Do Plant-based Psychedelics Offer a New Option for TBI Treatment?

Oneirogens are substances that produce or enhance dreamlike states of consciousness—could one of those, ibogaine, be key to relieving the sequelae of traumatic brain injury (TBI) in veterans?

An extract from the root bark of Tabernanthe iboga, an African shrub, ibogaine has both pharmacological and psychological effects. Acting on opioid receptors and the serotonin and dopamine systems, it can relieve withdrawal symptoms and reduce drug cravings—reportedly, often, in just a few hours—and reduce the risk of regular use. The results can last for weeks, months, or sometimes longer.

In the US, ibogaine is a Schedule I drug. Few controlled studies of ibogaine are available; most data come from anecdotal reports and case studies. Clinical research into ibogaine stalled due to legal restrictions that come with a Schedule I drug, as well as concerns about possible cardiac consequences. For example, some reports have described QT interval prolongation, with instances of subsequent fatal arrhythmia.  

That may change now, with findings from the Magnesium–Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), which took place at a treatment center in Mexico. Researchers from Stanford School of Medicine and the Veterans Affairs Palo Alto Health Care System combined prophylactic intravenous magnesium with ibogaine, in hopes of mitigating the cardiac risks. Magnesium supplementation has been shown to protect against QT interval prolongation when coadministered with medications that ordinarily would have such an effect.

The researchers studied 30 male Special Operations Forces veterans (SOVs) who had predominantly mild TBI. Of those, 15 participants met the criteria for major depressive disorder, 14 for an anxiety disorder, and 23 for PTSD; 19 had past suicidal ideation and 7 had attempted suicide.

Special Operations Forces, the researchers note, are “deployed at a greater pace and to higher intensity combat than conventional military, exposing them to greater allostatic load and risk of injury, including from blast exposure.” This, they say, may result in a “unique pattern” of physical, cognitive, behavioral, psychiatric, and endocrine-related problems across several domains.

Participants received a mean (SD) of 12.1 (1.2) mg kg^-1 of oral ibogaine. The researchers assessed changes in the World Health Organization Disability Assessment Schedule at baseline, immediately after treatment, and 1 month after treatment. They also assessed changes in posttraumatic stress disorder (PTSD), depression, and anxiety.

The treatment significantly improved functioning both immediately and at 1 month after treatment and PTSD, depression, and anxiety at 1 month after treatment. There were no unexpected or serious treatment-emergent adverse effects, nor were there instances of bradycardia, tachycardia, clinically meaningful QT prolongation, or hemodynamic instability. All participants experienced transient cerebellar signs, such as mild ataxia and intention tremor, that resolved within 24 hours. While experiencing oneirogenic effects, 12 participants were treated for headache, 7 for nausea, 3 for anxiety, 2 for hypertension, and 1 for insomnia. 

At 1 month, suicidal ideation had declined from 47% to 7%—a statistically significant change. “Given the alarming rates of suicide in veterans, as well as evidence that military-related TBI increases the risk of suicide,” the researchers say, “the substantial reduction in SI that we observed—which must be interpreted cautiously as an exploratory analysis—is noteworthy.” TBI also is associated with increased impulsivity, a well-known risk factor for suicide, they note. MISTIC resulted in a measurable improvement in cognitive inhibition.

Results of a neuropsychological battery indicated statistically significant improvements in processing speed and executive functioning (including inhibition, cognitive flexibility, problem-solving, phonemic fluency, and working memory), both immediately after treatment and at 1 month. No declines were noted across any performance domain.

Interestingly, mean performances on these tests moved from the average to the high average score range relative to same-age peers and, in all but one instance, phonemic fluency was high average at baseline and improved to the superior range relative to same-age peers at the 1-month follow-up. Learning and memory tests showed a significant improvement in visual memory and verbal memory. Sustained attention showed a significant improvement in accuracy (detection) and a weak but significant slowing of reaction time, consistent with a prioritization of accuracy over speed and reduced impulsivity.

In a Scientific American article, lead researcher Nolan Williams said he suspects the powerful effects of psychedelics have to do with their “profound ability to increase plasticity in the brain” by “bringing it back to a more juvenile state where reorganization can occur.” People often experience a life review that appears in their minds almost like a slideshow. “It somehow drives a particular sort of psychological phenomenon that you don’t achieve through guidance,” Williams said.

The data from the MISTIC trial in Mexico may spur more research in the US. The National Defense Authorization Act, signed by President Joe Biden last December, authorizes service members diagnosed with PTSD or TBI to take part in clinical studies of any “qualified plant-based alternative therapies.”

“It’s all really timely,” Williams said. “From my perspective, we should have some traction to make a strong argument that the risk-benefit is right.”

