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

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. File list (2) download file view on ChemRxiv Rodriguez et al ibo and noribo FST.pdf (1.94 MiB) download file view on ChemRxiv Rodriguez et al ibo and noribo Supporting Information.pdf (5.45 MiB)

EEG Gamma Band Alterations and REM-like Traits Underpin the Acute Effect of the Atypical Psychedelic Ibogaine in the Rat

“…In this manner, ibogaine and noribogaine should be considered to explain our results. Although affinities displayed to most of the CNS receptors by ibogaine and noribogaine are low (micromolar range), we estimated high free drug maximum concentrations in rat brain for both substances in brain ( ∼ 3.1-3.5 μ M) 19 . In this regard, noncompetitive antagonism at N-methyl-D-aspartate receptors (NMDA-R) by ibogaine (Ki ∼ 1.01-5.20 μ M 40,[47][48][49][50][51][52][53] ) and in a less extent by noribogaine (Ki ∼ 5.48-31.4 μ M 47,49,53 ) should be considered as a key factor to explain the effects on the gamma band found on this study, since ketamine (a non-competitive NMDA-R antagonist) administration also produces a marked increase in gamma power [54][55][56][57] while decreasing inter-regional gamma coherence 55,57 .…”

“…was employed in this work. This dose has the largest effect on sleep and motor behavior 18 and correlates with the high doses involved in shamanic and medicinal uses of ibogaine 19 .…”

“…In addition, the spectra were normalized to obtain the relative power by dividing the power value of each frequency by the sum across frequencies. The traditional frequency bands depicted in the figures were taken as: delta (1-4 Hz), theta (5-10 Hz), sigma (11)(12)(13)(14), beta (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and gamma (30-100 Hz). Spectral coherence : To measure synchronization between electrodes, we employed the magnitude squared coherence using the mscohere built-in function in Matlab (parameters: window = 1024, noverlap = [], fs = 1024, nfft = 1024), which corresponds to 1-s sliding windows with half-window overlap, and a frequency resolution of 1 Hz.…”

Efficient Access to the Iboga Skeleton: Optimized Procedure to Obtain Voacangine from Voacanga africana Root Bark

“…As mentioned in a recent review, there are many unsolved problems regarding the chemistry and neuropharmacology of ibogaine, which are of high importance considering the increased interest of psychedelic compounds as promising experimental therapeutics in neuropsychiatric disorders. Our group has recently published new findings regarding the intriguing neuropharmacology of ibogaine: its ability to induce the expression of neurotrophic factors in the brain, its antidepressive-like effect in rodents models, and the characterization of its unusual oneirogenic psychedelic effects through electrophysiological studies in the rat brain. , From a chemical standpoint, ibogaine and other structurally related iboga alkaloids still lack efficient and scalable enantioselective total syntheses despite the vast amount of outstanding synthetic studies found in the field . Thus, direct extraction from natural sources or semi-synthetic preparations are the methods of choice to obtain ibogaine and related analogues in a preparative scale.…”

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Use

“…[11][12][13] The clinical claims of ibogaine's anti-addictive properties have been recapitulated in numerous rodent models of substance use disorders (SUDs) and depression. [14][15][16][17] Ibogaine has a complex chemical structure where the tryptamine motif is intricately embedded in the isoquinuclidine ring, leading to a polycyclic tryptamine system that defines the iboga alkaloids (Fig. 1a, d).…”