Stanford MISTIC
Magnesium-Ibogaine: the Stanford Traumatic Injury to the CNS Protocol
Comprehensive Deep-Dive Report: Study Design, Clinical Results, Neurophysiology & Policy Impact
February 2026 | ClinicalTrials.gov: NCT04313712
1. Background & Unmet Medical Need
1.1 Traumatic Brain Injury in Special Operations Veterans
Traumatic brain injury (TBI) is among the most prevalent and disabling injuries sustained by military personnel, particularly Special Operations Forces (SOF). Hundreds of thousands of troops who served in Afghanistan and Iraq experienced TBI through blast exposures, vehicle collisions, and other combat-related impacts. Unlike civilian TBI, combat-related TBI frequently involves repeated blast exposures rather than a single discrete event, and is almost universally accompanied by a dense cluster of psychiatric sequelae.
The long-term consequences of combat TBI include a constellation of functional impairment, post-traumatic stress disorder (PTSD), depression, anxiety, cognitive deficits, chronic pain, endocrine disruption, and elevated suicide risk. SOF veterans — Navy SEALs, Army Special Forces, Rangers, and similar elite units — are disproportionately affected because of their higher deployment frequency and greater cumulative blast exposure. Studies suggest that SOF veterans with combat-related TBI face substantially elevated rates of suicidality compared to the general veteran population.
• TBI is a leading cause of injury-related disability globally and is expected to remain so through at least 2030
• No FDA-approved treatments exist for the chronic sequelae of combat-related TBI
• Current standard of care — cognitive rehabilitation, psychotherapy, and symptom-targeting medications — shows limited efficacy for many veterans
• Average time since military discharge in the MISTIC cohort was approximately 8 years, indicating that these were treatment-resistant, chronic cases — not acute presentations
1.2 Why Veterans Were Seeking Ibogaine
In the absence of effective conventional options, a significant number of special operations veterans began independently seeking out ibogaine treatment — a Schedule I substance in the United States — at clinics in Mexico and other countries where it is legal. This self-treatment trend preceded any formal scientific validation of ibogaine for TBI, driven largely by word-of-mouth reports of dramatic improvement within the veteran community.
This grassroots phenomenon created both a clinical opportunity and an ethical imperative for researchers: veterans were already receiving ibogaine, often without medical monitoring. The Stanford team, in collaboration with Veterans Exploring Treatment Solutions (VETS, Inc.) — a non-profit that helps fund psychedelic-assisted therapies for veterans — saw an opportunity to rigorously study this self-selecting population before, during, and after treatment, providing the first prospective scientific data on ibogaine in this context.
1.3 The Ibogaine Problem: Why It Hasn't Been Developed Sooner
Ibogaine is a naturally occurring indole alkaloid derived from the root bark of the Tabernanthe iboga shrub, a plant native to Central and West Africa that has been used ceremonially for centuries by indigenous groups including the Bwiti in Gabon. In Western research contexts since the 1960s, ibogaine has been most extensively studied as an anti-addiction compound, demonstrating remarkable ability to interrupt opioid and stimulant dependence after a single administration. Despite these properties, pharmaceutical development stalled for two reasons:
• Cardiotoxicity: Ibogaine inhibits hERG potassium channels, causing QT interval prolongation that can progress to fatal ventricular arrhythmias (torsades de pointes). Dozens of deaths associated with unmonitored ibogaine use — often in participants with pre-existing cardiac risk factors or concurrent drug use — have been documented in the literature
• Duration and intensity of the experience: The full ibogaine experience is an 18- to 36-hour oneirogenic (waking dream) state, often described as an intense, hallucinatory immersion in one's autobiographical memories, making clinical delivery logistically difficult and requiring extended inpatient monitoring
The MISTIC protocol's key innovation was co-administering intravenous magnesium sulfate as a cardiac-protective agent, based on magnesium's known ability to shorten the QT interval and act as a neuroprotective agent, and conducting the entire procedure under continuous cardiac monitoring with a full medical team.
