Magnesium-ibogaine therapy in veterans with traumatic brain injuries

Abstract

Traumatic brain injury (TBI) is a leading cause of disability. Sequelae can include functional impairments and psychiatric syndromes such as post-traumatic stress disorder (PTSD), depression and anxiety. Special Operations Forces (SOF) veterans (SOVs) may be at an elevated risk for these complications, leading some to seek underexplored treatment alternatives such as the oneirogen ibogaine, a plant-derived compound known to interact with multiple neurotransmitter systems that has been studied primarily as a treatment for substance use disorders. Ibogaine has been associated with instances of fatal cardiac arrhythmia, but coadministration of magnesium may mitigate this concern. In the present study, we report a prospective observational study of the Magnesium-Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), provided together with complementary treatment modalities, in 30 male SOVs with predominantly mild TBI. We assessed changes in the World Health Organization Disability Assessment Schedule from baseline to immediately (primary outcome) and 1 month (secondary outcome) after treatment. Additional secondary outcomes included changes in PTSD (Clinician-Administered PTSD Scale for DSM-5), depression (Montgomery-Åsberg Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale). MISTIC resulted in significant improvements in functioning both immediately (P_corrected < 0.001, Cohen's d = 0.74) and 1 month (P_corrected < 0.001, d = 2.20) after treatment and in PTSD (P_corrected < 0.001, d = 2.54), depression (P_corrected < 0.001, d = 2.80) and anxiety (P_corrected < 0.001, d = 2.13) at 1 month after treatment. There were no unexpected or serious adverse events. Controlled clinical trials to assess safety and efficacy are needed to validate these initial open-label findings. ClinicalTrials.gov registration: NCT04313712 .

Fig. 1. CONSORT diagram.

Participant numbers at screening, enrollment and throughout progression of the study.

Fig. 2. Primary, secondary and exploratory outcomes.

a–d, Baseline and follow-up results in WHODAS-2.0 total (a), CAPS-5 (b), MADRS (c) and HAM-A (d). Individual colored lines represent individual participants. The dashed black line represents the mean. LME models were used for each comparison with FDR correction applied for determination of significance. ^***P_FDR < 0.001.

Fig. 3. NPT.

a–e, Baseline and follow-up results in percentile relative to age-matched peers in sustained attention (lower scores for detection represent improvement) (a), learning and memory (b), processing speed (c), executive function (d) and language (e). The y axis represents the percentile and the x axis the mean; the middle line represents the median, the whisker lines the interquartile range (IQR) and single dots participants with a score >±1.5 IQR. LME models were used for each comparison with FDR correction applied for determination of significance. ^*P_FDR < 0.05; ^**P_FDR < 0.01; ^***P_FDR < 0.001. See Table 3 for P values and for the specific test item(s) included in each construct. The n for each construct at baseline, post-MISTIC and 1-month time points, respectively: detection, reaction time and sustained attention: 24, 28, and 20; verbal memory and working memory: 29, 30 and 27; visuospatial memory, processing speed, cognitive inhibition, cognitive flexibility composite, phonemic fluency and semantic fluency: 30, 30 and 27; problem-solving: 27, 30 and 27.