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

Rodríguez and colleagues introduce ibogaine, an indole alkaloid from Tabernanthe iboga, as an atypical psychedelic with anecdotal and open‑label clinical reports of rapid, durable reductions in drug withdrawal symptoms, craving and, in some studies, depressive symptoms following single therapeutic sessions. Extensive preclinical work has reproduced ibogaine’s anti‑addictive effects in rodent substance use disorder models, and noribogaine, the main metabolite, shows similar efficacy in these models. The authors note prior findings that a single ibogaine dose upregulates neurotrophic factors in rat brain, including GDNF in mesocorticolimbic and nigral regions and a marked increase of BDNF in prefrontal cortex, changes that are mechanistically linked to antidepressant actions of established treatments. Motivated by these clinical observations and mechanistic hints, the study set out to test whether a single acute administration of ibogaine or noribogaine produces antidepressant‑like effects in rats. The investigators used the forced swim test (FST), a standard preclinical assay sensitive to a broad range of clinically effective antidepressants, and combined behavioural testing with plasma and brain pharmacokinetic (PK) measurements to relate drug concentrations to behavioural outcomes. The work aimed to characterise dose‑ and time‑dependence of any effect and to explore whether ibogaine, noribogaine or both contribute to an antidepressant‑like response.

The study used adult male Wistar rats (behavioural experiments: 290–320 g; PK experiments used 280–300 g animals) housed under controlled conditions. Behavioural testing (FST and open field test, OFT) was carried out at the Instituto de Investigaciones Biológicas Clemente Estable (IIBCE, Uruguay). Pharmacokinetic studies (plasma and brain) were conducted at Sai Life Sciences (Pune, India). All procedures followed institutional and national animal‑care guidelines. For PK time course sampling, three rats per time point were used; behavioural group sizes inferred from reported ANOVAs were approximately 7–8 animals per group. Drug preparation and dosing regimens were described in detail. Chemically synthesised ibogaine·HCl (purity 98.3%) and noribogaine·HCl (purity 95.2%) were administered in warm saline/ethanol vehicle. Behavioural groups included: intraperitoneal (i.p.) ibogaine at 20 mg/kg (I20) or 40 mg/kg (I40), with FST assessed at 3 hours and 24 hours post‑dose; i.p. noribogaine at 20 mg/kg (N20) or 40 mg/kg (N40), with FST at 0.5 hours and 3 hours; intravenous (i.v.) ibogaine at 1 mg/kg (I1) or 5 mg/kg (I5) with immediate testing; and a fluoxetine control group given 40 mg/kg i.p. (single dose) for comparison. The forced swim test followed the standard two‑session protocol (15‑minute pre‑test, followed 24 hours later by a 5‑minute test). Observers scored immobility, swimming and climbing in real time; sessions were video‑recorded for confirmation when needed. The open field test measured horizontal locomotor activity (total distance moved) to assess potential motor confounds. Pharmacokinetic experiments involved single administrations of ibogaine (i.v. 5 mg/kg and i.p. 40 mg/kg) and noribogaine (i.p. 40 mg/kg), with plasma and brain collected at multiple time points; brains were rinsed, homogenised and stored for analysis. Plasma protein binding and brain tissue binding assays were performed to estimate free drug concentrations. Statistical analysis used one‑way ANOVA with Tukey post hoc tests, and unpaired t‑tests where appropriate, with significance at P < 0.05.

In the FST, a single i.p. dose of ibogaine 40 mg/kg (I40) produced a statistically significant reduction in immobility when assessed 3 hours after administration. One‑way ANOVA for immobility at this time gave F(2,20) = 4.11, P < 0.03, and Tukey post hoc testing indicated I40 versus vehicle P < 0.05. The I20 dose did not significantly alter immobility. Open field testing at 3 hours showed no significant change in locomotor activity after I40 (ANOVA F(2,15) = 2.58, P = 0.11), indicating the FST effect was not attributable to gross motor activation. Neither swimming nor climbing times were significantly changed by ibogaine at 3 hours (swimming F(2,20) = 2.73, P = 0.08; climbing F(2,20) = 0.65, P = 0.53). No significant antidepressant‑like effect was observed 24 hours after i.p. ibogaine for either dose. Noribogaine given i.p. at 40 mg/kg (N40) induced a robust, dose‑dependent reduction in immobility when the FST was performed 0.5 hours after dosing. One‑way ANOVA showed F(2,18) = 7.24, P < 0.01; Tukey post hoc tests found N40 reduced immobility versus vehicle (P < 0.01) and versus N20 (P < 0.05). Motor activity after N40 was unchanged (OFT F(2,12) = 0.60, P = 0.56). At 3 hours after noribogaine administration, immobility was not significantly different from control (F(2,14) = 0.77, P = 0.48), indicating a short‑lived behavioural effect. Intravenous administration of ibogaine at 1 and 5 mg/kg, tested 1 minute after dosing to favour high parent drug and low metabolite levels, did not produce a significant decrease in FST immobility (ANOVA F(2,20) = 0.73, P = 0.49). Brain PK at 1 minute after i.v. 5 mg/kg showed total ibogaine ≈ 23 μM and negligible noribogaine (~0.07 μM), indicating that ibogaine alone at this brain concentration did not replicate the antidepressant‑like effect seen after i.p. I40. Pharmacokinetic measurements after i.p. I40 showed a rapid metabolism to noribogaine; at 3 hours both compounds were present in brain with mean total concentrations of ≈9.9 μM ibogaine and ≈21 μM noribogaine. At 24 hours ibogaine was undetectable and noribogaine residual brain levels were ≈0.5 μM (≈2% of its Cmax). After i.p. N40, maximal brain total noribogaine concentration at 0.5 hours was ≈144 μM (Cmax), with an estimated 31 μM at 3 hours. The authors report brain/plasma concentration ratios of ≈7.7 for ibogaine and ≈7.9 for noribogaine. Using plasma protein and brain tissue binding data, free brain concentrations at 3 hours post I40 were estimated at ≈0.5 μM for ibogaine and ≈2.4 μM for noribogaine. Group sizes for behavioural assays were approximately 7–8 animals per group (N = 7–8 reported). For comparison with a classical SSRI, a single i.p. fluoxetine dose (40 mg/kg) did not alter immobility, swimming or climbing (t10 = 0.62, P = 0.55); a reduction in immobility required three fluoxetine doses in this experimental paradigm. Across behavioural outcomes, neither ibogaine nor noribogaine produced significant changes in the active behaviours (swimming, climbing), although there were trends toward increased swimming time in some groups.

