[Federal Register Volume 66, Number 43 (Monday, March 5, 2001)]
[Notices]
[Pages 13323-13326]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-5218]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 00N-1257]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; World Health 
Organization Scheduling Recommendations for 4-Bromo-2,5-
dimethoxyphenethylamine (2C-B); Gamma-hydroxybutyric acid (GHB); 4-
Methylthioamphetamine (4-MTA); Zolpidem (INN)

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is providing interested 
persons with the opportunity to submit written comments concerning 
recommendations by the World Health Organization (WHO) to impose 
international manufacturing and distribution restrictions, under 
international treaties, on certain drug substances. The comments 
received in response to this notice will be considered in preparing the 
U.S. position on these proposals for a meeting of the United Nations 
Commission on Narcotic Drugs (CND) in Vienna, Austria, March 20 to 29, 
2001. This notice is issued under the Controlled Substances Act.

DATES: Submit written comments by March 15, 2001.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. To ensure expeditious review of written comments, 
send a copy by facsimile or e-mail to: James R. Hunter (address below).

FOR FURTHER INFORMATION CONTACT: James R. Hunter, Controlled Substances 
Staff (HFD-9), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-2098, Fax: 301-443-9222, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    The United States is a party to the 1971 Convention on Psychotropic 
Substances (the Convention). Section 201(d)(2)(B) of the Controlled 
Substances Act (the CSA) (21 U.S.C. 811(d)(2)(B)) provides that when 
the United States is notified under Article 2 of the Convention that 
CND proposes to decide whether to add a drug or other substance to one 
of the schedules of the Convention, transfer a drug or substance from 
one schedule to another, or delete it from the schedules, the Secretary 
of State must transmit notice of such information to the Secretary of 
Health and Human Services (HHS). The Secretary of HHS must then publish 
a summary of such information in the Federal Register and provide 
opportunity for interested persons to submit comments. The Secretary of 
HHS must then evaluate the proposal and furnish a recommendation to the 
Secretary of State that shall be binding on the representative of the 
United States in discussions and negotiations relating to the proposal.
    As detailed below, the Secretary of State has received notification 
from the Secretary-General of the United Nations (the Secretary-
General) regarding substances to be considered for control under the 
Convention. The notification reflects the recommendations from the 31st 
WHO Expert Committee for Drug Dependence (ECDD), which met in June 
1998. In the Federal Register of April 28, 2000 (65 FR 24969), FDA 
announced the WHO ECDD review, and the agency invited interested 
persons to submit information for WHO's consideration.
    The full text of the notification from the Secretary-General is 
provided in section II of this document. Section 201(d)(2)(B) of the 
CSA requires the Secretary of HHS, after receiving a notification 
proposing scheduling, to publish a notice in the Federal Register to 
provide the opportunity for interested persons to submit information 
and comments on the proposed scheduling action.

II. United Nations Notification

    The formal United Nations notification that identifies the drug 
substances and explains the basis for the recommendations is reproduced 
below.
    Notification on 2C-B, 4-MTA, GHB and Zolpidem: Reference: NAR/
CL.26/2000 CU 2000/240.

C1971/WHO
UNDCP 42nd CND
TLACSB/CNDS-40/00
    The Secretary-General of the United Nations presents his 
compliments to the Secretary of State of the United States of

[[Page 13324]]

America and has the honour to inform the Government that, pursuant to 
article 2, paragraphs 1 and 4, of the Convention on Psychotropic 
Substances, 1971, he has received a notification from the World Health 
Organization (WHO) concerning proposed recommendations for 
international control in respect of the following four substances: 2C-
B, 4-MTA, GHB and zolpidem.
    In accordance with the provisions of article 2, paragraph 2, of the 
1971 Convention, the Secretary-General is transmitting the text of that 
notification as an annex to the present note.
    As will be seen from the notification and the attached assessments 
and recommendations, WHO recommends that 2C-B be included in Schedule 
II, 4-MTA in Schedule I, and GHB and zolpidem in Schedule IV of that 
Convention.
    Article 2, paragraph 1, of the Convention reads:


    If a Party or the World Health Organization has information 
relating to a substance not yet under international control which in 
its opinion may require the addition of that substance to any of the 
Schedules of this Convention, it shall notify the Secretary-General 
and furnish him with the information in support of that 
notification. The foregoing procedure shall also apply when a Party 
or the World Health Organization has information justifying the 
transfer of a substance from one Schedule to another among those 
Schedules, or the deletion of a substance from the Schedules.