2. Study Design & Protocol (NCT04313712)
2.1 Study Overview
Study type: Prospective, open-label observational study (no control group)
Registration: ClinicalTrials.gov NCT04313712; also pre-registered at OSF (osf.io/24trc/)
Enrollment period: November 2021 – September 2022
Lead institution: Brain Stimulation Lab, Department of Psychiatry & Behavioral Sciences, Stanford School of Medicine
Principal investigator: Nolan R. Williams, MD (Associate Professor, Stanford Psychiatry)
IRB approval: Stanford University Institutional Review Board
Partner organizations: Veterans Exploring Treatment Solutions (VETS, Inc.) — funded participant treatment; Ambio Life Sciences (Mexico) — treatment site
Published: Nature Medicine, January 5, 2024 (doi: 10.1038/s41591-023-02705-w)
2.2 Participant Selection
The study enrolled 30 male Special Operations Forces veterans (out of 34 screened; 33 initially enrolled) who had independently scheduled themselves for ibogaine treatment in Mexico. Participant characteristics at baseline:
• All male (reflecting the gender composition of SOF units)
• Mean age: 44.9 years
• All had a documented history of predominantly mild TBI with repeated blast/combat exposures
• 23 of 30 (77%) met diagnostic criteria for PTSD (CAPS-5)
• 15 of 30 (50%) met criteria for major depressive disorder (MDD)
• 14 of 30 (47%) met criteria for an anxiety disorder (generalized anxiety disorder, panic disorder, agoraphobia, social anxiety disorder, or combinations)
• Elevated suicidal ideation was present in a subset at baseline
• All participants were experiencing clinically meaningful levels of disability and psychiatric symptoms that had been refractory to conventional treatment
• Average time since military discharge: approximately 8 years — underscoring the chronic, treatment-resistant nature of their conditions
Importantly, the study used three pre-specified sensitivity analyses: results were verified excluding participants without the relevant comorbidity, excluding those with non-mild TBI, and using different analytic methods — all produced comparable findings, strengthening confidence in the results.
2.3 The MISTIC Protocol — Detailed Treatment Description
Pre-Treatment (Remote and In-Person)
Before traveling to Mexico, participants underwent comprehensive remote and in-person clinical and neuropsychological evaluations at Stanford. This included:
• Structured diagnostic interviews (DSM-5 diagnoses)
• World Health Organization Disability Assessment Schedule 2.0 (WHODAS-2.0) — primary outcome measure
• Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
• Montgomery-Åsberg Depression Rating Scale (MADRS)
• Hamilton Anxiety Rating Scale (HAM-A)
• Comprehensive neuropsychological battery covering attention, memory, processing speed, executive function, and language
• Cardiac screening (ECG, medical history review) to identify contraindications
• Pre-treatment coaching about the ibogaine experience by a licensed therapist
At the Treatment Site (Ambio Life Sciences, Mexico)
The full treatment protocol proceeded in several stages:
• 1–2 hours before ibogaine: participants received 1 gram of intravenous magnesium sulfate and an oral gastrointestinal protective agent to reduce nausea
• Ibogaine dosing: oral ibogaine was administered at an initial dose of 2–3 mg/kg, with an additional booster dose of up to 14 mg/kg administered at approximately 40 minutes if the initial response warranted it (i.e., if the full oneirogenic experience had not yet commenced)
• Mean total dose: 12.1 ± 1.2 mg/kg (approximately 850 mg for an average 70 kg participant)
• At 12 hours post-dose: participants received additional IV magnesium sulfate, along with oral and IV antioxidants and metabolic support agents
• No formal psychotherapy was conducted during the session — this is clinically important because ibogaine's effects were not augmented by concurrent guided therapy, unlike most other psychedelic-assisted therapy protocols (e.g., MDMA-AT, psilocybin-AT)
• Complementary treatment modalities were available (group activities, coaching, integration support) but were not standardized
• Post-dose monitoring: participants were medically monitored for 72 continuous hours after ibogaine administration, given that the drug's psychoactive effects can persist for 24–72 hours or longer
Key Innovation: By co-administering magnesium sulfate IV both before and during the ibogaine experience, the MISTIC protocol is specifically designed to mitigate the cardiac arrhythmia risk that has caused fatalities in unmonitored ibogaine use. The fact that zero cardiac adverse events occurred across all 30 participants validates the magnesium co-administration approach
Post-Treatment Assessment Schedule
• Immediately post-MISTIC (within days): primary outcome assessment (WHODAS-2.0 for functional disability)
• 1 month post-treatment: comprehensive reassessment of all primary and secondary outcomes, plus repeat neuropsychological battery
• 3, 6, 9, and 12 months: follow-up assessments (reported in 2025 follow-up publication)
• EEG recordings: obtained at baseline, 3.5 days post-treatment, and 1 month post-treatment (reported in Nature Mental Health, 2025)
3. Primary Clinical Results (Nature Medicine, 2024)
ALL primary and secondary outcomes reached statistical significance at p < 0.001 (FDR-corrected). Effect sizes (Cohen's d) for psychiatric outcomes ALL exceeded 2.0 — among the largest ever observed in neuropsychiatric clinical research.
