Inhibitory effects of ibogaine on cocaine self-administration in rats

Ibogaine is an indole alkaloid from the root bark of Tabernanthe iboga that has traditional stimulant and hallucinogenic uses and has attracted attention for possible anti-addictive effects. Previous animal and uncontrolled human observations suggested that ibogaine can attenuate opioid withdrawal symptoms and reduce self-administration of substances such as morphine, and anecdotal reports have claimed interruption of cocaine, amphetamine, alcohol and nicotine dependence. However, controlled preclinical data on ibogaine’s effects specifically on cocaine intake were limited and partly inconsistent. Cappendijk and colleagues set out to test whether ibogaine reduces cocaine self-administration in cocaine-dependent rats. The investigators examined both single and repeated intraperitoneal (i.p.) administrations of ibogaine, using standard operant self-administration procedures, to characterise dose dependence, duration of effect and whether spaced (weekly) versus consecutive-day dosing altered the magnitude or persistence of any inhibitory effect on cocaine intake.

Male Wistar rats (200–250 g at study start) were used. Animals were group-housed prior to surgery with food and water ad libitum, then surgically implanted with chronic intravenous jugular catheters under sodium pentobarbital anaesthesia. After surgery animals were housed singly and, beginning 2 days before testing, food was restricted to produce ≈20% weight reduction to facilitate acquisition of self-administration. A reversed 12-h light/dark cycle was maintained and sessions occurred during the dark period. Self-administration took place in operant conditioning chambers. Each cocaine infusion delivered 1.2 mg/kg (0.25 ml over 20 s) contingent on a lever press; the cue light was turned off during infusions and additional lever presses during infusion were without programmed consequence. After 5–6 days postoperative recovery, rats were connected to infusion pumps via swivels to permit free movement. Sessions were 3 h daily, 5 days per week, and baseline cocaine intake was considered stable when variation was <10% across three consecutive sessions, typically achieved after 12–16 sessions. Animals were randomly allocated to vehicle or ibogaine groups. Ibogaine hydrochloride (dissolved in distilled water) or vehicle (1.0 ml/kg i.p.) was administered 30 min prior to the 3-h self-administration session. Single-dose experiments tested 10, 20 and 40 mg/kg i.p. (n = 6–7 per dose); the 80 mg/kg dose was omitted from further testing because it produced severe locomotor disturbance in preliminary work. Repetitive administration was tested in two schedules using 40 mg/kg: once on each of 3 consecutive days (n = 5) and once at the beginning of each of 3 consecutive weeks (n = 5). Cocaine hydrochloride was dissolved in saline (pH 7.30–7.35). Primary outcome measures were responses summed over the 3-h session and corresponding cocaine intake (reported as mg/kg per session). Data were analysed by two-way analysis of variance (ANOVA) with repeated measures on days; individual comparisons used Student’s t-test with significance set at P < 0.05.

Administration of ibogaine produced an acute, dose-dependent behavioural syndrome characterised by hind-leg stiffness, tremor, ataxia and hypersensitivity (jumping or violent locomotion when touched). At 40 mg/kg the behavioural effects were dose-dependent but transient, lasting up to about 30 min; the investigators omitted 80 mg/kg from further study because it caused more severe disturbances (ataxia, prolonged tremor and jumping). Baseline cocaine intake before treatment was around 5.0 ± 0.5 mg/kg per 3-h session (different baseline values are reported for subgroups: 5.3 ± 0.4 and 4.9 ± 0.5 mg/kg in the repetitive-dosing cohorts). A single injection of 40 mg/kg ibogaine produced a significant reduction in cocaine intake compared both to baseline and to vehicle-treated controls (ANOVA and t-test, P < 0.05). Lower doses (10 and 20 mg/kg) were ineffective. The inhibitory effect of a single 40 mg/kg injection became more pronounced on the day after treatment and remained below control levels for at least 48 h. When 40 mg/kg ibogaine was administered once on each of 3 consecutive days (n = 5), vehicle given similarly produced no change, while ibogaine produced a significant decrease in cocaine intake beginning on the second day of treatment. After the third consecutive-day injection the inhibitory effect persisted for the next 24 h. The investigators noted that this consecutive-day regimen produced an effect that was not significantly different in magnitude from a single injection but was shorter in duration (24 h versus 48 h). In the regimen where ibogaine (40 mg/kg) was given once at the beginning of each of 3 consecutive weeks (n = 5), vehicle again had no effect, whereas each ibogaine injection significantly decreased cocaine intake. The reduction became more sustained after the second and third weekly injections, producing a gradual and longer-lasting suppression of cocaine self-administration across weeks. Throughout, statistical significance was reported at P < 0.05 for the described decreases.

Cappendijk and colleagues conclude that ibogaine inhibits cocaine self-administration in rats, with a single 40 mg/kg i.p. dose producing a suppression of intake that can last 1–2 days. Repeated dosing once each week appeared to potentiate and prolong the inhibitory effect more than repeated consecutive-day dosing. The authors note that these findings align with prior animal data showing long-lasting interruption of opiate intake and with uncontrolled clinical observations suggesting anti-addictive effects of ibogaine. A key pharmacokinetic puzzle the investigators discuss is that ibogaine’s half-life in rodents is reported to be about 1 h and plasma levels are undetectable a day after administration, yet behavioural suppression of cocaine intake persisted beyond 24 h. They propose two non-exclusive explanations: (1) one or more active, longer-lived metabolites of ibogaine mediate the prolonged effect, or (2) ibogaine produces an irreversible or long-lasting perturbation of neural mechanisms underlying cocaine dependence. The authors consider several possible mechanistic contributions. A transient effect on locomotion (tremor, ataxia) is unlikely to account for the protracted reduction in self-administration, because those disturbances lasted only about 30 min while the anti-addictive effect lasted days. Modulation of dopaminergic neurotransmission is discussed because cocaine’s rewarding effects relate to dopamine release in nucleus accumbens; some data cited indicate that ibogaine reduced cocaine-induced dopamine release, which would be consistent with reduced reinforcement. However, contradictory findings are noted: other work reported potentiation of cocaine-induced extracellular dopamine after ibogaine, so the interaction with dopaminergic systems remains unresolved. Potential involvement of the serotonergic system is raised because 5-HT uptake inhibition reduces cocaine self-administration and ibogaine inhibits peripheral enzymic oxidation of serotonin (5-HT); whether ibogaine perturbs central 5-HT systems relevant to reward is unknown. The investigators also mention effects on central neuronal excitability: unpublished EEG data indicated a proconvulsant effect after 40 mg/kg that lasted hours, which could suppress operant behaviour acutely but does not readily explain suppression more than 48 h later. Finally, the authors reiterate that while the data show a reproducible, long-lasting reduction in cocaine intake after ibogaine, the mechanism remains to be established and may involve active metabolites or long-lasting alterations of addiction-related neural processes. They present their findings as evidence of an anti-addictive effect in this animal model without claiming a definitive mechanistic explanation.