[Federal Register Volume 60, Number 13 (Friday, January 20, 1995)]
[Notices]
[Pages 4169-4173]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-1553]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 94N-0173]


International Drug Scheduling; Convention on Psychotropic 
Substances; World Health Organization Scheduling Recommendations for 
Seven Drug Substances

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 and to request 
an informal public meeting concerning recommendations by the World 
Health Organization (WHO) to impose international manufacturing and 
distributing restrictions, pursuant to international treaties, on 
certain drug substances. The comments received in response to this 
notice and/or public meeting 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, on March 14-23, 
1995. This notice is issued pursuant to the Controlled Substances Act 
(CSA).

DATES: Written comments by February 9, 1995; written requests for a 
public meeting and the reasons for such a request by January 30, 1995.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
Rockville, MD 20857; written requests for a public meeting and the 
reasons for such a request to Nicholas P. Reuter (address below).

FOR FURTHER INFORMATION CONTACT: Nicholas P. Reuter, Office of Health 
Affairs (HFY-20), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-443-1382.

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 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 shall then 
evaluate the proposal and furnish a recommendation to the Secretary of 
State which shall be binding on the representative of the United States 
in discussions and negotiations relating to the proposal.
    As detailed below in this document, the Secretary of State has 
received a notification from the Secretary-General of the United 
Nations. This notification reflects the recommendations from the 29th 
WHO Expert Committee for Drug Dependence (ECDD), which met in September 
1994. WHO recommends that the substances aminorex, brotizolam, and 
mesocarb be added to Schedule IV of the Convention. In addition, WHO 
recommends that etryptamine and methcathinone be [[Page 4170]] added to 
Schedule I of the Convention and that zipeprol be added to Schedule II. 
WHO also recommends that flunitrazepam, presently controlled in 
Schedule IV of the Convention, be transferred to Schedule III.
    A notice published in the Federal Register of June 20, 1994 (59 FR 
31639), announced the WHO review of these seven substances and provided 
an opportunity for interested parties to submit information to be 
forwarded to WHO. Information submitted in response to that notice was 
forwarded to WHO and was considered during the 29th meeting of the WHO 
Expert Committee on Drug Dependence in September, 1994.
    The full text of the notification from the Secretary-General of the 
United Nations is provided below in Section II of this notice. Section 
201(d)(2)(B) of the CSA (21 U.S.C. 811(d)(2)(B)) 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 parties to submit information and comments on the proposed 
scheduling action.

II. United Nations Notification

Reference:
    NAR/CL.10/1994
    UNDCP 421/12(1) 1971 CPS
    WHO 29th ECDD
    CU 94/231
    The Secretary-General of the United Nations presents his 
compliments to the Secretary of State of the United States of 
America and has the honour to inform the Government that, pursuant 
to article 2, paragraphs 1, 4 and 6, of the Convention on 
Psychotropic Substances of 1971, he has received a notification 
dated 11 November 1994, from the Director-General of the World 
Health Organization (WHO), concerning recommendations for 
international control of the following seven substances: aminorex, 
brotizolam, etryptamine, flunitrazapam, mesocarb, methcathinone and 
zipeprol.
    In accordance with the provisions of article 2, paragraph 2, of 
the 1971 Convention, the Secretary-General hereby transmits 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 aminorex, 
brotizolam and mesocarb be included in Schedule IV of the 1971 
Convention; that etryptamine and methcathinone be included in 
Schedule I; and that zipeprol be included in Schedule II. WHO also 
recommends that flunitrazepam be transferred from Schedule IV to 
Schedule III of the Convention.
    Pursuant to article 2, paragraph 2, of the Convention, the 
notification from WHO will be brought to the attention of the 
Commission on Narcotic Drugs at its thirty-eighth session (14-23 
March 1995). Any action or decision taken by the Commission with 
respect to the notification, pursuant to article 2, paragraph 5 or 
6, or the Convention, will be notified to States Parties in due 
course.
    Article 2, paragraph 5, 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.''
    Article 2, paragraph 6 reads:
     ``If a notification under paragraph 1 relates to a substance 
already listed in one of the Schedules, the World Health 
Organization shall communicate to the Commission its new findings, 
any new assessment of the substance it may make in accordance with 
paragraph 4 and any new recommendations on control measures it may 
find appropriate in the light of that assessment. The Commission 
taking into account the communication from the World Health 
Organization as under paragraph 5 and bearing in mind the factors 
referred in that paragraph, may decide to transfer the substance 
from one Schedule to another or to delete it from the Schedules.''
    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 or rescheduling of these 
seven substances could be communicated by 15 January 1995 to the 
United Nations International Drug Control Programme, c/o Secretariat 
of the Commission on Narcotic Drugs, P.O. Box 500, A-1400 Vienna, 
Austria (telefax 239397).
7 December 1994

