 22) carbon terpenoids found in the 
plant, as well as their carboxylic acids, analogues, and transformation 
products, known as cannabinoids (Agurell et al., 1984, 1986; Mechoulam, 
1973; Appendino et al., 2011). Thus far, more than 100 compounds 
classified as cannabinoids have been characterized (ElSohly and Slade, 
2005; Radwan, ElSohly et al., 2009; Appendino et al. 2011).
    Cannabinoids primarily exist in Cannabis, and published data 
suggest that most major cannabinoid compounds occurring naturally have 
been chemically identified. New and minor cannabinoids and other new 
compounds are continuously being characterized (Pollastro et al., 
2011). So far, only two cannabinoids (cannabigerol and its 
corresponding acid) have been obtained from a non-Cannabis source. A 
South African Helichrysum (H umbraculigerum) accumulates these 
compounds (Appendino et al. 2011).
    Among the cannabinoids found in marijuana, delta\9\-THC (alternate 
name delta\1\-THC) and delta-8-tetrahydrocannibinol (delta\8\-THC, 
alternate name delta\6\-THC) produce marijuana's characteristic 
psychoactive effects. Because delta\9\-THC is more abundant than 
delta\8\-THC, marijuana's psychoactivity is largely attributed to the 
former. Only a few varieties of marijuana analyzed contain delta\8\-THC 
at significant amounts (Hively et al., 1966). Delta\9\-THC is an 
optically active resinous substance, insoluble in water, and extremely 
lipid soluble. Chemically, delta\9\-THC is (6aR-trans)-6a,7,8,10a-
tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo-[b,d]pyran-l-ol, or (-)-
delta9-(trans)-tetrahydrocannabinol. The (-)-trans isomer of delta\9\-
THC is pharmacologically 6-100 times more potent than the (+)-trans 
isomer (Dewey et al., 1984).
    Other cannabinoids present in marijuana include CBD, CBC, and CBN. 
CBD, a major cannabinoid of marijuana, is insoluble in water and lipid-
soluble. Chemically, CBD is 2-[(1R,6R)-3-methyl-6-prop-1-en-2-
ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol. CBD does not have 
cannabinol-like psychoactivity (Adams and Martin, 1996; Agurell et al., 
1984, 1986; Hollister, 1986). CBC is another major cannabinoid in 
marijuana. Chemically, CBC is 2-methyl-2-(4-methylpent-3-enyl)-7-
pentyl-5-chromenol. CBN, a major metabolite of delta\9\-THC, is also a 
minor naturally-occurring cannabinoid with weak psychoactivity. 
Chemically, CBN is 6,6,9-trimethyl-3-pentyl-benzo[c]chromen-1-ol.
    Different marijuana samples derived from various cultivated strains 
may differ in chemical constituents including delta\9\-THC and other 
cannabinoids (Appendino et al. 2011). As a consequence, marijuana 
products from different strains may have different safety, biological, 
pharmacological, and toxicological profiles. In addition to differences 
between cultivated strains, the concentration of delta\9\-THC and other 
cannabinoids in marijuana may vary with growing conditions and 
processing after harvest. In addition to genetic differences among 
Cannabis species, the plant parts collected--for example, flowers, 
leaves, and stems--can influence marijuana's potency, quality, and 
purity (Adams and Martin, 1996; Agurell et al., 1984; Mechoulam, 1973). 
All these variations produce marijuana with potencies, as indicated by 
cannabinoid content, on average from as low as 1-2 percent to as high 
as 17 percent.
    Overall, these variations in the concentrations of cannabinoids and 
other chemical constituents in marijuana complicate the interpretation 
of clinical data using marijuana. The lack of consistent concentrations 
of delta\9\ -THC and other substances in marijuana from diverse sources 
makes interpreting the effect of different marijuana constituents 
difficult. In addition to different cannabinoid concentrations having 
different pharmacological and toxicological profiles, the non-
cannabinoid components in marijuana, such as other terpenoids and 
flavonoids, might also contribute to the overall pharmacological and 
toxicological profiles of various marijuana strains and products 
derived from those strains.
    The term marijuana is often used to refer to a mixture of the dried 
flowering tops and leaves from Cannabis. Marijuana in this limiting 
definition is one of three major derivatives sold as separate illicit 
products, which also include hashish and hash oil. According to the 
DEA, Cannabis saliva is the primary species of Cannabis currently 
marketed illegally in the United States.
    Marijuana can vary in cannabinoid content and potency (Agurell et 
al., 1984, 1986; Mechoulam 1973, Cascini et al., 2012). In the usual 
mixture of leaves and stems distributed as marijuana, the concentration 
of delta\9\-THC averages over 12 percent by weight. However, specially 
grown and selected marijuana can contain 15 percent or greater 
delta\9\-THC (Appendino et al., 2011). Thus, a 1-gram marijuana 
cigarette might

[[Page 53699]]

contain delta\9\-THC in a range from as little as 3 milligrams to as 
much as 150 milligrams or more. Additionally, a recent systematic 
review and meta-analysis found that marijuana's delta\9\-THC content 
has increased significantly from 1979-2009 (Cascini et al., 2012). In 
addition to smoking marijuana, individuals ingest marijuana through 
food made with butter or oil infused with marijuana and its extracts. 
These marijuana butters are generally made by adding marijuana to 
butter and heating it. The resultant butter is then used to cook a 
variety of foods. There are no published studies measuring the 
concentrations of cannabinoids in these marijuana food products.
    Hashish consists of the dried and compressed cannabinoid-rich 
resinous material of Cannabis and comes in a variety of forms (e.g. 
balls and cakes). Individuals may break off pieces, place it into a 
pipe and smoke it. DEA reports that cannabinoid content in hashish 
averages six percent (DEA, 2005). With the development and cultivation 
of more high potency Cannabis strains, the average cannabinoid content 
in hashish will likely increase.
    Hash oil is produced by solvent extraction of the cannabinoids from 
plant material. The extract's color and odor vary, depending on the 
solvent type used. Hash oil is a viscous brown- or amber-colored liquid 
containing approximately 50 percent cannabinoids. One or two drops of 
the liquid placed on a cigarette purportedly produce the equivalent of 
a single marijuana cigarette (DEA, 2005).
    In conclusion, marijuana has hundreds of cultivars containing 
variable concentrations of delta\9\-THC, cannabinoids, and other 
compounds. Thus, marijuana is not a single chemical with a consistent 
and reproducible chemical profile or predictable and consistent 
clinical effects. A guidance for industry, entitled Botanical Drug 
Products,\8\ provides information on the approval of botanical drug 
products. To investigate marijuana for medical use in a manner 
acceptable as support for marketing approval under an NDA, clinical 
studies under an IND of consistent batches of a particular marijuana 
product for particular disease indications should be conducted. In 
addition, information and data regarding the marijuana product's 
chemistry, manufacturing and control, pharmacology, and animal 
toxicology data, among others must be provided and meet the 
requirements for new drug approval (See 21 CFR 314.50).
---------------------------------------------------------------------------

    \8\ This guidance is available on the Internet at http://www.fda.gov/Drugs/default.htm under Guidance (Drugs).
---------------------------------------------------------------------------

Human Pharmacokinetics

    Marijuana can be taken in a variety of formulations by multiple 
routes of administration. Individuals smoke marijuana as a cigarette, 
weighing between 0.5 and 1.0 gram, or in a pipe. Additionally, 
individuals take marijuana orally in foods or as an extract in ethanol 
or other solvents. More recently, access to vaporizers provides another 
means for abusers to inhale marijuana,
    The absorption, metabolism, and pharmacokinetic profile of 
delta\9\-THC, cannabinoids, and drug products containing delta\9\-THC 
vary with route of administratfon and formulation (Adams and Martin, 
1996; Agurell et al., 1984, 1986).

Pharmacokinetics of Smoked Administration of Cannabinoids

    Characterization of the pharmacokinetics of delta\9\-THC and other 
cannabinoids from smoked marijuana is difficult because a subject's 
smoking behavior during an experiment varies (Agurell et al., 1986; 
Heming et al., 1986; Huestis et al., 1992a). Each puff delivers a 
discrete dose of delta\9\-THC. An experienced marijuana smoker can 
titrate and regulate the dose to obtain the desired acute psychological 
effects and minimize undesired effects. For example, under naturalistic 
conditions, users hold marijuana smoke in their lungs for an extended 
period of time which causes prolonged absorption and increases 
psychoactive effects. The effect of experience in the psychological 
response may explain why delta\9\-THC venous blood levels correlate 
poorly with intensity of effects and intoxication level (Agurell et al. 
1986; Barnett et al. 1985; Huestis et al., 1992a). Puff and inhalation 
volumes should be recorded in studies as the concentration (dose) of 
cannabinoids administered can vary at different stages of smoking.
    Smoked marijuana results in absorption of delta\9\-THC in the form 
of an aerosol within seconds. Psychoactive effects occur immediately 
following absorption, with mental and behavioral effects measurable for 
up to 6 hours (Grotenhermen, 2003; Hollister 1986, 1988). Delta\9\-THC 
is delivered to the brain rapidly and efficiently as expected of a very 
lipid soluble drug.
    The bioavailability of the delta\9\-THC, from marijuana in a 
cigarette or pipe, can range from 1 to 24 percent with the fraction 
absorbed rarely exceeding 10 to 20 percent (Agurell et al.,1986; 
Hollister, 1988). The relatively low and variable bioavailability 
results from significant loss of delta\9\-THC in side-stream smoke, 
variation in individual smoking behaviors, cannabinoid pyrolysis, 
incomplete absorption of inhaled smoke, and metabolism in the lungs. An 
individual's experience and technique with smoking marijuana also 
determines the dose absorbed (Heming et al., 1986; Johansson et al., 
1989). After smoking, delta\9\-THC venous levels decline precipitously 
within minutes, and continue to go down to about 5 to 10 percent of the 
peak level within an hour (Agurell et al., 1986, Huestis et al.,1992a, 
1992b).

Pharmacokinetics for Oral Administration of Cannabinoids

    After oral administration of delta\9\-THC or marijuana, the onset 
of effects starts within 30 to 90 minutes, reaches its peak after 2 to 
3 hours and then remains for 4 to 12 hours (Grotenhermen, 2003; Adams 
and Martin, 1996; Agurell et al., 1984, 1986). Due to the delay in 
onset of effects, users have difficulty in titrating oral delta\9\-THC 
doses compared to smoking marijuana. Oral bioavailability of delta\9\-
THC, whether pure or in marijuana, is low and extremely variable, 
ranging between 5 and 20 percent (Agurell et al., 1984, 1986). 
Following oral administration of radioactive-labeled delta\9\-THC, 
delta\9\-THC plasma levels are low relative to plasma levels after 
smoking or intravenous administration. Inter- and intra-subject 
variability occurs even with repeated dosing under controlled 
conditions. The low and variable oral bioavailability of delta\9\-THC 
is a consequence of its first-pass hepatic elimination from blood and 
erratic absorption from stomach and bowel.

Cannabinoid Metabolism and Excretion

    Cannabinoid metabolism is complex. Delta\9\-THC is metabolized via 
microsomal hydroxylation to both active and inactive metabolites 
(Lemberger et al., 1970, 1972a, 1972b; Agurell et al., 1986; Hollister, 
1988). The primary active metabolite of delta\9\-THC following oral 
ingestion is 11-hydroxy-delta\9\-THC. This metabolite is approximately 
equipotent to delta\9\-THC in producing marijuana-like subjective 
effects (Agurell et al., 1986, Lemberger and Rubin, 1975). After oral 
administration, metabolite levels may exceed that of delta\9\-THC and 
thus contribute greatly to the pharmacological effects of oral 
delta\9\-THC or marijuana.
    Plasma clearance of delta\9\-THC approximates hepatic blood flow at 
about 950 ml/min or greater. The rapid disappearance of delta\9\-THC 
from blood

[[Page 53700]]

is largely due to redistribution to other tissues in the body, rather 
than to metabolism (Agurell et al., 1984, 1986). Metabolism in most 
tissues is relatively slow or absent. Slow release of delta\9\-THC and 
other cannabinoids from tissues and subsequent metabolism results in a 
long elimination half-life. The terminal half-life of delta\9\-THC 
ranges from approximately 20 hours to as long as 10 to 13 days, though 
reported estimates vary as expected with any slowly cleared substance 
and the use of assays with variable sensitivities (Hunt and Jones, 
1980). Lemberger et al. (1970) determined the half-life of delta\9\-THC 
to range from 23 to 28 hours in heavy marijuana users to 60 to 70 hours 
in naive users. In addition to 11-hydroxy-delta\9\-THC, some inactive 
carboxy metabolites have terminal half-lives of 50 hours to 6 days or 
more. The latter substances serve as long-term markers in urine tests 
for earlier marijuana use.
    The majority of the absorbed delta\9\-THC dose is eliminated in 
feces, and about 33 percent in urine. Delta\9\-THC enters enterohepatic 
circulation and undergoes hydroxylation and oxidation to 11-nor-9-
carboxy-delta\9\-THC. The glucuronide is excreted as the major urine 
metabolite along with about 18 non-conjugated metabolites. Frequent and 
infrequent marijuana users metabolize delta\9\-THC similarly (Agurell 
et al., 1986).

Status of Research Into the Medical Uses for Marijuana

    State-level public initiatives, including laws and referenda in 
support of the medical use of marijuana, have generated interest in the 
medical community and the need for high quality clinical investigation 
as well as comprehensive safety and effectiveness data. In order to 
address the need for high quality clinical investigations, the state of 
California established the Center for Medicinal Cannabis Research 
(CMCR, www.cmcr.ucsd.edu) in 2000 ``in response to scientific evidence 
for therapeutic possibilities of cannabis \9\ and local legislative 
initiatives in favor of compassionate use'' (Grant, 2005). State 
legislation establishing the CMCR called for high quality medical 
research that would ``enhance understanding of the efficacy and adverse 
effects of marijuana as a pharmacological agent,'' but stressed the 
project ``should not be construed as encouraging or sanctioning the 
social or recreational use of marijuana.'' The CMCR funded many of the 
published studies on marijuana's potential use for treating multiple 
sclerosis, neuropathic pain, appetite suppression and cachexia. 
However, aside from the data produced by CMCR, no state-level medical 
marijuana laws have produced scientific data on marijuana's safety and 
effectiveness.
---------------------------------------------------------------------------

    \9\ In this quotation the term cannabis is interchangeable with 
marijuana.
---------------------------------------------------------------------------

    FDA approves medical use of a drug following a submission and 
review of an NDA or BLA. The FDA has not approved any drug product 
containing marijuana for marketing. Even so, results of small clinical 
exploratory studies have been published in the current medical 
literature. Many studies describe human research with marijuana in the 
United States under FDA-regulated IND applications.
    However, FDA approval of an NDA is not the only means through which 
a drug can have a currently accepted medical use in treatment in the 
United States. In general, a drug may have a ``currently accepted 
medical use'' in treatment in the United States if the drug meets a 
five-part test. Established case law (Alliance for Cannabis 
Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)) upheld the 
Administrator of DEA's application of the five-part test to determine 
whether a drug has a ``currently accepted medical use.'' The following 
describes the five elements that characterize ``currently accepted 
medical use'' for a drug: \10\
---------------------------------------------------------------------------

    \10\ 57 FR 10499, 10504-06 (March 26, 1992).
---------------------------------------------------------------------------

    i. the drug's chemistry must be known and reproducible.
    ``The substance's chemistry must be scientifically established to 
permit it to be reproduced into dosages which can be standardized. The 
listing of the substance in a current edition of one of the official 
compendia, as defined by section 201 G) of the Food, Drug and Cosmetic 
Act, 21 U.S.C. 321G), is sufficient to meet this requirement.''
    ii. there must be adequate safety studies.
    ``There must be adequate pharmacological and toxicological studies, 
done by all methods reasonably applicable, on the basis of which it 
could fairly and responsibly be concluded, by experts qualified by 
scientific training and experience to evaluate the safety and 
effectiveness of drugs, that the substance is safe for treating a 
specific, recognized disorder.''
    iii. there must be adequate and well-controlled studies proving 
efficacy.
    ``There must be adequate, well-controlled, well-designed, well-
conducted, and well-documented studies, including clinical 
investigations, by experts qualified by scientific training and 
experience to evaluate the safety and effectiveness of drugs, on the 
basis of which it could be fairly and responsibly concluded by such 
experts that the substance will have the intended effect in treating a 
specific, recognized disorder.''
    iv. the drug must be accepted by qualified experts.
    ``The drug has a New Drug Application (NDA) approved by the Food 
and Drug Administration, pursuant to the Food, Drug and Cosmetic Act, 
21 U.S.C. 355. Or, a consensus of the national community of experts, 
qualified by scientific training and experience to evaluate the safety 
and effectiveness of drugs, accepts the safety and effectiveness of the 
substance for use in treating a specific, recognized disorder. A 
material conflict of opinion among experts precludes a finding of 
consensus.'' and
    v. the scientific evidence must be widely available.
    ``In the absence of NDA approval, information concerning the 
chemistry, pharmacology, toxicology, and effectiveness of the substance 
must be reported, published, or otherwise widely available, in 
sufficient detail to permit experts, qualified by scientific training 
and experience to evaluate the safety and effectiveness of drugs, to 
fairly and responsibly conclude the substance is safe and effective for 
use in treating a specific, recognized disorder.''
    Marijuana does not meet any of the five elements necessary for a 
drug to have a ``currently accepted medical use.''
    Firstly, the chemistry of marijuana, as defined in the petition, is 
not reproducible in terms of creating a standardized dose. The petition 
defines marijuana as including all Cannabis cultivated strains. 
Different marijuana samples derived from various cultivated strains may 
have very different chemical constituents including delta\9\-THC and 
other cannabinoids (Appendino et al., 2011). As a consequence, 
marijuana products from different strains will have different safety, 
biological, pharmacological, and toxicological profiles. Thus, when 
considering all Cannabis strains together, because of the varying 
chemical constituents, reproducing consistent standardized doses is not 
possible. Additionally, smoking marijuana currently has not been shown 
to allow delivery of consistent and reproducible doses. However, if a 
specific Cannabis strain is grown and processed under strictly 
controlled conditions, the plant chemistry may be kept consistent 
enough to produce reproducible and standardized doses.

[[Page 53701]]

    As to the second and third criteria; there are neither adequate 
safety studies nor adequate and well-controlled studies proving 
marijuana's efficacy. To support the petitioners' assertion that 
marijuana has accepted medical use, the petitioners cite the American 
Medical Association's (AMA) 2009 report entitled ``Use of Cannabis for 
Medicinal Purposes.'' The petitioners claim the AMA report is evidence 
the AMA accepts marijuana's safety and efficacy. However, the 2009 AMA 
report clarifies that the report ``should not be viewed as an 
endorsement of state-based medical cannabis programs, the legalization 
of marijuana, or that scientific evidence on the therapeutic use of 
cannabis meets the same and current standards for a prescription drug 
product.'' \11\
---------------------------------------------------------------------------

    \11\ In this quotation the term cannabis is used interchangeably 
for marijuana.
---------------------------------------------------------------------------

    Currently, no published studies conducted with marijuana meet the 
criteria of an adequate and well-controlled efficacy study. The 
criteria for an adequate and well-controlled study for purposes of 
determining the safety and efficacy of a human drug are defined under 
the Code of Federal Regulations (CFR) in 21 CFR 314.126. In order to 
assess this element, FDA conducted a review of clinical studies 
published and available in the public domain before February, 2013. 
Studies were identified through a search of PubMed \12\ for articles 
published from inception to February 2013, for randomized controlled 
trials using marijuana to assess marijuana's efficacy in any 
therapeutic indication. Additionally, the review included studies 
identified through a search of bibliographic references in relevant 
systematic reviews and identified studies presenting original research 
in any language. Selected studies needed to be placebo-controlled and 
double-blinded. Additionally, studies needed to encompass administered 
marijuana plant material. There was no requirement for any specific 
route of administration, nor any age limits on study subjects. Studies 
were excluded that used placebo marijuana supplemented by the addition 
of specific amounts of THC or other cannabinoids. Additionally, studies 
administering marijuana plant extracts were excluded.
---------------------------------------------------------------------------

    \12\ The following search strategy was used, ``(cannabis OR 
marijuana) AND (therapeutic use OR therapy) AND (RCT OR randomized 
controlled trial OR ``systematic review'' OR clinical trial OR 
clinical trials) NOT (``marijuana abuse''[Mesh] OR addictive 
behavior OR substance related disorders).''
---------------------------------------------------------------------------

    The PubMed search yielded a total of 566 abstracts of scientific 
articles. Of these abstracts, a full-text review was conducted with 85 
papers to assess eligibility. Of the studies identified through the 
search of the references and the 566 abstracts from the PubMed search, 
only 11 studies met all the criteria for selection (Abrams et al., 
2007; Corey-Bloom et al., 2012; Crawford and Merritt, 1979; Ellis et 
al., 2009; Haney et al., 2005; Haney et al., 2007; Merritt et al., 
1980; Tashkin et al., 1974; Ware et al., 2010; Wilsey et al., 2008; 
Wilsey et al., 2013). These 11 studies were published between 1974 and 
2013. Ten of these studies were conducted in the United States and one 
study was conducted in Canada. The identified studies examine the 
effects of smoked and vaporized marijuana for the indications of 
chronic neuropathic pain, spasticity related to Multiple Sclerosis 
(MS), appetite stimulation in human immunodeficiency virus (HIV) 
patients, glaucoma, and asthma. All studies used adult subjects.
    The 11 identified studies were individually evaluated to determine 
if they successfully meet accepted scientific standards. Specifically, 
they were evaluated on study design including subject selection 
criteria, sample size, blinding techniques, dosing paradigms, outcome 
measures, and the statistical analysis of the results. The analysis 
relied on published studies, thus information available about 
protocols, procedures, and results were limited to documents published 
and widely available in the public domain. The review found that all 11 
studies that examined effects of inhaled marijuana do not currently 
prove efficacy of marijuana in any therapeutic indication based on a 
number of limitations in their study design; however, they may be 
considered proof of concept studies. Proof of concept studies provide 
preliminary evidence on a proposed hypothesis involving a drug's 
effect. For drugs under development, the effect often relates to a 
short-term clinical outcome being investigated. Proof of concept 
studies often serve as the link between preclinical studies and dose 
ranging clinical studies. Thus, proof of concept studies generally are 
not sufficient to prove efficacy of a drug because they provide only 
preliminary information about the effects of a drug.
    In addition to the lack of published adequate and well-controlled 
efficacy studies proving efficacy, the criteria for adequate safety 
studies has also not been met. Importantly, in its discussion of the 
five-part test used to determine whether a drug has a ``currently 
accepted medical use,'' DEA said, ``No drug can be considered safe in 
the abstract. Safety has meaning only when judged against the intended 
use of the drug, its known effectiveness, its known and potential 
risks, the severity of the illness to be treated, and the availability 
of alternative remedies'' (57 FR 10504). When determining whether a 
drug product is safe and effective for any indication, FDA performs an 
extensive risk-benefit analysis to determine whether the risks posed by 
the drug product's side effects are outweighed by the drug product's 
potential benefits for a particular indication. Thus, contrary to the 
petitioner's assertion that marijuana has accepted safety, in the 
absence of an accepted therapeutic indication which can be weighed 
against marijuana's risks, marijuana does not satisfy the element for 
having adequate safety studies such that experts may conclude that it 
is safe for treating a specific, recognized disorder.
    The fourth of the five elements for determining ``currently 
accepted medical use'' requires that the national community of experts, 
qualified by scientific training and experience to evaluate the safety 
and effectiveness of drugs, accepts the safety and effectiveness of the 
substance for use in treating a specific, recognized disorder. A 
material conflict of opinion among experts precludes a finding of 
consensus. Medical practitioners who are not experts in evaluating 
drugs are not qualified to determine whether a drug is generally 
recognized as safe and effective or meets NDA requirements (57 FR 
10499-10505).
    There is no evidence that there is a consensus among qualified 
experts that marijuana is safe and effective for use in treating a 
specific, recognized disorder. As discussed above, there are not 
adequate scientific studies that show marijuana is safe and effective 
in treating a specific, recognized disorder. In addition, there is no 
evidence that a consensus of qualified experts have accepted the safety 
and effectiveness of marijuana for use in treating a specific, 
recognized disorder. Although medical practitioners are not qualified 
by scientific training and experience to evaluate the safety and 
effectiveness of drugs, we also note that the AMA's report, entitled 
``Use of Cannabis for Medicinal Purposes,'' does not accept that 
marijuana currently has accepted medical use. Furthermore, based on the 
above definition of a ``qualified expert'', who is an individual 
qualified by scientific training and experience to evaluate the safety 
and effectiveness of a drug, state-level medical marijuana laws do not 
provide evidence of a consensus among qualified experts that marijuana 
is safe and effective for use in treating a specific, recognized 
disorder.

[[Page 53702]]

    As to the fifth part of the test, which requires that information 
concerning the chemistry, pharmacology, toxicology, and effectiveness 
of marijuana to be reported in sufficient detail, the scientific 
evidence regarding all of these aspects is not available in sufficient 
detail to allow adequate scientific scrutiny. Specifically, the 
scientific evidence regarding marijuana's chemistry in terms of a 
specific Cannabis strain that could produce standardized and 
reproducible doses is not currently available.
    Alternately, a drug can be considered to have a ``currently 
accepted medical use with severe restrictions'' (21 U.S.C. 
812(b)(2)(B)), as allowed under the stipulations for a Schedule II 
drug. Yet, as stated above, currently marijuana does not have any 
accepted medical use, even under conditions where its use is severely 
restricted.
    In conclusion, to date, research on marijuana's medical use has not 
progressed to the point where marijuana is considered to have a 
``currently accepted medical use'' or a ``currently accepted medical 
use with severe restrictions.''

4. Its History and Current Pattern of Abuse

    Under the fourth factor, the Secretary must consider the history 
and current pattern of marijuana abuse. A variety of sources provide 
data necessary to assess abuse patterns and trends of marijuana. The 
data indicators of marijuana use include the NSDUH, MTF, DAWN, and 
TEDS. The following briefly describes each data source, and summarizes 
the data from each source.

National Survey on Drug Use and Health (NSDUH) \13\
---------------------------------------------------------------------------

    \13\ NSDUH provides national estimates of the prevalence and 
incidence of illicit drug, alcohol and tobacco use in the United 
States. NSDUH is an annual study conducted by SAMHSA. Prior to 2002, 
the database was known as the National Household Survey on Drug 
Abuse (NHSDA). NSDUH utilizes a nationally representative sample of 
United States civilian, non-institutionalized population aged 12 
years and older. The survey excludes homeless people who do not use 
shelters, active military personnel, and residents of institutional 
group quarters such as jails and hospitals. The survey identifies 
whether an individual used a drug within a specific time period, but 
does not identify the amount of the drug used on each occasion. 
NSDUH defines ``current use'' as having used the substance within 
the month prior to the study.
---------------------------------------------------------------------------

    According to 2012 NSDUH \14\ data, the most recent year with 
complete data, the use of illicit drugs, including marijuana, is 
increasing. The 2012 NSDUH estimates that 23.9 million individuals over 
12 years of age (9.2 percent of the U.S. population) currently use 
illicit drugs, which is an increase of 4.8 million individuals from 
2004 when 19.1 million individuals (7.9 percent of the U.S. population) 
were current illicit drug users. NSDUH reports marijuana as the most 
commonly used illicit drug, with 18.9 million individuals (7.3 percent 
of the U.S. population) currently using marijuana in 2012. This 
represents an increase of 4.3 million individuals from 2004, when 14.6 
million individuals (6.1 percent of the U.S. population) were current 
marijuana users.
---------------------------------------------------------------------------

    \14\ 2013; http://www.samhsa.gov/data/NSDUH.aspx.
---------------------------------------------------------------------------

    The majority of individuals who try marijuana at least once in 
their lifetime do not currently use marijuana. The 2012 NSDUH estimates 
that 111.2 million individuals (42.8 percent of the U.S. population) 
have used marijuana at least once in their lifetime. Based on this 
estimate and the estimate for the number of individuals currently using 
marijuana, approximately 16.9 percent of those who have tried marijuana 
at least once in their lifetime currently use marijuana; conversely, 
83.1 percent do not currently use marijuana. In terms of the frequency 
of marijuana use, an estimated 40.3 percent of individuals who used 
marijuana in the past month used marijuana on 20 or more days within 
the past month. This amount corresponds to an estimated 7.6 million 
individuals who used marijuana on a daily or almost daily basis.
    Some characteristics of marijuana users are related to age, gender, 
and criminal justice system involvement. In observing use among 
different age cohorts, the majority of individuals who currently use 
marijuana are shown to be between the ages of 18-25, with 18.7 percent 
of this age group currently using marijuana. In the 26 and older age 
group, 5.3 percent of individuals currently use marijuana. 
Additionally, in individuals aged 12 years and older, males reported 
more current marijuana use than females.
    NSDUH includes a series of questions aimed at assessing the 
prevalence of dependence and abuse of different substances in the past 
12 months.\15\ In 2012, marijuana was the most common illicit drug 
reported by individuals with past year dependence or abuse. An 
estimated 4.3 million individuals meet the NSDUH criteria for marijuana 
dependence or abuse in 2012. The estimated rates and number of 
individuals with marijuana dependence or abuse has remained similar 
from 2002 to 2012. In addition to data on dependence and abuse, NSDUH 
includes questions aimed at assessing treatment for a substance use 
problem.\16\ In 2012, an estimated 957,000 persons received treatment 
for marijuana use during their most recent treatment in the year prior 
to the survey.
---------------------------------------------------------------------------

    \15\ ``These questions are used to classify persons as dependent 
on or abusing specific substances based on criteria specified in the 
Diagnostic and Statistical Manual of Mental Disorder, 4th edition 
(DSM-IV). The questions related to dependence ask about health and 
emotional problems associated with substance use, unsuccessful 
attempts to cut down on use, tolerance, withdrawal, reducing other 
activities to use substances, spending a lot time engaging in 
activities related to substance use, or using the substance in 
greater quantities or for longer time than intended. The questions 
on abuse ask about problems at work, home, and school; problems with 
family or friends; physical danger; and trouble with the law due to 
substance use. Dependence is considered to be a more severe 
substance use problem than abuse because it involves the 
psychological and physiological effects of tolerance and 
withdrawal.'' (NSDUH, 2013).
    \16\ ``Estimates . . . refer to treatment received for illicit 
drug or alcohol use, or for medical problems associated with the use 
of illicit drugs or alcohol. This includes treatment received in the 
past year at any location, such as a hospital (inpatient), 
rehabilitation facility (outpatient or inpatient), mental health 
center, emergency room, private doctor's office, prison or jail, or 
a self-help group, such as Alcoholics Anonymous or Narcotics 
Anonymous.'' (NSDUH, 2013).
---------------------------------------------------------------------------

Monitoring the Future (MTF) \17\
---------------------------------------------------------------------------

    \17\ Monitoring the Future is a national survey that tracks drug 
use prevalence and trends among adolescents in the United States. 
MTF is reported annually by the Institute for Social Research at the 
University of Michigan under a grant from NIDA. Every spring, MTF 
surveys 8th, 10th, and 12th graders in randomly selected U.S. 
schools. MTF has been conducted since 1975 for 12th graders and 
since 1991 for 8th and 10th graders. The MTF survey presents data in 
terms of prevalence among the sample interviewed. For 2012, the 
latest year with complete data, the sample sizes were 15,200--8th 
graders; 13,300--10th graders; and 13,200--12th graders. In all, a 
total of about 41,700 students of 389 schools participated in the 
2013 MTF.
---------------------------------------------------------------------------

    According to MTF,\18\ rates of marijuana and illicit drug use 
declined for all three grades from 2005 through 2007. However, starting 
around 2008, rates of annual use of illicit drugs and marijuana 
increased through 2013 for all three grades. Marijuana remained the 
most widely used illicit drug during all time periods. The prevalence 
of annual and past month marijuana use in 10th and 12th graders in 2013 
is greater than in 2005. Table 1 lists the lifetime, annual, and 
monthly prevalence rates of various drugs for 8th, 10th, and 12th 
graders in 2013.
---------------------------------------------------------------------------

    \18\ 2013; http://www.monitoringthefuture.org/index.html.

---------------------------------------------------------------------------

[[Page 53703]]

[GRAPHIC] [TIFF OMITTED] TP12AU16.005

Drug Abuse Warning Network (DAWN) \19\
---------------------------------------------------------------------------

    \19\ DAWN is a national probability survey of the U.S. hospitals 
with ED designed to obtain information on drug related ED visits. 
DAWN is sponsored by SAMHSA. The DAWN system provides information on 
the health consequences of drug use in the United States, as 
manifested by drug-related visits to ED. The ED data from a 
representative sample of hospital emergency departments are weighted 
to produce national estimates. Importantly, DAWN data and estimates, 
starting in 2004, are not comparable to those for prior years 
because of vast changes in the methodology used to collect the data. 
Furthermore, estimates for 2004 are the first to be based on a 
redesigned sample of hospitals, which ended in 2011.
---------------------------------------------------------------------------

    Importantly, many factors can influence the estimates of ED visits, 
including trends in overall use of a substance as well as trends in the 
reasons for ED usage. For instance, some drug users may visit EDs for 
life-threatening issues while others may visit to seek care for 
detoxification because they needed certification before entering 
treatment. Additionally, DAWN data do not distinguish the drug 
responsible for the ED visit from other drugs that may have been used 
concomitantly. As stated in a DAWN report, ``Since marijuana/hashish is 
frequently present in combination with other drugs, the reason for the 
ED visit may be more relevant to the other drug(s) involved in the 
episode.''
    For 2011, DAWN \20\ estimates a total of 5,067,374 (95 percent 
confidence interval [CI]: 4,616,753 to 5,517,995) drug-related ED 
visits from the entire United States. Of these, approximately 2,462,948 
([CI]: 2,112,868 to 2,813,028) visits involved drug misuse or abuse.
---------------------------------------------------------------------------

    \20\ 2011; http://www.samhsa.gov/data/dawn.aspx.
---------------------------------------------------------------------------

    During the same period, DAWN estimates that 1,252,500 (CI: 976,169 
to 1,528,831) drug related ED visits involved illicit drugs. Thus, over 
half of all drug-related ED visits associated with drug misuse or abuse 
involved an illicit drug. For ED visits involving illicit drugs, 56.3 
percent involved multiple drugs while 43.7 percent involved a single 
drug.
    Marijuana was involved in 455,668 ED visits (CI: 370,995 to 
540,340), while cocaine was involved in 505,224 (CI: 324,262 to 686, 
185) ED visits, heroin was involved in 258,482 (CI: 205,046 to 311,918) 
ED visits and stimulants including amphetamine and methamphetamine were 
involved in 159,840 (CI: 100,199 to 219,481) ED visits. Other illicit 
drugs, such as PCP, MDMA, GHB and LSD were much less frequently 
associated with ED visits. The number of ED visits involving marijuana 
has increased by 62 percent since 2004.
    Marijuana-related ED visits were most frequent among young adults 
and minors. Individuals under the age of 18 accounted for 13.2 percent 
of these marijuana-related visits, whereas this age group accounted for 
approximately 1.2 percent of ED visits involving cocaine, and less than 
1 percent of ED visits involving heroin. However, the age group with 
the most marijuana-related ED visits was between 25 and 29 years old. 
Yet, because populations differ between age groups, a standardized 
measure for population size is useful to make comparisons. For 
marijuana, the rates of ED visits per 100,000 population were highest 
for patients aged 18 to 20 (443.8 ED visits per 100,000) and for 
patients aged 21 to 24 (446.9 ED visits per 100,000).
    While DAWN provides estimates for ED visits associated with the use 
of medical marijuana for 2009-2011, the validity of these estimates is 
questionable. Because the drug is not approved by the FDA, reporting 
medical marijuana may be inconsistent and reliant on a number of 
factors including whether the patient self-reports the marijuana use as 
medicinal, how the treating health care provider records the marijuana 
use, and lastly how the SAMHSA coder interprets the report. All of 
these aspects will vary greatly between states with medical marijuana 
laws and states without medical marijuana laws. Thus, even though 
estimates are reported for medical marijuana related ED visits, medical 
marijuana estimates cannot be assessed with any acceptable accuracy at 
this time, as FDA has not approved marijuana treatment of any medical 
condition. These data show the difficulty in evaluating abuse of a 
product that is not currently approved by FDA, but authorized for 
medical use, albeit inconsistently, at the state level. Thus, we 
believe the likelihood of the treating health care provider or SAMHSA 
coder attributing the ED visit to ``medical marijuana'' versus 
``marijuana'' to be very low. Overall, the available data are 
inadequate to characterize its abuse at the community level.

