[Federal Register Volume 76, Number 131 (Friday, July 8, 2011)]
[Proposed Rules]
[Pages 40552-40589]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-16994]



[[Page 40551]]

Vol. 76

Friday,

No. 131

July 8, 2011

Part IV





Department of Justice





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Drug Enforcement Administration





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21 CFR Chapter II





Denial of Petition To Initiate Proceedings To Reschedule Marijuana; 
Proposed Rule

  Federal Register / Vol. 76 , No. 131 / Friday, July 8, 2011 / 
Proposed Rules  

[[Page 40552]]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Chapter II

[Docket No. DEA-352N]


Denial of Petition To Initiate Proceedings To Reschedule 
Marijuana

AGENCY: Drug Enforcement Administration (DEA), Department of Justice.

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

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SUMMARY: By letter dated June 21, 2011, the Drug Enforcement 
Administration (DEA) denied a petition to initiate rulemaking 
proceedings to reschedule marijuana.\1\ Because 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 (denying the 
petition), along with the supporting documentation that was attached to 
the letter.
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    \1\ 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.''

FOR FURTHER INFORMATION CONTACT: Imelda L. Paredes, Office of Diversion 
Control, Drug Enforcement Administration, 8701 Morrissette Drive, 
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Springfield, Virginia 22152; Telephone (202) 307-7165.

SUPPLEMENTARY INFORMATION: 

June 21, 2011.

    Dear Mr. Kennedy:
    On October 9, 2002, you petitioned the Drug Enforcement 
Administration (DEA) to initiate rulemaking proceedings under the 
rescheduling provisions of the Controlled Substances Act (CSA). 
Specifically, you petitioned DEA to have marijuana removed from 
schedule I of the CSA and rescheduled as cannabis in schedule III, IV 
or V.
    You requested that DEA remove marijuana from schedule I based on 
your assertion that:
    (1) Cannabis has an accepted medical use in the United States;
    (2) Cannabis is safe for use under medical supervision;
    (3) Cannabis has an abuse potential lower than schedule I or II 
drugs; and
    (4) Cannabis has a dependence liability that is lower than schedule 
I or II drugs.
    In accordance with the CSA rescheduling provisions, after gathering 
the necessary data, DEA requested a scientific and medical evaluation 
and scheduling recommendation from the Department of Health and Human 
Services (DHHS). DHHS 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, DHHS recommended that marijuana remain in schedule I. The 
scientific and medical evaluation and scheduling recommendation that 
DHHS submitted to DEA is attached hereto.
    Based on the DHHS evaluation and all other relevant data, DEA has 
concluded that there is no substantial evidence that marijuana should 
be removed from schedule I. A document prepared by DEA addressing these 
materials in detail also is attached hereto. 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 DHHS evaluation 
and the additional data gathered by DEA show that marijuana has a high 
potential for abuse.
    (2) Marijuana has no currently accepted medical use in treatment in 
the United States. According to established case law, marijuana has no 
``currently accepted medical use'' because: 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 U.S. Food and Drug Administration 
(FDA)-approved marijuana products, nor is marijuana under a New Drug 
Application (NDA) evaluation at the FDA for any indication. 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.
    You also argued that cannabis has a dependence liability that is 
lower than schedule I or II drugs. Findings as to the physical or 
psychological dependence of a drug are only one of eight factors to be 
considered. As discussed further in the attached documents, DHHS states 
that long-term, regular use of marijuana can lead to physical 
dependence and withdrawal following discontinuation as well as psychic 
addiction or dependence.
    The statutory mandate of 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).
    Accordingly, and as set forth in detail in the accompanying DHHS 
and DEA documents, there is no statutory basis under the CSA for DEA to 
grant your petition to initiate rulemaking proceedings to reschedule 
marijuana. Your petition is, therefore, hereby denied.
    Sincerely,

Michele M. Leonhart,
Administrator.

    Attachments:

Marijuana. Scheduling Review Document: Eight Factor Analysis

Basis for the recommendation for maintaining marijuana in schedule I 
of the Controlled Substances Act

Date: June 30, 2011

Michele M. Leonhart
Administrator

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

December 6, 2006.
The Honorable Karen P. Tandy
Administrator, Drug Enforcement Administration, U.S. Department of 
Justice, Washington, D.C. 20537

    Dear Ms. Tandy:
    This is in response to your request of July 2004, and pursuant 
to the Controlled Substances Act (CSA), 21 U.S.C. 811(b), (c), and 
(f), the Department of Health and Human Services (DHHS) recommends 
that marijuana continue to be subject to control under Schedule I of 
the CSA.
    Marijuana is currently controlled under Schedule I of the CSA. 
Marijuana continues to meet the three criteria for placing a 
substance in Schedule I of the CSA under 21 U.S.C. 812(b)(l). As 
discussed in the attached analysis, marijuana has a high potential 
for abuse, has no currently accepted medical use in treatment in the 
United States, and has a lack of an accepted level of safety for use 
under medical supervision. Accordingly, HHS recommends that 
marijuana continue to be subject to control under Schedule I of the 
CSA. Enclosed is a document prepared by FDA's Controlled Substance 
Staff that is the basis for this recommendation.
    Should you have any questions regarding this recommendation, 
please contact Corinne P. Moody, of the Controlled Substance Staff, 
Center for Drug Evaluation and Research. Ms. Moody can be reached at 
301-827-1999.

    Sincerely yours,
John O. Agwunobi,
Assistant Secretary for Health.

Enclosure:

[[Page 40553]]

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

BASIS FOR THE RECOMMENDATION FOR MAINTAINING MARIJUANA IN SCHEDULE I OF 
THE CONTROLLED SUBSTANCES ACT

    On October 9, 2002, the Coalition for Rescheduling Cannabis 
(hereafter known as the Coalition) submitted a petition to the Drug 
Enforcement Administration (DEA) requesting that proceedings be 
initiated to repeal the rules and regulations that place marijuana 
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 an abuse 
potential and a dependency liability that is lower than Schedule I 
or II drugs. The petition requests that marijuana be rescheduled as 
``cannabis'' in either Schedule III, IV, or V of the CSA. In July 
2004, the DEA Administrator requested that the 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).
    In accordance with 21 U.S.C. 811(b), DEA has gathered 
information related to the control of marijuana (Cannabis sativa) 
\2\ under the CSA. Pursuant to 21 U.S.C. 811(b), the Secretary 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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    \2\ 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 there from), 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

    The first factor the Secretary must consider is marijuana's 
actual or relative potential for abuse. The term ``abuse'' is not 
defined in the CSA. However, the legislative history of the CSA 
suggests the following in determining whether a particular drug or 
substance has a potential for abuse:
    a. 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.
    b. There is a significant diversion of the drug or substance 
from legitimate drug channels.
    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.
    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.

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.

    In considering these concepts in a variety of scheduling 
analyses over the last three decades, the Secretary has analyzed a 
range of factors when assessing the abuse liability of a substance. 
These factors have included the prevalence and frequency of use in 
the general public and in specific sub-populations, the amount of 
the material that is available for illicit use, the ease with which 
the substance may be obtained or manufactured, the reputation or 
status of the substance ``on the street,'' as well as evidence 
relevant to population groups that may be at particular risk.
    Abuse liability is a complex determination with many dimensions. 
There is no single test or assessment procedure that, by itself, 
provides a full and complete characterization. Thus, no single 
measure of abuse liability is ideal. Scientifically, a comprehensive 
evaluation of the relative abuse potential of a drug substance can 
include consideration of the drug's receptor binding affinity, 
preclinical pharmacology, reinforcing effects, discriminative 
stimulus effects, dependence producing potential, pharmacokinetics 
and route of administration, toxicity, assessment of the clinical 
efficacy-safety database relative to actual abuse, clinical abuse 
liability studies, and the public health risks following 
introduction of the substance to the general population. It is 
important to note that abuse may exist independent of a state of 
tolerance or physical dependence, because drugs may be abused in 
doses or in patterns that do not induce these phenomena. Animal 
data, human data, and epidemiological data are all used in 
determining a substance's abuse liability. Epidemiological data can 
also be an important indicator of actual abuse. Finally, evidence of 
clandestine production and illicit trafficking of a substance are 
also important factors.
    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.
    Marijuana is a widely abused substance. The pharmacology of the 
psychoactive constituents of marijuana, including delta\9\-
tetrahydrocannabinol (delta\9\-THC), the primary psychoactive 
ingredient in marijuana, has been studied extensively in animals and 
humans and is discussed in more detail below in Factor 2, 
``Scientific Evidence of its Pharmacological Effects, if Known.'' 
Data on the extent of marijuana abuse are available from HHS through 
NIDA and the Substance Abuse and Mental Health Services 
Administration (SAMHSA). These data are discussed in detail under 
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?''
    According to SAMHSA's 2004 National Survey on Drug Use and 
Health (NSDUH; the database formerly known as the National Household 
Survey on Drug Abuse (NHSDA)), the latest year for which complete 
data are available, 14.6 million Americans have used marijuana in 
the past month. This is an increase of 3.4 million individuals since 
1999, when 11.2 million individuals reported using marijuana 
monthly. (See the discussion of NSDUH data under Factor 4).
    The Drug Abuse Warning Network (DAWN), sponsored by SAMHSA, is a 
national probability survey of U.S. hospitals with emergency 
departments (EDs) designed to obtain information on ED visits in 
which recent drug use is implicated; 2003 is the latest year for 
which complete data are available. Marijuana was involved in 79,663 
ED visits (13 percent of drug-related visits). There are a number of 
risks resulting from both acute and chronic use of marijuana which 
are discussed in full below under Factors 2 and 6.
    b. There is significant diversion of the substance from 
legitimate drug channels.
    At present, cannabis is legally available through legitimate 
channels for research purposes only and thus has a limited potential 
for diversion. In addition, the lack of significant diversion of 
investigational supplies may result from the ready availability of 
illicit cannabis of equal or greater quality. The magnitude of the 
demand for illicit marijuana is evidenced by DEA/Office of National 
Drug Control Policy (ONDCP) seizure statistics. Data on marijuana 
seizures can often highlight trends in the overall trafficking 
patterns. DEA's Federal-Wide Drug Seizure System (FDSS) provides 
information on total federal drug seizures. FDSS reports total 
federal seizures of 2,700,282 pounds of marijuana in 2003, the 
latest year for which complete data are available (DEA, 2003). This 
represents nearly a doubling of marijuana seizures since 1995, when 
1,381,107 pounds of marijuana were seized by federal agents.
    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.

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    The 2004 NSDUH data show that 14.6 million American adults use 
marijuana on a monthly basis (SAMHSA, 2004), confirming that 
marijuana has reinforcing properties for many individuals. The FDA 
has not evaluated or approved a new drug application (NDA) for 
marijuana for any therapeutic indication, although several 
investigational new drug (IND) applications are currently active. 
Based on the large number of individuals who use marijuana, it can 
be concluded that the majority of individuals using cannabis do so 
on their own initiative, not on the basis of medical advice from a 
practitioner licensed to administer the drug in the course of 
professional practice.
    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.
    The primary psychoactive compound in botanical marijuana is 
delta\9\-THC. Other cannabinoids also present in the marijuana plant 
likely contribute to the psychoactive effects.
    There are two drug products containing cannabinoid compounds 
that are structurally related to the active components in marijuana. 
Both are controlled under the CSA. Marinol is a Schedule III drug 
product containing synthetic delta\9\-THC, known generically as 
dronabinol, formulated in sesame oil in soft gelatin capsules. 
Dronabinol is listed in Schedule I. Marinol was approved by the FDA 
in 1985 for the treatment of two medical conditions: nausea and 
vomiting associated with cancer chemotherapy in patients that had 
failed to respond adequately to conventional anti-emetic treatments, 
and for the treatment of anorexia associated with weight loss in 
patients with acquired immunodeficiency syndrome or AIDS. Cesamet is 
a drug product containing the Schedule II substance, nabilone, that 
was approved for marketing by the FDA in 1985 for the treatment of 
nausea and vomiting associated with cancer chemotherapy. All other 
structurally related cannabinoids in marijuana are already listed as 
Schedule I drugs under the CSA.

2. SCIENTIFIC EVIDENCE OF ITS PHARMACOLOGICAL EFFECTS, IF KNOWN

    The second factor the Secretary must consider is scientific 
evidence of marijuana's pharmacological effects. There are abundant 
scientific data 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

    Some 483 natural constituents have been identified in marijuana, 
including approximately 66 compounds that are classified as 
cannabinoids (Ross and El Sohly, 1995). Cannabinoids are not known 
to exist in plants other than marijuana, and most of the cannabinoid 
compounds that occur naturally have been identified chemically. 
Delta\9\-THC is considered the major psychoactive cannabinoid 
constituent of marijuana (Wachtel et al., 2002). The structure and 
function of delta\9\-THC was first described in 1964 by Gaoni and 
Mechoulam.
    The site of action of delta\9\-THC and other cannabinoids was 
verified with the cloning of cannabinoid receptors, first from rat 
brain tissue (Matsuda et al., 1990) and then from human brain tissue 
(Gerard et al., 1991). Two cannabinoid receptors, CB1 and 
CB2, have subsequently been characterized (Piomelli, 
2005).
    Autoradiographic studies have provided information on the 
distribution of cannabinoid receptors. CB1 receptors are 
found in the basal ganglia, hippocampus, and cerebellum of the brain 
(Howlett et al., 2004) as well as in the immune system. It is 
believed that the localization of these receptors may explain 
cannabinoid interference with movement coordination and effects on 
memory and cognition. The concentration of CB1 receptors 
is considerably lower in peripheral tissues than in the central 
nervous system (Henkerham et al., 1990 and 1992).
    CB2 receptors are found primarily in the immune 
system, predominantly in B lymphocytes and natural killer cells 
(Bouaboula et al., 1993). It is believed that the CB2-
type receptor is responsible for mediating the immunological effects 
of cannabinoids (Galiegue et al., 1995).
    However, CB2 receptors also have recently been 
localized in the brain, primarily in the cerebellum and hippocampus 
(Gong et al., 2006).
    The cannabinoid receptors belong to the family of G-protein-
coupled receptors and present a typical seven transmembrane-spanning 
domain structure. Many G-protein-coupled receptors are linked to 
adenylate cyclase either positively or negatively, depending on the 
receptor system. Cannabinoid receptors are linked to an inhibitory 
G-protein (Gi), so that when the receptor is activated, adenylate 
cyclase activity is inhibited, which prevents the conversion of 
adenosine triphosphate (ATP)to the second messenger cyclic adenosine 
monophosphate (cAMP). Examples of inhibitory-coupled receptors 
include: opioid, muscarinic cholinergic, alpha 2-
adrenoreceptors, dopamine (D2), and serotonin (5-
HT1).
    It has been shown that CB1, but not CB2 
receptors, inhibit N- and P/Q type calcium channels and activate 
inwardly rectifying potassium channels (Mackie et al., 1995; 
Twitchell et al., 1997). Inhibition of the N-type calcium channels 
decreases neurotransmitter release from several tissues and this may 
be the mechanism by which cannabinoids inhibit acetylcholine, 
norepinephrine, and glutamate release from specific areas of the 
brain. These effects might represent a potential cellular mechanism 
underlying the antinociceptive and psychoactive effects of 
cannabinoids (Ameri, 1999). When cannabinoids are given subacutely 
to rats, there is a down-regulation of CB1 receptors, as 
well as a decrease in GTPgammaS binding, the second messenger system 
coupled to CB1 receptors (Breivogel et al., 2001).
    Delta\9\-THC displays similar affinity for CB1 and 
CB2 receptors but behaves as a weak agonist for 
CB2 receptors, based on inhibition of adenylate cyclase. 
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 
psychotropic effects of cannabinoids are mediated through the 
activation of CB1-receptors (Hanus et al., 1999). 
Naturally-occurring cannabinoid agonists, such as delta\9\-THC, and 
the synthetic cannabinoid agonists such as WIN-55,212-2 and CP-
55,940 produce hypothermia, analgesia, hypoactivity, and cataplexy 
in addition to their psychoactive effects.
    In 2000, two endogenous cannabinoid receptor agonists, 
anandamide and arachidonyl glycerol (2-AG), were discovered. 
Anandamide is a low efficacy agonist (Breivogel and Childers, 2000), 
2-AG is a highly efficacious agonist (Gonsiorek et al., 2000). 
Cannabinoid endogenous ligands are present in central as well as 
peripheral tissues. The action of the endogenous ligands is 
terminated by a combination of uptake and hydrolysis. The 
physiological role of endogenous cannabinoids is an active area of 
research (Martin et al., 1999).
    Progress in cannabinoid pharmacology, including further 
characterization of the cannabinoid receptors, isolation of 
endogenous cannabinoid ligands, synthesis of agonists and 
antagonists with variable affinity, and selectivity for cannabinoid 
receptors, provide the foundation for the potential elucidation of 
cannabinoid-mediated effects and their relationship to psychomotor 
disorders, memory, cognitive functions, analgesia, anti-emesis, 
intraocular and systemic blood pressure modulation, bronchodilation, 
and inflammation.

Central Nervous System Effects

Human Physiological and Psychological Effects

Subjective Effects

    The physiological, psychological, and behavioral effects of 
marijuana vary among individuals. Common responses to cannabinoids, 
as described by Adams and Martin (1996) and others (Hollister, 1986 
and 1988; Institute of Medicine, 1982) are listed below:
    1) Dizziness, nausea, tachycardia, facial flushing, dry mouth, 
and tremor initially
    2) Merriment, happiness, and even exhilaration at high doses
    3) Disinhibition, relaxation, increased sociability, and 
talkativeness
    4) Enhanced sensory perception, giving rise to increased 
appreciation of music, art, and touch

[[Page 40555]]

    5) Heightened imagination leading to a subjective sense of 
increased creativity
    6) Time distortions
    7) Illusions, delusions, and hallucinations, especially at high 
doses
    8) Impaired judgment, reduced co-ordination and ataxia, which 
can impede driving ability or lead to an increase in risk-taking 
behavior
    9) Emotional lability, incongruity of affect, dysphoria, 
disorganized thinking, inability to converse logically, agitation, 
paranoia, confusion, restlessness, anxiety, drowsiness, and panic 
attacks, especially in inexperienced users or in those who have 
taken a large dose
    10) Increased appetite and short-term memory impairment
    These subjective responses to marijuana are pleasurable to many 
humans and are associated with drug-seeking and drug-taking 
(Maldonado, 2002).
    The short-term perceptual distortions and psychological 
alterations produced by marijuana have been characterized by some 
researchers as acute or transient psychosis (Favrat et al., 2005). 
However, the full response to cannabinoids is dissimilar to the DSM-
IV-TR criteria for a diagnosis of one of the psychotic disorders 
(DSM-IV-TR, 2000).
    As with many psychoactive drugs, an individual's response to 
marijuana can be influenced by that person's medical/psychiatric 
history and history with drugs. Frequent marijuana users (greater 
than 100 times) were better able to identify a drug effect from low 
dose delta\9\-THC than infrequent users (less than 10 times) and 
were less likely to experience sedative effects from the drug (Kirk 
and deWit, 1999). Dose preferences have been demonstrated for 
marijuana in which higher doses (1.95 percent delta\9\-THC) are 
preferred over lower doses (0.63 percent delta\9\-THC) (Chait and 
Burke, 1994).

Behavioral Impairment

    Acute administration of smoked marijuana impairs performance on 
tests of learning, associative processes, and psychomotor behavior 
(Block et al., 1992). These data demonstrate that the short-term 
effects of marijuana can interfere significantly with an 
individual's ability to learn in the classroom or to operate motor 
vehicles. Administration to human volunteers of 290 micrograms per 
kilogram ([mu]g/kg) delta\9\-THC in a smoked marijuana cigarette 
resulted in impaired perceptual motor speed and accuracy, two skills 
that are critical to driving ability (Kurzthaler et al., 1999). 
Similarly, administration of 3.95 percent delta\9\-THC in a smoked 
marijuana cigarette increased disequilibrium measures, as well as 
the latency in a task of simulated vehicle braking, at a rate 
comparable to an increase in stopping distance of 5 feet at 60 mph 
(Liguori et al., 1998).
    The effects of marijuana may not fully resolve until at least 1 
day after the acute psychoactive effects have subsided, following 
repeated administration. 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 minimal residual alterations in subjective 
or performance measures the day after subjects were exposed to 1.8 
percent or 3.6 percent smoked delta\9\-THC.
    The effects of chronic marijuana use have also been 
investigated. Marijuana did not appear to have residual 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). This conclusion is similar to the results from 
an earlier study of marijuana's effects on cognition in 1,318 
participants over a 15-year period, where there was no evidence of 
long-term residual effects (Lyketsos et al., 1999). In contrast, 
Solowij et al. (2002) demonstrated that 51 long-term cannabis users 
did less well than 33 non-using controls or 51 short-term users on 
certain tasks of memory and attention, but users in this study were 
abstinent for only 17 hours at time of testing. A recent study noted 
that heavy, frequent cannabis users, abstinent for at least 24 
hours, performed significantly worse than controls on verbal memory 
and psychomotor speed tests (Messinis et al, 2006).
    Pope et al. (2003) reported that no differences were seen in 
neuropsychological performance in early- or late-onset users 
compared to non-using controls, after adjustment for intelligence 
quotient (IQ). In another cohort of chronic, heavy marijuana users, 
some deficits were observed on memory tests up to a week following 
supervised abstinence, but these effects disappeared by day 28 of 
abstinence (Harrison et al., 2002). The authors concluded that, 
``cannabis-associated cognitive deficits are reversible and related 
to recent cannabis exposure, rather than irreversible and related to 
cumulative lifetime use.'' Other investigators have reported 
neuropsychological deficits in memory, executive functioning, 
psychomotor speed, and manual dexterity in heavy marijuana smokers 
who had been abstinent for 28 days (Bolla et al., 2002). A follow up 
study of heavy marijuana users noted decision-making deficits after 
25 days of abstinence (Bolla et al., 2005). Finally, when IQ was 
contrasted in adolescents at 9-12 years and at 17-20 years, current 
heavy marijuana users showed a 4-point reduction in IQ in later 
adolescence compared to those who did not use marijuana (Fried et 
al., 2002).
    Age of first use may be a critical factor in persistent 
impairment resulting from chronic marijuana use. Individuals with a 
history of marijuana-only use that began before the age of 16 were 
found to perform more poorly on a visual scanning task measuring 
attention than individuals who started using marijuana after age 16 
(Ehrenreich et al., 1999). Kandel and Chen (2000) assert that the 
majority of early-onset marijuana users do not go on to become heavy 
users of marijuana, and those that do tend to associate with 
delinquent social groups.
    Heavy marijuana users were contrasted with an age matched 
control group in a case-control design. The heavy users reported 
lower educational achievement and lower income than controls, a 
difference that persisted after confounding variables were taken 
into account. Additionally, the users also reported negative effects 
of marijuana use on cognition, memory, career, social life, and 
physical and mental health (Gruber et al., 2003).

Association with Psychosis

    Extensive research has been conducted recently to investigate 
whether exposure to marijuana is associated with schizophrenia or 
other psychoses. While many studies are small and inferential, other 
studies in the literature utilize hundreds to thousands of subjects.
    At present, the data do not suggest a causative link between 
marijuana use and the development of psychosis. Although some 
individuals who use marijuana have received a diagnosis of 
psychosis, most reports conclude that prodromal symptoms of 
schizophrenia appear prior to marijuana use (Schiffman et al., 
2005). When psychiatric symptoms are assessed in individuals with 
chronic psychosis, the ``schizophrenic cluster'' of symptoms is 
significantly observed among individuals who do not have a history 
of marijuana use, while ``mood cluster'' symptoms are significantly 
observed in individuals who do have a history of marijuana use 
(Maremmani et al., 2004).
    In the largest study evaluating the link between psychosis and 
drug use, 3 percent of 50,000 Swedish conscripts who used marijuana 
more than 50 times went on to develop schizophrenia (Andreasson et 
al., 1987). This was interpreted by the authors to suggest that 
marijuana use increased the risk for the disorder only among those 
individuals who were predisposed to develop psychosis. A similar 
conclusion was drawn when the prevalence of schizophrenia was 
modeled against marijuana use across birth cohorts in Australia 
between the years 1940 to 1979 (Degenhardt et al., 2003). Although 
marijuana use increased over time in adults born during the 4-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 induce schizophrenia in the majority of 
individuals who try or continue to use the drug.
    However, as might be expected, the acute intoxication produced 
by marijuana does exacerbate the perceptual and cognitive deficits 
of psychosis in individuals who have been previously diagnosed with 
the condition (Schiffman et al., 2005; Hall et al., 2004; Mathers 
and Ghodse, 1992; Thornicroft, 1990). This is consistent with a 25-
year longitudinal study of over 1,000 individuals who had a higher 
rate of experiencing some symptoms of psychosis (but who did not 
receive a diagnosis of psychosis) if they were daily marijuana users 
than if they were not (Fergusson et al., 2005). A shorter, 3-year 
longitudinal study with over 4,000 subjects similarly showed that 
psychotic symptoms, but not diagnoses, were more prevalent in 
subjects who used marijuana (van Os et al., 2002).

[[Page 40556]]

    Additionally, schizophrenic individuals stabilized with 
antipsychotics do not respond differently to marijuana than healthy 
controls (D'Souza et al., 2005), suggesting that psychosis and/or 
antipsychotics do not biochemically alter cannabinoid systems in the 
brain.
    Interestingly, cannabis use prior to a first psychotic episode 
appeared to spare neurocognitive deficits compared to patients who 
had not used marijuana (Stirling et al., 2005). Although adolescents 
diagnosed with a first psychotic episode used more marijuana than 
adults who had their first psychotic break, adolescents and adults 
had similar clinical outcomes 2 years later (Pencer et al., 2005).
    Heavy marijuana users, though, do not perform differently than 
non-users on the Stroop task, a classic psychometric instrument that 
measures executive cognitive functioning. Since psychotic 
individuals do not perform the Stroop task well, alterations in 
executive functioning consistent with a psychotic profile were not 
apparent following chronic exposure to marijuana (Gruber and 
Yurgelun-Todd, 2005; Eldreth et al., 2004).