ANNEX

Note dated 11 November 1994 addressed to the Secretary-General by the 
Director-General of the World Health Organization

    The Director-General of the World Health Organization presents 
his compliments to the Secretary-General of the United Nations and 
has the honour to transmit, in accordance with article 2, paragraph 
1, 4 and 6 of the Convention on Psychotropic Substances, 1971, 
assessments and recommendations of the World Health Organization, as 
set forth in the annex hereto, concerning proposed international 
control in respect of aminorex, brotizolam, etryptamine, 
flunitrazepam, mesocarb, methcathinone, and zipeprol.
    The Director-General of the World Health Organization avails 
himself of this opportunity to renew to the Secretary-General of the 
United Nations the assurance of his highest consideration.

Aminorex

1. Substance identification
    Aminorex (INN; CAS 2207-50-3), chemically 2-amino-5-phenyl-2-
oxazoline, is also known as aminoxaphen and aminozafen, and formerly 
as Apiquel and Monocil (aminorex fumarate). Aminorex has one 
asymmetric carbon atom in the molecule, so that two stereoisomeric 
forms and one racemate are possible.
2. Similarity to already known substances and affects on the central 
nervous system
    Aminorex is chemically similar to 4-methylaminorex, which is 
included in Schedule I of the Convention on Psychotropic Substances, 
1971. Aminorex produces effects that are characteristic of central 
nervous system stimulants such as amfetamine, and was used 
clinically for its anorectic effects. Aminorex produces adverse 
effects similar to those produced by central nervous system 
stimulants. In addition, when used as an anorectic, aminorex was 
considered to have been responsible for the occurrence of a 
significant incidence of pulmonary hypertension. This led to its 
withdrawal from the market in 1968.
3. Dependence potential
    In drug discrimination studies, aminorex generalized to 
amfetamine and cocaine. Animal self-administration studies indicate 
that aminorex has some reinforcing effects. These animal studies 
suggest that aminorex has a moderate dependence potential.
4. Actual abuse and/or evidence of likelihood of abuse
    Police and forensic reports indicate that aminorex is illicitly 
distributed in the United States of America as well as to a limited 
degree in Germany. These cases document the distribution of aminorex 
as amfetamine or metamfetamine on the street, suggesting that the 
population using the drug mainly comprises stimulant abusers. In 
spite of the limited level of actual abuse, aminorex is assessed to 
have a moderate abuse liability, taking into account the relative 
simplicity of its manufacturing in clandestine laboratories.
5. Therapeutic usefulness
    Because of serious adverse effects, aminorex is assessed to have 
very little, if any, therapeutic usefulness.
6. Recommendation
    Based on the available data concerning its pharmacological and 
toxicological profile, dependence potential and likelihood of abuse, 
the degree of seriousness of the public health and social problems 
associated with the abuse of aminorex is assessed to be significant. 
On the basis of this and the assessment of its therapeutic 
usefulness, it is recommended that aminorex be included in Schedule 
IV of the Convention on Psychotropic Substances, 1971.

