Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile

Ibogaine is an indole alkaloid extracted from Tabernanthe iboga and has drawn attention for reported anti-addictive effects in animals and humans. Earlier preclinical work shows ibogaine reduces self-administration of opioids, cocaine, alcohol and nicotine, and anecdotal and observational human reports describe vivid, dream-like cognitive episodes during wakefulness (oneirogenic effects). Despite this interest, the effects of ibogaine on vigilance states and sleep architecture have been little studied; a few older animal studies reported EEG activation and changes in wakefulness (W), slow wave sleep (SWS) and rapid-eye-movement (REM) sleep, but findings are incomplete and mechanistic interpretations remain uncertain. Baumann and colleagues aimed to characterise the acute effects of intraperitoneal ibogaine on wakefulness, sleep stages and motor behaviour in rats. Specifically, the study tested two doses used in addiction models (20 and 40 mg/kg), using polysomnographic recordings across a 6 h light-period session to quantify W, light sleep, SWS and REM, and a separate open-field assay with video tracking and behavioural scoring to profile locomotion and serotonin-related behaviours during 2 h after administration. The goal was to determine dose-dependent effects on sleep architecture and to describe any distinctive motor/serotonin-like behaviours associated with the induced waking state.

Baumann and colleagues used adult Wistar rats maintained on a 12 h light/dark cycle. Twenty-six animals were used in total: eight rats underwent chronic electrode implantation for polysomnography and 18 naive rats were used for open-field motor testing. Ibogaine hydrochloride was prepared from root-bark alkaloid extract and characterised; the final i.p. formulations were dissolved in warm, degassed saline. Two doses were tested: 20 mg/kg (I20) and 40 mg/kg (I40), each compared with saline vehicle. For sleep experiments, eight rats were surgically implanted with skull EEG electrodes (frontal, parietal, occipital, olfactory bulb) and neck EMG electrodes under ketamine–xylazine anaesthesia. After recovery and habituation, polysomnographic recordings were conducted in individual cages in a sound-attenuated, temperature-controlled chamber during the light period (10:00–16:00). States were scored in 10 s epochs using standard EEG/EMG criteria: wakefulness, light sleep, SWS and REM sleep. Each animal received vehicle, I20 and I40 on separate days in a counterbalanced within-subject design with 3-day wash-out. Total time in each state, episode number and duration, and latencies were analysed over 6 h and in 2 h blocks. Motor behaviour was assessed in 18 naive rats (n = 6 per treatment) in a 45 × 45 cm open-field under low indirect lighting. Video-tracking (Ethovision XT) recorded total distance travelled in 5 min bins for 120 min starting immediately after i.p. dosing. A trained observer scored rearing and serotonin syndrome-like behaviours every 30 min for 5 min sessions, using graded scales for continuous signs (tremor, flat body posture, piloerection, hind limb abduction, Straub tail) and additive counts for intermittent behaviours (forepaw treading). Head shake response (HSR) was also counted. Statistical analysis used repeated-measures one-way ANOVA for sleep data (with Greenhouse-Geisser correction when needed) and two-way repeated-measures ANOVA for motor time courses; post hoc tests included Bonferroni or Newman–Keuls. Significance was set at p < 0.05.