[[Page 53704]]

Treatment Episode Data Set (TEDS) \21\
---------------------------------------------------------------------------

    \21\ The TEDS system is part of SAMHSA's Drug and Alcohol 
Services Information System (Office of Applied Science, SAMHSA). The 
TEDS report presents information on the demographic and substance 
use characteristics of the 1.8 million annual admissions to 
treatment for alcohol and drug abuse in facilities that report to 
individual state administrative data systems. Specifically, TEDS 
includes facilities licensed or certified by the states to provide 
substance abuse treatment and is required by the states to provide 
TEDS client-level data. Facilities that report TEDS data are those 
receiving State alcohol and drug agency funds for the provision of 
alcohol and drug treatment services. Since TEDS is based only on 
reports from these facilities, TEDS data do not represent the total 
national demand for substance abuse treatment or the prevalence of 
substance abuse in the general population. The primary goal for TEDS 
is to monitor the characteristics of treatment .episodes for 
substance abusers. Importantly, TEDS is an admissions-based system, 
where admittance to treatment is counted as an anonymous tally. For 
instance, a given individual who is admitted to treatment twice 
within a given year would be counted as two admissions. The most 
recent year with complete data is 2011.
---------------------------------------------------------------------------

    Primary marijuana abuse accounted for 18.1 percent of all 2011 TEDS 
\22\ admissions. Individuals admitted for primary marijuana abuse were 
nearly three-quarters (73.4 percent) male, and almost half (45.2 
percent) were white. The average age at admission was 24 years old, and 
31.1 percent of individuals admitted for primary marijuana abuse were 
under the age of 18. The reported frequency of marijuana use was 24.3 
percent reporting daily use. Almost all (96.8 percent) primary 
marijuana users utilized the substance by smoking. Additionally, 92.9 
percent reported using marijuana for the first time before the age of 
18.
---------------------------------------------------------------------------

    \22\ 2011; http://www.samhsa.gov/data/DASIS.aspx?qr=t#TEDS.
---------------------------------------------------------------------------

    An important aspect of TEDS admission data for marijuana is of the 
referral source for treatment. Specifically, primary marijuana 
admissions were less likely than all other admissions to either be 
self-referred or referred by an individual for treatment. Instead, the 
criminal justice system referred more than half (51.6 percent) of 
primary marijuana admissions.
    Since 2003, the percent of admissions for primary marijuana abuse 
increased from 15.5 percent of all admissions in 2003 to 18.1 percent 
in 2011. This increase is less than the increase seen for admissions 
for primary opioids other than heroin, which increased from 2.8 percent 
in 2003 to 7.3 percent in 2011. In contrast, the admissions for primary 
cocaine abuse declined from 9.8 percent in 2003 to 2.0 percent in 2011.

5. The Scope, Duration, and Significance of Abuse

    Under the fifth factor, the Secretary must consider the scope, 
duration, and significance of marijuana abuse. According to 2012 data 
from NSDUH and 2013 data from MTF, marijuana remains the most 
extensively used illegal drug in the United States, with 42.8 percent 
of U.S. individuals over age 12 (111.2 million) and 45.5 percent of 
12th graders having used marijuana at least once in their lifetime. 
Although the majority of individuals over age 12 (83.1 percent) who 
have ever used marijuana in their lifetime do not use the drug monthly, 
18.9 million individuals (7.3 percent of the U.S. population) report 
that they used marijuana within the past 30 days. An examination of use 
among various age cohorts through NSDUH demonstrates that monthly use 
occurs primarily among college-aged individuals, with use dropping off 
sharply after age 25. Additionally, NSDUH data show the number of 
individuals reporting past-month use of marijuana has increased by 4.3 
million individuals since 2004. Data from MTF shows that annual 
prevalence of marijuana use declined for all three grades from 2005 
through 2007, then began to rise through 2013. Additionally, in 2013, 
1.1 percent of 8th graders, 4.0 percent of 10th graders, and 6.5 
percent of 12th graders reported daily use of marijuana, defined as use 
on 20 or more days within the past 30 days.
    The 2011 DAWN data show that marijuana use was mentioned in 455,668 
ED visits, which amounts to approximately 36.4 percent of all illicit 
drug-related ED visits.\23\
---------------------------------------------------------------------------

    \23\ Many factors can influence the estimates of ED visits, 
including trends in the reasons for ED usage. For instance, some 
drug users may visit EDs for life-threatening issues while others 
may visit to seek care for detoxification because they needed 
certification before entering treatment. Additionally, DAWN data do 
not distinguish the drug responsible for the ED visit from other 
drugs that may have been used concomitantly. As stated in a DAWN 
report, ``Since marijuana/hashish is frequently present in 
combination with other drugs, the reason for the ED visit may be 
more relevant to the other drug(s) involved in the episode.''
---------------------------------------------------------------------------

    TEDS data for 2011 show that 18.1 percent of all admissions were 
for primary marijuana abuse.\24\ Between 2003 and 2011, there was a 2.6 
percent increase in the number of TEDS admissions for primary marijuana 
use. Approximately 61.5 percent of primary marijuana admissions in 2011 
were for individuals under the age of 25 years.
---------------------------------------------------------------------------

    \24\ An important aspect of TEDS admission data for marijuana is 
of the referral source for treatment. Specifically, primary 
marijuana admissions were less likely than all other admissions to 
either be self-referred or referred by an individual for treatment. 
Instead, the criminal justice system referred more than half (51.6 
percent) of primary marijuana admissions.
---------------------------------------------------------------------------

6. WHAT, if Any, Risk There Is to the Public Health

    Under the sixth factor, the Secretary must consider the risks posed 
to the public health by marijuana. Factors 1, 4, and 5 include a. 
discussion of the risk to the public health as measured by emergency 
room episodes and drug treatment admissions. Additionally, Factor 2 
includes a discussion of marijuana's central nervous system, cognitive, 
cardiovascular, autonomic, respiratory, and immune system effects. 
Factor 6 focuses on the health risks to the individual user in terms of 
the risks from acute and chronic use of marijuana, as well as the 
``gateway hypothesis.''

Risks From Acute Use of Marijuana

    Acute use of marijuana impairs psychomotor performance, including 
complex task performance, which makes operating motor vehicles or heavy 
equipment after using marijuana inadvisable (Ramaekers et al., 2004; 
Ramaekers et al., 2006a). A meta-analysis conducted by Li et al. (2011) 
showed an association between marijuana use by the driver and a 
significantly increased risk of involvement in a car accident. 
Additionally, in a minority of individuals who use marijuana, some 
potential responses include dysphoria and psychological distress, 
including prolonged anxiety reactions (Haney et al., 1999).

Risks From Chronic Use of Marijuana

    A distinctive marijuana withdrawal syndrome following long term or 
chronic use has been identified. The withdrawal syndrome indicates that 
marijuana produces physical dependence that is mild, short-lived, and 
comparable to tobacco withdrawal (Budney et al., 2008). Marijuana 
withdrawal syndrome is described in detail below under Factor 7.
    The following states how the DSM-V (2013) of the American 
Psychiatric Association describes the consequences of Cannabis \25\ 
abuse:
---------------------------------------------------------------------------

    \25\ Cannabis is the term used in the DSM-V to refer to 
marijuana. In the following excerpt the term Cannabis is 
interchangeable for the term marijuana.
---------------------------------------------------------------------------

    Individuals with cannabis use disorder may use cannabis throughout 
the day over a period of months or years, and thus may spend many hours 
a day under the influence. Others may use less frequently, but their 
use causes recurrent problems related to family,

[[Page 53705]]

school, work, or other important activities (e.g., repeated absences at 
work; neglect of family obligations). Periodic cannabis use and 
intoxication can negatively affect behavioral and cognitive functioning 
and thus interfere with optimal performance at work or school, or place 
the individual at increased physical risk when performing activities 
that could be physically hazardous (e.g., driving a car; playing 
certain sports; performing manual work activities, including operating 
machinery). Arguments with spouses or parents over the use of cannabis 
in the home, or its use in the presence of children, can adversely 
impact family functioning and are common features of those with 
cannabis use disorder. Last, individuals with cannabis use disorder may 
continue using marijuana despite knowledge of physical problems (e.g., 
chronic cough related to smoking) or psychological problems (e.g., 
excessive sedation or exacerbation of other mental health problems) 
associated with its use.

Marijuana as a ``Gateway Drug''

    Kandel (1975) proposed nearly 40 years ago the hypothesis that 
marijuana is a ``gateway drug'' that leads to the use or abuse of other 
illicit drugs. Since that time, epidemiological research explored this 
premise. Overall, research does not support a direct causal 
relationship between regular marijuana use and other illicit drug use. 
The studies examining the gateway hypothesis are limited. First, in 
general, studies recruit individuals influenced by a myriad of social, 
biological, and economic factors that contribute to extensive drug 
abuse (Hall & Lynskey, 2005). Second, most studies that test the 
hypothesis that marijuana use causes abuse of illicit drugs use the 
determinative measure any use of an illicit drug, rather than DSM-5 
criteria for drug abuse or dependence on an illicit drug (DSM-5, 2013). 
Consequently, although an individual who used marijuana may try other 
illicit drugs, the individual may not regularly use drugs, or have a 
diagnosis of drug abuse or dependence.
    Little evidence supports the hypothesis that initiation of 
marijuana use leads to an abuse disorder with other illicit substances. 
For example, one longitudinal study of 708 adolescents demonstrated 
that early onset marijuana use did not lead to problematic drug use 
(Kandel & Chen, 2000). Similarly, Nace et al. (1975) examined Vietnam-
era soldiers who extensively abused marijuana and heroin while they 
were in the military, and found a lack of correlation of a causal 
relationship demonstrating marijuana use leading to heroin addiction. 
Additionally, in another longitudinal study of 2,446 adolescents, 
marijuana dependence was uncommon but when it did occur, the common 
predictors of marijuana dependence were the following: Parental death, 
deprived socio-economic status, and baseline illicit drug use other 
than marijuana (von Sydow et al., 2002).
    When examining the association between marijuana and illicit drugs, 
focusing on drug use versus abuse or dependence, different patterns 
emerge. For example, a study examining the possible causal relationship 
of the gateway hypothesis found a correlation between marijuana use in 
adolescents and other illicit drug use in early adulthood and, 
adjusting for age-linked experiences, did not effect this correlation 
(Van Gundy and Rebellon, 2010). However, when examining the association 
in terms of development of drug abuse; age-linked stressors and social 
roles moderated the correlation between marijuana use in adolescents 
and other illicit drug abuse. Similarly, Degenhardt et al. (2009) 
examined the development of drug dependence and found an association 
that did not support the gateway hypothesis. Specifically, drug 
dependence was significantly associated with the use of other illicit 
drugs prior to marijuana use.
    Interestingly, the order of initiation of drug use seems to depend 
on the prevalence of use of each drug, which varies by country. Based 
on the World Health Organization (WHO) World Mental Health Survey that 
includes data from 17 different countries, the order of drug use 
initiation varies by country and relates to prevalence of drug use in 
each country (Degenhardt et al., 2010). Specifically, in the countries 
with the lowest prevalence of marijuana use, use of other illicit drugs 
before marijuana was common. This sequence of initiation is less common 
in countries with higher prevalence of marijuana use. A study of 9,282 
households in the United States found that marijuana use often preceded 
the use of other illicit drugs; however, prior non-marijuana drug 
dependence was also frequently correlated with higher levels of illicit 
drug abuse (Degenhardt et al., 2009). Additionally, in a large 25-year 
longitudinal study of 1,256 New Zealand children, the author concluded 
that marijuana use correlated to an increased risk of abuse of other 
drugs, including cocaine and heroin (Fergusson et al., 2005).
    Although many individuals with a drug abuse disorder may have used 
marijuana as one of their first illicit drugs, this fact does not 
correctly lead to the reverse inference that most individuals who used 
marijuana will inherently go on to try or become regular users of other 
illicit drugs. Specifically, data from the 2011 NSDUH survey 
illustrates this issue (SAMHSA, 2012). NSDUH data estimates 107.8 
million individuals have a lifetime history of marijuana use, which 
indicates use on at least one occasion, compared to approximately 36 
million individuals having a lifetime history of cocaine use and 
approximately 4 million individuals having a lifetime history of heroin 
use. NSDUH data do not provide information about each individual's 
specific drug history. However, even if one posits that every cocaine 
and heroin user previously used marijuana, the NSDUH data show that 
marijuana use at least once in a lifetime does not predict that an 
individual will also use another illicit drug at least once.
    Finally, a review of the gateway hypothesis by Vanyukov et al. 
(2012) notes that because the gateway hypothesis only addresses the 
order of drug use initiation, the gateway hypothesis does not specify 
any mechanistic connections between drug ``stages'' following exposure 
to marijuana and does not extend to the risks for addiction. This 
concept contrasts with the concept of a common liability to addiction 
that involves mechanisms and biobehavioral characteristics pertaining 
to the entire course of drug abuse risk and disorders.

7. Its Psychic or Physiologic Dependence Liability

    Under the seventh factor, the Secretary must consider marijuana's 
psychic or physiological dependence liability.
    Psychic or psychological dependence has been shown in response to 
marijuana's psychoactive effects. Psychoactive responses to marijuana 
are pleasurable to many humans and are associated with drug-seeking and 
drug-taking (Maldonado, 2002). Moreover, high levels of psychoactive 
effects, notably positive reinforcement, are associated with increased 
marijuana use, abuse, and dependence (Scherrer et al., 2009; Zeiger et 
al., 2010). Epidemiological data support these findings through 2012 
NSDUH statistics that show that of individuals years 12 or older who 
used marijuana in the past month, an estimated 40.3 percent used 
marijuana on 20 or more days within the past month. This equates to 
approximately 7.6 million individuals aged 12 or older who used 
marijuana on a daily or almost daily basis.

[[Page 53706]]

Additionally, the 2013 MTF data report the prevalence of daily 
marijuana use, defined as use on 20 or more days within the past 30 
days, in 8th, 10th, and 12th graders is 1.1 percent, 4.0 percent, and 
6.5 percent, respectively.
    Tolerance is a state of adaptation where exposure to a drug induces 
changes that result in a diminution of one or more of the drug's 
effects over time (American Academy of Pain Medicine, American Pain 
Society and American Society of Addiction Medicine consensus document, 
2001). Tolerance can develop to some, but not all, of marijuana's 
effects. Specifically, tolerance does not seem to develop in response 
to many of marijuana's psychoactive effects. This lack of tolerance may 
relate to electrophysiological data demonstrating that chronic 
delta\9\-THC administration does not affect increased neuronal firing 
in the ventral tegmental area, a region known to play a critical role 
in drug reinforcement and reward (Wu and French, 2000). In the absence 
of other abuse indicators, such as rewarding properties, the presence 
of tolerance or physical dependence does not determine whether a drug 
has abuse potential.
    However, humans can develop tolerance to marijuana's 
cardiovascular, autonomic, and behavioral effects (Jones et al., 1981). 
Tolerance to some of marijuana's behavioral effects seems to develop 
after heavy marijuana use, but not after occasional marijuana use. For 
instance, following acute administration of marijuana, heavy marijuana 
users did not exhibit impairments in tracking and attention tasks, as 
were seen in occasional marijuana users (Ramaekers et al., 2009). 
Furthermore, a neurophysiological assessment administered through an 
electroencephalograph (EEG) which measures event-related potentials 
(ERP) conducted in the same subjects as the previous study, found a 
corresponding effect in the P100 \26\ component of ERPs. Specifically, 
corresponding to performance on tracking and attention tasks, heavy 
marijuana users showed no changes in P100 amplitudes following acute 
marijuana administration, although occasional users showed a decrease 
in P100 amplitudes (Theunissen et al., 2012). A possible mechanism 
underlying tolerance to marijuana's effects may be the down-regulation 
of cannabinoid receptors (Hirvonen et al., 2012; Gonzalez et al., 2005; 
Rodriguez de Fonseca et al., 1994; Oviedo et al., 1993).
---------------------------------------------------------------------------

    \26\ The P100 component of ERPs is thought to relate to the 
visual processing of stimuli and can be modulated by attention.
---------------------------------------------------------------------------

    Importantly, pharmacological tolerance alone does not indicate a 
drug's physical dependence liability. In order for physical dependence 
to exist, evidence of a withdrawal syndrome is needed. Physical 
dependence is a state of adaptation, manifested by a drug-class 
specific withdrawal syndrome produced by abrupt cessation, rapid dose 
reduction, decreasing blood level of the drug, and/or administration of 
an antagonist (ibid). Many medications not associated with abuse or 
addiction can produce physical dependence and withdrawal symptoms after 
chronic use.
    Discontinuation of heavy, chronic marijuana use has been shown to 
lead to physical dependence and withdrawal symptoms (American 
Psychiatric Association DSM-V, 2013; Budney and Hughes, 2006; Haney et 
al., 1999). In heavy, chronic marijuana users, the most commonly 
reported withdrawal symptoms are sleep difficulties, decreased appetite 
or weight loss, irritability, anger, anxiety or nervousness, and 
restlessness. Some less commonly reported withdrawal symptoms are 
depressed mood, sweating, shakiness, physical discomfort, and chills 
(Budney and Hughes, 2006; Haney et al., 1999). The occurrence of 
marijuana withdrawal symptoms in light or non-daily marijuana users has 
not been established. The American Psychiatric Association's DSM-V 
(2013) includes a list of symptoms of ``cannabis withdrawal.'' Most 
marijuana withdrawal symptoms begin within 24-48 hours of 
discontinuation, peak within 4-6 days, and last for 1-3 weeks. 
Marijuana withdrawal syndrome has been reported in adolescents and 
adults admitted for substance abuse treatment.
    Based on clinical descriptions, this syndrome appears to be mild 
compared to classical alcohol and barbiturate withdrawal syndromes, 
which can include more serious symptoms such as agitation, paranoia, 
and seizures. Multiple studies comparing marijuana and tobacco 
withdrawal symptoms in humans demonstrate that the magnitude and time 
course of the two withdrawal syndromes are similar (Budney et al., 
2008; Vandrey et al., 2005, 2008).

8. Whether the Substance Is an Immediate Precursor of a Substance 
Already Controlled Under This Article

    Under the eight factor analysis, the Secretary must consider 
whether marijuana is an immediate precursor of a controlled substance. 
Marijuana is not an immediate precursor of another controlled 
substance.

Recommendation

    After consideration of the eight factors discussed above, FDA 
recommends that marijuana remain in Schedule I of the CSA. NIDA concurs 
with this scheduling recommendation. Marijuana meets the three criteria 
for placing a substance in Schedule I of the CSA under 21 U.S.C. 
812(b)(l):
    (1) Marijuana has a high potential for abuse:
    A number of factors indicate marijuana's high abuse potential, 
including the large number of individuals regularly using marijuana, 
marijuana's widespread use, and the vast amount of marijuana available 
for illicit use. Approximately 18.9 million individuals in the United 
States (7.3 percent of the U.S. population) used marijuana monthly in 
2012. Additionally, approximately 4.3 million individuals met 
diagnostic criteria for marijuana dependence or abuse in the year prior 
to the 2012 NSDUH survey. A 2013 survey indicates that by 12th grade, 
36.4 percent of students report using marijuana within the past year, 
and 22.7 percent report using marijuana monthly. In 2011, 455,668 ED 
visits were marijuana-related, representing 36.4 percent of all illicit 
drug-related episodes. Primary marijuana use accounted for 18.1 percent 
of admissions to drug treatment programs in 2011. Additionally, 
marijuana has dose-dependent reinforcing effects, as demonstrated by 
data showing that humans prefer relatively higher doses to lower doses. 
Furthermore, marijuana use can result in psychological dependence.
    (2) Marijuana has no currently accepted medical use in treatment in 
the United States:
    FDA has not approved a marketing application for a marijuana drug 
product for any indication. The opportunity for scientists to conduct 
clinical research with marijuana exists, and there are active INDs for 
marijuana; however, marijuana does not have a currently accepted 
medical use for treatment in the United States, nor does marijuana have 
an accepted medical use with severe restrictions.
    A drug has a ``currently accepted medical use'' if all of the 
following five elements have been satisfied:
    a. the drug's chemistry is known and reproducible;
    b. there are adequate safety studies;
    c. there are adequate and well-controlled studies proving efficacy;
    d. the drug is accepted by qualified experts; and
    e. the scientific evidence is widely available.


[[Page 53707]]


[57 FR 10499, March 26, 1992]

    Marijuana does not meet any of the elements for having a 
``currently accepted medical use.''
    First, FDA broadly evaluated marijuana, and did not focus its 
evaluation on particular strains of marijuana or components or 
derivatives of marijuana. Since different strains may have different 
chemical constituents, marijuana, as identified in this petition, does 
not have a known and reproducible chemistry, which would be needed to 
provide standardized doses.
    Second, there are not adequate safety studies on marijuana in the 
medical literature in relation to a specific, recognized disorder. 
Third, there are no published adequate and well controlled studies 
proving efficacy of marijuana. Fourth, there is no evidence that 
qualified experts accept marijuana for use in treating a specific, 
recognized disorder. Lastly, the scientific evidence regarding 
marijuana's chemistry in terms of a specific Cannabis strain that could 
produce standardized and reproducible doses is not currently available, 
so the scientific evidence on marijuana is not widely available.
    Alternately, a Schedule II drug can be considered to have a 
``currently accepted medical use with severe restrictions'' (21 U.S.C. 
812(b)(2)(B)). Yet as stated above, the lack of accepted medical use 
for a specific, recognized disorder precludes the use of marijuana even 
under conditions where its use is severely restricted.
    In conclusion, to date, research on marijuana's medical use has not 
developed to the point where marijuana is considered to have a 
``currently accepted medical use'' or a ``currently accepted medical 
use with severe restrictions.''
    (3) There is a lack of accepted safety for use of marijuana under 
medical supervision:
    There are currently no FDA-approved marijuana drug products. 
Marijuana does not have a currently accepted medical use in treatment 
in the United States or a currently accepted medical use with severe 
restrictions. Thus, FDA has not determined that marijuana is safe for 
use under medical supervision.
    In addition, FDA cannot conclude that marijuana has an acceptable 
level of safety relative to its effectiveness in treating a specific, 
recognized disorder without evidence that the substance is 
contamination free, and assurance of a consistent and predictable dose. 
Investigations into the medical use of marijuana should include 
information and data regarding the chemistry, manufacturing, and 
specifications of marijuana. Additionally, a procedure for delivering a 
consistent dose of marijuana should also be developed. Therefore, FDA 
concludes marijuana does not currently have an accepted level of safety 
for use under medical supervision.

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The Medical Application of Marijuana: A Review of Published Clinical 
Studies

March 19, 2015
Prepared by:
U.S. Food and Drug Administration
Center for Drug Evaluation and Research (FDA/CDER)
Controlled Substance Staff (CSS)

                            Table of Contents
1. Introduction............................................           71
2. Methods.................................................           73
    2.1 Define the Objective of the Review.................           73
    2.2 Define ``Marijuana''...............................           73
    2.3 Define ``Adequate and Well-Controlled Clinical                74
     Studies''.............................................
    2.4 Search Medical Literature Databases and Identify              74
     Relevant Studies......................................
    2.5 Review and Analyze Qualifying Clinical Studies.....           77
3. Results and Discussion..................................           77
    3.1 Neuropathic Pain...................................           77
        3.1.1 Neuropathic Pain Associated with HIV-Sensory            77
         Neuropathy........................................
        3.1.2 Central and Peripheral Neuropathic Pain......           81
    3.2 Appetite Stimulation in HIV........................           85
    3.3 Spasticity in Multiple Sclerosis...................           88
    3.4 Asthma.............................................           89
    3.5 Glaucoma...........................................           91
    3.6 Conclusions........................................           91
        3.6.1 Conclusions for Chronic Neuropathic Pain.....           91
        3.6.2 Conclusions for Appetite Stimulation in HIV..           92
        3.6.3 Conclusions for Spasticity in MS.............           92
        3.6.4 Conclusions for Asthma.......................           92
        3.6.5 Conclusions for Glaucoma.....................           93
    3.7 Design Challenges for Future Studies...............           93
        3.7.1 Sample Size..................................           93
        3.7.2 Marijuana Dose Standardization...............           94
        3.7.3 Acute vs. Chronic Therapeutic Marijuana Use..           95
        3.7.4 Smoking as a Route of Administration.........           96
        3.7.5 Difficulty in Blinding of Drug Conditions....           96
        3.7.6 Prior Marijuana Experience...................           97
        3.7.7 Inclusion and Exclusion Criteria.............           98
        3.7.8 Number of Female Subjects....................           98
Appendix (Tables)..........................................          103
List of Figure:
    Figure 1: Identification of Studies from PubMed Search.           76
List of Tables:
    Table 1: Randomized, controlled, double-blind trials             103
     examining smoked marijuana in treatment of neuropathic
     pain..................................................
    Table 2: Randomized, controlled, double-blind trials             108
     examining smoked marijuana in treatment of appetite
     stimulation in HIV/AIDS...............................
    Table 3: Randomized, controlled, double-blind trails             111
     examining smoked marijuana in treatment of spasticity
     in Multiple Sclerosis.................................
    Table 4: Randomized, controlled, double-blind trails             112
     examining smoked marijuana in treatment of intraocular
     pressure in Glaucoma..................................
    Table 5: Randomized, controlled, double-blind trails             114
     examining smoked marijuana in treatment of asthma.....
 


[[Page 53713]]

Executive Summary

    Marijuana is a Schedule I substance under the Controlled Substances 
Act (CSA). Schedule I indicates a high potential for abuse, no 
currently accepted medical use in the United States, and a lack of 
accepted safety for use under medical supervision. To date, marijuana 
has not been subject to an approved new drug application (NDA) that 
demonstrates its safety and efficacy for a specific indication under 
the Food Drug and Cosmetic Act (FDCA).
    Nevertheless, as of October 2014, twenty-three states and the 
District of Columbia have passed state-level medical marijuana laws 
that allow for marijuana use within that state; similar bills are 
pending in other states.
    The present review was undertaken by the Food and Drug 
Administration (FDA) to analyze the clinical studies published in the 
medical literature investigating the use of marijuana in any 
therapeutic areas. First, we discuss the context for this scientific 
review. Next, we describe the methods used in this review to identify 
adequate and well-controlled studies evaluating the safety and efficacy 
of marijuana for particular therapeutic uses.
    The FDA conducted a systematic search for published studies in the 
medical literature that meet the described criteria for study design 
and outcome measures prior to February 2013. While not part of our 
systematic review, we have continued to routinely follow the literature 
beyond that date for subsequent studies. Studies were considered to be 
relevant to this review if the investigators administered marijuana to 
patients with a diagnosed medical condition in a well-controlled, 
double-blind, placebo-controlled clinical trial. Of the eleven studies 
that met the criteria for review, five different therapeutic areas were 
investigated:
 Five studies examined chronic neuropathic pain
 Two studies examined appetite stimulation in human 
immunodeficiency virus (HIV) patients
 Two studies examined glaucoma
 One study examined spasticity and pain in multiple sclerosis 
(MS)
 One study examined asthma.
    For each of these eleven clinical studies, information is provided 
regarding the subjects studied, the drug conditions tested (including 
dose and method of administration), other drugs used by subjects during 
the study, the physiological and subjective measures collected, the 
outcome of these measures comparing treatment with marijuana to 
placebo, and the reported and observed adverse events. The conclusions 
drawn by the investigators are then described, along with potential 
limitations of these conclusions based on the study design. A brief 
summary of each study's findings and limitations is provided at the end 
of the section.
    The eleven clinical studies that met the criteria and were 
evaluated in this review showed positive signals that marijuana may 
produce a desirable therapeutic outcome, under the specific 
experimental conditions tested. Notably, it is beyond the scope of this 
review to determine whether these data demonstrate that marijuana has a 
currently accepted medical use in the United States. However, this 
review concludes that these eleven clinical studies serve as proof-of-
concept studies, based on the limitations of their study designs, as 
described in the study summaries. Proof-of-concept studies provide 
preliminary evidence on a proposed hypothesis regarding a drug's 
effect. For drugs under development, the effect often relates to a 
short-term clinical outcome being investigated. Proof-of-concept 
studies serve as the link between preclinical studies and dose ranging 
clinical studies. Therefore, proof-of-concept studies are not 
sufficient to demonstrate efficacy of a drug because they provide only 
preliminary information about the effects of a drug. However, the 
studies reviewed produced positive results, suggesting marijuana should 
be further evaluated as an adjunct treatment for neuropathic pain, 
appetite stimulation in HIV patients, and spasticity in MS patients.
    The main limitations identified in the eleven studies testing the 
medical applications of marijuana are listed below:
     The small numbers of subjects enrolled in the studies, 
which limits the statistical analyses of safety and efficacy.
     The evaluation of marijuana only after acute 
administration in the studies, which limits the ability to determine 
efficacy following chronic administration.
     The administration of marijuana typically through smoking, 
which exposes ill patients to combusted material and introduces 
problems with determining the doses delivered.
     The potential for subjects to identify whether they 
received marijuana or placebo, which breaks the blind of the studies.
     The small number of cannabinoid na[iuml]ve subjects, which 
limits the ability to determine safety and tolerability in these 
subjects.
     The low number of female subjects, which makes it 
difficult to generalize the study findings to subjects of both genders.
    Thus, this review discusses the following methodological changes 
that may be made in order to resolve these limitations and improve the 
design of future studies which examine the safety and efficacy of 
marijuana for specific therapeutic indications:
     Determine the appropriate number of subjects studied based 
on recommendations in various FDA Guidances for Industry regarding the 
conduct of clinical trials for specific medical indications.
     Administer consistent and reproducible doses of marijuana 
based on recommendations in the FDA Guidance for Industry: Botanical 
Drug Products (2004).\27\
---------------------------------------------------------------------------

    \27\ This Guidance is available on the internet at http://www.fda.gov/Drugs/default.htm under Guidance (Drugs).
---------------------------------------------------------------------------

     Evaluate the effects of marijuana under therapeutic 
conditions following both acute and chronic administration.
     Consider alternatives to smoked marijuana (e.g., 
vaporization).
     Address and improve whenever possible the difficulty in 
blinding of marijuana and placebo treatments in clinical studies.
     Evaluate the effect of prior experience with marijuana 
with regard to the safety and tolerability of marijuana.
     Strive for gender balance in the subjects used in studies.
    In conclusion, the eleven clinical studies conducted to date do not 
meet the criteria required by the FDA to determine if marijuana is safe 
and effective in specific therapeutic areas. However, the studies can 
serve as proof-of-concept studies and support further research into the 
use of marijuana in these therapeutic indications. Additionally, the 
clinical outcome data and adverse event profiles reported in these 
published studies can beneficially inform how future research in this 
area is conducted. Finally, application of the recommendations listed 
above by investigators when designing future studies could greatly 
improve the available clinical data that can be used to determine if 
marijuana has validated and reliable medical applications.

1. Introduction

    In response to citizen petitions submitted to the Drug Enforcement 
Administration (DEA) requesting DEA to reschedule marijuana, the DEA 
Administrator requested that the U.S. Department of Health and Human

[[Page 53714]]

Services (HHS) provide a scientific and medical evaluation of the 
available information and a scheduling recommendation for marijuana, in 
accordance with 21 U.S.C. 811(b). The Secretary of HHS is required to 
consider in a scientific and medical evaluation eight factors 
determinative of control under the Controlled Substance Act (CSA). 
Administrative responsibilities for evaluating a substance for control 
under the CSA are performed by the Food and Drug Administration (FDA), 
with the concurrence of the National Institute on Drug Abuse (NIDA). 
Part of this evaluation includes an assessment of whether marijuana has 
a currently accepted medical use in the United States. This assessment 
necessitated a review of the available data from published clinical 
studies to determine whether there is adequate scientific evidence of 
marijuana's effectiveness.
    Under Section 202 of the CSA, marijuana is currently controlled as 
a Schedule I substance (21 U.S.C. 812). Schedule I includes those 
substances that have a high potential for abuse, have no currently 
accepted medical use in treatment in the United States, and lack 
accepted safety for use under medical supervision (21 U.S.C. Sec.  
812(b)(1)(A)-(C)).
    A drug product which has been approved by FDA for marketing in the 
United States is considered to have a ``currently accepted medical 
use.'' Marijuana is not an FDA-approved drug product, as a New Drug 
Application (NDA) or Biologics License application (BLA) for marijuana 
has not been approved by FDA. However, FDA approval of an NDA is not 
the only means through which a drug can have a currently accepted 
medical use in the United States.
    In general, a drug may have a ``currently accepted medical use'' in 
the United States if the drug meets a five-part test. Established case 
law (Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 
(D.C. Cir. 1994)) upheld the Administrator of DEA's application of the 
five-part test to determine whether a drug has a ``currently accepted 
medical use.'' The following describes the five elements that 
characterize ``currently accepted medical use'' for a drug: \28\
---------------------------------------------------------------------------

    \28\ 57 FR 10499, 10504-06 (March 26, 1992).
---------------------------------------------------------------------------

    i. the drug's chemistry must be known and reproducible.
    ``The substance's chemistry must be scientifically established to 
permit it to be reproduced into dosages which can be standardized. The 
listing of the substance in a current edition of one of the official 
compendia, as defined by section 201(j) of the Food, Drug and Cosmetic 
Act, 21 U.S.C. 321(j), is sufficient to meet this requirement.''
    ii. there must be adequate safety studies.
    ``There must be adequate pharmacological and toxicological studies, 
done by all methods reasonably applicable, on the basis of which it 
could fairly and responsibly be concluded, by experts qualified by 
scientific training and experience to evaluate the safety and 
effectiveness of drugs, that the substance is safe for treating a 
specific, recognized disorder.''
    iii. there must be adequate and well-controlled studies proving 
efficacy.
    ``There must be adequate, well-controlled, well-designed, well-
conducted, and well-documented studies, including clinical 
investigations, by experts qualified by scientific training and 
experience to evaluate the safety and effectiveness of drugs, on the 
basis of which it could be fairly and responsibly concluded by such 
experts that the substance will have the intended effect in treating a 
specific, recognized disorder.''
    iv. the drug must be accepted by qualified experts.
    ``The drug has a New Drug Application (NDA) approved by the Food 
and Drug Administration, pursuant to the Food, Drug and Cosmetic Act, 
21 U.S.C. 355. Or, a consensus of the national community of experts, 
qualified by scientific training and experience to evaluate the safety 
and effectiveness of drugs, accepts the safety and effectiveness of the 
substance for use in treating a specific, recognized disorder. A 
material conflict of opinion among experts precludes a finding of 
consensus.'' and
    v. the scientific evidence must be widely available.
    ``In the absence of NDA approval, information concerning the 
chemistry, pharmacology, toxicology, and effectiveness of the substance 
must be reported, published, or otherwise widely available, in 
sufficient detail to permit experts, qualified by scientific training 
and experience to evaluate the safety and effectiveness of drugs, to 
fairly and responsibly conclude the substance is safe and effective for 
use in treating a specific, recognized disorder.''
    One way to pass the five-part test for having ``currently accepted 
medical use'' is through submission of an NDA or BLA which is approved 
by FDA. However, FDA approval of an NDA or BLA is not required for a 
drug to pass the five-part test.
    This review focuses on FDA's analysis of one element of the five-
part test for determining whether a drug has ``currently accepted 
medical use''. Specifically, the present review assesses the 3rd 
criterion that addresses whether marijuana has ``adequate and well-
controlled studies proving efficacy''. Thus, this review evaluates 
published clinical studies that have been conducted using marijuana in 
subjects who have a variety of medical conditions by assessing the 
adequacy of the summarized study designs and the study data. The 
methodology for selecting the studies that were evaluated is delineated 
below.
    FDA's evaluation and conclusions regarding the remaining four 
criteria for whether marijuana has a ``currently accepted medical 
use,'' as well as the eight factors pertaining to the scheduling of 
marijuana, are outside the scope of this review. A detailed discussion 
of these factors is contained in FDA's scientific and medical 
evaluation of marijuana.