    Article 2, paragraph 4, reads:

    If the World Health Organization finds: (a) That the substance 
has the capacity to produce (i)(1) a state of dependence and (2) 
central nervous system stimulation or depression, resulting in 
hallucinations or disturbances in motor function or thinking or 
behaviour or perception or mood, or (ii) similar abuse and similar 
ill effects as a substance in Schedule I, II, III or IV, and (b) 
That there is sufficient evidence that the substance is being or is 
likely to be abused so as to constitute a public health and social 
problem warranting the placing of the substance under international 
control, the World Health Organization shall communicate to the 
Commission an assessment of the substance, including the extent or 
likelihood of abuse, the degree of seriousness of the public health 
and social problem and the degree of usefulness of the substance in 
medical therapy, together with recommendations on control measures, 
if any, that would be appropriate in the light of its assessment.

    Pursuant to article 2, paragraph 2, of the Convention, the 
notification, together with the assessments and recommendations from 
WHO as well as any data received from Governments on any of these 
substances, will be brought to the attention of the Commission on 
Narcotic Drugs at its forty-fourth session in March 2001. Any action or 
decision taken by the Commission with respect to that notification, 
pursuant to article 2, paragraph 5, of the Convention, will be notified 
to States Parties in due course.
    Article 2, paragraph 5, of the Convention reads:

    The Commission, taking into account the communication from the 
World Health Organization, whose assessments shall be determinative 
as to medical and scientific matters, and bearing in mind the 
economic, social, legal, administrative and other factors it may 
consider relevant, may add the substance to Schedule I, II, III or 
IV. The Commission may seek further information from the World 
Health Organization or from other appropriate sources.

    The Secretary-General would appreciate it if the Government would 
submit data on seizures of any of these substances or on the existence 
of clandestine laboratories manufacturing them. Such data would assist 
the Commission in its consideration of possible international control 
of some or all of the substances under review.
    In order to further assist the Commission in reaching a decision, 
it would be appreciated if any economic, social, legal, administrative 
or other factors the Government may consider relevant to the question 
of the possible scheduling of these four substances could be 
communicated by 12 December 2000 to the Executive Director of the 
United Nations International Drug Control Programme, c/o Commission on 
Narcotic Drugs Secretariat Section, P.O. Box 500, A-1400 Vienna, 
Austria, fax: 43-1-26060-5885.

2 November 2000
NAR/CL.26/2000

Annex--Note Dated 4 October 2000 Addressed to the Secretary-General 
by the Director-General of the World Health Organization

    The Director-General of the World Health Organization presents her 
compliments to the Secretary-General of the United Nations and has the 
honour to submit, in accordance with Article 2, paragraphs 1 and 4, of 
the Convention on Psychotropic Substances, 1971, assessments and 
recommendations of the World Health Organization, as set forth on the 
annex hereto, concerning the proposed international control in respect 
of 2C-B, 4-MTA, GHB, and zolpidem.
    The Director-General of the World Health Organization avails 
herself of this opportunity to renew to the Secretary-General of the 
United Nations the assurances of her highest consideration.

2C-B (4-Bromo-2,5-dimethoxyphenylethylamine) Substance identification

    2C-B is chemically 4-bromo-2,5-dimethoxyphenylethylamine; 2-(4-
bromo-2,5-dimethoxyphenyl) ethylamine (CAS 66142-81-2). Other names 
include: -desmethyl DOB; BDMPEA; MFT; Erox; Nexus; Performax. 
There are no chiral centres; therefore, no stereoisomers or racemates 
are possible.
Similarity to Known Substances and Effects on the Central Nervous 
System
    2C-B has structural and pharmacological similarities to 
brolamfetamine and mescaline. 2C-B is a selective partial agonist for 
5-HT2A- and 5-HT2C-serotonin receptors. In 
humans, 2C-B is more potent than mescaline but less potent than 
brolamfetamine. In low doses it has sensory enhancing effects: skin 
sensitivity, heightened responsiveness to smells, tastes and sexual 
stimulation. In higher doses 2C-B is a strong hallucinogen. 2C-B 
produces particularly marked visual hallucinations with an intense 
colour play, intriguing patterns emerging on surfaces and distortions 
of objects and faces. It was reported to enhance sexual feelings, 
sexual perception and performance.
Dependence Potential
    There are no animal or human studies about the dependence potential 
of 2C-B.
Actual Abuse and/or Evidence of Likelihood of Abuse
    In the 1990s, 2C-B was sold as an aphrodisiac in several countries 
and some abuse of 2C-B has been reported by a number of countries. 
These suggest that 2C-B has modest abuse liability like other 
hallucinogens. Although hallucinogens are rarely associated with 
compulsive use or dependent use, they are known to have modest abuse 
potential, particularly in polydrug abusers.
Therapeutic Usefulness
    Apart from the controversial experimental use to facilitate 
psychotherapy, hallucinogens, such as 2C-B, do not have any therapeutic 
usefulness.
Recommendation
    Despite the limited availability of studies, the chemical and 
pharmacological similarity of 2C-B to the hallucinogen mescaline has 
been demonstrated. The altered state of mind induced by hallucinogens 
such as 2C-B may result in harm to the user and to

