Ibogaine is a naturally occurring substance which has been increasingly used in the lay-scene to reduce craving and relapse in patients with substance use disorders (SUDs). Although human clinical trials on the safety and efficacy of ibogaine are lacking, animal studies do support the efficacy of ibogaine. In this systematic review and meta-analysis (MA), we summarise these animal findings, addressing three questions: (1) does ibogaine reduce addictive behaviour in animal models of SUDs?; (2) what are the toxic effects of ibogaine on motor functioning, cerebellum and heart rhythm?; (3) what are neuropharmacological working mechanisms of ibogaine treatment in animal models of SUDs? MA of 27 studies showed that ibogaine reduced drug self-administration, particularly during the first 24 h after administration. Ibogaine had no effect on drug-induced conditioned place preference. Ibogaine administration resulted in motor impairment in the first 24 h after supplementation, and cerebral cell loss even weeks after administration. Data on ibogaines effect on cardiac rhythm, as well as on its neuropharmacological working mechanisms are limited. Our results warrant further studies into the clinical efficacy of ibogaine in SUD patients in reducing craving and substance use, but close monitoring of the patients is recommended because of the possible toxic effects. In addition, more work is needed to unravel the neuropharmacological working mechanisms of ibogaine and to investigate its effects on heart rhythm.

Background and aims: Ibogaine is an indole alkaloid used in rituals of the African Bwiti tribe. It is also used in non‐medical settings to treat addiction. However, ibogaine has been linked to several deaths, mainly due to cardiac events called torsades des pointes preceded by QTc prolongation as well as other safety concerns. This study aimed to evaluate the cardiac, cerebellar and psychomimetic safety of ibogaine in patients with opioid use disorder.Design: A descriptive open‐label observational study.Setting: Department of psychiatry in a university medical center, the Netherlands.Participants: Patients with opioid use disorder (n = 14) on opioid maintenance treatment with a lasting wish for abstinence, who failed to reach abstinence with standard care.Intervention and measurements: After conversion to morphine‐sulphate, a single dose of ibogaine‐HCl 10 mg/kg was administered and patients were monitored at regular intervals for at least 24 hours assessing QTc, blood pressure and heart rate, scale for the assessment and rating of ataxia (SARA) to assess cerebellar side effects and the delirium observation scale (DOS) to assess psychomimetic effects.Findings: The maximum QTc (Fridericia) prolongation was on average 95ms (range 29‐146ms). Fifty percent of subjects reached a QTc of over 500ms during the observation period. In six out 14 subjects prolongation above 450ms lasted beyond 24 hours after ingestion of ibogaine. No torsades des pointes were observed. Severe transient ataxia with inability to walk without support was seen in all patients. Withdrawal and psychomimetic effects were mostly well‐tolerated and manageable (11/14 did not return to morphine within 24 hours, DOS scores remained below threshold).Conclusions: This open‐label observational study found that ibogaine treatment of patients with opioid use disorder can induce a clinically relevant but reversible QTc prolongation, bradycardia, and severe ataxia.

(1) Background: Current evidence-based treatments for alcohol use disorder (AUD) are moderately effective. Studies testing repetitive transcranial magnetic stimulation (rTMS) in AUD commonly apply a limited number of rTMS sessions with different rTMS settings, showing inconsistent effects on craving for alcohol. This study tested the efficacy of a robust rTMS protocol on craving and alcohol use. (2) Methods: In a single-blind randomized controlled trial in recently detoxified patients with AUD, ten days of high-frequency rTMS over the right dorsolateral prefrontal cortex on top of treatment as usual (n = 14) was compared with sham rTMS (n = 16). Outcome measures were alcohol craving and use over a follow-up period of one year. Analysis was performed by means of repeated measures multivariate analysis of variance. (3) Results: The results showed a main group-by-time interaction effect on craving (Wilks’ Λ = 0.348, F (12, 17) = 2.654, p = 0.032) and an effect of group on alcohol use (Wilk’s Λ = 0.44, F (6, 23) = 4.9, p = 0.002), with lower alcohol craving and use in the group with active rTMS compared to the control group. Differences in craving between groups were most prominent three months after treatment. At 12 months follow-up, there was no effect of rTMS on craving or abstinence. (4) Conclusions: This small-scale randomized controlled trial showed the efficacy of high-frequency rTMS over the right dlPFC diminished alcohol craving and use in recently detoxified patients with AUD during the first months after detoxification. These findings suggest that rTMS might be an effective add-on in treating patients with AUD and warrant replication in future large-scale studies.

Post-traumatic stress disorder (PTSD) is a debilitating condition that affects millions of veterans. A recent observational study in 30 veterans showed that a single dose of the atypical psychedelic ibogaine can be highly effective at treating PTSD up to twelve months later. Although a prior study demonstrated that ibogaine transiently alters electroencephalography (EEG) power in various frequency bands, the long-term, network-level neural mechanisms targeted by ibogaine are unclear. Here, we investigated whether ibogaine-related clinical improvements are associated with the reorganization of certain brain networks. We applied a novel framework, FREQuency-resolved brain Network Estimation via Source Separation (FREQ-NESS), to identify frequency-specific brain networks in resting-state EEG data acquired at baseline, three to four days after treatment (immediate-post), and one month after ibogaine. At both the immediate-post and one month-post timepoints, high-beta (24 and 25 Hz) networks shifted away from frontal areas and towards posterior regions, an effect that was replicated in an independent EEG dataset on ibogaine treatment for opioid use disorder. This posterior shift was significantly correlated with improvements in PTSD symptoms at both timepoints. Neural field modeling demonstrated that these posterior high-beta shifts are associated with increases in corticocortical, but not corticothalamic, connectivity. Our results are consistent with prior evidence implicating aberrant frontal beta-band activity in PTSD. Overall, we demonstrate that the reconfiguration of high-beta brain networks could be a robust biomarker for ibogaine’s therapeutic effects.

Repetitive transcranial magnetic stimulation (rTMS) presents a promising approach for treating patients with alcohol use disorder (AUD). However, its neuropsychological working mechanisms are to be elucidated. Therefore, we investigated the effect of rTMS treatment on event‐related potentials (ERPs) evoked by a flanker task and a passive picture task using electro‐encephalography, in 30 recently detoxified patients. Participants were randomly assigned to receive either 10 sessions of rTMS or sham rTMS. Measurements were made at baseline, and after 5 and 10 treatments. The results revealed no significant effect of rTMS on any of the assessed ERPs (N100, N200, and P300). These findings suggest that high‐frequency rTMS applied over the right dlPFC, in addition to treatment as usual (TAU), does not impact performance monitoring or attentional bias in recently detoxified patients with AUD. Bayesian analyses did suggest a potential effect of rTMS on N100 amplitude at frontal electrode FZ. These preliminary findings warrant further study of the effects of rTMS on ERP outcomes in AUD patients, and exploration of ERPs related to performance monitoring and attentional bias as potential neuropsychological markers for the clinical effects of rTMS. However, other neuropsychological markers, like brain network connectivity, should also be explored. Clinical Trial Registration: Registered in a trial Register ( ClinicalTrials.gov Identifier: NCT01973127)f.