2. Methods

    The methods for selecting the studies to include in this review 
involved the following steps, which are described in detail in the 
subsections below:
    1. Define the objective of the review.
    2. Define ``marijuana'' in order to facilitate the medical 
literature search for studies that administered the substance,
    3. Define ``adequate and well-controlled studies'' in order to 
facilitate the search for relevant data and literature,
    4. Search medical literature databases and identify relevant 
adequate and well-controlled studies, and
    5. Review and analyze the adequate and well-controlled clinical 
studies to determine if they demonstrate efficacy of marijuana for any 
therapeutic indication.

2.1 Define the Objective of the Review

    The objective of this review is to assess the study designs and 
resulting data from clinical studies published in the medical 
literature that were conducted with marijuana (as defined below) as a 
treatment for any therapeutic indication, in order to determine if they 
meet the criteria of ``adequate and well-controlled studies proving 
efficacy''.

2.2 Define ``Marijuana''

    In this review, the term ``marijuana'' refers to the flowering tops 
or leaves of the Cannabis plant. There were no restrictions on the 
route of administration used for marijuana in the studies.
    Studies which administered individual cannabinoids (whether

[[Page 53715]]

experimental substances or marketed drug products) or marijuana 
extracts were excluded from this review. Additionally, studies of 
administered neutral plant material or placebo marijuana (marijuana 
with all cannabinoids extracted) that had subsequently been 
supplemented by the addition of specific amounts of THC or other 
cannabinoids were also excluded (Chang et al., 1979).

2.3 Define ``Adequate and Well-Controlled Clinical Studies''

    The criteria for an ``adequate and well-controlled study'' for 
purposes of determining the safety and efficacy of a human drug is 
defined under the Code of Federal Regulations (CFR) in 21 CFR 314.126. 
The elements of an adequate and well-controlled study as described in 
21 CFR 314.126 can be summarized as follows:
    1. The main objective must be to assess a therapeutically relevant 
outcome.
    2. The study must be placebo-controlled.
    3. The subjects must qualify as having the medical condition being 
studied.
    4. The study design permits a valid comparison with an appropriate 
control condition.
    5. The assignment of subjects to treatment and control groups must 
be randomized.
    6. There is minimization of bias through the use of a double-blind 
study design.
    7. The study report contains a full protocol and primary data.
    8. Analysis of the study data is appropriately conducted.
    As noted above, the current review examines only those data 
available in the public domain and thus relies on clinical studies 
published in the medical literature. Published studies by their nature 
are summaries that do not include the level of detail required by 
studies submitted to FDA in an NDA.
    While the majority of the elements defining an adequate and well-
controlled study can be satisfied through a published paper (elements 
#1-6), there are two elements that cannot be met by a study published 
in the medical literature: element #7 (availability of a study report 
with full protocol and primary data) and element #8 (a determination of 
whether the data analysis was appropriate). Thus, for purposes of this 
review, only elements #1-6 will be used to qualify a study as being 
adequate and well-controlled.

2.4 Search Medical Literature Databases and Identify Relevant Studies

    We identified randomized, double-blind, placebo-controlled clinical 
studies conducted with marijuana to assess marijuana's efficacy in any 
therapeutic indication. Two primary medical literature databases were 
searched for all studies posted to the databases prior to February 
2013: \29\
---------------------------------------------------------------------------

    \29\ While not a systematic review, we have followed the recent 
published literature on marijuana use for possible therapeutic 
purposes and, as of January 2015, we found only one new study that 
would meet our criteria (Naftali et al., 2013). This study examined 
the effects of smoked marijuana on Crohn's disease.
---------------------------------------------------------------------------

     PubMed: PubMed is a database of published medical and 
scientific studies that is maintained by the U.S. National Library of 
Medicine (NLM) at NIH as a part of the Entrez system of information 
retrieval. PubMed comprises more than 24 million citations for 
biomedical literature from MEDLINE, life science journals, and online 
books (http://www.ncbi.nlm.nih.gov/pubmed).
     ClinicalTrials.gov: ClinicalTrials.gov is a database of 
publicly and privately supported clinical studies that is maintained by 
the NLM. Information about the clinical studies is provided by the 
Sponsor or Principal Investigator of the study. Information about the 
studies is submitted to the Web site (``registered'') when the studies 
begin, and is updated throughout the study. In some cases, results of 
the study or resulting publication citations are submitted to the Web 
site after the study ends (https://clinicaltrials.gov/ct2/about-site/background).
    ClinicalTrials.gov was searched for all studies administering 
marijuana. The results of this search were used to confirm that no 
completed studies with published data were missed in the literature 
search. During the literature search, references found in relevant 
studies and systematic reviews were evaluated for additional relevant 
citations. All languages were included in the search. The PubMed search 
yielded a total of 566 abstracts.\30\ Of these abstracts, a full-text 
review was conducted with 85 papers to assess eligibility. From this 
evaluation, only eleven of 85 studies met the 6 CFR elements for 
inclusion as adequate and well-controlled studies.
---------------------------------------------------------------------------

    \30\ The following search strategy was used, ``(cannabis OR 
marijuana) AND (therapeutic use OR therapy) AND (RCT OR randomized 
controlled trial OR ``systematic review'' OR clinical trial OR 
clinical trials) NOT (``marijuana abuse'' [Mesh] OR addictive 
behavior OR substance related disorders)''.
---------------------------------------------------------------------------

    Figure 1 (below) provides an overview of the process used to 
identify studies from the PubMed search. The eleven studies reviewed 
were published between 1974 and 2013. Ten of these studies were 
conducted in the United States and one study was conducted in Canada. 
These eleven studies examined the effects of smoked and vaporized 
marijuana for the indications of chronic neuropathic pain, spasticity 
related to multiple sclerosis (MS), appetite stimulation in patients 
with human immunodeficiency virus (HIV), glaucoma, and asthma. All 
included studies used adult patients as subjects. All studies conducted 
in the United States were conducted under an IND as Phase 2 
investigations.

[[Page 53716]]

[GRAPHIC] [TIFF OMITTED] TP12AU16.007

    Two qualifying studies, which assessed marijuana for glaucoma, were 
previously reviewed in the 1999 Institute of Medicine (IOM) report 
entitled ``Marijuana and Medicine: Assessing the Science Base''.\31\ We 
did our own analysis of these two studies and concurred with the 
conclusions in the IOM report. Thus, a detailed discussion of the two 
glaucoma studies is not included in the present review. The present 
review only discusses 9 of the identified 11 studies. For a summary of 
the study design for all eleven qualifying studies, see Tables 1-5 
(located in the Appendix).
---------------------------------------------------------------------------

    \31\ In January 1997, the White House Office of National Drug 
Control Policy (ONDCP) requested that the IOM conduct a review of 
the scientific evidence to assess the potential health benefits and 
risks of marijuana and its constituent cannabinoids. Information for 
this study was gathered through scientific workshops, site visits to 
cannabis buyers' clubs and HIV/Acquired Immunodeficiency Syndrome 
(AIDS) clinics, analysis of the relevant scientific literature, and 
extensive consultation with biomedical and social scientists. The 
report was finalized and published in 1999.
---------------------------------------------------------------------------

    Based on the selection criteria for relevant studies described in 
Section 2.3 (Define Adequate and Well-Controlled Clinical Studies), a 
number of clinical studies that investigated marijuana, as defined in 
this review, were excluded from this review. Studies that examined the 
effects of marijuana in healthy subjects were excluded because they did 
not test a patient population with a medical condition (Flom et al., 
1975; Foltin et al., 1986; Foltin et al., 1988; Hill et al., 1974; 
Milstein et al., 1974; Milstein et al., 1975; Soderpalm et al., 2001; 
Wallace et al., 2007; Greenwald and Stitzer, 2000). A 1975 study by 
Tashkin et al. was excluded because it had a single-blind, rather than 
double-blind, study design. Two other studies were excluded because the 
primary outcome measure assessed safety rather than a therapeutic 
outcome (Greenberg et al., 1994; Abrams et al., 2003).

2.5 Review and Analyze Qualifying Clinical Studies

    Qualified clinical studies that evaluated marijuana for therapeutic 
purposes were examined in terms of adequacy of study design including 
method of drug administration, study size, and subject inclusion and 
exclusion criteria. Additionally, the measures and methods of analysis 
used in the studies to assess the treatment effect were examined.

3. Results and Discussion

    The eleven qualifying studies in this review assessed a variety of 
therapeutic indications. In order to better facilitate analysis and 
discussion of the studies, the following sections group the studies by 
therapeutic area. Within each section, each individual study is 
summarized in terms of its design, outcome data and important 
limitations. This information is also provided in the Appendix in 
tabular form for each study.

3.1 Neuropathic Pain

    Five randomized, double-blind, placebo-controlled Phase 2 clinical 
studies have been conducted to examine the effects of inhaled marijuana 
smoke on neuropathic pain associated with HIV-sensory neuropathy 
(Abrams et al., 2007; Ellis et al., 2009) and chronic neuropathic pain 
from multiple causes (Wilsey et al., 2008; Ware et al., 2010; Wilsey et 
al., 2013). Table 1 of the Appendix summarizes these studies.

[[Page 53717]]

3.1.1 Neuropathic Pain Associated with HIV-Sensory Neuropathy
    Two studies examined the effect of marijuana to reduce the pain 
induced by HIV-sensory neuropathy.
    Abrams et al. (2007) conducted the first study entitled, ``Cannabis 
in painful HIV-associated sensory neuropathy: A randomized placebo-
controlled trial''. The subjects were 50 adult patients with 
uncontrolled HIV-associated sensory neuropathy, who had at least 6 
experiences with smoking marijuana. The subjects were split into two 
parallel groups of 25 subjects each. More than 68% of subjects were 
current marijuana users, but all individuals were required to 
discontinue using marijuana prior to the study. Most subjects were 
taking medication for pain during the study, with the most common 
medications being opioids and gabapentin. Upon entry into the study, 
subjects had an average daily pain score of at least 30 on a 0-100 
visual analog scale (VAS).
    Subjects were randomized to receive either smoked marijuana (3.56% 
THC \32\) or smoked placebo cigarettes three times per day for 5 days, 
using a standardized cued smoking procedure: (1) 5 second inhale, (2) 
10 second holding smoke in the lungs, (3) 40 second exhale and 
breathing normally between puffs. The authors did not specify how many 
puffs the subjects smoked at each smoking session, but they stated that 
one cigarette was smoked per smoking session.
---------------------------------------------------------------------------

    \32\ The drug dose is reported as percentage of THC present in 
the marijuana rather than milligrams of THC present in each 
cigarette because of the difficulty in determining the amount of THC 
delivered by inhalation (see discussion in the section entitled 
``3.7.2 Marijuana Dose Standardization'').
---------------------------------------------------------------------------

    Primary outcome measures included daily VAS ratings of chronic pain 
and the percentage of subjects who reported a result of more than 30% 
reduction in pain intensity. The ability of smoked marijuana to induce 
acute analgesia was assessed using both thermal heat model and 
capsaicin sensitization model, while anti-hyperalgesia was assessed 
with brush and von Frey hair stimuli. The immediate analgesic effects 
of smoked marijuana was assessed using a 0-100 point VAS at 40-minute 
intervals three times before and three times after the first and last 
smoking sessions, which was done to correspond to the time of peak 
plasma cannabinoid levels. Notably, not all subjects completed the 
induced pain portion of the study (n = 11 in marijuana group, 9 in 
placebo group) because of their inability to tolerate the stimuli. 
Throughout the study, subjects also completed the Profile of Mood 
States (POMS) questionnaire, as well as subjective VAS measures of 
anxiety, sedation, disorientation, paranoia, confusion, dizziness, and 
nausea.
    As a result, the median daily pain was reduced 34% by smoked 
marijuana compared to 17% by placebo (p = 0.03). Fifty-two percent of 
subjects who smoked marijuana reported a >30% reduction in pain 
compared to 24% in the placebo group (p = 0.04). Although marijuana 
reduced experimentally-induced hyperalgesia (p <= 0.05) during the 
first smoking sessions, marijuana did not alter responses to acutely 
painful stimuli.
    There were no serious AEs and no episodes of hypertension, 
hypotension, or tachycardia requiring medical intervention. No subjects 
withdrew from the study for drug related reasons. Subjects in the 
marijuana group reported higher ratings on the subjective measures of 
anxiety, sedation, disorientation, confusion, and dizziness compared to 
the placebo group. There was one case of severe dizziness in a 
marijuana-treated subject. By the end of the study, subjects treated 
with marijuana and placebo reported a reduction in total mood 
disturbance as measured by POMS.
    The authors conclude that smoked marijuana effectively reduced 
chronic neuropathic pain from HIV-associated sensory neuropathy with 
tolerable side effects. However, limitations of this study include: 
maintenance of subjects on other analgesic medication while being 
tested with marijuana and a lack of information about the number of 
puffs during each inhalation of smoke. These limitations make it 
difficult to conclude that marijuana has analgesic properties on its 
own and that the actual AEs experienced during the study in response to 
marijuana are tolerable. However, the study produced positive results 
suggesting that marijuana should be studied further as an adjunct 
treatment for uncontrolled HIV-associated sensory neuropathy.
    Ellis et al. (2009) conducted a more recent study entitled ``Smoked 
medicinal cannabis for neuropathic pain in HIV: A randomized, crossover 
clinical trial''. The subjects were 28 HIV-positive adult male patients 
with intractable neuropathic pain that was refractory to the effects of 
at least two drugs taken for analgesic purposes. Upon entry into the 
study, subjects had a mean score of >5 on the Pain Intensity subscale 
of the Descriptor Differential Scale (DDS). Subjects were allowed to 
continue taking their current routine of pain medications, which 
included opioids, non-narcotic analgesics, antidepressants, and 
anticonvulsants. Previous experience with marijuana was not required 
for participation in the study, but 27 of 28 subjects (96%) reported 
previous experience with marijuana. However, of these 27 experienced 
subjects, 63% (n = 18) reported no marijuana use within the past year.
    The study procedures compared the effects of the target dose of 
marijuana and placebo during two treatment periods lasting 5 days, with 
2 weeks washout periods. The marijuana strengths available were 1%, 2%, 
4%, 6%, or 8% THC concentration by weight. Subjects smoked marijuana or 
placebo cigarettes four times per day, approximately 90-120 minutes 
apart, using a standardized cued smoking procedure: (1) 5 second smoke 
inhalation, (2) 10 second hold of smoke in lungs, (3) 40 second exhale 
and normal breathing between puffs. The investigators did not provide a 
description of the number of puffs taken at any smoking session. All 
subjects practiced the smoking procedures using placebo marijuana prior 
to test sessions.
    On the first day of each test period, dose titration occurred 
throughout the four smoking sessions scheduled for that day, with a 
starting strength of 4% THC concentration. Subjects were allowed to 
titrate to a personalized ``target dose'', which was defined as the 
dose that provided the best pain relief without intolerable adverse 
effects. This dose titration was accomplished by allowing subjects to 
either increase the dose incrementally (to 6% or 8% THC) to improve 
analgesia, or to decrease the dose incrementally (to 1% or 2% THC) if 
AEs were intolerable. For the next 4 days of each test period, the 
subjects smoked their target dose during each of the four daily smoking 
sessions. To maintain the blind, placebo marijuana was represented as 
containing 1%-8% THC, even though it did not contain any cannabinoids.
    The primary outcome measure was the change in pain magnitude on the 
DDS at the end of each test period compared to baseline, with a 
clinically significant level of analgesia considered to be a reduction 
in pain of at least 30%. Additional measures included the POMS, the 
Sickness Impact Profile (SIP), the Brief Symptom Inventory (BSI) and 
the UKU Side Effect Rating Scale and a subjective highness/sedation 
VAS.
    During the marijuana treatment week, 19 subjects titrated to the 
2%-4% THC dose while the 6%-8% dose was preferred by 8 subjects and 1 
subject chose the 1% dose. In contrast, during the placebo treatment 
week, all 28 subjects titrated to the highest possible

[[Page 53718]]

dose of ``8% THC'' that contained no actual cannabinoids, suggesting 
that placebo treatment provided little analgesic relief.
    The degree of pain reduction was significantly greater after 
administration of marijuana compared to placebo (median change of 3.3 
points on DDS, p = 0.016). The median change from baseline in VAS pain 
scores was -17 for marijuana treatment compared to -4 for placebo 
treatment (p < 0.001). A larger proportion of subjects who were treated 
with marijuana (0.46) reported a >30% reduction in pain, compared to 
placebo (0.18). Additionally, the authors report improvements in total 
mood disturbance, physical disability, and quality of life as measured 
on POMS, SIP, and BSI scales after both placebo and marijuana treatment 
(data not provided in paper).
    In terms of safety, there were no alterations in HIV disease 
parameters in response to marijuana or placebo. The authors report that 
marijuana led to a greater degree of UKU responses as well as AEs such 
as difficulty in concentration, fatigue, sleepiness or sedation, 
increased duration of sleep, reduced salivation and thirst compared to 
placebo (data not provided in paper). Two subjects withdrew from the 
study because of marijuana-related AEs: one subject developed an 
intractable smoking-related cough during marijuana administration and 
the sole marijuana-na[iuml]ve subject in the study experienced an 
incident of acute cannabis-induced psychosis.\33\
---------------------------------------------------------------------------

    \33\ At the time of the study, the following criteria from the 
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR, 
2000) were used to diagnose substance-induced psychotic disorders: 
Prominent hallucinations or delusions; Hallucinations and/or 
delusions that develop during, or within one month of, intoxication 
or withdrawal; The disturbance is not better accounted for by a 
psychotic disorder that is not substance induced. The disturbance 
does not occur exclusively during the course of a delirium.
---------------------------------------------------------------------------

    The authors conclude that smoked marijuana effectively reduced 
chronic neuropathic pain from HIV-associated sensory neuropathy. The 
limitations of this study include: a lack of information about the 
number of puffs during each inhalation of smoke; a lack of information 
about the specific timing of the subjective assessments and collection 
of AEs relative to initiation of the smoking sessions; and the 
inclusion of only one marijuana-na[iuml]ve subject. These limitations 
make it difficult to conclude that the actual AEs experienced during 
the study in response to marijuana are tolerable. It is especially 
concerning that the only marijuana-na[iuml]ve subject left the study 
because of serious psychiatric responses to marijuana exposure at 
analgesic doses. However, the study produced positive results 
suggesting that marijuana should be studied further as an adjunct 
treatment for uncontrolled HIV-associated sensory neuropathy.
3.1.2 Central and Peripheral Neuropathic Pain
    Three studies examined the effect of marijuana on chronic 
neuropathic pain.
    Wilsey et al. (2008) examined chronic neuropathic pain from 
multiple causes in the study entitled, ``A Randomized, Placebo-
Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic 
Pain''. The subjects were 32 patients with a variety of neuropathic 
pain conditions, including 22 with complex regional pain syndrome, 6 
with spinal cord injury, 4 with multiple sclerosis, 3 with diabetic 
neuropathy, 2 with ilioinguinal neuralgia, and 1with lumbosacral 
plexopathy. All subjects reported a pain intensity of at least 30 on a 
0-100 VAS and were allowed to continue taking their regular medications 
during the study period, which included opioids, antidepressants, 
anticonvulsants, and NSAIDs. All subjects were required to have 
experience with marijuana but could not use any cannabinoids for 30 
days before study sessions.
    The study consisted of three test sessions with an interval of 3-21 
days between sessions. Treatment conditions were high-strength 
marijuana (7% delta-9-THC), low-strength marijuana (3.5% delta-9-THC), 
and placebo cigarettes, administered through a standardized cued-puff 
procedure: (1) ``light the cigarette'' (30 seconds), (2) ``get ready'' 
(5 seconds), (3) ``inhale'' (5 seconds), (4) ``hold smoke in lungs'' 
(10 seconds), (5) ``exhale,'' and (6) wait before repeating the puff 
cycle (40 seconds). Participants took 2 puffs after baseline 
measurements, 3 puffs an hour later, and 4 puffs an hour after that, 
for a cumulative dose of 9 puffs per test session.
    Hourly assessment periods were scheduled before and after each set 
of puffs and for 2 additional hours during the recovery period. Plasma 
cannabinoids were measured at baseline, 5 minutes after the first puff 
and again at 3 hours after the last puff cycle.
    The primary outcome measure was spontaneous pain relief, as 
measured by a 0-100 point VAS for current pain. Pain unpleasantness was 
measured on a 0-100 point VAS, and degree of pain relief was measured 
on a 7-point Patient Global Impression of Change (PGIC) scale. 
Secondary measures included the Neuropathic Pain Scale (NPS), a 0-100 
point VAS for allodynia, and changes in thermal pain threshold. 
Subjective measures were also evaluated with unipolar 0-100 point VAS 
for any drug effect, good drug effect, bad drug effect, high, drunk, 
impaired, stoned, like the drug effect, sedated, confused, nauseated, 
desire more of the drug, anxious, down, hungry, and bipolar 0-100 point 
VAS for sad/happy, anxious/relaxed, jittery/calm, bad/good, paranoid/
self-assured, fearful/unafraid. Neurocognitive assessments measured 
attention and concentration, learning and memory, and fine motor speed.
    Marijuana produced a reduction in pain compared to placebo, as 
measured by the pain VAS, the PGIC and on pain descriptors in the NPS, 
including sharp (P < .001), burning (P < .001), aching (P < .001), 
sensitive (P = .03), superficial (P < .01) and deep pain (P < .001). 
Notably, there were no additional benefits from the 7% THC strength of 
marijuana compared to the 3.5% THC strength, seemingly because of 
cumulative drug effects over time. There were no changes in allodynia 
or thermal pain responsivity following administration of either dose of 
marijuana.
    Marijuana at both strengths produced increases on measures of any 
drug effect, good drug effect, high, stoned, impairment, sedation, 
confusion, and hunger. The 7% THC marijuana increased anxiety scores 
and bad drug effect (later in session) compared to placebo. Neither 
strength of marijuana affected the measures of mood. On neurocognitive 
measures, both the 3.5% THC and 7% THC marijuana produced impairment in 
learning and memory, while only the 7% THC marijuana impaired attention 
and psychomotor speed, compared to placebo. There were no adverse 
cardiovascular side effects and no subjects dropped out because of an 
adverse event related to marijuana.
    The authors conclude that marijuana may be effective at 
ameliorating neuropathic pain at doses that induce mild cognitive 
effects, but that smoking is not an optimum route of administration. 
The limitations of this study include: inclusion of subjects with many 
forms of neuropathic pain and maintenance of subjects on other 
analgesic medication while being tested with marijuana. These 
limitations make it difficult to conclude that marijuana has analgesic 
properties on its own and that the actual AEs experienced during the 
study in response to marijuana are tolerable. The authors compared pain 
score results by the type of pain condition, with no significant 
differences found; however, the sample size of this study was small 
thus a type II error may have been present. Thus, it

[[Page 53719]]

is difficult to determine if any particular subset of neuropathic pain 
conditions would benefit specifically from marijuana administration. 
However, the study produced positive results suggesting that marijuana 
should be studied further as an adjunct treatment for uncontrolled 
neuropathic pain.
    The second study, conducted by Ware et al. (2010) in Canada is 
entitled, ``Smoked cannabis for chronic neuropathic pain: a randomized 
controlled trial''. The subjects were 21 adult patients with 
neuropathic pain caused by trauma or surgery compounded with allodynia 
or hyperalgesia, and a pain intensity score greater than 4 on a 10 
point VAS. All subjects maintained their current analgesic medication 
and they were allowed to use acetaminophen for breakthrough pain. 
Eighteen subjects had previous experience with marijuana but none of 
them had used marijuana within a year before the study.
    The study design used a four-period crossover design, testing 
marijuana (2.5%, 6.0% and 9.4% THC) and placebo marijuana. The 2.5% and 
6.0% doses of marijuana were included to increase successful blinding. 
Each period was 14 days in duration, beginning with 5 days on the study 
drug followed by a 9-day washout period. Doses were delivered as 25 mg 
of marijuana that was smoked in a single inhalation using a titanium 
pipe. The first dose of each period was self-administered using a 
standardized puff procedure: (1) Inhale for 5 seconds, (2) hold the 
smoke in their lungs for 10 seconds, and (3) exhale. Subsequent doses 
were self-administered in the same manner for a total of three times 
daily at home on an outpatient basis for the first five days of each 
period.
    The primary measure was an 11-point pain intensity scale, averaged 
over the 5 day treatment period, which was administered once daily for 
present, worst, least and average pain intensity during the previous 24 
hours. Secondary measures included an acute pain 0-100 point VAS, pain 
quality assessed with the McGill Pain Questionnaire, sleep assessed 
with the Leeds Sleep Evaluation Questionnaire, mood assessed with the 
POMS, quality of life assessed using the EQ-5D health outcome 
instrument. Subjective measures included 0-100 point VAS scales for 
high, relaxed, stressed and happy.
    Over the first three hours after smoking marijuana, ratings of 
pain, high, relaxation, stress, happiness and heart rate were recorded. 
During the five days of each study period, participants were contacted 
daily to administer questionnaires on pain intensity, sleep, medication 
and AEs. Subjects returned on the fifth day to complete questionnaires 
on pain quality, mood, quality of life and assessments of potency. At 
the end of the study, participants completed final adverse event 
reports and potency assessments.
    The average daily pain intensity was significantly lower on 9.4% 
THC marijuana (5.4) than on placebo marijuana (6.1) (p = 0.023). The 
9.4% THC strength also produced more drowsiness, better sleep, with 
less anxiety and depression, compared to placebo (all p < 0.05). 
However, there were no significant differences on POMS scores or on VAS 
scores for high, happy, relaxed or stressed between THC doses.
    The most frequent drug-related adverse events reported in the group 
receiving 9.4% THC marijuana were headache, dry eyes, burning 
sensation, dizziness, numbness and cough. Reports of high and euphoria 
occurred on only three occasions, once in each dose of THC. There were 
no significant changes in vital signs, heart-rate variability, or renal 
function. One subject withdrew from the study due to increased pain 
during administration of 6% THC marijuana.
    The authors conclude that smoked marijuana reduces neuropathic 
pain, improves mood and aids in sleep, but that smoking marijuana is 
not a preferable route of administration. The limitations of this study 
include: The lack of information on timing of assessments during the 
outpatient portion of the study and maintenance of subjects on other 
analgesic medication while being tested with marijuana. These 
limitations make it difficult to conclude that marijuana has analgesic 
properties on its own and that the actual AEs experienced during the 
study in response to marijuana are tolerable. However, the study 
produced positive results suggesting that marijuana should be studied 
further as an adjunct treatment for uncontrolled neuropathic pain.
    Wilsey et al. (2013) conducted the most recent study entitled, 
``Low-Dose Vaporized Cannabis Significantly Improves Neuropathic 
Pain''. This study is the only one in this review that utilized 
vaporization as a method of marijuana administration. The subjects were 
36 patients with a neuropathic pain disorder (CRPS, thalamic pain, 
spinal cord injury, peripheral neuropathy, radiculopathy, or nerve 
injury) who were maintained on their current medications (opioids, 
anticonvulsants, antidepressants, and NSAIDs). Although subjects were 
required to have a history of marijuana use, they refrained from use of 
cannabinoids for 30 days before study sessions.
    Subjects participated in three sessions in which they received 
1.29% or 3.53% THC marijuana or placebo marijuana. The marijuana was 
vaporized using the Volcano vaporizer and a standardized cued-puff 
procedure: (1) ``hold the vaporizer bag with one hand and put the 
vaporizer mouthpiece in their mouth'' (30 seconds), (2) ``get ready'' 
(5 seconds), (3) ``inhale'' (5 seconds), (4) ``hold vapor in lungs'' 
(10 seconds), (5) ``exhale and wait'' before repeating puff cycle (40 
seconds). Subjects inhaled 4 puffs at 60 minutes. At 180 minutes, the 
vaporizer was refilled with marijuana vapor and subjects were allowed 
to inhale 4 to 8 puffs using the cued procedure. Thus, cumulative 
dosing allowed for a range of 8 to12 puffs in total for each session, 
depending on the subjects desired response and tolerance. The washout 
time between each session ranged from 3-14 days.
    The primary outcome variable was spontaneous pain relief, as 
assessed using a 0-100 point VAS for current pain. Secondary measures 
included the Patient Global Impression of Change (PGIC), the 
Neuropathic Pain Scale (NPS), a 0-100 point VAS for allodynia. Acute 
pain threshold was measured with a thermal pain model. Subjective 
measures included 0-100 point unipolar VAS for any drug effect, good 
drug effect, bad drug effect, high, drunk, impaired, stoned, drug 
liking, sedated, confused, nauseated, desire more drug, anxious, down 
and hungry. Bipolar 0-100 point VAS included sad/happy, anxious/
relaxed, jittery/calm, bad/good, paranoid/self-assured, and fearful/
unafraid. Neurocognitive assessments assessed attention and 
concentration, learning and memory, and fine motor speed.
    A 30% reduction in pain was achieved in 61% of subjects who 
received the 3.53% THC marijuana, in 57% of subjects who received the 
1.29% THC marijuana and in 26% of subjects who received the placebo 
marijuana (p = 0.002 for placebo vs. 3.53% THC, p = 0.007 for placebo 
vs 1.29% THC; p > 0.05 1.29% THC vs. 3.53% THC). Both strengths of 
marijuana significantly decreased pain intensity, unpleasantness, 
sharpness, and deepness on the NPS, as well as pain ratings on the 
PGIC, compared to placebo. These effects on pain were maximal with 
cumulative dosing over the course of the study session, with maximal 
effects at 180 minutes. There were no effects of marijuana compared to 
placebo on measures of allodynia or

[[Page 53720]]

thermal pain. Subjects correctly identified the study treatment 63% of 
the time for placebo, 61% of the time for 1.29% THC, and 89% of the 
time for 3.53% THC.
    On subjective measures, marijuana produced dose-dependent increases 
compared to placebo on ratings for: any drug effect, good drug effect, 
drug liking, high, stoned, sedated, confused, and hungry. Both 
strengths of marijuana produced similar increases in drunk or impaired 
compared to placebo. In contrast, desire for drug was rated as higher 
for the 1.29% THC marijuana compared to the 3.53% THC marijuana. There 
were no changes compared to placebo for bad effect, nauseous, anxiety, 
feeling down or any of the bipolar mood assessments. There was dose-
dependent impairment on learning and memory from marijuana compared to 
placebo, but similar effects between the two strengths of marijuana on 
attention.
    The authors conclude that vaporization of relatively low doses of 
marijuana can produce improvements in analgesia in neuropathic pain 
patients, especially when patients are allowed to titrate their 
exposure. However, this individualization of doses may account for the 
general lack of difference between the two strengths of marijuana. No 
data were presented regarding the total amount of THC consumed by each 
subject, so it is difficult to determine a proper dose-response 
evaluation. Additional limitations of this study are the inclusion of 
subjects with many forms of neuropathic pain and maintenance of 
subjects on other analgesic medication while being tested with 
marijuana. These limitations make it difficult to conclude that 
marijuana has analgesic properties on its own. It is also difficult to 
determine if any particular subset of neuropathic pain conditions would 
benefit specifically from marijuana administration. However, the study 
produced positive results suggesting that marijuana should be studied 
further as an adjunct treatment for uncontrolled neuropathic pain.

