Drug discrimination studies with ibogaine.

Ibogaine appears to produce its effects through selective interactions with multiple brain receptors, specifically 5-HT2A, 5-HT2C, and sigma 2 receptors, with possible involvement of opiate receptors. Sigma 1, PCP/MK-801, 5-HT3, and 5-HT1A receptors do not play a major role. The hallucinogenic effects may stem from 5-HT2A and 5-HT2C receptor interactions, while antiaddictive properties may result from sigma 2 and opiate receptor interactions. Alternatively, the hallucinogenic properties themselves could underlie the antiaddictive effects, supporting a role for 5-HT2 receptors in therapeutic actions. Many questions remain, and future research combining drug discrimination with other techniques promises to clarify ibogaine's mechanism of action.

Study at a glance

Abstract

The results of the studies described here support the hypothesis that ibogaine produces its effects via selective interactions with multiple receptors. It appears that 5-HT2A, 5-HT2C, and sigma 2 receptors are involved in mediating the stimulus effects of ibogaine. In addition, opiate receptors may also be involved. In contrast, sigma 1, PCP/MK-801, 5-HT3, and 5-HT1A receptors do not appear to play a major role. Ibogaine's hallucinogenic effects may be explained by its interactions with 5-HT2A and 5-HT2C receptors, while its putative antiaddictive properties may result from its interactions with sigma 2 and opiate receptors. Alternatively, the possibility that ibogaine's hallucinogenic properties underlie its antiaddictive effects, as previously suggested (34), would support a role for 5-HT2 receptors in mediating the reported therapeutic effects of ibogaine. Certainly many questions remain regarding ibogaine's mechanism of action. Although drug discrimination will be useful for answering some of those questions, the true potential of this technique is realized whin it is combined with other techniques. The next few years promise to be fruitful with respect to our understanding of this agent. Reasons supporting this belief include advances in the study of sigma receptors, interest in ibogaine's effects on second messenger systems, and the development of ibogaine congeners such as 18-methoxycoronaridine (35). In conclusion, the aforementioned studies should serve to guide further endeavors. Pertinent questions have been generated: What is the role of sigma receptors in the effects of ibogaine, especially with regard to addiction? How does ibogaine affect opiate neurotransmission? What effects, if any, do the Harmala alkaloids have on addiction phenomena? What is the mechanism of action of harmaline? Can 10-hydroxyibogamine serve as a discriminative stimulus and, if so, what receptor interactions mediate its stimulus effects? Does the ibogaine-trained stimulus generalize to novel agents, including 18-methoxycoronaridine?