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.
Similarity to known substances and effects on the central nervous system
Amineptine is a synthetic, atypical tricyclic antidepressant with
central nervous system stimulating effects. It is an indirect dopamine agonist,
selectively inhibiting dopamine uptake and inducing dopamine release, with
additional stimulation of the adrenergic system. Its antidepressant effects are
similar to other tricyclic antidepressant drugs but it has a more rapid action,
is better tolerated and has little cardiovascular, analgesic or anorectic
effects. It produces a similar spectrum of pharmacological effects to
psychomotor stimulants in Schedule II of the 1971 Convention on Psychotropic
Substances.
Dependence potential
There have been few animal studies regarding the dependence or abuse
potential of amineptine. However, some clinical studies indicated that
amineptine has both dependence and abuse potential, particularly in patients
with a previous history of substance abuse. Clinical observations of
significant abuse and dependence are reported in patients treated with
amineptine in France. Its dependence potential appeared to be associated with
its psychomotor stimulant effect. Withdrawal has been clinically manifested by
anxiety, insomnia, psychomotor agitation or bulimia. Instances of dependence
have been reported in Europe and Asia.
Actual abuse and/or evidence of likelihood of abuse
Amineptine abuse has mainly been reported in Europe and Asia. It has
been withdrawn from the market in France, where the drug was developed a few
decades ago, for reasons of considerable hepatotoxicity and abuse. Despite this
measure, medical use in developing countries, as well as abuse still continues. The abuse-related adverse drug reaction
reports for amineptine collected by the international drug monitoring programme
indicate a larger number of case reports of abuse and dependence than anorectic
stimulants currently placed in Schedule IV of the 1971 Convention on
Psychotropic Substances, such as amfepramone.
Response of governments to the WHO questionnaire also indicated limited
diversion and abuse of the drug. Some reported hospital admissions due to
adverse consequences of amineptine abuse.
Therapeutic usefulness
The therapeutic usefulness of amineptine is low because of
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.
Recommendation
Given its significant hepatotoxicity, the degree of risk to public health and society associated with the abuse liability of amineptine is assessed to be substantial. Its therapeutic usefulness is rated to be from little to moderate, at best. Despite its withdrawal from the market in several countries, amineptine continues to be available in a number of countries. The likelihood of its abuse therefore warrants its placement under international control. On the basis of the above, it is recommended that amineptine be placed in Schedule II of the 1971 Convention on Psychotropic Substances.