3.1 Primary Outcome: Functional Disability (WHODAS-2.0)
The World Health Organization Disability Assessment Schedule 2.0 measures disability across 6 life domains: cognition, mobility, self-care, getting along, life activities, and participation. Results:
• Immediately post-MISTIC: WHODAS total score improved from 30.2 ± 14.7 to 19.9 ± 16.3 (Cohen's d = 0.74; p < 0.001)
• 1 month post-MISTIC: WHODAS total score declined further to 5.1 ± 8.1 (Cohen's d = 2.20; p < 0.001)
• Mean percentage improvement at 1 month: approximately 83% reduction in disability score
The continuation of improvement from immediately post-treatment to the 1-month follow-up is particularly noteworthy, suggesting that the therapeutic benefits continued to consolidate and expand over the first month after treatment — a pattern seen with other psychedelic-assisted therapies and consistent with the hypothesis that ibogaine promotes ongoing neuroplasticity.
3.2 Secondary Outcomes: Psychiatric Symptoms
The following table summarizes all primary and secondary clinical outcomes at 1-month follow-up:
Outcome Measure |
Scale |
Baseline Mean |
1-Month Mean |
Effect Size (d) |
Response / Remission |
Functional Disability (WHODAS-2.0) |
0–100 |
30.2 ± 14.7 |
5.1 ± 8.1 (also improved immediately: d=0.74) |
2.20 |
— |
PTSD (CAPS-5) |
0–136 |
Clinically severe |
Significant reduction |
2.54 |
Response 100% / Remission 86% |
Depression (MADRS) |
0–60 |
Clinically severe |
Significant reduction |
2.80 |
Response 97% / Remission 83% |
Anxiety (HAM-A) |
0–56 |
Clinically severe |
Significant reduction |
2.13 |
Response 93% / Remission 83% |
Suicidal Ideation (MADRS item) |
0–6 |
Elevated in subset |
Statistically significant reduction |
— |
Exploratory finding |
To appreciate the magnitude of these effect sizes: a Cohen's d of 0.2 is considered small, 0.5 medium, and 0.8 large. Effect sizes above 1.0 are rare in psychiatric drug trials. MISTIC produced effect sizes of 2.13 to 2.80 — a level of signal essentially unprecedented in controlled or observational psychiatric research.
3.3 Response and Remission Rates
Response was defined as a clinically meaningful reduction in scale score (at least 10 points for CAPS-5, 50% for MADRS, 50% for HAM-A). Remission was defined as loss of clinical diagnosis plus total score falling below threshold values. At 1-month follow-up:
• PTSD (CAPS-5): Response rate 100%, Remission rate 86%
• Depression (MADRS): Response rate 97%, Remission rate 83%
• Anxiety (HAM-A): Response rate 93%, Remission rate 83%
These rates are extraordinary by any clinical benchmark. For context, approved pharmacological treatments for PTSD (SSRIs/SNRIs) typically achieve response rates of 40–60% and remission rates below 30% in clinical trials, and many SOF veterans with chronic, blast-related PTSD are classified as treatment-resistant even to first-line agents.
3.4 Suicidal Ideation
An exploratory analysis examined suicidal ideation using the suicidal ideation item of the MADRS. Among participants with elevated suicidal ideation at baseline, a statistically significant reduction was observed post-treatment. The authors were careful to flag this as exploratory and noted that specific suicidality instruments (rather than a single MADRS item) would be required before strong conclusions can be drawn. However, the signal was considered important enough to include in the primary publication, and future controlled trials are expected to include validated suicidality assessments as a dedicated outcome.
3.5 Cognitive Outcomes
Participants underwent a comprehensive neuropsychological battery benchmarked against age-matched normative data. Key findings:
Cognitive Domain |
Baseline (vs. Age-Matched Peers) |
Post-MISTIC |
1-Month Follow-up |
Executive function |
Significantly impaired |
Significant improvement (p<0.001) |
Maintained |
Processing speed |
Significantly impaired |
Significant improvement |
Maintained |
Learning & memory (verbal + working) |
Impaired |
Improvement trend |
Maintained |
Sustained attention (CPT-3) |
Impaired |
Significant improvement |
Maintained |
Language (phonemic + semantic fluency) |
Borderline impaired |
Improvement |
Maintained |
Cognitive inhibition / flexibility |
Borderline impaired |
Improvement |
Maintained |
Statistically significant improvements were observed in executive function and processing speed, and significant trends were evident for other domains. The authors noted that because the tests used (particularly the Conners Continuous Performance Test-3 for sustained attention) are specifically designed to minimize practice effects, the cognitive improvements are unlikely to reflect mere test familiarity.