Alteration in Brain Structure

    Although evidence suggests that some drugs of abuse can lead to 
changes in the density or structure of the brain in humans, there 
are currently no data showing that exposure to marijuana can induce 
such alterations. A recent comparison of long-term marijuana smokers 
to non-smoking control subjects using magnetic resonance imaging 
(MRI) did not reveal any differences in the volume of grey or white 
matter, in the hippocampus, or in cerebrospinal fluid volume, 
between the two groups (Tzilos et al., 2005).

Behavioral Effects of Prenatal Exposure

    The impact of in utero marijuana exposure on performance in a 
series of cognitive tasks has been studied in children at different 
stages of development. However, since many marijuana users have 
abused other drugs, it is difficult to determine the specific impact 
of marijuana on prenatal exposure.
    Differences in several cognitive domains distinguished the 4-
year-old children of heavy marijuana users. In particular, memory 
and verbal measures are negatively associated with maternal 
marijuana use (Fried and Watkinson, 1987). Maternal marijuana use is 
predictive of poorer performance on abstract/visual reasoning tasks, 
although it is not associated with an overall lowered IQ in 3-year 
old children (Griffith et al., 1994). At 6 years of age, prenatal 
marijuana history is associated with an increase in omission errors 
on a vigilance task, possibly reflecting a deficit in sustained 
attention (Fried et al., 1992). When the effect of prenatal exposure 
in 9-12 year old children is analyzed, in utero marijuana exposure 
is negatively associated with executive function tasks that require 
impulse control, visual analysis, and hypothesis testing, and it is 
not associated with global intelligence (Fried et al., 1998).

Marijuana as a ``Gateway Drug''

    The Institute of Medicine (IOM) reported that the widely held 
belief that marijuana is a ``gateway drug,'' leading to subsequent 
abuse of other illicit drugs, lacks conclusive evidence (Institute 
of Medicine, 1999). Recently, Fergusson et al. (2005) in a 25-year 
study of 1,256 New Zealand children concluded that use of marijuana 
correlates to an increased risk of abuse of other drugs, including 
cocaine and heroin. Other sources, however, do not support a direct 
causal relationship between regular marijuana and other illicit drug 
use. In general, such studies are selective in recruiting 
individuals who, in addition to having extensive histories of 
marijuana use, are influenced by myriad social, biological, and 
economic factors that contribute to extensive drug abuse (Hall and 
Lynskey, 2005). For most studies that test the hypothesis that 
marijuana causes abuse of harder drugs, the determinative measure of 
choice is any drug use, rather than DSM-IV-TR criteria for drug 
abuse or dependence (DSM-IV-TR, 2000).
    According to Golub & Johnson (2001), the rate of progression to 
hard drug use by youth born in the 1970's, as opposed to youth born 
between World War II and the 1960's, is significantly decreased, 
although overall marijuana use among youth appears to be increasing. 
Nace et al. (1975) reported that even in the Vietnam-era soldiers 
who extensively abused marijuana and heroin, there was a lack of 
correlation of a causal relationship demonstrating marijuana use 
leading to heroin addiction. A recent longitudinal study of 708 
adolescents demonstrated that early onset marijuana use did not lead 
to problematic drug use (Kandel and Chen, 2000). Similarly, among 
2,446 adolescents followed longitudinally, cannabis dependence was 
uncommon but when it did occur, it was predicted primarily by 
parental death, deprived socio-economic status, and baseline use of 
illicit drugs other than marijuana (von Sydow et al., 2002).

Animal behavioral effects

Self-Administration

    Self-administration is a method that assesses whether a drug 
produces rewarding effects that increase the likelihood of 
behavioral responses in order to obtain additional drug. Drugs that 
are self-administered by animals are likely to produce rewarding 
effects in humans, which is indicative of abuse liability. 
Generally, a good correlation exists between those drugs that are 
self-administered by rhesus monkeys and those that are abused by 
humans (Balster and Bigelow, 2003).
    Interestingly, self-administration of hallucinogenic-like drugs, 
such as cannabinoids, lysergic acid diethylamide (LSD), and 
mescaline, has been difficult to demonstrate in animals (Yanagita, 
1980). However, when it is known that humans voluntarily consume a 
particular drug (such as cannabis) for its pleasurable effects, the 
inability to establish self-administration with that drug in animals 
has no practical importance in the assessment of abuse potential. 
This is because the animal test is a predictor of human behavioral 
response in the absence of naturalistic data.
    The experimental literature generally reports that na[iuml]ve 
animals will not self-administer cannabinoids unless they have had 
previous experience with other drugs of abuse. However, when 
squirrel monkeys are first trained to self-administer intravenous 
cocaine, they will continue to bar-press at the same rate as when 
delta\9\-THC is substituted for cocaine, at doses that are 
comparable to those used by humans who smoke marijuana (Tanda et 
al., 2000). This effect is blocked by the cannabinoid receptor 
antagonist, SR 141716. New studies show that monkeys without a 
history of any drug exposure can be successfully trained to self-
administer delta\9\-THC intravenously (Justinova et al., 2003). The 
maximal rate of responding is 4 [mu]g/kg/injection, which is 2-3 
times greater than that observed in previous studies using cocaine-
experienced monkeys.
    These data demonstrate that under specific pretreatment 
conditions, an animal model of reinforcement by cannabinoids now 
exists for future investigations. Rats will self-administer 
delta\9\-THC when it is applied intracerebroventricularly (i.c.v.), 
but only at the lowest doses tested (0.01-0.02 [mu]g/infusion) 
(Braida et al., 2004). This effect is antagonized by the cannabinoid 
antagonist SR141716 and by the opioid antagonist naloxone (Braida et 
al., 2004). Additionally, mice will self-administer WIN 55212, a 
CB1 receptor agonist with a non-cannabinoid structure 
(Martellotta et al., 1998).
    There may be a critical dose-dependent effect, though, since 
aversive effects, rather than reinforcing effects, have been 
described in rats that received high doses of WIN 55212 (Chaperon et 
al., 1998) or delta\9\-THC (Sanudo-Pena et al., 1997). SR 141716 
reversed these aversive effects in both studies.

Conditioned Place Preference

    Conditioned place preference (CPP) is a less rigorous method 
than self-administration of determining whether drugs have rewarding 
properties. In this behavioral test, 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 will choose to spend 
more time in the environment paired with the drug than the one 
paired with the placebo, when both options are presented 
simultaneously.
    Animals show CPP to delta\9\-THC, but only at the lowest doses 
tested (0.075-0.75 mg/kg, i.p.) (Braida et al., 2004). This effect 
is antagonized by the cannabinoid antagonist, SR141716, as well as 
by the opioid antagonist, naloxone (Braida et al., 2004). However, 
SR141716 may be a partial agonist, rather than a full antagonist, 
since it is also able to induce CPP (Cheer et al., 2000). 
Interestingly, in knockout mice, animals without [mu]-opioid 
receptors do not develop CPP to delta\9\-THC (Ghozland et al., 
2002).

Drug Discrimination Studies

    Drug discrimination is a method in which 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. A challenge session with the 
test drug determines which of the two

[[Page 40557]]

bars the animal presses more often, as an indicator of whether the 
test drug is like the known drug of abuse.
    Animals, including monkeys and rats (Gold et al., 1992), as well 
as humans (Chait, 1988), can discriminate cannabinoids from other 
drugs or placebo. Discriminative stimulus effects of delta\9\-THC 
are pharmacologically specific for marijuana-containing cannabinoids 
(Balster and Prescott, 1992; Barnett et al., 1985; Browne and 
Weissman, 1981; Wiley et al., 1993; Wiley et al., 1995). 
Additionally, the major active metabolite of delta\9\-THC, 11-
hydroxy-delta\9\-THC, also generalizes to the stimulus cue elicited 
by delta\9\-THC (Browne and Weissman, 1981). Twenty-two other 
cannabinoids found in marijuana also fully substitute for delta\9\-
THC.
    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.

Tolerance and Physical Dependence

    Tolerance is a state of adaptation in which 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). 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).
    The presence of tolerance or physical dependence does not 
determine whether a drug has abuse potential, in the absence of 
other abuse indicators such as rewarding properties. Many 
medications that are not associated with abuse or addiction, such as 
antidepressants, beta-blockers, and centrally acting 
antihypertensive drugs, can produce physical dependence and 
withdrawal symptoms after chronic use.
    Tolerance to the subjective and performance effects of marijuana 
has not been demonstrated in studies with humans. For example, 
reaction times are not altered by acute administration of marijuana 
in long term marijuana users (Block and Wittenborn, 1985). This may 
be related to recent electrophysiological data showing that the 
ability of delta\9\-THC to increase neuronal firing in the ventral 
tegmental area (a region known to play a critical role in drug 
reinforcement and reward) is not reduced following chronic 
administration of the drug (Wu and French, 2000). On the other hand, 
tolerance can develop in humans to marijuana-induced cardiovascular 
and autonomic changes, decreased intraocular pressure, and sleep 
alterations (Jones et al., 1981). Down-regulation of cannabinoid 
receptors has been suggested as the mechanism underlying tolerance 
to the effects of marijuana (Rodriguez de Fonseca et al., 1994; 
Oviedo et al., 1993).
    Acute administration of marijuana containing 2.1 percent 
delta\9\-THC does not produce ``hangover effects'' (Chait et al., 
1985). In chronic marijuana users, though, a marijuana withdrawal 
syndrome has been described that consists of restlessness, 
irritability, mild agitation, insomnia, sleep EEG disturbances, 
nausea, and cramping that resolves within a few days (Haney et al., 
1999). However, the American Psychiatric Association's Diagnostic 
and Statistical Manual (DSM-IV-TR, 2000) does not include a listing 
for cannabis withdrawal syndrome because, ``symptoms of cannabis 
withdrawal . . . have been described . . . but their clinical 
significance is uncertain.'' A review of all current clinical 
studies on cannabis withdrawal led to the recommendation by Budney 
et al. (2004) that the DSM introduce a listing for cannabis 
withdrawal that includes such symptoms as sleep difficulties, 
strange dreams, decreased appetite, decreased weight, anger, 
irritability, and anxiety. 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. A recent study 
comparing marijuana and tobacco withdrawal symptoms in humans 
demonstrated that the magnitude and timecourse of the two withdrawal 
syndromes are similar (Vandrey et al., 2005).
    The production of an overt withdrawal syndrome in animals 
following chronic delta\9\-THC administration has been variably 
demonstrated under conditions of natural discontinuation. This may 
be the result of the slow release of cannabinoids from adipose 
storage, as well as the presence of the major psychoactive 
metabolite, 11-hydroxy-delta\9\-THC. When investigators have shown 
such a withdrawal syndrome in monkeys following the termination of 
cannabinoid administration, the behaviors included transient 
aggression, anorexia, biting, irritability, scratching, and yawning 
(Budney et al., 2004). However, in rodents treated with a 
cannabinoid antagonist following subacute administration of 
delta\9\-THC, pronounced withdrawal symptoms, including wet dog 
shakes, can be provoked (Breivogel et al., 2003).

Behavioral Sensitization

    Sensitization to the effects of drugs is the opposite of 
tolerance: instead of a reduction in behavioral response upon 
repeated drug administration, animals that are sensitized 
demonstrate an increase in behavioral response. Cadoni et al. (2001) 
demonstrated that repeated exposure to delta\9\-THC can induce 
sensitization to a variety of cannabinoids. These same animals also 
have a sensitized response to administration of opioids, an effect 
known as cross-sensitization. Conversely, when animals were 
sensitized to the effects of morphine, there was cross-sensitization 
to cannabinoids. Thus, the cannabinoid and opioids systems appear to 
operate symmetrically in terms of cross-sensitization.

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). However, prolonged delta\9\-THC ingestion produces 
significant heart rate slowing and blood pressure lowering (Benowitz 
and Jones, 1975). Both plant-derived cannabinoids and 
endocannabinoids have been shown to elicit hypotension and 
bradycardia via activation of peripherally-located CB1 
receptors (Wagner et al., 1998). This study suggests that 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.
    The impaired circulatory responses following delta\9\-THC 
administration to standing, exercise, Valsalva maneuver, and cold 
pressor testing suggest that cannabinoids induce a state of 
sympathetic insufficiency. In humans, tolerance can develop to the 
orthostatic hypotension (Jones, 2002; Sidney, 2002), possibly 
related to plasma volume expansion, but does not develop to the 
supine hypotensive effects (Benowitz and Jones, 1975). During 
chronic marijuana ingestion, nearly complete tolerance develops to 
tachycardia and psychological effects when subjects are challenged 
with smoked marijuana. Electrocardiographic changes are minimal even 
after large cumulative doses of delta\9\-THC. (Benowitz and Jones, 
1975).
    It is notable that marijuana smoking by older patients, 
particularly those with some degree of coronary artery or 
cerebrovascular disease, poses risks related to increased cardiac 
work, increased catecholamines, carboxyhemoglobin, and postural 
hypotension (Benowitz and Jones, 1981; Hollister, 1988).

Respiratory Effects

    Transient bronchodilation is the most typical effect following 
acute exposure to marijuana (Gong et al., 1984). Long-term use of 
marijuana can lead to an increased frequency of chronic bronchitis 
and pharyngitis, as well as chronic cough and increased sputum. 
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).
    The evidence that marijuana may lead to cancer associated with 
respiratory effects is inconsistent, with some studies suggesting a 
positive correlation while others do not (Tashkin, 2005). Several 
cases of lung cancer have been reported in young marijuana users 
with no history of tobacco smoking 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 the largest study to date with 1,650 subjects, no 
positive association was found between marijuana use and lung cancer 
(Tashkin et al., 2006). This finding held true regardless of extent 
of marijuana use, when tobacco use and other potential confounding 
factors were controlled.
    The lack of evidence for carcinogenicity related to cannabis may 
be related to the fact that intoxication from marijuana does not 
require large amounts of smoked material.

[[Page 40558]]

This may be especially pertinent since marijuana is reportedly more 
potent today than a generation ago. Thus, individuals may consume 
much less marijuana than in previous decades to reach the desired 
subjective effects, exposing them to less potential carcinogens.

Endocrine System

    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). Acute delta\9\-THC 
releases corticosterone, but tolerance develops to this effect with 
chronic administration (Eldridge et al., 1991).
    Experimental administration of marijuana to humans does not 
consistently alter 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 were observed (Cone et al., 1986). However, two 
later studies showed no changes in hormones. Male subjects who were 
experimentally exposed to smoked delta\9\-THC (18 mg/marijuana 
cigarette) or oral delta\9\-THC (10 mg t.i.d. for 3 days and on the 
morning of the fourth day) showed no changes in plasma prolactin, 
ACTH, cortisol, 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).
    Relatively little research has been performed on the effects of 
experimentally administered marijuana on female reproductive system 
functioning. In monkeys, delta\9\-THC administration suppressed 
ovulation (Asch et al., 1981) and reduced progesterone levels 
(Almirez et al., 1983). However, when women were studied following 
experimental exposure to smoked marijuana, no hormonal or menstrual 
cycle changes were observed (Mendelson and Mello, 1984). Brown and 
Dobs (2002) suggest that the discrepancy between animal and human 
hormonal response to cannabinoids may be attributed to the 
development of tolerance in humans.
    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 cell growth, as well as decreases in expression of androgen 
receptors and prostate-specific antigens (Sarfaraz et al., 2005).

Immune System

    Immune functions are altered by cannabinoids, but there can be 
differences between the effects of synthetic, natural, and 
endogenous cannabinoids, often in an apparently biphasic manner 
depending on dose (Croxford and Yamamura, 2005).
    Abrams et al. (2003) investigated the effect of marijuana on 
immunological functioning in 62 AIDS patients who were taking 
protease inhibitors. Subjects received one of the following three 
times a day: smoked marijuana cigarette containing 3.95 percent 
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 or HIV RNA levels or protease inhibitor levels between 
groups, demonstrating no short-term adverse virologic effects from 
using cannabinoids in individuals with compromised immune systems.
    These human data contrast with data generated in immunodeficient 
mice showing 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

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

Chemistry

    According to the DEA, Cannabis sativa is the primary species of 
cannabis currently marketed illegally in the United States of 
America. From this plant, three derivatives are sold as separate 
illicit drug products: marijuana, hashish, and hashish oil.
    Each of these derivatives contains a complex mixture of 
chemicals. Among the components are the 21 carbon terpenes found in 
the plant as well as their carboxylic acids, analogues, and 
transformation products known as cannabinoids (Agurell et al., 1984 
and 1986; Mechoulam, 1973). The cannabinoids appear to naturally 
occur only in the marijuana plant and most of the botanically-
derived cannabinoids have been identified. Among the cannabinoids, 
delta\9\-THC (alternate name delta\1\-THC) and delta-8-
tetrahydrocannabinol (delta\8\-THC, alternate name delta\6\-THC) are 
both found in marijuana and are able to produce the characteristic 
psychoactive effects of marijuana. Because delta\9\-THC is more 
abundant than delta\8\-THC, the activity of marijuana is largely 
attributed to the former. Delta\8\-THC is found only in few 
varieties of the plant (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-1-ol or (-)-delta\9\-(trans)-
tetrahydrocannabinol. The (-)-trans isomer of delta\9\-THC is 
pharmacologically 6 to 100 times more potent than the (+)-trans 
isomer (Dewey et al., 1984).
    Other cannabinoids, such as cannabidiol (CBD) and cannabinol 
(CBN), have been characterized. CBD is not considered to have 
cannabinol-like psychoactivity, but is thought to have significant 
anticonvulsant, sedative, and anxiolytic activity (Adams and Martin, 
1996; Agurell et al., 1984 and 1986; Hollister, 1986).
    Marijuana is a mixture of the dried flowering tops and leaves 
from the plant and is variable in content and potency (Agurell et 
al., 1984 and 1986; Graham, 1976; Mechoulam, 1973). Marijuana is 
usually smoked in the form of rolled cigarettes while hashish and 
hash oil are smoked in pipes. Potency of marijuana, as indicated by 
cannabinoid content, has been reported to average from as low as 1 
to 2 percent to as high as 17 percent.
    The concentration of delta\9\-THC and other cannabinoids in 
marijuana varies with growing conditions and processing after 
harvest. Other variables that can influence the strength, quality, 
and purity of marijuana are genetic differences among the cannabis 
plant species and which parts of the plant are collected (flowers, 
leaves, stems, etc.) (Adams and Martin, 1996; Agurell et al., 1984; 
Mechoulam, 1973). In the usual mixture of leaves and stems 
distributed as marijuana, the concentration of delta\9\-THC ranges 
widely from 0.3 to 4.0 percent by weight. However, specially grown 
and selected marijuana can contain even 15 percent or greater 
delta\9\-THC. Thus, a 1 gm marijuana cigarette might contain as 
little as 3 mg or as much as 150 mg or more of delta\9\-THC.
    Hashish consists of the cannabinoid-rich resinous material of 
the cannabis plant, which is dried and compressed into a variety of 
forms (balls, cakes, etc.). Pieces are then broken off, placed into 
a pipe and smoked. DEA reports that cannabinoid content in hashish 
averages 6 percent.
    Hash oil is produced by solvent extraction of the cannabinoids 
from plant material. Color and odor of the extract vary, depending 
on the type of solvent used. Hash oil is a viscous brown or amber-
colored liquid that contains approximately 15 percent cannabinoids. 
One or two drops of the liquid placed on a cigarette purportedly 
produce the equivalent of a single marijuana cigarette (DEA, 2005).
    The lack of a consistent concentration of delta\9\-THC in 
botanical marijuana from diverse sources complicates the 
interpretation of clinical data using marijuana. If marijuana is to 
be investigated more widely for medical use, information and data 
regarding the chemistry, manufacturing, and specifications of 
marijuana must be developed.

Human Pharmacokinetics

    Marijuana is generally smoked as a cigarette (weighing between 
0.5 and 1.0 gm), or in a pipe. It can also be taken orally in foods 
or as extracts of plant material in ethanol or other solvents.
    The absorption, metabolism, and pharmacokinetic profile of 
delta\9\-THC (and other cannabinoids) in marijuana or other drug 
products containing delta\9\-THC vary with route of administration 
and formulation (Adams and Martin, 1996; Agurell et al., 1984 and 
1986). When marijuana is administered by smoking, delta\9\-THC in 
the form of an aerosol is absorbed within seconds. The psychoactive 
effects of marijuana occur immediately following absorption, with 
mental and behavioral effects measurable up to 6 hours 
(Grotenhermen, 2003; Hollister,

[[Page 40559]]

1986 and 1988). Delta\9\-THC is delivered to the brain rapidly and 
efficiently as would be 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 the following: 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. A individual's experience and technique 
with smoking marijuana is an important determinant of the dose that 
is absorbed (Herning et al., 1986; Johansson et al., 1989).
    After smoking, venous levels of delta\9\-THC decline 
precipitously within minutes, and within an hour are about 5 to 10 
percent of the peak level (Agurell et al., 1986; Huestis et al., 
1992a and 1992b). Plasma clearance of delta\9\-THC is approximately 
950 ml/min or greater, thus approximating hepatic blood flow. The 
rapid disappearance of delta\9\-THC from blood is largely due to 
redistribution to other tissues in the body, rather than to 
metabolism (Agurell et al., 1984 and 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 is estimated to range from approximately 20 hours to as 
long as 10 to 13 days (Hunt and Jones, 1980), though reported 
estimates vary as expected with any slowly cleared substance and the 
use of assays of variable sensitivities. 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 na[iuml]ve 
users.
    Characterization of the pharmacokinetics of delta\9\-THC and 
other cannabinoids from smoked marijuana is difficult (Agurell et 
al., 1986; Herning et al., 1986; Huestis et al., 1992a), in part 
because a subject's smoking behavior during an experiment is 
variable. 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 to avoid overdose 
and/or minimize undesired effects. For example, under naturalistic 
conditions, users will hold marijuana smoke in the lungs for an 
extended period of time, in order to prolong absorption and increase 
psychoactive effects. The effect of experience in the psychological 
response may explain why venous blood levels of delta\9\-THC 
correlate poorly with intensity of effects and level of intoxication 
(Agurell et al., 1986; Barnett et al., 1985; Huestis et al., 1992a).
    Additionally, puff and inhalation volume changes with phase of 
smoking, tending to be highest at the beginning and lowest at the 
end of smoking a cigarette. Some studies found frequent users to 
have higher puff volumes than less frequent marijuana users. During 
smoking, as the cigarette length shortens, the concentration of 
delta\9\-THC in the remaining marijuana increases; thus, each 
successive puff contains an increasing concentration of delta\9\-
THC.
    In contrast to smoking, the onset of effects after oral 
administration of delta\9\-THC or marijuana is 30 to 90 min, which 
peaks after 2 to 3 hours and continues for 4 to 12 hours 
(Grotenhermen, 2003; Adams and Martin, 1996; Agurell et al., 1984 
and 1986). 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 and 1986). Following oral 
administration of radioactive-labeled delta\9\-THC, delta\9\-THC 
plasma levels are low relative to those levels after smoking or 
intravenous administration. There is inter- and intra-subject 
variability, even when repeated dosing occurs 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. It is more 
difficult for a user to titrate the oral delta\9\-THC dose than 
marijuana smoking because of the delay in onset of effects after an 
oral dose (typically 1 to 2 hours).
    Cannabinoid metabolism is extensive. Delta\9\-THC is metabolized 
via microsomal hydroxylation to both active and inactive metabolites 
(Lemberger et al., 1970, 1972a, and 1972b; Agurell et al., 1986; 
Hollister, 1988) of which the primary active metabolite was 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. 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 of 
earlier marijuana use in urine tests. 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 nonconjugated metabolites. Frequent and infrequent 
marijuana users are similar in the way they metabolize delta\9\-THC 
(Agurell et al., 1986).

Medical Uses for Marijuana

    A NDA for marijuana/cannabis has not been submitted to the FDA 
for any indication and thus no medicinal product containing 
botanical cannabis has been approved for marketing. However, small 
clinical studies published in the current medical literature 
demonstrate that research with marijuana is being conducted in 
humans in the United States under FDA-authorized investigational new 
drug (IND) applications.
    HHS states in a published guidance that it is committed to 
providing ``research-grade marijuana for studies that are the most 
likely to yield usable, essential data'' (HHS, 1999). The 
opportunity for scientists to conduct clinical research with 
botanical marijuana has increased due to changes in the process for 
obtaining botanical marijuana from NIDA, the only legitimate source 
of the drug for research in the United States. In May 1999, HHS 
provided guidance on the procedures for providing research-grade 
marijuana to scientists who intend to study marijuana in 
scientifically valid investigations and well-controlled clinical 
trials (DHHS, 1999). This action was prompted by the increasing 
interest in determining whether cannabinoids have medical use 
through scientifically valid investigations.
    In February 1997, a National Institutes of Health (NIH)-
sponsored workshop analyzed available scientific information and 
concluded that ``in order to evaluate various hypotheses concerning 
the potential utility of marijuana in various therapeutic areas, 
more and better studies would be needed'' (NIH, 1997). In addition, 
in March 1999, the Institute of Medicine (IOM) issued a detailed 
report that supported the need for evidence-based research into the 
effects of marijuana and cannabinoid components of marijuana, for 
patients with specific disease conditions. The IOM report also 
emphasized that smoked marijuana is a crude drug delivery system 
that exposes individuals to a significant number of harmful 
substances and that ``if there is any future for marijuana as a 
medicine, it lies in its isolated components, the cannabinoids and 
their synthetic derivatives.'' As such, the IOM recommended that 
clinical trials should be conducted with the goal of developing safe 
delivery systems (Institute of Medicine, 1999). Additionally, state-
level public initiatives, including referenda in support of the 
medical use of marijuana, have generated interest in the medical 
community for high quality clinical investigation and comprehensive 
safety and effectiveness data.
    For example, in 2000, the state of California established the 
Center for Medicinal Cannabis Research (CMCR) (www.cmcr.ucsd.edu) 
``in response to scientific evidence for therapeutic possibilities 
of cannabis and local legislative initiatives in favor of 
compassionate use'' (Grant, 2005). State legislation establishing 
the CMCR called for high quality medical research that will 
``enhance understanding of the efficacy and adverse effects of 
marijuana as a pharmacological agent,'' but stressed that the 
project ``should not be construed as encouraging or sanctioning the 
social or recreational use of marijuana.'' CMCR has thus far funded 
studies on the potential use of cannabinoids for the treatment of 
multiple sclerosis, neuropathic pain, appetite suppression and 
cachexia, and severe pain and nausea related to cancer or its 
treatment by chemotherapy. To date, though, no NDAs utilizing 
marijuana for these indications have been submitted to the FDA.
    However, 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. According to established case law, 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

[[Page 40560]]

    e. the scientific evidence is widely available.

[Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. 
Cir. 1994)]

    Although the structures of many cannabinoids found in marijuana 
have been characterized, a complete scientific analysis of all the 
chemical components found in marijuana has not been conducted. 
Safety studies for acute or subchronic administration of marijuana 
have been carried out through a limited number of Phase 1 clinical 
investigations approved by the FDA, but there have been no NDA-
quality studies that have scientifically assessed the efficacy and 
full safety profile of marijuana for any medical condition. A 
material conflict of opinion among experts precludes a finding that 
marijuana has been accepted by qualified experts. At this time, it 
is clear that there is not a consensus of medical opinion concerning 
medical applications of marijuana. Finally, the scientific evidence 
regarding the safety or efficacy of marijuana is typically available 
only in summarized form, such as in a paper published in the medical 
literature, rather than in a raw data format. As such, there is no 
opportunity for adequate scientific scrutiny of whether the data 
demonstrate safety or efficacy.
    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. However, as stated above, a material conflict of opinion among 
experts precludes a finding that marijuana has been accepted by 
qualified experts, even under conditions where its use is severely 
restricted. Thus, to date, research on the medical use of marijuana 
has not progressed to the point that marijuana can be 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

    The fourth factor the Secretary must consider is the history and 
current pattern of abuse of marijuana. A variety of sources provide 
data necessary to assess abuse patterns and trends of marijuana. The 
data indicators of marijuana use include NSDUH, Monitoring the 
Future (MTF), DAWN, and Treatment Episode Data Set (TEDS), which are 
described below:

National Survey on Drug Use and Health

    The National Survey on Drug Use and Health (NSDUH, 2004; http://oas.samhsa.gov/nsduh.htm) is conducted annually by SAMHSA, an agency 
of HHS. NSDUH provides estimates of the prevalence and incidence of 
illicit drug, alcohol, and tobacco use in the United States. This 
database was known until 2001 as the National Household Survey on 
Drug Abuse. The survey is based on a nationally representative 
sample of the civilian, non-institutionalized population 12 years of 
age and older. The survey identifies whether an individual used a 
drug during a certain period, but not the amount of the drug used on 
each occasion. Excluded groups include homeless people, active 
military personnel, and residents of institutions, such as jails.
    According to the 2004 NSDUH, 19.1 million individuals (7.9 
percent of the U.S. population) illicitly used drugs other than 
alcohol and nicotine on a monthly basis, compared to 14.8 million 
(6.7 percent of the U.S. population) users in 1999. This is an 
increase from 1999 of 4.3 million (2.0 percent of the U.S. 
population). The most frequently used illicit drug was marijuana, 
with 14.6 million individuals (6.1 percent of the U.S. population) 
using it monthly. Thus, regular illicit drug use, and more 
specifically marijuana use, for rewarding responses is increasing. 
The 2004 NSDUH estimated that 96.8 million individuals (40.2 percent 
of the U.S. population) have tried marijuana at least once during 
their lifetime. Thus, 15 percent of those who have tried marijuana 
on one occasion go on to use it monthly, but 85 percent of them do 
not.

Monitoring the Future

    MTF (2005, http://www.monitoringthefuture.org) is a NIDA-
sponsored annual national survey that tracks drug use trends among 
adolescents in the United States. The MTF surveys 8th, 10th, and 
12th graders every spring in randomly selected U.S. schools. The MTF 
survey has been conducted since 1975 for 12th graders and since 1991 
for 8th and 10th graders by the Institute for Social Research at the 
University of Michigan under a grant from NIDA. The 2005 sample 
sizes were 17,300--8th graders; 16,700--10th graders; and 15,400--
12th graders. In all, a total of 49,300 students in 402 schools 
participated.
    Since 1999, illicit drug use among teens decreased and held 
steady through 2005 in all three grades (Table 1). Marijuana 
remained the most widely used illicit drug, though its use has 
steadily decreased since 1999. For 2005, the annual prevalence rates 
for marijuana use in grades 8, 10, and 12 were, respectively, 12.2 
percent, 26.6 percent, and 33.6 percent. Current monthly prevalence 
rates for marijuana use were 6.6 percent, 15.2 percent, and 19.8 
percent. (See Table 1). According to Gruber and Pope (2002), when 
adolescents who used marijuana reach their late 20's, the vast 
majority of these individuals will have stopped using marijuana.

Table 1--Trends in Annual and Monthly Prevalence of Use of Various Drugs for Eighth, Tenth, and Twelfth Graders,
From Monitoring the Future. Percentages Represent Students in Survey Responding That They had Used a Drug Either
                                     in the Past Year or in the Past 30 Days
----------------------------------------------------------------------------------------------------------------
                                                             Annual                           30-Day
                                               -----------------------------------------------------------------
                                                   2003       2004       2005       2003       2004       2005
----------------------------------------------------------------------------------------------------------------
Any illicit drug (a):
    8th Grade.................................       16.1       15.2       15.5        9.7        8.4        8.5
    10th Grade................................       32.0       31.1       29.8       19.5       18.3       17.3
    12th Grade................................       39.3       38.8       38.4       24.1       23.4       23.1
Any illicit drug other than cannabis (a):
    8th Grade.................................        8.8        7.9        8.1        4.7        4.1        4.1
    10th Grade................................       13.8       13.5       12.9        6.9        6.9        6.4
    12th Grade................................       19.8       20.5       19.7       10.4       10.8       10.3
Marijuana/hashish:
    8th Grade.................................       12.8       11.8       12.2        7.5        6.4        6.6
    10th Grade................................       28.2       27.5       26.6       17.0       15.9       15.2
12th Grade....................................       34.9       34.3       33.6       21.2       19.9       19.8
----------------------------------------------------------------------------------------------------------------
 SOURCE: The Monitoring the Future Study, the University of Michigan.
 a. For 12th graders only, ``any illicit drug'' includes any use of marijuana, LSD, other hallucinogens, crack,
  other cocaine, or heroin, or any use of other opiates, stimulants, barbiturates, or tranquilizers not under a
  doctor's orders. For 8th and 10th graders, the use of other opiates and barbiturates was excluded.

Drug Abuse Warning Network

    DAWN (2006, http://dawninfo.samhsa.gov/) is a national 
probability survey of U.S. hospitals with EDs designed to obtain 
information on ED visits in which recent drug use is implicated. The 
ED data from a representative sample of hospital emergency 
departments are weighted to produce national estimates. It is 
critical to note that DAWN data and estimates for 2004 are not 
comparable to those for any prior years because of vast

[[Page 40561]]

changes in the methodology used to collect the data. Further, 
estimates for 2004 are the first to be based on a new, redesigned 
sample of hospitals. Thus, the most recent estimates available are 
for 2004.
    Many factors can influence the estimates of ED visits, including 
trends in the ED usage in general. Some drug users may have visited 
EDs for a variety of reasons, some of which may have been life-
threatening, whereas others may have sought care at the ED for 
detoxification because they needed certification before entering 
treatment. DAWN data do not distinguish the drug responsible for the 
ED visit from others used concomitantly. As stated in a recent DAWN 
report, ``Since marijuana/hashish is frequently present in 
combination with other drugs, the reason for the ED contact may be 
more relevant to the other drug(s) involved in the episode.''
    For 2004, DAWN estimates a total of 1,997,993 (95 percent 
confidence interval [CI]: 1,708,205 to 2,287,781) drug-related ED 
visits for the entire United States. During this period, DAWN 
estimates 940,953 (CI: 773,124 to 1,108,782) drug-related ED visits 
involved a major drug of abuse. Thus, nearly half of all drug-
related visits involved alcohol or an illicit drug. Overall, drug-
related ED visits averaged 1.6 drugs per visit, including illicit 
drugs, alcohol, prescription and over-the-counter (OTC) 
pharmaceuticals, dietary supplements, and non-pharmaceutical 
inhalants.
    Marijuana was involved in 215,665 (CI: 175,930 to 255,400) ED 
visits, while cocaine was involved in 383,350 (CI: 284,170 to 
482,530) ED visits, heroin was involved in 162,137 (CI: 122,414 to 
201,860) ED visits, and stimulants, including amphetamine and 
methamphetamine, were involved in 102,843 (CI: 61,520 to 144,166) ED 
visits. Other illicit drugs, such as PCP, MDMA, and GHB, were much 
less frequently associated with ED visits.
    Approximately 18 percent of ED visits involving marijuana were 
for patients under the age of 18, whereas this age group accounts 
for less than 1 percent of the ED visits involving heroin/morphine 
and approximately 3 percent of the visits involving cocaine. Since 
the size of the population differs across age groups, a measure 
standardized 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 (225 ED visits per 100,000) and 
for patients aged 21 to 24 (190 ED visits per 100,000).

Treatment Episode Data Set

    TEDS (TEDS, 2003; http://oas.samhsa.gov/dasis.htm#teds2) system 
is part of SAMHSA's Drug and Alcohol Services Information System 
(Office of Applied Science, SAMHSA). TEDS comprises data on 
treatment admissions that are routinely collected by States in 
monitoring their substance abuse treatment systems. The TEDS report 
provides information on the demographic and substance use 
characteristics of the 1.8 million annual admissions to treatment 
for abuse of alcohol and drugs in facilities that report to 
individual State administrative data systems.
    TEDS is an admission-based system, and TEDS admissions do not 
represent individuals. Thus, a given individual admitted to 
treatment twice within a given year would be counted as two 
admissions. Additionally, TEDS does not include all admissions to 
substance abuse treatment. TEDS includes facilities that are 
licensed or certified by the States to provide substance abuse 
treatment and that are required by the States to provide TEDS 
client-level data. Facilities that report TEDS data are those that 
receive State alcohol and/or drug agency funds for the provision of 
alcohol and/or drug treatment services. The primary goal for TEDS is 
to monitor the characteristics of treatment episodes for substance 
abusers.
    Primary marijuana abuse accounted for 15.5 percent of TEDS 
admissions in 2003, the latest year for which data are available. 
Three-quarters of the individuals admitted for marijuana were male 
and 55 percent of the admitted individuals were white. The average 
age at admission was 23 years. The largest proportion (84 percent) 
of admissions to ambulatory treatment was for primary marijuana 
abuse. More than half (57 percent) of marijuana treatment admissions 
were referred through the criminal justice system.
    Between 1993 and 2003, the percentage of admissions for primary 
marijuana use increased from 6.9 percent to 15.5 percent, comparable 
to the increase for primary opioid use from 13 percent in 1993 to 
17.6 percent in 2003. In contrast, the percentage of admissions for 
primary cocaine use declined from 12.6 percent in 1993 to 9.8 
percent in 2003, and for primary alcohol use from 56.9 percent in 
1993 to 41.7 percent in 2003.
    Twenty-six percent of those individuals who were admitted for 
primary use of marijuana reported its daily use, although 34.6 
percent did not use marijuana in the past month. Nearly all (96.2 
percent) of primary marijuana users utilized the drug by smoking it. 
Over 90 percent of primary marijuana admissions used marijuana for 
the first time before the age of 18.

5. THE SCOPE, DURATION, AND SIGNIFICANCE OF ABUSE

    The fifth factor the Secretary must consider is the scope, 
duration, and significance of marijuana abuse. According to 2004 
data from NSDUH and MTF, marijuana remains the most extensively used 
illegal drug in the United States, with 40.6 percent of U.S. 
individuals over age 12 (96.6 million) and 44.8 percent of 12th 
graders having used marijuana at least once in their lifetime. While 
the majority of individuals over age 12 (85 percent) who have used 
marijuana do not use the drug monthly, 14.6 million individuals (6.1 
percent of the U.S. population) report that they used marijuana 
within the past 30 days. An examination of use among various age 
cohorts in NSDUH demonstrates that monthly use occurs primarily 
among college age individuals, with use dropping off sharply after 
age 25.
    DAWN data show that marijuana was involved in 79,663 ED visits, 
which amounts to 13 percent of all drug-related ED visits. Minors 
accounted for 15 percent of these marijuana-related visits, making 
marijuana the drug most frequently associated with ED visits for 
individuals under the age of 18 years.
    Data from TEDS show that 15.5 percent of all admissions were for 
primary marijuana abuse. Approximately 90 percent of these primary 
marijuana admissions were for individuals under the age of 18 years.

6. WHAT, IF ANY, RISK THERE IS TO THE PUBLIC

    The sixth factor the Secretary must consider is the risk 
marijuana poses to the public health. The risk to the public health 
as measured by emergency room episodes, marijuana-related deaths, 
and drug treatment admissions is discussed in full under Factors 1, 
4, and 5, above. Accordingly, Factor 6 focuses on the health risks 
to the individual user.
    All drugs, both medicinal and illicit, have a broad range of 
effects on the individual user that are dependent on dose and 
duration of use among others. FDA-approved drug products can produce 
adverse events (or ``side effects'') in some individuals even at 
doses in the therapeutic range. 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 potential or actual side effects are 
outweighed by the drug product's potential benefits. As marijuana is 
not FDA-approved for any medicinal use, any potential benefits 
attributed to marijuana use have not been found to be outweighed by 
the risks. However, cannabinoids are generally potent psychoactive 
substances and are pharmacologically active on multiple organ 
systems.
    The discussion of marijuana's central nervous system, cognitive, 
cardiovascular, autonomic, respiratory, and immune system effects 
are fully discussed under Factor 2. Consequences of marijuana use 
and abuse are discussed below in terms of the risk from acute and 
chronic use of the drug to the individual user (Institute of 
Medicine, 1999).

Risks from acute use of marijuana

    Acute use of marijuana impairs psychomotor performance, 
including performance of complex tasks, which makes it inadvisable 
to operate motor vehicles or heavy equipment after using marijuana 
(Ramaekers et al., 2004). Dysphoria and psychological distress, 
including prolonged anxiety reactions, are potential responses in a 
minority of individuals who use marijuana (Haney et al., 1999).

Risks from chronic use of marijuana

    Chronic exposure to marijuana smoke is considered to be 
comparable to tobacco smoke with respect to increased risk of 
cancer, lung damage, and poor pregnancy outcome. Although a 
distinctive marijuana withdrawal syndrome has been identified, 
indicating that marijuana produces physical dependence, this 
phenomenon is mild and short-lived (Budney et al., 2004), as 
described above under Factor 2.
    The Diagnostic and Statistical Manual (DSM-IV-TR, 2000) of the 
American Psychiatric Association states that the

[[Page 40562]]

consequences of cannabis abuse are as follows:
    [P]eriodic cannabis use and intoxication can interfere with 
performance at work or school and may be physically hazardous in 
situations such as driving a car. Legal problems may occur as a 
consequence of arrests for cannabis possession. There may be 
arguments with spouses or parents over the possession of cannabis in 
the home or its use in the presence of children. When psychological 
or physical problems are associated with cannabis in the context of 
compulsive use, a diagnosis of Cannabis Dependence, rather than 
Cannabis Abuse, should be considered.
    Individuals with Cannabis Dependence have compulsive use and 
associated problems. Tolerance to most of the effects of cannabis 
has been reported in individuals who use cannabis chronically. There 
have also been some reports of withdrawal symptoms, but their 
clinical significance is uncertain. There is some evidence that a 
majority of chronic users of cannabinoids report histories of 
tolerance or withdrawal and that these individuals evidence more 
severe drug-related problems overall. Individuals with Cannabis 
Dependence may use very potent cannabis throughout the day over a 
period of months or years, and they may spend several hours a day 
acquiring and using the substance. This often interferes with 
family, school, work, or recreational activities. Individuals with 
Cannabis Dependence may also persist in their use despite knowledge 
of physical problems (e.g., chronic cough related to smoking) or 
psychological problems (e.g., excessive sedation and a decrease in 
goal-oriented activities resulting from repeated use of high doses).

7. ITS PSYCHIC OR PHYSIOLOGIC DEPENDENCE LIABILITY

    The seventh factor the Secretary must consider is marijuana's 
psychic or physiologic dependence liability. 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 (American Academy of Pain Medicine, American Pain Society 
and American Society of Addiction Medicine consensus document, 
2001). Long-term, regular use of marijuana can lead to physical 
dependence and withdrawal following discontinuation as well as 
psychic addiction or dependence. The marijuana withdrawal syndrome 
consists of symptoms such as restlessness, mild agitation, insomnia, 
nausea, and cramping that may resolve after 4 days, and may require 
in-hospital treatment. It is distinct from the withdrawal syndromes 
associated with alcohol and heroin use (Budney et al., 1999; Haney 
et al., 1999). Lane and Phillips-Bute (1998) describes milder cases 
of dependence including symptoms that are comparable to those from 
caffeine withdrawal, including decreased vigor, increased fatigue, 
sleepiness, headache, and reduced ability to work. The marijuana 
withdrawal syndrome has been reported in adolescents who were 
admitted for substance abuse treatment or in individuals who had 
been given marijuana on a daily basis during research conditions. 
Withdrawal symptoms can also be induced in animals following 
administration of a cannabinoid antagonist after chronic delta\9\-
THC administration (Breivogel et al., 2003).
    Tolerance is a state of adaptation in which 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 marijuana-
induced cardiovascular and autonomic changes, decreased intraocular 
pressure, sleep and sleep EEG, and mood and behavioral changes 
(Jones et al., 1981). Down-regulation of cannabinoid receptors has 
been suggested as the mechanism underlying tolerance to the effects 
of marijuana (Rodriguez de Fonseca et al., 1994). Pharmacological 
tolerance does not indicate the physical dependence liability of a 
drug.

8. WHETHER THE SUBSTANCE IS AN IMMEDIATE PRECURSOR OF A SUBSTANCE 
ALREADY CONTROLLED UNDER THIS ARTICLE

    The eighth factor the Secretary must consider is 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, HHS 
recommends that marijuana remain in Schedule I of the CSA. 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 large number of individuals using marijuana on a regular 
basis, its widespread use, and the vast amount of marijuana that is 
available for illicit use are indicative of the high abuse potential 
for marijuana. Approximately 14.6 million individuals in the United 
States (6.1 percent of the U.S. population) used marijuana monthly 
in 2003. A 2003 survey indicates that by 12th grade, 33.6 percent of 
students report having used marijuana in the past year, and 19.8 
percent report using it monthly. In Q3 to Q4 2003, 79,663 ED visits 
were marijuana-related, representing 13 percent of all drug-related 
episodes. Primary marijuana use accounted for 15.5 percent of 
admissions to drug treatment programs in 2003. Marijuana has dose-
dependent reinforcing effects, as demonstrated by data that humans 
prefer higher doses of marijuana to lower doses. In addition, there 
is evidence that marijuana use can result in psychological 
dependence in at risk individuals.

2) Marijuana has no currently accepted medical use in treatment in the 
United States:

    The FDA has not yet approved an NDA for marijuana. The 
opportunity for scientists to conduct clinical research with 
marijuana exists under the HHS policy supporting clinical research 
with botanical marijuana. While there are INDs for marijuana active 
at the FDA, marijuana does not have a currently accepted medical use 
for treatment in the United States, nor does it 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.

[Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. 
Cir. 1994)]

    Although the structures of many cannabinoids found in marijuana 
have been characterized, a complete scientific analysis of all the 
chemical components found in marijuana has not been conducted. 
Safety studies for acute or subchronic administration of marijuana 
have been carried out through a limited number of Phase 1 clinical 
investigations approved by the FDA, but there have been no NDA-
quality studies that have scientifically assessed the efficacy of 
marijuana for any medical condition. A material conflict of opinion 
among experts precludes a finding that marijuana has been accepted 
by qualified experts. At this time, it is clear that there is not a 
consensus of medical opinion concerning medical applications of 
marijuana. Finally, the scientific evidence regarding the safety or 
efficacy of marijuana is typically available only in summarized 
form, such as in a paper published in the medical literature, rather 
than in a raw data format. As such, there is no opportunity for 
adequate scientific scrutiny of whether the data demonstrate safety 
or efficacy.
    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. However, as stated above, a material conflict of opinion among 
experts precludes a finding that marijuana has been accepted by 
qualified experts, even under conditions where its use is severely 
restricted. To date, research on the medical use of marijuana has 
not progressed to the point that marijuana can be 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.

    At present, there are no FDA-approved marijuana products, nor is 
marijuana under NDA evaluation at the FDA for any indication. 
Marijuana does not have a currently accepted medical use in 
treatment in the United States or a currently accepted medical use 
with severe restrictions. The Center for Medicinal Cannabis Research 
in California, among others, is conducting research with marijuana 
at the IND level, but these studies have not yet progressed to the 
stage of submitting an NDA. Thus, at this time, the known risks of 
marijuana use have

[[Page 40563]]

not been shown to be outweighed by specific benefits in well-
controlled clinical trials that scientifically evaluate safety and 
efficacy.
    In addition, the agency cannot conclude that marijuana has an 
acceptable level of safety without assurance of a consistent and 
predictable potency and without proof that the substance is free of 
contamination. If marijuana is to be investigated more widely for 
medical use, information and data regarding the chemistry, 
manufacturing, and specifications of marijuana must be developed. 
Therefore, HHS concludes that, even under medical supervision, 
marijuana has not been shown at present to have an acceptable level 
of safety.

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Marijuana

Scheduling Review Document: Eight Factor Analysis

Drug and Chemical Evaluation Section
Office of Diversion Control
Drug Enforcement Administration, April 2011

INTRODUCTION

    On October 9, 2002, the Coalition for Rescheduling Cannabis 
submitted a petition to the Drug Enforcement Administration (DEA) to 
initiate proceedings for a repeal of the rules or regulations that 
place marijuana \3\ in schedule I of the Controlled Substances Act 
(CSA). The petition requests that marijuana be rescheduled as 
``cannabis'' in either schedule III, IV, or V of the CSA. The 
petitioner claims that:
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    \3\ The Controlled Substances Act (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 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 originally used in the 
CSA. This document uses the spelling that is more common in current 
usage, ``marijuana.''
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    1. Cannabis has an accepted medical use in the United States;
    2. Cannabis is safe for use under medical supervision;
    3. Cannabis has an abuse potential lower than schedule I or II 
drugs; and
    4. Cannabis has a dependence liability that is lower than 
schedule I or II drugs.
    The DEA accepted this petition for filing on April 3, 2003. In 
accordance with 21 U.S.C. 811(b), after gathering the necessary 
data, the DEA requested a medical and scientific evaluation and 
scheduling recommendation for cannabis from the Department of Health 
and Human Services (DHHS) on July 12, 2004. On December 6, 2006, the 
DHHS provided its scientific and medical evaluation titled Basis for 
the Recommendation for Maintaining Marijuana in Schedule I of the 
Controlled Substances Act and recommended that marijuana continue to 
be controlled in schedule I of the CSA.
    The CSA requires DEA to determine whether the DHHS scientific 
and medical evaluation and scheduling recommendation and ``all other 
relevant data'' constitute substantial evidence that the drug should 
be rescheduled as proposed in the petition. 21 U.S.C. 811(b). This 
document is prepared accordingly.
    The Attorney General ``may by rule'' transfer a drug or other 
substance between schedules if he finds that such drug or other 
substance has a potential for abuse, and makes with respect to such 
drug or other substance the findings prescribed by subsection (b) of 
Section 812 for the schedule in which such drug is to be placed. 21 
U.S.C. 811(a)(1). In order for a substance to be placed in schedule 
I, the Attorney General 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.

21 U.S.C. 812(b)(1)(A)-(C). To be classified in one of the other 
schedules (II through V), a drug of abuse must have either a 
``currently accepted medical use in treatment in the United States 
or a currently accepted medical use with severe restrictions.'' 21 
U.S.C. 812(b)(2)-(5). 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, 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.''').
    In deciding whether to grant a petition to initiate rulemaking 
proceedings with respect to a particular drug, DEA must determine 
whether there is sufficient 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). To do so, the CSA requires that DEA 
and DHHS consider eight factors as specified in 21 U.S.C. 811(c). 
This document is organized according to these eight factors.
    With specific regard to the issue of whether the drug has a 
currently accepted medical use in treatment in the United States, 
DHHS states that the FDA has not evaluated nor approved a new drug 
application (NDA) for marijuana. The long-established factors 
applied by the DEA for determining whether a drug has a ``currently 
accepted medical use'' under the CSA are:

[[Page 40567]]

    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. The scientific evidence must be widely available.

