CLINICAL AND NEURAL OUTCOMES OF MAGNESIUM-IBOGAINE FOR TRAUMATIC BRAIN INJURY IN SPECIAL OPERATIONS FORCES VETERANS

Chronic sequelae of traumatic brain injury (TBI) can include functional impairments and psychiatric syndromes such as post-traumatic stress disorder (PTSD), depression, and anxiety, and some Veterans with TBI have sought treatment with the oneirogen ibogaine. Ibogaine has been associated with fatal cardiac arrhythmias, but coadministration of magnesium may mitigate this risk. As an initial exploration of outcomes and neural mechanisms of ibogaine, we performed a prospective observational study in 30 male Veterans with a history of TBI. Clinically, we assessed changes in the WHODAS 2.0 from baseline to immediately (primary outcome) and 1 month (secondary outcome) after treatment. Additional secondary outcomes included changes in PTSD (CAPS-5), depression (MADRS) and anxiety (HAM-A). We identified significant improvements in functioning both immediately (Cohen’s d = 0.74) and 1 month (d = 2.20) after treatment and in PTSD (d = 2.54), depression (d = 2.80) and anxiety (d = 2.13) at 1 month after treatment. Next, we performed a long-term follow-up study to assess the durability of these findings. 27 of the original 30 participants completed at least one such assessment. Significant reductions in disability and PTSD, depression, and anxiety symptoms were sustained at 12 months posttreatment (d ≥ 2.18). Similar improvements were observed at 3-, 6-, and 9-month follow-ups (d ≥1.81). Kaplan-Meier survival analyses estimated the probability of sustained remission 12 months after treatment as 84% for PTSD, 66% for depression, and 61%, for anxiety. Biologically, we collected MRI scans and resting-state EEG. Post-hoc pairwise comparisons revealed an estimated marginal mean reduction of 1.3 years between predicted brain age at the baseline and 1-month visits. Regional linear mixed effect (LME) models revealed a significant main effect of study visit on cortical thickness in 13 of 62 examined regions of interest (ROIs) and 8 of 28 subcortical ROIs. Post-hoc testing revealed significant volumetric expansion between the baseline and both post-treatment visits.We also assessed the effects of ibogaine on cortical oscillations and complexity. After treatment, slower oscillations (theta– alpha) increased in power, and power at higher frequencies (beta–gamma) decreased. Accordingly, the theta/beta ratio increased post-treatment, which correlated with improved cognitive inhibition, and peak alpha frequency and neural complexity also were lower. These neurophysiological markers correlated with improved executive function, PTSD, and anxiety. Finally, we assessed the level of mystical experience during the treatment using the MEQ-30. Using LME models, we observed that higher MEQ-30 scores were associated with significantly greater reductions in both the CAPS-5 score and peak alpha frequency. Themes from the narrative accounts portrayed an accelerated, self-directed psychotherapeutic process. Altogether, these findings suggest that magnesium-ibogaine treatment may provide durable symptomatic improvements in veterans with TBI-related sequelae. Potential mechanisms of these improvements include sustained neuroplastic changes in brain morphometry, reduced spatiotemporal complexity of brain activity, ‘slowing’ of cortical oscillations in the brain at rest, and a mystical self-directed psychotherapeutic experience. Randomized controlled trials with long-term follow-up are needed to validate these initial results.

References

Cherian KN, Keynan JN, Anker L, et al. Magnesium-ibogaine therapy in veterans with traumatic brain injuries. Nature Medicine. 2024;30(2):373-381. Lissemore JI, Chaiken A, Cherian KN, et al. Magnesium-ibogaine therapy effects on cortical oscillations and neural complexity in veterans with traumatic brain injury. Nature Mental Health. 2025;3:918–931.