Brotizolam

1. Substance identification
    Brotizolam (INN; CAS 57801-81-7), chemically 2-bromo-4-
(-chloropenyl)-9- [[Page 4171]] methyl-6H-thianol[3,2-f]-s-
triazolol[4,3-a][1,4]diazepine, is also known as Ladormin, Lendorm, 
Lendormin, Lindormin, Noctilan, Dormex, and Sintonal.
2. Similarity to already known substances and affects on the central 
nervous system
    Brotizolam produces pharmacological effects typical of the class 
of benzodiazepines. It binds with high affinity to benzodiazepine 
receptors. A number of studies have demonstrated the therapeutic 
effects of brotizolam as a short-acting hypnotic with a mean 
elimination half-life of 4-5 hours.
3. Dependence potential
    Animal studies have shown that brotizolam has barbiturate type 
subjective effects. It produces alcohol-barbiturate type mild-to-
severe withdrawal syndromes, and has some reinforcing effects. The 
few clinical studies available demonstrate the occurrence of rebound 
insomnia upon withdrawal of the drug. These findings collectively 
indicate that brotizolam has a moderate dependence potential similar 
to other benzodiazepine hypnotics.
4. Actual abuse and/or evidence of likelihood of abuse
    In spite of its pharmacological similarity to other 
benzodiazepine hynotics, and its marketing in 18 countries, actual 
abuse of brotizolam has been reported only in Germany and Hong Kong. 
In Germany, although there has been some abuse and illicit activity 
involving brotizolam, this was not considered serious enough to 
subject the drug to the distribution control measures which are 
applicable to controlled drugs. In Hong Kong, following its 
introduction to the local market in 1988, the abuse of brotizolam 
increased rapidly among young people, leading to the application of 
stricter regulatory control measures in 1990. The company withdrew 
the product from the market in 1992.
    Based on the experiences of Germany and Hong Kong with 
brotizolam, it is assessed that brotizolam has an appreciable abuse 
liability. The problem may be more acute in situations where 
prescription requirements for dispensing are not effectively 
implemented or are not applicable.
5. Therapeutic usefulness
    Brotizolam is marketed as a hypnotic in 18 countries and may be 
considered to have a moderate to great therapeutic usefulness.
6. Recommendation
    Based on the available data concerning its pharmacological and 
toxicological profile, dependence potential and likelihood of abuse, 
the degree of seriousness of the public health and social problems 
associated with the abuse of brotizolam is assessed to be 
significant, in cases where prescription requirements are not 
effectively implemented or required, a situation which exists in 
many developing countries. On the basis of this and the assessment 
of its therapeutic usefulness, it is recommended that brotizolam be 
included in Schedule IV of the Convention on Psychotropic 
Substances, 1971.

Etryptamine

1. Substance identification
    Etryptamine (INN; CAS 2235-90-7), chemically 3-(2-
aminobutyl)indole, is also known as -ethyltryptamine and 
Monase. Etryptamine has a single chiral centre, so that two 
stereoisomeric forms and one racemate are possible.
2. Similarity to already known substances and affects on the central 
nervous system
    Chemically, etryptamine is similar to hallucinogenic 
tryptamines, some of which are already in Schedule I of the 1971 
Convention. Animal studies indicate that etryptamine produces 
effects similar to those produced by 3,4,-
methylenedioxymetamfetamine (MDMA), but its hallucinogenic effects 
are more pronounced than its stimulant effects. Like amfetamine, 
etryptamine increases locomotor activity in rodents. In a study 
using the behaviour pattern monitoring method, etryptamine 
significantly decreased investigatory behaviour, which is typical of 
hallucinogens and MDMA-like substances. The stimulant effects of 
etryptamine are slower in onset and more prolonged in duration than 
those of amfetamine. In addition, etryptamine inhibits monoamine 
oxidase.
    In the early 1960s, etryptamine acetate was placed on the United 
States market as an anti-depressant. Soon after its release on the 
market, it was reported that etryptamine was associated with a high 
incidence of agranulocytosis, a potentially fatal condition. More 
recently, there were isolated reports of etryptamine being 
associated with the deaths of drug abusers in Germany, Spain, and 
the United States of America.
3. Dependence potential
    Animal drug discrimination studies indicate that etryptamine has 
subjective effects resembling MDMA. Self-administration studies 
indicate that etryptamine has a moderate dependence potential, which 
is lower than that of cocaine.
4. Actual abuse and/or evidence of likelihood of abuse
    Information available from various sources indicates that there 
has been some abuse of etryptamine in Germany, Spain and the United 
States of America. Etryptamine is estimated to have a high abuse 
liability.
5. Therapeutic usefulness
    In view of its association with serious adverse reactions such 
as agranulocytosis, the therapeutic usefulness of etryptamine is 
assessed to be very limited, if any.
6. Recommendation
    Based on the available data concerning its pharmacological and 
toxicological profile, dependence potential and likelihood of abuse, 
the degree of seriousness of the public health and social problems 
associated with the abuse of etryptamine is assessed to be 
especially serious. On the basis of this and the assessment of its 
therapeutic usefulness, it is recommended that etryptamine be 
included in Schedule I of the Convention on Psychotropic Substances, 
1971.