57 FR 10,499, 10,506 (1992); Alliance for Cannabis Therapeutics v. 
DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994) (ACT) (upholding these 
factors as valid criteria for determining ``accepted medical use''). 
A drug will be deemed to have a currently accepted medical use for 
CSA purposes only if all five of the foregoing elements are 
demonstrated. This test is considered here under the third factor.
    Accordingly, as the eight factor analysis sets forth in detail 
below, the evidence shows:
    1. Actual or relative potential for abuse. Marijuana has a high 
abuse potential. It is the most widely used illicit substance in the 
United States. 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 has improved. Marijuana produces various 
pharmacological effects, including subjective (e.g., euphoria, 
dizziness, disinhibition), cardiovascular, acute and chronic 
respiratory, immune system, cognitive impairment, and prenatal 
exposure effects as well as possible increased risk of schizophrenia 
among those predisposed to psychosis.
    3. Current scientific knowledge. There is no currently accepted 
medical use for marijuana in the United States. Under the five-part 
test for currently accepted medical use approved in ACT, 15 F.3d at 
1135, there is no complete scientific analysis of marijuana's 
chemical components; there are no adequate safety studies; there are 
no 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. While a number of states have 
passed voter referenda or legislative actions authorizing the use of 
marijuana for medical purposes, this does not establish a currently 
accepted medical use under federal law. 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 use has been 
relatively stable from 2002 to 2009, and it continues to be the most 
widely used illicit drug. In 2009, there were 16.7 million current 
users. There were also 2.4 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 
laboratories. High consumption of marijuana is fueled by increasing 
amounts of both domestically grown and illegally smuggled foreign 
source marijuana, and an increasing percentage of seizures involve 
high potency marijuana.
    5. Scope, duration, and significance of abuse. Abuse of 
marijuana is widespread and significant. In 2008, for example, an 
estimated 3.9 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 treatment for substance 
abuse are for primary marijuana abuse: in 2007, 16 percent of all 
admissions were for primary marijuana abuse, representing 287,933 
individuals. Of individuals under the age of 19 admitted to 
substance abuse treatment, more than half were treated for primary 
marijuana 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, including impaired driving, and impaired 
performance on tests of learning and associative processes. Public 
health risks from chronic use of marijuana include respiratory 
effects, physical dependence, and psychological problems.
    7. Psychic or physiological dependence liability. Long-term, 
regular use of marijuana can lead to physical dependence and 
withdrawal following discontinuation, as well as psychic addiction 
or dependence.
    8. Immediate precursor. Marijuana is not an immediate precursor 
of any controlled substance.
    This review shows, in particular, that the evidence is 
insufficient with respect to the specific issue of whether marijuana 
has a currently accepted medical use under the five-part test. The 
evidence was insufficient in this regard on the prior two occasions 
when DEA considered petitions to reschedule marijuana in 1992 (57 FR 
10499) \4\ and in 2001 (66 FR 20038).\5\ Little has changed since 
then with respect to the lack of clinical evidence necessary to 
establish that marijuana has a currently accepted medical use: only 
a limited number of FDA-approved Phase 1 clinical investigations 
have been carried out, and there have been no studies that have 
scientifically assessed the efficacy and full safety profile of 
marijuana for any medical condition.\6\ The limited existing 
clinical evidence is not adequate to warrant rescheduling of 
marijuana under the CSA.
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    \4\ Petition for review dismissed, Alliance for Cannabis 
Therapeutics v. DEA, 15 F.3d 1131 (D.C. Cir. 1994).
    \5\ Petition for review dismissed, Gettman v. DEA, 290 F.3d 430 
(D.C. Cir. 2002).
    \6\ Clinical trials generally proceed in three phases. See 21 
CFR 312.21 (2010). Phase I trials encompass initial testing in human 
subjects, generally involving 20 to 80 patients. Id. They are 
designed primarily to assess initial safety, tolerability, 
pharmacokinetics, pharmacodynamics, and preliminary studies of 
potential therapeutic benefit. 62 FR 66113, 1997. Phase II and Phase 
III studies involve successively larger groups of patients: usually 
no more than several hundred subjects in Phase II, and usually from 
several hundred to several thousand in Phase III. 21 CFR 312.21. 
These studies are designed primarily to explore (Phase II) and to 
demonstrate or confirm (Phase III) therapeutic efficacy and benefit 
in patients. 62 FR 66113, 1997. See also Riegel v. Medtronic, Inc., 
128 S.Ct. 999, 1018-19 n.15 (2008) (Ginsburg, J., dissenting).
---------------------------------------------------------------------------

    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 American 
high-schoolers. Marijuana is the most frequently identified drug in 
state, local and federal forensic laboratories, with increasing 
amounts both of domestically grown and of illicitly smuggled 
marijuana. Marijuana's main psychoactive ingredient, [Delta]\9\-THC, 
is an effective reinforcer in laboratory animals, including primates 
and rodents. 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. Indicators of Abuse Potential

    DHHS 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. 91-144, 91st 
Cong., Sess.1 (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 other substance in amounts sufficient to create a hazard to their 
health or to the safety of other individuals or to the community; or
     There is significant diversion of the drug or other 
substance from legitimate drug channels; or
     Individuals are taking the drug or substance on their 
own initiative rather than on the basis of medical advice from a 
practitioner licensed by law to administer such drugs; or
     The drug is a new drug so related in its action to a 
drug or other substance already listed as having a potential for 
abuse to make it likely that the drug substance will have the same 
potential for abuse as such drugs, thus

[[Page 40568]]

making it reasonable to assume that there may be significant 
diversion 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.
    After considering the above items, DHHS has found that marijuana 
has a high potential for abuse.
    1. There is evidence that individuals are taking the drug or 
other substance in amounts sufficient to create a hazard to their 
health or to the safety of other individuals or to the community.
    Marijuana is the most highly used illicit substance in the 
United States. Smoked marijuana exerts a number of cardiovascular 
and respiratory effects, both acutely and chronically and can cause 
chronic bronchitis and inflammatory abnormalities of the lung 
tissue. Marijuana's main psychoactive ingredient [Delta]\9\-THC 
alters immune function and decreases resistance to microbial 
infections. The cognitive impairments caused by marijuana use that 
persist beyond behaviorally detectable intoxication may have 
significant consequences on workplace performance and safety, 
academic achievement, and automotive safety, and adolescents may be 
particularly vulnerable to marijuana's cognitive effects. Prenatal 
exposure to marijuana was linked to children's poorer performance in 
a number of cognitive tests. Data on the extent and scope of 
marijuana abuse are presented under factors 4 and 5 of this 
analysis. DHHS's discussion of the harmful health effects of 
marijuana and additional information gathered by DEA are 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 other substance 
from legitimate drug channels.
    DHHS states that at present, marijuana is legally available 
through legitimate channels for research only and thus has a limited 
potential for diversion. (DEA notes that while a number of states 
have passed voter referenda or legislative actions authorizing the 
use of marijuana for medical purposes, this does not establish a 
currently accepted medical use under federal law.) In addition, the 
lack of significant diversion of investigational supplies may result 
from the ready availability of illicit cannabis of equal or greater 
quality.
    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 abused 
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 both of domestically grown and 
of illicitly smuggled marijuana. An observed increase in the potency 
of seized marijuana also raises concerns.
    3. Individuals are taking the drug or substance on their own 
initiative rather than on the basis of medical advice from a 
practitioner licensed by law to administer such drugs.
    16.7 million adults over the age of 12 reported having used 
marijuana in the past month, according to the 2009 National Survey 
on Drug Use and Health (NSDUH), as further described later in this 
factor. DHHS states in its 2006 analysis of the petition that the 
FDA has not evaluated or approved a new drug application (NDA) for 
marijuana for any therapeutic indication, although several 
investigational new drug (IND) applications are currently active. 
Based on the large number of individuals who use marijuana, DHHS 
concludes that the majority of individuals using cannabis do so on 
their own initiative, not on the basis of medical advice from a 
practitioner licensed to administer the drug in the course of 
professional practice.
    4. The drug is a new drug so related in its action to a drug or 
other substance already listed as having a potential for abuse to 
make it likely that the drug substance will have the same potential 
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.
    Marijuana is not a new drug. Marijuana's primary psychoactive 
ingredient delta-9-tetrahydrocannabinol ([Delta]\9\-THC) is 
controlled in schedule I of the CSA. DHHS states that there are two 
drug products containing cannabinoid compounds that are structurally 
related to the active components in marijuana. Both are controlled 
under the CSA. Marinol is a schedule III drug product containing 
synthetic [Delta]\9\-THC, known generically as dronabinol, 
formulated in sesame oil in soft gelatin capsules. Marinol was 
approved by the FDA in 1985 for the treatment of two medical 
conditions: nausea and vomiting associated with cancer chemotherapy 
in patients that had failed to respond adequately to conventional 
anti-emetic treatments, and for the treatment of anorexia associated 
with weight loss in patients with acquired immunodeficiency syndrome 
(AIDS). Cesamet is a drug product containing the schedule II 
substance, nabilone, that was approved for marketing by the FDA in 
1985 for the treatment of nausea and vomiting associated with cancer 
chemotherapy. All other structurally related cannabinoids in 
marijuana are already listed as Schedule I drugs under the CSA.
    In addition, DEA notes that marijuana and its active ingredient 
[Delta]\9\-THC are related in their action to other controlled drugs 
of abuse when tested in preclinical and clinical tests of abuse 
potential. Data showing that marijuana and [Delta]\9\-THC exhibit 
properties common to other controlled drugs of abuse in those tests 
are described below in this factor.
    In summary, examination of the indicators set forth in the 
legislative history of the CSA demonstrates that marijuana has a 
high potential for abuse. Indeed, marijuana is abused in amounts 
sufficient to create hazards to public health and safety; there is 
significant trafficking of the substance; individuals are using 
marijuana on their own initiative, for the vast majority, rather 
than on the basis of medical advice; and finally, marijuana exhibits 
several properties common to those of drugs already listed as having 
abuse potential.
    The petitioner states that, ``widespread use of cannabis is not 
an indication of its abuse potential [...] .'' (Exh. C, Section 
IV(15), pg. 87).
    To the contrary, according to the indicators set forth in the 
legislative history of the CSA as described above, the fact that 
``Individuals are taking the drug or substance on their own 
initiative rather than on the basis of medical advice from a 
practitioner licensed by law to administer such drugs'' is indeed 
one of several indicators that a drug has high potential for abuse.

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-OH- [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 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. Discriminative Stimulus Effects

    The drug discrimination paradigm is used as an animal model of 
human subjective effects (Solinas et al., 2006). This procedure 
provides a direct measure of stimulus

[[Page 40569]]

specificity of a test drug in comparison with a known standard drug 
or a neutral stimulus (e.g., injection of saline water). The light-
headedness and warmth associated with drinking alcohol or the 
jitteriness and increased heart rate associated with drinking coffee 
are examples of substance-specific stimulus effects. The drug 
discrimination paradigm is based on the ability of nonhuman and 
human subjects to learn to identify the presence or absence of these 
stimuli and to differentiate among the constellation of stimuli 
produced by different pharmacological classes. In drug 
discrimination studies, the drug stimuli function as cues to guide 
behavioral choice, which is subsequently reinforced with other 
rewards. Repeated pairing of the reinforcer with only drug-
appropriate responses can engender reliable discrimination between 
drug and no-drug or amongst several drugs. Because some 
interoceptive stimuli are believed to be associated with the 
reinforcing effects of drugs, the drug discrimination paradigm is 
used to evaluate the abuse potential of new substances.
    DHHS states that in the drug discrimination test, animals are 
trained to respond by pressing one bar when they receive the known 
drug of abuse and another bar when they receive placebo.
    DHHS states that cannabinoids appear to provide unique 
discriminative stimulus effects because stimulants, non-cannabinoid 
hallucinogens, opioids, benzodiazepines, barbiturates, NMDA 
antagonists and antipsychotics do not fully substitute for 
[Delta]\9\-THC (Browne and Weissman, 1981; Balster and Prescott, 
1992, Gold et al., 1992; Barrett et al., 1995; Wiley et al., 1995). 
Animals, including monkeys and rats (Gold et al., 1992), as well as 
humans (Chait et al., 1988), can discriminate cannabinoids from 
other drugs or placebo.
    DEA notes several studies that show that the discriminative 
stimulus effects of [Delta]\9\-THC are mediated via a cannabinoid 
receptor, specifically, the CB1 receptor subtype, and 
that the CB1 antagonist rimonabant (SR 141716A) 
antagonizes the discriminative stimulus effects of [Delta]\9\-THC in 
several species (P[eacute]rio et al., 1996; Mansbach et al., 1996; 
J[auml]rbe et al., 2001). The subjective effects of marijuana and 
[Delta]\9\-THC are, therefore, mediated by a neurotransmitter system 
in the brain that is specific to [Delta]\9\-THC and cannabinoids.

b. Self-Administration Studies

    Self-administration is a behavioral assay that measures the 
rewarding effects of a drug that increase the likelihood of 
continued drug-taking behavior. Drugs that are self-administered by 
animals are likely to produce rewarding effects in humans. A strong 
correlation exists between drugs and other substances that are 
abused by humans and those that maintain self-injection in 
laboratory animals (Schuster and Thompson, 1969; Griffiths et al., 
1980). As a result, intravenous self-injection of psychoactive 
substances in laboratory animals is considered to be useful for the 
prediction of human abuse liability of these compounds (Johanson and 
Balster, 1978; Collins et al., 1984).
    DHHS states that self-administration of hallucinogenic-like 
drugs, such as cannabinoids, lysergic acid diethylamide (LSD), and 
mescaline, has been difficult to demonstrate in animals (Yanagita, 
1980). DHHS further states that an inability to establish self-
administration has no practical importance in the assessment of 
abuse potential, because it is known that humans voluntarily consume 
a particular drug (such as cannabis) for its pleasurable effects.
    DHHS states that the experimental literature generally reports 
that na[iuml]ve animals will not self-administer cannabinoids unless 
they have had previous experience with other drugs of abuse, 
however, animal research in the past decade has provided several 
animal models of reinforcement by cannabinoids to allow for pre-
clinical research into cannabinoids' reinforcing effects. Squirrel 
monkeys trained to self-administer intravenous cocaine will continue 
to respond at the same rate as when [Delta]\9\-THC is substituted 
for cocaine, at doses that are comparable to those used by humans 
who smoke marijuana (Tanda et al., 2000). This effect is blocked by 
the cannabinoid receptor antagonist, SR 141716. Squirrel monkeys 
without a history of any drug exposure can be successfully trained 
to self-administer [Delta]\9\-THC intravenously (Justinova et al., 
2003). The maximal rate of responding is 4 [micro]g/kg/injection, 
which is 2-3 times greater than that observed in previous studies 
using cocaine-experienced monkeys. Rats will self-administer 
[Delta]\9\-THC when it is applied intracerebroventricularly 
(i.c.v.), but only at the lowest doses tested (0.01:-0.02/[micro]g/
infusion) (Braida et al., 2004). This effect is antagonized by the 
cannabinoid antagonist SR141716 and by the opioid antagonist 
naloxone (Braida et al., 2004). Additionally, mice will self-
administer WIN 55212, a synthetic CB1 receptor agonist 
with a non-cannabinoid structure (Martellotta et al., 1998).
    DEA notes a study showing that the opioid antagonist naltrexone 
reduces the self-administration responding for [Delta]\9\-THC in 
squirrel monkeys (Justinova et al., 2004). These investigators, 
using second-order schedules of drug-seeking procedures, also showed 
that pre-session administration of [Delta]\9\-THC and other 
cannabinoid agonists, or morphine, but not cocaine, reinstates the 
[Delta]\9\-THC seeking behavior following a period of abstinence 
(Justinova et al., 2008). Furthermore, the endogenous cannabinoid 
anandamide and its synthetic analog methanandamide are self-
administered by squirrel monkeys, and CB1 receptor 
antagonism blocks the reinforcing effect of both substances 
(Justinova et al., 2005).

c. Place Conditioning Studies

    Conditioned place preference (CPP) is another behavioral assay 
used to determine if a drug has rewarding properties. In this test, 
animals in a drug-free state 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.
    DHHS states that animals exhibit CPP to [Delta]\9\-THC, but only 
at the lowest doses tested (0.075-0.75 mg/kg, i.p.) (Braida et al., 
2004). The effect is antagonized by the cannabinoid antagonist, 
rimonabant, as well as the opioid antagonist, naloxone. The effect 
of naloxone on CPP to [Delta]\9\-THC raises the possibility that the 
opioid system may be involved in the rewarding properties of 
[Delta]\9\-THC and marijuana. DEA notes a recent review (Murray and 
Bevins, 2010) that further explores the currently available 
knowledge on [Delta]\9\-THC's ability to induce CPP and conditioned 
place aversion (CPA), and further supports that low doses of 
[Delta]\9\-THC appear to have conditioned rewarding effects, whereas 
higher doses have aversive effects.

2. Clinical Studies

    DHHS states that the physiological, psychological, and 
behavioral effects of marijuana vary among individuals and presents 
a list of common responses to cannabinoids, as described in the 
scientific literature (Adams and Martin, 1996; Hollister, 1986, 
1988; Institute of Medicine, 1982):

    1. Dizziness, nausea, tachycardia, facial flushing, dry mouth 
and tremor initially
    2. Merriment, happiness and even exhilaration at high doses
    3. Disinhibition, relaxation, increased sociability, and 
talkativeness
    4. Enhanced sensory perception, giving rise to increased 
appreciation of music, art and touch
    5. Heightened imagination leading to a subjective sense of 
increased creativity
    6. Time distortions
    7. Illusions, delusions and hallucinations are rare except at 
high doses
    8. Impaired judgment, reduced coordination and ataxia, which can 
impede driving ability or lead to an increase in risk-taking 
behavior
    9. Emotional lability, incongruity of affect, dysphoria, 
disorganized thinking, inability to converse logically, agitation, 
paranoia, confusion, restlessness, anxiety, drowsiness and panic 
attacks may occur, especially in inexperienced users or in those who 
have taken a large dose
    10. Increased appetite and short-term memory impairment are 
common

    These subjective responses to marijuana are pleasurable to many 
humans and are associated with drug-seeking and drug-taking 
(Maldonado, 2002). DHHS states that, as with most psychoactive 
drugs, an individual's response to marijuana can be influenced by a 
person's medical/psychiatric history as well as their experience 
with drugs. Frequent marijuana users (used more than 100 times) were 
better able to identify a drug effect from low-dose [Delta]\9\-THC 
than infrequent users (used less than 10 times) and were less likely 
to experience sedative effects from the drug (Kirk and de Wit, 
1999). However, dose preferences have been demonstrated for 
marijuana in which higher doses (1.95 percent [Delta]\9\-THC) are 
preferred over lower doses (0.63 percent [Delta]\9\-THC) (Chait and 
Burke, 1994).
    DEA notes that an extensive review of the reinforcing effects of 
marijuana in humans was included in DEA/DHHS's prior review of

[[Page 40570]]

marijuana (Notice of Denial of Petition, 66 FR 20038, 2001). While 
additional studies have been published on the reinforcing effects of 
marijuana in humans (e.g., see review by Cooper and Haney, 2009), 
they are consistent with the information provided in DEA/DHHS's 
prior review of this matter. Excerpts are provided below, with some 
citations omitted.

    Both marijuana and THC can serve as positive reinforcers in 
humans. Marijuana and [Delta]\9\-THC produced profiles of behavioral 
and subjective effects that were similar regardless of whether the 
marijuana was smoked or taken orally, as marijuana in brownies, or 
orally as THC-containing capsules, although the time course of 
effects differed substantially. There is a large clinical literature 
documenting the subjective, reinforcing, discriminative stimulus, 
and physiological effects of marijuana and THC and relating these 
effects to the abuse potential of marijuana and THC (e.g., Chait et 
al., 1988; Lukas et al., 1995; Kamien et al., 1994; Chait and Burke, 
1994; Chait and Pierri, 1992; Foltin et al., 1990; Azorlosa et al., 
1992; Kelly et al., 1993, 1994; Chait and Zacny, 1992; Cone et al., 
1988; Mendelson and Mello, 1984).
    These listed studies represent a fraction of the studies 
performed to evaluate the abuse potential of marijuana and THC. In 
general, these studies demonstrate that marijuana and THC dose-
dependently increases heart rate and ratings of ``high'' and ``drug 
liking'', and alters behavioral performance measures (e.g., Azorlosa 
et al., 1992; Kelly et al., 1993, 1994; Chait and Zacny, 1992; 
Kamien et al., 1994; Chait and Burke, 1994; Chait and Pierri, 1992; 
Foltin et al., 1990; Cone et al., 1988; Mendelson and Mello, 1984). 
Marijuana also serves as a discriminative stimulus in humans and 
produces euphoria and alterations in mood. These subjective changes 
were used by the subjects as the basis for the discrimination from 
placebo (Chait et al., 1988).
    In addition, smoked marijuana administration resulted in 
multiple brief episodes of euphoria that were paralleled by rapid 
transient increases in EEG alpha power (Lukas et al., 1995); these 
EEG changes are thought to be related to CNS processes of 
reinforcement (Mello, 1983).
    To help elucidate the relationship between the rise and fall of 
plasma THC and the self-reported psychotropic effects, Harder and 
Rietbrock (1997) measured both the plasma levels of THC and the 
psychological ``high'' obtained from smoking a marijuana cigarette 
containing 1% THC. As can be seen from these data, a rise in plasma 
THC concentrations results in a corresponding increase in the 
subjectively reported feelings of being ``high''. However, as THC 
levels drop the subjectively reported feelings of ``high'' remain 
elevated. The subjective effects seem to lag behind plasma THC 
levels. Similarly, Harder and Rietbrock compared lower doses of 0.3% 
THC-containing and 0.1% THC-containing cigarettes in human subjects.
    As can be clearly seen from these data, even low doses of 
marijuana, containing 1%, 0.3% and even 0.1% THC, typically referred 
to as ``non-active'', are capable of producing subjective reports 
and physiological markers of being ``high'.
    THC and its major metabolite, 11-OH-THC, have similar 
psychoactive and pharmacokinetic profiles in man (Wall et al., 1976; 
DiMarzo et al., 1998; Lemberger et al., 1972). Perez-Reyes et al. 
(1972) reported that THC and 11-OH-THC were equipotent in generating 
a ``high'' in human volunteers. However, the metabolite, 11-OH-THC, 
crosses the blood-brain barrier faster than the parent THC compound 
(Ho et al., 1973; Perez-Reyes et al., 1976). Therefore, the changes 
in THC plasma concentrations in humans may not be the best 
predictive marker for the subjective and physiological effects of 
marijuana in humans. Cocchetto et al. (1981) have used hysteresis 
plots to clearly demonstrate that plasma THC concentration is a poor 
predictor of simultaneous occurring physiological (heart rate) and 
psychological (``high'') pharmacological effects. Cocchetto et al. 
demonstrated that the time course of tachycardia and psychological 
responses lagged behind the plasma THC concentration-time profile. 
As recently summarized by Martin and Hall (1997, 1998)
    ``There is no linear relationship between blood [THC] levels and 
pharmacological effects with respect to time, a situation that 
hampers the prediction of cannabis-induced impairment based on THC 
blood levels (p90)''.

    Drug craving is an urge or desire to re-experience the drug's 
effects and is considered to be one component of drug dependence, in 
part responsible for continued drug use and relapse after treatment 
or during periods of drug abstinence. DEA notes that Budney and 
colleagues (1999) reported that 93 percent of marijuana-dependent 
adults seeking treatment reported experiencing mild craving for 
marijuana, and 44 percent rated their past craving as severe. 
Heishman and colleagues developed in 2001 a Marijuana Craving 
Questionnaire (MCQ). When they administered their MCQ to 217 current 
marijuana smokers who were not attempting to quit or reduce their 
marijuana use, they found that marijuana craving can be measured in 
current smokers that are not seeking treatment. Most subjects (83 
percent) reported craving marijuana 1-5 times per day, and 82 
percent reported that each craving episode lasted 30 minutes or 
less. Furthermore, they determined that craving for marijuana can be 
characterized by four components: (1) compulsivity, an inability to 
control marijuana use; (2) emotionality, use of marijuana in 
anticipation of relief from withdrawal or negative mood; (3) 
expectancy, anticipation of positive outcomes from smoking 
marijuana; and (4) purposefulness, intention and planning to use 
marijuana for positive outcomes.

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

    Marijuana use has been relatively stable from 2002 to 2008, and 
it 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. DHHS provided in its 2006 documents 
data relevant to actual abuse of marijuana including data from the 
National Survey on Drug Use and Health (NSDUH; formally known as the 
National Household Survey on Drug Abuse), the Drug Abuse Warning 
Network (DAWN), Monitoring the Future (MTF) survey, and the 
Treatment Episode Data Set (TEDS). These data collection and 
reporting systems provide quantitative data on many factors related 
to abuse of a particular substance, including incidence, pattern, 
consequence and profile of the abuser of specific substances. DEA 
provides here updates to these databases as well as additional data 
on trafficking and illicit availability of marijuana using 
information from databases it produces, such as the National 
Forensic Laboratory Information System (NFLIS), the System to 
Retrieve Information from Drug Evidence (STRIDE) and 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, formerly known as 
the National Household Survey on Drug Abuse (NHSDA), is conducted 
annually by the Department of Health and Human Service's Substance 
Abuse and Mental Health Services Administration (SAMHSA). It 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 2009 NSDUH report, marijuana was the most 
commonly used illicit drug (16.7 million past month users) in the 
United States. (Note that NSDUH figures on marijuana use include 
hashish use; the relative proportion of hashish use to marijuana use 
is very low). Marijuana was also the most widely abused drug. The 
2009 NSDUH report stated that 4.3 million persons were classified 
with substance dependence or abuse of marijuana in the past year 
based on criteria specified in the Diagnostic and Statistical Manual 
of Mental Disorders, 4th edition (DSM-IV). Among persons aged 12 or 
older, the past month marijuana use in 2009 (6.6 percent) was 
statistically significantly higher than in 2008 (6.1 percent). In 
2008, among adults aged 18 or older who first tried marijuana at age 
14 or younger, 13.5 percent were classified with illicit drug 
dependence or abuse, higher than the 2.2 percent of adults who had 
first used marijuana at age 18 or older.
    In 2008, among past year marijuana users aged 12 or older, 15.0 
percent used marijuana on 300 or more days within the previous 12 
months. This translates into 3.9 million people using marijuana on a 
daily or almost

[[Page 40571]]

daily basis over a 12-month period, higher than the estimate of 3.6 
million (14.2 percent of past year users) in 2007. Among past month 
marijuana users, 35.7 percent (5.4 million) used the drug on 20 or 
more days in the past month.