4. Safety Profile
4.1 Adverse Event Summary
The safety profile of MISTIC is central to understanding its potential for clinical translation. Ibogaine's history of fatalities in unmonitored settings made cardiac safety the top priority. The results were reassuring:
Adverse Event |
Frequency |
Notes |
Headache |
40% (12/30) |
Managed during oneirogenic phase; resolved |
Nausea |
23% (7/30) |
Managed during oneirogenic phase; resolved |
Anxiety (acute, during session) |
10% (3/30) |
Managed during oneirogenic phase; resolved |
Hypertension (transient) |
7% (2/30) |
Transient; resolved without sequelae |
Insomnia |
3% (1/30) |
Resolved |
Cerebellar signs (mild ataxia + intention tremor) |
100% (30/30) |
EXPECTED — resolved within 24 hours in all participants |
Cardiac events (bradycardia, tachycardia, QTc prolongation, hemodynamic instability) |
0% |
NO instances observed — magnesium protocol appears effective |
Unexpected or serious adverse events |
0% |
None reported across all 30 participants |
4.2 The Cardiac Safety Question
Ibogaine inhibits the hERG potassium channel, which is responsible for the cardiac repolarization current (IKr). This inhibition prolongs the QT interval on ECG and, in susceptible individuals, can trigger torsades de pointes — a potentially fatal arrhythmia. Historical ibogaine-associated deaths have typically involved one or more of: pre-existing cardiac disease, concurrent substance use (particularly opioids or stimulants), excessive doses, and lack of cardiac monitoring.
The MISTIC protocol addressed this through several mechanisms:
• Rigorous pre-treatment cardiac screening (ECG, medical history, exclusion of high-risk individuals)
• IV magnesium sulfate pre-administration: magnesium is a physiological calcium channel antagonist and shortens the QT interval
• Repeat magnesium administration at 12 hours
• Continuous cardiac monitoring throughout the 72-hour post-dosing observation period
• Exclusion of participants with significant cardiac risk factors, electrolyte abnormalities, or medications known to prolong QT
The zero incidence of clinically meaningful QT prolongation across 30 participants receiving a mean dose of 12.1 mg/kg is a strong signal that the MISTIC cardiac safety protocol works — though a larger, controlled study is needed to confirm this and establish the safety boundaries more precisely.
4.3 The Oneirogenic Experience: Clinical Considerations
All participants experienced the characteristic oneirogenic (waking dream) effects of ibogaine, lasting up to 24–72 hours. This experience is qualitatively different from other psychedelics: ibogaine is not primarily a serotonergic psychedelic but rather an atypical compound that produces dream-like states of autobiographical memory immersion, often characterized by vivid re-experiencing of past events, sometimes including traumatic memories. Unlike psilocybin or MDMA sessions, no formal psychotherapy was conducted during the MISTIC experience — yet benefits were profound, raising important questions about whether the phenomenological experience itself is therapeutic (see Section 6 on mystical experiences).
5. Neurophysiology: EEG & Brain Function (Nature Mental Health, 2025)
5.1 Study Design for EEG Sub-Study
A neurophysiology sub-study nested within the main MISTIC trial used resting-state electroencephalography (EEG) to examine how ibogaine alters cortical brain activity. Published in Nature Mental Health on July 24, 2025 (Lissemore et al., Nat Mental Health 3:918–931), this study provided the first in-human characterization of ibogaine's effects on cortical oscillations and neural complexity — both of which are known to be altered by TBI and to correlate with cognitive and psychiatric function. EEG recordings were obtained at three time points:
• Baseline (before treatment)
• 3.5 days after MISTIC (to capture early post-treatment brain state)
• 1 month after MISTIC
5.2 Key EEG Findings
Oscillatory Changes: A 'Slowing' of Brain Rhythms
After a single MISTIC treatment, the EEG power spectrum shifted in a consistent and significant direction:
• Theta oscillations (4–8 Hz): increased in power
• Alpha oscillations (8–12 Hz): increased in power
• Beta oscillations (13–30 Hz): decreased in power
• Gamma oscillations (30+ Hz): decreased in power
This pattern represents a net 'slowing' of cortical oscillatory activity — a shift from faster, higher-frequency rhythms toward slower, lower-frequency ones. In EEG neuroscience, this pattern is associated with neuroplasticity and consolidative states. Frontal theta oscillations in particular are strongly linked to cognitive control, working memory, and learning. The post-ibogaine increase in theta power is consistent with ibogaine's known promotion of neurotrophin expression (particularly BDNF and GDNF) and neuroplastic remodeling.