Flunitrazepam

1. Substance identification
    Flunitrazepam (INN; CAS 1622-62-4), chemically 5-(-
fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-
one, is also known as Absint, Darkene, Fluninoc, Flunipam, Fluinita, 
Flunitrazepan-ratiopharm, Hypnodrom, Hipnosedon, Inervon, Narcozep, 
Parnox, Primun, Rohipnol, Rohypnol and Valsers.
2. Similarity to already known substances and affects on the central 
nervous system
    Flunitrazepam has typical benzodiazepine effects, with a greater 
sedative-hypnotic potency than diazepam or chlordiazepoxide. 
Flunitrazepam binds with high affinity to central benzodiazepine 
receptors. Flunitrazepam is rapidly absorbed after oral 
administration. The elimination half-life of flunitrazepam following 
a single oral dose ranges between 9 and 25 hours in humans. 
Accumulation occurs with chronic administration.
3. Dependence potential
    Drug discrimination, drug withdrawal and self-administration 
studies indicate that flunitrazepam has a dependence potential 
similar to other benzodiazepines. Rebound insomnia, which is 
considered a form of withdrawal from sedative-hypnotics, may be 
contributing to the tendency of continuing the medication. These 
data do not suggest any substantive difference between flunitrazepam 
and other benzodiazepine hypnotics.
    However, drug preference studies in opiod users have shown that 
flunitrazepam and diazepam stand out from other benzodiazepines in 
terms of producing a strong positive reinforcing effect in these 
subjects.
    Based on the above, flunitrazepam is estimated to have a 
moderate abuse potential which may be higher than other 
benzodiazepines. The rapid onset and longer duration of action, 
coupled with the strong sedative-hypnotic effects, may be 
contributing to its higher abuse potential.
4. Actual abuse and/or evidence of likelihood of abuse
    Information available indicates that the non-medical use or 
abuse of flunitrazepam is widespread among drug abusers, 
particularly opioid and cocaine abusers. Flunitrazepam is reported 
to be the most widely abused benzodiazepine by opioid abusers in 
many large cities in Europe, Asia and Oceania. Flunitrazepam abuse 
is reported even in the United States of America where the drug is 
not marketed for therapeutic use.
    Reported reasons for the abuse of flunitrazepam include 
potentiation of opioid effects, substitution for the opioid when it 
is difficult to obtain, and self-medication for opioid withdrawal. 
Oral intake is the most common route of administration of 
flunitrazepam but some abusers take the drug by intravenous 
injection or by smoking. Health problems associated with the abuse 
of flunitrazepam include deaths directly or indirectly related with 
the drug use, drug dependence, withdrawal syndrome, paranoia, 
amnesia and other psychiatric disorders. [[Page 4172]] 
    Information on the extent of association of 37 benzodiazepines 
with illicit activities during the period 1984-1989, available to 
the 27th meeting of the WHO Expert Committee on Drug Dependence in 
1980, clearly indicated a higher incidence of association with 
illicit activities of both diazepam and flunitrazepam in comparison 
with other benzodiazepines. At that time, however, the data were not 
evaluated in relation to drug availability. After and adjustment for 
the amounts manufactured and for potency, flunitrazepam further 
stands out in both seizures and the number of illicit cases 
involving the drug, whereas diazepam is no longer outstanding.
    Information on drug involvement in illicit activities after 
1980, received from governments in response to the WHO questionnaire 
in 1994, is limited, and does not allow a comparison among a large 
number of benzodiazepines. However, the recent report from Interpol 
and the increasing trend in the United States of America, despite 
the lack of licit medical supplies in that country, together with 
several recent reports showing flunitrazepam as being the main non-
opioid drug abused by opioid abusers in major European cities, 
further substantiate its high abuse liability.
5. Therapeutic usefulness
    Flunitrazepam is useful for the treatment of insomnia. It is 
also indicated as a pre-anaesthetic medication to assist in the 
induction and maintenance of anaesthesia. Flunitrazepam has a 
therapeutic usefulness similar to other benzodiazepine hypnotics, 
within the range from moderate to great.
6. Recommendation
    Flunitrazepam has a greater likelihood of abuse than other 
benzodiazepines. Although there is some element of self-medication 
for opioid withdrawal, the abuse of flunitrazepam by opioid abusers 
complicates the clinical picture, leading to multiple drug 
dependence. Its abuse is prevalent also among youths and cocaine 
abusers. In addition to its oral and intravenous use, abuse by 
``snorting'' has recently been reported. As yet, no other 
benzodiazepine has been reported as being abused by three different 
routes of administration: oral, nasal and intravenous. Flunitrazepam 
abuse has been associated with dependence and other behavioural 
problems. Illicit activities involving flunitrazepam are increasing 
even in the United States of America, where it is available 
illegally despite the lack of marketing for therapeutic use.
    Based on the available data concerning its pharmacological and 
toxicological profile, dependence potential and likelihood of abuse, 
and paying particular regard to the above characteristics, the 
degree of seriousness of the public health and social problems 
associated with the abuse of flunitrazepam is assessed to have 
become substantial. On the basis of this and the assessment of its 
therapeutic usefulness, it is recommended that flunitrazepam be 
rescheduled into Schedule III of the Convention on Psychotropic 
Substances, 1971.

