A Single Administration of the Atypical Psychedelic Ibogaine or its Metabolite Noribogaine Induces an Antidepressant-like Effect in Rats

Ibogaine and its main metabolite noribogaine produce antidepressant-like effects in rats in a dose- and time-dependent manner, without altering locomotor activity. Noribogaine's effect is short-lived (30 minutes) and correlates with high brain concentrations (estimated > 8 µM free drug), while ibogaine's effect is significant at 3 hours. At that time, both compounds are present in the brain at concentrations (ibogaine ~0.5 µM, noribogaine ~2.4 µM) that alone cannot produce the same behavioral outcome, suggesting a polypharmacological mechanism underlies their antidepressant-like effects.

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Abstract

Anecdotal reports and open label case studies in humans indicated that the psychedelic alkaloid ibogaine exert profound anti-addictive effects. Ample preclinical evidence demonstrated the efficacy of ibogaine, and its main metabolite noribogaine, in substance use disorder rodent models. In contrast to addiction research, depression-relevant effects of ibogaine or noribogaine in rodents have not been previously examined. We have recently reported that the acute ibogaine administration induced a long-term increase of brain-derived neurotrophic factor mRNA levels in the rat prefrontal cortex, which led us to hypothesize that ibogaine may elicit antidepressant-like effects in rats. Accordingly, we characterized behavioral effects (dose and time-dependence) induced by the acute ibogaine and noribogaine (20 and 40 mg/kg, i.p.) administration in rats using the forced swim test (FST). We also examined the correlation between plasma and brain concentrations of ibogaine and noribogaine and the elicited behavioral response. We found that ibogaine and noribogaine induced a dose- and time-dependent antidepressant-like effect without significant changes of animal locomotor activity. Noribogaine’s FST effect was short lived (30 minutes) and correlated with high brain concentrations (estimated > 8 mM of free drug), while the ibogaine’s antidepressant-like effect was significant at 3 hours. At this time point, both ibogaine and noribogaine were present in rat brain, at concentrations which cannot produce the same behavioral outcome on their own (ibogaine ~ 0.5 mM, noribogaine ~ 2.4 mM). Our data suggest a polypharmacological mechanism underpinning the antidepressant-like effects of ibogaine and noribogaine.