3.2 Appetite Stimulation in HIV

    Two randomized, double-blind, placebo-controlled Phase 2 studies 
examined the effects of smoked marijuana on appetite in HIV-positive 
subjects (Haney et al., 2005; Haney et al., 2007). Table 2 of the 
Appendix summarizes both studies.
    The first study, conducted by Haney et al. (2005) is entitled, 
``Dronabinol and marijuana in HIV+ marijuana smokers: acute effects on 
caloric intake and mood''. The subjects were 30 HIV-positive patients 
who were maintained on two antiretroviral medications and either had 
clinically significant decreases in lean muscle mass \34\ (low-BIA 
group, n = 15) or normal lean muscle mass (normal-BIA group, n = 15). 
All subjects had a history of smoking marijuana at least twice weekly 
for 4 weeks prior to entry into the study. On average, individuals had 
smoked 3 marijuana cigarettes per day, 5-6 times per week for 10-12 
years.
---------------------------------------------------------------------------

    \34\ Lean muscle mass was assessed using bioelectrical impedance 
analysis (BIA). The low-BIA group was classified with having <90% 
BIA, and the normal-BIA group was classified with having >90% BIA.
---------------------------------------------------------------------------

    Subjects participated in 8 sessions that tested the acute effects 
of 0, 10, 20, and 30 mg dronabinol oral capsules and marijuana 
cigarettes with 0%, 1.8%, 2.8%, and 3.9% THC concentration by weight, 
using a double-dummy design (with only one active drug per session). 
The doses of dronabinol are higher than those doses typically 
prescribed for appetite stimulation in order to help preserve the 
blinding. There was a one-day washout period between test sessions.
    Marijuana was administered using a standardized cued procedure: (1) 
``light the cigarette'' (30 seconds), (2) ``prepare'' (5 seconds), (3) 
``inhale'' (5 seconds), (4) ``hold smoke in lungs'' (10 seconds), and 
(5) ``exhale.'' Each subject smoked three puffs in this manner, with a 
40-second interval between each puff.
    Caloric intake was used as a surrogate measure for weight gain. 
Subjects received a box containing a variety of food and beverage items 
and were told to record consumption of these items following that day's 
administration of the test drug. Subjective measures included 0-100 
point VAS for feel drug effect, good effect, bad effect, take drug 
again, drug liking, hungry, full, nauseated, thirsty, desire to eat. 
Neurocognitive measures and vital signs were monitored.
    The low BIA group consumed significantly more calories in the 1.8% 
and 3.9% THC marijuana conditions (p < 0.01) and the 10, 20, and 30 mg 
dronabinol conditions (p < 0.01) compared with the placebo condition. 
In contrast, in the normal BIA group, neither marijuana nor dronabinol 
significantly affected caloric intake. This lack of effect may be 
accountable, however, by the fact that this group consumed 
approximately 200 calories more than the low BIA group under baseline 
conditions.
    Ratings of high and good drug effect were increased by all drug 
treatments in both the low-BIA and normal-BIA groups, except in 
response to the 10 mg dose of dronabinol. The 3.9% THC marijuana 
increased ratings of good drug effect, drug liking and desire to smoke 
again compared with placebo. Ratings of sedation were increased in both 
groups by 10 and 30 mg dronabinol, and in the normal BIA group by the 
2.8% THC marijuana. Ratings of stimulation were increased in the normal 
BIA group by 2.8% and 3.9% THC marijuana and by 20 mg dronabinol. 
Increases in ratings of forgetfulness, withdrawn, dreaming, clumsy, 
heavy limbs, heart pounding, jittery, and decreases in ratings of 
energetic, social, and talkative were reported in the normal BIA group 
with 30 mg dronabinol. There were no significant changes in vital signs 
or performance on neurocognitive measures in response to marijuana. 
Notably, the time course of subjective effects peaked quickly and 
declined thereafter for smoked marijuana, while oral dronabinol 
responses took longer to peak and persisted longer. Additionally, 
marijuana but not dronabinol produced dry mouth and thirst.
    In general, AEs reported in this study were low in both drug 
conditions for both subject groups. In the low BIA group, nausea was 
reported by one subject in both the 10 and 20 mg dronabinol conditions, 
while an uncomfortable level of intoxication was produced by the 30 mg 
dose in two subjects. There were no AEs reported in this group 
following marijuana at any dose. In the normal BIA group, the 30 mg 
dose of dronabinol produced an uncomfortable level of intoxication in 
three subjects and headache in one subject, while the 3.9% marijuana 
produced diarrhea in one subject.
    The authors conclude that smoked marijuana can acutely increase 
caloric intake in low BIA subjects without significant cognitive 
impairment. However, it is possible that the low degree of cognitive 
impairment reported in this study may reflect the development of 
tolerance to cannabinoids in this patient population, since all 
individuals had current histories of chronic marijuana use. Additional 
limitations in this study include not utilizing actual weight gain as a 
primary measure. However, the study produced positive results 
suggesting that marijuana should be studied further as a treatment for 
appetite stimulation in HIV patients.
    A second study conducted by Haney et al. (2007) is entitled, 
``Dronabinol and marijuana in HIV-positive marijuana smokers: Caloric 
intake, mood, and sleep''. The design of this study was nearly 
identical to the one conducted by this laboratory in 2005 (see above), 
but

[[Page 53721]]

there was no stratification of subjects by BIA. The subjects were 10 
HIV-positive patients who were maintained on two antiretroviral 
medications and had a history of smoking marijuana at least twice 
weekly for 4 weeks prior to entry into the study. On average, 
individuals had smoked 3 marijuana cigarettes per day, 5 times per week 
for 19 years.
    Subjects participated in 8 sessions that tested the acute effects 
of 0, 5 and 10 mg dronabinol oral capsules and marijuana cigarettes 
with 0, 2.0% and 3.9% THC concentration by weight, using a double-dummy 
design (with 4 sessions involving only one active drug and 4 
interspersed placebo sessions). Both drug and placebo sessions lasted 
for 4 days each, with active drug administration occurring 4 times per 
day (every 4 hours). Testing occurred in two 16-day inpatient stays. In 
the intervening outpatient period, subjects were allowed to smoke 
marijuana prior to re-entry to the study unit for the second inpatient 
stay.
    Marijuana was administered using a standardized cued procedure: (1) 
``light the cigarette'' (30 seconds), (2) ``prepare'' (5 seconds), (3) 
``inhale'' (5 seconds), (4) ``hold smoke in lungs'' (10 seconds), and 
(5) ``exhale.'' Each subject smoked three puffs in this manner, with a 
40-second interval between each puff.
    Caloric intake was used as a surrogate measure for weight gain, but 
subjects were also weighed throughout the study (a measure which was 
not collected in the 2005 study by this group). Subjects received a box 
containing a variety of food and beverage items and were told to record 
consumption of these items following that day's administration of the 
test drug. Subjective measures included 0-100 point VAS for drug 
effect, good effect, bad effect, take drug again, drug liking, hungry, 
full, nauseated, thirsty, desire to eat. Neurocognitive measures and 
vital signs were monitored. Sleep was assessed using both the Nightcap 
sleep monitoring system and selected VAS measures related to sleep.
    Both 5 and 10 mg dronabinol (p < 0.008) and 2.0% and 3.9% THC 
marijuana (p < 0.01) dose-dependently increased caloric intake compared 
with placebo. This increase was generally accomplished through 
increases in incidents of eating, rather than an increase in the 
calories consumed in each incident. Subjects also gained similar 
amounts of weight after the highest dose of each cannabinoid treatment: 
1.2 kg (2.6 lbs) after 4 days of 10 mg dronabinol, and 1.1 kg (2.4 lbs) 
after 4 days of 3.9% THC marijuana. The 3.9% THC marijuana dose also 
increased the desire to eat and ratings of hunger.
    Ratings of good drug effect, high, drug liking, and desire to smoke 
again were significantly increased by 10 mg dronabinol and 2.0% and 
3.9% THC marijuana doses compared to placebo. Both marijuana doses 
increased ratings of stimulated, friendly, and self-confident. The 10 
mg dose of dronabinol increased ratings of concentration impairment, 
and the 2.0% THC marijuana dose increased ratings of anxious. Dry mouth 
was induced by 10 mg dronabinol (10 mg) and 2.0% THC marijuana. There 
were no changes in neurocognitive performance or objective sleep 
measures from administration of either cannabinoid. However, 3.9% THC 
marijuana increased subjective ratings of sleep.
    The authors conclude that both dronabinol and smoked marijuana 
increase caloric intake and produce weight gain in HIV-positive 
patients. However, it is possible that the low degree of cognitive 
impairment reported in this study may reflect the development of 
tolerance to cannabinoids in this subject population, since all 
individuals had current histories of chronic marijuana use. This study 
produced positive results suggesting that marijuana should be studied 
further as a treatment for appetite stimulation in HIV patients.

3.3 Spasticity in Multiple Sclerosis

    Only one randomized, double-blind, placebo-controlled Phase 2 study 
examined the effects of smoked marijuana on spasticity in MS.
    This study was conducted by Corey-Bloom et al. (2012) and is 
entitled, ``Smoked cannabis for spasticity in multiple sclerosis: A 
randomized, placebo-controlled trial''. The subjects were 30 patients 
with MS-associated spasticity and had moderate increase in tone (score 
>= 3 points on the modified Ashworth scale). Participants were allowed 
to continue other MS medications, with the exception of 
benzodiazepines. Eighty percent of subjects had a history of marijuana 
use and 33% had used marijuana within the previous year.
    Subjects participated in two 3-day test sessions, with an 11 day 
washout period. During each test session they smoked a 4.0% THC 
marijuana cigarette once per day or a placebo cigarette once per day. 
Smoking occurred through a standardized cued-puff procedure: (1) 
Inhalation for 5 seconds, (2) breath-hold and exhalation for 10 
seconds, (3) pause between puffs for 45 seconds. Subjects completed an 
average of four puffs per cigarette.
    The primary outcome measure was change in spasticity on the 
modified Ashworth scale. Additionally, subjects were assessed using a 
VAS for pain, a timed walk, and cognitive tests (Paced Auditory Serial 
Addition Test) and AEs.
    Treatment with 4.0% THC marijuana reduced subject scores on the 
modified Ashworth scale by an average of 2.74 points more than placebo 
(p < 0.0001) and reduced VAS pain scores compared to placebo (p = 
0.008). Scores on the cognitive measure decreased by 8.7 points more 
than placebo (p = 0.003). However, marijuana did not affect scores for 
the timed walk compared to placebo. Marijuana increased rating of 
feeling high compared to placebo.
    7 subjects did not complete the study due to adverse events (two 
subjects felt uncomfortably ``high'', two had dizziness and one had 
fatigue). Of those 7 subjects who withdrew, 5 had little or no previous 
experience with marijuana. When the data were re-analyzed to include 
these drop-out subjects, with the presumption they did not have a 
positive response to treatment, the effect of marijuana was still 
significant on spasticity.
    The authors conclude that smoked marijuana had usefulness in 
reducing pain and spasticity associated with MS. It is concerning that 
marijuana-na[iuml]ve subjects dropped out of the study because they 
were unable to tolerate the psychiatric AEs induced by marijuana. The 
authors suggest that future studies should examine whether different 
doses can result in similar beneficial effects with less cognitive 
impact. However, the current study produced positive results suggesting 
that marijuana should be studied further as an adjunct treatment for 
spasticity in MS patients.

3.4 Asthma

    Tashkin et al. (1974) examined bronchodilation in 10 subjects with 
bronchial asthma in the study entitled, ``Acute Effects of Smoked 
Marijuana and Oral [Delta]\9\-Tetrahydrocannabinol on Specific Airway 
Conductance in Asthmatic Subjects''. The study was a double-blind, 
placebo-controlled, crossover design. All subjects were clinically 
stable at the time of the study; four subjects were symptom free, and 
six subjects had chronic symptoms of mild to moderate severity. 
Subjects were tested with 0.25ml of isoproterenol HCl prior to the 
study to ensure they responded to bronchodilator medications. Subjects 
were not allowed to take bronchodilator medication within 8 hours prior 
to the study. Previous experience with marijuana was not required for 
participation in the study, but 7 of the 10 subjects reported

[[Page 53722]]

previous use of marijuana at a rate of less than 1 marijuana cigarette 
per month. No subjects reported marijuana use within 7 days of the 
study.
    The study consisted of four test sessions with an interval of at 
least 48 hours between sessions. On two test sessions subjects smoked 7 
mg/kg of body weight of either marijuana, with 2% THC concentration by 
weight, or placebo marijuana. During the other two test sessions, 
subjects ingested capsules with either 15mg of synthetic THC or 
placebo. Marijuana was administered using a uniform smoking technique: 
subjects inhaled deeply for 2-4 seconds, held smoke in lungs for 15 
seconds, and resumed normal breathing for approximately 5 seconds. The 
author did not provide a description of the number of puffs taken at 
any smoking session. The authors state that the smoking procedure was 
repeated until the cigarette was consumed, which took approximately 10 
minutes.
    The outcome measure used was specific airway conductance (SGaw), as 
calculated using measurements of thoracic gas volume (TGV) and airway 
resistance (Raw) using a variable-pressure body plethysmograph. 
Additionally, an assessment of degree of intoxication was administered 
only to those subjects reporting previous marijuana use. This 
assessment consisted of subjects rating ``how `high' they felt'' on a 
scale of 0-7, 7 representing ``the `highest' they had ever felt after 
smoking marijuana''.
    Marijuana produced a significant increase of 33-48% in average SGaw 
compared to both baseline and placebo (P < 0.05). This significant 
increase in SGaw lasted for at least 2 hours after administration. The 
average TGV significantly decreased by 4-13% compared to baseline and 
placebo (P < 0.05). The author stated that all subjects reported 
feelings of intoxication after marijuana administration.
    The authors conclude that marijuana produced bronchodilation in 
clinically stable asthmatic subjects with minimal to moderate 
bronchospasms. Study limitations include: inclusion of subjects with 
varying severity of asthmatic symptoms, use of SGaw to measure lung 
responses to marijuana administration, and administration of smoke to 
asthmatic subjects. Smoke delivers a number of harmful substances and 
is not an optimal delivery symptom, especially for asthmatic patients. 
FEV1 via spirometry is the gold standard to assess changes in lung 
function, pre and post asthma treatment, by pharmacotherapy. SGaw has 
been shown to be a valid tool in bronchoconstriction lung assessment; 
however, since the FEV1 method was not utilized, it is unclear whether 
these results would correlate if the FEV1 method had been employed.

3.5 Glaucoma

    Two randomized, double-blind, placebo-controlled Phase 2 clinical 
studies examined smoked marijuana in glaucoma (Crawford and Merritt, 
1979; Merritt et al., 1980). In both studies, intraocular pressure 
(IOP) was significantly reduced 30 minutes after smoking marijuana. 
Maximal effects occurred 60-90 minutes after smoking, with IOP 
returning to baseline within 3-4 hours. These two studies were included 
in the 1999 IOM report on the medical uses of marijuana. Because our 
independent analysis of these studies concurred with the conclusions 
from the 1999 IOM report, these studies will not be discussed in 
further detail in this review. No recent studies have been conducted 
examining the effect of inhaled marijuana on IOP in glaucoma patients. 
This lack of recent studies may be attributed to the conclusions made 
in the 1999 IOM report that while cannabinoids can reduce intraocular 
pressure (IOP), the therapeutic effects require high doses that produce 
short-lasting responses, with a high degree of AEs. This high degree of 
AEs means that the potential harmful effects of chronic marijuana 
smoking may outweigh its modest benefits in the treatment of glaucoma.

3.6 Conclusions

    Of the eleven randomized, double-blind, placebo-controlled Phase 2 
clinical studies that met the criteria for review (see Sections 2.2 and 
2.3), ten studies administered marijuana through smoking, while one 
study utilized marijuana vaporization. In these eleven studies, there 
were five different therapeutic indications: Five examined chronic 
neuropathic pain, two examined appetite stimulation in HIV patients, 
two examined glaucoma, one examined spasticity in MS, and one examined 
asthma.
    There are limited conclusions that can be drawn from the data in 
these published studies evaluating marijuana for the treatment of 
different therapeutic indications. The analysis relied on published 
studies, thus information available about protocols, procedures, and 
results were limited to documents published and widely available in the 
public domain. The published studies on medical marijuana are 
effectively proof-of-concept studies. Proof-of-concept studies provide 
preliminary evidence on a proposed hypothesis regarding a drug's 
effect. For drugs under development, the effect often relates to a 
short-term clinical outcome being investigated. Proof-of-concept 
studies serve as the link between preclinical studies and dose ranging 
clinical studies. Therefore, proof-of-concept studies are not 
sufficient to demonstrate efficacy of a drug because they provide only 
preliminary information about the effects of a drug. Although these 
studies do not provide evidence that marijuana is effective in treating 
a specific, recognized disorder, these studies do support future larger 
well-controlled studies to assess the safety and efficacy of marijuana 
for a specific medical indication. Overall, the conclusions below are 
preliminary, based on very limited evidence.
3.6.1 Conclusions for Chronic Neuropathic Pain
    In subjects with chronic neuropathic pain who are refractory to 
other pain treatments, five proof-of-concept studies produced positive 
results regarding the use of smoked marijuana for analgesia. However, 
the subjects in these studies continued to use their current analgesic 
drug regime, and thus no conclusions can be made regarding the 
potential efficacy of marijuana for neuropathic pain in patients not 
taking other analgesic drugs. Subjects also had numerous forms of 
neuropathic pain, making it difficult to identify whether a specific 
set of symptoms might be more responsive to the effects of marijuana. 
It is especially concerning that some marijuana-na[iuml]ve subjects had 
intolerable psychiatric responses to marijuana exposure at analgesic 
doses.
3.6.2 Conclusions for Appetite Stimulation in HIV
    In subjects who were HIV-positive, two proof-of-concept studies 
produced positive results with the use of both dronabinol and smoked 
marijuana to increase caloric intake and produce weight gain in HIV-
positive patients. However, the amount of THC in the marijuana tested 
in these studies is four times greater than the dose of dronabinol 
typically tested for appetite stimulation (10 mg vs. 2.5 mg; Haney et 
al., 2005). Thus, it is possible that the low degree of AEs reported in 
this study may reflect the development of tolerance to cannabinoids in 
this patient population, since all individuals had current histories of 
chronic marijuana use. Thus, individuals with little prior exposure to 
marijuana may not respond similarly and may not be able to tolerate 
sufficient marijuana to produce appetite stimulation.

[[Page 53723]]

3.6.3 Conclusions for Spasticity in MS
    In subjects with MS, a proof of concept study produced positive 
results using smoked marijuana as a treatment for pain and symptoms 
associated with treatment-resistant spasticity. The subjects in this 
study continued to take their current medication regiment, and thus no 
conclusions can be made regarding the potential efficacy of marijuana 
when taken on its own. It is also concerning that marijuana-na[iuml]ve 
subjects dropped out of the study because they were unable to tolerate 
the psychiatric AEs induced by marijuana. The authors suggest that 
future studies should examine whether different doses can result in 
similar beneficial effects with less cognitive impact.
3.6.4 Conclusions for Asthma
    In subjects with clinically stable asthma, a proof of concept study 
produced positive results of smoked marijuana producing 
bronchodilation. However, in this study marijuana was administered at 
rest and not while experiencing bronchospasms. Additionally, the 
administration of marijuana through smoking introduces harmful and 
irritating substances to the subject, which is undesirable especially 
in asthmatic patients. Thus the results suggest marijuana may have 
bronchodilator effects, but it may also have undesirable adverse 
effects in subjects with asthma.
3.6.5 Conclusions for Glaucoma
    As noted in Sections 3.5, the two studies that evaluated smoked 
marijuana for glaucoma were conducted decades ago, and they have been 
thoroughly evaluated in the 1999 IOM report. The 1999 IOM report 
concludes that while the studies with marijuana showed positive results 
for reduction in IOP, the effect is short-lasting, requires a high 
dose, and is associated with many AEs. Thus, the potential harmful 
effects may outweigh any modest benefit of marijuana for this 
condition. We agree with the conclusions drawn in the 1999 IOM report.

3.7 Design Challenges for Future Studies

    The positive results reported by the studies discussed in this 
review support the conduct of more rigorous studies in the future. This 
section discusses methodological challenges that have occurred in 
clinical studies with smoked marijuana. These design issues should be 
addressed when larger-scale clinical studies are conducted to ensure 
that valid scientific data are generated in studies evaluating 
marijuana's safety and efficacy for a particular therapeutic use.
3.7.1 Sample Size
    The ability for results from a clinical study to be generalized to 
a broader population is reliant on having a sufficiently large study 
sample size. However, as noted above, all of the 11 studies reviewed in 
this document were early Phase 2 proof of concept studies for efficacy 
and safety. Thus, the sample sizes used in these studies were 
inherently small, ranging from 10 subjects per treatment group (Tashkin 
et al., 1974; Haney et al., 2007) to 25 subjects per treatment group 
(Abrams et al., 2007). These sample sizes are statistically inadequate 
to support a showing of safety or efficacy. FDA's recommendations about 
sample sizes for clinical trials can be found in the Guidance for 
Industry: E9 Statistical Principles for Clinical Trials (1998).\35\ For 
example, ``the number of subjects in a clinical trial should always be 
large enough to provide a reliable answer to the questions addressed. 
This number is usually determined by the primary objective of the 
trial. The method by which the sample size is calculated should be 
given in the protocol, together with the estimates of any quantities 
used in the calculations (such as variances, mean values, response 
rates, event rates, difference to be detected).'' (pg. 21). Other 
clinical FDA Guidance for Industry \36\ may also contain 
recommendations regarding the appropriate number of subjects that 
should be investigated for a specific medical indication.
---------------------------------------------------------------------------

    \35\ The Guidance for Industry: E9 Statistical Principles for 
Clinical Trials can be found at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073137.pdf.
    \36\ Other Guidances for Industry can be found at: www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064981.htm.
---------------------------------------------------------------------------

3.7.2 Marijuana Dose Standardization
    Dose standardization is critical for any clinical study in order to 
ensure that each subject receives a consistent exposure to the test 
drug. The Guidance for Industry: Botanical Drug Products (2004) \37\ 
provides specific information on the development of botanical drug 
products. Specifically, this guidance includes information about the 
need for well-characterized and consistent chemistry for the botanical 
plant product and for consistent and reliable dosing. Specifically for 
marijuana studies, dose standardization is important because if 
marijuana leads to plasma levels of cannabinoids that are significantly 
different between subjects, this variation may lead to differences in 
therapeutic responsivity or in the prevalence of psychiatric AEs.
---------------------------------------------------------------------------

    \37\ The Guidance for Industry: Botanical Drug Products can be 
found at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070491.pdf.
---------------------------------------------------------------------------

    In most marijuana studies discussed in this review, investigators 
use a standardized cued smoking procedure. In this procedure, a subject 
is instructed to inhale marijuana smoke for 5 seconds, hold the smoke 
in the lungs for 10 seconds, exhale and breathe normally for 40 
seconds. This process is repeated to obtain the desired dose of the 
drug. However, this procedure may not lead to equivalent exposure to 
marijuana and its constituent cannabinoids, based on several factors:
     Intentional or unintentional differences in the depth of 
inhalation may change the amount of smoke in the subject's lungs.
     Smoking results in loss from side stream smoke, such that 
the entire dose is not delivered to the subject.
     There may be differences in THC concentration along the 
length of a marijuana cigarette. According to Tashkin et al. (1991), 
the area of the cigarette closest to the mouth tends to accumulate a 
higher concentration of THC, but this section of the cigarette is not 
smoked during a study.
    For example, Wilsey et al. (2008) used this standardized smoking 
procedure. The reported mean (range) of marijuana cigarettes consumed 
was 550 mg (200-830mg) for the low strength marijuana (3.5% THC) and 
490 mg (270-870mg) for the high strength marijuana (7% THC). This wide 
range of amounts of marijuana cigarette smoked by the individual 
subjects, even with standardized smoking procedure and controlled 
number of puffs, supports the issues with delivering consistent doses 
with smoke marijuana.
    In other marijuana studies that do not use a cued smoking 
procedure, subjects are simply told to smoke the marijuana cigarette 
over a specific amount of time (usually 10 minutes) without further 
instruction (Crawford and Merritt, 1979; Merritt et al., 1980; Ellis et 
al., 2009). The use of a nonstandardized procedure may lead to non-
equivalent exposures to marijuana and its constituent cannabinoids 
between subjects because of additional factors that are not listed 
above, such as:
     Differences in absorption and drug response if subjects 
(especially marijuana-na[iuml]ve ones) are not instructed to hold 
marijuana smoke in their lungs for a certain period of time.

[[Page 53724]]

     Prolonged periods between puffs may increase loss to side 
stream smoke.
     Subjects may attempt to smoke the marijuana cigarette in 
the way they would smoke a tobacco cigarette, which relies primarily on 
short, shallow puffs.
    In both standardized and non-standardized smoking procedures, 
subjects may seek to control the dose of THC through self-titration 
(Crawford and Merritt, 1979; Merritt et al., 1980; Tashkin et al., 
1974; Abrams et al., 2007; Ellis et al., 2009). Self-titration involves 
an individual moderating the amount of marijuana smoke inhaled over 
time in order to obtain a preferred level of psychoactive or clinical 
response. The ability of an individual to self-titrate by smoking is 
one reason given by advocates of ``medical marijuana'' in support of 
smoking of marijuana rather than through its ingestion via edibles. 
However, for research purposes, self-titration interferes with the 
ability to maintain consistent dosing levels between subjects, and 
thus, valid comparisons between study groups.
    All of these factors can make the exact dose of cannabinoids 
received by a subject in a marijuana study difficult to determine with 
accuracy. Testing whether plasma levels of THC or other cannabinoids 
are similar between subjects following the smoking procedure would 
establish whether the procedure is producing appropriate results. 
Additionally, studies could be conducted to determine if vaporization 
can be used to deliver consistent doses of cannabinoids from marijuana 
plant material. Specifically, vaporization devices that involve the 
collection of vapors in an enclosed bag or chamber may help with 
delivery of consistent doses of marijuana. Thus, more information could 
be collected on whether vaporization is comparable to or different than 
smoking in terms of producing similar plasma levels of THC in subjects 
using identical marijuana plant material.
3.7.3 Acute vs. Chronic Therapeutic Marijuana Use
    The studies that were reviewed administered the drug for short 
durations lasting no longer than 5 days (Abrams et al., 2007; Ellis et 
al., 2009; Ware et al., 2010). Thus all studies examined the short-term 
effect of marijuana administration for therapeutic purposes. However, 
many of the medical conditions that have been studied are persistent or 
expected to last the rest of a patient's life. Therefore, data on 
chronic exposure to smoked marijuana in clinical studies is needed. In 
this way, more information will be available regarding whether 
tolerance, physical dependence, or specific adverse events develop over 
the course of time with continuing use of therapeutic marijuana.
3.7.4 Smoking as a Route of Administration
    As has been pointed out by the IOM and other groups, smoking is not 
an optimum route of administration for marijuana-derived therapeutic 
drug products, primarily because introducing the smoke from a burnt 
botanical substance into the lungs of individuals with a disease state 
is not recommended when their bodies may be physically compromised. The 
1999 IOM report on medicinal uses of marijuana noted that alternative 
delivery methods offering the same ability of dose titration as smoking 
marijuana will be beneficial and may limit some of the possible long-
term health consequences of smoking marijuana. The primary alternative 
to smoked marijuana is vaporization, which can reduce exposure to 
combusted plant material containing cannabinoids. The only study to use 
vaporization as the delivery method was Wilsey et al. (2013). The 
results from Wilsey et al. (2013) showed a similar effect of decreased 
pain as seen in the other studies using smoking as the delivery method 
(Ware et al., 2010; Wilsey et al., 2008). This similar effect of 
decrease pain supports vaporization as a possibly viable route to 
administer marijuana in research, while potentially limiting the risks 
associated with smoking.
3.7.5 Difficulty in Blinding of Drug Conditions
    An adequate and well-controlled clinical study involves double-
blinding, where both the subjects and the investigators are unable to 
tell the difference between the test treatments (typically consisting 
of at least a test drug and placebo) when they are administered. All of 
the studies reviewed in this document administered study treatments 
under double-blind conditions and thus were considered to have an 
appropriate study design.
    However, even under the most rigorous experimental conditions, 
blinding can be difficult in studies with smoked marijuana because the 
rapid onset of psychoactive effects readily distinguishes active from 
placebo marijuana. The presence of psychoactive effects also occurs 
with other drugs. However, most other drugs have a similar psychoactive 
effect with substances with similar mechanisms of actions. These 
substances can be used as positive controls to help maintain blinding 
to the active drug being tested. Marijuana on the other hand, has a 
unique set of psychoactive effects which makes the use of appropriate 
positive controls difficult (Barrett et al., 1995). However, two 
studies did use Dronabinol as a positive control drug to help maintain 
blinding (Haney et al., 2005; Haney et al., 2007).
    When blinding is done using only placebo marijuana, the ability to 
distinguish active from placebo marijuana may lead to expectation bias 
and an alteration in perceived responsivity to the therapeutic outcome 
measures. With marijuana-experienced subjects, for example, there may 
be an early recognition of the more subtle cannabinoid effects that can 
serve as a harbinger of stronger effects, which is less likely to occur 
with marijuana-na[iuml]ve subjects. To reduce this possibility, 
investigators have tested doses of marijuana other than the one they 
were interested in experimentally to maintain the blind (Ware et al., 
2010).
    Blinding can also be compromised by differences in the appearance 
of marijuana plant material based on THC concentration. Marijuana with 
higher concentrations of THC tends to be heavier and seemingly darker, 
with more ``tar-like'' substance. Subjects who have experience with 
marijuana have reported being able to identify marijuana from placebo 
cigarettes by sight alone when the plant material in a cigarette was 
visible (Tashkin et al., 1974; Ware et al., 2010). Thus, to maintain a 
double-blind design, many studies obscure the appearance of plant 
material by closing both ends of the marijuana cigarette and placing it 
in in an opaque plastic tube.
    While none of these methods to secure blinding may be completely 
effective, it is important to reduce bias as much as possible to 
produce consistent results between subjects under the same experimental 
conditions.
3.7.6 Prior Marijuana Experience
    Marijuana use histories in test subjects may influence outcomes, 
related to both therapeutic responsivity and psychiatric AEs. 
Marijuana-na[iuml]ve subjects may also experience a marijuana drug 
product as so aversive that they would not want to use the drug 
product. Thus, subjects' prior experience with marijuana may affect the 
conduct and results of studies.
    Most of the studies reviewed in this document required that 
subjects have a history of marijuana use (see tables in Appendix that 
describe specific requirements for each study). However, in studies 
published in the scientific literature, the full inclusion criteria 
with

[[Page 53725]]

regard to specific amount of experience with marijuana may not be 
provided. For those studies that do provide inclusion criteria, 
acceptable experience with marijuana can range from once in a lifetime 
to use multiple times a day.
    The varying histories of use might affect everything from scores on 
adverse event measures, safety measures, or efficacy measures. 
Additionally, varying amounts of experience can impact cognitive effect 
measures assessed during acute administration studies. For instance, 
Schreiner and Dunn (2012) contend cognitive deficits in heavy marijuana 
users continue for approximately 28 days after cessation of smoking. 
Studies requiring less than a month of abstinence prior to the study 
may still see residual effects of heavy use at baseline and after 
placebo marijuana administration, thus showing no significant effects 
on cognitive measures. However, these same measurements in occasional 
or na[iuml]ve marijuana users may demonstrate a significant effect 
after acute marijuana administration. Therefore, the amount of 
experience and the duration of abstinence of marijuana use are 
important to keep in mind when analyzing results for cognitive and 
other adverse event measures. Lastly, a study population with previous 
experience with marijuana may underreport the incidence and severity of 
adverse events. Because most studies used subjects with prior marijuana 
experience, we are limited in our ability to generalize the results, 
especially for safety measures, to marijuana na[iuml]ve populations.
    Five of 11 studies reviewed in this document included both 
marijuana-na[iuml]ve and marijuana-experienced subjects (Corey-Bloom et 
al., 2012; Ellis et al., 2009; Ware et al., 2010; Merritt et al., 1980; 
Tashkin et al., 1974). Since the number of marijuana-na[iuml]ve 
subjects in these studies was low, it was not possible to conduct a 
separate analysis compared to experienced users. However, 
systematically evaluating the effect of marijuana experience on study 
outcomes is important, since many patients who might use a marijuana 
product for a therapeutic use will be marijuana-na[iuml]ve.
    Research shows that marijuana-experienced subjects have a higher 
ability to tolerate stronger doses of oral dronabinol than marijuana-
na[iuml]ve subjects (Haney et al., 2005). Possibly, this increased 
tolerance is also the case when subjects smoke or vaporize marijuana. 
Thus, studies could be conducted that investigate the role of marijuana 
experience in determining tolerability of and responses to a variety of 
THC concentrations in marijuana.
3.7.7 Inclusion and Exclusion Criteria
    For safety reasons, all clinical studies have inclusion and 
exclusion criteria that restrict the participation of individuals with 
certain medical conditions. For studies that test marijuana, these 
criteria may be based on risks associated with exposure to smoked 
material and the effects of THC. Thus, most studies investigating 
marijuana require that subjects qualify for the study based on 
restrictive symptom criteria such that individuals do not have other 
symptoms that may be known to interact poorly with cannabinoids.
    Similarly, clinical studies with marijuana typically exclude 
individuals with cardiac or pulmonary problems, as well as psychiatric 
disorders. These exclusion criteria are based on the well-known effects 
of marijuana smoke to produce increases in heart rate and blood 
pressure, lung irritation, and the exacerbation of psychiatric 
disturbances in vulnerable individuals. Although these criteria are 
medically reasonable for research protocols, it is likely that future 
marijuana products will be used in patients who have cardiac, pulmonary 
or psychiatric conditions. Thus, individuals with these conditions 
should be evaluated, whenever possible.
    Additionally, all studies reviewed in this document allowed the 
subjects to continue taking their current regimen of medications. Thus 
all results evaluated marijuana as an adjunct treatment for each 
therapeutic indication.
3.7.8 Number of Female Subjects
    A common problem in clinical research is the limited number of 
females who participate in the studies. This problem is present in the 
11 studies reviewed in this document, in which one study did not 
include any female subjects (Ellis et al., 2009), and three studies had 
a low percentage of female subjects (Abrams et al., 2007; Haney et al., 
2005; Haney et al., 2007). However, each of these four studies 
investigated an HIV-positive patient population, where there may have 
been a larger male population pool from which to recruit compared to 
females.
    Since there is some evidence that the density of CB1 receptors in 
the brain may vary between males and females (Crane et al., 2012), 
there may be differing therapeutic or subjective responsivity to 
marijuana. Studies using a study population that is equal parts male 
and female may show whether and how the effects of marijuana differ 
between male and female subjects.

4. References

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Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, 
Mulligan K, Bacchetti P, McCune JM, and Schambelan M. 2003. Short-
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Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, 
Rowbotham MC, and Petersen KL. 2007. Cannabis in painful HIV-
associated sensory neuropathy: a randomized placebo-controlled 
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Appendino G, Chianese G, Taglialatela-Scafati O. 2011. Cannabinoids: 
occurrence and medicinal chemistry. Curr Med Chem. 18(7):1085-99.
Barrett RL, Wiley JL, Balster RL, and Martin BR. 1995. 
Pharmacological specificity of [Delta]\9\-tetrahydrocannabinol 
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Chait LD, and Pierri J. 1989. Some physical characteristics of NIDA 
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Chang AE, Shiling DJ, Stillman RC, Godlberg NH, Seipp CA, Barofsky 
I, Simon RM, and Rosenberg SA. 1979. Delta-9-tetrahydrocannabinol as 
an antiemetic in cancer patients receiving high-dose methotrexate. 
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Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, 
and Gouaux B. 2012. Smoked cannabis for spasticity in multiple 
sclerosis: a randomized, placebo-controlled trial. Canadian Medical 
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Crane NA, Schuster RM, Fusar-Poli P, and Gonzalez R. 2012. Effects 
of Cannabis on Neurocognitive Functioning: Recent Advances, 
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Crawford WJ, and Merritt JC. 1979. Effects of tetrahydrocannabinol 
on arterial and intraocular hypertension. International Journal of 
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Ellis RJ, Toperoff W, Vaida F, Van Den Brande G, Gonzales J, Gouaux 
B, Bentley H, and Atkinson JH. 2009. Smoked medicinal cannabis for 
neuropathic pain in HIV: a randomized, crossover clinical trial. 
Neuropsychopharmacology 34 (3): 672-680.
Flom MC, Adams AJ, and Jones RT. 1975. Marijuana smoking and reduced 
pressure in human eyes: drug action or epiphenomenon? Investigative 
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Foltin RW, Brady JV, and Fischamn MW. 1986. Behavioral analysis of 
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Foltin RW, Fischman MW, and Byrne MF. 1988. Effects of smoked 
marijuana on food intake and body weight of humans living in a 
residential laboratory. Appetite 11: 1-14.
Greenberg HS, Werness SA, Pugh JE, Andrus RO, Anderson DJ, and 
Domino EF. 1994. Short-term effects of smoking marijuana on balance 
in patients with multiple sclerosis and normal volunteers. Clinical 
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Greenwald MK and Stitzer ML. 2000. Antinociceptive, subjective, and 
behavioral effects of smoked marijuana in humans. Drug and Alcohol 
Dependence 59: 261-275.
Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, and 
Foltin RW. 2007. Dronabinol and marijuana in HIV-positive marijuana 
smokers. Caloric intake, mood, and sleep. Journal of Acquired Immune 
Deficiency Syndromes (1999) 45 (5): 545-554.
Haney M, Rabkin J, Gunderson E, and Foltin RW. 2005. Dronabinol and 
marijuana in HIV(+) marijuana smokers: acute effects on caloric 
intake and mood. Psychopharmacology 181 (1): 170-178.
Hill SY, Schwin R, Goodwin DW, and Powell BJ. 1974. Marihuana and 
pain. Journal of Pharmacology and Experimental Therapeutics 188(2): 
415-418.
Jampel H. 2010. American glaucoma society position statement: 
marijuana and the treatment of glaucoma. Journal of Glaucoma 19 (2): 
75-76.
Merritt JC, Crawford WJ, Alexander PC, Anduze AL, and Gelbart SS. 
1980. Effect of marihuana on intraocular and blood pressure in 
glaucoma. Ophthalmology 87 (3): 222-228.
Milstein SL, MacCannell KL, Karr GW, and Clark S. 1974. Marijuana 
produced changes in cutaneous sensitivity and affect: users and non-
users. Pharmacology Biochemistry and Behavior 2:367-374.
Milstein SL, MacCannell K, Karr G, and Clark S. 1975. Marijuana-
produced changes in pain tolerance: Experiences and non-experienced 
subjects. Int. Pharmacopsychiat 10: 177-182.
Naftali T, Schleider LB, Dotan I, Lansky EP, Benjaminov FS, and 
Konikoff FM. 2013. Cannabis induces a clinical response in patients 
with Crohn's disease: A prospective placebo-controlled study. 
Clinical Gastroenterology and Hepatology 11: 1276-1280.
Russo E, Mathre ML, Byrne A, Velin R, Bach PJ, Sanchez-Ramos J, and 
Kirlin KA. 2002. Chronic Cannabis Use in the Compassionate 
Investigational New Drug Program: An Examination of Benefits and 
Adverse Effects of Legal Clinical Cannabis. Journal of Cannabis 
Therapeutics 2 (1): 3-57.
Soderpalm AHV, Schuster A, and de Wit H. 2001. Antiemetic efficacy 
of smoked marijuana subjective and behavioral effects on nausea 
induced by syrup of ipecac. Pharmacology Biochemistry and Behavior 
69: 343-350.
Tashkin DP, Gliederer F, Rose J, Chang P, Hui KK, Yu JL, and Wu TC. 
1991. Tar, CO and delta 9THC delivery from the 1st and 2nd halves of 
a marijuana cigarette. Pharmacology Biochemistry and Behavior 40 
(3): 657-661.
Tashkin DP, Shapiro BJ, Lee YE, Harper CE. 1975. Effects of smoked 
marijuana in experimentally induced asthma. American Review of 
Respiratory Disease 112: 377-386.
Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, 
Bentley H, Gouaux B, and Abramson I. 2007. Dose-dependent effects of 
smoked cannabis on capsaicin-induced pain and hyperalgesia in 
healthy volunteers. Anesthesiology 107 (5): 785-796.
Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, 
Bennett GJ, and Collet JP. 2010. Smoked cannabis for chronic 
neuropathic pain: a randomized controlled trial. Canadian Medical 
Association Journal 182 (14): E694-E701.
Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, 
and Fishman S. 2008. A randomized, placebo-controlled, crossover 
trial of cannabis cigarettes in neuropathic pain. J. Pain 9 (6): 
506-521.
Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, and Donaghe H. 
2013. Low-dose vaporized cannabis significantly improves neuropathic 
pain. J. Pain 14(2):136-48.