Neural Complexity: A Reduction in Brain Signal Variability
Neural complexity refers to the statistical unpredictability and richness of EEG time series. In healthy brains, an intermediate level of complexity is associated with optimal cognitive function. Brains with TBI often show altered complexity — either pathologically high (hyperexcitable, reactive) or low (rigid, dysregulated). After MISTIC:
• Permutation entropy (a measure of signal complexity/unpredictability) decreased significantly
• The brain's spatiotemporal signal became more orderly, less chaotic, and more predictable
The researchers described this as a shift toward a more 'stable' brain state — potentially less reactive to stress, more organized in information processing, and more amenable to recovery. Strikingly, the lead author Jennifer Lissemore noted that the pattern of EEG changes observed after ibogaine treatment resembled changes associated with long-term meditation practice.
“The changes in brain function that we saw after a single treatment with ibogaine were a lot like the changes we see in the brain after long-term meditation practice. — Jennifer Lissemore, PhD, Stanford Brain Stimulation Lab”
Correlation with Clinical Outcomes
Critically, the EEG changes were not merely epiphenomenal — they correlated with clinical improvements:
• Post-treatment increases in theta and alpha power were significantly correlated with improvements in executive function
• Neurophysiological changes correlated with reductions in PTSD symptoms
• Neurophysiological changes correlated with reductions in anxiety
This mechanistic correlation — brain changes predicting and correlating with symptom changes — substantially strengthens the case that ibogaine is producing genuine neurobiological effects rather than merely expectancy-driven improvements.
Predictive Biomarkers: Who Responds Best?
An important exploratory finding was that baseline EEG patterns predicted treatment response:
• Veterans with lower peak alpha frequency at baseline showed greater clinical benefit
• Veterans with lower neural complexity at baseline (i.e., more disrupted brain state pre-treatment) were more likely to respond
These biomarker findings, if replicated in controlled trials, could enable precision medicine approaches — identifying in advance which patients are most likely to benefit from ibogaine therapy. This would be particularly valuable given the logistical complexity and safety requirements of the MISTIC protocol.
6. Subjective Experience: Mystical States & PTSD (2025)
6.1 Mystical Experiences During Ibogaine
A third publication from the MISTIC data examined the subjective phenomenology of the ibogaine experience and its relationship to clinical outcomes. Ibogaine is an 'atypical psychedelic' — its subjective profile differs from classical serotonergic psychedelics (LSD, psilocybin) in that it produces primarily oneirogenic rather than visionary effects. Veterans frequently reported intense autobiographical memory re-experiencing, sometimes including traumatic events, in a state that was described as simultaneously real and dream-like.
The key finding was that mystical-type experiences during ibogaine treatment correlated with greater clinical benefit:
• Ibogaine treatment frequently evoked mystical experiences (high baseline occurrence in this cohort)
• Greater intensity of mystical experiences correlated significantly with greater PTSD symptom reduction at 1 month
• A sustained shift in peak alpha frequency (a neurophysiological signature of altered consciousness) was identified as potentially mediating the relationship between mystical experience and clinical outcome
6.2 Clinical Implications of the Phenomenological Data
The finding that subjective experience quality predicts outcome is consistent with the broader psychedelic-assisted therapy literature, where 'mystical experience' scores (measured by instruments like the Mystical Experience Questionnaire) have been shown to mediate therapeutic benefits following psilocybin and other compounds. However, ibogaine appears to produce a qualitatively distinct form of this experience — one characterized by memory immersion and narrative processing rather than ego dissolution.
This has important practical implications: it suggests that although no formal psychotherapy was conducted during the MISTIC sessions, the drug itself may have been catalyzing a form of internal processing — a self-directed confrontation and integration of traumatic material — that underlies the psychiatric benefits. Future trials may investigate whether structured integration support after ibogaine amplifies these effects further.
7. Long-Term Durability (12-Month Follow-Up, 2025)
7.1 Study Details
A prospective 12-month follow-up study tracked the durability of MISTIC effects. Published in December 2025 as a preprint on Research Square (and in a peer-reviewed journal by Mary Ann Liebert) by Faerman et al., the study followed 25 of the original 30 participants (83% retention) through assessments at 3, 6, 9, and 12 months post-treatment.