Oneirogens are substances that produce or enhance dreamlike states of consciousness—could one of those, ibogaine, be key to relieving the sequelae of traumatic brain injury (TBI) in veterans?

An extract from the root bark of Tabernanthe iboga, an African shrub, ibogaine has both pharmacological and psychological effects. Acting on opioid receptors and the serotonin and dopamine systems, it can relieve withdrawal symptoms and reduce drug cravings—reportedly, often, in just a few hours—and reduce the risk of regular use. The results can last for weeks, months, or sometimes longer.

In the US, ibogaine is a Schedule I drug. Few controlled studies of ibogaine are available; most data come from anecdotal reports and case studies. Clinical research into ibogaine stalled due to legal restrictions that come with a Schedule I drug, as well as concerns about possible cardiac consequences. For example, some reports have described QT interval prolongation, with instances of subsequent fatal arrhythmia.  

That may change now, with findings from the Magnesium–Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), which took place at a treatment center in Mexico. Researchers from Stanford School of Medicine and the Veterans Affairs Palo Alto Health Care System combined prophylactic intravenous magnesium with ibogaine, in hopes of mitigating the cardiac risks. Magnesium supplementation has been shown to protect against QT interval prolongation when coadministered with medications that ordinarily would have such an effect.

The researchers studied 30 male Special Operations Forces veterans (SOVs) who had predominantly mild TBI. Of those, 15 participants met the criteria for major depressive disorder, 14 for an anxiety disorder, and 23 for PTSD; 19 had past suicidal ideation and 7 had attempted suicide.

Special Operations Forces, the researchers note, are “deployed at a greater pace and to higher intensity combat than conventional military, exposing them to greater allostatic load and risk of injury, including from blast exposure.” This, they say, may result in a “unique pattern” of physical, cognitive, behavioral, psychiatric, and endocrine-related problems across several domains.

Participants received a mean (SD) of 12.1 (1.2) mg kg^-1 of oral ibogaine. The researchers assessed changes in the World Health Organization Disability Assessment Schedule at baseline, immediately after treatment, and 1 month after treatment. They also assessed changes in posttraumatic stress disorder (PTSD), depression, and anxiety.

The treatment significantly improved functioning both immediately and at 1 month after treatment and PTSD, depression, and anxiety at 1 month after treatment. There were no unexpected or serious treatment-emergent adverse effects, nor were there instances of bradycardia, tachycardia, clinically meaningful QT prolongation, or hemodynamic instability. All participants experienced transient cerebellar signs, such as mild ataxia and intention tremor, that resolved within 24 hours. While experiencing oneirogenic effects, 12 participants were treated for headache, 7 for nausea, 3 for anxiety, 2 for hypertension, and 1 for insomnia. 

At 1 month, suicidal ideation had declined from 47% to 7%—a statistically significant change. “Given the alarming rates of suicide in veterans, as well as evidence that military-related TBI increases the risk of suicide,” the researchers say, “the substantial reduction in SI that we observed—which must be interpreted cautiously as an exploratory analysis—is noteworthy.” TBI also is associated with increased impulsivity, a well-known risk factor for suicide, they note. MISTIC resulted in a measurable improvement in cognitive inhibition.

Results of a neuropsychological battery indicated statistically significant improvements in processing speed and executive functioning (including inhibition, cognitive flexibility, problem-solving, phonemic fluency, and working memory), both immediately after treatment and at 1 month. No declines were noted across any performance domain.

Interestingly, mean performances on these tests moved from the average to the high average score range relative to same-age peers and, in all but one instance, phonemic fluency was high average at baseline and improved to the superior range relative to same-age peers at the 1-month follow-up. Learning and memory tests showed a significant improvement in visual memory and verbal memory. Sustained attention showed a significant improvement in accuracy (detection) and a weak but significant slowing of reaction time, consistent with a prioritization of accuracy over speed and reduced impulsivity.

In a Scientific American article, lead researcher Nolan Williams said he suspects the powerful effects of psychedelics have to do with their “profound ability to increase plasticity in the brain” by “bringing it back to a more juvenile state where reorganization can occur.” People often experience a life review that appears in their minds almost like a slideshow. “It somehow drives a particular sort of psychological phenomenon that you don’t achieve through guidance,” Williams said.

The data from the MISTIC trial in Mexico may spur more research in the US. The National Defense Authorization Act, signed by President Joe Biden last December, authorizes service members diagnosed with PTSD or TBI to take part in clinical studies of any “qualified plant-based alternative therapies.”

“It’s all really timely,” Williams said. “From my perspective, we should have some traction to make a strong argument that the risk-benefit is right.”