Mesocarb

1. Substance identification
    Mesocarb (INN; CAS 34262-84-5), is chemically 3-(-
methlylphenethyl)-N-(phenylcarbamoyl)syndone imine, is also known as 
Pharbamocarb, Sidnocarb and Sydnocarb. Mesocarb has one asymmetric 
carbon atom in the molecule, so that two stereoisomeric forms and 
one racemate are possible.
2. Similarity to already known substances and effects on the central 
nervous system
    Chemically, mesocarb is a sydnone imine having an amfetamine-
like moiety in its molecule. Of the two optical isomers of mesocarb, 
only the levorotatory isomer exerts a stimulant effect on the 
central nervous system. This effect is significantly weaker than 
that of dexamfetamine. Mesocarb produces locomotor stimulation, 
anorectic activity, enhancement of conditioned reflexes, and 
shortening of the period of action of hypnotic agents. In addition, 
there are several pharmacological studies on mesocarb used in 
combination with other substances in animals, such as mesocarb-
acetylsalicylic acid combination. Mesocarb has been reported to 
increase work capacity and improve cardiovascular function while 
maintaining normal oxygen consumption. Adverse reactions are similar 
to those of other CNS stimulants. Several studies in humans have 
shown that mesocarb increases resistance to environmental stress 
such as cold temperature, low gravity, and low oxygen levels in the 
air.
3. Dependence potential
    Animal studies indicate that mesocarb has discriminative 
stimulus effects similar to CNS stimulants such as dexamfetamine and 
cocaine, as well as some reinforcing effects in monkeys, suggesting 
a low to moderate dependence potential.
4. Actual abuse and/or evidence of likelihood of abuse
    There is some evidence to indicate that mesocab is abused in 
sports, and its use has been banned by the International Olympic 
Committee.
    Though reportedly discontinued, information from the 
International Narcotics Control Board indicated that large 
quantities of a pharmaceutical preparation containing mesocarb and 
acetylsalicylic acid were illegally exported to western Africa. 
Although epidemiological data are not available, it is believed that 
most, if not all, of the exported combination products was abused. 
On the basis of available information, mesocarb is assessed to have 
an appreciable abuse liability.
5. Therapeutic usefulness
    Mesocarb is used in several countries, mainly in eastern Europe, 
as a stimulant to counteract acute intoxication by depressants; for 
the treatment of hyperactivity and nocturnal enureses in children; 
and as an ``energizer'' to enhance resistance to environmental 
stress. The therapeutic usefulness of mesocarb is estimated to be 
within the range between little and moderate.
6. Recommendation
    Although no epidemiological data are available on health 
problems associated with the actual abuse of mesocarb, mesocarb is 
abused in sports, and illicit activities involving mesocarb have 
been reported. Based on this and the available data concerning its 
pharmacological and toxicological profile, dependence potential and 
likelihood of abuse, the degree of seriousness of the public health 
and social problems associated with the abuse of mesocarb is 
assessed to be significant. On the basis of this and the assessment 
of its therapeutic usefulness, it is recommended that mesocarb be 
included in Schedule IV of the Convention on Psychotropic 
Substances, 1971.