7.2 Durability Results
Outcome |
Baseline |
1 Month |
3–6 Months |
12 Months (d) |
12-Month Remission (KM) |
PTSD (CAPS-5) |
Severe |
d=2.54 |
Sustained |
d ≥ 2.18 |
84% |
Depression (MADRS) |
Severe |
d=2.80 |
Sustained |
d ≥ 2.18 |
66% |
Anxiety (HAM-A) |
Severe |
d=2.13 |
Sustained |
d ≥ 2.18 |
61% |
Functional Disability (WHODAS) |
Severe |
d=2.20 |
Sustained |
d ≥ 2.18 |
— |
• All four psychiatric/functional outcome domains maintained large effect sizes (Cohen's d ≥ 2.18) at 12 months
• Kaplan-Meier survival analysis estimated 84% probability of sustained PTSD remission at 12 months
• 66% probability of sustained depression remission at 12 months
• 61% probability of sustained anxiety remission at 12 months
• No statistically significant differences in time to relapse were observed across the three diagnostic categories — suggesting comparable durability profiles for PTSD, depression, and anxiety
A single treatment with magnesium-ibogaine produced durable remission lasting 12 months in the majority of treated participants — after an average of 8 years of treatment-resistant symptoms. No FDA-approved intervention for TBI-related PTSD or depression comes close to this efficacy profile.
7.3 Caveats on Durability
The authors appropriately note several limitations on interpreting the 12-month follow-up:
• 21 of 25 participants had received some form of formal mental health treatment during the follow-up year — making it difficult to attribute maintained improvement exclusively to ibogaine
• Participants reported significant positive life events during the follow-up period, which may have contributed independently to sustained well-being
• The study remains uncontrolled — no placebo or active comparator group exists
• The sample is highly specific (male, SOF veterans, predominantly mild TBI) and may not generalize to other TBI populations or to women
8. Limitations & Scientific Criticisms
8.1 Absence of a Control Group
The most significant methodological limitation of the MISTIC study is that it was an open-label, uncontrolled observational study. There was no placebo group, no active comparator, and no blinding. This means the following alternative explanations for the observed improvements cannot be definitively ruled out:
• Expectancy/placebo effects: All participants self-selected into ibogaine treatment and had high expectations of benefit. The natural history of expectancy effects in psychedelic trials is well-documented and can produce meaningful short-term improvements
• Non-specific effects of the program: The MISTIC experience included international travel, group cohesion with other veterans, pre-treatment coaching, and integration support — any of which might have therapeutic effects independent of ibogaine
• Regression to the mean: Participants were assessed during a period when they were actively seeking treatment (a behavioral state often associated with temporarily elevated distress scores that subsequently improve regardless of intervention)
• Natural history: Some TBI-related symptoms do improve over time even without intervention
The authors explicitly acknowledge all of these limitations in the Nature Medicine paper and strongly call for randomized, controlled trials to establish causality.
8.2 Sample Characteristics and Generalizability
• All 30 participants were male — limiting generalizability to women, who have different TBI epidemiology and different presentations of PTSD
• All participants were SOF veterans — a highly trained, psychologically resilient, highly motivated population that may not represent typical TBI patients
• The study focused primarily on mild TBI — the most common form, but sensitivity analyses were conducted to verify that including the few participants with more severe TBI histories did not drive results
• The treatment occurred at a single site (Ambio Life Sciences, Mexico), limiting assessment of protocol reproducibility
8.3 Measurement and Follow-Up
• The primary outcome (WHODAS-2.0) was assessed immediately post-treatment without a standard post-treatment stabilization period, potentially capturing effects of the acute drug state rather than durable change
• The 1-month follow-up, while the pre-specified primary secondary endpoint, may still capture residual pharmacological effects of ibogaine's long-acting metabolite noribogaine
• Neuropsychological assessments were subject to potential practice effects (though the use of CPT-3 was specifically selected to minimize this)
8.4 Competing Interests
The authors disclose meaningful competing interests that should be considered when evaluating the findings:
• Principal investigator Nolan Williams has served on scientific advisory boards for Soneira (the company developing MISTIC commercially) and holds equity in Soneira
• Co-investigator Ian Kratter currently receives salary from Soneira
• Williams and Kratter are named inventors on Stanford-owned intellectual property related to magnesium-ibogaine
• Three co-authors (Inzunza, Millar, Dickinson) are shareholders in Ambio Life Sciences, the treatment site, and named inventors on related patents
These disclosures do not invalidate the findings, but they underscore the importance of independent replication by groups without financial stakes in the outcome.
