18‐Methoxycoronaridine (18‐MC) and Ibogaine: Comparison of Antiaddictive Efficacy, Toxicity, and Mechanisms of Action

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Abstract
18‐MC, a novel iboga alkaloid congener, is being developed as a potential treatment for multiple forms of drug abuse. 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 nondrug reinforcer (water). Both ibogaine and 18‐MC ameliorate opioid withdrawal signs. Both ibogaine and 18‐MC decrease extracellular levels of dopamine in the nucleus accumbens, but only ibogaine increases extracellular levels of serotonin in the nucleus accumbens. Both ibogaine and 18‐MC block morphine‐induced and nicotine‐induced dopamine release in the nucleus accumbens; only ibogaine enhances cocaine‐induced increases in accumbal dopamine. Both ibogaine and 18‐MC enhance the locomotor and/or stereotypic effects of stimulants. Ibogaine attenuates, but 18‐MC potentiates, the acute locomotor effects of morphine; both compounds attenuate morphine‐induced locomotion in morphine‐experienced rats. Ibogaine produces whole body tremors and, at high doses (≥100 mg/kg), cerebellar damage; 18‐MC does not produce these effects. Ibogaine, but not 18‐MC, decreases heart rate at high doses. While 18‐MC and ibogaine have similar affinities for kappa opioid and possibly nicotinic receptors, 18‐MC has much lower affinities than ibogaine for NMDA and sigma‐2 receptors, sodium channels, and the 5‐HT transporter. Both 18‐MC and ibogaine are sequestered in fat and, like ibogaine, 18‐MC probably has an active metabolite. The data suggest that 18‐MC has a narrower spectrum of actions and will have a substantially greater therapeutic index than ibogaine.