2. Monitoring the Future

    Monitoring the Future (MTF) is a national survey conducted by 
the Institute for Social Research at the University of Michigan 
under a grant from the National Institute on Drug Abuse (NIDA) that 
tracks drug use trends among American adolescents in the 8th, 10th, 
and 12th grades. Marijuana was the most commonly used illicit drug 
reported in the 2010 MTF report. Approximately 8.0 percent of 8th 
graders, 16.7 percent of the 10th graders, and 21.4 percent of 12th 
graders surveyed in 2010 reported marijuana use during the past 
month prior to the survey. Monitoring the Future participants 
reported a statistically significant increase of daily use in the 
past month in 2010, compared to 2009, 1.2 percent, 3.3 percent, and 
6.1 percent of eighth, tenth and twelfth graders, respectively.

3. DAWN ED (Emergency Department)

    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. DAWN provides a picture of the impact of 
drug use, misuse, and abuse on metropolitan areas and across the 
nation. DAWN gathers data on drug abuse-related ED visits from a 
representative sample of hospitals in the coterminous United States. 
DAWN ED gathers data on emergency department visits relating to 
substance use including, but not limited to, alcohol, illicit drugs, 
and other substances categorized as psychotherapeutic, central 
nervous system, respiratory, cardiovascular, alternative medication, 
anti-infective, hormone, nutritional product and gastrointestinal 
agents. 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.
    In 2009, marijuana was involved in 376,467 ED visits, out of 
1,948,312 drug-related ED visits, as estimated by DAWN ED for the 
entire United States. This compares to a higher number of ED visits 
involving cocaine (422,896), and lower numbers of ED visits 
involving heroin (213,118) and stimulants (amphetamine, 
methamphetamine) (93,562). 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 182.2 per 
100,000 population aged 12 to 17, 484.8 per 100,000 population aged 
18 to 20, and 360.2 per 100,000 population aged 21 to 24.

4. Treatment Episode Data Set (TEDS) System

    Users can become dependent on marijuana to the point that they 
seek treatment to stop abusing it or are referred to a drug abuse 
treatment program. The TEDS system is part of the SAMHSA Drug and 
Alcohol Services Information System. TEDS comprises data on 
treatment admissions that are routinely collected by states in 
monitoring their substance abuse treatment systems. The primary goal 
of the TEDS is to monitor the characteristics of treatment episodes 
for substances abusers. The TEDS report provides information on both 
the demographic and substance use characteristics of admissions to 
treatment for abuse of alcohol and drugs in facilities that report 
to individual state administrative data systems. TEDS does not 
include all admissions to substance abuse treatment. It includes 
admissions to facilities that are licensed or certified by the state 
substance abuse agency to provide substance abuse treatment (or are 
administratively tracked by the agency for other reasons). In 
general, facilities reporting to TEDS are those that receive state 
alcohol and/or drug agency funds (including federal block grant 
funds) for the provision of alcohol and/or drug treatment services. 
The primary substances reported by TEDS are alcohol, cocaine, 
marijuana (marijuana is considered together with hashish), heroin, 
other opiates, PCP, hallucinogens, amphetamines, other stimulants, 
tranquilizers, sedatives, inhalants and other/unknown. TEDS defines 
Primary Substance of Abuse 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). A client may be 
abusing more than three substances at the time of admission, but 
only three are recorded in TEDS.
    Admissions for primary abuse of marijuana/hashish accounted for 
16 percent of all treatment admissions reported to the TEDS system 
in 2006 and 2007. In 2006, 2007 and 2008, 1,933,206, 1,920,401 and 
2,016,256 people were admitted to drug and alcohol treatment in the 
United States, respectively. The marijuana/hashish admissions 
represented 16 percent (308,670), 16 percent (307,123) and 17.2 
percent (346,679) of the total drug/alcohol treatment admissions in 
2006, 2007 and 2008, respectively. In 2008, 65.8 percent of the 
individuals admitted for marijuana were aged 12-17, 18-20 and 21-25 
(30.5 percent, 15.3 percent and 20.0 percent, respectively). Among 
the marijuana/hashish admissions in 2007 in which age of first use 
was reported (286,194), 25.1 percent began using marijuana at age 12 
or younger.

5. Forensic Laboratory Data

    Marijuana is widely available in the United States, fueled by 
increasing marijuana production at domestic grow sites as well as 
increasing production in Mexico and Canada. Data on marijuana 
seizures from federal, state, and local law enforcement laboratories 
have indicated that there is significant trafficking of marijuana. 
The National Forensic Laboratory Information System (NFLIS) is a 
program sponsored by the Drug Enforcement Administration's Office of 
Diversion Control. NFLIS compiles information on exhibits analyzed 
in state and local law enforcement laboratories. The System to 
Retrieve Information from Drug Evidence (STRIDE) is a DEA database 
which compiles information on exhibits analyzed in DEA laboratories. 
NFLIS and STRIDE together capture data for all substances reported 
by forensic laboratory analyses. More than 1,700 unique substances 
are reported to these two databases.
    NFLIS showed that marijuana was the most frequently identified 
drug in state and local laboratories from January 2001 through 
December 2010. Marijuana accounted for between 34 percent and 38 
percent of all drug exhibits analyzed during that time frame. 
Similar to NFLIS, STRIDE data showed that marijuana was the most 
frequently identified drug in DEA laboratories for the same 
reporting period. From January 2001 through December 2010, a range 
of between 17 percent and 21 percent of all exhibits analyzed in DEA 
laboratories were identified as marijuana (Table 1).

 Table 1--Marijuana (Other Than Hashish) (Exhibits and Cases) Reported by NFLIS and STRIDE, 2001-2010, Forensic
                                                 Laboratory Data
----------------------------------------------------------------------------------------------------------------
                                                             NFLIS                            STRIDE
                                               -----------------------------------------------------------------
                                                 Exhibits  (percent               Exhibits  (percent
                                                  total exhibits)       Cases      total exhibits)       Cases
----------------------------------------------------------------------------------------------------------------
2001..........................................      314,002 (37.9%)     261,191       16,523 (20.7%)      13,256
2002..........................................      373,497 (36.6%)     312,161       14,010 (19.4%)      11,306
2003..........................................      407,046 (36.7%)     339,995       13,946 (19.9%)      10,910
2004..........................................      440,964 (35.5%)     371,841       13,657 (18.4%)      10,569
2005..........................................      469,186 (33.5%)     394,557       14,004 (18.3%)      10,661

[[Page 40572]]

 
2006..........................................      506,472 (33.6%)     421,943       13,597 (18.5%)      10,277
2007..........................................      512,082 (34.7%)     423,787       13,504 (19.2%)      10,413
2008..........................................      513,644 (35.1%)     421,782       12,828 (18.8%)      10,109
2009..........................................      524,827 (35.6%)     414,006       12,749 (17.7%)      10,531
2010..........................................      464,059 (36.3%)     362,739       11,293 (16.7%)       7,158
----------------------------------------------------------------------------------------------------------------
Data queried 03-04-2011.


Table 2--Hashish (Exhibits and Cases) Reported by NFLIS and STRIDE, 2001-
                     2010, Forensic Laboratory Data
------------------------------------------------------------------------
                                      NFLIS                STRIDE
                             -------------------------------------------
                               Exhibits    Cases     Exhibits    Cases
------------------------------------------------------------------------
2001........................      1,689      1,671         53         50
2002........................      2,278      2,254         40         38
2003........................      2,533      2,503         48         42
2004........................      2,867      2,829         63         51
2005........................      2,674      2,639        122         90
2006........................      2,836      2,802        102         76
2007........................      3,224      3,194        168        122
2008........................      2,988      2,920        124        102
2009........................      2,952      2,843        119         96
2010........................      2,473      2,392        141         84
------------------------------------------------------------------------
Data queried 03-04-2011.

    Since 2001, the total number of exhibits and cases of marijuana 
and the amount of marijuana seized federally has remained high and 
the number of marijuana plants eradicated has considerably increased 
(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 by the Drug Enforcement Administration, the 
Federal Bureau of Investigation, United States Customs and Border 
Protection, and United States Immigration and Customs Enforcement, 
within the jurisdiction of the United States. 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, contraband (chemicals and precursors, 
currency, drugs, equipment and weapons). FDSS reports total federal 
drug seizures (kg) of substances such as cocaine, heroin, MDMA, 
methamphetamine, and cannabis (marijuana and hashish). The yearly 
volume of cannabis seized (Table 3), consistently exceeding a 
thousand metric tons per year, shows that cannabis is very widely 
trafficked in the United States.

                                                                           Table 3--Total Federal Seizures of Cannabis
                                                                                        [Expressed in kg]
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        2002          2003          2004          2005          2006          2007          2008          2009          2009
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Cannabis..........................................................     1,103,173     1,232,711     1,179,230     1,116,977     1,141,915     1,459,220     1,590,793     1,911,758     1,858,808
Marijuana.........................................................     1,102,556     1,232,556     1,179,064     1,116,589     1,141,737     1,458,883     1,590,505     1,910,775     1,858,422
Hashish...........................................................           618           155           166           388           178           338           289           983           386
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

7. Potency Monitoring Project

    Rising availability of high potency (i.e., with high [Delta]\9\-
THC concentrations) marijuana has pushed the average marijuana 
potency to its highest recorded level. 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 cannabis, 
hashish and hash oil samples provided by DEA regional laboratories 
and by state and local police agencies.
    DEA notes studies showing that when given the choice between 
low- and high-potency marijuana, subjects chose the high-potency 
marijuana significantly more often than the low-potency marijuana 
(Chait and Burke, 1994), supporting the hypothesis that the 
reinforcing effects of marijuana, and possibly its abuse liability, 
are positively related to THC content.

[[Page 40573]]

[GRAPHIC] [TIFF OMITTED] TP08JY11.012

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 fifty states were participants. 
Cannabis is cultivated in remote locations and frequently on public 
lands. Data provided by the DCE/SP (Table 4) shows that in 2009, 
there were 9,980,038 plants eradicated in outdoor cannabis 
cultivation areas in the United States. Marijuana is illicitly grown 
in all states. Major domestic outdoor cannabis cultivation areas 
were found in California, Kentucky, Tennessee and Hawaii. 
Significant quantities of marijuana were also eradicated from indoor 
cultivation operations. There were 414,604 indoor plants eradicated 
in 2009 compared to 217,105 eradicated in 2000. As indoor 
cultivation is generally associated with plants that have higher 
concentrations of [Delta]\9\-THC, the larger numbers of indoor grow 
facilities may be impacting the higher average [Delta]\9\-THC 
concentrations of seized materials.

                                   Table 4--Domestic Cannabis Eradication, Outdoor and Indoor Plants Seized, 2000-2009
                                               [Source: Domestic Cannabis Eradication/Suppression Program]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                    2000        2001        2002        2003        2004        2005        2006        2007        2008         2009
--------------------------------------------------------------------------------------------------------------------------------------------------------
Outdoor........................   2,597,798   3,068,632   3,128,800   3,427,923   2,996,144   3,938,151   4,830,766   6,599,599   7,562,322    9,980,038
Indoor.........................     217,105     236,128     213,040     223,183     203,896     270,935     400,892     434,728     450,986      414,604
                                ------------------------------------------------------------------------------------------------------------------------
    Total......................   2,814,903   3,304,760   3,341,840   3,651,106   3,200,040   4,209,086   5,231,658   7,034,327   8,013,308   10,394,642
--------------------------------------------------------------------------------------------------------------------------------------------------------

    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.
    The petitioner states that, ``The abuse potential of cannabis is 
insufficient to justify the prohibition of medical use.'' The 
petitioner also states that, ``[s]everal studies demonstrate that 
abuse rates for cannabis are lower than rates for other common 
drugs.'' (Exh. C, Section IV(16), pg. 92).
    DHHS states, to the contrary, ``the large number of individuals 
using marijuana on a regular basis, its widespread use, and the vast 
amount of marijuana that is available for illicit use are indicative 
of the high abuse potential for marijuana.'' Indeed, the data 
presented in this section shows that marijuana has a high potential 
for abuse as determined using the indicators identified in the CSA's 
legislative history. Both clinical and preclinical studies have 
demonstrated that marijuana and its principal psychoactive 
constituent [Delta]\9\-THC possess the attributes associated with 
drugs of abuse. They function as positive reinforcers and as 
discriminative stimuli to maintain drug-seeking behavior.
    In addition, marijuana is the most highly abused and trafficked 
illicit substance in the United States. Chronic abuse has resulted 
in a considerable number of individuals seeking substance abuse 
treatment according to national databases such as TEDS. Abuse of 
marijuana is associated with significant public health and safety 
risks that are described under factors 2, 6 and 7.
    The issue of whether marijuana has a currently accepted medical 
use is discussed under Factor 3.

[[Page 40574]]

    The petitioner claims that, ``[[hellip]]widespread use of 
marijuana without dependency supports the argument that marijuana is 
safe for use under medical supervision.'' (Exh. C, Section IV(15), 
pg. 87).
    Petitioner's claim of widespread use without dependency is not 
supported by abuse-related data. In particular, this claim 
disregards the high numbers of admissions to treatment facilities 
for marijuana abuse. Indeed, TEDS admissions for primary abuse of 
marijuana/hashish accounted for roughly 17 percent of all treatment 
admissions in 2008. In 2008, 2,016,256 people were admitted to drug 
and alcohol treatment in the United States and 346,679 of those 
admissions were for marijuana/hashish abuse. These drug treatment 
numbers are not consistent with this claim. Marijuana is not safe 
for use under medical supervision, and this point is addressed 
further in Factor 3.
    The petitioner also claims that, ``Data on both drug treatment 
and emergency room admissions also distinguishes the abuse potential 
of marijuana from that of other drugs and establishes its relative 
abuse potential as lower than schedule I drugs such as heroin and 
schedule II drugs such as cocaine.'' (Exh. C, Section IV(17), pg. 
99). The petitioner then presents data from TEDS in 1998, in which a 
larger proportion of all marijuana treatment admissions are referred 
to by the criminal justice system (54 percent), compared to much 
smaller percentages for heroin and cocaine. The petitioner argues 
that the abuse potential of these other drugs is more severe such 
that addicts seek treatment on their own or through persuasion of 
their associates, and claims that this difference establishes 
marijuana's relative abuse potential as lower than the other drugs.
    Petitioner's claim is not supported by an examination of the 
absolute numbers of admissions for treatment for each drug 
discussed. Regardless of proportions of referrals from the criminal 
justice systems, the absolute numbers of admissions for treatment 
for marijuana, heroin, or cocaine dependence are very high. 
Furthermore, data from TEDS in 2007 (SAMHSA, 2009) show that both 
primary marijuana and methamphetamine/amphetamine admissions had the 
largest proportion of admissions referred through the criminal 
justice system (57 percent each), followed by PCP (54 percent). Both 
methamphetamine/amphetamine and PCP have very high potential for 
abuse (Lile, 2006; Crider, 1986). Accordingly, this illustrates that 
it is not possible to establish or predict relative abuse potentials 
from the ranking of proportions of treatment admissions referred by 
the criminal justice system.

FACTOR 2: SCIENTIFIC EVIDENCE OF THE DRUG'S PHARMACOLOGICAL EFFECTS, IF 
KNOWN

    DHHS states that there are abundant scientific data available on 
the neurochemistry, toxicology, and pharmacology of marijuana. 
Following is a summary of the current scientific understanding of 
the endogenous cannabinoid system and of marijuana's pharmacological 
effects, including its effects on the cardiovascular, respiratory, 
and immune systems, as well as its effects on mental health and 
cognitive function and the effect of prenatal exposure to marijuana.

Neurochemistry of the Psychoactive Constituents of Marijuana

    DHHS states that of 483 natural constituents identified in 
marijuana, 66 are classified as cannabinoids (Ross and El Sohly, 
1995). Cannabinoids are not known to exist in plants other than 
marijuana and most of the cannabinoid compounds have been identified 
chemically. The activity of marijuana is largely attributed to 
[Delta]\9\-THC (Wachtel et al., 2002).
    DEA notes that [Delta]\9\-THC and delta-8-tetrahydrocannabinol 
([Delta]\8\-THC) are the only known compounds in the cannabis plant 
which show all the psychoactive effects of marijuana. [Delta]\9\-THC 
is more abundant than [Delta]\8\-THC and [Delta]\9\-THC 
concentrations vary within portions of the cannabis plant (Hanus and 
Subiv[aacute], 1989; Hanus et al., 1975). The pharmacological 
activity of [Delta]\9\-THC is stereospecific: the (-)-trans isomer 
is 6-100 times more potent than the (+)-trans isomer (Dewey et al., 
1984).
    The mechanism of action of [Delta]\9\-THC was verified with the 
cloning of cannabinoid receptors, first from rat brain tissue 
(Matsuda et al., 1990) and then from human brain tissue (Gerard et 
al., 1991). Two cannabinoid receptors have been identified and 
characterized, CB1 and CB2 (Piomelli, 2005). 
Autoradiographic studies have provided information on the 
distribution of CB1 and CB2 receptors. High 
densities of CB1 receptors are found in the basal 
ganglia, hippocampus, and cerebellum of the brain (Howlett et al., 
2004; Herkenham et al., 1990; Herkenham, 1992). These brain regions 
are associated with movement coordination and cognition and the 
location of CB1 receptors in these areas may explain 
cannabinoid interference with these functions. Although 
CB1 receptors are predominantly expressed in the brain, 
they have also been detected in the immune system (Bouaboula et al., 
1993). CB2 receptors are primarily located in B 
lymphocytes and natural killer cells of the immune system and it is 
believed that this receptor is responsible for mediating 
immunological effects of cannabinoids (Galiegue et al., 1995). 
Recently, however, CB2 receptors have been localized in 
the brain, primarily in the cerebellum and hippocampus (Gong et al., 
2006).
    Cannabinoid receptors are linked to an inhibitory G-protein 
(Breivogel and Childers, 2000). When the receptor is activated, 
adenylate cyclase activity is inhibited, preventing the conversion 
of adenosine triphosphate (ATP) to the second messenger cyclic 
adenosine monophosphate (cAMP). Other examples of inhibitory-coupled 
receptors include opioid, muscarinic cholinergic, alpha2-
adrenoreceptors, dopamine and serotonin receptors. However, several 
studies also suggest a link to stimulatory G-proteins, through which 
activation of CB1 stimulates adenylate cyclase activity 
(Glass and Felder, 1997; Maneuf and Brotchie, 1997; Felder et al., 
1998).
    Activation of CB1 receptors inhibits N-and P/Q-type 
calcium channels and activate inwardly rectifying potassium channels 
(Mackie et al., 1995; Twitchell et al., 1997). Inhibition of N-type 
calcium channels decreases neurotransmitter release from a number of 
tissues and may be the mechanism by which cannabinoids inhibit 
acetylcholine, norepinephrine, and glutamate release from specific 
areas of the brain. These effects on G protein-mediated pathways and 
on calcium and potassium channels may represent potential cellular 
mechanisms underlying the antinociceptive and psychoactive effects 
of cannabinoids (Ameri, 1999).
    Delta\9\-THC displays similar affinity for both cannabinoid 
receptors but behaves as a weak agonist at CB2 receptors, 
based on inhibition of adenylate cyclase. The identification of 
synthetic cannabinoid ligands that selectively bind to 
CB2 receptors but do not have the typical [Delta]\9\-THC-
like psychoactive properties, along with the respective anatomical 
distribution of the two receptor subtypes suggests that the 
psychoactive effects of cannabinoids are mediated through the 
activation of CB1 receptors (Hanus et al., 1999). 
Naturally occurring cannabinoids and synthetic cannabinoid agonists 
(such as WIN-55,212-2 and CP-55,940) produce hypothermia, analgesia, 
hypoactivity, and catalepsy in addition to their psychoactive 
effects.
    In 2000, two endogenous cannabinoid receptor agonists were 
discovered, anandamide and arachidonyl glycerol (2-AG). Anandamide 
is a low efficacy agonist (Breivogel and Childers, 2000) and 2-AG is 
a highly efficacious agonist (Gonsiorek et al., 2000). These 
endogenous ligands are present in both central and peripheral 
tissues. The physiological role of these endogenous ligands is an 
active area of research (Martin et al., 1999).
    In summary, two receptors have been cloned, CB1 
(found in the central nervous system) and CB2 (predominantly found 
in the periphery), that bind [Delta]\9\-THC and other cannabinoids. 
Activation of these inhibitory G-protein-coupled receptors inhibits 
calcium channels and adenylate cyclase. Endogenous cannabinoid 
agonists have been identified, anandamide and arachidonyl glycerol 
(2-AG).

Pharmacological Effects of Marijuana

    Marijuana produces a number of central nervous system effects. 
Many of these effects are directly related to the abuse potential of 
marijuana, and are discussed in Factor 1. Other effects are 
discussed herein.

Cardiovascular and Autonomic Effects

    DHHS states that acute use of marijuana causes an increase in 
heart rate (tachycardia) and may cause a modest increase in blood 
pressure as well (Capriotti et al., 1988; Benowitz and Jones, 1975). 
Conversely, chronic exposure to marijuana will produce a decrease in 
heart rate (bradycardia) and decrease of blood pressure. In heavy 
smokers of marijuana, the degree of increased heart rate is 
diminished due to the development of tolerance (Jones, 2002 and 
Sidney, 2002). 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).

[[Page 40575]]

    DHHS cites a review (Jones, 2002) of studies showing that smoked 
marijuana causes orthostatic hypotension (sympathetic insufficiency, 
a sudden drop in blood pressure upon standing up) often accompanied 
by dizziness. DHHS states that tolerance can develop to this effect.
    Marijuana smoking by older patients, particularly those with 
some degree of coronary artery or cerebrovascular disease, poses 
risks related to increased cardiac work, increased catecholamines, 
carboxyhemoglobin, and postural hypotension (Benowitz and Jones, 
1981; Hollister, 1988).
    DEA further notes studies in which marijuana has been 
administered under controlled conditions to marijuana-experienced 
users that showed that marijuana causes a substantial increase, 
compared to placebo, in heart rate (tachycardia) ranging from 20 
percent to 100 percent above baseline. This effect was seen as 
usually greatest starting during the 10 minutes or so it takes to 
smoke a marijuana cigarette and lasting 2 to 3 hours (reviewed in 
Jones et al., 2002).
    DEA also notes a randomized, double-blind, placebo-controlled 
study by Mathew and colleagues (2003) that examined pulse rate, 
blood pressure (BP), and plasma [Delta]\9\-THC levels during 
reclining and standing for 10 minutes before and after smoking one 
marijuana cigarette (3.55 percent [Delta]\9\-THC) by twenty-nine 
volunteers. Marijuana induced postural dizziness, with 28 percent of 
subjects reporting severe symptoms. Intoxication and dizziness 
peaked immediately after drug intake. The severe dizziness group 
showed the most marked postural drop in blood pressure and showed a 
drop in pulse rate after an initial increase during standing.

Respiratory Effects

    Both acute and chronic respiratory effects are associated with 
marijuana smoking.
    DHHS states that acute exposure to marijuana produces transient 
bronchodilation (Gong et al., 1984). DHHS states that long-term use 
of smoked marijuana can lead to increased frequency of chronic 
cough, increased sputum, large airway obstruction, as well as 
cellular inflammatory histopathological abnormalities in bronchial 
epithelium (Adams and Martin, 1996; Hollister, 1986).
    DEA notes a study showing that both smoked marijuana and oral 
[Delta]\9\-THC increases specific airway conductance in asthmatic 
subjects (Tashkin et al., 1974). In addition, other studies have 
suggested that chronic marijuana smoking is also associated with 
increased incidence of emphysema and asthma (Tashkin et al., 1987).
    DHHS states that the evidence that marijuana may lead to cancer 
is inconsistent, with some studies suggesting a positive correlation 
while others do not. DHHS cited a large clinical study with 1,650 
subjects in which 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. 
DHHS also cites other studies reporting lung cancer occurrences in 
young marijuana users with no history of tobacco smoking (Fung et 
al., 1999), and suggesting a dose-dependent effect of marijuana on 
the risk of head and neck cancer (Zhang et al., 1999).
    DEA notes the publication of a more recent case-control study of 
lung cancer in adults under 55 years of age, conducted in New 
Zealand by Aldington and colleagues (2008). Interviewer-administered 
questionnaires were used to assess possible risk factors, including 
cannabis use. In total, 79 cases of lung cancer and 324 controls 
were included in the study. The risk of lung cancer increased 8 
percent (95 percent confidence interval (CI) 2-15) for each joint-
year of cannabis smoking (one joint-year being equivalent to one 
joint per day for a year), after adjustment for confounding 
variables including cigarette smoking; it went up 7 percent (95 
percent CI 5-9) for each pack-year of cigarette smoking (one pack-
year being equivalent to one pack per day for a year), after 
adjustment for confounding variables including cannabis smoking. 
Thus, a major differential risk between cannabis and cigarette 
smoking was observed, with one joint of cannabis being similar to 20 
cigarettes for risk of lung cancer. Users reporting over 10.5 joint-
years of exposure had a significantly increased risk of developing 
lung cancer (relative risk 5.7 (95 percent CI 1.5-21.6)) after 
adjustment for confounding variables including cigarette smoking. 
DEA notes that the authors of this study concluded from their 
results that long-term cannabis use increases the risk of lung 
cancer in young adults.
    Some studies discuss marijuana smoke and tobacco smoke. DHHS 
states that chronic exposure to marijuana smoke is considered to be 
comparable to tobacco smoke with respect to increased risk of cancer 
and lung damage. DEA notes studies showing that marijuana smoke 
contains several of the same carcinogens and co-carcinogens as 
tobacco smoke and suggesting that pre-cancerous lesions in bronchial 
epithelium also seem to be caused by long-term marijuana smoking 
(Roth et al., 1998).
    In summary, studies are still needed to clarify the impact of 
marijuana on the risk of developing lung cancer as well as head and 
neck cancer. DHHS states that the evidence that marijuana may lead 
to cancer is inconsistent, with some studies suggesting a positive 
correlation while others do not.

