The WHO Expert Committee on Drug Dependence fulfils a fundamental role within the framework of the international drug control system of the UN Conventions. The WHO Expert Committee is entrusted with determining the level of international control to be applied to the medical and scientific evaluation of dependence-producing drugs with a view to providing recommendations to the United Nations Commission on Narcotic Drugs (CND). This is a unique function whereby no drug can be scheduled or controlled internationally without prior evaluation by WHO. The following is an outline of the work undertaken during the Thirty-second meeting of the Expert Committee held in September 2000.

A new review procedure

In 1986, in order to ensure a consistent approach to evaluation, WHO developed a guideline on the formal procedure to be used in the review of dependence- producing psychoactive substances. An updated version of these guidelines was adopted in January 2000 by the WHO Executive Board (1). One major improvement on previous guidelines is the clarification of roles of the 1988 United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances (1988 Convention) and that of the 1971 Convention on Psychotropic Substances (1971 Convention).

Although WHO is not given any formal role to play in the implementation of the 1988 Convention as such, one of the objectives of the new guidelines is to avoid unnecessary duplication of controls. A particular example of this is discussed below in relation to the scheduling of ephedrine. The successful application of the new guidelines will involve enhanced strengthening and collaboration between WHO and the International Narcotics Control Board (INCB). This latter body holds the mandate to formulate scheduling recommendations with regard to chemicals frequently used in the illicit manufacture of narcotic drugs and psychotropic substances under the 1988 Convention.

Scheduling of ephedrine

During its Thirty-first meeting, the Expert Committee conducted a critical review of ephedrine and recommended that (+)-ephedrine and (+)-ephedrine be placed in Schedule IV of the 1971 Convention (2). However, the UN Commission on Narcotic Drugs (CND) subsequently decided not to vote on this recommendation (3). The Thirty-second meeting conducted a review in accordance with the new guidelines. These provide for the scheduling of a psychotropic substance under the 1971 Convention when that substance is also subject to control as a chemical frequently used in illicit manufacture of narcotic drugs and psychotropic substances under the 1988 Convention.

The section of the new guidelines applicable to ephedrine states: In the case of a review of a psychoactive substance which is already included in Table I or Table II of the 1988 Convention (such as ephedrine) or has already been recommended by INCB for inclusion therein, the Expert Committee should be guided by three principles. These include the rule that a proposal for a change in the existing status of the substance is to be made when specific new control measures are necessary in order to decrease the extent or likelihood of abuse, while not unduly limiting availability for legitimate medical and scientific purposes.

At the time of the ephedrine review, seven countries reported ephedrine abuse of some significance. However, none of these countries indicated the need for additional control measures, since those introduced in the past have been successfully implemented. The Committee therefore proposed withdrawal of the 1998 recommendation concerning the placement of ephedrine in Schedule IV of the 1971 Convention because WHO has no information to justify recommending international control of ephedrine under the 1971 Convention.

Interpretation guidelines on control status of stereoisomers

Although the Committee had previously rejected a proposed extension of control to isomers, esters, ethers and analogues of psychotropic substances in Schedules I and II of the 1971 Convention, it now recommended that a phrase be added to Schedule I of the 1971 Convention to clarify the scope of control of stereoisomers. The CND had adopted this recommendation in March 1999 (3).

In addition, with regard to stereoisomers of substances listed in Schedules II through IV of the 1971 Convention, the CND decided that interpretative guidelines should be developed by WHO in collaboration with INCB in order to eliminate any confusion arising from inconsistencies in the present nomenclature. In response to this request, the Committee provided the following guidelines.

1. When the substance listed can exist as stereochemical variants the following should apply:

(i) if the chemical designation of the substance used in the Convention (or in a subsequent scheduling decision of the CND) does not include any stereochemical descriptors or indicates a racemic form of the substance:

(a) if the molecule contains one chiral centre, both the R- and S enantiomers and the RSracemate are controlled, unless specifically excepted by a decision of the CND; and

(b) if the molecule contains more than one chiral centre, all the diastereoisomers and their racemic pairs are controlled, unless specifically excepted by a decision of the CND.

(ii) if the chemical designation used in the Convention (or in a subsequent scheduling decision of the CND) for the substance which contains one chiral centre in the molecule includes a stereochemical descriptor indicating a specific enantiomer, the racemic form of the substance is also controlled unless specifically excepted by a decision of the CND while the other enantiomer is not controlled; and

(iii) if the chemical designation used in the Convention (or subsequent scheduling decision) for the substance which contains more than one chiral centre in the molecule includes stereo-chemical descriptors indicating a specific diastereoisomer, only that diastereoisomer is controlled.

2. When one enantiomer is controlled, then a mixture of that enantiomer with the other enantiomeric substance is controlled.

3. The chemical designations and International Nonproprietary Names (INN) used in the scheduling decisions to define substances in Schedules II, III, and IV of the 1971 Convention were considered appropriate at the time such a decision was made. It should be understood that:

(i) alternative chemical designations constructed according to modified chemical nomenclature rules may be used in official documents as long as they preserve the stereospecificity, when appropriate; and

(ii) if any subsequent modification of an INN definition uses a chemical designation which is different to that in the scheduling decision, such an INN should be omitted from official documents.

