Effects of low dose ibogaine on subjective mood state and psychological performance

Forsyth and colleagues place ibogaine in its ethnobotanical and pharmacological context, noting it is an indole alkaloid from Tabernanthe iboga root bark used sacramentally in West African traditions. Earlier reports describe dose-dependent effects ranging from stimulant-like vigilance enhancement at low doses to hallucinogenic effects at much higher doses, and there are anecdotal and case-series reports of ibogaine ameliorating opioid withdrawal. Despite extensive descriptive work on high-dose effects, the authors identify a clear gap: there are very few controlled data on psychological responses to low doses of ibogaine, which are of clinical interest because of recent cardiac safety findings and because low-dose use is reported anecdotally to be stimulant-like. This substudy therefore aimed to evaluate whether single low doses of ibogaine influence subjective mood state and a range of cognitive functions, and specifically to examine the relationship between combined blood concentrations of ibogaine plus its active metabolite noribogaine (termed AM, the active moiety) and changes in psychometric test scores. The investigation builds on prior pharmacokinetic work by the group that demonstrated paroxetine-mediated inhibition of CYP2D6 raises AM exposure after a 20 mg ibogaine dose; here the investigators report the psychological data collected around that pharmacokinetic study.

The study enrolled 21 healthy, drug- and medication-free male volunteers aged 20–40 years (mean 23.5 years). Participants underwent medical screening and provided informed consent; the protocol had ethical approval and trial registration. Subjects were randomised, using a computer-generated code, to receive double-blind capsules of paroxetine or matched placebo from Days 2–15: 10 mg on Days 2–3 and 20 mg on Days 4–15. Paroxetine was used to inhibit CYP2D6 and thereby increase exposure to noribogaine following ibogaine dosing. On Day 8, after an overnight fast, all subjects received a single oral 20 mg dose of ibogaine; blood samples were taken pre-dose and at multiple post-dose times (text truncated in the extraction) to determine AM concentrations. Psychological assessment occurred at two time points: baseline (T3) and approximately 2 hours post-ibogaine when AM concentrations were expected to peak (T4). The battery took about 20 minutes and started with six self-rated mood scales (happy, sad, calm, tense, energetic, sleepy) scored 0–100. Eight computerised cognitive tests followed: Pro (simple visuomotor reaction), Anti (inhibitory control), Pro/Anti (switching), Simon (ability to ignore irrelevant spatial information; congruent and incongruent conditions), Flanker (ability to ignore identity-based distractors; congruent and incongruent), Forward Spatial and Backward Spatial (short-term memory capacity and manipulation, Corsi-like tasks), and a 2-back working memory task. These tasks were selected because they have shown sensitivity to opioid and serotonergic agents in prior work. For analysis the primary explanatory variable was the increase in AM from T3 to T4 (because AM was zero at T3 for all subjects, this equated to AM at T4). The response variables were the change scores for each psychological test (T4 minus T3); for reaction time variables, positive change indicated slower performance. Linear and quadratic polynomial regression models were fitted to each response variable using R. Model assumptions were validated with the gvlma package, and up to three outlying observations per response variable were removed when identified. Slope t-statistics were adjusted for multiple testing using the Holm method. The study analysed relationships between AM exposure and changes in mood and cognitive performance rather than testing a placebo-controlled drug effect per se.

At the approximately 2-hour post-dose assessment (T4) all subjects had detectable AM and none had detectable AM at baseline (T3). Mean (SD) AM concentrations at T4 were 49.9 (17.5) nM in the placebo pretreatment group and 121.0 (40.4) nM in the paroxetine pretreatment group, reflecting the intended CYP2D6 inhibition effect of paroxetine. Across the psychological outcome measures most response variables showed a broadly linear relationship with AM, with quadratic terms rarely providing substantial improvement. After adjustment for multiple comparisons, the only statistically significant association was between Increase in AM and Change in Simon Congruent Median reaction time (RT). The linear slope estimate was 0.56 (SE 0.13), with an adjusted p-value of 0.016, indicating that for every 1 unit increase in AM the mean change in Simon Congruent Median RT increased by 0.56 (the unit of AM is nM and RT units derive from the task measurement). The pattern observed was that subjects with lower AM concentrations (<89 nM) tended to show negative change scores (faster RTs at T4 than T3), whereas those with higher AM concentrations (>89 nM) showed positive change scores (slower RTs at T4 than T3). No other cognitive or mood outcome exhibited a significant association with AM after multiple testing correction. In particular there was no evidence of AM-related changes in subjective mood ratings (happy, energetic, sleepy, calm, sad, tense), basic visuomotor performance (Pro), inhibitory control (Anti), switching (Pro/Anti), Simon Incongruent RT, Flanker measures of identity-based distractor processing, Forward or Backward Spatial memory scores, or 2-back working memory performance. The authors note that some models required removal of outliers (up to three subjects per response variable) and that several response variables showed only weak quadratic effects where model fit improved slightly.

Forsyth and colleagues interpret the findings as showing no substantive effect of a single 20 mg dose of ibogaine, as indexed by combined ibogaine and noribogaine concentrations, on subjective mood state or on a wide range of cognitive functions at the time when AM concentrations were highest. The investigators did not observe evidence supporting anecdotal stimulant-like effects of low-dose ibogaine: mood self-ratings for energetic, happy or sleepy did not change, and cognitive tasks sensitive to various neurotransmitter systems were largely unaffected. The only positive association—between AM and Simon Congruent RT—was treated cautiously. The authors emphasise that this result was limited to the congruent (less challenging) condition of the Simon task and did not extend to the incongruent Simon condition or to the Flanker task, which also probes selective attention. Consequently, they question the reliability and functional significance of the isolated finding. Pharmacologically, the investigators note that ibogaine and noribogaine have complex interactions with serotonergic, glutamatergic, opioid and cholinergic systems, making a priori predictions difficult. Several limitations acknowledged by the authors temper the conclusions. The study administered only a single low dose and assessed psychological outcomes at one post-dose timepoint, so dose–response and time course effects remain untested. There was no placebo-controlled arm for the ibogaine administration itself (all subjects received ibogaine), and the sample was small, reducing statistical power and making assessment of model assumptions harder. The authors also suggest that unmodelled lifestyle factors (for example physical activity) might confound weak associations and recommend that future studies incorporate additional covariates, a wider dose range, multiple post-dose assessments and ideally a placebo arm. Overall, the study concludes that a single 20 mg ibogaine dose produced no detectable stimulant or broadly deleterious effects on the tests administered, but that the selective attention finding requires replication before any firm inferences can be drawn.