Magnesium-ibogaine therapy effects on cortical oscillations and neural complexity in veterans with traumatic brain injury

Traumatic brain injury (TBI) commonly produces persistent psychiatric and cognitive problems such as post-traumatic stress disorder (PTSD), depression, anxiety and executive dysfunction, and these sequelae have been linked to alterations in cortical oscillations and measures of neural complexity. Previous clinical observations reported improvements in function and symptoms after a single ibogaine treatment in veterans with TBI, but the effects of ibogaine on human cortical rhythms and spatiotemporal complexity have not been quantified. Animal work and studies of other psychedelics suggest that psychedelics can modulate oscillatory power and neural complexity, yet ibogaine differs pharmacologically and phenomenologically from classic hallucinogens, motivating direct human electrophysiological investigation. Lissemore and colleagues set out to characterise the post-acute and 1-month effects of magnesium‑ibogaine therapy on resting-state EEG measures in combat veterans with TBI, and to relate those neurophysiological changes to psychiatric and cognitive outcomes. The study hypothesised that (1) band-limited oscillatory power (delta to gamma) and Lempel–Ziv complexity would change after treatment, (2) treatment-evoked changes in rhythms would correlate with symptom improvement, and (3) pretreatment EEG markers would predict individual clinical responses.

This was a prospective, single-arm, open-label observational study of magnesium‑co‑administered ibogaine carried out in Special Operations Forces veterans with a history of TBI (the MISTIC protocol). Thirty participants completed pre- and post-treatment assessments (mean age 44.9 ± 7.5 years). Most TBIs were classified as mild (n = 28), with one moderate and one moderately severe; the reported mean number of prior TBIs was 38.6 ± 52.4. Psychiatric comorbidities at entry included PTSD (n = 23), major depression (n = 15) and anxiety disorders (n = 14). Participants discontinued medications with potential drug–drug interactions before dosing. Treatment consisted of oral ibogaine (mean total dose 12.1 ± 1.2 mg kg-1) with intravenous magnesium sulfate for cardioprotection; monitoring and preparatory coaching were provided but no psychotherapy during dosing. Resting-state eyes-open EEG was recorded ~2–3 days before dosing (baseline, n = 30), 3.5 days after dosing (post, n = 30) and 1 month after dosing (follow-up, n = 27), using 64 channels, Cz reference, and 6 minutes of recording per session (two 3-minute segments). Preprocessing included downsampling, filtering (1–50 Hz), semi-automated bad-channel rejection, epoching into 2-second segments, independent component analysis (Infomax) for artifact removal, interpolation and average re-referencing; an experienced rater blind to visit number inspected quality. A subset of participants had individual T1 MRI scans for EEG–MRI coregistration; two used a template. Primary EEG measures were normalised band power in canonical bands (delta 1–4 Hz, theta 4–8 Hz, alpha 8–13 Hz, beta 13–30 Hz, gamma 30–50 Hz) computed with Welch’s method, theta/beta ratio, peak alpha frequency (PAF), and Lempel–Ziv complexity (LZc for spatiotemporal complexity, LZs for temporal complexity). Two priori ROIs were used (medial frontal and medial posterior). The FOOOF algorithm characterised aperiodic spectral components (offset and exponent), and analyses were repeated after removing the aperiodic component. Source localisation used minimum norm estimates. Primary statistical analyses employed linear mixed-effects models with time point as a fixed effect and participant as a random effect, controlling for age, combat exposure and number of TBIs; FDR correction was applied across bands and ROIs. Post hoc Dunnett’s tests, cluster-based permutation tests (5,000 permutations) and FDR-corrected Spearman correlations with clinical and cognitive outcomes were reported. Sensitivity analyses examined preprocessing choices, exclusion criteria, and potential placebo effects using an age-matched EMBARC placebo dataset.