Methcathinone

1. Substance identification
    Methcathinone (CAS 5650-44-2) chemically 2-(methylamino)-1-
phenylpropan-1-one, is also know as ephedrone and metylcathinone. It 
has one chiral centre, so that two stereoisomeric forms and one 
racemate are possible.
2. Similarity to already known substances and affects on the central 
nervous system
    Methcathinone is the N-methyl derivative of cathinone, and is 
closely related to metamfetamine. Animal studies have shown that 
methcathinone produces CNS stimulant effects similar to those 
produces by amfetamine, metamfetamine, cathinone and cocaine. Of the 
two optical isomers, the levorotatory form is more active.
3. Dependence potential
    Drug discrimination and self-administration studies in animal 
indicate that methcathinone has a dependence potential similar to 
central nervous system stimulants such as amfetamine and cocaine. 
Case reports and a study conducted in the United States of America 
on methcathinone abusers also suggest that methcathinone has a high 
dependence potential similar to that of metamfetamine.
4. Actual abuse and/or evidence of likelihood of abuse
    Significant abuse of methcathinone has been reported in Estonia, 
Latvia, the Russian Federation, and in some countries of the 
Commonwealth of Independent States as well as in the United States 
of America. Methcathinone is readily manufactured from ephedrine by 
oxidation. Methcathinone is assessed to have a high abuse liability.
5. Therapeutic usefulness
    Methcathinone has not been marketed for therapeutic purposes. 
Its therapeutic usefulness is assessed to be very limited, if any.
6. Recommendation
    Studies from the United States of America and the Russian 
Federation have confirmed that methcathinone abuse results in 
adverse health effects similar to those associated with the abuse of 
metamfetamine, including fatal cases of acute intoxication. Illicit 
activities involving methcathinone, including clandestine 
manufacturing, are also reported widely.
    Based on the available data concerning its pharmacological and 
toxicological profile, dependence potential and likelihood of abuse, 
and paying particular regard to the above characteristics, the 
degree of [[Page 4173]] seriousness of the public health and social 
problems associated with the abuse of methcathinone is assessed to 
be especially serious. On the basis of this and the assessment of 
its therapeutic usefulness, it is recommended that methcathinone be 
included in Schedule I of the Convention on Psychotropic Substances, 
1971.