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U.S. Department of Justice--Drug Enforcement Administration

Schedule of Controlled Substances: Maintaining Marijuana in Schedule I 
of the Controlled Substances Act

Background, Data, and Analysis: Eight Factors Determinative of Control 
and Findings Pursuant to 21 U.S.C. 812(b)

Prepared by: Office of Diversion Control, Drug and Chemical Evaluation 
Section, Washington, DC 20537

July 2016

Background

    On November 30, 2011, Governors Lincoln D. Chafee of Rhode Island 
and Christine O. Gregoire of Washington submitted a petition to the 
Drug Enforcement Administration (DEA) to initiate proceedings for a 
repeal of the rules or regulations that place marijuana \38\ in 
schedule I of the Controlled Substances Act (CSA). The petition 
requests that marijuana \39\ and ``related items'' be rescheduled in 
schedule II of the CSA. The petitioners claim that:
---------------------------------------------------------------------------

    \38\ The Controlled Substances Act (CSA) defines marijuana as: 
``All parts of the plant Cannabis sativa L., whether growing or not; 
the seeds thereof; the resin extracted from any part of such plant; 
and every compound, manufacture, salt, derivative, mixture, or 
preparation of such plant, its seeds or resin. Such term does not 
include the mature stalks of such plant, fiber produced from such 
stalks, oil or cake made from the seeds of such plant, any other 
compound, manufacture, salt, derivative, mixture, or preparation of 
such mature stalks (except the resin extracted there from), fiber, 
oil, or cake, or the sterilized seed of such plant which is 
incapable of germination.'' 21 U.S.C. 802(16). Note that 
``marihuana'' is the spelling used in the CSA. This document uses 
the spelling that is more common in current usage, ``marijuana.''
    \39\ Petitioners defined marijuana as all cultivated strains of 
cannabis.
---------------------------------------------------------------------------

    1. Cannabis has accepted medical use in the United States;
    2. Cannabis is safe for use under medical supervision;
    3. Cannabis for medical purposes has a relatively low potential for 
abuse, especially in comparison with other schedule II drugs.
    The DEA accepted this petition for filing on January 30, 2012.
    The Attorney General may by rule transfer a drug or other substance 
between schedules of the CSA if she finds that such drug or other 
substance has a potential for abuse, and makes the findings prescribed 
by 21 U.S.C. 812(b) for the schedule in which such drug is to be 
placed. 21 U.S.C. 811(a)(1). The Attorney General has delegated this 
responsibility to the Acting Administrator of the DEA. 28 CFR 0.100(b).
    In accordance with 21 U.S.C. 811(b), after gathering the necessary 
data, the DEA submitted the petition and necessary data to the 
Department of Health and Human Services (HHS) on June 11, 2013, and 
requested that HHS provide a scientific and medical evaluation and 
scheduling recommendation for marijuana. In documents dated June 3 and 
June 25, 2015, the acting Assistant Secretary for Health of the HHS 
\40\ recommended to the DEA that marijuana continue to be controlled in 
Schedule I of the CSA, and provided to the DEA its scientific and 
medical evaluation titled ``Basis for the Recommendation for 
Maintaining Marijuana in Schedule I of the Controlled Substances Act.'' 
The HHS's recommendations are binding on the DEA as to scientific and 
medical matters. 21 U.S.C. 811(b).
---------------------------------------------------------------------------

    \40\ As set forth in a memorandum of understanding entered into 
by the HHS, the Food and Drug Administration (FDA), and the National 
Institute on Drug Abuse (NIDA), the FDA acts as the lead agency 
within the HHS in carrying out the Secretary's scheduling 
responsibilities under the CSA, with the concurrence of the NIDA. 50 
FR 9518, Mar. 8, 1985. The Secretary of the HHS has delegated to the 
Assistant Secretary for Health of the HHS the authority to make 
domestic drug scheduling recommendations.
---------------------------------------------------------------------------

    Before initiating proceedings to reschedule a substance, the CSA 
requires the Acting Administrator to determine whether the HHS 
scheduling recommendation, scientific and medical evaluation, and ``all 
other relevant data'' constitute substantial evidence that the drug 
should be rescheduled as proposed. 21 U.S.C. 811(b). The Acting 
Administrator must determine whether there is substantial evidence to 
conclude that the drug meets the criteria for placement in another 
schedule based on the criteria set forth in 21 U.S.C. 812(b). The CSA 
requires that both the DEA and the HHS consider the eight factors 
specified by Congress in 21 U.S.C. 811(c). This document lays out those 
considerations and is organized according to the eight factors. As DEA 
sets forth in detail below, the evidence shows:
    1. Actual or relative potential for abuse. Marijuana has a high 
potential for abuse. Preclinical and clinical data show that it has 
reinforcing effects characteristic of drugs of abuse. National 
databases on actual abuse show marijuana is the most widely abused 
drug, including significant numbers of substance abuse treatment 
admissions. Data on marijuana seizures show widespread availability and 
trafficking.
    2. Scientific evidence of its pharmacological effect. The 
scientific understanding of marijuana, cannabinoid receptors, and the 
endocannabinoid system continues to be studied and elucidated. 
Marijuana produces various pharmacological effects, including 
subjective (e.g., euphoria, dizziness, disinhibition), cardiovascular, 
acute and chronic respiratory, immune system, and prenatal exposure 
effects, as well as behavioral and cognitive impairment.
    3. Current scientific knowledge. There is no currently accepted 
medical use for marijuana in the United States. Marijuana sources are 
derived from numerous cultivated strains and may have different levels 
of [Delta]\9\-THC and other cannabinoids. Under the five-element test 
for currently accepted medical use discussed in more detail below and 
upheld by the Court of Appeals for the District of Columbia in Alliance 
for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994) 
(hereinafter ``ACT''), there is no complete scientific analysis of 
marijuana's chemical components; there are not adequate safety studies; 
there are not adequate and well-controlled efficacy studies; there is 
not a consensus of medical opinion concerning medical applications of 
marijuana; and the scientific evidence regarding marijuana's safety and 
efficacy is not widely available. To date, scientific and medical 
research has not progressed to the point that marijuana has a currently 
accepted medical use, even under conditions where its use is severely 
restricted.
    4. History and current pattern of abuse. Marijuana continues to be 
the most widely used illicit drug. In 2014, there were 22.2 million 
current users. There were also 2.6 million new users, most of whom were 
less than 18 years of age. During the same period, marijuana was the 
most frequently identified drug exhibit in federal, state, and local 
forensic laboratories.
    5. Scope, duration, and significance of abuse. Abuse of marijuana 
is widespread and significant. In 2014, for example, an estimated 6.5 
million people aged 12 or older used marijuana on a daily or almost 
daily basis over a 12-month period. In addition, a significant 
proportion of all admissions for substance abuse treatment are for 
marijuana/hashish as their primary drug of abuse. In 2013, 16.8% of all 
such admissions--281,991 over the course of the year--were for primary 
marijuana/hashish abuse.
    6. Risk, if any, to public health. Together with the health risks 
outlined in terms of pharmacological effects above, public health risks 
from acute use of marijuana include impaired psychomotor performance, 
impaired driving, and impaired performance on tests of learning and 
associative

[[Page 53740]]

processes. Chronic use of marijuana poses a number of other risks to 
the public health including physical as well as psychological 
dependence.
    7. Psychic or physiological dependence liability. Long-term, heavy 
use of marijuana can lead to physical dependence and withdrawal 
following discontinuation, as well as psychic or psychological 
dependence. In addition, a significant proportion of all admissions for 
treatment for substance abuse are for primary marijuana abuse; in 2013, 
16.8% of all admissions were for primary marijuana/hashish abuse, 
representing 281,991 individuals.
    8. Immediate precursor. Marijuana is not an immediate precursor of 
any controlled substance.
    As specified in 21 U.S.C. 812(b)(1), in order for a substance to be 
placed in schedule I, the Acting Administrator must find that:
    A. The drug or other substance has a high potential for abuse.
    B. The drug or other substance has no currently accepted medical 
use in treatment in the United States.
    C. There is a lack of accepted safety for use of the drug or other 
substance under medical supervision.
    To be classified in another schedule under the CSA (e.g., II, III, 
IV, or V), a substance must have a ``currently accepted medical use in 
treatment in the United States.'' 21 U.S.C. 812(b)(2)-(5). A substance 
also may be placed in schedule II if it is found to have ``a currently 
accepted medical use with severe restrictions.'' 21 U.S.C. 812(b)(2). 
If a controlled substance has no such currently accepted medical use, 
it must be placed in schedule I. See Notice of Denial of Petition, 66 
FR 20038 (Apr. 18, 2001) (``Congress established only one schedule--
schedule I--for drugs of abuse with `no currently accepted medical use 
in treatment in the United States' and `lack of accepted safety for use 
. . . under medical supervision.' '').
    A drug that is the subject of an approved new drug application 
(NDA) or abbreviated new drug application (ANDA) under Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 355), is considered to have a 
currently accepted medical use in treatment in the United States for 
purposes of the CSA. The HHS stated in its review, however, that FDA 
has not approved any NDA for marijuana for any indication.
    In the absence of NDA or ANDA approval, DEA has established a five-
element test for determining whether the drug has a currently accepted 
medical use in treatment in the United States. Under this test, a drug 
will be considered to have a currently accepted medical use only if the 
following five elements are satisfied:
    1. The drug's chemistry is known and reproducible;
    2. There are adequate safety studies;
    3. There are adequate and well-controlled studies proving efficacy;
    4. The drug is accepted by qualified experts; and
    5. The scientific evidence is widely available.

(57 FR 10499, 10506 (March 26, 1992)). See also ACT, 15 F.3d at 1135.
    As discussed in Factor 3, below, HHS concluded, and DEA agrees, 
that the scientific evidence is insufficient to demonstrate that 
marijuana has a currently accepted medical use under the five-element 
test. The evidence was insufficient in this regard also when the DEA 
considered petitions to reschedule marijuana in 1992 (57 FR 10499),\41\ 
in 2001 (66 FR 20038), and in 2011 (76 FR 40552).\42\ Little has 
changed since 2011 with respect to the lack of clinical evidence 
necessary to establish that marijuana has a currently accepted medical 
use. No studies have scientifically assessed the efficacy and full 
safety profile of marijuana for any specific medical condition.
---------------------------------------------------------------------------

    \41\ See Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131 
(D.C. Cir. 1994).
    \42\ See Americans for Safe Access v. DEA, 706 F.3d 438 (D.C. 
Cir. 2013) (rhg den. 2013).
---------------------------------------------------------------------------

    The limited existing clinical evidence is not adequate to warrant 
rescheduling of marijuana under the CSA. To the contrary, the data in 
this scheduling review document show that marijuana continues to meet 
the criteria for schedule I control under the CSA for the following 
reasons:
    1. Marijuana has a high potential for abuse.
    2. Marijuana has no currently accepted medical use in treatment in 
the United States.
    3. Marijuana lacks accepted safety for use under medical 
supervision.

Factor 1: The Drug's Actual or Relative Potential for Abuse

    Marijuana is the most commonly abused illegal drug in the United 
States. It is also the most commonly used illicit drug by high school 
students in the United States. Further, marijuana is the most 
frequently identified drug by state, local and federal forensic 
laboratories. Marijuana's main psychoactive ingredient, [Delta]\9\-
tetrahydrocannabinol ([Delta]\9\-THC),\43\ is an effective reinforcer 
in laboratory animals, including primates and rodents. These animal 
studies both predict and support the observations that marijuana 
produces reinforcing effects in humans. Such reinforcing effects can 
account for the repeated abuse of marijuana.
---------------------------------------------------------------------------

    \43\ The terms [Delta]\9\-THC and THC are used interchangeably 
though out this document.
---------------------------------------------------------------------------

A. Indicators of Abuse Potential

    The HHS has concluded in its document, ``Basis for the 
Recommendation for Maintaining Marijuana in Schedule I of the 
Controlled Substances Act,'' that marijuana has a high potential for 
abuse. The finding of ``abuse potential'' is critical for control under 
the Controlled Substances Act (CSA). Although the term is not defined 
in the CSA, guidance in determining abuse potential is provided in the 
legislative history of the Act (Comprehensive Drug Abuse Prevention and 
Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 2 (1970), 
reprinted in 1970 U.S.C.C.A.N. 4566, 4603). Accordingly, the following 
items are indicators that a drug or other substance has potential for 
abuse:
     There is evidence that individuals are taking the drug or 
drugs containing such a substance in amounts sufficient to create a 
hazard to their health or to the safety of other individuals or of the 
community; or
     There is significant diversion of the drug or drugs 
containing such a substance from legitimate drug channels; or
     Individuals are taking the drug or drugs containing such a 
substance on their own initiative rather than on the basis of medical 
advice from a practitioner licensed by law to administer such drugs in 
the course of his professional practice; or
     The drug or drugs containing such a substance are new 
drugs so related in their action to a drug or drugs already listed as 
having a potential for abuse to make it likely that the drug will have 
the same potentiality for abuse as such drugs, thus making it 
reasonable to assume that there may be significant diversions from 
legitimate channels, significant use contrary to or without medical 
advice, or that it has a substantial capability of creating hazards to 
the health of the user or to the safety of the community.
    Of course, evidence of actual abuse of a substance is indicative 
that a drug has a potential for abuse.
    In its recommendation, the HHS analyzed and evaluated data on 
marijuana as applied to each of the above four criteria. The analysis 
presented in the recommendation (HHS, 2015) is discussed below:
    1. There is evidence that individuals are taking the drug or drugs 
containing such a substance in amounts sufficient to create a hazard to 
their health or to

[[Page 53741]]

the safety of other individuals or of the community.
    The HHS stated that some individuals are taking marijuana in 
amounts sufficient to create a hazard to their health and to the safety 
of other individuals and the community. Data from national databases on 
actual abuse of marijuana support the idea that a large number of 
individuals use marijuana. In its recommendation (HHS, 2015), the HHS 
presented data from the National Survey on Drug and Health (NSDUH) of 
the Substance Abuse and Mental Health Services Administration (SAMHSA) 
and the Monitoring the Future (MTF) survey of the National Institute on 
Drug Abuse (NIDA), and the DEA has since updated this information. The 
most recent data from SAMHSA's NSDUH in 2014 reported that marijuana 
was the most used illicit drug. Among Americans aged 12 years and 
older, an estimated 22.2 million Americans used marijuana within the 
past month according to the 2014 NSDUH. In 2004, an estimated 14.6 
million individuals reported using marijuana within the month prior to 
the study. The estimated rates in 2014 thus reflect an increase of 
approximately 7.6 million individuals over a 10-year period. According 
to the 2013 NSDUH report, an estimated 19.8 million individuals 
reported using marijuana. Thus, over a period of one year (2013 NSDUH-
2014 NSDUH), there was an estimated increase of 2.4 million individuals 
in the United States using marijuana.
    The results from the 2015 Monitoring the Future survey of 8th, 
10th, and 12th grade students indicate that marijuana was the most 
widely used illicit drug in these age groups. Current monthly use was 
6.5% of 8th graders, 14.8% of 10th graders, and 21.3% of 12th graders. 
The Treatment Episode Data Set (TEDS) in 2013 reported that marijuana 
abuse was the primary factor in 16.8 percent of non-private substance-
abuse treatment facility admissions. In 2011, SAMHSA's Drug Abuse 
Warning Network (DAWN) reported that marijuana was mentioned in 36.4% 
(455,668 out of approximately 1.25 million) of illicit drug-related 
Emergency Department (ED) visits.
    Data on the extent and scope of marijuana abuse are presented under 
Factors 4 and 5 of this analysis. Discussion of the health effects of 
marijuana is presented under Factor 2, and the assessment of risk to 
the public health posed by acute and chronic marijuana abuse is 
presented under Factor 6 of this analysis.
    2. There is significant diversion of the drug or drugs containing 
such a substance from legitimate drug channels.
    In accordance with the CSA, the only lawful source of marijuana in 
the United States is that produced and distributed for research 
purposes under the oversight of NIDA and in conformity with United 
States obligations under the Single Convention on Narcotic Drugs.\44\ 
The HHS stated that there is a lack of significant diversion from 
legitimate drug sources, but that this is likely due to high 
availability of marijuana from illicit sources. Marijuana is not an 
FDA-approved drug product. Neither a New Drug Application (NDA) nor a 
Biologics License Application (BLA) has been approved for marketing in 
the United States. However, the marijuana used for nonclinical and 
clinical research represents a very small amount of the total amount of 
marijuana available in the United States and therefore information 
about marijuana diversion from legitimate sources is limited or not 
available.
---------------------------------------------------------------------------

    \44\ See 76 FR 51403, 51409-51410 (2011) (discussing cannabis 
controls required under the Single Convention).
---------------------------------------------------------------------------

    The DEA notes that the magnitude of the demand for illicit 
marijuana is evidenced by information from a number of databases 
presented under Factor 4. Briefly, marijuana is the most commonly used 
illegal drug in the United States. It is also the most commonly used 
illicit drug by American high schoolers. Marijuana is the most 
frequently identified drug in state, local, and federal forensic 
laboratories, with increasing amounts of both domestically grown and of 
illicitly smuggled marijuana.
    Given that marijuana has long been the most widely trafficked and 
abused controlled substance in the United States, and that all aspects 
of such illicit activity are entirely outside of the closed system of 
distribution mandated by the CSA, it may well be the case that there is 
little thought given to diverting marijuana from the small supplies 
produced for legitimate research purposes. Thus, the lack of data 
indicating diversion of marijuana from legitimate channels to the 
illicit market is not indicative of a lack of potential for abuse of 
the drug.
    3. Individuals are taking the drug or drugs containing such a 
substance on their own initiative rather than on the basis of medical 
advice from a practitioner licensed by law to administer such drugs in 
the course of his professional practice.
    The HHS stated that the FDA has not evaluated or approved an NDA or 
BLA for marijuana for any therapeutic indication. Consistent with 
federal law, therefore, an individual legitimately can take marijuana 
based on medical advice from a practitioner only by participating in 
research that is being conducted under an Investigational New Drug 
(IND) application. The HHS noted that there are several states as well 
as the District of Columbia which have passed laws allowing for 
individuals to use marijuana for purported ``medical'' use under 
certain circumstances, but data are not available yet to determine the 
number of individuals using marijuana under these state laws. 
Nonetheless, according to 2014 NSDUH data, 22.2 million American adults 
currently use marijuana (SAMHSA, 2015a). Based on the large number of 
individuals who use marijuana and the lack of an FDA-approved drug 
product, the HHS concluded that the majority of individuals using 
marijuana do so on their own initiative rather than by following 
medical advice from a licensed practitioner.
    4. The drug or drugs containing such a substance are new drugs so 
related in their action to a drug or drugs already listed as having a 
potential for abuse to make it likely that the drug will have the same 
potentiality for abuse as such drugs, thus making it reasonable to 
assume that there may be significant diversions from legitimate 
channels, significant use contrary to or without medical advice, or 
that it has a substantial capability of creating hazards to the health 
of the user or to the safety of the community.
    Marijuana and its primary psychoactive ingredient, [Delta]\9\-THC, 
are controlled substances in schedule I under the CSA.
    The HHS stated that one approved, marketed drug product contains 
synthetic [Delta]\9\-THC, also known as dronabinol, and another 
approved, marketed drug product contains a cannabinoid-like synthetic 
compound that is structurally related to [Delta]\9\-THC, the main 
active component in marijuana. Both products are controlled under the 
CSA.
    Marinol is a schedule III drug product containing synthetic 
[Delta]\9\-THC (dronabinol) formulated in sesame oil in soft gelatin 
capsules. Marinol was approved by the FDA in 1985 for the treatment of 
nausea and vomiting associated with cancer chemotherapy in patients who 
did not respond to conventional anti-emetic treatments. In 1992, FDA 
approved Marinol for the treatment of anorexia associated with weight 
loss in patients with acquired immunodeficiency syndrome (AIDS). 
Marinol was originally placed into schedule II and later rescheduled to 
schedule III under the CSA due to the

[[Page 53742]]

low reports of abuse relative to marijuana.
    Cesamet is a drug product containing the schedule II substance 
nabilone, a synthetic substance structurally related to [Delta]\9\-THC. 
Cesamet was approved for marketing by the FDA in 1985 for the treatment 
of nausea and vomiting associated with cancer chemotherapy. All other 
naturally occurring cannabinoids in marijuana and their synthetic 
equivalents with similar chemical structure and pharmacological 
activity are already included as schedule I drugs under the CSA.

B. Abuse Liability Studies

    In addition to the indicators suggested by the CSA's legislative 
history, data as to preclinical and clinical abuse liability studies, 
as well as actual abuse, including clandestine manufacture, 
trafficking, and diversion from legitimate sources, are considered in 
this factor.
    Abuse liability evaluations are obtained from studies in the 
scientific and medical literature. There are many preclinical measures 
of a drug's effects that when taken together provide an accurate 
prediction of the human abuse liability. Clinical studies of the 
subjective and reinforcing effects in humans and epidemiological 
studies provide quantitative data on abuse liability in humans and some 
indication of actual abuse trends. Both preclinical and clinical 
studies have clearly demonstrated that marijuana and [Delta]\9\-THC 
possess the attributes associated with drugs of abuse: They function as 
a positive reinforcer to maintain drug-seeking behavior, they function 
as a discriminative stimulus, and they have dependence potential.
    Preclinical and most clinical abuse liability studies have been 
conducted with the psychoactive constituents of marijuana, primarily 
[Delta]\9\-THC and its metabolite, 11-hydroxy-[Delta]\9\-THC. 
[Delta]\9\-THC's subjective effects are considered to be the basis for 
marijuana's abuse liability. The following studies provide a summary of 
that data.

1. Preclinical Studies

    [Delta]\9\-THC, the primary psychoactive component in marijuana, is 
an effective reinforcer in laboratory animals, including primates and 
rodents, as these animals will self-administer [Delta]\9\-THC. These 
animal studies both predict and support the observations that 
[Delta]\9\-THC, whether smoked as marijuana or administered by other 
routes, produces reinforcing effects in humans. Such reinforcing 
effects can account for the repeated abuse of marijuana.
a. Drug Discrimination Studies
    The drug discrimination paradigm is used as an animal model of 
human subjective effects (Solinas et al., 2006) and is a method where 
animals are able to indicate whether a test drug is able to produce 
physical or psychological changes similar to a known drug of abuse. 
Animals are trained to press one bar (in an operant chamber) when they 
receive a known drug of abuse and another bar when they receive a 
placebo. When a trained animal receives a test drug, if the drug is 
similar to the known drug of abuse, it will press the bar associated 
with the drug.
    Discriminative stimulus effects of [Delta]\9\-THC have specificity 
for the pharmacological effects of cannabinoids found in marijuana 
(Balster and Prescott, 1992; Browne and Weissman, 1981; Wiley et al., 
1993; Wiley et al., 1995). As mentioned by the HHS, the discriminative 
stimulus effects of cannabinoids appear to be unique because abused 
drugs of other classes including stimulants, hallucinogens, opioids, 
benzodiazepines, barbiturates, NMDA antagonists, and antipsychotics do 
not fully substitute for [Delta]\9\-THC.
    Laboratory animals including monkeys (McMahon et al., 2009), mice 
(McMahon et al., 2008), and rats (Gold et al., 1992) are able to 
discriminate cannabinoids from other drugs and placebo. The major 
active metabolite of [Delta]\9\-THC, 11-hydroxy-[Delta]\9\-THC, 
generalizes to [Delta]\9\-THC (Browne and Weissman, 1981). In addition, 
according to the HHS, twenty-two other cannabinoids found in marijuana 
also substitute for [Delta]\9\-THC. At least one cannabinoid, CBD, does 
not substitute for [Delta]\9\-THC in rats (Vann et al., 2008).
b. Self-Administration Studies
    Animal self-administration behavior associated with a drug is a 
commonly used method for evaluating if the drug produces rewarding 
effects and for predicting abuse potential (Balster, 1991; Balster and 
Bigelow, 2003). Drugs that are self-administered by animals are likely 
to produce rewarding effects in humans. As mentioned in the HHS review 
document, earlier attempts to demonstrate self-administration of 
[Delta]\9\-THC were unsuccessful and confounded by diet restrictions, 
animal restraint, and known analgesic activity of [Delta]\9\-THC at 
testing doses (Tanda and Goldberg, 2003; Justinova et al., 2003). Self-
administration of [Delta]\9\-THC was first demonstrated by Tanda et al. 
(2000). Tanda et al. (2000) showed that squirrel monkeys that were 
initially trained to self-administer cocaine (30 [micro]g/kg, i.v.) 
self-administered 2 [micro]g/kg [Delta]\9\-THC (i.v.) and at a rate of 
30 injections per one hour session. Tanda et al. (2000) used a lower 
dose of [Delta]\9\-THC that was rapidly delivered (0.2 ml injection 
over 200 ms) than in previous self-administration studies such that 
analgesic activity of [Delta]\9\-THC was not a confounding factor. The 
authors also stated that the doses were comparable to those doses used 
by humans who smoke marijuana. A CB1 receptor antagonist (SR141716) 
blocked this rewarding effect of THC.
    Justinova et al. (2003) were able to demonstrate self-
administration of [Delta]\9\-THC in drug-na[iuml]ve squirrel monkeys 
(no previous exposure to other drugs). The authors tested the monkeys 
with several doses of [Delta]\9\-THC (1, 2, 4, 8, and 16 [micro]g/kg, 
i.v.) and found that the maximal rates of self-administration were 
observed with the 4 [micro]g/kg/infusion. Subsequently, Braida et al. 
(2004) reported that rats will self-administer [Delta]\9\-THC when 
delivered intracerebroventricularly (i.c.v.), but only at the lowest 
doses tested (0.01-0.02 [micro]g/infusion, i.c.v.).
    Self-administration behavior with [Delta]\9\-THC was found to be 
antagonized in rats and squirrel monkeys by rimonabant (SR141716A, CB1 
antagonist) and the opioid antagonists (naloxone and naltrexone) (Tanda 
et al., 2000; Braida et al., 2004; Justinova et al., 2004).
c. Conditioned Place Preference Studies
    Conditioned place preference (CPP) is a behavioral assay where 
animals are given the opportunity to spend time in two distinct 
environments: one where they previously received a drug and one where 
they received a placebo. If the drug is reinforcing, animals in a drug-
free state will choose to spend more time in the environment paired 
with the drug when both environments are presented simultaneously.
    CPP has been demonstrated with [Delta]\9\-THC in rats but only at 
low doses (0.075-1.0 mg/kg, i.p.; Braida et al., 2004). Rimonabant 
(0.25-1.0 mg/kg, i.p.) and naloxone (0.5-2.0 mg/kg, i.p.) antagonized 
[Delta]\9\-THC-mediated CPP (Braida et al., 2004). However, in another 
study with rats, rimonabant was demonstrated to induce CPP at doses 
ranging from 0.25-3.0 mg/kg (Cheer et al., 2000). Mice without [micro]-
opioid receptors did not exhibit CPP to [Delta]\9\-THC (paired with 1 
mg/kg [Delta]\9\-THC, i.p.) (Ghozland et al., 2002).

2. Clinical Studies

    In its scientific review (HHS, 2015), the HHS provided a list of 
common subjective psychoactive responses to cannabinoids based on 
information from several references (Adams and Martin, 1996; Gonzalez, 
2007; Hollister, 1986;

[[Page 53743]]

Hollister, 1988; Institute of Medicine, 1982). Furthermore, Maldonado 
(2002) characterized these subjective responses as pleasurable to most 
humans and are generally associated with drug-seeking and/or drug-
taking. Later studies (Scherrer et al., 2009; Zeiger et al., 2010) 
reported that high levels of positive psychoactive effects correlate 
with increased marijuana use, abuse, and dependence. The list of the 
common subjective psychoactive effects provided by the HHS (HHS, 2015) 
is presented below:
    (1) Disinhibition, relaxation, increased sociability, and 
talkativeness.
    (2) Increased merriment and appetite, and even exhilaration at high 
doses.
    (3) Enhanced sensory perception, which can generate an increased 
appreciation of music, art, and touch.
    (4) Heightened imagination, which can lead to a subjective sense of 
increased creativity.
    (5) Initial dizziness, nausea, tachycardia, facial flushing, dry 
mouth, and tremor.
    (6) Disorganized thinking, inability to converse logically, time 
distortions, and short-term memory impairment.
    (7) Ataxia and impaired judgment, which can impede driving ability 
or lead to an increase in risk-taking behavior.
    (8) Illusions, delusions, and hallucinations that intensify with 
higher doses.
    (9) Emotional lability, incongruity of affect, dysphoria, 
agitation, paranoia, confusion, drowsiness, and panic attacks, which 
are more common in inexperienced or high-dosed users.
    The HHS mentioned that marijuana users prefer higher concentrations 
of the principal psychoactive component ([Delta]\9\-THC) over lower 
concentrations. In a clinical study with marijuana users (n = 12, usage 
ranged from once a month to 4 times a week), subjects were given a 
choice of 1.95% [Delta]\9\-THC marijuana or 0.63% [Delta]\9\-THC 
marijuana after sampling both marijuana cigarettes in two choice 
sessions. The marijuana cigarette with high THC was chosen in 21 out of 
24 choice sessions or 87.5% of the time (Chait and Burke, 1994). 
Furthermore, in a double-blind study, frequent marijuana users (n = 11, 
usage at least 2 times per month with at least 100 occasions) when 
given a low-dose of oral [Delta]\9\-THC (7.5 mg) were able to 
distinguish the psychoactive effects better than occasional users (n = 
10, no use within the past 4 years with 10 or fewer lifetime uses) and 
also experienced fewer sedative effects (Kirk and de Wit, 1999).
    Marijuana has also been recognized by scientific experts to have 
withdrawal symptoms (negative reinforcement) following moderate and 
heavy use. As discussed further in Factor 7, the DEA notes that the 
American Psychiatric Association's (APA) Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) included a list of 
withdrawal symptoms following marijuana [cannabis] use (DSM-5, 2013).

C. Actual Abuse of Marijuana--National Databases Related to Marijuana 
Abuse and Trafficking

    Marijuana continues to be the most widely used illicit drug. 
Evidence of actual abuse can be defined by episodes/mentions in 
databases indicative of abuse/dependence. The HHS provided in its 
recommendation (HHS, 2015) information relevant to actual abuse of 
marijuana including data results from the National Survey on Drug Use 
and Health (NSDUH), a Monitoring the Future (MTF) survey, the Drug 
Abuse Warning Network (DAWN), and the Treatment Episode Data Set 
(TEDS). These data sources provide quantitative information on many 
factors related to abuse of a particular substance, including incidence 
and patterns of use, and profile of the abuser of specific substances. 
The DEA is providing updated information from these databases in this 
discussion. The DEA also includes data on trafficking and illicit 
availability of marijuana from DEA databases including the National 
Forensic Laboratory Information System (NFLIS) and the National Seizure 
System (NSS), formerly the Federal-wide Drug Seizure System (FDSS), as 
well as other sources of data specific to marijuana, including the 
Potency Monitoring Project and the Domestic Cannabis Eradication and 
Suppression Program (DCE/SP).

1. National Survey on Drug Use and Health (NSDUH)

    The National Survey on Drug Use and Health (NSDUH) is conducted 
annually by the Department of Health and Human Service's Substance 
Abuse and Mental Health Services Administration (SAMHSA). SAMHSA is the 
primary source of estimates of the prevalence and incidence of 
pharmaceutical drugs, illicit drugs, alcohol, and tobacco use in the 
United States. The survey is based on a nationally representative 
sample of the civilian, non-institutionalized population 12 years of 
age and older. The survey excludes homeless people who do not use 
shelters, active military personnel, and residents of institutional 
group quarters such as jails and hospitals.
    According to the 2014 NSDUH report, marijuana was the most commonly 
used and abused illicit drug. That data showed that there were 22.2 
million people who were past month users (8.4%) among those aged 12 and 
older in the United States. (Note: NSDUH figures on marijuana use 
include hashish use; the relative proportion of hashish use to 
marijuana use is very low.) Marijuana had the highest rate of past-year 
dependence or abuse in 2014. The NSDUH report estimates that 3.0 
million people aged 12 or older used an illicit drug for the first time 
in 2014; a majority (70.3%) of these past year initiates reported that 
their first drug used was marijuana. Among those who began using 
illicit drugs in the past year, 65.6%, 70.3%, and 67.6% reported 
marijuana as the first illicit drug initiated in 2012, 2013, and 2014 
respectively. In 2014, the average age of marijuana initiates among 12- 
to 49-year-olds was 18.5 years. These usage rates and demographics are 
relevant in light of the risks presented.
    Marijuana had the highest rate of past year dependence or abuse of 
any illicit drug in 2014. The 2014 NSDUH report stated that 4.2 million 
persons were classified with substance dependence or abuse of marijuana 
in the past year (representing 1.6% of the total population aged 12 or 
older, and 59.0% of those classified with illicit drug dependence or 
abuse) based on criteria specified in the Diagnostic and Statistical 
Manual of Mental Disorders, 4th edition (DSM-IV).
    Among past year marijuana users age 12 or older, 18.5% used 
marijuana on 300 or more days within the previous 12 months in 2014. 
This translates into 6.5 million people using marijuana on a daily or 
almost daily basis over a 12-month period, significantly more than the 
estimated 5.7 million daily or almost daily users in just the year 
before. Among past month marijuana users, 41.6% (9.2 million) used the 
drug on 20 or more days in the past month, a significant increase from 
the 8.1 million who used marijuana 20 days or more in 2013.

2. Monitoring the Future (MTF)

    Monitoring the Future (MTF) is an ongoing study which is funded 
under a series of investigator-initiated competing research grants from 
the National Institute on Drug Abuse (NIDA). MTF tracks drug use trends 
among American adolescents in the 8th, 10th, and 12th grades. According 
to its 2015 survey results, marijuana was the most commonly used 
illicit drug, as was the case in previous years. Approximately 6.5% of 
8th graders,

[[Page 53744]]

14.8% of 10th graders, and 21.3% of 12th graders surveyed in 2015 
reported marijuana use during the past month prior to the survey. A 
number of high school students in 2015 also reported daily use in the 
past month, including 1.1%, 3.0%, and 6.0% of 8th, 10th, and 12th 
graders, respectively.