Endocrine Effects

    DHHS states 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.
    DHHS states that experimental administration of marijuana to 
humans does not consistently alter the endocrine system. In an early 
study, four male subjects administered smoked marijuana showed a 
significant depression in luteinizing hormone and a significant 
increase in cortisol (Cone et al., 1986). However, later studies in 
male subjects receiving smoked [Delta]\9\-THC (18 mg/marijuana 
cigarette) or oral [Delta]\9\-THC (10 mg t.i.d. for 3 days) showed 
no changes in plasma prolactin, ACTH, cortisol, luteinizing hormone 
or testosterone levels (Dax et al., 1989). Similarly, a study with 
93 males and 56 female subjects showed that chronic marijuana use 
did not significantly alter concentrations of testosterone, 
luteinizing hormone, follicle stimulating hormone, prolactin or 
cortisol (Block et al., 1991).
    DHHS cites a study (Sarfaraz et al., 2005) which showed that the 
cannabinoid agonist WIN 55,212-2 induces apoptosis in prostate 
cancer cells growth and decreases expression of androgen receptors. 
DHHS states that this data suggests a potential therapeutic value 
for cannabinoid agonists in the treatment of prostate cancer, an 
androgen-stimulated type of carcinoma.
    In summary, while animal studies have suggested that 
cannabinoids can alter multiple hormonal systems, the effects in 
humans, in particular the consequences of long-term marijuana abuse, 
remain unclear.

Immune System Effects

    DHHS states that cannabinoids alter immune function but that 
there can be differences between the effects of synthetic, natural, 
and endogenous cannabinoids (Croxford and Yamamura, 2005).
    DHHS cites a study by Roth et al. (2005) that examined the 
effect of [Delta]\9\-THC exposure on immune function and response to 
HIV infection in immunodeficient mice that were implanted with human 
blood cells infected with HIV. The study shows 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. DEA notes that the authors of this study state that 
their results suggest a dynamic interaction between [Delta]\9\-THC, 
immunity, and the pathogenesis of HIV and support epidemiologic 
studies that have identified marijuana use as a risk factor for HIV 
infection and the progression of AIDS. However, DHHS discusses a 
recent study by Abrams et al. (2003) that investigated the effect of 
marijuana on immunological functioning in 67 AIDS patients who were 
taking protease inhibitors. Subjects received one of three 
treatments, three times a day: smoked marijuana cigarette containing 
3.95 percent [Delta]\9\-THC; oral tablet containing [Delta]\9\-THC 
(2.5 mg oral dronabinol); or oral placebo. There were no changes in 
HIV-RNA levels between groups, demonstrating no short-term adverse 
virologic effects from using cannabinoids.
    DEA notes a review suggesting that [Delta]\9\-THC and 
cannabinoids decrease resistance to microbial infections in 
experimental animal models and in vitro (see review by Cabral and 
Staab, 2005). Various studies have been conducted in drug-abusing 
human subjects, experimental animals exposed to marijuana smoke or 
injected with cannabinoids, and in in vitro models using immune cell 
cultures treated with various cannabinoids. DEA notes that for the 
most part, these studies suggest that cannabinoids modulate the 
function of various cells of the human immune system, including T- 
and B-

[[Page 40576]]

lymphocytes as well as natural killer (NK) cells and macrophages. 
Macrophages engulf and destroy foreign matter, NK cells target cells 
(e.g., cancerous cells) and destroy them, B-lymphocytes produce 
antibodies against infective organisms, and T-lymphocytes kill cells 
or trigger the activity of other cells of the immune system.
    In addition to studies examining cannabinoid effects on immune 
cell function, DEA also notes other reports which have documented 
that cannabinoids modulate resistance to various infectious agents. 
Viruses such as herpes simplex virus and murine retrovirus have been 
studied as well as bacterial agents such as members of the genera 
Staphylococcus, Listeria, Treponema, and Legionella. These studies 
suggest that cannabinoids modulate host resistance, especially the 
secondary immune response (reviewed in Cabral and Dove-Pettit, 
1998).
    Finally, DEA notes a review suggesting that cannabinoids 
modulate the production and function of cytokines as well as 
modulate the activity of network cells such as macrophages and T 
helper cells. Cytokines are the chemicals produced by cells of the 
immune system in order to communicate and orchestrate the attack. 
Binding to specific receptors on target cells, cytokines recruit 
many other cells and substances to the field of action. Cytokines 
also encourage cell growth, promote cell activation, direct cellular 
traffic, and destroy target cells (see review by Klein et al., 
2000).
    In summary, as DHHS states, cannabinoids alter immune function, 
but there can be differences between the effects of synthetic, 
natural, and endogenous cannabinoids. While there is a large body of 
evidence to suggest that [Delta]\9\-THC alters immune function, 
research is still needed to clarify the effects of cannabinoids and 
marijuana on the immune system in humans, in particular the risks 
posed by smoked marijuana in immunocompromized individuals.

Association with Psychosis

    The term psychosis is generally used in research as a generic 
description of severe mental illnesses characterized by the presence 
of delusions, hallucinations and other associated cognitive and 
behavioral impairments. Psychosis is measured either by using 
standardized diagnostic criteria for psychotic conditions such as 
schizophrenia or by using validated scales that rank the level of 
psychotic symptoms from none to severe (Fergusson et al., 2006).
    DHHS states that extensive research has been conducted recently 
to investigate whether exposure to marijuana is associated with 
schizophrenia or other psychoses. DHHS states that, at the time of 
their review, the data does not suggest a causative link between 
marijuana use and the development of psychosis.
    DHHS discusses an early epidemiological study conducted by 
Andreasson and colleagues (1987), which examined the link between 
psychosis and marijuana use. In this study, 45,000 18- and 19-year-
old male Swedish subjects provided detailed information on their 
drug-taking history. The incidence of schizophrenia was then 
recorded over the next 15 years. Those individuals who claimed, on 
admission, to have taken marijuana on more than 50 occasions were 
six times more likely to be diagnosed with schizophrenia in the 
following 15 years than those who had never consumed the drug. When 
confounding factors were taken into account, the risk of developing 
schizophrenia remained statistically significant. The authors 
concluded that marijuana users who are vulnerable to developing 
psychoses are at the greatest risk for schizophrenia. DHHS states 
that therefore marijuana per se does not appear to induce 
schizophrenia in the majority of individuals who try or continue to 
use the drug.
    DHHS discusses another large longitudinal study in which the 
prevalence of schizophrenia was modeled against marijuana use across 
birth cohorts in Australia from 1940 to 1979 (Degenhardt et al., 
2003). The authors found that marijuana use may precipitate 
disorders in vulnerable individuals and worsen the course of the 
disorder among those that have already developed it. They did not 
find any causal relationship between marijuana use and increased 
incidence of schizophrenia.
    DEA notes that Degenhardt and colleagues (2003) acknowledged 
that several environmental risk factors for schizophrenia had been 
reduced (i.e., poor maternal nutrition, infectious disease and poor 
antenatal and prenatal care) and that the diagnostic criteria for 
schizophrenia had changed over the span of this study making the 
classification of schizophrenia more rigorous. These confounders 
could reduce the reported prevalence of schizophrenia.
    DHHS also discusses several longitudinal studies that found a 
dose-response relationship between marijuana use and an increasing 
risk of psychosis among those who are vulnerable to developing 
psychosis (Fergusson et al., 2005; van Os et al., 2002).
    DEA notes several longitudinal studies (Arseneault et al., 2002, 
Caspi et al., 2005; Henquet et al., 2005) that found increased rates 
of psychosis or psychotic symptoms in people using cannabis. 
Finally, DEA notes some studies that observe that individuals with 
psychotic disorders have higher rates of cannabis use compared to 
the general population (Regier et al., 1990; Green et al., 2005).
    DEA also notes that, more recently, Moore and colleagues (2007) 
performed a meta-analysis of the longitudinal studies on the link 
between cannabis use and subsequent psychotic symptoms. Authors 
observed that there was an increased risk of any psychotic outcome 
in individuals who had ever used cannabis (pooled adjusted odds 
ratio=1.41, 95 percent CI 1.20-1.65). Furthermore, findings were 
consistent with a dose-response effect, with greater risk in people 
who used cannabis most frequently (2.09, 1.54-2.84). The authors 
concluded that their results support the view that cannabis 
increases risk of psychotic outcomes independently of confounding 
and transient intoxication effects.
    DEA also notes another more recent study examining the 
association between marijuana use and psychosis-related outcome in 
pairs of young adult siblings in Brisbane, Australia (McGrath et 
al., 2010). This study found a dose-response relationship where the 
longer the duration of time since the first cannabis use, the higher 
the risk of psychosis-related outcome. Those patients with early-
onset psychotic symptoms were also likely to report early marijuana 
use. Authors suggest that their results support the hypothesis that 
early cannabis use is a risk-modifying factor for psychosis-related 
outcomes in young adults.

Cognitive Effects

    DHHS states that acute administration of smoked marijuana 
impairs performance on tests of learning, associative processes, and 
psychomotor behavior (Block et al., 1992; Heishman et al., 1990). 
Marijuana may therefore considerably interfere with an individual's 
ability to learn in a classroom or to operate motor vehicles. DHHS 
cites a study conducted by Kurzthalar and colleagues (1999) with 
human volunteers, in which the administration of 290 [mu]g/kg of 
[Delta]\9\-THC in a smoked cigarette resulted in impaired perceptual 
motor speed and accuracy, skills of paramount importance for safe 
driving. Similarly, administration of 3.95 percent [Delta]\9\-THC in 
a smoked cigarette increased disequilibrium measures, as well as the 
latency in a task of simulated vehicle braking (Liguori et al., 
1998).
    DHHS states that the effects of marijuana may not be fully 
resolved until at least one day after the acute psychoactive effects 
have subsided, following repeated administration. Heishman and 
colleagues (1988) showed that impairment on memory tasks persists 
for 24 hours after smoking marijuana cigarettes containing 2.57 
percent [Delta]\9\-THC. However, Fant and colleagues (1998) showed 
minimal residual alterations in subjective or performance measures 
the day after subjects were exposed to 1.8 percent or 3.6 percent 
smoked [Delta]\9\-THC.
    DHHS discussed a study by Lyons and colleagues (2004) on the 
neuropsychological consequences of regular marijuana use in fifty-
four monozygotic male twin pairs, with one subject being a regular 
user and its co-twin a non-user, and neither twin having used any 
other illicit drug regularly. Marijuana-using twins significantly 
differed from their non-using co-twins on the general intelligence 
domain. However, only one significant difference was noted between 
marijuana-using twins and their non-using co-twins on measures of 
cognitive functioning. Authors of the study proposed that the 
results indicate an absence of any marked long-term residual effects 
of marijuana use on cognitive abilities. This conclusion is similar 
to the results found by Lyketsos and colleagues (1999), who 
investigated the possible adverse effects of cannabis use on 
cognitive decline after 12 years in persons under 65 years of age. 
There were no significant differences in cognitive decline between 
heavy users, light users, and nonusers of cannabis. The authors 
conclude that over long time periods, in persons under age 65 years, 
cognitive decline occurs in all age groups. This decline is closely 
associated with aging and educational level but does not appear to 
be associated with cannabis use.
    DEA notes that while Lyketsos and colleagues (1999) propose that 
their results

[[Page 40577]]

provide strong evidence of the absence of a long term residual 
effect of cannabis use on cognition, they also acknowledge a number 
of limitations to their study. Notably, authors remark that it is 
possible that some cannabis users in the study may have used 
cannabis on the day the test was administered. Given the acute 
effects on cannabis on cognition, this would have tended to reduce 
their test score on that day. This may have adversely affected 
accurate measurement of test score changes over time in cannabis 
users. The authors also noted, as another important limitation, that 
the test used is not intended for the purpose for which it was used 
in this study and is not a very sensitive measure of cognitive 
decline, even though it specifically tests memory and attention. 
Thus, small or subtle effects of cannabis use on cognition or 
psychomotor speed may have been missed.
    DHHS also discussed a study by Solowij and colleagues (2002) 
which examined the effects of duration of cannabis use on specific 
areas of cognitive functioning among users seeking treatment for 
cannabis dependence. They compared 102 near-daily cannabis users (51 
long-term users: mean, 23.9 years of use; 51 shorter-term users: 
mean, 10.2 years of use) with 33 nonuser controls. They collected 
measures from nine standard neuropsychological tests that assessed 
attention, memory, and executive functioning, and that were 
administered prior to entry to a treatment program and following a 
median 17-hour abstinence. Authors found that long-term cannabis 
users performed significantly less well than shorter-term users and 
controls on tests of memory and attention. Long-term users showed 
impaired learning, retention, and retrieval compared with controls. 
Both user groups performed poorly on a time estimation task. 
Performance measures often correlated significantly with the 
duration of cannabis use, being worse with increasing years of use, 
but were unrelated to withdrawal symptoms and persisted after 
controlling for recent cannabis use and other drug use. Authors of 
this study state that their results support the hypothesis that 
long-term heavy cannabis users show impairments in memory and 
attention that endure beyond the period of intoxication and worsen 
with increasing years of regular cannabis use.
    DHHS cited a study by Messinis and colleagues (2006) which 
examined neurophysiological functioning for heavy, frequent cannabis 
users. The study compared 20 long-term (LT) and 20 shorter-term (ST) 
heavy, frequent cannabis users after abstinence for at least 24 
hours prior to testing with 24 non-using controls. LT users 
performed significantly worse on verbal memory and psychomotor 
speed. LT and ST users had a higher proportion of deficits on verbal 
fluency, verbal memory, attention and psychomotor speed. Authors 
conclude from their study that specific cognitive domains appear to 
deteriorate with increasing years of heavy frequent cannabis use.
    DHHS discussed a study by Pope and colleagues (2003) which 
reported no differences in neuropsychological performance in early- 
or late-onset users compared to non-using controls, after adjustment 
for intelligence quotient (IQ). In another cohort of chronic, heavy 
marijuana users, some deficits were observed on memory tests up to a 
week following supervised abstinence but these effects disappeared 
by day 28 of abstinence (Pope et al., 2002). The authors concluded 
that ``cannabis-associated cognitive deficits are reversible and 
related to recent cannabis exposure rather than irreversible and 
related to cumulative lifetime use.'' Conversely, DHHS notes that 
other investigators have reported persistent neuropsychological 
deficits in memory, executive functioning, psychomotor speed, and 
manual dexterity in heavy marijuana smokers who had been abstinent 
for 28 days (Bolla et al., 2002). Furthermore, when dividing the 
group into light, middle, and heavy user groups, Bolla and 
colleagues (2002) found that the heavy user group performed 
significantly below the light user group on 5 of 35 measures. A 
follow-up study of heavy marijuana users noted decision-making 
deficits after 25 days of abstinence (Bolla et al., 2005). When IQ 
was contrasted in adolescents 9-12 years of age and at 17-20 years 
of age, current heavy marijuana users showed a 4-point reduction in 
IQ in later adolescence compared to those who did not use marijuana 
(Fried et al., 2002).
    DHHS states that age of first use may be a critical factor in 
persistent impairment from chronic marijuana use. Individuals with a 
history of marijuana-only use that began before the age of 16 were 
found to perform more poorly on a visual scanning task measuring 
attention than individuals who started using marijuana after 16 
(Ehrenreich et al., 1999). DHHS's document noted that Kandel and 
Chen (2000) assert that the majority of early-onset marijuana users 
do not go on to become heavy users of marijuana, and those that do 
tend to associate with delinquent social groups.
    DEA notes an additional recent study that indicates that because 
neuromaturation continues through adolescence, results on the long-
lasting cognitive effects of marijuana use in adults cannot 
necessarily generalize to adolescent marijuana users. Medina and 
colleagues (2007) examined neuropsychological functioning in 31 
adolescent abstinent marijuana users, after a period of abstinence 
from marijuana of 23 to 28 days, and in 34 demographically similar 
control adolescents, all 16-18 years of age. After controlling for 
lifetime alcohol use and depressive symptoms, adolescent marijuana 
users demonstrated slower psychomotor speed (p .05), and poorer 
complex attention (p .04), story memory (p .04), and planning and 
sequencing ability (p .001) compared with nonusers. The number of 
lifetime marijuana use episodes was associated with poorer cognitive 
function, even after controlling for lifetime alcohol use. The 
general pattern of results suggested that, even after a month of 
monitored abstinence, adolescent marijuana users demonstrate subtle 
neuropsychological deficits compared with nonusers. The authors of 
this study suggest that frequent marijuana use during adolescence 
may negatively influence neuromaturation and cognitive development.
    In summary, acute administration of marijuana impairs 
performance on tests of learning, associative processes, and 
psychomotor behavior. The effects of chronic marijuana use have also 
been studied. While a few studies did not observe strong persistent 
neurocognitive consequences of long-term cannabis use (Lyketsos et 
al., 1999; Lyons et al., 2004), others provide support for the 
existence of persistent consequences (Bolla et al., 2002, 2005). The 
cognitive impairments that are observed 12 hours to seven days after 
marijuana use (Messinis et al., 2006; Solowij et al., 2002; Harrison 
et al., 2002), and that persist beyond behaviorally detectable 
intoxication, are noteworthy and may have significant consequences 
on workplace performance and safety, academic achievement, and 
automotive safety. In addition, adolescents may be particularly 
vulnerable to the long-lasting deleterious effects of marijuana on 
cognition. The overall significant effect on general intelligence as 
measured by IQ should also not be overlooked.

Behavioral Effects of Prenatal Exposure

    The impact of in utero marijuana exposure on performance in a 
series of cognitive tasks has been studied in children of various 
ages. DHHS concludes in its analysis of the presently examined 
petition that since many marijuana users have abused other drugs, it 
is difficult to determine the specific impact of marijuana on 
prenatal exposure. Fried and Watkinson (1990) found that four year 
old children of heavy marijuana users have deficits in memory and 
verbal measures. Maternal marijuana use is predictive of poorer 
performance on abstract/visual reasoning tasks of three year old 
children (Griffith et al., 1994) and an increase in omission errors 
on a vigilance task of six year olds (Fried et al., 1992). When the 
effect of prenatal exposure in nine to 12 year old children is 
analyzed, in utero exposure to marijuana is negatively associated 
with executive function tasks that require impulse control, visual 
analysis, and hypothesis testing (Fried et al., 1998).
    DEA notes studies showing that [Delta]\9\-THC passes the 
placental barrier (Idanpaan-Heikkila et al., 1969) and that fetal 
blood concentrations are at least equal to those found in the 
mother's blood (Grotenhermen, 2003).
    In summary, smoked marijuana exerts a number of cardiovascular 
and respiratory effects, both acutely and chronically. Marijuana's 
main psychoactive ingredient [Delta]\9\-THC alters immune function. 
The cognitive impairments caused by marijuana use that persist 
beyond behaviorally detectable intoxication may have significant 
consequences on workplace performance and safety, academic 
achievement, and automotive safety, and adolescents may be 
particularly vulnerable to marijuana's cognitive effects. Prenatal 
exposure to marijuana was linked to children's poorer performance in 
a number of cognitive tests.

FACTOR 3: THE STATE OF THE CURRENT SCIENTIFIC KNOWLEDGE REGARDING THE 
DRUG OR SUBSTANCE

    DHHS states that marijuana is a mixture of the dried leaves and 
flowering tops of the cannabis plant (Agurell et al., 1984; Graham,

[[Page 40578]]

1976; Mechoulam, 1973). These portions of the plant have the highest 
levels of [Delta]\9\-THC, the primary psychoactive ingredient in 
marijuana. The most potent product (i.e., that having the highest 
percentage of [Delta]\9\-THC) of dried material is sinsemilla, 
derived from the unpollinated flowering tops of the female cannabis 
plant. Generally, this potent marijuana product is associated with 
indoor grow sites and may have a [Delta]\9\-THC content of 15 to 20 
percent or more. Other, less common forms of marijuana found on the 
illicit market are hashish and hashish oil. Hashish is a [Delta]\9\-
THC-rich resinous material of the cannabis plant which is dried and 
compressed into a variety of forms (balls, cakes or sticks). Dried 
pieces are generally broken off and smoked. [Delta]\9\-THC content 
is usually about five percent. The Middle East, North Africa and 
Pakistan/Afghanistan are the main sources of hashish. Hashish oil is 
produced by extracting the cannabinoids from plant material with a 
solvent. Hashish oil is a light to dark brown viscous liquid with a 
[Delta]\9\-THC content of about 15 percent. The oil is often 
sprinkled on cigarettes, allowed to dry, and then smoked.

Chemistry

    DHHS states that some 483 natural constituents have been 
identified in marijuana, including 66 compounds that are classified 
as cannabinoids (Ross and El Sohly, 1995). Cannabinoids are not 
known to exist in plants other than marijuana, and most naturally 
occurring cannabinoids have been identified chemically. The 
psychoactive properties of cannabis are attributed to one or two of 
the major cannabinoid substances, namely delta-9- 
tetrahydrocannabinol ([Delta]\9\-THC) and delta-8-
tetrahydrocannabinol ([Delta]\8\-THC). Other natural cannabinoids, 
such as cannabidiol (CBD) and cannabinol (CBN), have been 
characterized. CBD does not possess [Delta]\9\-THC-like 
psychoactivity. Its pharmacological properties appear to include 
anticonvulsant, anxiolytic and sedative properties (Agurell et al., 
1984, 1986; Hollister, 1986).
    DHHS states that [Delta]\9\-THC is an optically active resinous 
substance, extremely lipid soluble, and insoluble in water. 
Chemically, [Delta]\9\-THC is known as (6aR-trans)-6a,7,8,10a-
tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo-[b,d]pyran-1-ol or (-
)[Delta]\9\-(trans)-tetrahydrocannabinol. The pharmacological 
activity of [Delta]\9\-THC is stereospecific: the (-)-trans isomer 
is 6-100 times more potent than the (+)-trans isomer (Dewey et al., 
1984).
    DEA notes a review of the contaminants and adulterants that can 
be found in marijuana (McPartland, 2002). In particular, DEA notes 
that many studies have reported contamination of both illicit and 
NIDA-grown marijuana with microbial contaminants, bacterial or 
fungal (McLaren et al., 2008; McPartland, 1994, 2002; Ungerleider et 
al., 1982; Taylor et al., 1982; Kurup et al., 1983). Other microbial 
contaminants include Klebsiella pneumoniae, salmonella enteritidis, 
and group D Streptococcus (Ungerlerder et al., 1982; Kagen et al., 
1983; Taylor et al., 1982). DEA notes that a review by McLaren and 
colleagues (2008) discusses studies showing that heavy metals 
present in soil may also contaminate cannabis, and states that these 
contaminants have the potential to harm the user without harming the 
plant. Other sources of contaminants discussed by McLaren and 
colleagues (2008) include growth enhancers and pest control products 
related to marijuana cultivation and storage.

Human Pharmacokinetics

    DHHS states that marijuana is generally smoked as a cigarette 
(weighing between 0.5 and 1.0 gm; Jones, 1980) or in a pipe. It can 
also be taken orally in foods or as extracts of plant material in 
ethanol or other solvents. The absorption, metabolism, and 
pharmacokinetic profile of [Delta]\9\-THC (and other cannabinoids) 
in marijuana or other drug products containing [Delta]\9\-THC vary 
with route of administration and formulation (Adams and Martin, 
1996; Agurell et al., 1984, 1986). When marijuana is administered by 
smoking, [Delta]\9\-THC in the form of an aerosol is absorbed within 
seconds. The psychoactive effects of marijuana occur immediately 
following absorption, with mental and behavioral effects measurable 
up for to six hours after absorption (Grotenhermen, 2003; Hollister, 
1986, 1988). [Delta]\9\-THC is delivered to the brain rapidly and 
efficiently as would be expected of a highly lipid-soluble drug.
    The petitioner provided a discussion of new, or less common, 
routes and methods of administration being currently explored (pg. 
57, line 1). These include vaporization for the inhalation route, as 
well as rectal, sublingual, and transdermal routes.
    DEA notes that respiratory effects are only part of the harmful 
health effects of prolonged marijuana exposure, as described further 
under factor 2 of this document. DEA also notes that at this time, 
the majority of studies exploring the potential therapeutic uses of 
marijuana use smoked marijuana, and the pharmacokinetics and 
bioavailability from routes of administration other than smoked and 
oral are not well-known.
    The pharmacokinetics of smoked and orally ingested marijuana are 
thoroughly reviewed in DHHS's review document.

