Ibogaine Produces Neurodegeneration in Rat, but Not Mouse, Cerebellum.

Abstract

The compound Ibogaine is being intensively studied as a possible therapeutic aid to interrupt addictive cravings of various sorts (e.g., Ref. 1). Structurally, ibogaine closely resembles serotonin (FIG. 1). It binds, but with only moderate (micromolar) affinity, to a variety of membrane and transporter sites including serotonin, opiate, and NMDA-re~eptors.~-’ Initial clinical reports indicate that ibogaine is a promising therapeutic agent for the difficult, even intractable, downward cycle of drug addiction. However, placebo effects may exert considerable influence on such single-blind trials.6 Fur- ther clinical trials are now being undertaken to evaluate the efficacy of this com- pound in human cocaine addicts. However, no double-blind clinical studies from which to judge the efficacy of ibogaine have yet been reported. Indeed, the potent psychoactive effects of ibogaine make the design of an effective double-blind study quite challenging. A psychoactive control substance as unfamiliar as ibogaine itself to the patients would be needed. Preclinical animal studies attempting to establish the mechanism of action and the efficacy of ibogaine against self-administration or withdrawal of such compounds as morphine,’-14 ~ocaine,‘’-’~ and amphetamine10~22-22 have been con- ducted. As in the clinical studies, the evidence is promising but remains inconclu- sive regarding the utility of ibogaine as a therapeutic agent. Ibogaine has also been proposed, but remains unstudied, as a treatment for nicotine and alcohol addiction. In addition to serotonin, ibogaine also structurally resembles harmaline (FIG. l), a tremorigenic agent known to produce neurotoxic damage to the cerebellum. This observation lead O’Hearn and colleague^^^^^^ to evaluate the neurohistology of rat cerebellum following acute exposure to ibogaine. As with harmaline, they observed necrosis of Purkinje neurons in the cerebellar vermis as indicated by several neurohistological biomarkers: argyrophilic degeneration, loss of calbindin immunoreactivity, astrocytosis, and microgliosis. The dose levels they employed were within the same order of magnitude as those being utilized in human trials. Efforts by other laboratories (unpublished observations) failed to obtain any evi- dence for the neurotoxicity of ibogaine in nonhuman primates; however, the methods used in those studies were primarily conventional hematoxylin and eosin

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