3. Drug Abuse Warning Network (DAWN), Emergency Department (ED) Visits

    The Drug Abuse Warning Network (DAWN) is a public health 
surveillance system that monitors drug-related hospital emergency 
department (ED) visits to track the impact of drug use, misuse, and 
abuse in the United States. For the purposes of DAWN, the term ``drug 
abuse'' applies if the following conditions are met: (1) The case 
involved at least one of the following: use of an illegal drug, use of 
a legal drug contrary to directions, or inhalation of a non-
pharmaceutical substance; and (2) the substance was used for one of the 
following reasons: Because of drug dependence, to commit suicide (or 
attempt to commit suicide), for recreational purposes, or to achieve 
other psychic effects. Importantly, many factors can influence the 
estimates of ED visits, including trends in overall use of a substance 
as well as trends in the reasons for ED usage. For instance, some drug 
users may visit EDs for life-threatening issues while others may visit 
to seek care for detoxification because they needed certification 
before entering treatment. Additionally, DAWN data do not distinguish 
the drug responsible for the ED visit from other drugs that may have 
been used concomitantly. As stated in a DAWN report, ``Since marijuana/
hashish is frequently present in combination with other drugs, the 
reason for the ED visit may be more relevant to the other drug(s) 
involved in the episode.''
    In 2011, marijuana was involved in 455,668 ED visits out of 
2,462,948 total ED visits involving all abuse or misuse in the United 
States and out of 1.25 million visits involving abuse or misuse of 
illicit drugs (excluding alcohol-related visits), as estimated by DAWN. 
This is lower than the number of ED visits involving cocaine (505,224) 
and higher than the number of ED visits involving heroin (258,482) and 
stimulants (e.g., amphetamine, methamphetamine) (159,840). Visits 
involving the other major illicit drugs, such as MDMA, GHB, LSD and 
other hallucinogens, PCP, and inhalants, were much less frequent, 
comparatively.
    In young patients, marijuana is the illicit drug most frequently 
involved in ED visits, according to DAWN estimates, with 240.2 
marijuana-related ED visits per 100,000 population ages 12 to 17, 443.8 
per 100,000 population ages 18 to 20, and 446.9 per 100,000 population 
ages 21 to 24.

4. Treatment Episode Data Set (TEDS) System

    The Treatment Episode Data Set (TEDS) system is part of the SAMHSA 
Drug and Alcohol Services Information System and is a national census 
of annual admissions to state licensed or certified, or 
administratively tracked, substance abuse treatment facilities. The 
TEDS system contains information on patient demographics and substance 
abuse problems of admissions to treatment for abuse of alcohol and/or 
drugs in facilities that report to state administrative data systems. 
For this database, the primary substance of abuse is defined as the 
main substance of abuse reported at the time of admission. TEDS also 
allows for the recording of two other substances of abuse (secondary 
and tertiary).
    In 2011, the TEDS system included 1,928,792 admissions to substance 
abuse treatment; in 2012 there were 1,801,385 admissions; and in 2013 
there were 1,683,451 admissions. Marijuana/hashish was the primary 
substance of abuse for 18.3% (352,397) of admissions in 2011; 17.5% 
(315,200) in 2012; and 16.8% (281,991) in 2013. Of the 281,991 
admissions for marijuana/hashish treatment in 2013, 24.3% used 
marijuana/hashish daily. Among those treated for marijuana/hashish as 
the primary substance in 2013, 27.4% were ages 12 to 17 years and 29.7% 
were ages 18 to 24 years. Those admitted for marijuana/hashish were 
mostly male (72.6%) and non-Hispanic (82.2%). Non-hispanic whites 
(43.2%) represented the largest ethnic group of marijuana admissions.

5. Forensic Laboratory Data

    Data on marijuana seizures from federal, state, and local forensic 
laboratories have indicated that there is significant trafficking of 
marijuana. The National Forensic Laboratory System (NFLIS) is a program 
sponsored by the Drug Enforcement Administration's Office of Diversion 
Control. NFLIS systematically collects drug identification results and 
associated information from drug exhibits encountered by law 
enforcement and analyzed in federal, state, and local forensic 
laboratories. NFLIS is a comprehensive information system that includes 
data from 278 individual forensic laboratories that report more than 
91% of the drug caseload in the U.S. NFLIS captures data for all drugs 
and chemicals identified and reported by forensic laboratories. More 
than 1,700 unique substances are represented in the NFLIS database.
    Data from NFLIS showed that marijuana was the most frequently 
identified drug in federal, state, and local laboratories from January 
2004 through December 2014. Marijuana accounted for between 29.47% and 
34.84% of all drug exhibits analyzed annually during that time frame 
(Table 1).

[[Page 53745]]

[GRAPHIC] [TIFF OMITTED] TP12AU16.020

    Since 2004, the total number of reports of marijuana and the amount 
of marijuana encountered federally has remained high (see data from 
Federal-wide Drug Seizure System and Domestic Cannabis Eradication and 
Suppression Program below).

6. Federal-Wide Drug Seizure System

    The Federal-wide Drug Seizure System (FDSS) contains information 
about drug seizures made within the jurisdiction of the United States 
by the Drug Enforcement Administration, the Federal Bureau of 
Investigation, United States Customs and Border Protection, and United 
States Immigration and Customs Enforcement. It also records maritime 
seizures made by the United States Coast Guard. Drug seizures made by 
other Federal agencies are included in the FDSS database when drug 
evidence custody is transferred to one of the agencies identified 
above. FDSS is now incorporated into the National Seizure System (NSS), 
which is a repository for information on clandestine laboratory and 
contraband (chemicals and precursors, currency, drugs, equipment and 
weapons). FDSS reports total federal drug seizures [in kilograms (kg)] 
of substances such as cocaine, heroin, MDMA, methamphetamine, and 
cannabis (marijuana and hashish). The yearly volume of cannabis seized 
(Table 2), consistently exceeding a thousand metric tons per year, 
shows that cannabis is very widely trafficked in the United States.
[GRAPHIC] [TIFF OMITTED] TP12AU16.021

7. Potency Monitoring Project

    The University of Mississippi's Potency Monitoring Project (PMP), 
through a contract with the National Institute on Drug Abuse (NIDA), 
analyzes and compiles data on the [Delta]\9\-THC concentrations of 
marijuana, hashish and hash oil samples provided by DEA regional 
laboratories and by state and local police agencies. After 2010, PMP 
has analyzed only marijuana samples provided by DEA regional 
laboratories. As indicated in Figure 1, the percentage of [Delta]\9\-
THC increased from 1995 to 2010 with an average THC content of 3.75% in 
1995 and 9.53% in 2010. In examining marijuana samples only provided by 
DEA laboratories, the average [Delta]\9\-THC content was 3.96% in 1995 
in comparison to 11.16% in 2015.

[[Page 53746]]

[GRAPHIC] [TIFF OMITTED] TP12AU16.022

8. The Domestic Cannabis Eradication and Suppression Program

    The Domestic Cannabis Eradication and Suppression Program (DCE/SP) 
was established in 1979 to reduce the supply of domestically cultivated 
marijuana in the United States. The program was designed to serve as a 
partnership between federal, state, and local agencies. Only California 
and Hawaii were active participants in the program at its inception. 
However, by 1982 the program had expanded to 25 states and by 1985 all 
50 states were participants. Cannabis is cultivated in remote locations 
and frequently on public lands and illicitly grown in all states. Data 
provided by the DCE/SP (Table 3) show that in the United States in 
2014, there were 3,904,213 plants eradicated in outdoor cannabis 
cultivation areas compared to 2,597,798 plants in 2000. Significant 
quantities of marijuana were also eradicated from indoor cultivation 
operations. There were 396,620 indoor plants eradicated in 2014 
compared to 217,105 eradicated in 2000.

[[Page 53747]]

[GRAPHIC] [TIFF OMITTED] TP12AU16.023

    The recent statistics from these various surveys and databases show 
that marijuana continues to be the most commonly used illicit drug, 
with considerable rates of heavy abuse and dependence. They also show 
that marijuana is the most readily available illicit drug in the United 
States.
Petitioners' Major Comments in Relation to Factor 1 and the 
Government's Responses
    (1) In Exhibit B, the petitioners compared the effects of marijuana 
to currently controlled schedule II substances and made repeated claims 
about the comparative effects.
    The HHS noted that comparisons between marijuana and schedule II 
substances are difficult because of differences in the actions of 
different pharmacological classes of schedule II drugs in the CSA. The 
HHS notes that schedule II substances include stimulant-like drugs 
(e.g., cocaine, amphetamine), opioids (e.g., fentanyl, oxycodone), 
depressant drugs (e.g., pentobarbital), dissociative anesthetics (e.g., 
phencyclidine), and naturally occurring plant components (e.g., coca 
leaves and poppy straw). The mechanism of action of [Delta]\9\-THC and 
marijuana, which act primarily through the cannabinoid receptors 
(discussed further in Factor 2) are completely different from the 
above-mentioned classes of schedule II substances. The HHS concludes 
that the differences in the mechanisms of action in the various classes 
of schedule II substances make it inappropriate to compare the range of 
those substances with marijuana.
    Furthermore, as noted by the HHS, many substances scheduled under 
the CSA are evaluated within the context of drug development using data 
submitted under a New Drug Application (NDA). However, the petitioners 
have not identified a specific indication for use of marijuana and 
therefore the HHS notes that an appropriate comparator based on 
indication cannot be identified.
    (2) The petitioners indicated that the actual or relative potential 
of abuse of marijuana is low. The petitioners state, ``Some researchers 
claim that cannabis is not particularly addictive. Experts assert that 
cannabis's addictive potential parallels caffeine's.'' (Exhibit B, page 
19, lines 20-21). Furthermore, petitioners stated that, ``Cannabis use 
indicates a lower likelihood of addiction and abuse potential as 
compared to other substances.'' (Exhibit B, page 22, lines 12-13).
    Under the CSA, for a substance to be placed in schedule II, III, 
IV, or V, it must have a currently accepted medical use in treatment in 
the United States.\45\ As DEA has previously stated, Congress 
established only one schedule, schedule I, for drugs of abuse with ``no 
currently accepted medical use in treatment in the United States.'' 76 
FR 40552 (2011). Thus, any attempt to compare the relative abuse 
potential of schedule I substance to that of a substance in another 
schedule is inconsequential since a schedule I substance must remain in 
schedule I until it has been found to have a currently accepted medical 
use in treatment in the United States.
---------------------------------------------------------------------------

    \45\ See Americans for Safe Access, 706 F.3d at 440.
---------------------------------------------------------------------------

    Moreover, the petitioners failed to review the indicators of abuse 
potential, as discussed in the legislative history of the CSA. The 
petitioners did not use data on marijuana usage, diversion, 
psychoactive properties, and dependence in their evaluation of 
marijuana abuse potential. The HHS and the DEA discuss those indicators 
above in this factor. HHS's evaluation of the full range of data led 
HHS and DEA to conclude that marijuana has a high potential for abuse.
    The petitioners, based on their review of a survey by Gore and 
Earleywine (2007), concluded that marijuana has a low abuse potential. 
Gore and Earleywine surveyed 746 mental health professionals and asked 
them to rate the addictiveness (based on a seven-point scale) of 
several drugs (heroin, nicotine, cocaine/crack, oxycodone, 
methamphetamine, amphetamine, caffeine, alcohol, and marijuana). The 
petitioners stated that the health professionals rated marijuana as 
least addictive of the drugs surveyed. The DEA notes that the survey 
cited by the petitioners is based on subjective opinions from health 
professionals.
    (3) The petitioners mentioned that many of the cannabinoids in 
marijuana decrease the psychoactive effects of [Delta]\9\-THC, and 
therefore marijuana lacks sufficient abuse potential for placement into 
schedule I. Further, the petitioners mentioned on page 4 in Exhibit B 
(lines 11-15), ``While the DEA considers cannabis a schedule I drug, it 
classifies dronabinol (Marinol) as schedule III. Dronabinol is 100 
percent THC and is

[[Page 53748]]

potentially very psychoactive. Natural cannabis typically would be no 
more than 15 percent THC by weight. Thus it is inconsistent that 
cannabis, with 15 percent weight THC, remains a [s]chedule I drug, 
while dronabinol, at 100 percent THC, is schedule III.''
    The HHS addressed this issue by indicating that the modulating 
effects of the other cannabinoids in marijuana on [Delta]\9\-THC have 
not been demonstrated in controlled studies. The HHS and the DEA also 
note that the determination of the abuse potential of a substance 
considers not only psychoactive effects but also chemistry, 
pharmacology, pharmacokinetics, usage patterns, and diversion history 
among other measures.
    Marinol (dronabinol in sesame oil) was rescheduled from schedule II 
to schedule III on July 2, 1999 (64 FR 35928, DEA 1999). In assessing 
Marinol, HHS compared Marinol to marijuana on several aspects of abuse 
potential and found that major differences between the two, such as 
formulation, availability, and usage, contribute to differences in 
abuse potential. The psychoactive effects from smoking are generally 
more rapid and intense than those that occur through oral 
administration (HHS, 2015; Wesson and Washburn, 1990; Hollister and 
Gillespie, 1973). Therefore, as concluded by both the HHS and the DEA, 
the delayed onset of action and longer duration of action from an oral 
dose of Marinol may contribute in limiting the abuse potential of 
Marinol relative to marijuana, which is most often smoked. The HHS also 
stated that the extraction and purification of dronabinol from the 
encapsulated sesame oil mixture of Marinol is highly complex and 
difficult, and that the presence of sesame oil mixture may preclude the 
smoking of Marinol-laced cigarettes.
    Furthermore, marijuana and Marinol show significant differences in 
actual abuse and illicit trafficking. There have been no reports of 
abuse, diversion, or public health risks due to Marinol. In contrast, 
22.2 million American adults report currently using marijuana (SAMHSA, 
2015a). The DEA database, NFLIS, showed that marijuana was the most 
frequently identified drug in state and local forensic laboratories 
from January 2001 to December 2014 and indicates the high availability 
of marijuana. The differences in composition, actual abuse, and 
diversion contribute to the differences in scheduling between marijuana 
and Marinol.
    Additionally, the FDA approved a New Drug Application (NDA) for 
Marinol, indicating a legitimate medical use for Marinol in the United 
States and allowing for Marinol to be rescheduled into schedule II and 
subsequently into schedule III of the CSA. The HHS mentioned that 
marijuana and Marinol differ on a wide variety of factors and these 
differences are major reasons for differential scheduling of marijuana 
and Marinol. Marijuana, as discussed more fully in Factors 3 and 6, 
does not have a currently accepted medical use in the United States, is 
highly abused, and has a lack of accepted safety.

Factor 2: Scientific Evidence of the Drug Pharmcological Effects, if 
Known

    The HHS stated that there are large amounts of scientific data on 
the neurochemistry, mechanistic effects, toxicology, and pharmacology 
of marijuana. A scientific evaluation, as conducted by the HHS and the 
DEA, of marijuana's neurochemistry, human and animal behavioral 
pharmacology, central nervous system effects, and other pharmacological 
effects (e.g., cardiovascular, immunological effects) is presented 
below.

Neurochemistry

    Marijuana contains numerous constituents such as cannabinoids that 
have a variety of pharmacological actions. The petition defined 
marijuana as including all cannabis cultivated strains. The HHS stated 
that different marijuana samples derived from various cultivated 
strains may differ in their chemical constituents including [Delta]\9\-
THC and other cannabinoids. Therefore marijuana products from different 
strains will have different biological and pharmacological effects. The 
chemical constituents of marijuana are discussed further in Factor 3.
    The primary site of action for cannabinoids such as [Delta]\9\-THC 
is at the cannabinoid receptor. Two cannabinoid receptors, CB1 and CB2, 
have been identified and characterized (Battista et al., 2012; 
Piomelli, 2005) and are G-protein-coupled receptors. Activation of 
these inhibitory G-protein-coupled receptors inhibits adenylate cyclase 
activity, which prevents conversion of ATP to cyclic AMP. Cannabinoid 
receptor activation also results in inhibition of N- and P/Q-type 
calcium channels and activates inwardly rectifying potassium channels 
(Mackie et al., 1995; Twitchell et al., 1997). The HHS mentioned that 
inhibition of N-type calcium channels decreases neurotransmitter 
release and this may be the underlying mechanism in the ability of 
cannabinoids to inhibit acetylcholine, norepinephrine and glutamate 
from specific areas of the brain. These cellular actions may underlie 
the antinociceptive and psychoactive effects of cannabinoids. 
[Delta]\9\-THC acts as an agonist at cannabinoid receptors.
    CB1 receptors are primarily found in the central nervous system and 
are located mainly in the basal ganglia, hippocampus and cerebellum of 
the brain (Howlett et al., 2004). CB1 receptors are also located in 
peripheral tissues such as the immune system (De Petrocellis and Di 
Marzo, 2009), but the concentration of CB1 receptors there is 
considerably lower than in the central nervous system (Herkenham et 
al., 1990; 1992). CB2 receptors are found primarily in the immune 
system and predominantly in B lymphocytes and natural killer cells 
(Bouaboula et al., 1993). CB2 receptors are also found in the central 
nervous system, primarily in the cerebellum and hippocampus (Gong et 
al., 2006).
    Two endogenous ligands to the cannabinoid receptors, anandamide and 
arachidonyl glycerol (2-AG), were identified in 1992 (Devane et al., 
1992) and 1995 (Mechoulam et al., 1995), respectively. Anandamide is a 
low-efficacy agonist (Brievogel and Childers, 2000) and 2-AG is a high 
efficacy agonist (Gonsiorek et al., 2000) to the cannabinoid receptors. 
These endogenous ligands are present in both the central nervous system 
and in the periphery (HHS, 2015).
    [Delta]\9\-THC and cannabidiol (CBD) are two of the major 
cannabinoids in marijuana. [Delta]\9\-THC is the major psychoactive 
cannabinoid (Wachtel et al., 2002). [Delta]\9\-THC has similar affinity 
for CB1 and CB2 receptors and acts as a weak agonist at CB2 receptors. 
The HHS indicated that activation of CB1 receptors mediates 
psychotropic effects of cannabinoids. CBD has low affinity for both CB1 
and CB2 receptors. CBD has antagonistic effects at CB1 receptors, and 
some inverse agonistic properties at CB2 receptors.

Animal Behavioral Effects

    Animal abuse potential studies (drug discrimination, self-
administration, conditioned place preference) are discussed more fully 
in Factor 1. Briefly, it was consistently demonstrated that [Delta]\9\-
THC, the primary psychoactive component in marijuana, and other 
cannabinoids in marijuana have a distinct drug discriminative profile. 
In addition, animals self-administer [Delta]\9\-THC, and [Delta]\9\-THC 
in low doses produces conditioned place preference.

[[Page 53749]]

Central Nervous System Effects

Psychoactive Effects
    The clinical psychoactive effects of marijuana are discussed more 
fully in Factor 1. Briefly, the psychoactive effects from marijuana use 
are considered pleasurable and associated with drug-seeking or drug-
taking (HHS, 2015; Maldonado, 2002). Further, it was noted by HHS that 
marijuana users prefer higher concentrations of the principal 
psychoactive component ([Delta]\9\-THC) over lower concentrations (HHS, 
2015).
    Studies have evaluated psychoactive effects of THC in the presence 
of high CBD, CBC, or CBN ratios. Even though some studies suggest that 
CBD may decrease some of [Delta]\9\-THC's psychoactive effects, the HHS 
found that the ratios of CBD to [Delta]\9\-THC administered in the 
studies were not comparable to the amounts found in marijuana used by 
most people (Dalton et al., 1976; Karniol et al., 1974; Zwardi et al., 
1982). In fact, the CBD ratios in these studies are significantly 
higher than the CBD found in most marijuana currently found on the 
streets (Mehmedic et al., 2010). HHS indicated that most of the 
marijuana available on the street has a high THC and low CBD content 
and therefore any lessening of THC's psychoactive effects by CBD will 
not occur for most marijuana users (HHS, 2015). Dalton et al. (1976) 
reported that when volunteers smoked cigarettes with a ratio of 7 CBD 
to 1 [Delta]\9\-THC (0.15 mg/kg CBD and 0.025 mg/kg [Delta]\9\-THC), 
there was a significant decrease in ratings of acute subjective effects 
and achieving a ``high'' in comparison to smoking [Delta]\9\-THC alone. 
In oral administration studies, the subjective effects and anxiety 
produced by combination of CBD and THC in a ratio of at least 1:2 CBD 
to [Delta]\9\-THC (15, 30, 60 mg CBD to 30 mg [Delta]\9\-THC; Karniol 
et al., 1974) or a ratio of 2:1 CBD to [Delta]\9\-THC (1 mg/kg CBD to 
0.5 mg/kg [Delta]\9\-THC; Zuardi et al., 1982) are less than those 
produced by [Delta]\9\-THC administered alone.
    In one study (Ilan et al., 2005), the authors calculated the 
naturally occurring concentrations of CBC and CBD in marijuana 
cigarettes with either 1.8 or 3.6% [Delta]\9\-THC by weight. The 
authors varied the concentrations of CBC and CBD for each concentration 
of [Delta]\9\-THC in the marijuana cigarettes. Administrations in 
healthy marijuana users (n=23) consisted of either: (1) Low CBC (0.1% 
by weight) and low CBD (0.2% by weight); (2) high CBC (0.5% by weight) 
and low CBD; (3) low CBC and high CBD (1.0% by weight); or (4) high CBC 
and high CBD and the users were divided into low [Delta]\9\-THC (1.8% 
by weight) and high [Delta]\9\-THC (3.6% by weight) groups. Subjective 
psychoactive effects were significantly greater for all groups in 
comparison to placebo and there were no significant differences in 
effects among the treatments (Ilan et al., 2005).
    The HHS also referred to a study with [Delta]\9\-THC and cannabinol 
(CBN) (Karniol et al., 1975). In this study, oral administration of 
either 12.5, 25, or 50 mg CBN combined with 25 mg [Delta]\9\-THC (ratio 
of at least 1:2 CBN to [Delta]\9\-THC) significantly increased 
subjective psychoactive ratings of [Delta]\9\-THC compared to 
[Delta]\9\-THC alone (Karniol et al., 1975).
Behavioral Impairment
    Several factors may influence marijuana's behavioral effects 
including the duration (chronic or short term), frequency (daily, 
weekly, or occasionally), and amount of use (heavy or moderate). 
Researchers have examined how long behavioral impairments persist 
following chronic marijuana use. These studies used self-reported 
histories of exposure duration, frequency, and amount of marijuana use, 
and administered several performance and cognitive tests at different 
time points following marijuana abstinence. According to HHS, 
behavioral impairments may persist for up to 28 days of abstinence in 
chronic marijuana users.
    Psychoactive effects of marijuana can lead to behavioral impairment 
including cognitive decrements and decreased ability to operate motor 
vehicles (HHS, 2015). Block et al. (1992) evaluated cognitive measures 
in 48 healthy male subjects following smoking a marijuana cigarette 
that contained 2.57% or 19 mg [Delta]\9\-THC by weight or placebo. Each 
subject participated in eight sessions (four sessions with marijuana; 
four sessions with placebo) and several cognitive and psychomotor tests 
were administered (e.g. verbal recall, facial recognition, text 
learning, reaction time). Marijuana significantly impaired performances 
in most of these cognitive and psychomotor tests (Block et al., 1992).
    Ramaekers et al. (2006) reported that in 20 recreational users of 
marijuana, acute administration of 250 [micro]g/kg and 500 [micro]g/kg 
[Delta]\9\-THC in smoked marijuana resulted in dose-dependent 
impairments in cognition, motor impulsivity, motor control (tracking 
impairments), and risk taking. In another study (Kurzthaler et al., 
1999), when 290 [micro]g/kg [Delta]\9\-THC was administered via a 
smoked marijuana cigarette in 30 healthy volunteers with no history of 
substance abuse there were significant impairments of motor speed and 
accuracy. Furthermore, administration of 3.95% [Delta]\9\-THC in a 
smoked marijuana cigarette increased the latency in a task of simulated 
braking in a vehicle (Liguori et al., 1998). The HHS noted that the 
motor impairments reported in these studies (Kurzthaler et al., 1999; 
Liguori et al., 1998) are critical skills needed for operating a 
vehicle.
    As mentioned in the HHS document, some studies examined the 
persistence of the behavioral impairments immediately after marijuana 
administration. Some of marijuana's acute effects may still be present 
for at least 24 hours after the acute psychoactive effects have 
subsided. In a brief communication, Heishmann et al. (1990) reported 
that there were cognitive impairments (digit recall and arithmetic 
tasks) in two out of three experienced marijuana smokers for 24 hours 
after smoking marijuana cigarettes containing 2.57% [Delta]\9\-THC. 
However, Fant et al. (1998) evaluated subjective effects and 
performance measures for up to 25 hours in 10 healthy males after 
exposure to either 1.8% or 3.6% [Delta]\9\-THC in marijuana cigarettes. 
Peak decrements in subjective and performance measures were noted 
within 2 hours of marijuana exposure but there were minimal residual 
alterations in subjective or performance measures at 23-25 hours after 
exposure.
    Persistence of behavioral impairments following repeated and 
chronic use of marijuana has also been investigated and was reviewed in 
the HHS document (HHS, 2015). In particular, researchers examined how 
long behavioral impairments last following chronic marijuana use. In 
studies examining persistence of effects in chronic and heavy marijuana 
users, there were significant decrements in cognitive and motor 
function tasks in all studies of up to 27 days, and in most studies at 
28 days (Solowij et al., 2002; Messinis et al., 2006; Lisdahl and 
Price, 2012; Pope et al., 2002; Bolla et al., 2002; Bolla et al., 
2005). In studies that followed heavy marijuana users for longer than 
28 days and up to 20 years of marijuana abstinence, cognitive and 
psychomotor impairments were no longer detected (Fried et al., 2005; 
Lyons et al., 2004; Tait et al., 2011). For example, Fried et al. 
(2005) reported that after 3 months of abstinence from marijuana, any 
deficits in intelligence (IQ), memory, and processing speeds following 
heavy marijuana use were no longer observed (Fried et al., 2005). In a 
meta-analysis that examined non-acute and long-lasting effects of 
marijuana, any deficits in neurocognitive performance that were 
observed within the first month

[[Page 53750]]

were no longer apparent after approximately one month of abstinence 
(Schreiner and Dunn, 2012). HHS further notes that in moderate 
marijuana users deficits in decision-making skills were not observed 
after 25 days of abstinence and additionally IQ, immediate memory and 
delayed memory skills were not significantly impacted as observed with 
heavy and chronic marijuana users (Fried et al., 2005; HHS, 2015).
    As mentioned in the HHS document (HHS, 2015), the intensity and 
persistence of neurological impairment from chronic marijuana use also 
may be dependent on the age of first use. In two separate smaller scale 
studies (less than 100 participants per exposure group), Fontes et al. 
(2011) and Gruber et al. (2012) compared neurological function in early 
onset (chronic marijuana use prior to age 15 or 16) and late onset 
(chronic marijuana use after age 15 or 16) heavy marijuana users and 
found that there were significant deficits in executive neurological 
function in early onset users which were not observed or were less 
apparent in late onset users. In a prospective longitudinal birth 
cohort study following 1,037 individuals (Meier et al., 2012), a 
significant decrease in IQ and neuropsychological performance was 
observed in adolescent-onset users and persisted even after abstinence 
from marijuana for at least one year. However, Meier et al. (2012) 
reported in there was no significant change in IQ in adult-onset users.
    The HHS noted that there is some evidence that the severity of the 
persistent neurological impairments may also be due in part to the 
amount of marijuana usage. In the study mentioned above, Gruber et al. 
(2012) found that the early onset users consumed three times as much 
marijuana per week and used it twice as often as late onset users. 
Meier et al. (2012) reported in their study, mentioned above, that 
there was a correlation between IQ deficits in adolescent onset users 
and the increased amount of marijuana used.
Behavioral Effects of Prenatal Exposure
    In studies that examined effects of prenatal marijuana exposure, 
many of the pregnant women also used alcohol and tobacco in addition to 
marijuana. Even though other drugs were used in conjunction with 
marijuana, there is evidence of an association between heavy prenatal 
marijuana exposure and deficits in some cognitive function. There have 
been two prospective longitudinal birth cohort studies following 
individuals prenatally exposed to marijuana from birth until adulthood: 
The Ottawa Prenatal Prospective Study (OPPS; Fried et al., 1980), and 
the Maternal Health Practices and Child Development Project (MHPCD; Day 
et al., 1985). Both longitudinal studies report that heavy prenatal 
marijuana use is associated with decreased performance on tasks 
assessing memory, verbal and quantitative reasoning in 4-year-olds 
(Fried and Watkinson, 1990) and in 6 year olds (Goldschmidt et al., 
2008). In subsequent studies with the OPPS cohort, deficits in 
sustained attention were reported in children ages 6 and 13-16 years 
(Fried et al., 1992; Fried, 2002) and deficits in executive 
neurological function were observed in 9- and 12-year-old children 
(Fried et al., 1998). DEA further notes that with the MHPCD cohort, 
follow-up studies reported an increased rate of delinquent behavior 
(Day et al., 2011) and decreased achievement test scores (Goldschmidt 
et al., 2012) at age 14. When the MHPCD cohort was followed to age 22, 
there was a marginal (p = 0.06) increase in psychosis with prenatal 
marijuana exposure and early onset of marijuana use (Day et al., 2015).
Association of Marijuana Use With Psychosis
    There has been extensive research to determine whether marijuana 
usage is associated with development of schizophrenia or other 
psychoses, and the HHS indicated that the available data do not suggest 
a causative link between marijuana and the development of psychosis 
(HHS, 2015; Minozzi et al., 2010). As mentioned in the HHS review (HHS, 
2015), numerous large scale longitudinal studies demonstrated that 
subjects who used marijuana do not have a greater incidence of 
psychotic diagnoses compared to non-marijuana users (van Os et al., 
2002; Fergusson et al., 2005; Kuepper et al., 2011). Further, the HHS 
commented that when analyzing the available data examining the 
association between marijuana and psychosis, it is critical to 
differentiate whether the patients in a study are already diagnosed 
with psychosis or if the individuals have a limited number of symptoms 
associated with psychosis without qualifying for a diagnosis of the 
disorder.
    As mentioned by the HHS, some of the studies examining the 
association between marijuana and psychosis utilized non-standard 
methods to categorize psychosis and these methods did not conform to 
the criteria in the Diagnostic and Statistical Manual (DSM-5) or the 
International Classification of Diseases (ICD-10) and would not be 
appropriate for use in evaluating the association between marijuana use 
and psychosis. For example, researchers characterized psychosis as 
``schizophrenic cluster'' (Maremmani et al., 2004), ``subclinical 
psychotic symptoms'' (van Gastel et al., 2012), ``pre-psychotic 
clinical high risk'' (van der Meer et al., 2012), and symptoms related 
to ``psychosis vulnerability'' (Griffith-Lendering et al., 2012).
    The HHS discussed an early epidemiological study conducted by 
Andreasson et al. (1987), which examined the link between psychosis and 
marijuana use. In this study, about 45,000 18- and 19-year-old male 
Swedish subjects provided detailed information on their drug-taking 
history and 274 of these subjects were diagnosed with schizophrenia 
over a 14-year period (1969-1983). Out of the 274 subjects diagnosed 
with psychosis, 21 individuals (7.7%) had used marijuana more than 50 
times, while 197 individuals (72%) never used marijuana. As presented 
by the authors (Andreasson et al., 1987), individuals who claimed to 
take marijuana on more than 50 occasions were 6 times more likely to be 
diagnosed with schizophrenia than those who had never consumed the 
drug. The authors concluded that marijuana users who are vulnerable to 
developing psychoses are at the greatest risk for schizophrenia. In a 
35 year follow up to the subjects evaluated in Andreasson et al. 
(1987), Manrique-Garcia et al. (2012) reported similar findings. In the 
follow up study, 354 individuals developed schizophrenia. Of those, 32 
individuals (9%) had used marijuana more than 50 times and were 6.3 
times more likely to develop schizophrenia. 255 of the 354 individuals 
(72%) never used marijuana.
    The HHS also noted that many studies support the assertion that 
psychosis from marijuana usage may manifest only in individuals already 
predisposed to development of psychotic disorders. Marijuana use may 
precede diagnosis of psychosis (Schimmelmann et al., 2011), but most 
reports indicate that prodromal symptoms of schizophrenia are observed 
prior to marijuana use (Schiffman et al., 2005). In a review examining 
gene-environmental interaction between marijuana exposure and the 
development of psychosis, it was concluded that there is some evidence 
to support that marijuana use may influence the development of 
psychosis but only for susceptible individuals (Pelayo-Teran et al., 
2012).

[[Page 53751]]

    Degenhardt et al. (2003) modeled the prevalence of schizophrenia 
against marijuana use across eight birth cohorts in individuals born 
during 1940 to 1979 in Australia. Even though there was an increase in 
marijuana use in the adult subjects over this time period, there was 
not an increase in diagnoses of psychosis for these same subjects. The 
authors concluded that use of marijuana may increase schizophrenia only 
in persons vulnerable to developing psychosis.

Cardiovascular and Autonomic Effects

    The HHS stated that acute use of marijuana causes an increase in 
heart rate (tachycardia) and may increase blood pressure (Capriotti et 
al., 1988; Benowitz and Jones, 1975). There is some evidence that 
associates the increased heart rate from [Delta]\9\-THC exposure with 
excitation of the sympathetic and depression of the parasympathetic 
nervous systems (Malinowska et al., 2012). Tolerance to tachycardia 
develops with chronic exposure to marijuana (Jones, 2002; Sidney, 
2002).
    Prolonged exposure to [Delta]\9\-THC results in a decrease in heart 
rate (bradycardia) and hypotension (Benowitz and Jones, 1975). These 
effects are thought to be mediated through peripherally located, 
presynaptic CB1 receptor inhibition of norepinephrine release with 
possible direct activation of vascular cannabinoid receptors (Wagner et 
al., 1998; Pacher et al., 2006).
    As stated in the HHS recommendation (HHS, 2015), marijuana exposure 
causes orthostatic hypotension (fainting-like feeling; sudden drop in 
blood pressure upon standing up) and tolerance can develop to this 
effect upon repeated, chronic exposure (Jones, 2002). Tolerance to 
orthostatic hypotension is potentially related to plasma volume 
expansion, but tolerance does not develop to supine hypotensive effects 
(Benowitz and Jones, 1975).
    Marijuana smoking, particularly by those with some degree of 
coronary artery or cerebrovascular disease, poses risks such as 
increased cardiac work, increased catecholamines and carboxyhemoglobin, 
myocardial infarction and postural hypotension (Benowitz and Jones, 
1981; Hollister, 1988; Mittleman et al., 2001; Malinowska et al., 
2012). However, electrocardiographic changes were minimal after 
administration of large cumulative doses of [Delta]\9\-THC (Benowitz 
and Jones, 1975).
    The DEA notes two recent reports that reviewed several case studies 
on marijuana and cardiovascular complications (Panayiotides, 2015; 
Hackam, 2015). Panayiotides (2015) reported that approximately 25.6% of 
the cardiovascular cases from marijuana use resulted in death from data 
provided by the French Addictovigilance Network during the period of 
2006-2010. Several case studies on marijuana usage and cardiovascular 
events were discussed and it was concluded that although a causal link 
cannot be established due to not knowing exact amounts of marijuana 
used in the cases and confounding variables, the available evidence 
supports a link between marijuana and cardiotoxicity. Hackham (2015) 
reviewed 34 case reports or case series reports of marijuana and 
stroke/ischemia in 64 stroke patients and reported that in 81% of the 
cases there was a temporal relationship between marijuana usage and 
stroke or ischemic event. The author concluded that collective analysis 
of the case reports supports a causal link between marijuana use and 
stroke.