9. Proposed Mechanisms of Action in TBI
9.1 Ibogaine's Multi-Target Pharmacology
The mechanisms by which ibogaine produces therapeutic effects in TBI are not fully elucidated, but its known pharmacology suggests several plausible pathways that are highly relevant to TBI pathophysiology:
• NMDA receptor antagonism: NMDA receptors are central to excitotoxicity — the process by which excessive glutamate activity after TBI causes neuronal damage. Ibogaine's NMDA blockade may interrupt this excitotoxic cascade and protect surviving neurons
• Serotonin transporter modulation: Ibogaine is a serotonin reuptake inhibitor with additional effects as a pharmacochaperone, helping to correctly fold and traffic misfolded serotonin transporters. Serotonin dysregulation is a central feature of TBI-related PTSD and depression
• Sigma receptor activity: Ibogaine is a sigma-1 and sigma-2 receptor ligand. Sigma-1 receptors have known neuroprotective and neuroplasticity-promoting functions and are expressed in areas critical to memory and emotion regulation (hippocampus, amygdala, prefrontal cortex)
• GDNF induction: Ibogaine increases expression of glial cell line-derived neurotrophic factor (GDNF) in the midbrain and striatum. GDNF is a potent neurotrophin that promotes the survival and growth of dopaminergic neurons, which are particularly vulnerable to TBI
• Kappa opioid receptor (KOR) agonism: KOR signaling affects stress reactivity, dissociation, and mood. Ibogaine's KOR effects may contribute to its ability to process trauma-related emotional states
• BDNF upregulation: Like other psychedelics, ibogaine appears to promote BDNF expression, supporting synaptic plasticity and the formation of new neural connections that may underlie cognitive recovery
9.2 Why Ibogaine May Be Especially Suited to TBI
Several features of ibogaine's pharmacology make it particularly well-matched to the pathophysiology of TBI:
• TBI causes diffuse axonal injury, synaptic disruption, and neuroinflammation — ibogaine promotes neuroplastic remodeling that may help compensate for or repair these disruptions
• TBI disrupts the dopamine and serotonin systems that regulate mood, motivation, and reward — ibogaine's multi-neurotransmitter pharmacology addresses all of these simultaneously
• TBI impairs the default mode network and large-scale brain connectivity — the EEG findings suggest ibogaine shifts brain dynamics in ways that may restore healthier large-scale brain states
• Combat TBI is almost always accompanied by PTSD from the same traumatic events that caused the physical injury — ibogaine's oneirogenic state, which often involves processing autobiographical traumatic memories, may address both the neurological and psychological wounds simultaneously
10. Regulatory Status & Policy Impact
10.1 Legal Status of Ibogaine
• United States: Schedule I controlled substance under the Controlled Substances Act — illegal to manufacture, distribute, possess, or administer
• Mexico: Legal and unregulated — multiple clinics operate, including Ambio Life Sciences where MISTIC was conducted
• Canada: Listed as a Prescription Drug (not Schedule I) — facilitates research and medical use
• United Kingdom: MHRA approved Phase 1/2a clinical trial for ibogaine HCl (DemeRx/Atai) in opioid use disorder
10.2 Texas $50 Million Initiative
In 2025, the Texas Legislature approved a $50 million state initiative specifically to fund clinical trials of ibogaine — the largest government investment in psychedelic therapy in US history and one of the most significant government interventions in the psychedelic research space globally. The Stanford MISTIC data on veterans with TBI were directly cited as a key rationale for this initiative, which was championed by former Texas Governor Rick Perry. The initiative provides matching state funds to private investments in ibogaine trials that may ultimately support FDA approval.
The political significance of this cannot be overstated: the veteran TBI angle — bipartisan, patriotic, and medically compelling — succeeded in generating government support for ibogaine research where addiction-focused arguments had previously failed in politically conservative contexts.
10.3 Pathway to Controlled Trials
The MISTIC team (now partially housed within Soneira Therapeutics, co-founded by Nolan Williams) is actively seeking IRB approval and funding for randomized controlled trials. Several design challenges must be addressed in future trials:
• Blinding: It is essentially impossible to blind participants to whether they received ibogaine — they will know. Active placebos or open-label designs with waitlist controls are the most realistic options
• Ethical considerations: Given the dramatic effect sizes, equipoise for a placebo-controlled design is ethically strained. Some argue that a waitlist-control or active-comparator design is more appropriate
• Clinical setting: Moving the protocol from Mexico to US clinical sites requires navigating Schedule I regulatory barriers, requiring either an FDA IND (Investigational New Drug application) or state-level authorization
• Dose optimization: The MISTIC dose was not titrated systematically — future trials should explore dose-response relationships
• Broader populations: Future trials should include women, non-SOF veterans, and civilians with TBI, as well as participants with moderate/severe TBI
11. Complete Publication Record
Date |
Journal |
Title / Focus |