The investigators interpret their results as showing that a single i.p. administration of ibogaine or noribogaine can produce acute antidepressant‑like effects in the rat FST, but with distinct time courses: noribogaine’s effect is short‑lived and evident at 0.5 hours, whereas the ibogaine effect after I40 emerges at 3 hours and is absent at 24 hours. Correlating PK and behavioural data, Rodríguez and colleagues emphasise that the I40 effect at 3 hours occurs when both ibogaine and noribogaine are present in brain at modest total concentrations; by contrast, either compound alone at the measured single‑compound concentrations (e.g. ibogaine 23 μM after i.v. dosing, or noribogaine 31 μM at 3 hours after N40) did not produce a significant FST effect. From these observations the authors suggest a putative additive or synergistic interaction between parent drug and metabolite, or alternatively the involvement of an additional metabolite formed after i.p. but not i.v. administration. Mechanistically, the authors note that both compounds inhibit the serotonin transporter (SERT), noribogaine being ≈10‑fold more potent (in vitro IC50 ≈ 50–300 nM), and estimate that free brain concentrations at 3 hours post I40 (≈0.5 μM ibogaine, ≈2.4 μM noribogaine) are within a range relevant for SERT modulation. They reference in vivo microdialysis evidence that both drugs increase extracellular 5‑HT in nucleus accumbens, similar in magnitude to SSRIs. Nevertheless, the authors argue that SERT inhibition alone is unlikely to explain all findings: noribogaine required high estimated free brain concentrations (> ≈8 μM) to elicit FST effects when administered alone, a level >20‑fold higher than its in vitro SERT potency. Consequently, a polypharmacological mechanism is proposed, with possible contributions from NMDA receptor non‑competitive antagonism (described for ibogaine) and noribogaine‑induced neuritogenesis, among other targets. Rodríguez and colleagues position their results relative to clinical observations of antidepressant effects after ibogaine in opioid‑dependent subjects and suggest their preclinical data provide reverse translational confirmation and a starting point for mechanistic dissection. They acknowledge limitations: the FST’s limited translational predictive power for clinical efficacy, the need for additional neurochemical studies to measure extracellular 5‑HT and other neurotransmitters in depression‑relevant regions (prefrontal cortex, hippocampus), and the necessity of broader behavioural testing (motivational and anhedonic assays) to probe other depression‑relevant domains. The authors also note technical considerations such as differences in PK metrics reported in other studies and the possibility that route of administration influences metabolite formation and behavioural outcomes. They conclude that further work is needed to elucidate the precise neurochemical and molecular basis of the observed antidepressant‑like effects.

The study demonstrates for the first time in rodents that single i.p. administrations of ibogaine and noribogaine produce acute, dose‑ and time‑dependent antidepressant‑like effects in the forced swim test. At 40 mg/kg, ibogaine showed an effect at 3 hours, whereas noribogaine’s effect was present at 30 minutes but absent at 3 hours. The antidepressant‑like response after i.p. ibogaine correlates with simultaneous brain presence of both ibogaine and noribogaine at concentrations that do not produce the same outcome individually, suggesting additive or synergistic interactions or an unidentified active metabolite. A single equivalent dose of the SSRI fluoxetine did not reproduce these effects, indicating potential mechanistic differences between the iboga alkaloids and classical SSRIs. The authors view these findings as a first preclinical step toward understanding ibogaine’s antidepressant potential and its possible contribution to anti‑addictive properties, and they propose further behavioural and neurochemical studies to clarify mechanisms.