Respiratory Effects

    The HHS stated that transient bronchodilation is the most typical 
respiratory effect of acute exposure to marijuana (Gong et al., 1984). 
In a recent longitudinal study, information on marijuana use and 
pulmonary data function were collected from 5,115 individuals over 20 
years from 4 communities in the United States (Oakland, CA; Chicago, 
IL; Minneapolis, MN; Birmingham, AL) (Pletcher et al., 2012). Of the 
5,115 individuals, 795 individuals reported use of only marijuana 
(without tobacco). The authors reported that occasional use of 
marijuana (7 joint-years for lifetime or 1 joint/day for 7 years or 1 
joint/week for 49 years) does not adversely affect pulmonary function. 
Pletcher et al. (2012) further concluded that there is some preliminary 
evidence suggesting that heavy marijuana use may have a detrimental 
effect on pulmonary function, but the sample size of heavy marijuana 
users in the study was too small. Further, as mentioned in the HHS 
recommendation document (HHS, 2015), long-term use of marijuana may 
lead to chronic cough, increased sputum, as well as increased frequency 
of chronic bronchitis and pharyngitis (Adams and Martin, 1996; 
Hollister, 1986).
    The HHS stated that the evidence that marijuana may lead to cancer 
of the respiratory system is inconsistent, with some studies suggesting 
a positive correlation while others do not (Lee and Hancox, 2011; 
Tashkin, 2005). The HHS noted a case series that reported lung cancer 
occurrences in three marijuana smokers (age range 31-37 years) with no 
history of tobacco smoking (Fung et al., 1999). Furthermore, in a case-
control study (n = 173 individuals with squamous cell carcinoma of the 
head and neck; n = 176 controls; Zhang et al., 1999), prevalence of 
marijuana use was 9.7% in controls and 13.9% in cases and the authors 
reported that marijuana use may dose-dependently interact with 
mutagenic sensitivity, cigarette smoking, and alcohol use to increase 
risk associated with head and neck cancers (Zhang et al., 1999). 
However, in a large clinical study with 1,650 subjects, no positive 
correlation was found between marijuana use and lung cancer (Tashkin et 
al., 2006). This finding held true regardless of the extent of 
marijuana use when both tobacco use and other potential confounding 
factors were controlled. The HHS concluded that new evidence suggests 
that the effects of smoking marijuana on respiratory function and 
cancer are different from the effects of smoking tobacco (Lee and 
Hancox, 2011).
    The DEA further notes the publication of recent review articles 
critically evaluating the association between marijuana and lung 
cancer. Most of the reviews agree that the association is weak or 
inconsistent (Huang et al., 2015; Zhang et al., 2015; Gates et al., 
2014; Hall and Degenhardt, 2014). Huang et al. (2015) identified and 
reviewed six studies evaluating the association between marijuana use 
and lung cancer and the authors concluded that an association is not 
supported most likely due to the small amounts of marijuana smoked in 
comparison to tobacco. Zhang et al. (2015) examined six case control 
studies from the US, UK, New Zealand, and Canada within the 
International Lung Cancer Consortium and found that there was a weak 
association between smoking marijuana and lung cancer in individuals 
who never smoked tobacco, but precision of the association was low at 
high marijuana exposure levels. Hall and Degenhardt (2014) noted that 
even though marijuana smoke contains several of the same carcinogens 
and co-carcinogens as tobacco smoke (Roth et al., 1998) and has been 
found to be mutagenic and carcinogenic in the mouse skin test, 
epidemiological studies have been inconsistent, but more consistent 
positive associations have been reported in case control studies. 
Finally Gates et al. (2014), reviewed the studies evaluating marijuana 
use and lung cancer and concluded that there is evidence that marijuana 
produces changes in the respiratory system (precursors to cancer) that 
could lead to

[[Page 53752]]

lung cancer, but overall association is weak between marijuana use and 
lung cancer especially when controlling for tobacco use.

Endocrine System

Reproductive Hormones
    The HHS stated that administration of marijuana to humans does not 
consistently alter the endocrine system. In a controlled human exposure 
study (n = 4 males), subjects were acutely administered smoked 
marijuana containing 2.8% [Delta]\9\-THC or placebo and an immediate 
significant decrease in luteinizing hormone and an increase in cortisol 
was reported in the subjects that smoked marijuana (Cone et al., 1986). 
Furthermore, as cited by the HHS, two later studies (Dax et al., 1989; 
Block et al., 1991) reported no changes in hormone levels. Dax et al. 
(1989) recruited male volunteers (n = 17) that were occasional or heavy 
users of marijuana. Following exposure to smoked [Delta]\9\-THC (18 mg/
cigarette) or oral [Delta]\9\-THC (10 mg three times per day for three 
days and on the morning of the fourth day), the subjects in that study 
showed no changes in plasma adrenocorticotropic hormone (ACTH), 
cortisol, prolactin, luteinizing hormone, or testosterone levels. 
Additionally, Block et al. (1991) compared plasma hormone levels 
amongst non-users as well as infrequent, moderate, and frequent users 
of marijuana (n = 93 men and 56 women) and found that chronic use of 
marijuana (infrequent, moderate, and frequent users) did not 
significantly alter concentrations of testosterone, luteinizing 
hormone, follicle stimulating hormone, prolactin, or cortisol.
    The HHS noted that there is a discrepancy in the effect of 
marijuana on female reproductive system functionality between animals 
and humans (HHS, 2015). Female rhesus monkeys that were administered 
2.5 mg/kg [Delta]\9\-THC, i.m., during days 1-18 of the menstrual cycle 
had reduced progesterone levels and ovulation was suppressed (Asch et 
al., 1981). However, women who smoked marijuana (1 gram marijuana 
cigarette with 1.8% [Delta]\9\-THC) during the periovulatory period 
(24-36 hours prior to ovulation) did not exhibit changes in 
reproductive hormone levels or their menstrual cycles (Mendelson and 
Mello, 1984). In a review article by Brown and Dobs (2002), the authors 
state that endocrine changes observed with marijuana are no longer 
observed with chronic administration and this may be due to drug 
tolerance.
Reproductive Cancers
    The HHS stated that recent studies support a possible association 
between frequent, long-term marijuana use and increased risk of 
testicular germ cell tumors. In a hospital-based case-control study, 
the frequency of marijuana use was compared between testicular germ 
cell tumor (TGCT) patients (n = 187) and controls (n = 148) (Trabert et 
al., 2011).
    TGCT patients were more likely to be frequent marijuana users than 
controls with an odds ratio (OR) of 2.2 (95% confidence limits of 1.0-
5.1) and were less likely to be infrequent or short-term users with 
odds ratios of 0.5 and 0.6, respectively in comparison to controls 
(Trabert et al., 2011). The DEA further notes that in two population-
based case-control studies (Daling et al., 2009; Lacson et al., 2012), 
marijuana use was compared between patients diagnosed with TGCT and 
matched controls in Washington State or Los Angeles County. In both 
studies, it was reported that TCGT patients were twice as likely as 
controls to use marijuana. Authors of both studies concluded that 
marijuana use is associated with an elevated risk of TGCT (Daling et 
al., 2009; Lacson et al., 2012).
    The HHS cited a study (Sarfaraz et al., 2005) demonstrating that 
WIN 55,212-2 (a mixed CB1/CB2 agonist) induces apoptosis (one form of 
cell death) in prostate cancer cells and decreases expression of 
androgen receptors and prostate specific antigens, suggesting a 
potential therapeutic value for cannabinoid agonists in the treatment 
of prostate cancer, an androgen-stimulated type of carcinoma.
Other Hormones (e.g. Thyroid, Appetite)
    In more recent studies, as cited by the HHS, chronic marijuana use 
by subjects (n = 39) characterized as dependent on marijuana according 
to the ICD-10 criteria did not affect serum levels of thyroid hormones: 
TSH (thyrotropin), T4 (thyroxine), and T3 (triiodothyronine) (Bonnet, 
2013). With respect to appetite hormones, in a pilot study with HIV-
positive males, smoking marijuana dose-dependently increased plasma 
levels of ghrelin and leptin and decreased plasma levels of peptide YY 
(Riggs et al., 2012).
    The HHS stated that [Delta]\9\-THC reduces binding of the 
corticosteroid dexamethasone in hippocampal tissue from 
adrenalectomized rats and acute [Delta]\9\-THC releases corticosterone, 
with tolerance developing to this effect with chronic administration 
(Eldridge et al., 1991). These data suggest that [Delta]\9\-THC may 
interact with the glucocorticoid receptor system.
Immune System
    The HHS stated that cannabinoids alter immune function but that 
there can be differences between the effects of synthetic, natural, and 
endogenous cannabinoids (Croxford and Yamamura, 2005; Tanasescu and 
Constantinescu, 2010).
    The HHS noted that there are conflicting results in animal and 
human studies with respect to cannabinoid effects on immune functioning 
in subjects with compromised immune systems. Abrams et al. (2003) 
examined the effects of marijuana and [Delta]\9\-THC in 62 HIV-1-
infected patients. Subjects received one of three treatments, three 
times a day: smoked marijuana cigarette containing 3.95% [Delta]\9\-
THC, oral tablet containing [Delta]\9\-THC (2.5 mg oral dronabinol), or 
oral placebo. There were no changes in CD4+ and CD8+ cell counts, HIV 
RNA levels, or protease inhibitor levels in any of the treatment groups 
(Abrams et al., 2003). Therefore, use of cannabinoids showed no short-
term adverse virologic effects in individuals with compromised immune 
systems. Conversely, Roth et al. (2005) reported that in 
immunodeficient mice implanted with human blood cells infected with 
HIV, exposure to [Delta]\9\-THC in vivo suppresses immune function, 
increases HIV co-receptor expression, and acts as a cofactor to enhance 
HIV replication.
    The DEA notes two recent clinical studies reporting a decrease in 
cytokine and interleukin levels following marijuana use. Keen et al. 
(2014) compared the differences in the levels of IL-6 (interleukin-6), 
a proinflammatory cytokine, amongst non-drug users (n = 78), marijuana 
only users (n = 46) and marijuana plus other drug users (n = 45) in a 
community-based sample of middle-aged African Americans (Keen et al., 
2014). After adjusting for confounders, analyses revealed that lifetime 
marijuana only users had significantly lower IL-6 levels than the 
nonuser group. Further, Sexton et al. (2014) compared several immune 
parameters in healthy individuals and subjects with multiple sclerosis 
(MS) and found that the chronic use of marijuana resulted in reduced 
monocyte migration, and decreased levels of CCL2 and IL-17 in both 
healthy and MS groups.
    The DEA also notes a review suggesting that [Delta]\9\-THC 
suppresses the immune responses in experimental animal models and in 
vitro and that these changes may be primarily

[[Page 53753]]

mediated through the CB2 cannabinoid receptor (Eisenstein and Meissler, 
2015).

Petitioners' Major Comments in Relation to Factor 2 and the 
Government's Responses

    (1) The petitioners state that ``[m]edical use of cannabis is 
considered safe.'' (Exhibit B, page 7); and that ``[t]here are adequate 
and well-controlled studies proving the medical efficacy of cannabis.'' 
(Exhibit B, page 10). The petitioners also allege that ``Cannabis is 
safer than current, legal Schedule II opiate drugs'' and that it 
presents milder side effects (Exhibit B, page 9-10).
    As detailed in the HHS review and as discussed later in this 
document (see Factor 3), there are neither adequate safety studies nor 
adequate, well-controlled studies proving marijuana's efficacy. The DEA 
notes that neither the CSA nor established scheduling criteria suggest 
that the HHS and DEA should consider the relative safety profiles of 
drugs when determining the proper schedule. To the extent that the 
petitioners were referring to abuse and dependence liability, this 
document discusses those effects in factors 1, 4, and 7.
    (2) The petitioners state that ``scientific evidence regarding the 
safety and efficacy of cannabis is readily available directly from the 
National Library of Medicine.'' (Exhibit B, page 14).
    The government agrees that many articles discuss marijuana and its 
constituents. Yet, these articles in no way demonstrate that marijuana 
is safe and effective for the treatment of any disease or condition. As 
mentioned in the HHS review and as discussed later in this document 
(see Factor 3), the current research does not provide adequate detailed 
scientific evidence regarding chemistry, pharmacology, toxicology, and 
effectiveness derived from well-controlled clinical investigations to 
permit a conclusion that marijuana is safe and effective for treating a 
specific, recognized disorder.
    (3) The petitioners mentioned on page 9 of exhibit B that ``[t]here 
has never been a lethal overdose of marijuana reported in humans'' and 
that ``[t]here is no known LD50 for any form of cannabis.''
    As more fully discussed in Factor 3 below, the HHS and DEA conclude 
that there are not adequate studies to determine the safety of 
marijuana. As discussed in the HHS document and below, the 
determination of safety is more complex than a mere determination of 
the rate or likelihood of death. Moreover, the lack of overdose deaths 
attributed to a drug is not evidence that the drug is safe for medical 
use.

Factor 3: The State of the Current Scientific Knowledge Regarding the 
Drug or Substance

Chemistry

    The HHS stated that marijuana, also known as Cannabis sativa L., is 
part of the Cannabaceae plant family and is one of the oldest 
cultivated crops. The term ``marijuana'' is generally used to refer to 
a mixture of the dried flowering tops and leaves from Cannabis. 
Marijuana users primarily smoke the marijuana leaves, but individuals 
also ingest marijuana through food infused with marijuana and its 
extracts. Cannabis sativa is the primary species of Cannabis that is 
illegally marketed in the United States. Marijuana is one of three 
major derivatives sold as separate illicit products, the other two 
being hashish and hash oil. Hashish is composed of the dried and 
compressed cannabinoid-rich resinous material of Cannabis and is found 
as balls and cakes as well as other forms. Individuals may break off 
pieces and place them into a pipe to smoke. Hash oil, a viscous brown 
or amber colored liquid, is produced by solvent extraction of 
cannabinoids from Cannabis and contains approximately 50% cannabinoids. 
One to two drops of hash oil on a cigarette has been reported to 
produce the equivalent of a single marijuana cigarette (DEA, 2015).
    The HHS indicated in its evaluation that the petitioners defined 
marijuana as including all Cannabis cultivated strains. However, 
different marijuana samples are derived from numerous cultivated 
strains and may have different chemical compositions including levels 
of [Delta]\9\-THC and other cannabinoids (Appendino et al., 2011). A 
consequence of having different chemical compositions in the various 
marijuana samples is that there will be significant differences in 
safety, biological, pharmacological, and toxicological profiles and 
therefore, according to the HHS, all Cannabis strains cannot be 
considered collectively because of the variations in chemical 
composition. Furthermore, the concentration of [Delta]\9\-THC and other 
cannabinoids present in marijuana may vary due to growing conditions 
and processing of the plant after harvesting. For example, the plant 
parts collected such as flowers, leaves and stems can influence 
marijuana's potency, quality, and purity (Adams and Martin, 1996; 
Agurell et al., 1984; Mechoulam, 1973). Variations in marijuana 
harvesting have resulted in potencies ranging from a low of 1 to 2% up 
to a high of 17% as indicated by cannabinoid content. The concentration 
of [Delta]\9\-THC averages approximately 12% by weight in a typical 
marijuana mixture of leaves and stems. However, some specifically grown 
and selected marijuana samples can contain 15% or greater [Delta]\9\-
THC (Appendino et al., 2011). As a result, the [Delta]\9\-THC content 
in a 1 gram marijuana cigarette can range from as little as 3 
milligrams to 150 milligrams or more. In a systematic review conducted 
by Cascini et al. (2012), it was reported that marijuana's [Delta]\9\-
THC content has increased significantly from 1979-2009.
    Since there is considerable variability in the cannabinoid 
concentrations and chemical constituency among marijuana samples, the 
interpretation of clinical data with marijuana is complicated. A 
primary issue is the lack of consistent concentrations of [Delta]\9\-
THC and other substances in marijuana which complicates the 
interpretation of the effects of different marijuana constituents. An 
added issue is that the non-cannabinoid components in marijuana may 
potentially modify the overall pharmacological and toxicological 
properties of various marijuana strains and products.
    Various Cannabis strains contain more than 525 identified natural 
constituents including cannabinoids, 21 (or 22) carbon terpenoids found 
in the plant, as well as their carboxylic acids, analogues, and 
transformation products (Agurell et al., 1984; 1986; Mechoulam, 1973; 
Appendino et al., 2011). To date, more than 100 cannabinoids have been 
characterized (ElSohly and Slade, 2005; Radwan et al., 2009; Appendino 
et al., 2011), and most major cannabinoid compounds occurring naturally 
have been identified. There are still new and comparably more minor 
cannabinoids being characterized (Pollastro et al., 2011). The majority 
of the cannabinoids are found in Cannabis. One study reported 
accumulation of two cannabinoids, cannabigerol and its corresponding 
acid, in Helichrysum (H. umbraculigerum) which is a non-Cannabis source 
(Appendino et al., 2011).
    Of the cannabinoids found in marijuana, [Delta]\9\-THC (previously 
known as [Delta]\1\-THC) and delta-8-tetrahydrocannabinol ([Delta]\8\-
THC, [Delta]\6\-THC) have been demonstrated to produce marijuana's 
psychoactive effects. Psychoactive effects from marijuana usage have 
been mainly attributed to [Delta]\9\-THC because [Delta]\9\-THC is 
present in significantly more quantities than [Delta]\8\-THC in most 
marijuana varieties. There are only a few marijuana strains that

[[Page 53754]]

contain [Delta]\8\-THC in significant amounts (Hively et al., 1966). 
[Delta]\9\-THC is an optically active resinous substance that is 
extremely lipophilic. The chemical name for [Delta]\9\-THC is (6aR-
trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo-
[b,d]pyran-1-ol, or (-)-delta9-(trans)-tetrahydrocannabinol. The (-)-
trans [Delta]\9\-THC isomer is pharmacologically 6 to 100 times more 
potent than the (+)-trans isomer (Dewey et al., 1984).
    Other relatively well-characterized cannabinoids present in 
marijuana include cannabidiol (CBD), cannabichromene (CBC), and 
cannabinol (CBN). CBD and CBC are major cannabinoids in marijuana and 
are both lipophilic. The chemical name for CBD is 2-[(1R,6R)-3-methyl-
6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and the 
chemical name for CBC is 2-methyl-2-(4-methylpent-3-enyl)-7-pentyl-5-
chromenol. CBN is a minor naturally-occurring cannabinoid with weak 
psychoactivity and is also a major metabolite of [Delta]\9\-THC. The 
chemical name for CBN is 6,6,9-trimethyl-3-pentyl-benzo[c]chromen-1-ol.
    In summary, marijuana has several strains with high variability in 
the concentrations of [Delta]\9\-THC, the main psychoactive component, 
as well as other cannabinoids and compounds. Marijuana is not a single 
chemical and does not have a consistent and reproducible chemical 
profile with predictable or consistent clinical effects. In the HHS 
recommendation for marijuana scheduling (HHS, 2015), it was recommended 
that investigators consult a guidance for industry entitled, Botanical 
Drug Products,\46\ which provides information on the approval of 
botanical drug products. Specifically, in order to investigate 
marijuana in support of a New Drug Application (NDA), clinical studies 
under an Investigational New Drug (IND) application should include 
``consistent batches of a particular marijuana product for [a] 
particular disease.'' (HHS, 2015). Furthermore, the HHS noted that 
investigators must provide data meeting the requirements for new drug 
approval as stipulated in 21 CFR 314.50 (HHS, 2015).
---------------------------------------------------------------------------

    \46\ Available at http://www.fda.gov/Drugs/default.htm under 
Guidance (Drugs).
---------------------------------------------------------------------------

Human Pharmacokinetics

    Pharmacokinetics of marijuana in humans is dependent on the route 
of administration and formulation (Adams and Martin, 1996; Agurell et 
al., 1984; Agurell et al., 1986). Individuals primarily smoke marijuana 
as a cigarette (weighing between 0.5 and 1 gram) or in a pipe. More 
recently, vaporizers have been used as another means for individuals to 
inhale marijuana. Marijuana may also be ingested orally in foods or as 
an extract in ethanol or other solvents. Pharmacokinetic studies with 
marijuana focused on evaluating the absorption, metabolism, and 
elimination profile of [Delta]\9\-THC and other cannabinoids (Adams and 
Martin, 1996; Agurell et al., 1984; Agurell et al., 1986).
Absorption and Distribution of Inhaled Marijuana Smoke
    There is high variability in the pharmacokinetics of [Delta]\9\-THC 
and other cannabinoids from smoked marijuana due to differences in 
individual smoking behavior even under controlled experimental 
conditions (Agurell et al., 1986; Herning et al., 1986; Huestis et al., 
1992a). Experienced marijuana users can titrate and regulate the dose 
by holding marijuana smoke in their lungs for an extended period of 
time resulting in increased psychoactive effects by prolonging 
absorption of the smoke. This property may also help explain why there 
is a poor correlation between venous levels of [Delta]\9\-THC and the 
intensity of effects and intoxication (Agurell et al., 1986; Barnett et 
al., 1985; Huestis et al., 1992a). The HHS recommended that puff and 
inhalation volumes should be tracked in experimental studies because 
the concentration of cannabinoids can vary at different stages of 
smoking.
    [Delta]\9\-THC from smoked marijuana is rapidly absorbed within 
seconds. Psychoactive effects are observed immediately following 
absorption with measurable neurological and behavioral changes for up 
to 6 hours (Grotenhermen, 2003; Hollister, 1986; Hollister, 1988). 
[Delta]\9\-THC is distributed to the brain in a rapid and efficient 
manner. Bioavailability of [Delta]\9\-THC from marijuana (from a 
cigarette or pipe) ranges from 1 to 24% with the fraction absorbed 
rarely exceeding 10 to 20% (Agurell et al., 1986; Hollister, 1988). The 
low and variable bioavailability of [Delta]\9\-THC is due to loss in 
side-stream smoke, variation in individual smoking behaviors and 
experience, incomplete absorption of inhaled smoke, and metabolism in 
lungs (Herning et al., 1986; Johansson et al., 1989). After cessation 
of smoking, [Delta]\9\-THC venous levels decline within minutes and 
continue to decline to about 5% to 10% of the peak level within an hour 
(Agurell et al., 1986; Huestis et al., 1992a; Huestis et al., 1992b).
Absorption and Distribution of Orally Administered Marijuana
    Following oral administration of [Delta]\9\-THC or marijuana, onset 
of effects start within 30 to 90 minutes, peak after 2 to 3 hours and 
effects remain for 4 to 12 hours (Grotenhermen, 2003; Adams and Martin, 
1996; Agurell et al., 1984; Agurell et al., 1986). Dose titration of 
[Delta]\9\-THC from orally ingested marijuana is difficult for users in 
comparison to smoked or inhaled marijuana due to the delay in the onset 
of effects. Oral bioavailability of [Delta]\9\-THC, either in its pure 
form or in marijuana, is low and variable with a range from 5% to 20% 
(Agurell et al., 1984; Agurell et al., 1986). There is also inter- and 
intra-subject variability of orally administered [Delta]\9\-THC under 
experimental conditions and even under repeated dosing experiments 
(HHS, 2015). The HHS noted that in bioavailability studies using 
radiolabeled [Delta]\9\-THC, [Delta]\9\-THC plasma levels following 
oral administration of [Delta]\9\-THC were low relative to plasma 
levels after inhaled or intravenously administered [Delta]\9\-THC. The 
low and variable bioavailability of orally administered [Delta]\9\-THC 
is due to first pass hepatic elimination from blood and erratic 
absorption from stomach and bowel (HHS, 2015).
Metabolism and Excretion of Cannabinoids From Marijuana
    Studies evaluating cannabinoid metabolism and excretion focused on 
[Delta]\9\-THC because it is the primary psychoactive component in 
marijuana. [Delta]\9\-THC is metabolized via microsomal hydroxylation 
and oxidation to both active and inactive metabolites (Lemberger et 
al., 1970; Lemberger et al., 1972a; Lemberger et al., 1972b; Agurell et 
al., 1986; Hollister, 1988). Metabolism of [Delta]\9\-THC is consistent 
among frequent and infrequent marijuana users (Agurell et al., 1986). 
The primary active metabolite of [Delta]\9\-THC following oral 
ingestion is 11-hydroxy-[Delta]\9\-THC which is equipotent to 
[Delta]\9\-THC in producing marijuana-like subjective effects (Agurell 
et al., 1986; Lemberger and Rubin, 1975). Metabolite levels following 
oral administration may be greater than that of [Delta]\9\-THC and may 
contribute greatly to the pharmacological effects of oral [Delta]\9\-
THC or marijuana.
    Plasma clearance of [Delta]\9\-THC approximates hepatic blood flow 
at a rate of approximately 950 ml/min or greater. Rapid clearance of 
[Delta]\9\-THC from blood is primarily due to redistribution to other 
tissues in the body rather than to metabolism (Agurell et al., 1984; 
Agurell et al., 1986). Outside of the

[[Page 53755]]

liver, metabolism in most tissues is considerably slow or does not 
occur. The elimination half-life of [Delta]\9\-THC ranges from 20 hours 
to between 10 and 13 days (Hunt and Jones, 1980). Lemberger et al. 
(1970) reported that the half-life of [Delta]\9\-THC ranged from 23-28 
hours in heavy marijuana users and up to 60 to 70 hours in na[iuml]ve 
users. The long elimination half-life of [Delta]\9\-THC is due to slow 
release of [Delta]\9\-THC and other cannabinoids from tissues and 
subsequent metabolism. Inactive carboxy metabolites of [Delta]\9\-THC 
have terminal half-lives of 50 hours to 6 days or more and serve as 
long-term markers in urine tests for marijuana use.
    Most of the absorbed [Delta]\9\-THC dose is eliminated in the feces 
and about 33% in urine. The glucuronide metabolite of [Delta]\9\-THC is 
excreted as the major urine metabolite along with 18 non-conjugated 
metabolites (Agurell et al., 1986).

Research Status and Test of Currently Accepted Medical Use for 
Marijuana

    According to the HHS, there are numerous human clinical studies 
with marijuana in the United States under FDA-regulated IND 
applications. Results of small clinical exploratory studies have been 
published in the medical literature. Approval of a human drug for 
marketing, however, is contingent upon FDA approval of a New Drug 
Application (NDA) or a Biologics License Application (BLA). According 
to the HHS, the FDA has not approved any drug product containing 
marijuana for marketing.
    The HHS noted that a drug may be found to have a medical use in 
treatment in the United States for purposes of the CSA if the drug 
meets the five elements described by the DEA in 1992. Those five 
elements ``are both necessary and sufficient to establish a prima facie 
case of currently accepted medical use'' in treatment in the United 
States.'' (57 FR 10499, 10504 (March 26, 1992)). This five-element 
test, which the HHS and DEA have utilized in all such analyses for more 
than two decades, has been upheld by the Court of Appeals. ACT, 15 F.3d 
at 1135. The five elements that characterize ``currently accepted 
medical use'' for a drug are summarized here and expanded upon in the 
discussion below:
    1. The drug's chemistry must be known and reproducible;
    2. There must be adequate safety studies;
    3. There must be adequate and well-controlled studies proving 
efficacy;
    4. The drug must be accepted by qualified experts; and
    5. Scientific evidence must be widely available.
    In its review (HHS, 2015), the HHS evaluated the five elements with 
respect to the currently available research for marijuana. The HHS 
concluded that marijuana does not meet any of the five elements--all of 
which must be demonstrated to find that a drug has a ``currently 
accepted medical use.'' A brief summary of the HHS's evaluation is 
provided below.
    Element #1: The drug's chemistry must be known and reproducible.
    ``The substance's chemistry must be scientifically established to 
permit it to be reproduced into dosages which can be standardized. The 
listing of the substance in a current edition of one of the official 
compendia, as defined by section 201(j) of the Food, Drug and Cosmetic 
Act, 21 U.S.C. 321(j), is sufficient generally to meet this 
requirement.'' 57 FR 10499, 10506 (March 26, 1992).
    Marijuana, as defined in the petition, includes all Cannabis 
strains. (For purposes of the CSA, marijuana includes all species of 
the genus Cannabis, including all strains therein \47\). Based on the 
definition of marijuana in the petition, the chemistry of marijuana is 
not reproducible such that a standardized dose can be created. Chemical 
constituents including [Delta]\9\-THC and other cannabinoids vary 
significantly in marijuana samples derived from different strains 
(Appendino et al., 2011). As a result, there will be significant 
differences in safety, biological, pharmacological, and toxicological 
parameters amongst the various marijuana samples. Due to the variation 
of the chemical composition in marijuana samples, it is not possible to 
reproduce a standardized dose when considering all strains together. 
The HHS does advise that if a specific Cannabis strain is cultivated 
and processed under controlled conditions, the plant chemistry may be 
consistent enough to derive reproducible and standardized doses.
---------------------------------------------------------------------------

    \47\ Although the CSA definition of marijuana refers only to the 
species ``Cannabis sativa L.,'' federal courts have consistently 
ruled that all species of the genus cannabis are included in this 
definition. See United States v. Kelly, 527 F.2d 961, 963-964 (9th 
Cir. 1976) (collecting and examining cases). The Single Convention 
(article 1, par. 1(c)) likewise defines the ``cannabis plant'' to 
mean ``any plant of the genus Cannabis.'' As explained above in the 
attachment titled ``Preliminary Note Regarding Treaty 
Considerations,'' 21 U.S.C. 811(d)(1) provides that, where a drug is 
subject to control under the Single Convention, the DEA 
Administrator must control the drug under the schedule he deems most 
appropriate to carry out such treaty obligations, without regard to 
the findings required by 21 U.S.C. 811(a) or 812(b) and without 
regard to the procedures prescribed by 21 U.S.C. 811(a) and (b).
---------------------------------------------------------------------------

    Element #2: There must be adequate safety studies.
    ``There must be adequate pharmacological and toxicological studies, 
done by all methods reasonably applicable, on the basis of which it 
could fairly and responsibly be concluded, by experts qualified by 
scientific training and experience to evaluate the safety and 
effectiveness of drugs, that the substance is safe for treating a 
specific, recognized disorder.'' 57 FR 10499, 10506 (March 26, 1992).
    The HHS stated that there are no adequate safety studies on 
marijuana. As indicated in their evaluation of Element #1, the 
considerable variation in the chemistry of marijuana complicates the 
safety evaluation. The HHS concluded that marijuana does not satisfy 
Element #2 for having adequate safety studies such that medical and 
scientific experts may conclude that it is safe for treating a specific 
ailment.
    Element #3: There must be adequate and well-controlled studies of 
efficacy.
    ``There must be adequate, well-controlled, well-designed, well-
conducted and well-documented studies, including clinical 
investigations, by experts qualified by scientific training and 
experience to evaluate the safety and effectiveness of drugs, on the 
basis of which it could be fairly and responsibly concluded by such 
experts that the substance will have the intended effect in treating a 
specific, recognized disorder.'' 57 FR 10499, 10506 (March 26, 1992).
    As indicated in the HHS's review of marijuana (HHS, 2015), there 
are no adequate or well-controlled studies that prove marijuana's 
efficacy. The FDA independently reviewed (FDA, 2015) publicly available 
clinical studies on marijuana published prior to February 2013 to 
determine if there were appropriate studies to determine marijuana's 
efficacy (please refer to FDA, 2015 and HHS, 2015 for more details). 
After review, the FDA determined that out of the identified articles, 
including those identified through a search of bibliographic references 
and 566 abstracts located on PubMed, 11 studies met the a priori 
selection criteria, including placebo control and double-blinding. FDA 
and HHS critically reviewed each of the 11 studies to determine if the 
studies met accepted scientific standards. FDA and HHS concluded that 
these studies do not ``currently prove efficacy of marijuana'' for any 
therapeutic indication due to limitations in the study designs. The HHS 
indicated that these studies could be used as proof of

[[Page 53756]]

concept studies, providing preliminary evidence on a proposed 
hypothesis involving a drug's effect.
    Element #4: The drug must be accepted by qualified experts.
    ``[A] consensus of the national community of experts, qualified by 
scientific training and experience to evaluate the safety and 
effectiveness of drugs, accepts the safety and effectiveness of the 
substance for use in treating a specific, recognized disorder. A 
material conflict of opinion among experts precludes a finding of 
consensus.'' 57 FR 10499, 10506 (March 26, 1992).
    The HHS concluded that there is currently no evidence of a 
consensus among qualified experts that marijuana is safe and effective 
in treating a specific and recognized disorder. The HHS indicated that 
medical practitioners who are not experts in evaluating drugs cannot be 
considered qualified experts (HHS, 2015; 57 FR 10499, 10505). Further, 
the HHS noted that the 2009 American Medical Association (AMA) report 
entitled, ``Use of Cannabis for Medicinal Purposes'' does not conclude 
that there is a currently accepted medical use for marijuana. HHS also 
pointed out that state-level ``medical marijuana'' laws do not provide 
evidence of such a consensus among qualified experts.
    Element #5: The scientific evidence must be widely available.
    ``In the absence of NDA approval, information concerning the 
chemistry, pharmacology, toxicology, and effectiveness of the substance 
must be reported, published, or otherwise widely available, in 
sufficient detail to permit experts, qualified by scientific training 
and experience to evaluate the safety and effectiveness of drugs, to 
fairly and responsibly conclude the substance is safe and effective for 
use in treating a specific, recognized disorder.'' 57 FR 10499, 10506 
(March 26, 1992).
    The HHS concluded that the currently available data and information 
on marijuana is not sufficient to allow scientific scrutiny of the 
chemistry, pharmacology, toxicology, and effectiveness. In particular, 
scientific evidence demonstrating the chemistry of a specific Cannabis 
strain that could provide standardized and reproducible doses is not 
available.

