Traumatic brain injuries (TBIs) resulting from head trauma or blast explosions are a leading cause of post-traumatic stress disorder, anxiety, depression, and suicide among military veterans. Few treatments have been effective at diminishing the long-term effects of TBI, leaving many veterans feeling hopeless.

Researchers at Stanford School of Medicine have now reported the results of a clinical trial demonstrating that the plant-based psychoactive drug ibogaine, when combined with magnesium to protect the heart, safely and effectively reduced PTSD, anxiety and depression, and improved functioning in veterans with TBI.

“No other drug has ever been able to alleviate the functional and neuropsychiatric symptoms of traumatic brain injury,” said research lead Nolan Williams, MD, an associate professor of psychiatry and behavioral sciences. “The results are dramatic, and we intend to study this compound further.” Williams and colleagues at Stanford, and at Palo Alto University, Veterans Affairs Palo Alto Health Care System, and at Ambio Life Sciences, reported on the trial results in Nature Medicine, in a paper titled “Magnesium–ibogaine therapy in veterans with traumatic brain injuries.” In their paper, the researchers concluded “This is possibly the first study to report evidence for a single treatment with a drug that can improve chronic disability related to repeated TBI from combat/blast exposures.”

Traumatic brain injury is defined as a disruption in the normal functioning of the brain resulting from external forces—such as explosions, vehicle collisions or other bodily impacts. The trauma associated with TBI can lead to changes in the function and/or structure of the brain, which, in turn, contributes to neuropsychiatric symptoms. “Traumatic brain injury (TBI) is a leading cause of disability,” the authors wrote. “Sequelae can include functional impairments and psychiatric syndromes such as post-traumatic stress disorder (PTSD), depression and anxiety … The sequelae of TBI may also include both subjective and objective changes in memory, attention, processing speed and executive functions that can substantially impact quality of life.”

For military veterans, including special operations forces (SOFs) and special operations veterans (SOVs), TBIs are suspected of playing a role in the high rates of depression and suicide, and with mainstream treatment options not fully effective for some veterans, researchers have sought therapeutic alternatives. “Given this substantial burden of ongoing disability and suicide risk in SOVs, additional treatment options are needed,” the investigators noted.

Ibogaine is a naturally occurring compound found in the roots of the African shrub Tabernanthe iboga, and it has been used for centuries in spiritual and healing ceremonies. More recently, it has gained interest from the medical and scientific communities for its potential to treat opioid and cocaine addiction, and research has suggested that it increases signaling of several important molecules within the brain, some of which have been linked to drug addiction and depression. Since 1970 ibogaine has been designated as a Schedule I drug, preventing its use within the U.S., “Such legal restrictions have limited research, as have concerns related to neuro- and cardiotoxicity,” the authors continued, although clinics in both Canada and Mexico offer legal ibogaine treatments.

“There were a handful of veterans who had gone to this clinic in Mexico and were reporting anecdotally that they had great improvements in all kinds of areas of their lives after taking ibogaine,” Williams said. “Our goal was to characterize those improvements with structured clinical and neurobiological assessments.”

For their study Williams and his colleagues at Stanford teamed up with VETS, a foundation that helps facilitate psychedelic-assisted therapies for veterans, to undertake a prospective study examining the safety and efficacy of the Magnesium–Ibogaine: the Stanford Traumatic Injury to the CNS (MISTIC) protocol  in SOVs.

The study involved 30 SOVs with a history of TBI and repeated blast exposures, almost all of whom were experiencing clinically severe psychiatric symptoms and functional disabilities, had independently scheduled themselves for treatment with magnesium and ibogaine at a clinic in Mexico.

Before the treatment, the participants’ levels of PTSD, anxiety, depression and functioning were gauged, based on a combination of self-reported questionnaires and clinician-administered assessments. Participants then traveled to a clinic in Mexico run by Ambio Life Sciences, where under medical monitoring they received oral ibogaine along with magnesium to help prevent heart complications that have been associated with the drug. The veterans then returned to Stanford for post-treatment assessments.

At the beginning of the study, participants were experiencing clinically significant levels of disability as measured by the World Health Organization Disability Assessment Scale 2.0, which assesses disability in six functional domains, including cognition, mobility, self-care, getting along, life activities and community participation. In addition, 23 met the criteria for PTSD, 14 for an anxiety disorder and 15 for alcohol use disorder. In their lifetimes, 19 participants had been suicidal and seven had attempted suicide.

“These men were incredibly intelligent, high-performing individuals who experienced life-altering functional disability from TBI during their time in combat,” Williams said. “They were all willing to try most anything that they thought might help them get their lives back.”

The trial results indicated that on average, treatment with ibogaine immediately led to significant improvements in functioning, PTSD, depression and anxiety. The effects persisted until at least one month after treatment—the endpoint of the study. Before treatment, the veterans had an average disability rating of 30.2 on the disability assessment scale, equivalent to mild to moderate disability. One month after treatment, that rating improved to 5.1, indicating no disability. Similarly, one month after treatment participants experienced average reductions of 88% in PTSD symptoms, 87% in depression symptoms and 81% in anxiety symptoms relative to how they were before ibogaine treatment. “After MISTIC, participants showed a remarkable reduction in these symptoms with large effect sizes (Cohen’s d > 2 on clinician-rated psychiatric assessments) and the benefits were sustained at the 1-month follow-up,” the authors wrote.

Formal cognitive testing also revealed improvements in participants’ concentration, information processing, memory and impulsivity…“Neuropsychological testing (NPT) revealed areas of improvement after treatment, particularly in processing speed and executive function, without any detrimental changes observed.”

During treatment, veterans reported typical symptoms such as headaches and nausea, but there were no serious side effects associated with ibogaine treatment, and no instances of the heart problems.

Noting limitations of their study, and the need for additional trials to replicate their findings, particularly in non-mild TBI cases, the investigates concluded, “In summary, 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… Importantly, our results indicate that ibogaine can be administered safely.”

The research team is now planning further analysis of additional data collected on the veterans but not included in the reported study, including brain scans that could help reveal how ibogaine led to improvements in cognition. They also hope to launch studies in the future that will provide additional understanding into how the drug might be used to treat TBI.

The drastic effects of ibogaine on TBI may also suggest that the drug holds broader therapeutic potential for other neuropsychiatric conditions. The authors stated, “Although outside the context of TBI and veterans, our findings are consistent with previous studies suggesting benefits of treatment with psychedelic substances across several psychiatric disorders.” Williams added, “In addition to treating TBI, I think this may emerge as a broader neuro-rehab drug. I think it targets a whole host of different brain areas and can help us better understand how to treat other forms of PTSD, anxiety and depression that aren’t necessarily linked to TBI.”