[[Page 13325]]

others. Based on its perceived aphrodisiac effects and known modest 
abuse potential of hallucinogenic drugs in general, it is estimated 
that 2C-B may be abused so as to constitute a public health and social 
problem warranting its placement under international control. However, 
hallucinogens are rarely associated with compulsive use and abuse of 
2C-B has been infrequent, suggesting that abuse of 2C-B is likely to 
constitute a substantial, rather than an especially serious, risk to 
public health. On these bases, it is recommended that 2C-B be placed in 
Schedule II of the 1971 Convention on Psychotropic Substances.

4-MTA (4-methylthioamphetamine) Substance Identification

    4-MTA is chemically 4-methylthioamphetamine (CAS 14116-06-4) Other 
names include: -methyl 4-methylthiophenetylarnine, p-
methylthioamphetamine; 4-MTA; p-MTA; MTA; MK; S5; S5; 
Flatliner; The One and Only Dominator. 4-MTA has one chiral centre and 
can exist in two enatiomers and a racemate. Only the racemic mixture 
has been reported to have been synthesised.
Similarity to Known Substances and Effects on the Central Nervous 
System
    4-MTA is a potent serotonin-releasing agent and reversible 
inhibitor of monoamine oxidase-A, and is structurally similar to 4-
methoxyamphetamine. Pharmacologically, it is similar to MDA and MDMA; 
studies suggest that 4-MTA is six times more potent than MDMA and MDA 
in inhibiting 5-HT uptake.
Dependence Potential
    Drug discrimination studies in rats suggest that 4-MTA produces 
discriminative stimulus effects similar to MDMA. 4-MTA did not 
substitute for amphetamine, LSD or phencyclidine. Reports from the 
United Kingdom indicate that 4-MTA is abused for its stimulant/euphoric 
effects similar to MDMA.
Actual Abuse and/or Evidence of Likelihood of Abuse
    4-MTA is mainly abused in Europe. It appears that 4-MTA is part of 
the dance music culture although its use is relatively less widespread 
probably because of perceptions by users that the drug is stronger and 
more harmful than other ``club drugs'' such as MDMA. 4-MTA has resulted 
in a number of fatalities and hospital admissions. It appears that 
toxic effects can be produced directly from the drug and that the 
presence of other drugs or alcohol may exacerbate such effects.
Therapeutic Usefulness
    4-MTA has no recognized therapeutic use.
Recommendation
    4-MTA is chemically and pharmacologically similar to MDA and MDMA. 
4-MTA is a new synthetic drug which was seized for the first time in 
1997. Although evidence of its actual abuse is available only in 
several countries in Europe, seizures, including those of large 
quantities reported from a wider range of countries, suggest that the 
trafficking and abuse of 4-MTA are more widespread than have been 
reported. Based on this and its similarity to known MDA-type 
psychotropic substances, as well as data from drug discrimination 
studies in animals, it is estimated that 4-MTA is likely to be abused 
so as to constitute a public health and social problem warranting its 
placement under international control. Taking into consideration that 
4-MTA has no recognized therapeutic use and that it has resulted in a 
number of fatalities, abuse of 4-MTA is estimated to constitute an 
especially serious risk to public health. It is therefore recommended 
that 4-MTA be placed in Schedule I of the 1971 Convention on 
Psychotropic Substance.

