Development of novel medications for drug addiction. The legacy of an African shrub

Abstract

Ibogaine, one of several alkaloids found in the root bark of the African shrub Tabernanthe iboga, has been claimed to be effective in treating multiple forms of drug abuse. Problems associated with side effects of ibogaine have spawned a search for more effective and safer structural derivatives. 18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener, appears to have substantial potential for broad use as an anti-addictive therapy. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a non-drug reinforcer (water). Ibogaine and 18-MC appear to reduce the reinforcing efficacies, rather than the potencies, of drugs of abuse. Both ibogaine and 18-MC decreases extracellular levels of dopamine in the nucleus accumbens while only ibogaine increases serotonin levels in this brain region. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the accumbens; only ibogaine enhances cocaine-induced increases in dopamine levels. Ibogaine produces whole body tremors and, at high doses (at least 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, causes bradycardia at high doses. Ibogaine and its metabolite noribogaine have low microM affinities for kappa and mu opioid receptors, NMDA receptors, 5HT-3 receptors, sigma-2 sites, sodium channels and the serotonin transporter. 18-MC has low microM affinities at all three opioid receptors and at 5HT-3 receptors but much lower or no affinities for NMDA and sigma-2 receptors, sodium channels, and the 5HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. 18-MC also has (+) and (-) enantiomers, both of which are active. Considered together, all of the data indicate that 18-MC should be safer than ibogaine and at least as efficacious as an anti-addictive medication.