Key Finding |
Jan 5, 2024 |
Nature Medicine (Vol 30, 373–381) |
Magnesium–ibogaine therapy in veterans with TBIs — primary clinical outcomes |
Large, rapid improvements in disability, PTSD, depression, anxiety; no serious adverse events |
Jul 24, 2025 |
Nature Mental Health (Vol 3, 918–931) |
Effects on cortical oscillations and neural complexity — EEG neurophysiology |
Theta/alpha power increased; beta/gamma decreased; reduced neural complexity; correlates with clinical improvement |
2025 |
Psychiatry Research / npj Mental Health Research |
Qualitative phenomenology — mystical experiences and PTSD outcomes |
More intense mystical experiences correlated with greater PTSD reduction; ibogaine evokes unique oneirogenic states |
Dec 17, 2025 (preprint) |
Research Square (in review) |
12-month follow-up — durability of MISTIC effects |
Effects sustained at 12 months (d ≥ 2.18); 84% PTSD remission probability; 66% depression; 61% anxiety |
2025 |
Journal of Psychedelic Studies (Mary Ann Liebert) |
12-month follow-up (peer-reviewed version) |
Confirms durable outcomes; safety maintained throughout follow-up period |
12. Expert Commentary & Scientific Context
“For patients with persistent symptoms following traumatic brain injury — especially those unresponsive to conventional care — this study suggests that magnesium-ibogaine may offer a rapid-acting treatment option. — Study authors, Nature Medicine (2024)”
“Our study provides initial evidence to suggest that MISTIC could be a powerful therapeutic for the transdiagnostic psychiatric symptoms that can emerge after TBI and repeated exposure to blasts and combat, including suicidality. — Cherian et al., Nature Medicine (2024)”
“In addition to treating TBI, I think this may emerge as a broader neuro-rehab drug. I think it targets a unique set of brain mechanisms and can help us better understand how to treat other forms of PTSD, anxiety and depression that aren't necessarily linked to TBI. — Nolan Williams, MD, Stanford (January 2024)”
“Clinically, the extent of improvement in symptoms after ibogaine treatment was surprising. Neurobiologically, the changes in brain function that we saw were a lot like the changes we see in the brain after long-term meditation practice. — Jennifer Lissemore, PhD, Stanford (September 2025)”
Within the scientific community, the MISTIC findings have generated both excitement and appropriate caution. The effect sizes are without precedent in controlled or observational neuropsychiatric research, which is precisely the reason why many researchers caution against over-interpretation before randomized trials are completed. The key questions that the field is now asking are:
• How much of the benefit is attributable to ibogaine pharmacology vs. expectancy, group effects, or integration support?
• Are the effects durable because ibogaine produces lasting neurobiological changes, or because participants made life changes enabled by their improved state?
• Can the protocol be replicated in controlled settings under FDA oversight?
• Which patient populations benefit most, and can EEG biomarkers predict responders?
• Is the magnesium co-administration protocol reliably sufficient to eliminate cardiac risk across larger and more diverse populations?
13. Bottom Line Assessment
MISTIC represents the strongest clinical evidence yet published for ibogaine as a neuropsychiatric treatment. The signal — unprecedented effect sizes, broad symptom coverage, rapid onset, durability, and a neurophysiological mechanistic signature — is compelling. But the study design (open-label, uncontrolled, single site, 30 participants, self-selected) means it is hypothesis-generating, not hypothesis-confirming. The next critical milestone is a randomized, controlled trial.
For the field of ibogaine therapeutics, MISTIC has accomplished three things: (1) it proved that ibogaine can be administered safely in a medically supervised setting with magnesium co-administration; (2) it established a neurophysiological signature that provides mechanistic credibility; and (3) it generated political and financial momentum — most notably the Texas $50 million initiative — that is accelerating the entire field toward the controlled trials needed for regulatory approval.
For veterans with TBI, MISTIC represents hope that a disease that has claimed thousands of lives to suicide and has left tens of thousands in disability after all conventional treatments failed may have a viable pharmacological solution — pending the confirmatory trials now in planning.
KEY REFERENCES
1. Cherian KN, Keynan JN, et al. Magnesium–ibogaine therapy in veterans with traumatic brain injuries. Nat Med. 2024;30(2):373-381. doi:10.1038/s41591-023-02705-w
2. Lissemore JI, Chaiken A, Cherian KN, et al. Magnesium–ibogaine therapy effects on cortical oscillations and neural complexity in veterans with traumatic brain injury. Nat Mental Health. 2025;3:918-931. doi:10.1038/s44220-025-00463-x
3. Brown RE, Lissemore JI, et al. Mystical experiences during magnesium-ibogaine are associated with improvements in PTSD symptoms in veterans. Journal of Affective Disorders. 2025.
4. Faerman A, Cherian K, Lissemore J, et al. Is ibogaine treatment durable? 12-month follow-up of MISTIC in Special Operations Veterans with TBI. Preprint: Research Square, December 17, 2025. doi:10.21203/rs.3.rs-6909189/v1. Also published in Journal of Psychedelic Studies (Mary Ann Liebert, 2025).