Acute intraperitoneal ibogaine altered vigilance states in a dose- and time-dependent manner. Compared with saline, both I20 and I40 increased total time spent awake and reduced total SWS and REM sleep across the 6 h recording. The wakefulness and SWS effects were most prominent during the first 2 h after dosing, whereas the reduction in REM sleep persisted throughout the 6 h session. REM sleep latency was significantly increased after I40 [F(2,14) = 9.6, p < 0.05]. Quantitatively, the duration of individual wake episodes increased after I20 [F(1.1,7.9) = 6.4, p < 0.05], while the duration of SWS episodes decreased following I40 [F(2,14) = 9.5, p < 0.005]. Both doses reduced the total number of REM episodes [F(1.2,8.5) = 10.5; p < 0.05] without altering REM episode duration. Open-field testing revealed a dose-dependent and time-dependent motor profile. Two-way ANOVA of locomotion showed significant effects of treatment [F(2,15) = 8.7, p < 0.01], time [F = 12.2, p < 0.001], and treatment × time interaction [F(46,345) = 1.43, p < 0.05]. I40 produced an early decrease in distance moved during the first 5 min relative to control and I20 (p < 0.001), whereas I20 produced an overall increase in total locomotor activity relative to control (one-way ANOVA F(2,15) = 8.7, p < 0.01; I20 vs control p < 0.01; I20 vs I40 p < 0.05). Rearing (vertical exploration) was suppressed early after I40 (treatment effect F(2,15) = 4.0, p < 0.05; time F(4,60) = 14.6, p < 0.001), suggesting altered habituation to novelty; total rearing did not differ significantly across groups (F(2,15) = 3.4, p = 0.06). Serotonin syndrome-like continuous signs differed by dose. Tremor and flat body posture were significantly increased after I40 (tremor F(2,15) = 35.9, p < 0.0001; flat body posture F(2,15) = 9.3, p < 0.01) and were most prominent immediately after injection but absent by 60 min. Forepaw treading and piloerection were not significantly affected (forepaw treading F(2,15) = 1.2, p = 0.3; piloerection F(2,15) = 1.2, p = 0.1). Straub tail and hind limb abduction were not observed. Head shake response, a behaviour linked to 5-HT2A agonists, was not changed by either dose (HSR F(2,15) = 1.1, p = 0.36). The sleep experiments used eight animals and the motor experiments 18 animals (n = 6 per treatment group).

Baumann and colleagues interpret their findings as showing that acute ibogaine administration promotes wakefulness while producing a robust, long-lasting suppression of REM sleep. The temporal pattern suggests that the early increase in wakefulness and reduction in SWS occur mainly in the first 2 h after dosing, whereas REM suppression endures across the 6 h recording. The authors note that this profile resembles some reports from humans of sleep disturbance after ibogaine and is broadly consistent with earlier animal studies reporting EEG activation and increased wake. Pharmacokinetic considerations underlie the authors' interpretation: ibogaine is rapidly metabolised to noribogaine, which peaks later and persists longer. The authors suggest that early effects (including tremor seen after I40) are compatible with parent ibogaine exposure and that enduring REM suppression could relate to noribogaine. Mechanistically, the investigators highlight serotonergic effects as a plausible contributor: in vitro and in vivo data indicate that ibogaine and noribogaine inhibit serotonin reuptake and raise extracellular serotonin, and serotonin is known to promote wakefulness and suppress REM sleep. Cholinergic activation has also been implicated in older studies (atropine blocked ibogaine-induced EEG activation in cats), and the authors acknowledge that interactions with multiple neurotransmitter systems (including possible sigma or NMDA receptor effects) complicate mechanistic assignment. The lack of a head shake response distinguishes ibogaine from classical 5-HT2A agonist psychedelics, and the authors emphasise pharmacological differences: classical hallucinogens bind 5-HT2A in the nanomolar range, whereas ibogaine's affinity is weak or negligible. Behaviourally, lower ibogaine doses produced a stimulant-like increase in locomotion while the higher dose produced impaired habituation, tremor and flat body posture, consistent with dose-dependent qualitative differences in the waking state. The authors acknowledge limits to causal inference: the drug's complex pharmacology and the presence of an active metabolite complicate interpretation, and they highlight the need for further quantitative EEG analyses to test whether the ibogaine-induced waking state carries REM-like electrophysiological features that could explain the oneirogenic reports. They also note that no behaviours suggesting pain or irritation were observed and reference evidence that ibogaine may be anti-nociceptive. Overall, the investigators call for additional experiments to disentangle parent drug versus metabolite effects and to examine cortical EEG signatures of the pharmacologically induced wakefulness.

The study found that intraperitoneal ibogaine at 20 and 40 mg/kg increases wakefulness, reduces SWS and produces a pronounced suppression of REM sleep in rats. Motor outcomes differed by dose: I20 produced a stimulant-like increase in locomotion, while I40 produced impaired habituation to novelty and transient serotonin-like signs (tremor, flat body posture). The authors propose that future work should characterise the EEG features of the induced wakefulness (power spectra and coherence) and disentangle the contributions of ibogaine and its metabolite noribogaine to the observed sleep and behavioural effects.