Petitioners' Major Comments in Relation to Factor 3 and the 
Government's Responses

    (1) The petitioners indicate that there is medical support and 
acceptance for the medical use of marijuana and stated that 
``[c]annabis has been accepted by the medical community as meeting the 
current, modern accepted standards for what constitutes medicine.'' 
(Exhibit B, page 13). On page 3 of the cover letter of the petition, 
the petitioners stated, ``The American medical community supports 
rescheduling, and there are safe pharmacy-based methods to dispense 
medical cannabis.''
    Furthermore, they stated that ``[i]n 2009, the American Medical 
Association (AMA) reversed its earlier position that supported 
[s]chedule I classification of cannabis. The AMA now supports 
investigation and clinical research of cannabis for medicinal use, and 
urged the federal government to reassess the [s]chedule I 
classification. The American College of Physicians [ACP] recently 
expressed similar support.'' In addition, they note that the Institute 
of Medicine (IOM) also documented the scientific basis and therapeutic 
effects of cannabis (Exhibit B, page 13).
    The DEA notes that the statements by the cited organizations (AMA, 
ACP, IOM) support more research into the potential medical properties 
associated with marijuana. The HHS did not find that the statements by 
these organizations provide evidence supporting a conclusion that 
adequate safety studies and adequate, well-controlled efficacy studies 
demonstrate the safety and efficacy of marijuana (HHS, 2015). The AMA's 
official policy on medicinal use of marijuana is as follows: ``Our AMA 
urges that marijuana's status as a federal [s]chedule I controlled 
substance be reviewed with the goal of facilitating the conduct of 
clinical research and development of cannabinoid-based medicines, and 
alternative delivery methods. This should not be viewed as an 
endorsement of state-based medical cannabis programs, the legalization 
of marijuana, or that scientific evidence on the therapeutic use of 
cannabis meets the current standards for a prescription drug product.'' 
(AMA, 2009).
    The DEA further notes that the 2013 AMA House of Delegates report 
states that, ``cannabis is a dangerous drug and as such is a public 
health concern.'' (AMA, 2013). In 2008, the ACP indicated that 
``further research is needed to compare cannabinoids' efficacy and 
safety with current treatments.'' (ACP, 2008). The ACP stated that, 
``ACP urges an evidence-based review of marijuana's status as a 
[s]chedule I controlled substance to determine whether it should be 
reclassified to a different schedule. This review should consider the 
scientific findings regarding marijuana's safety and efficacy in some 
clinical conditions as well as evidence on the health risks associated 
with marijuana consumption, particularly in its crude smoked form'' 
(ACP, 2008). The IOM, consistent with others in the medical community, 
endorses further studies into the potential therapeutic uses of 
marijuana, but did not advocate for medicinal use without further 
testing (IOM, 2009).
    As detailed in the HHS review, in order for a drug to be found to 
have a ``currently accepted medical use,'' it must be accepted by 
qualified experts. There is no evidence that there is a consensus among 
qualified experts that marijuana is safe and effective for use in 
treating a specific, recognized disorder.
    (2) The petitioners claim that, ``The chemistry of cannabis is 
known and reproducible'' (Exhibit B, page 6) and ``newer medicinal 
strains of cannabis are lower in THC and higher in the non-
psychoactive, more therapeutic cannabinoids, such as CBD, and CBN. 
These compounds further improved the efficacy of cannabis.'' (Exhibit 
B, page 10).
    As indicated by the HHS, the petitioners defined marijuana to 
include all Cannabis strains. As such, the chemistry of marijuana is 
not reproducible such that a standardized dose can be created. Chemical 
constituents including [Delta]\9\-THC and other cannabinoids vary 
significantly in different marijuana samples (Appendino et al., 2011). 
Furthermore, the HHS cited a published report that indicates that new 
substances in marijuana are continually being characterized (Pollastro 
et al., 2011). If there is significant variance in the chemical 
composition of marijuana between samples, it is not possible for the 
chemistry to be reproducible.
    Because the petition defines marijuana as including all cultivated 
strains, the DEA believes that the THC and CBD level of specific 
strains is not relevant to this consideration. In fact, the average 
[Delta]\9\-THC content in marijuana has steadily risen from 1995 to 
2014 as reported by the University of Mississippi Potency Monitoring 
Project, as presented in Factor 1. In 1995, the [Delta]\9\-THC content 
was 4% on average and by 2015, the average content of THC had risen to 
11.2% over a 20 year period. In the same time period, CBD and CBN 
percentages have ranged from 0.15% to 0.60% on average.
    The DEA also notes statements in the petitioners' document that 
support the conclusion reached by DEA and HHS that the chemistry of 
marijuana as broadly defined by the petitioners is not reproducible or 
well-defined. For example, the petitioners acknowledge that ``Cannabis 
is a complex plant, with several subtypes of cannabis.'' (Exhibit

[[Page 53757]]

B, page 6). The petitioners also acknowledge that ``the ratios of the 
various cannabinoids differ according to the plant strain, and, to some 
extent, how the plant is grown.'' (Exhibit B, page 12).
    (3) The petitioners stated in Exhibit B, page 8, that ``[o]verall, 
the 33 completed and published American controlled clinical trials with 
cannabis have studied its safety, routes of administration, and use in 
comparison with placebos, standard drugs, and in some cases dronabinol 
. . . ,'' and further cited a systematic review by Wang et al. (2008), 
that evaluated 23 randomized controlled trials and 8 observational 
studies, stating that, ``[o]f all the adverse events reported, 97 
percent were considered `not serious,' with the most commonly reported 
`dizziness.' ''
    The petitioners also cited in Exhibit B, page 8, ``There has been a 
long-term, prospective, federally funded cannabis clinical study 
jointly administered by National Institute on Drug Abuse (NIDA) and 
FDA. This study has been running for over 30 years without any 
demonstrable adverse outcomes related to chronic medicinal cannabis 
use.''
    As cited in the HHS recommendation document (HHS, 2015), the FDA 
conducted its own evaluation of the published clinical studies on the 
medical application of marijuana prior to February 2013 (FDA, 2015). 
Further details on the FDA review can be found in the published report 
(FDA, 2015). Based on the analysis, 11 studies were evaluated further 
and the FDA concluded that none of these studies ``meet the criteria 
required by the FDA to determine if marijuana is safe and effective in 
specific therapeutic areas.'' (page 6; FDA, 2015).
    The DEA has reviewed the systematic review by Wang et al. (2008) 
and notes that most of the studies included in the review were 
synthetic cannabinoid medicines (e.g. dronabinol) or cannabinoid 
extracts (e.g. Sativex[supreg]); these types of studies were excluded 
in the FDA review as the analysis focused solely on natural forms of 
marijuana (FDA, 2015). Wang et al. (2008) concluded that ``good safety 
and efficacy data on smoked cannabis are urgently needed.''
    With respect to the 30-year study cited by the petitioners (Russo 
et al., 2001) on page 8 of Exhibit B, it should be clarified that the 
referenced study was not jointly administered by NIDA and the FDA. As 
with other clinical studies, an IND application was approved by the FDA 
and marijuana was supplied by NIDA. The authors evaluated only 8 
patients over this period, of which one patient died. While the 
findings cited by the petitioners and authors (e.g. no adverse outcomes 
with long term marijuana use) are informative, conclusions on long-term 
use of marijuana cannot be applied to the general population.

Factor 4: Its History and Current Pattern of Abuse

    Marijuana continues to be the most widely used illicit drug. In 
2013, an estimated 24.6 million Americans age 12 or older were current 
(past month) illicit drug users. Of those, 19.8 million were current 
(past month) marijuana users. As of 2013, an estimated 114.7 million 
Americans age 12 and older had used marijuana or hashish in their 
lifetime and 33.0 million had used it in the past year.
    According to the NSDUH estimates, 3.0 million people age 12 or 
older used an illicit drug for the first time in 2014. Marijuana 
initiates totaled 2.6 million in 2014. Nearly half (46.8%) of the 2.6 
million new users were less than 18 years of age. In 2014, marijuana 
was used by 82.2% of current (past month) illicit drug users. In 2014, 
among past year marijuana users age 12 or older, 18.5% used marijuana 
on 300 or more days within the previous 12 months. This translates into 
6.5 million people using marijuana on a daily or almost daily basis 
over a 12-month period, a significant increase from the 3.1 million 
daily or almost daily users in 2006 and from the 5.7 million in just 
the previous year. In 2014, among past month marijuana users, 41.6% 
(9.2 million people) used the drug on 20 or more days in the past 
month, a significant increase from the 8.1 million in 2013.
    Marijuana is also the illicit drug with the highest numbers of past 
year dependence or abuse in the U.S. population. According to the 2014 
NSDUH report, of the 7.1 million persons aged 12 or older who were 
classified with illicit drug dependence or abuse, 4.2 million of them 
abused or were dependent on marijuana (representing 59.0% of all those 
classified with illicit drug dependence or abuse and 1.6% of the total 
U.S. non-institutionalized population aged 12 or older).
    According to the 2015 Monitoring the Future (MTF) survey, marijuana 
is used by a large percentage of American youths, and is the most 
commonly used illicit drug among American youth. Among students 
surveyed in 2015, 15.5% of 8th graders, 31.1% of 10th graders, and 
44.7% of 12th graders reported that they had used marijuana in their 
lifetime. In addition, 11.8%, 25.4%, and 34.9% of 8th, 10th, and 12th 
graders, respectively, reported using marijuana in the past year. A 
number of high school students reported daily use in the past month, 
including 1.1%, 3.0%, and 6.0% of 8th, 10th, and 12th graders, 
respectively.
    The prevalence of marijuana use and abuse is also indicated by 
criminal investigations for which drug evidence was analyzed in 
federal, state, and local forensic laboratories, as discussed above in 
Factor 1. The National Forensic Laboratory System (NFLIS), a DEA 
program, systematically collects drug identification results and 
associated information from drug cases submitted to and analyzed by 
federal, state, and local forensic laboratories. NFLIS data shows that 
marijuana was the most frequently identified drug from January 2001 
through December 2014. In 2014, marijuana accounted for 29.3% (432,989) 
of all drug exhibits in NFLIS.
    The high consumption of marijuana is being fueled by increasing 
amounts of domestically grown marijuana as well as increased amounts of 
foreign source marijuana being illicitly smuggled into the United 
States. In 2014, the Domestic Cannabis Eradication and Suppression 
Program (DCE/SP) reported that 3,904,213 plants were eradicated in 
outdoor cannabis cultivation areas compared to 2,597,798 in 2000, as 
shown above in Table 3. Significant quantities of marijuana were also 
eradicated from indoor cultivation operations. There were 396,620 
indoor plants eradicated in 2014 compared to 217,105 eradicated in 
2000. As shown in Table 2 above, in 2014, the National Seizure System 
(NSS) reported seizures of 1,767,741 kg of marijuana.

Petitioners' Major Comments in Relation to Factor 4 and the 
Government's Responses

    (1) The petitioners indicated that the history and current pattern 
of abuse is difficult to estimate since ``a large percentage of United 
States citizens'' have used marijuana at least once in their lifetime 
and some estimates have indicated that ``over 40 percent of the nation 
has tried the plant.'' Further, the petitioners stated that ``trying 
marijuana once should not be confused with a health problem, let alone 
a diagnosis of dependence or abuse.'' (Exhibit B, page 26).
    Marijuana usage numbers mentioned in both the HHS Recommendation 
and this DEA document include surveys from NSDUH and MTF. These surveys 
measure extent of use of marijuana. As mentioned in this Factor, 
according to the results of the 2013 NSDUH survey, 17.4% of past year 
marijuana users age 12 or older used marijuana on 300 or

[[Page 53758]]

more days within the previous 12 months. This indicates that 5.7 
million people used marijuana on a daily or almost daily basis over 
this 12-month period, which is a 1.8-fold increase from the 3.1 million 
daily or almost daily users in 2006. Furthermore, 6% of all twelfth 
graders in the United States reported daily use of marijuana in the 
2015 MTF survey. These data strongly indicate that there is a 
significant portion of the U.S. population using marijuana on a daily 
basis.
    (2) As stated in Exhibit B on page 26, subpart A, ``Rates of 
dependence or abuse are remarkably low'' and further suggest that 
``[i]nterviews for the National Longitudinal Alcohol Epidemiological 
Survey ([NLAES] [sic] and National Epidemiological Survey on Alcohol 
and Related Conditions ([NESARC] [sic] each confirm that rates of 
dependence or abuse of cannabis have never exceed (sic) two percent in 
a given year.''
    The authors of study cited by the petitioners (Compton et al., 
2004) concluded that a higher percentage of American adults had a 
marijuana use disorder in 2001-2002 (1.5%) than in 1991-1992 (1.2%). 
Compton et al. (2004) noted that the marijuana use disorder increase of 
0.3% over the 10 year period would equate to an increase from 2.2 
million people to 3 million people in the United States. The 
petitioners failed to explain the impact of 1.5% (or less than 2 
percent) of the U.S. population having a marijuana use disorder. In 
order to put these numbers into perspective, the DEA reviewed the 
literature and found that non-medical prescription drug use and abuse 
rates were examined in the same NLAES and NESARC (1991-1992 and 2001-
2002) populations (Blanco et al., 2007). Blanco et al (2007) examined 
non-medical prescription drug use and abuse rates from the periods of 
1991-1992 and 2001-2002. In 1991 through 1992, the prevalence of non-
medical prescription drug (opioid, stimulant, and tranquilizer) abuse 
and dependence was 0.1%. Non-medical prescription drug (primarily 
opioid-based drugs) abuse and dependence increased to 0.3% in 2001 
through 2002. Therefore, in the same 2001-2002 NLAES and NESARC 
populations, the percentage of people with a marijuana use disorder was 
approximately five-fold higher (1.5% versus 0.3%) than those with 
opioid abuse and dependence resulting from non-medical prescription 
drug use.
    Further, Volkow et al. (2014) reported that in long-term or heavy 
marijuana users, 9% of users become addicted to marijuana. This 
percentage increases to 17% when marijuana use starts in adolescence 
and it increases to 25 to 50% of those who are daily users.

Factor 5: The Scope, Duration, and Significance of Abuse

    Abuse of marijuana is widespread and significant. As previously 
noted, according to the NSDUH, in 2014, an estimated 117.2 million 
Americans (44.2%) age 12 or older had used marijuana or hashish in 
their lifetime, 35.1 million (13.2%) had used it in the past year, and 
22.2 million (8.4%) had used it in the past month. Past year and past 
month marijuana use has increased significantly since 2013. Past month 
marijuana use is highest among 18-21 year olds and it declines among 
those 22 years of age and older. In 2014, an estimated 18.5% of past 
year marijuana users age 12 or older used marijuana on 300 or more days 
within the past 12 months. This translates into 6.5 million persons 
using marijuana on a daily or almost daily basis over a 12-month 
period. In 2014, an estimated 41.6% (9.2 million) of past month 
marijuana users age 12 or older used the drug on 20 or more days in the 
past month (SAMHSA, NSDUH). Chronic use of marijuana is associated with 
a number of health risks (see Factors 2 and 6).
    Furthermore, the average percentage of [Delta]\9\-THC in seized 
marijuana has increased over the past two decades (The University of 
Mississippi Potency Monitoring Project). Additional studies are needed 
to clarify the impact of greater potency, but one study shows that 
higher levels of [Delta]\9\-THC in the body are associated with greater 
psychoactive effects (Harder and Rietbrock, 1997), which can be 
correlated with higher abuse potential (Chait and Burke, 1994).
    TEDS data show that in 2013, marijuana/hashish was the primary 
substance of abuse in 16.8% of all admissions to substance abuse 
treatment among patients age 12 and older. TEDS data also show that 
marijuana/hashish was the primary substance of abuse for 77.0% of all 
12- to 14-year-olds admitted for drug treatment and 75.5% of all 15- to 
17-year-olds admitted for drug treatment in 2013. Among the 281,991 
admissions to drug treatment in 2013 in which marijuana/hashish was the 
primary drug, the average age at admission was 25 years and the peak 
age cohort was 15 to 17 years (22.5%). Thirty-nine percent of the 
281,991 primary marijuana/hashish admissions (35.9%) were under the age 
of 20.
    In summary, the recent statistics from these various surveys and 
databases (see Factor 1 for more details) demonstrate that marijuana 
continues to be the most commonly used illicit drug, with large 
incidences of heavy use and dependence in teenagers and young adults.

Petitioners' Major Comment in Relation to Factor 5 and DEA's Response

    (1) Petitioners' contend that, ``The prevalence and significance of 
potential abuse are limited for cannabis, especially in relation to 
other [s]chedule II substances.'' The petitioners cited results from 
the 1990 NIDA Household Survey on Drug Abuse and indicated that, ``more 
than four out of five people who had used cannabis in the previous year 
reported no problems related to the drug.'' (Exhibit B, page 28).
    The prevalence of marijuana usage and marijuana dependence is 
significant in the United States. The 2014 NSDUH findings indicate that 
there are approximately 6.5 million Americans using marijuana on a 
daily or almost daily basis. Further, Volkow et al. (2014) reported 
that in long-term or heavy marijuana users, 9% of users become addicted 
to marijuana. Among those who began using marijuana in adolescence, 
marijuana dependence increases to 17%, and it further increases to 25 
to 50% of daily users that started using marijuana during adolescence. 
These collective findings indicate that there is considerable 
significance associated with marijuana use and abuse since 9% of users 
become addicted to marijuana, 25 to 50% of daily marijuana users 
started during adolescence, and prevalence of usage is significantly 
high based on the data presented from Volkow et al (2014) and the 2014 
NSDUH survey.

Factor 6: What, if any, Risk There is to the Public Health

    In its recommendation, the HHS discussed public health risks 
associated with acute and chronic marijuana use in Factor 6. Public 
health risks as measured by emergency department visits and drug 
treatment admissions are discussed by HHS and DEA in Factors 1, 4, and 
5. Similarly, Factor 2 discusses marijuana's pharmacology and presents 
some of the adverse health effects associated with use. Marijuana use 
may affect the physical and/or psychological functioning of an 
individual user, but may also have broader public impacts including 
driving impairments and fatalities from car accidents.

Risks From Acute Use of Marijuana

    As discussed in the HHS review document (HHS, 2015), acute usage of 
marijuana impairs psychomotor performance including motor control and 
impulsivity, risk taking and executive function (Ramaekers et al., 
2004; Ramaekers et al., 2006). In a

[[Page 53759]]

minority of individuals using marijuana, dysphoria, prolonged anxiety, 
and psychological distress may be observed (Haney et al., 1999). The 
DEA further notes a recent review of acute marijuana effects (Wilkinson 
et al., 2014) that reported impaired neurological function including 
altered perception, paranoia, delayed response time, and memory 
deficits.
    In its recommendation, HHS references a meta-analysis conducted by 
Li et al (2012) where the authors concluded that psychomotor 
impairments associated with acute marijuana usage have also been 
associated with increased risk of car accidents with individuals 
experiencing acute marijuana intoxication (Li et al., 2012; HHS, 2015). 
The DEA further notes more recent studies examining the risk associated 
with marijuana use and driving. Younger drivers (under 21) have been 
characterized as the highest risk group associated with marijuana use 
and driving (Whitehill et al., 2014). Furthermore, in 2013, marijuana 
was found in 13% of the drivers involved in automobile-related fatal 
accidents (McCartt, 2015). The potential risk of automobile accidents 
associated with marijuana use appears to be increasing since there has 
been a steady increase in individuals intoxicated with marijuana over 
the past 20 years (Wilson et al., 2014). However, a recent study 
commissioned by the National Highway Traffic Safety Administration 
(NHTSA) reported that when adjusted for confounders (e.g., alcohol use, 
age, gender, ethnicity), there was not a significant increase in crash 
risk (fatal and nonfatal, n = 2,682) associated with marijuana use 
(Compton and Berning, 2015).
    The DEA also notes recent studies examining unintentional exposures 
of children to marijuana (Wang et al., 2013; 2014). Wang et al. (2013) 
reviewed emergency department (ED) visits at a children's hospital in 
Colorado from January 1, 2005 to December 31, 2011. As stated by the 
authors, in 2000 Colorado passed Amendment 20 which allowed for the use 
of marijuana. Following the passage of ``a new Justice Department 
policy'' instructing ``federal prosecutors not to seek arrest of 
medical marijuana users and suppliers as long as they conform to state 
laws'' (as stated in Wang et al., 2013), 14 patients in Colorado under 
the age of 12 were admitted to the ED for the unintended use of 
marijuana over a 27 month period. Prior to the passage of this policy, 
from January 1, 2005 to September 30, 2009 (57 months), there were no 
pediatric ED visits due to unintentional marijuana exposure (Wang et 
al., 2013). The DEA also notes a larger scale evaluation of pediatric 
exposures using the National Poison Data System (Wang et al., 2014). 
That study reported that there were 985 unintentional marijuana 
exposures in children (9 years and younger) between January 1, 2005 to 
December 31, 2011. The authors stratified the ED visits by states with 
laws allowing medical use of marijuana, states transitioning to 
legalization for medical use, and states with no such laws. Out of the 
985 exposures, 495 were in non-legal states (n = 33 states), 93 in 
transitional states (n = 8 states), and 396 in ``legal'' states (n = 9 
states). The authors reported that there was a twofold increase (OR = 
2.1) in moderate or major effects in children with unintentional 
marijuana use and a threefold increase (OR = 3.4) in admissions to 
critical care units in states allowing medical use of marijuana, in 
comparison to non-legal states.

Risks Associated With Chronic Use of Marijuana

    The HHS noted that a major risk from chronic marijuana use is a 
distinctive withdrawal syndrome, as described in the 2013 DSM-5. The 
HHS analysis also quoted the following description of risks associated 
with marijuana [cannabis] abuse from the DSM-5:

    Individuals with cannabis use disorder may use cannabis 
throughout the day over a period of months or years, and thus may 
spend many hours a day under the influence. Others may use less 
frequently, but their use causes recurrent problems related to 
family, school, work, or other important activities (e.g., repeated 
absences at work; neglect of family obligations). Periodic cannabis 
use and intoxication can negatively affect behavioral and cognitive 
functioning and thus interfere with optimal performance at work or 
school, or place the individual at increased physical risk when 
performing activities that could be physically hazardous (e.g. 
driving a car; playing certain sports; performing manual work 
activities, including operating machinery). Arguments with spouses 
or parents over the use of cannabis in the home, or its use in the 
presence of children, can adversely impact family functioning and 
are common features of those with cannabis use disorder. Last, 
individuals with cannabis use disorder may continue using marijuana 
despite knowledge of physical problems (e.g. chronic cough related 
to smoking) or psychological problems (e.g. excessive sedation or 
exacerbation of other mental health problems) associated with its 
use. (HHS 2015, page 34).

    The HHS stated that chronic marijuana use produces acute and 
chronic adverse effects on the respiratory system, memory and learning. 
Regular marijuana smoking can produce a number of long-term pulmonary 
consequences, including chronic cough and increased sputum (Adams and 
Martin, 1996), and histopathologic abnormalities in bronchial 
epithelium (Adams and Martin, 1996).

Marijuana as a ``Gateway Drug''

    The HHS reviewed the clinical studies evaluating the gateway 
hypothesis in marijuana and found them to be limited. The primary 
reasons were: (1) Recruited participants were influenced by social, 
biological, and economic factors that contribute to extensive drug 
abuse (Hall and Lynskey, 2005), and (2) most studies testing the 
gateway drug hypothesis for marijuana use the determinative measure any 
use of an illicit drug rather than applying DSM-5 criteria for drug 
abuse or dependence (DSM-5, 2013).
    The HHS cited several studies where marijuana use did not lead to 
other illicit drug use (Kandel and Chen, 2000; von Sydow et al., 2002; 
Nace et al., 1975). Two separate longitudinal studies with adolescents 
using marijuana did not demonstrate an association with use of other 
illicit drugs (Kandel and Chen, 2000; von Sydow et al., 2002).
    It was noted by the HHS that, when evaluating the gateway 
hypothesis, differences appear when examining use versus abuse or 
dependence of other illicit drugs. Van Gundy and Rebellon (2010) 
reported that there was a correlation between marijuana use in 
adolescence and other illicit drug use in early adulthood, but when 
examined in terms of drug abuse of other illicit drugs, age-linked 
stressors and social roles were confounders in the association. 
Degenhardt et al. (2009) reported that marijuana use often precedes use 
of other illicit drugs, but dependence involving drugs other than 
marijuana frequently correlated with higher levels of illicit drug 
abuse. Furthermore, Degenhardt et al. (2010) reported that in countries 
with lower prevalence of marijuana usage, use of other illicit drugs 
before marijuana was often documented.
    Based on these studies among others, the HHS concluded that 
although many individuals with a drug abuse disorder may have used 
marijuana as one of their first illicit drugs, this does not mean that 
individuals initiated with marijuana inherently will go on to become 
regular users of other illicit drugs.

[[Page 53760]]

Petitioners' Major Comment in Relation to Factor 6 and the Government's 
Responses

    (1) The petitioners commented that marijuana does not significantly 
impact social behavior in domains such as motivation, driving, 
aggression, or hostility (Exhibit B, pages 30-41).
    The HHS concluded that ``Marijuana's acute effects can 
significantly interfere with a person's ability . . . to operate motor 
vehicles.'' (HHS, 2015) As mentioned in this factor, there is a 
significant risk with marijuana use and driving. Marijuana was found in 
13% of drivers involved in automobile fatal accidents (McCartt, 2015). 
Furthermore, in a meta-analysis conducted by Li et al. (2011), an 
association was identified between marijuana use by the driver and an 
increased risk of getting into a car accident.
    The DEA notes that the petitioners only considered whether 
marijuana creates social problems, and did not consider physiological 
changes and impacts that also should be evaluated in determining the 
risk to public health. The HHS and DEA considered the public health 
impacts of such physiological effects, as discussed in this factor and 
others above. Marijuana may result in acute cardiovascular toxicity as 
indicated by recent reviews examining these associations (Hackham, 
2015; Panayiotides, 2015). There is a possible association between 
frequent, long-term marijuana use and increased risk of testicular germ 
cell cancers and some evidence that chronic marijuana use may lead to 
lung cancer although the evidence is inconsistent. Furthermore, a more 
recent risk is the increase in ED visits of children unintentionally 
exposed to marijuana with increased risk factors for major adverse 
effects or admission to critical care units in states that have 
legalized marijuana for medical purposes (Wang et al., 2014).

Factor 7: Its Psychic or Physiological Dependence Liability

Physiological (Physical) Dependence in Humans

    The HHS stated that heavy and chronic use of marijuana can lead to 
physical dependence (DSM-5, 2013; Budney and Hughes, 2006; Haney et 
al., 1999). Tolerance is developed following repeated administration of 
marijuana and withdrawal symptoms are observed as following 
discontinuation of marijuana usage (HHS, 2015).
    The HHS mentioned that tolerance can develop to some of marijuana's 
effects, but does not appear to develop with respect to the 
psychoactive effects. It is believed that lack of tolerance to 
psychoactive effects may relate to electrophysiological data 
demonstrating that chronic [Delta]\9\-THC administration does not 
affect increased neuronal firing in the ventral tegmental area, a brain 
region that plays a critical role in drug reinforcement and reward (Wu 
and French, 2000). Humans can develop tolerance to marijuana's 
cardiovascular, autonomic, and behavioral effects (Jones et al., 1981). 
Tolerance to some behavioral effects appears to develop with heavy and 
chronic use, but not with occasional usage. Ramaekers et al. (2009) 
reported that following acute administration of marijuana, occasional 
marijuana users still exhibited impairments in tracking and attention 
tasks whereas performance of heavy users on the these tasks was not 
affected. In a follow-up study with the same subjects that participated 
in the study by Ramaekers et al. (2009), a neurophysiological 
assessment was conducted where event-related potentials (ERPs) were 
measured using electroencephalography (EEG) (Theunissen et al., 2012). 
Similar to the earlier results, the heavy marijuana users (n = 11; 
average of 340 marijuana uses per year) had no changes in their ERPs 
with the acute marijuana exposure. However, occasional users (n = 10; 
average of 55 marijuana uses per year) had significant decreases in the 
amplitude of an ERP component (categorized as P100) on tracking and 
attention tasks and ERP amplitude change is indicative of a change in 
brain activity (Theunissen et al., 2012).
    The HHS indicated that down-regulation of cannabinoid receptors may 
be a possible mechanism for tolerance to marijuana's effects (Hirvonen 
et al., 2012; Gonzalez et al., 2005; Rodriguez de Fonseca et al., 1994; 
Oviedo et al., 1993).
    As indicated by the HHS, the most common withdrawal symptoms in 
heavy, chronic marijuana users are sleep difficulties, decreased 
appetite or weight loss, irritability, anger, anxiety or nervousness, 
and restlessness (Budney and Hughes, 2006; Haney et al., 1999). As 
reported by HHS, most marijuana withdrawal symptoms begin within 24-48 
hours of discontinuation, peak within 4-6 days, and last for 1-3 weeks.
    The HHS pointed out that the American Psychiatric Association's 
(APA's) Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) 
included a list of withdrawal symptoms following marijuana [cannabis] 
use (DSM-5, 2013). The DEA notes that a DSM-5 working group report 
indicated that marijuana withdrawal symptoms were added to DSM-5 (they 
were not previously included in DSM-IV) because marijuana withdrawal 
has now been reliably presented in several studies (Hasin et al., 
2013). In short, marijuana withdrawal signs are reported in up to one-
third of regular users and between 50% and 90% of heavy users (Hasin et 
al., 2013). According to DSM-5 criteria, in order to be characterized 
as having marijuana withdrawal, an individual must develop at least 
three of the seven symptoms within one week of decreasing or stopping 
the heavy and prolonged use (DSM-5, 2013). These seven symptoms are: 
(1) Irritability; anger or aggression, (2) nervousness or anxiety, (3) 
sleep difficulty, (4) decreased appetite or weight loss, (5) 
restlessness, (6) decreased mood, (7) somatic symptoms causing 
significant discomfort (DSM-5, 2013).

Psychological (Psychic) Dependence in Humans

    High levels of psychoactive effects such as positive reinforcement 
correlate with increased marijuana abuse and dependence (Scherrer et 
al., 2009; Zeiger et al., 2010). Epidemiological marijuana use data 
reported by NSDUH, MTF, and TEDS support this assertion as presented in 
the HHS 2015 review of marijuana and updated by the DEA. According to 
the findings in the 2014 NSDUH survey, an estimated 9.2 million 
individuals 12 years and older used marijuana daily or almost daily (20 
or more days within the past month). In the 2015 MTF report, daily 
marijuana use (20 or more days within the past 30 days) in 8th, 10th, 
and 12th graders is 1.1%, 3.0%, and 6.0%, respectively.
    The 2014 NSDUH report stated that 4.2 million persons were 
classified with dependence on or abuse of marijuana in the past year 
(representing 1.6% of the total population age 12 or older, and 59.0% 
of those classified with illicit drug dependence or abuse) based on 
criteria specified in the Diagnostic and Statistical Manual of Mental 
Disorders, 4th edition (DSM-IV). Furthermore, of the admissions to 
licensed substance abuse facilities, as presented in TEDS, marijuana/
hashish was the primary substance of abuse for; 18.3% (352,297) of 2011 
admissions; 17.5% (315,200) of 2012 admissions; and 16.8% (281,991) of 
2013 admissions. Of the 281,991 admissions in 2013 for marijuana/
hashish as the primary substance, 24.3% used marijuana/hashish daily. 
Among admissions to treatment for marijuana/hashish as the primary 
substance in 2013, 27.4% were ages 12 to 17 years and 29.7% were ages 
20 to 24 years.

[[Page 53761]]

Petitioners' Major Comment in Relation to Factor 7 and the Government's 
Response

    (1) The petitioners stated, ``There is no severe physical 
withdrawal syndrome associated with cannabis. Cannabis addiction is 
amenable to treatment.'' (Exhibit B, page 10). The petitioners further 
indicated that marijuana ``may be psychologically addictive, but much 
less so than other Scheduled [sic] II drugs,'' (Exhibit B, page 10) and 
that there is a low risk of dependence associated with marijuana use. 
Petitioners further stated in Exhibit B, page 23, ``Cannabis has low 
relative dependence risk and does not reach the severity associated 
with other drugs.''
    The HHS states that marijuana withdrawal syndrome ``appears to be 
mild compared to classical alcohol and barbiturate withdrawal 
syndromes'' and is similar in magnitude and time course to tobacco 
withdrawal syndrome.
    DSM-5 now recognizes and describes a marijuana [cannabis] 
withdrawal syndrome. The lifetime risk of dependence to marijuana is 
approximately 9% among heavy or long-term users (Volkow et al., 2014). 
Marijuana results in tolerance and withdrawal as described earlier in 
this Factor 7. The data from NSDUH indicate that there is constant 
desire for marijuana as noted by the consistently high numbers of 
current daily users in adults and adolescents. Marijuana use also 
persists despite problems associated with the drug. Changes in IQ have 
been noted in adolescent-onset, chronic or dependent marijuana users, 
in addition to withdrawal symptoms. However, marijuana use has not 
declined in the time that usage of this drug has been monitored. 
Additionally, there has been an increase in content of the primary 
psychoactive chemical, [Delta]\9\-THC, in marijuana samples analyzed by 
the University of Mississippi's Potency Monitoring Project, suggesting 
preference for marijuana strains with higher levels of [Delta]\9\-THC.

Factor 8: Whether the Substance is an Immediate Precursor of a 
Substance Already Controlled Under the CSA

    Marijuana is not an immediate precursor of another controlled 
substance.

Determination

    After consideration of the eight factors discussed above and of the 
HHS's Recommendation, the DEA finds that marijuana meets the three 
criteria for placing a substance in schedule I of the CSA under 21 
U.S.C. 812(b)(1):
    1. Marijuana has a high potential for abuse.
    The HHS concluded that marijuana has a high potential for abuse 
based on a large number of people regularly using marijuana, its 
widespread use, and the vast amount of marijuana that is available 
through illicit channels.
    Marijuana is the most abused and trafficked illicit substance in 
the United States. Approximately 22.2 million individuals in the United 
States (8.4% of the United States population) were past month users of 
marijuana according to the 2014 NSDUH survey. A 2015 national survey 
(Monitoring the Future) that tracks drug use trends among high school 
students showed that by 12th grade, 21.3% of students reported using 
marijuana in the past month, and 6.0% reported having used it daily in 
the past month. In 2011, SAMHSA's Drug Abuse Warning Network (DAWN) 
reported that marijuana was mentioned in 36.4% of illicit drug-related 
emergency department (ED) visits, corresponding to 455,668 out of 
approximately 1.25 million visits. The Treatment Episode Data Set 
(TEDS) showed that 16.8% of non-private substance-abuse treatment 
facility admissions in 2013 were for marijuana as the primary drug.
    Marijuana has dose-dependent reinforcing effects that encourage its 
abuse. Both clinical and preclinical studies have demonstrated that 
marijuana and its principle psychoactive constituent, [Delta]\9\-THC, 
possess the pharmacological attributes associated with drugs of abuse. 
They function as discriminative stimuli and as positive reinforcers to 
maintain drug use and drug-seeking behavior. Additionally, use of 
marijuana can result in psychological dependence.
    2. Marijuana has no currently accepted medical use in treatment in 
the United States.
    The HHS stated that the FDA has not approved an NDA for marijuana. 
The HHS noted that there are opportunities for scientists to conduct 
clinical research with marijuana and there are active INDs for 
marijuana, but marijuana does not have a currently accepted medical use 
in the United States, nor does it have an accepted medical use with 
severe restrictions.
    FDA approval of an NDA is not the sole means through which a drug 
can be determined to have a ``currently accepted medical use'' under 
the CSA. Applying the five-part test summarized below, a drug has a 
currently accepted medical use if all of the following five elements 
have been satisfied. As detailed in the HHS evaluation and as set forth 
below, none of these elements has been fulfilled for marijuana:
    i. The drug's chemistry must be known and reproducible.
    Chemical constituents including [Delta]\9\-THC and other 
cannabinoids in marijuana vary significantly in different marijuana 
strains. In addition, the concentration of [Delta]\9\-THC and other 
cannabinoids may vary between strains. Therefore the chemical 
composition among different marijuana samples is not reproducible. Due 
to the variation of the chemical composition in marijuana strains, it 
is not possible to derive a standardized dose. The HHS does advise that 
if a specific Cannabis strain is cultivated and processed under 
controlled conditions, the plant chemistry may be consistent enough to 
derive standardized doses.
    ii. There must be adequate safety studies.
    There are not adequate safety studies on marijuana for use in any 
specific, recognized medical condition. The considerable variation in 
the chemistry of marijuana results in differences in safety, 
biological, pharmacological, and toxicological parameters amongst the 
various marijuana samples.
    iii. There must be adequate and well-controlled studies proving 
efficacy.
    There are no adequate and well-controlled studies that determine 
marijuana's efficacy. In an independent review performed by the FDA of 
publicly available clinical studies on marijuana (FDA, 2015), FDA 
concluded that these studies do not have enough information to 
``currently prove efficacy of marijuana'' for any therapeutic 
indication.
    iv. The drug must be accepted by qualified experts.
    At this time, there is no consensus of opinion among experts 
concerning the medical utility of marijuana for use in treating 
specific recognized disorders.
    v. The scientific evidence must be widely available.
    The currently available data and information on marijuana is not 
sufficient to address the chemistry, pharmacology, toxicology, and 
effectiveness. The scientific evidence regarding marijuana's chemistry 
with regard to a specific cannabis strain that could be formulated into 
standardized and reproducible doses is not currently available.
    3. There is a lack of accepted safety for use of marijuana under 
medical supervision.
    Currently, there are no FDA-approved marijuana products. The HHS 
also concluded that marijuana does not have a currently accepted 
medical use in treatment in the United States or a currently accepted 
medical use with severe restrictions. According to the HHS, the FDA is 
unable to conclude that marijuana has an acceptable level of

[[Page 53762]]

safety in relation to its effectiveness in treating a specific and 
recognized disorder due to lack of evidence with respect to a 
consistent and reproducible dose that is contamination free. The HHS 
indicated that marijuana research investigating potential medical use 
should include information on the chemistry, manufacturing, and 
specifications of marijuana. The HHS further indicated that a procedure 
for delivering a consistent dose of marijuana should also be developed. 
Therefore, the HHS concluded that marijuana does not have an acceptable 
level of safety for use under medical supervision.

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[FR Doc. 2016-17954 Filed 8-11-16; 8:45 am]
 BILLING CODE 4410-09-P