Iboga interactions with psychomotor stimulants: panacea in the paradox?

No approved therapy exists for stimulant addiction, but ibogaine and its synthetic analog 18-methoxycoronaridine (18-MC) reduce stimulant self-administration in animals. Early findings suggested these agents paradoxically enhance dopamine release and motor behaviors, leading to the hypothesis that they increase sensitivity to stimulant effects. However, recent observations show 18-MC does not affect acute cocaine-induced dopamine, and both ibogaine and 18-MC block sensitized dopamine levels from chronic cocaine. This positive relationship between iboga pretreatment and reversal of dopamine sensitization indicates these agents may attenuate self-administration by reversing neuroadaptations linked to craving and compulsive drug-seeking.

Study at a glance

Abstract

Currently, no effective therapy has been approved for the treatment of addiction to stimulant drugs (e.g., cocaine, amphetamine and its methylated derivatives). However, preclinical studies indicate that the naturally-occurring indole alkaloid, ibogaine, and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), attenuate stimulant self-administration in laboratory animals. The in vivo pharmacological interactions between iboga agents and stimulant drugs are unclear. Ibogaine enhances the increase in accumbal dopamine produced by the acute administration of stimulant drugs. Consistent with these data, both ibogaine and 18-MC potentiate the expression of stimulant-induced motor behaviors in acute and chronic stimulant-treated animals. To account for the paradox between their effects on self-administration and motor behavior, we proposed that iboga agents interfere with stimulant self-administration by increasing sensitivity to their psychomotor-activating effects. However, this interpretation is contradicted by very recent observations that 18-MC is without effect on the dopamine response to acute cocaine and that both ibogaine and 18-MC block the expression of sensitized levels of dopamine in the nucleus accumbens produced by chronic cocaine administration. Thus, a positive relationship exists between the effects of iboga pretreatment on stimulant-induced dopamine sensitization and stimulant self-administration behavior. These data indicate that iboga agents might attenuate stimulant self-administration by reversing the neuroadaptations theoretically implicated in drug craving and compulsive drug-seeking behavior.