Medical Utility

    The petition filed by the Coalition to Reschedule Cannabis 
(Marijuana) aims to repeal the rule placing marijuana in schedule I 
of the CSA, based in part on the proposition that marijuana has an 
accepted medical use in the United States. However DHHS has 
concluded in its 2006 analysis that marijuana has no accepted 
medical use in treatment in the United States. Following is a 
discussion of the petitioner's specific points and a presentation of 
DHHS's evaluation and recommendation on the question of accepted 
medical use for marijuana.
    The petitioner states (pg. 48, line 2), ``Results from clinical 
research demonstrated that both dronabinol and whole plant cannabis 
can offer a safe and effective treatment for the following 
illnesses: muscle spasm in multiple sclerosis, Tourette syndrome, 
chronic pain, nausea and vomiting in HIV/AIDS and cancer 
chemotherapy, loss of appetite from cancer, hyperactivity of the 
bladder in patients with multiple sclerosis and spinal cord injury, 
and dyskinesia caused by levodopa in Parkinson's disease.''
    To support its claim that marijuana has an accepted medical use 
in the United States, the petitioner listed supporting evidence that 
included the following:
     Evidence from clinical research and reviews of earlier 
clinical research (Exh. C, Section I (4, 6), pg. 29)
     Acceptance of the medical use of marijuana by eight 
states since 1996 and state officials in these states establishing 
that marijuana has an accepted medical use in the United States 
(Exh. C, Section I (1), pg. 13)
     Increased recognition by health care professionals and 
the medical community, including the Institute of Medicine (IOM) 
(Exh. C, Section I (2), pg. 15)
     Patients' experience in which they reported benefits 
from smoking marijuana (Exh. C, Section I (3), pg. 22)
     Evidence from clinical research (Exh. C, Section I (4, 
6), pg. 29)
    DHHS states that a new drug application (NDA) for marijuana has 
not been submitted to the FDA for any indication and thus no 
medicinal product containing botanical cannabis has been approved 
for marketing. Only small clinical studies published in the current 
medical literature demonstrate that research with marijuana is being 
conducted in humans in the United States under FDA-authorized 
investigational new drug (IND) applications.
    There are ongoing clinical studies of the potential utility of 
marijuana in medical applications. DHHS states that in 2000, the 
state of California established the Center for Medicinal Cannabis 
Research (CMCR) which has funded studies on the potential use of 
cannabinoids for the treatment of multiple sclerosis, neuropathic 
pain, appetite suppression and cachexia, and severe pain and nausea 
related to cancer or its treatment by chemotherapy. To date, though, 
no NDAs utilizing marijuana for these indications have been 
submitted to the FDA.
    To establish accepted medical use, among other criteria, the 
effectiveness of a drug must be established in well-controlled 
scientific studies performed in a large number of patients. To date, 
such studies have not been performed for marijuana. Small clinical 
trial studies with limited patients and short duration such as those 
cited by the petitioner are not sufficient to establish medical 
utility. Larger studies of longer duration are needed to fully 
characterize the drug's efficacy and safety profile. Anecdotal 
reports, patients' self-reported effects, and isolated case reports 
are not adequate evidence to support an accepted medical use of 
marijuana (57 FR 10499, 1992).
    In addition to demonstrating efficacy, adequate safety studies 
must be performed to show that the drug is safe for treating the 
targeted disease. DHHS states that safety studies for acute or 
subchronic administration of marijuana have been carried out through 
a limited number of Phase 1 clinical investigations approved by the 
FDA, but there have been no NDA-quality studies that have 
scientifically assessed the efficacy and full safety profile of 
marijuana for any medical condition.
    DEA further notes that a number of clinical studies from CMCR 
have been discontinued. Most of these discontinuations were due to

[[Page 40579]]

recruitment difficulties (http://www.cmcr.ucsd.edu/geninfo/research.htm (last retrieved 07/07/2010) (listing 6 discontinued 
studies, 5 of which were discontinued because of recruitment 
issues)).
    The petitioner states that the pharmacological effects are well 
established for marijuana and [Delta]\9\-THC, using the argument 
that Marinol (containing synthetic [Delta]\9\-THC, known generically 
as dronabinol) and Cesamet (containing nabilone, a synthetic 
cannabinoid not found in marijuana) are approved for several 
therapeutic indications. The approvals of Marinol and Cesamet were 
based on well-controlled clinical studies that established the 
efficacy and safety of these drugs as a medicine. Smoked marijuana 
has not been demonstrated to be safe and effective in treating these 
medical conditions. Marijuana is a drug substance composed of 
numerous cannabinoids and other constituents; hence the safety and 
efficacy of marijuana cannot be evaluated solely on the effects of 
[Delta]\9\-THC. Adequate and well-controlled studies must be 
performed with smoked marijuana to establish efficacy and safety. 
DHHS states that there is a lack of accepted safety for the use of 
marijuana under medical supervision.
    The petitioner has not submitted any new data meeting the 
requisite scientific standards to support the claim that marijuana 
has an accepted medical use in the United States. Hence, the new 
information provided by the petitioner does not change the federal 
government's evaluation of marijuana's medical use in the United 
States.

     Petitioner's claim of acceptance of the medical use of 
marijuana by eight states since 1996 and state officials in these 
states establishing that marijuana has an accepted medical use in 
the United States

    Petitioner argues that, ``[t]he acceptance of cannabis's medical 
use by eight states since 1996 and the experiences of patients, 
doctors, and state officials in these states establish marijuana's 
accepted medical use in the United States.'' Petition at 10, 13. 
This argument is contrary to the CSA's statutory scheme. The CSA 
does not assign to the states the authority to make findings 
relevant to CSA scheduling determinations. Rather, the CSA expressly 
delegates the task of making such findings--including whether a 
substance has any currently accepted medical use in treatment in the 
United States--to the Attorney General. 21 U.S.C. 811(a). The CSA 
also expressly tasks the Secretary of DHHS to provide a scientific 
and medical evaluation and scheduling recommendations to inform the 
Attorney General's findings. 21 U.S.C. 811(b); see also 21 C.F.R. 
308.43. That Congress explicitly provided scheduling authority to 
these two federal entities in this comprehensive and exclusive 
statutory scheme precludes the argument that state legislative 
action can establish accepted medical use under the CSA.
    The CSA explicitly provides that in making a scheduling 
determination, the Attorney General shall consider the following 
eight factors:

    1. The drug's actual or relative potential for abuse
    2. Scientific evidence of its pharmacological effect, if known;
    3. The state of current scientific knowledge regarding the drug;
    4. Its history and current pattern of abuse;
    5. The scope, duration, and significance of abuse;
    6. What, if any, risk there is to the public health;
    7. The drug's psychic or physiological dependence liability; and
    8. Whether the substance is an immediate precursor of a 
substance already controlled under the CSA.

21 U.S.C. 811(c). These factors embody Congress's view of the 
specialized agency expertise required for drug rescheduling 
decisions. The CSA's statutory text thus further evidences that 
Congress did not envision such a role for state law in establishing 
the schedules of controlled substances under the CSA. See Krumm v. 
Holder, 2009 WL 1563381, at *16 (D.N.M. 2009) (``The CSA does not 
contemplate that state legislatures' determinations about the use of 
a controlled substance can be used to bypass the CSA's rescheduling 
process.'').
    The long-established factors applied by DEA for determining 
whether a drug has a ``currently accepted medical use'' under the 
CSA are:

    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. The scientific evidence must be widely available.

57 FR 10,499, 10,506 (1992), ACT, 15 F.3d at 1135 (upholding these 
factors as valid criteria for determining ``currently accepted 
medical use''). A drug will be deemed to have a currently accepted 
medical use for CSA purposes only if all five of the foregoing 
elements are demonstrated. The following is a summary of information 
as it relates to each of these five elements.

1. The drug's chemistry must be known and reproducible

    DHHS states that although the structures of many cannabinoids 
found in marijuana have been characterized, a complete scientific 
analysis of all the chemical components found in marijuana has not 
been conducted.
    DEA notes that in addition to changes due to its own genetic 
plasticity, marijuana and its chemistry have been throughout the 
ages, and continue to be, modified by environmental factors and 
human manipulation (Paris and Nahas, 1984).

2. There must be adequate safety studies

    DHHS states that safety studies for acute or subchronic 
administration of marijuana have been carried out only through a 
limited number of Phase 1 clinical investigations approved by the 
FDA. There have been no NDA-quality studies that have scientifically 
assessed the safety profile of marijuana for any medical condition. 
DHHS also states that 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.
    DHHS further states that it cannot conclude that marijuana has 
an acceptable level of safety without assurance of a consistent and 
predictable potency and without proof that the substance is free of 
contamination.
    As discussed in Factors 1 and 2, current data suggest that 
marijuana use produces adverse effects on the respiratory system, 
memory and learning. Marijuana use is associated with dependence and 
addiction. In addition, large epidemiological studies indicate that 
marijuana use may exacerbate symptoms in individuals with 
schizophrenia.
    Therefore DHHS concludes that, even under medical supervision, 
marijuana has not been shown to have an accepted level of safety. 
Furthermore, if marijuana is to be investigated more widely for 
medical use, information and data regarding the chemistry, 
manufacturing, and specifications of marijuana must be developed.

3. There must be adequate and well-controlled studies proving 
efficacy

    DHHS states that no studies have been conducted with marijuana 
showing efficacy for any indication in controlled, large scale, 
clinical trials.
    To establish accepted medical use, the effectiveness of a drug 
must be established in well-controlled, well-designed, well-
conducted, and well-documented scientific studies, including studies 
performed in a large number of patients (57 FR 10499, 1992). To 
date, such studies have not been performed. The small clinical trial 
studies with limited patients and short duration are not sufficient 
to establish medical utility. Studies of longer duration are needed 
to fully characterize the drug's efficacy and safety profile. 
Scientific reliability must be established in multiple clinical 
studies. Furthermore, anecdotal reports and isolated case reports 
are not adequate evidence to support an accepted medical use of 
marijuana (57 FR 10499, 1992). The evidence from clinical research 
and reviews of earlier clinical research does not meet this 
standard.
    As noted, DHHS states that a limited number of Phase I 
investigations have been conducted as approved by the FDA. Clinical 
trials, however, generally proceed in three phases. See 21 C.F.R. 
312.21 (2010). Phase I trials encompass initial testing in human 
subjects, generally involving 20 to 80 patients. Id. They are 
designed primarily to assess initial safety, tolerability, 
pharmacokinetics, pharmacodynamics, and preliminary studies of 
potential therapeutic benefit. (62 FR 66113, 1997). Phase II and 
Phase III studies involve successively larger groups of patients: 
usually no more than several hundred subjects in Phase II and 
usually from several hundred to several thousand in Phase III. 21 
C.F.R. 312.21. These studies are designed primarily to explore 
(Phase II) and to demonstrate or confirm (Phase III) therapeutic 
efficacy and benefit in patients. (62 FR 66113, 1997). No Phase II 
or Phase III studies of marijuana have been conducted. Even in 2001, 
DHHS acknowledged that there is ``suggestive evidence that marijuana 
may have beneficial

[[Page 40580]]

therapeutic effects in relieving spasticity associated with multiple 
sclerosis, as an analgesic, as an antiemetic, as an appetite 
stimulant and as a bronchodilator.'' (66 FR 20038, 2001). But there 
is still no data from adequate and well-controlled clinical trials 
that meets the requisite standard to warrant rescheduling.
    DHHS states in a published guidance that it is committed to 
providing ``research-grade marijuana for studies that are the most 
likely to yield usable, essential data'' (DHHS, 1999). DHHS states 
that the opportunity for scientists to conduct clinical research 
with botanical marijuana has increased due to changes in the process 
for obtaining botanical marijuana from NIDA, the only legitimate 
source of the drug for research in the United States. It further 
states that in May 1999, DHHS provided guidance on the procedures 
for providing research-grade marijuana to scientists who intend to 
study marijuana in scientifically valid investigations and well-
controlled clinical trials (DHHS, 1999).

4. The drug must be accepted by qualified experts

    A material conflict of opinion among experts precludes a finding 
that marijuana has been accepted by qualified experts (57 FR 10499, 
1992). DHHS states that, at this time, it is clear that there is not 
a consensus of medical opinion concerning medical applications of 
marijuana, even under conditions where its use is severely 
restricted. DHHS also concludes that, to date, research on the 
medical use of marijuana has not progressed to the point that 
marijuana can be considered to have a ``currently accepted medical 
use'' or a ``currently accepted medical use with severe 
restrictions.''

5. The scientific evidence must be widely available

    DHHS states that the scientific evidence regarding the safety or 
efficacy of marijuana is typically available only in summarized 
form, such as in a paper published in the medical literature, rather 
than in a raw data format. As such, there is no opportunity for 
adequate scientific scrutiny of whether the data demonstrate safety 
or efficacy. Furthermore, as stated before, there have only been a 
limited number of small clinical trials and no controlled, large-
scale clinical trials have been conducted with marijuana on its 
efficacy for any indications or its safety.
    In summary, from DHHS's statements on the five cited elements 
required to make a determination of ``currently accepted medical 
use'' for marijuana, DEA has determined that none has been 
fulfilled. A complete scientific analysis of all the chemical 
components found in marijuana is still missing. There has been no 
NDA-quality study that has assessed the efficacy and full safety 
profile of marijuana for any medical use. At this time, it is clear 
that there is not a consensus of medical opinion concerning medical 
applications of marijuana. To date, research on the medical use of 
marijuana has not progressed to the point that marijuana can be 
considered to have a ``currently accepted medical use'' or even a 
``currently accepted medical use with severe restrictions.'' 21 
U.S.C. 812(b)(2)(B)). Additionally, scientific evidence as to the 
safety or efficacy of marijuana is not widely available.

     Petitioner's claim of increased recognition by health 
care professionals and the medical community, including the 
Institute of Medicine (IOM)

    The petitioner states (pg. 15 line 2), ``Cannabis's accepted 
medical use in the United States is increasingly recognized by 
healthcare professionals and the medical community, including the 
Institute of Medicine.''
    DHHS describes that in February 1997, a National Institutes of 
Health (NIH)-sponsored workshop analyzed available scientific 
evidence on the potential utility of marijuana. In March 1999, the 
Institute of Medicine (IOM) issued a detailed report on the 
potential medical utility of marijuana. Both reports concluded that 
there need to be more and better studies to determine potential 
medical applications of marijuana. The IOM report also recommended 
that clinical trials should be conducted with the goal of developing 
safe delivery systems (NIH, 1997; IOM, 1999).
    DEA notes that in its recommendations, the 1999 IOM report 
states,

If there is any future for marijuana as a medicine, it lies in its 
isolated components, the cannabinoids and their synthetic 
derivatives. Isolated cannabinoids will provide more reliable 
effects than crude plant mixtures. Therefore, the purpose of 
clinical trials of smoked marijuana would not be to develop 
marijuana as a licensed drug but rather to serve as a first step 
toward the development of nonsmoked rapid-onset cannabinoid delivery 
systems.

    Thus, while the IOM report did support further research into 
therapeutic uses of cannabinoids, the IOM report did not ``recognize 
marijuana's accepted medical use'' but rather the potential 
therapeutic utility of cannabinoids.
    DEA notes that the lists presented by the petitioner (pg. 16-18) 
of ``Organizations Supporting Access to Therapeutic Cannabis'' 
(emphasis added) and ``[Organizations Supporting] No Criminal 
Penalty'' contain a majority of organizations that do not 
specifically represent medical professionals. By contrast, the 
petitioner also provides a list of ``Organizations Supporting 
Research on the Therapeutic Use of Cannabis'' (emphasis added), 
which does contain a majority of organizations specifically 
representing medical professionals.
    The petitioner discusses (pg. 20, line 11) the results of a 
United States survey presented at the annual meeting of the American 
Society of Addiction Medicine, and states that the study's results,

indicate that physicians are divided on the medical use of cannabis 
(Reuters of 23 April 2001). Researchers at Rhode Island Hospital in 
Providence asked 960 doctors about their attitude towards the 
statement, ``Doctors should be able to legally prescribe marijuana 
as medical therapy.'' 36 percent of the responders agreed, 38 
percent disagreed and 26 percent were neutral.

    DEA notes that the results of the study, later published in full 
(Charuvastra et al., 2005) show that a slight majority of medical 
doctors polled were opposed to the legalization of medical 
prescription of marijuana. This supports the finding that there is a 
material conflict of opinion among medical professionals.

     Patients' experience in which they reported benefits 
from smoking marijuana (Exh. C, Section I(3), pg. 22);

    Under the petition's section C. I. 3., the petitioner proposes 
both anecdotal self-reported effects by patients and clinical 
studies. The petitioner states (pg. 22, line 2),

[. . .] an increasing number of patients have collected experience 
with cannabis. Many reported benefits from its use. Some of this 
experience has been confirmed in reports and clinical investigations 
or stimulated clinical research that confirmed these patients' 
experience on other patients suffering from the same disease.

    Anecdotal self-reported effects by patients are not adequate 
evidence for the determination of a drug's accepted medical use. DEA 
previously ruled in its final order denying the petition of the 
National Organization for Reform of Marijuana Laws (NORML) to 
reschedule marijuana from Schedule I to Schedule II of the 
Controlled Substances Act (57 FR 10499, 1992) that,

Lay testimonials, impressions of physicians, isolated case studies, 
random clinical experience, reports so lacking in details they 
cannot be scientifically evaluated, and all other forms of anecdotal 
proof are entirely irrelevant.

    DEA further explained in the same ruling that,

Scientists call [stories by marijuana users who claim to have been 
helped by the drug] anecdotes. They do not accept them as reliable 
proofs. The FDA's regulations, for example, provide that in deciding 
whether a new drug is a safe and effective medicine, ``isolated case 
reports will not be considered.'' 21 CFR 314.126(e). Why do 
scientists consider stories from patients and their doctors to be 
unreliable?
    First, sick people are not objective scientific observers, 
especially when it comes to their own health. [. . .] Second, most 
of the stories come from people who took marijuana at the same time 
they took prescription drugs for their symptoms. [. . .] Third, any 
mind-altering drug that produces euphoria can make a sick person 
think he feels better. [. . .] Fourth, long-time abusers of 
marijuana are not immune to illness.
    [. . .] Thanks to scientific advances and to the passage of the 
Federal Food, Drug and Cosmetic Act (FDCA) in 1906, 21 U.S.C. 301 et 
seq., we now rely on rigorous scientific proof to assure the safety 
and effectiveness of new drugs. Mere stories are not considered an 
acceptable way to judge whether dangerous drugs should be used as 
medicines.

    Thus, patients' anecdotal experiences with marijuana are not 
adequate evidence when evaluating whether marijuana has a currently 
accepted medical use.
    In summary, marijuana contains some 483 natural constituents and 
exists in several forms, including dried leaves and flowering

[[Page 40581]]

tops, hashish and hashish oil. It is generally smoked as a 
cigarette. Research with marijuana is being conducted in humans in 
the United States under FDA-authorized IND applications, and using 
marijuana cigarettes provided by NIDA. Adequate studies have not 
been published to support the safety and efficacy of marijuana as a 
medicine. No NDA for marijuana has been submitted to the FDA for any 
indication and thus no medicinal product containing botanical 
cannabis has been approved for marketing. DEA notes that state laws 
do not establish a currently accepted medical use under federal law. 
Furthermore, DEA previously ruled that anecdotal self-reported 
effects by patients are not adequate evidence of a currently 
accepted medical use under federal law. A material conflict of 
opinion among experts precludes a finding that marijuana has been 
accepted by qualified experts. At present, there is no consensus of 
medical opinion concerning medical applications of marijuana. In 
short, the limited number of clinical trials involving marijuana 
that have been conducted to date--none of which have progressed 
beyond phase 1 of the three phases needed to demonstrate safety and 
efficacy for purposes of FDA approval--fails by a large measure to 
provide a basis for any alteration of the prior conclusions made by 
HHS and DEA (in 1992 and in 2001) that marijuana has no currently 
accepted medical use in treatment in the United States.

FACTOR 4: ITS HISTORY AND CURRENT PATTERN OF ABUSE

    Marijuana use has been relatively stable from 2002 to 2009, and 
it continues to be the most widely used illicit drug. According to 
the NSDUH, there were 2.4 million new users (6,000 initiates per 
day) in 2009 and 16.7 million current (past month) users of 
marijuana aged 12 and older. Past month use of marijuana was 
statistically significantly higher in 2009 (16.7 million) than in 
2008 (15.2 million), according to NSDUH. An estimated 104.4 million 
Americans age 12 or older had used marijuana or hashish in their 
lifetime and 28.5 million had used it in the past year. In 2008, 
most (62.2 percent) of the 2.2 million new users were less than 18 
years of age. In 2008, marijuana was used by 75.7 percent of current 
illicit drug users and was the only drug used by 57.3 percent of 
these users. In 2008, among past year marijuana users aged 12 or 
older, 15.0 percent used marijuana on 300 or more days within the 
previous 12 months. This translates into 3.9 million people using 
marijuana on a daily or almost daily basis over a 12-month period. 
In 2008, among past month marijuana users, 35.7 percent (5.4 
million) used the drug on 20 or more days in the past month.
    Marijuana is also the illicit drug with the highest rate of past 
year dependence or abuse. According to the 2009 NSDUH report, 4.3 
million persons were classified with marijuana dependence or abuse 
based on criteria specified in the Diagnostic and Statistical Manual 
of Mental Disorders, 4th edition (DSM-IV).
    According to the 2010 Monitoring the Future (MTF) survey, 
marijuana is used by a large percentage of American youths. Among 
students surveyed in 2010, 17.3 percent of eighth graders, 33.4 
percent of tenth graders, and 43.8 percent of twelfth graders 
reported lifetime use (i.e., any use in their lifetime) of 
marijuana. In addition, 13.7, 27.5 and 34.8 percent of eighth, tenth 
and twelfth graders, respectively, reported using marijuana in the 
past year. A number of high-schoolers reported daily use in the past 
month, including 1.2, 3.3 and 6.1 percent of eighth, tenth and 
twelfth graders, respectively.
    The prevalence of marijuana use and abuse is also indicated by 
criminal investigations for which drug evidences were analyzed in 
DEA and state laboratories. The National Forensic Laboratory System 
(NFLIS), which compiles information on exhibits analyzed in state 
and local law enforcement laboratories, showed that marijuana was 
the most frequently identified drug from January 2001 through 
December 2010: In 2010, marijuana accounted for 36.3 percent 
(464,059) of all drug exhibits in NFLIS. Similar findings were 
reported by the System to Retrieve Information from Drug Evidence 
(STRIDE), a DEA database which compiles information on exhibits 
analyzed in DEA laboratories, for the same reporting period. From 
January 2001 through December 2010, marijuana was the most 
frequently identified drug. In 2010, there were 11,293 marijuana 
exhibits associated with 7,158 law enforcement cases representing 
16.7 percent of all exhibits in STRIDE.
    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 2009, the Domestic Cannabis Eradication and Suppression 
Program (DCE/SP) reported that 9,980,038 plants were eradicated in 
outdoor cannabis cultivation areas in the United States. Major 
domestic outdoor cannabis cultivation areas were found in 
California, Kentucky, Tennessee and Hawaii. Significant quantities 
of marijuana were also eradicated from indoor cultivation 
operations. There were 414,604 indoor plants eradicated in 2009 
compared to 217,105 eradicated in 2000. Most foreign-source 
marijuana smuggled into the United States enters through or between 
points of entry at the United States-Mexico border. However, drug 
seizure data show that the amount of marijuana smuggled into the 
United States from Canada via the United States-Canada border has 
risen to a significant level. In 2009, the Federal-wide Drug Seizure 
System (FDSS) reported seizures of 1,910,600 kg of marijuana.
    While most of the marijuana available in the domestic drug 
markets is lower potency commercial-grade marijuana, usually derived 
from outdoor cannabis grow sites in Mexico and the United States, an 
increasing percentage of the available marijuana is high potency 
marijuana derived from indoor, closely controlled cannabis 
cultivation in Canada and the United States. The rising prevalence 
of high potency marijuana is evidenced by a nearly two-fold increase 
in average potency of tested marijuana samples, from 4.87 percent 
[Delta]\9\-THC in 2000 to 8.49 percent [Delta]\9\-THC in 2008.
    In summary, marijuana is the most commonly used illegal drug in 
the United States, and it is used by a large percentage of American 
high-schoolers. Marijuana is the most frequently identified drug in 
state, local and federal forensic laboratories, with increasing 
amounts both of domestically grown and of illicitly smuggled 
marijuana. An observed increase in the potency of seized marijuana 
also raises concerns.

FACTOR 5: THE SCOPE, DURATION, AND SIGNIFICANCE OF ABUSE

    Abuse of marijuana is widespread and significant. DHHS presented 
data from the NSDUH, and DEA has updated this information. As 
previously noted, according to the NSDUH, in 2009, an estimated 
104.4 million Americans age 12 or older had used marijuana or 
hashish in their lifetime, 28.5 million had used it in the past 
year, and 16.7 million (6.6 percent) had used it in the past month. 
In 2008, an estimated 15.0 percent of past year marijuana users aged 
12 or older used marijuana on 300 or more days within the past 12 
months. This translates into 3.9 million persons using marijuana on 
a daily or almost daily basis over a 12-month period. In 2008, an 
estimated 35.7 percent (5.4 million) of past month marijuana users 
aged 12 or older used the drug on 20 or more days in the past month 
(SAMHSA, NSDUH and TEDS). Chronic use of marijuana is associated 
with a number of health risks (see Factors 2 and 6).
    Marijuana's widespread availability is being fueled by 
increasing marijuana production domestically and increased illicit 
importation from Mexico and Canada. Domestically both indoor and 
outdoor grow sites have been encountered. In 2009, nearly 10 million 
marijuana plants were seized from outdoor grow sites and over 
410,000 were seized from indoor sites for a total of over 10 million 
plants in 2009 compared to about 2.8 million plants in 2000 
(Domestic Cannabis Eradication/Suppression Program). An increasing 
percentage of the available marijuana being trafficked in the United 
States is higher potency marijuana derived from the indoor, closely 
controlled cultivation of marijuana plants in both the US and Canada 
(Domestic Cannabis Eradication/Suppression Program) and the average 
percentage of [Delta]\9\-THC in seized marijuana increased almost 
two-fold from 2000 to 2008 (The University of Mississippi Potency 
Monitoring Project). Additional studies are needed to clarify the 
impact of greater potency, but DEA notes one study showing 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).
    Data from TEDS show that in 2008, 17.2 percent of all admissions 
were for primary marijuana abuse. In 2007, more than half of the 
drug-related treatment admissions involving individuals under the 
age of 15 (60.8 percent) and more than half of the drug-related 
treatment admissions involving individuals 15 to 19 years of age 
(55.9 percent), were for primary marijuana abuse. In 2007, among the 
marijuana/hashish admissions (286,194), 25.1 percent began using 
marijuana at age 12 or younger.
    In summary, the recent statistics from these various surveys and 
databases show that

[[Page 40582]]

marijuana continues to be the most commonly used illicit drug, with 
significant rates of heavy use and dependence in teenagers and 
adults.
    The petitioner states, ``The use and abuse of cannabis has been 
widespread in the United States since national drug use surveys 
began in the 1970s. A considerable number of cannabis users suffer 
from problems that meet the criteria for abuse. However, the large 
majority of cannabis users do not experience any relevant problems 
related to their use.'' (pg. 4, line 31).
    Petitioner acknowledges that a considerable number of cannabis 
users suffer from problems that meet the criteria for abuse. DEA 
provides data under this Factor, as well as Factors 1, 2, and 7, 
that support this undisputed issue. Briefly, current data suggest 
that marijuana use produces adverse effects on the respiratory 
system, memory and learning. Marijuana use is associated with 
dependence and addiction. In addition, large epidemiological studies 
indicate that marijuana use may exacerbate symptoms in individuals 
with schizophrenia, and may precipitate schizophrenic disorders in 
those individuals who are vulnerable to developing psychosis.