GHB (Gamma-hydroxybutyric acid) Substance Identification

    GHB is chemically -hydroxybutyric acid; 4-hydroxybutyric 
acid (CAS 591-81-1). GHB usually exists as either the free acid or as 
the sodium salt. Sodium oxybate (CAS 502-85-2) is a national 
nonproprietary name for its sodium salt. There are no chiral centres; 
therefore, no stereoisomers or racemates are possible.
Similarity to Known Substances and Effects on the Central Nervous 
System
    GHB is an endogenous compound and is structurally similar to the 
neurotransmitter GABA. Pharmacologically, it produces sedative and 
anaesthetic effects at high doses. Such depressant effects of GHB 
appear to be associated with its cataleptic effects and are different 
from those of barbiturates and benzodiazepines. GHB sedation possessed 
distinct excitatory properties, which may be due to its effect on the 
dopaminergic system (increase in intracellular neuronal dopamine). GHB 
has been found to induce anesthesia (but does not provide pain relief), 
(slow-wave) sleep, bradycardia, vomiting, random clonic movements, 
hypothermia, reduction in potassium levels, decrease in ventilatory 
rate and apnoea. However, the respiratory centre remains sensitive to 
an increase in carbon dioxide.
Dependence Potential
    In drug discrimination studies in animals, none of the known abused 
drugs has the ability to fully substitute for GHB. Morphine, 
dexamphetamine, LSD and some benzodiazepines produced, at best, partial 
substitution. There have been few studies regarding the dependence/
abuse potential of GHB. However, during the numerous studies involving 
administration of GHB to patients at varying concentrations, no 
dependence has been observed at low doses of GHB. At prolonged high 
doses, however, a withdrawal syndrome including insomnia, muscular 
cramping, tremor and anxiety has been noted upon discontinuation in 
some cases.
Actual Abuse and/or Evidence of Likelihood of Abuse
    GHB abuse has been reported in Australia, USA and many countries in 
Europe. Precursors of GHB, such as -butyrolaztone and 1,4-
butanediol, which are metabolized to GHB in the body, have also been 
abused. Although initially abused by body-builders for its apparent 
growth hormone promoting properties, the more recent primary mode of 
abuse worldwide has been the use of GHB for its subjective hypnotic, 
euphoric and hallucinogenic effects, especially in the context of the 
dance music culture (i.e. ``raves''). Some users have also claimed to 
use GHB as an alternative to alcohol (for relaxation), as a sexual 
adjunct, appetite suppressant, anti-aging product and has also been 
implicated in cases of sexual assault.
    It appears that toxic effects can be produced directly from the 
drug and the presence of other depressant or sedative drugs (e.g. 
opiates, benzodiazepines, alcohol and barbiturates) and possibly other 
psychoactive compounds (e.g. amphetamine) may exacerbate the effects of 
GHB. Hospital admissions and deaths have been linked to GHB ingestion 
and generally involve the onset of coma and respiratory depression.
Therapeutic Usefulness
    GHB has been used as an anaesthetic agent and as an aid to alcohol/
opiate withdrawal, primarily in France, Germany and Italy, 
respectively. In USA and Canada it is currently under evaluation for 
the treatment of narcolepsy-associated cataplexy.

[[Page 13326]]

Recommendation
    Although GHB is an endogenous compound that exists in the human 
body, GHB has psychoactive and toxic effects when administered. The 
pattern and consequences of its abuse in a number of countries in 
Europe and the USA seem to suggest that its liability to abuse 
constitutes a significant risk to public health. The current easy 
availability of GHB and some of its precursors has contributed to its 
recent abuse. The wide availability is likely to be reduced once GHB is 
placed under international control. On these bases, it is recommended 
that GHB be placed in Schedule IV of the 1971 Convention on 
Psychotropic Substances.