Oneirogens are substances that produce or enhance dreamlike states of consciousness—could one of those, ibogaine, be key to relieving the sequelae of traumatic brain injury (TBI) in veterans?

An extract from the root bark of Tabernanthe iboga, an African shrub, ibogaine has both pharmacological and psychological effects. Acting on opioid receptors and the serotonin and dopamine systems, it can relieve withdrawal symptoms and reduce drug cravings—reportedly, often, in just a few hours—and reduce the risk of regular use. The results can last for weeks, months, or sometimes longer.

In the US, ibogaine is a Schedule I drug. Few controlled studies of ibogaine are available; most data come from anecdotal reports and case studies. Clinical research into ibogaine stalled due to legal restrictions that come with a Schedule I drug, as well as concerns about possible cardiac consequences. For example, some reports have described QT interval prolongation, with instances of subsequent fatal arrhythmia.  

That may change now, with findings from the Magnesium–Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), which took place at a treatment center in Mexico. Researchers from Stanford School of Medicine and the Veterans Affairs Palo Alto Health Care System combined prophylactic intravenous magnesium with ibogaine, in hopes of mitigating the cardiac risks. Magnesium supplementation has been shown to protect against QT interval prolongation when coadministered with medications that ordinarily would have such an effect.

The researchers studied 30 male Special Operations Forces veterans (SOVs) who had predominantly mild TBI. Of those, 15 participants met the criteria for major depressive disorder, 14 for an anxiety disorder, and 23 for PTSD; 19 had past suicidal ideation and 7 had attempted suicide.

Special Operations Forces, the researchers note, are “deployed at a greater pace and to higher intensity combat than conventional military, exposing them to greater allostatic load and risk of injury, including from blast exposure.” This, they say, may result in a “unique pattern” of physical, cognitive, behavioral, psychiatric, and endocrine-related problems across several domains.

Participants received a mean (SD) of 12.1 (1.2) mg kg^-1 of oral ibogaine. The researchers assessed changes in the World Health Organization Disability Assessment Schedule at baseline, immediately after treatment, and 1 month after treatment. They also assessed changes in posttraumatic stress disorder (PTSD), depression, and anxiety.

The treatment significantly improved functioning both immediately and at 1 month after treatment and PTSD, depression, and anxiety at 1 month after treatment. There were no unexpected or serious treatment-emergent adverse effects, nor were there instances of bradycardia, tachycardia, clinically meaningful QT prolongation, or hemodynamic instability. All participants experienced transient cerebellar signs, such as mild ataxia and intention tremor, that resolved within 24 hours. While experiencing oneirogenic effects, 12 participants were treated for headache, 7 for nausea, 3 for anxiety, 2 for hypertension, and 1 for insomnia. 

At 1 month, suicidal ideation had declined from 47% to 7%—a statistically significant change. “Given the alarming rates of suicide in veterans, as well as evidence that military-related TBI increases the risk of suicide,” the researchers say, “the substantial reduction in SI that we observed—which must be interpreted cautiously as an exploratory analysis—is noteworthy.” TBI also is associated with increased impulsivity, a well-known risk factor for suicide, they note. MISTIC resulted in a measurable improvement in cognitive inhibition.

Results of a neuropsychological battery indicated statistically significant improvements in processing speed and executive functioning (including inhibition, cognitive flexibility, problem-solving, phonemic fluency, and working memory), both immediately after treatment and at 1 month. No declines were noted across any performance domain.

Interestingly, mean performances on these tests moved from the average to the high average score range relative to same-age peers and, in all but one instance, phonemic fluency was high average at baseline and improved to the superior range relative to same-age peers at the 1-month follow-up. Learning and memory tests showed a significant improvement in visual memory and verbal memory. Sustained attention showed a significant improvement in accuracy (detection) and a weak but significant slowing of reaction time, consistent with a prioritization of accuracy over speed and reduced impulsivity.

In a Scientific American article, lead researcher Nolan Williams said he suspects the powerful effects of psychedelics have to do with their “profound ability to increase plasticity in the brain” by “bringing it back to a more juvenile state where reorganization can occur.” People often experience a life review that appears in their minds almost like a slideshow. “It somehow drives a particular sort of psychological phenomenon that you don’t achieve through guidance,” Williams said.

The data from the MISTIC trial in Mexico may spur more research in the US. The National Defense Authorization Act, signed by President Joe Biden last December, authorizes service members diagnosed with PTSD or TBI to take part in clinical studies of any “qualified plant-based alternative therapies.”

“It’s all really timely,” Williams said. “From my perspective, we should have some traction to make a strong argument that the risk-benefit is right.”