FACTOR 6: WHAT, IF ANY, RISK THERE IS TO THE PUBLIC HEALTH

    The risk marijuana poses to the public health may manifest 
itself in many ways. Marijuana use may affect the physical and/or 
psychological functioning of an individual user, but may also have 
broader public impacts, for example, from a marijuana-impaired 
driver. The impacts of marijuana abuse and dependence are more 
disruptive for an abuser, but also for the abuser's family, friends, 
work environment, and society in general. Data regarding marijuana 
health risks are available from many sources, including forensic 
laboratory analyses, crime laboratories, medical examiners, poison 
control centers, substance abuse treatment centers, and the 
scientific and medical literature. Risks have been associated with 
both acute and chronic marijuana use, including risks for the 
cardiovascular and respiratory systems, as well as risks for mental 
health and cognitive function and risks related to prenatal exposure 
to marijuana. The risks of marijuana use and abuse have previously 
been discussed in terms of the scientific evidence of its 
pharmacological effects on physical systems under Factor 2. Below, 
some of the risks of marijuana use and abuse are discussed in 
broader terms of the effects on the individual user and the public 
from acute and chronic use of the drug.

Risks Associated with Acute Use of Marijuana

    DHHS states that acute use of marijuana impairs psychomotor 
performance, including performance of complex tasks, which makes it 
inadvisable to operate motor vehicles or heavy equipment after using 
marijuana (Ramaekers et al., 2004). DHHS further describes a study 
showing that acute administration of smoked marijuana impairs 
performance on tests of learning, associative processes, and 
psychomotor behavior (Block et al., 1992). DHHS also describes 
studies showing that administration to human volunteers of 
[Delta]\9\-THC in a smoked marijuana cigarette produced impaired 
perceptual motor speed and accuracy, two skills that are critical to 
driving ability (Kurzthaler et al., 1999) and produced increases in 
disequilibrium measures, as well as in the latency in a task of 
simulated vehicle braking, at a rate comparable to an increase in 
stopping distance of 5 feet at 60 mph (Liguori et al., 1998).
    The petitioner states that (pg., 65, line 10), ``Although the 
ability to perform complex cognitive operations is assumed to be 
impaired following acute marijuana smoking, complex cognitive 
performance after acute marijuana use has not been adequately 
assessed under experimental conditions.'' As described above, DHHS 
presents evidence of marijuana's acute effects on complex cognitive 
tasks.
    DHHS states that dysphoria and psychological distress, including 
prolonged anxiety reactions, are potential responses in a minority 
of individuals who use marijuana (Haney et al., 1999). DEA notes 
reviews of studies describing that some users report unpleasant 
psychological reactions. Acute anxiety reactions to cannabis may 
include restlessness, depersonalization, derealization, sense of 
loss of control, fear of dying, panic and paranoid ideas (see 
reviews by Thomas, 1993 and Weil, 1970).
    DEA notes a review of studies showing that the general 
depressant effect of moderate to high doses of cannabis might 
contribute to slowed reaction times, inability to maintain 
concentration and lapses in attention (see review by Chait and 
Pierri, 1992). The review suggests that fine motor control and 
manual dexterity are generally adversely affected although simple 
reaction time may or may not be. DEA also notes studies showing that 
choice or complex reaction time is more likely to be affected, with 
reaction time consistently increasing with the difficulty of the 
task (e.g., Block and Wittenborn, 1985).
    DEA also notes additional studies showing marijuana use 
interferes with the ability to operate motor vehicles. Studies show 
that marijuana use can cause impairment in driving (Robbe and 
O'Hanlon, 1999). The National Highway Traffic Safety Administration 
(NHTSA) conducted a study with the Institute for Human 
Psychopharmacology at Maastricht University in the Netherlands 
(Robbe and O'Hanlon, 1999) to evaluate the effects of low and high 
doses of smoked [Delta]\9\-THC alone and in combination with alcohol 
on the following tests: 1) the Road Tracking Test, which measures 
the driver's ability to maintain a constant speed of 62 mph and a 
steady lateral position between the boundaries of the right traffic 
lane; and 2) the Car Following Test, which measures a driver's 
reaction times and ability to maintain distance between vehicles 
while driving 164 ft behind a vehicle that executes a series of 
alternating accelerations and decelerations. Mild to moderate 
impairment of driving was observed in the subjects after treatment 
with marijuana. The study found that marijuana in combination with 
alcohol had an additive effect resulting in severe driving 
impairment.
    DEA also notes a study by Bedard and colleagues (2007), which 
used a cross-sectional, case-control design with drivers aged 20-49 
who were involved in a fatal crash in the United States from 1993 to 
2003. Drivers were included if they had been tested for the presence 
of cannabis and had a confirmed blood alcohol concentration of zero. 
Cases were drivers who had at least one potentially unsafe driving 
action recorded in relation to the crash (e.g., speeding); controls 
were drivers who had no such driving action recorded. Authors 
calculated the crude and adjusted odds ratios (ORs) of any 
potentially unsafe driving action in drivers who tested positive for 
cannabis but negative for alcohol consumption. Five percent of 
drivers tested positive for cannabis. The crude OR of a potentially 
unsafe action was 1.39 (99 percent CI = 1.21-1.59) for drivers who 
tested positive for cannabis. Even after controlling for age, sex, 
and prior driving record, the presence of cannabis remained 
associated with a higher risk of a potentially unsafe driving action 
(1.29, 99 percent CI = 1.11-1.50). Authors of the study concluded 
that cannabis had a negative effect on driving, as predicted from 
various human performance studies.
    In 2001, estimates derived from the United States Census Bureau 
and Monitoring the Future show that approximately 600,000 of the 
nearly 4 million United States high-school seniors drive under the 
influence of marijuana. Approximately 38,000 seniors reported that 
they had crashed while driving under the influence of marijuana in 
2001 (MTF, 2001).
    DEA further notes studies suggesting that marijuana can affect 
the performance of pilots. Yeswavage and colleagues (1985) evaluated 
the acute and delayed effects of smoking one marijuana cigarette 
containing 1.9 percent [Delta]\9\-THC (19 mg of [Delta]\9\-THC) on 
the performance of aircraft pilots. Ten subjects were trained in a 
flight simulator prior to marijuana exposure. Flight simulator 
performance was measured by the number of aileron (lateral control) 
and elevator (vertical control) and throttle changes, the size of 
these control changes, the distance off the center of the runaway on 
landing, and the average lateral and vertical deviation from an 
ideal glideslope and center line over the final mile of the 
approach. Compared to the baseline performance, significant 
differences occurred at 4 hours. Most importantly, at 24 hours after 
a single marijuana cigarette, there were significant impairments in 
the number and size of aileron changes, size of elevator changes, 
distance off-center on landing, and vertical and lateral deviations 
on approach to landing. Interestingly, despite these performance 
deficits, the pilots reported no significant subjective awareness of 
their impairments at 24 hours.
    DEA notes a review of the contaminants and adulterants that can 
be found in marijuana (McPartland, 2002). In particular, DEA notes 
that many studies have reported contamination of both illicit and 
NIDA-grown marijuana with microbial contaminants, bacterial or 
fungal (McLaren et al., 2008; McPartland, 1994, 2002; Ungerleider et 
al., 1982; Taylor et al., 1982; Kurup et al., 1983). In a study by 
Kagen and

[[Page 40583]]

colleagues (1983), fungi was found in 13 of the 14 samples, and 
evidence of exposure to Aspergillus fungi was found in the majority 
of marijuana smokers (13 of 23), but only one of the 10 control 
participants. Aspergillus can cause aspergillosis, a fatal lung 
disease and DEA notes studies suggesting an association between this 
disease and cannabis smoking among patients with compromised immune 
systems (reviewed in McLaren et al., 2008). Other microbial 
contaminants include bacteria such as Klebsiella pneumoniae, 
salmonella enteritidis, and group D Streptococcus (Ungerlerder et 
al., 1982; Kagen et al., 1983; Taylor et al., 1982). DEA notes 
reports that Salmonella outbreaks have been linked to marijuana 
(Taylor et al., 1982, CDC, 1981).

Risks Associated with Chronic Use of Marijuana

    DHHS states that chronic exposure to marijuana smoke is 
considered to be comparable to tobacco smoke with respect to 
increased risk of cancer and lung damage. DEA notes studies showing 
that marijuana smoke contains several of the same carcinogens and 
co-carcinogens as tobacco smoke and suggesting that pre-cancerous 
lesions in bronchial epithelium also seem to be caused by long-term 
marijuana smoking (Roth et al., 1998). DEA also notes the 
publication of a recent case-control study of lung cancer in adults 
(Aldington et al., 2008), in which users reporting over 10.5 joint-
years of exposure had a significantly increased risk of developing 
lung cancer, leading the study's authors to conclude that long-term 
cannabis use increases the risk of lung cancer in young adults. In 
addition, a distinctive marijuana withdrawal syndrome has been 
identified, indicating that marijuana produces physical dependence 
(Budney et al., 2004), as described in Factor 7.
    DHHS further quotes the Diagnostic and Statistical Manual (DSM-
IV-TR, 2000) of the American Psychiatric Association, which states 
that the consequences of cannabis abuse are as follows:

    [P]eriodic cannabis use and intoxication can interfere with 
performance at work or school and may be physically hazardous in 
situations such as driving a car. Legal problems may occur as a 
consequence of arrests for cannabis possession. There may be 
arguments with spouses or parents over the possession of cannabis in 
the home or its use in the presence of children. When psychological 
or physical problems are associated with cannabis in the context of 
compulsive use, a diagnosis of Cannabis Dependence, rather than 
Cannabis Abuse, should be considered.
    Individuals with Cannabis Dependence have compulsive use and 
associated problems. Tolerance to most of the effects of cannabis 
has been reported in individuals who use cannabis chronically. There 
have also been some reports of withdrawal symptoms, but their 
clinical significance is uncertain. There is some evidence that a 
majority of chronic users of cannabinoids report histories of 
tolerance or withdrawal and that these individuals evidence more 
severe drug-related problems overall. Individuals with Cannabis 
Dependence may use very potent cannabis throughout the day over a 
period of months or years, and they may spend several hours a day 
acquiring and using the substance. This often interferes with 
family, school, work, or recreational activities. Individuals with 
Cannabis Dependence may also persist in their use despite knowledge 
of physical problems (e.g., chronic cough related to smoking) or 
psychological problems (e.g., excessive sedation and a decrease in 
goal-oriented activities resulting from repeated use of high doses).

    In addition, DHHS states that marijuana use produces acute and 
chronic adverse effects on the respiratory system, memory and 
learning. Regular marijuana smoking produces a number of long-term 
pulmonary consequences, including chronic cough and sputum (Adams 
and Martin, 1996), and histopathologic abnormalities in bronchial 
epithelium (Adams and Martin, 1996). DEA also notes studies 
suggesting marijuana use leads to evidence of widespread airway 
inflammation and injury (Roth et al., 1998, Fligiel et al., 1997) 
and immunohistochemical evidence of dysregulated growth of 
respiratory epithelial cells that may be precursors to lung cancer 
(Baldwin et al., 1997). In addition, very large epidemiological 
studies indicate that marijuana may increase risk of psychosis in 
vulnerable populations, i.e., individuals predisposed to develop 
psychosis (Andreasson et al., 1987) and exacerbate psychotic 
symptoms in individuals with schizophrenia (Schiffman et al., 2005; 
Hall et al., 2004; Mathers and Ghodse, 1992; Thornicroft, 1990; see 
Factor 2).
    The petitioner cited ``The Missoula Chronic Clinical Cannabis 
Use Study'' as evidence that long-term use of marijuana does not 
cause significant harm in patients (Russo et al., 2002). DEA notes 
that this article describes the case histories and clinical 
examination of only four patients that were receiving marijuana 
cigarettes from the National Institute on Drug Abuse for a variety 
of medical conditions. The number of patients included in the study 
is not adequate for this evaluation.
    The petitioner states, ``Studies have shown the long-term use of 
cannabis to be safe. In contrast to many other medicinal drugs, the 
long-term use of cannabis does not harm stomach, liver, kidneys and 
heart.'' (Exh. C, Section II (10), pg. 66).
    However, DHHS states that marijuana has not been shown to have 
an accepted level of safety for medical use. There have been no NDA-
quality studies that have scientifically assessed the full safety 
profile of marijuana for any medical condition. DEA notes in 
addition, as described above, the risks associated with chronic 
marijuana use, including, as described in Factor 2, risks for the 
cardiovascular and respiratory systems, as well as risks for mental 
health and cognitive function and risks related to prenatal exposure 
to marijuana.

Marijuana as a ``Gateway Drug''

    A number of studies have examined the widely held premise that 
marijuana use leads to subsequent abuse of other illicit drugs, thus 
functioning as a ``gateway drug.'' DHHS discussed a 25-year study of 
1,256 New Zealand children, Fergusson et al. (2005), which concluded 
that the use of marijuana correlates to an increased risk of abuse 
of other drugs. Other studies, however, do not support a direct 
causal relationship between regular marijuana use and other illicit 
drug abuse. DHHS cited the IOM report (1999), which states that 
marijuana is a ``gateway drug'' in the sense that its use typically 
precedes rather than follows initiation of other illicit drug use. 
However, as cited by DHHS, the IOM states that, ``[t]here is no 
conclusive evidence that the drug effects of marijuana are causally 
linked to the subsequent abuse of other illicit drugs.'' DHHS noted 
that for most studies that test the hypothesis that marijuana causes 
abuse of harder drugs, the determinative measure for testing this 
hypothesis is whether marijuana leads to ``any drug use'' rather 
than that marijuana leads to ``drug abuse and dependence'' as 
defined by DSM-IV criteria.

FACTOR 7: ITS PSYCHIC OR PHYSIOLOGICAL DEPENDENCE LIABILITY

    DHHS states that many medications that are not associated with 
abuse or addiction, such as antidepressants, beta-blockers, and 
centrally acting antihypertensive drugs, can produce physical 
dependence and withdrawal symptoms after chronic use. However, 
psychological and physical dependence of drugs that have abuse 
potential are important factors contributing to increased or 
continued drug taking. This section provides scientific evidence 
that marijuana causes physical and psychological dependence.

Physiological (Physical) Dependence in Humans

    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 (American Academy of Pain 
Medicine, American Pain Society and American Society of Addiction 
Medicine consensus document, 2001).
    DHHS states that long-term, regular use of marijuana can lead to 
physical dependence and withdrawal following discontinuation as well 
as psychic addiction or dependence. The marijuana withdrawal 
syndrome consists of symptoms such as restlessness, irritability, 
mild agitation, insomnia, EEG disturbances, nausea, cramping and 
decrease in mood and appetite that may resolve after 4 days, and may 
require in-hospital treatment (Haney et al., 1999). It is distinct 
and mild compared to the withdrawal syndromes associated with 
alcohol and heroin use (Budney et al., 1999; Haney et al., 1999). 
DEA notes that Budney et al. (1999) examined the withdrawal 
symptomatology in 54 chronic marijuana abusers seeking treatment for 
their dependence. The majority of the subjects (85 percent) reported 
that they had experienced symptoms of at least moderate severity. 
Fifty seven percent (57 percent) reported having six or more 
symptoms of a least moderate severity while 47 percent experienced 
four or more symptoms rated as severe. The most reported mood 
symptoms associated with the

[[Page 40584]]

withdrawal were irritability, nervousness, depression, and anger. 
Some of the other behavioral characteristics of the marijuana 
withdrawal syndrome were craving, restlessness, sleep disruptions, 
strange dreams, changes in appetite, and violent outbursts.
    DHHS discusses a study by Lane and Phillips-Bute (1998) which 
describes milder cases of dependence including symptoms that are 
comparable to those from caffeine withdrawal, including decreased 
vigor, increased fatigue, sleepiness, headache, and reduced ability 
to work. The marijuana withdrawal syndrome has been reported in 
adolescents who were admitted for substance abuse treatment or in 
individuals who had been given marijuana on a daily basis during 
research conditions. Withdrawal symptoms can also be induced in 
animals following administration of a cannabinoid antagonist after 
chronic [Delta]\9\-THC administration (Maldonado, 2002; Breivogel et 
al., 2003). DHHS also discusses a study comparing marijuana and 
tobacco withdrawal symptoms in humans (Vandrey et al., 2005) which 
demonstrated that the magnitude and time course of the two 
withdrawal syndromes are similar.
    DHHS states that a review by Budney and colleagues (2004) of 
studies of cannabinoid withdrawal, with a particular emphasis on 
human studies, led to the recommendation that the Diagnostic and 
Statistical Manual of Mental Disorders (DSM) introduce a listing for 
cannabis withdrawal. In this listing, common symptoms would include 
anger or aggression, decreased appetite or weight loss, 
irritability, nervousness/anxiety, restlessness and sleep 
difficulties including strange dreams. Less common symptoms/
equivocal symptoms would include chills, depressed mood, stomach 
pain, shakiness and sweating.

Psychological Dependence in Humans

    In addition to physical dependence, DHHS states that long-term, 
regular use of marijuana can lead to psychic addiction or 
dependence. Psychological dependence on marijuana is defined by the 
American Psychiatric Association in the DSM-IV and cited by DHHS.
    The Diagnostic and Statistical Manual of Mental Disorders (DSM-
IV) is published by the American Psychiatric Association (2000), and 
provides diagnostic criteria to improve the reliability of 
diagnostic judgment of mental disorders by mental health 
professionals. DSM-IV currently defines ``Cannabis Dependence'' 
(DSM-IV diagnostic category 304.30) as follows:
    Cannabis dependence: A destructive pattern of cannabis use, 
leading to clinically significant impairment or distress, as 
manifested by three (or more) of the following, occurring when the 
cannabis use was at its worst:

    1. Cannabis tolerance, as defined by either of the following:
    a. A need for markedly increased amounts of cannabis to achieve 
intoxication,
    b. Markedly diminished effect with continued use of the same 
amount of cannabis.
    2. Greater use of cannabis than intended: Cannabis was often 
taken in larger amounts or over a longer period than was intended.
    3. Unsuccessful efforts to cut down or control cannabis use: 
Persistent desire or unsuccessful efforts to cut down or control 
cannabis use.
    4. Great deal of time spent in using cannabis, or recovering 
from hangovers.
    5. Cannabis caused reduction in social, occupational or 
recreational activities: Important social, occupational, or 
recreational activities given up or reduced because of cannabis use.
    6. Continued using cannabis despite knowing it caused 
significant problems: Cannabis use is continued despite knowledge of 
having a persistent or recurrent physical or psychological problem 
that is likely to have been worsened by cannabis.
    In addition, the DSM-IV added a specifier to this diagnostic by 
which it can be with or without physiological (physical) dependence.
    DEA notes additional clinical studies showing that frequency of 
[Delta]\9\-THC use (most often as marijuana) escalates over time. 
Individuals increase the number, doses, and potency of marijuana 
cigarettes. Several studies have reported that patterns of marijuana 
smoking and increased quantity of marijuana smoked were related to 
social context and drug availability (Kelly et al., 1994; Mendelson 
and Mello, 1984; Mello, 1989).
    DEA further notes that Budney et al. (1999) reported that 93 
percent of marijuana-dependent adults seeking treatment reported 
experiencing mild craving for marijuana, and 44 percent rated their 
past craving as severe. Craving for marijuana has also been 
documented in marijuana users not seeking treatment (Heishman et 
al., 2001). Two hundred seventeen marijuana users completed a 47-
item Marijuana Craving Questionnaire and forms assessing 
demographics, drug use history, marijuana-quit attempts and current 
mood. The results indicate that craving for marijuana was 
characterized by 1) the inability to control marijuana use 
(compulsivity); 2) the use of marijuana in anticipation of relief 
from withdrawal or negative mood (emotionality); 3) anticipation of 
positive outcomes from smoking marijuana (expectancy); and 4) 
intention and planning to use marijuana for positive outcomes 
(purposefulness).
    In summary, long-term, regular use of marijuana can lead to 
physical dependence and withdrawal following discontinuation as well 
as psychic addiction or dependence.

FACTOR 8: WHETHER THE SUBSTANCE IS AN IMMEDIATE PRECURSOR OF A 
SUBSTANCE ALREADY CONTROLLED UNDER THE CSA

    Marijuana is not an immediate precursor of any controlled 
substance.

DETERMINATION

    After consideration of the eight factors discussed above and of 
DHHS's recommendation, 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

    Marijuana is the most highly abused and trafficked illicit 
substance in the United States. Approximately 16.7 million 
individuals in the United States (6.6 percent of the United States 
population) used marijuana monthly in 2009. A 2009 national survey 
that tracks drug use trends among high school students showed that 
by 12th grade, 32.8 percent of students reported having used 
marijuana in the past year, 20.6 percent reported using it in the 
past month, and 5.2 percent reported having used it daily in the 
past month. Its widespread availability is being fueled by 
increasing marijuana production domestically and increased 
trafficking from Mexico and Canada.
    Marijuana has dose-dependent reinforcing effects that encourage 
its abuse. Both clinical and preclinical studies have clearly 
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.
    Significant numbers of chronic users of marijuana seek substance 
abuse treatment. Compared to all other specific drugs included in 
the 2008 NSDUH survey, marijuana had the highest levels of past year 
dependence and abuse.

2. Marijuana has no currently accepted medical use in treatment in the 
United States

    DHHS states that the FDA has not evaluated nor approved an NDA 
for marijuana. The long-established factors applied by DEA for 
determining whether a drug has a ``currently accepted medical use'' 
under the CSA are as follows. A drug will be deemed to have a 
currently accepted medical use for CSA purposes only if all of the 
following five elements have been satisfied. As set forth below, 
none of these elements has been fulfilled:

i. The drug's chemistry must be known and reproducible

    Although the structures of many cannabinoids found in marijuana 
have been characterized, a complete scientific analysis of all the 
chemical components found in marijuana has not been conducted. 
Furthermore, many variants of the marijuana plant are found due to 
its own genetic plasticity and human manipulation.

ii. There must be adequate safety studies

    Safety studies for acute or sub-chronic administration of 
marijuana have been carried out through a limited number of Phase I 
clinical investigations approved by the FDA, but there have been no 
NDA-quality studies that have scientifically assessed the full 
safety profile of marijuana for any medical condition. Large, 
controlled studies have not been conducted to evaluate the risk-
benefit ratio of marijuana use, and any potential benefits 
attributed to marijuana use currently do not outweigh the known 
risks.

iii. There must be adequate and well-controlled studies proving 
efficacy

    DHHS states that there have been no NDA-quality studies that 
have scientifically assessed the efficacy of marijuana for any 
medical condition. To establish accepted medical use, the 
effectiveness of a drug must be established in well-controlled, 
well-

[[Page 40585]]

designed, well-conducted, and well-documented scientific studies, 
including studies performed in a large number of patients. To date, 
such studies have not been performed for any indications.

    Small clinical trial studies with limited patients and short 
duration are not sufficient to establish medical utility. Studies of 
longer duration are needed to fully characterize the drug's efficacy 
and safety profile. Scientific reliability must be established in 
multiple clinical studies. Anecdotal reports and isolated case 
reports are not sufficient evidence to support an accepted medical 
use of marijuana. The evidence from clinical research and reviews of 
earlier clinical research does not meet the requisite standards.

iv. The drug must be accepted by qualified experts

    At this time, it is clear that there is no consensus of opinion 
among experts concerning medical applications of marijuana. To date, 
research on the medical use of marijuana has not progressed to the 
point that marijuana can be considered to have a ``currently 
accepted medical use'' or a ``currently accepted medical use with 
severe restrictions.

v. The scientific evidence must be widely available

    DHHS states that the scientific evidence regarding the safety 
and efficacy of marijuana is typically available only in summarized 
form, such as in a paper published in the medical literature, rather 
than in a raw data format. In addition, as noted, there have only 
been a limited number of small clinical trials and no controlled, 
large scale, clinical trials have been conducted with marijuana on 
its efficacy for any indications or its safety.

3. There is a lack of accepted safety for use of marijuana under 
medical supervision

    At present, there are no FDA-approved marijuana products, nor is 
marijuana under NDA evaluation at the FDA for any indication. 
Marijuana does not have a currently accepted medical use in 
treatment in the United States or a currently accepted medical use 
with severe restrictions. The Center for Medicinal Cannabis Research 
in California, among others, is conducting research with marijuana 
at the IND level, but these studies have not yet progressed to the 
stage of submitting an NDA. Current data suggest that marijuana use 
produces adverse effects on the respiratory system, memory and 
learning. Marijuana use is associated with dependence and addiction. 
In addition, very large epidemiological studies indicate that 
marijuana use may be a causal factor for the development of 
psychosis in individuals predisposed to develop psychosis and may 
exacerbate psychotic symptoms in individuals with schizophrenia. 
Thus, 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. In 
sum, at present, marijuana lacks an acceptable level of safety even 
under medical supervision.

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