Zolpidem (INN) Substance Identification

    Zolpidem is chemically N,N,6-trimethyl-2-p-tolylimidazo [1,2- 
a]pyridine-3-acetamide; N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-
a]pyridine-3-acetamide (CAS 82626-48-0). Trade names include: Ambien, 
Bikalm, Niotal, Stilnoct, Stilnox.
Similarity to Known Substances and Effects on the Central Nervous 
System
    Though chemically different from benzodiazepines, zolpidem produces 
benzodiazepine-like effects. It acts as an agonist binding with high 
and low affinity to BZ1 and BZ2 receptor 
subtypes, respectively. It is generally believed to produce relatively 
greater hypnotic effects than other benzodiazepine-like effects.
Dependence Potential
    The results of human laboratory studies suggest that zolpidem and 
triazolam are generally similar in terms of producing subjective 
reinforcing effects. As with many of the benzodiazepines, there have 
been a number of case reports describing withdrawal symptoms after 
cessation of zolpidem administration. Though withdrawal discomfort does 
not necessarily lead to compulsory drug taking (drug dependence) in 
humans, there are reports of clinically diagnosed cases of drug 
dependence resulting from a prolonged use of zolpidem.
Actual Abuse and/or Evidence of Likelihood of Abuse
    Epidemiological studies indicate that zolpidem is associated with 
relatively low incidence of abuse. Sporadic case reports in the 
scientific literature have indicated that zolpidem is abused, but these 
cases usually involved patients with histories of drug abuse or chronic 
psychiatric disorders. Cases of zolpidem overdose requiring emergency 
treatment have been reported. Death due to zolpidem overdose is rare. 
Rates of actual abuse and dependence of zolpidem appear to be similar 
to other hypnotic benzodiazepines in Schedule IV. In terms of the 
numbers of cases of abuse, dependence and withdrawal reported as 
adverse drug reactions to the WHO adverse drug reaction database, less 
than ten benzodiazepines are ranked higher than zolpidem.
Therapeutic Usefulness
    Zolpidem is used for treatment of insomnia in more than 80 
countries.
Recommendation
    Although zolpidem has a somewhat novel neuropharmacological profile 
relative to classic benzodiazepines, studies of its abuse potential 
suggest that it may be comparable to that of many benzodiazepines. 
Furthermore, rates of actual abuse and dependence of zolpidem in 
medical use, as well as the risk to public health of its abuse, appear 
to be similar to hypnotic benzodiazepines presently placed in Schedule 
IV. On these bases, it is recommended that zolpidem be placed in 
Schedule IV of the 1971 Convention on Psychotropic Substances.

I. Discussion

    Although WHO has made specific scheduling recommendations for each 
of the drug substances, the CND is not obliged to follow the WHO 
recommendations. Options available to the CND for substances considered 
for control under the Psychotropic Convention include: (1) Acceptance 
of the WHO recommendations; (2) acceptance of the recommendations to 
control, but control the drug substance in a schedule other than that 
recommended; or (3) rejection of the recommendations entirely.
    4-Bromo-2,5-dimethoxyphenethylamine (2C-B) is a Schedule I 
controlled substance in the United States. The U.S. Drug Enforcement 
Administration (DEA) placed 2C-B (including salts, isomers, and salts 
of isomers: isomers include optical, positional, and geometric) in 
Schedule I of the Controlled Substance Act (CSA) in June 1995. 4-
methylthioamphetamine (4-MTA) is not marketed in the United States and 
is not currently a controlled substance in the United States. Gamma 
hydroxybutyric acid (GHB) is a Schedule I controlled substance in the 
United States. GHB, including its salts, optical isomers, and salts of 
optical isomers, became a Schedule I controlled substance in March 
2000. Registered manufacturers and distributors of GHB when it is 
manufactured, distributed, or possessed in accordance with an FDA 
authorized investigational new drug exemption under Section 505(i) of 
the Federal Food, Drug, and Cosmetic Act (21 USC 355(i)) are subject to 
Schedule III security requirements. If FDA approves a drug product 
containing GHB for marketing, the approved product will be placed into 
Schedule III under Public Law 106-172. Zolpidem, its salts, isomers, 
and salts of isomers, is a Schedule IV controlled substance in the 
United States. The DEA placed zolpidem in Schedule IV in February 1993. 
With the exception of 4-MTA, current controls in the United States on 
the substances under consideration for international control appear to 
meet the requirements of the recommended Psychotropic Convention 
schedules.

IV. Comments

    Interested persons may, on or before March 15, 2001, submit to the 
Dockets Management Branch (address above) written comments regarding 
this notice. This abbreviated comment period is necessary to allow HHS 
to furnish a recommendation to the Secretary of State in time for the 
March 2001 meeting of the United Nations Commission on Narcotic Drugs. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Dockets Management Branch (address above) between 9 a.m. and 4 p.m., 
Monday through Friday.

    Dated: February 27, 2001.
Ann M. Witt,
Acting Associate Commissioner for Policy.
[FR Doc. 01-5218 Filed 2-28-01; 11:36 am]
BILLING CODE 4160-01-P