Zipeprol

1. Substance identification
    Zipeprol (INN; CAS 34758-83-3), chemically -(-
methoxybenzyl--4-(-methoxyphenethyl)-1-piperazineethanol, 
is also know as Antituxil-Z, Carm-3024, Chilvax, Delaviral, 
Dovavixin, Jactus, Eritos, Mirsol, Ogyline, Rospilene, Respirase, 
Respirax, Sanotus, Sentus, Silentos, Sousibim, Talasa, Tusigen, 
Tussiflex and Zitoxil. Zipeprol has three asymmetric carbon atoms in 
the molecule, so that eight stereoisomeric forms are possible.
2. Similarity to already known substances and affects on the central 
nervous system
    In laboratory animals, zipeprol has been shown to have an 
antitussive activity weaker than codeine and comparable to 
dextromethorphan. Its pharmacological properties are different from 
those of opioid antitussives, such as codeine, in that zipeprol has 
anti-cholinergic activities. It also does not produce respiratory 
depression, bile duct constriction or constipation, which are often 
associated with narcotic antitussives.
    Unlike opioids, zipeprol is essentially devoid of analgesic 
activity, but at higher doses, zipeprol acts like a weak opioid 
agonist. Zipeprol showed a bi-phasic effect in competing for binding 
sites in rat brain homogenates.
3. Dependence potential
    In rats, lower doses of zipeprol amplify some opioid withdrawal 
manifestations whereas at higher doses it suppresses several 
morphine withdrawal symptoms. In the monkey, zipeprol suppresses 
morphine abstinence. Zipeprol is assessed to have a moderate 
dependence potential.
4. Actual abuse and/or evidence of likelihood of abuse
    There have been a number of reports on the abuse of zipeprol 
from Brazil, Chile, Italy, Mexico, the Republic of Korea, 
Switzerland, and the former Yugoslavia. These reports suggest that 
its sedative, hallucinatory and euphorigenic effects, and its 
ability to suppress some signs of opioid withdrawal at high doses, 
may be the reasons for its abuse. Over-the-counter distribution of 
zipeprol preparations may have contributed to its widespread abuse 
in some places. Taking this into account, zipeprol is assessed to 
have a moderate abuse liability.
    Adverse health consequences of zipeprol abuse include seizures, 
hallucinations, confusion and amnesia. Dose escalation is not 
uncommon and fatal cases from intoxication were reported from 
several countries. The tablet form has been used for intravenous 
administration.
5. Therapeutic usefulness
    A number of clinical studies have demonstrated the therapeutic 
efficacy of zipeprol in the treatment of cough. The therapeutic 
usefulness of zipeprol is assessed to be within the range between 
little to moderate.
6. Recommendation
    Although zipeprol is a weak opioid agonist at high doses, its 
toxicity, hallucinogenic and other psychotropic effects constitute a 
significant element in its abuse. It is therefore appropriate to 
consider its control under the Convention on Psychotropic 
Substances, 1971.
    Based on the available data concerning its pharmacological and 
toxicological profile, dependence potential and likelihood of abuse, 
the degree of seriousness of the public health and social problems 
associated with the abuse of zipeprol is assessed to be substantial. 
On the basis of this and the assessment of its therapeutic 
usefulness, it is recommended that zipeprol be included in Schedule 
II of the Convention on Psychotropic Substances, 1971.

III. Discussion

    Although WHO has made specific scheduling recommendations for each 
of the drug substances, CND is not obliged to follow the WHO 
recommendations. Options available to CND 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) reject the recommendations entirely.
    Methcathinone, etryptamine and aminorex, are controlled under the 
CSA in Schedule I. The proposed international drug scheduling actions, 
if adopted by CND, will result in no greater degree of control of these 
substances than are currently applied domestically. Flunitrazepam is 
controlled domestically in Schedule IV of the CSA; additional controls 
may be necessary if the United Nations moves this substance to Schedule 
III of the Convention. Brotizolam, mesocarb, and zipeprol are neither 
controlled domestically nor currently marketed for medical use in the 
United States. In order to comply with obligations under the 
Convention, these three substances would have to be controlled under 
the CSA if the United Nations endorses the WHO recommendations.
    FDA, on behalf of the Secretary of HHS, invites interested persons 
to submit comments on the United Nations notifications concerning these 
seven drug substances. FDA, in cooperation with the National Institute 
on Drug Abuse, will consider the comments on behalf of HHS in 
evaluating the WHO scheduling recommendations. Then, pursuant to 
section 811(d)(2)(B) of the CSA, HHS will recommend to the Secretary of 
State what position the United States should take when voting on the 
recommendations at the CND meeting in March 1995.

IV. Submission of Comments and Opportunity for Public Meeting

    Interested persons may, on or before February 9, 1995, submit to 
the Dockets Management Branch (address above) written comments 
regarding this notice. FDA does not presently plan to hold a public 
meeting. If any person believes that, in addition to its written 
comments, a public meeting would contribute to the development of the 
U.S. position on any of these two substances, a request for a public 
meeting and the reasons for such a request should be sent to Nicholas 
P. Reuter (address above) on or before January 30, 1995. The short time 
period for the submission of comments and requests for a public meeting 
is needed to assure that HHS may, in a timely fashion, carry out the 
required action and be responsive to the United Nations. 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: January 17, 1995.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 95-1553 Filed 1-19-95; 8:45 am]
BILLING CODE 4160-01-F