(2003; 31 pages) [French] [Spanish]
3.3 Amineptine (INN)
Amineptine (7-[(10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl)amino] heptanoic acid) is available as either the free base (CAS 57574-09-1) or as the hydrochloride salt (CAS 30272-08-3). There are no chiral carbon atoms, therefore, no stereoisomers or racemates are possible.
Amineptine was pre-reviewed at the thirty-second meeting of the Committee (4) and critical review was recommended.
Similarity to known substances and effects on the central nervous system
Amineptine is a synthetic, atypical tricyclic antidepressant with stimulating effects on the central nervous system. It is an indirect dopamine agonist, which selectively inhibits dopamine uptake and induces dopamine release, with additional stimulation of the adrenergic system. Its antidepressant effects are similar to those of other tricyclic antidepressant drugs but amineptine has a more rapid action, is better tolerated and has few cardiovascular, analgesic or anorectic effects. It produces a similar spectrum of pharmacological effects to the psychomotor stimulants in Schedule II of the 1971 Convention.
There have been few animal studies on the potential for dependence or abuse of amineptine. However, some clinical studies have indicated that amineptine has the potential both for dependence and abuse, particularly in patients with a previous history of substance abuse. Members of the Committee reported on their observations of significant abuse and dependence in patients treated with amineptine in France. The dependence potential of the drug appeared to be associated with its psychomotor stimulant effect. The clinical manifestations of withdrawal include anxiety, insomnia, psychomotor agitation and bulimia. Instances of dependence have been reported in Asia and Europe.
Actual abuse and/or evidence of likelihood of abuse
Amineptine abuse has been reported mainly in Asia and Europe. The drug has been withdrawn from the market in France, where it was developed a few decades ago, because of its considerable hepatotoxicity and abuse. However, its medical use in developing countries, as well as its abuse continue. The reports of adverse drug reactions collected by the international drug monitoring programme indicated a larger number of case reports of abuse and dependence for amineptine than for other anorectic stimulants currently placed in Schedule IV of the 1971 Convention, such as amfepramone. The responses of governments to the WHO questionnaire also indicated limited diversion and abuse of the drug although some reported hospital admissions have been linked to the use or abuse of amineptine.
The therapeutic usefulness of amineptine is limited because of its hepatotoxicity, secondary features such as acne eruption and anxiety, and the availability of safer antidepressants. Of the 103 countries that responded to the WHO questionnaire, only 17 indicated amineptine use.
The Committee considered that the degree of risk to public health and society associated with the abuse liability of amineptine is substantial and noted that its use is associated with significant hepatotoxicity. Its therapeutic usefulness has been assessed to be from little to moderate, at best. Although it has already been withdrawn from the market in several countries, amineptine continues to be available in a number of others. The Committee therefore considered that the likelihood of its abuse warranted its placement under international control. The Committee recommended that amineptine be placed in Schedule II of the 1971 Convention.