Scheduling recommendations

Out of the six substances under critical review, the Committee recommended that the following four substances should be controlled under the 1971 Convention.

2C-B (4-bromo-2,5-dimethoxyphenylethylamine)

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 others. Based on its perceived aphrodisiac effects and known modest abuse potential compared to hallucinogenic drugs in general, it is estimated that 2C-B has a potential for abuse which could constitute a public health and social problem warranting its placement under international control. The Committee noted, however, that hallucinogens are rarely associated with compulsive use and that abuse of 2C-B has been infrequent, suggesting that any abuse is likely to constitute a substantial, rather than a particularly serious risk to public health. Based on these considerations, the Committee recommended that 2C-B be placed in Schedule II of the 1971 Convention.

4-MTA (4-methylthioamphetamine) is chemically and pharmacologically similar to 4-methoxyamphetamine, 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 drugs, as well as drug discrimination studies in animals, it is estimated that 4-MTA has a potential for abuse which could constitute a public health and social problem and warrant 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, the Committee concluded that abuse of 4-MTA presents an especially serious risk to public health. The Committee therefore recommended that 4-MTA be placed in Schedule I of the 1971 Convention.

GHB (Gamma-hydroxybutyric acid)

Although GHB is an endogenous compound that exists in the human body, it 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 for abuse constitutes a significant risk to public health. The current easy availability of GHB and some of its precursors has furthermore contributed to recent reports of abuse. Its wide availability is likely to be reduced once GHB is placed under international control. Based on this situation, the Committee recommended that GHB be placed in Schedule IV of the 1971 Convention.

Zolpidem

Although zolpidem has a somewhat novel neuropharmacological profile relative to classic benzodiazepines, studies suggest that its abuse potential may be comparable. Furthermore, rates of actual abuse and dependence of zolpidem, as well as the risk to public health of abuse, appear to be similar to hypnotic benzodiazepines presently placed in Schedule IV. The Committee therefore recommended that zolpidem be placed in Schedule IV of the1971 Convention.

Substances reviewed but not recommended for scheduling or re-scheduling were MBDB (2- (methylamino)-1-(3,4 methylenedioxyphenyl)- butane) and diazepam.

Substances for future review

The Committee identified the following substances for critical review.

Amfepramone

In response to recent reports of widespread abuse and illicit traffic, the Committee recommended that a critical review be undertaken to determine the extent of public health and social problems associated with recent reports of increased illicit activities.

Amineptine Unlike most antidepressants, amineptine elicits CNS stimulation by dopamine uptake blockade. Abuse and/or dependence has been reported from France, Italy, Pakistan and Spain. It has been placed under national control in France. Critical review is recommended as there is a likelihood of amineptine abuse in other countries constituting a significant public health and social problem.

Buprenorphine is a partial agonist at µ-opioid receptors and an antagonist at κ-opioid receptors. In this respect it is different from prototypical µ- opioid agonists such as morphine and methadone. However, the pattern of diversion and abuse of buprenorphine as reported to INCB indicates its similarity to opiates from an epidemiological point of view. It was also noted that the Committee did not provide in the past an adequate pharmacological explanation about its psychotropic effects nor a clear rationale for the decision to recommend control under the 1971 Convention rather than the 1961 Convention. In consideration of these issues and the increasing rates of abuse and illicit traffic, the Committee recommended critical review of buprenorphine.

Dronabinol

No data are available to demonstrate that individuals are taking dronabinol for non-medical use. The public health problems associated with dronabinol are at present only a potential risk. Dronabinol is not widely available, and diversion or off-label use has not been documented to be significant. Illicit manufacture of dronabinol or δ (delta)-THC has rarely been reported. Whether synthesized or isolated from the cannabis plant, δ-THC is considerably more expensive than its natural preparation (cannabis), thus limiting the likelihood of widespread abuse. In the case of pharmaceutical preparations of dronabinol, the delayed onset and longer duration of action may be additional contributing factors limiting abuse of the product in relation to cannabis. The present scheduling of δ-THC is based on the therapeutic usefulness and risk assessment of δ-THC made at the Twenty-seventh meeting of the Expert Committee in 1990. The very low rate of actual abuse of δ-THC suggests that the risk to public health may actually be less than that required of substances in Schedule II. The Committee therefore recommended a critical review of δ- THC.

Tramadol

In humans, tramadol has the potential to produce dependence of the morphine-type (µ-opioid). Tramadol is among the top 10 drugs reported for both withdrawal and dependence from data gathered by the WHO International Drug Monitoring Programme, including cases of abuse. Convulsions were reported after the first dose, at the recommended dosage range and at higher doses. Risk of occurrence of convulsions is increased in patients taking concomitant medications that may reduce the seizure threshold, including certain tricyclic compounds and selective serotonin reuptake inhibitors (SSRIs) and with certain medical conditions. The Committee recommended a critical review of tramadol.

References

1. World Health Organization. Guidelines for the WHO Review of Dependence-Producing Psychoactive Substances for International Control. EB105/2000/REC/1, Annex 9, (2000).

2. World Health Organization. WHO Expert Committee on Drug Dependence. Thirty-first report. WHO Technical Report Series, No. 887. Geneva, 1999.

3. United Nations. Commission on Narcotic Drugs. Report of the Forty-second session. Vienna, 2000.