Sample and recordings: Thirty male SOVs completed baseline and 3.5-day EEG; 27 completed 1-month follow-up EEG. No clear relationship was found between total ibogaine dose or time since dosing and EEG changes. Most ROI EEG measures showed high within-session test–retest reliability. Band-limited power and theta/beta ratio: Linear mixed models indicated significant post-treatment increases in slower rhythms and decreases in faster rhythms. Theta power increased in both ROIs (posterior: F 2,52 = 4.11, P FDR = 0.033; frontal: F 2,52 = 5.78, P FDR = 0.027), with post hoc Dunnett’s tests showing significant increases post‑ibogaine (posterior theta: P = 0.014, Cohen’s d = 0.47; frontal theta: P = 0.0041, Cohen’s d = 0.61). Posterior alpha power also increased (F 2,54 = 4.08, P FDR = 0.033; posterior alpha post: P = 0.021, Cohen’s d = 0.45). Frontal beta power decreased significantly post-treatment (F 2,54 = 9.82, P FDR = 0.0023; post-ibogaine P = 0.0001, Cohen’s d = 0.73). Gamma power decreased in both ROIs (posterior: F 2,55 = 4.16, P FDR = 0.033; frontal: F 2,55 = 4.05, P FDR = 0.033), with post-ibogaine decreases (posterior: P = 0.025, d = 0.70; frontal: P = 0.016, d = 0.50). Cluster-based permutation tests at the sensor level corroborated widespread theta increases and posterior alpha increases post-treatment (theta cluster P = 0.0004; alpha cluster P = 0.023), and showed reductions in beta (P = 0.002) and gamma (clusters P = 0.001 and P = 0.035) power post‑ibogaine. Temporal persistence: Many effects were strongest at 3.5 days and did not uniformly persist at 1 month. PAF slowing and reduced LZc did persist at 1 month. Specifically, global PAF was lowered (F 2,47 = 7.38, P FDR = 0.0024) with large post-ibogaine effect (P = 0.00090, Cohen’s d = 1.05) and a smaller but significant effect at 1 month (P = 0.036, d = 0.41); posterior PAF reductions were significant both post-treatment and at 1 month. Gamma reductions persisted in the posterior ROI at 1 month (p = 0.039, Cohen’s d = 0.37), whereas some theta and alpha effects did not remain significant at 1 month by ROI-level tests, though cluster analyses on flattened spectra found some enduring theta/alpha increases at 1 month. Neural complexity and aperiodic components: Global spatiotemporal Lempel–Ziv complexity (LZc) decreased after ibogaine (F 2,55 = 4.14, P = 0.021), significant both post-ibogaine (P = 0.023, d = 0.55) and at 1 month (P = 0.044, d = 0.41). Temporal-only complexity (LZs) was modulated but did not survive phase-randomized normalisation. The aperiodic exponent (1/f slope) increased post‑ibogaine in both ROIs (frontal: F 2,55 = 3.93, P = 0.025; posterior: F 2,55 = 4.25, P = 0.019), indicating a steeper 1/f slope; offsets were unchanged. Removing the aperiodic component preserved many theta and alpha increases but attenuated some beta/gamma decreases. Correlations with clinical and cognitive outcomes: Increased theta/beta ratio post‑ibogaine correlated with improved cognitive inhibition (Stroop) in both frontal (rho = 0.54, P FDR = 0.0026) and posterior (rho = 0.59, P FDR = 0.0015) ROIs. Changes in other EEG metrics (power, PAF, LZc, aperiodic measures) did not correlate significantly with cognitive outcomes after FDR correction, though posterior theta increase and posterior beta decrease showed moderate uncorrected correlations with improved inhibition (theta rho = 0.50, P uncorrected = 0.0052). Lowered posterior PAF after treatment correlated with greater percentage improvement in PTSD symptoms at 1 month (CAPS‑5 rho = 0.54, P FDR = 0.011) and with reductions in arousal/reactivity subscale scores (rho = 0.53, P = 0.0050). The posterior aperiodic exponent change also correlated with percentage PTSD reduction at 1 month (rho = 0.53, P FDR = 0.015). Pretreatment predictors: Lower baseline PAF and lower baseline LZc were associated with greater improvement in cognitive inhibition after treatment (global PAF rho = -0.54, P FDR = 0.0045; posterior PAF rho = -0.63, P FDR = 0.0012; LZc rho = -0.51, P = 0.0038). Baseline spectral patterns (lower alpha, higher delta/gamma or higher beta/gamma depending on ROI) were associated with greater 1-month PTSD and anxiety improvement after FDR correction. Channel- and source-level results localised many changes to frontal, parietal and temporal regions, including default mode network hubs such as precuneus and superior frontal cortex. Robustness and controls: Sensitivity analyses (preprocessing choices, excluding participants without MRI coregistration, excluding moderate/moderately severe TBI cases, controlling for alcohol use) did not materially alter primary findings. An age-matched placebo subset from the EMBARC dataset did not show the theta, beta or gamma changes observed here, though placebo produced an increase in left parietal alpha power.

Lissemore and colleagues interpret the post‑acute pattern—enhanced theta/alpha power, reduced beta/gamma power, increased theta/beta ratio, slowed peak alpha frequency and reduced global spatiotemporal complexity—as evidence of an overall slowing of spontaneous cortical oscillations and a shift toward more stable spatiotemporal brain activity after magnesium‑ibogaine therapy. The authors note that the posterior PAF slowing and LZc reductions persisted at 1 month, whereas many band-power effects were strongest at 3.5 days. They highlight that the spatial distribution of changes included frontal and temporal cortices, regions commonly affected by TBI and overlapping hubs of the default mode network. The investigators relate increased theta/beta ratio to improved executive function, pointing out prior evidence linking frontal theta to cognitive control, and they propose that theta enhancement after ibogaine could reflect a brain state more amenable to neuroplastic change. The authors situate the reduced complexity within a neural 'annealing' model in which an acute entropy increase during psychedelic administration is followed by a post‑acute reduction in baseline complexity; they also contrast the present post‑acute profile with acute effects reported for classic psychedelics (which often show broadband power reductions and increased complexity). Increased aperiodic exponent (steeper 1/f slope) is discussed as potentially indexing an excitation–inhibition shift favouring inhibition. Potential clinical implications offered by the authors include using EEG measures as objective biomarkers to guide ibogaine dosing, to select candidates most likely to respond, and to target specific therapeutic mechanisms. They stress that pretreatment PAF and LZc may have predictive utility for cognitive outcomes. At the same time, the authors acknowledge key limitations: the single-arm, open-label design precludes causal attribution and leaves room for expectation and contextual effects; the modest, homogeneous sample of male SOVs limits generalisability; non-oscillatory spectral components may have influenced some beta/gamma findings; and low variability in clinical outcomes (many participants showed >80% improvement on several scales at 1 month) constrained correlational analyses. They therefore call for randomised controlled trials, larger and more diverse samples, and further multimodal work to clarify whether the observed EEG changes represent normalising versus compensatory or plasticity-related mechanisms.

In summary, the study reports both post‑acute and persisting alterations in cortical oscillations and neural complexity after magnesium‑ibogaine therapy in veterans with TBI, and links several of these neurophysiological changes to improvements in executive function, PTSD and anxiety. The authors propose that these EEG markers could serve as candidate biomarkers for early drug effects and treatment response, with potential applications in brain-based dosing optimisation, mechanism-specific treatment refinement and patient stratification, pending validation in controlled and larger-scale studies.