Ketamine could treat depression by interacting with the brain’s ‘opioid system’
Ketamine is a highly effective, fast-acting antidepressant that works even for patients who have not responded to other medications. However, the brain mechanisms important for these rapid treatment effects are yet to be determined.
Researchers at King’s College London, who are investigating why ketamine could be a good treatment for some people with depression, have discovered that the drug’s antidepressant effects involve the brain’s opioid system.
The study, led by King’s College London and published in Nature Medicine, included 26 individuals with clinically diagnosed depression who were given a low dose ketamine infusion across two sessions during neuroimaging.
Before receiving the ketamine infusion, in one session they were given naltrexone, which blocks the opioid receptors in the brain, and in the other they were given a placebo.
Participants were monitored during the infusion in a brain scanner using a method called magnetic resonance spectroscopy (MRS). MRS measured dynamic changes in a brain chemical called glutamate. Depressive symptoms were then assessed using the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) 24-hours after infusion, when ketamine’s antidepressive symptoms peak.
They found that blocking the opioid system reduced both the brain’s glutamatergic response and the antidepressant effects observed the following day, suggesting that the opioid system plays a key role in mediating the antidepressant response.
The study also identified a sex-related effect: the effect of naltrexone on glutamatergic activity appeared more pronounced in males with depression than in the females with depression.
These insights into how ketamine works for different people is essential to personalising treatments.
Dr Luke Jelen, lead author of the study and a Clinical Lecturer in Psychiatry at King’s College London, said: “Ketamine often makes the news for negative reasons. However, at a low dose, ketamine shows enormous potential to offer relief from the symptoms of depression.”
“Understanding whether the opioid system is involved ketamine’s antidepressant effects is a really important question, given how much we still don't know about how ketamine works. “Our study shows that the opioid system is involved and offers insight into how it contributes to ketamine’s effects.”
The authors are keen to highlight that ketamine is not classified as an opioid and does not bind to opioid receptors with high affinity like morphine or heroin. Instead, the findings point to a dynamic interplay between the glutamatergic and opioid systems, which may work together to support ketamine’s rapid antidepressant effects.
Opiates can offer relief from the systems of depression however they are highly addictive. Understanding if and how the opioid system is involved in the effects of ketamine is important to understand why ketamine works and develop new, alternative treatments.
Low-dose ketamine is currently being used to treat depression in private clinics and a small number of NHS clinics. At higher doses it is also used in medicinal anaesthesia. However, it is also used recreationally and if misused can cause serious health problems including irreversible damage to the bladder and kidneys.
Professor Mitul Mehta, a professor of neuroimaging & psychopharmacology at King’s College London, said: “The brain’s different neurochemical systems work together to produce our experiences and behaviour so it is no surprise that the opiate system may have a role in ketamine’s antidepressant effect.”
“We need these kinds of studies to understand exactly what the important brain mechanisms are for antidepressant effects. Understanding more about how ketamine works can lead to treatment being personalised for different people, which is vital for creating safe and effective treatments."
ENDS
Notes to editor:
- If you would like to speak to the researchers involved in this study, please email Jo Dungate at the King’s College London press office at joanna.dungate@kcl.ac.uk.
About King’s College London
King’s College London is amongst the top 40 universities in the world and 5th best in the UK (QS World University Rankings 2026), and one of England’s oldest and most prestigious universities. With an outstanding reputation for world-class teaching and cutting-edge research, King’s maintained its sixth position for ‘research power’ in the UK (2021 Research Excellence Framework).
King's has more than 33,000 students (including more than 12,800 postgraduates) from some 150 countries worldwide, and 8,500 staff.
For nearly 200 years, King’s students and staff have used their knowledge and insight to make a positive impact on people, society and the planet. Focused on delivering positive change at home in London, across the UK and around the world, King’s is building on its history of addressing the world’s most urgent challenges head on to accelerate progress, make discoveries and pioneer innovation. Visit the website to find out more about Vision 2029, which sets out bold ambitions for the future of King’s as we look towards our 200th anniversary.
World-changing ideas. Life-changing impact: kcl.ac.uk/news
Journal
Nature Medicine
Method of Research
Randomized controlled/clinical trial
Subject of Research
People
Article Publication Date
24-Jul-2025
Ibogaine appears to treat traumatic brain injuries in veterans
Stanford Medicine
For military veterans, many of the deepest wounds of war are invisible: Traumatic brain injuries resulting from head trauma or blast explosions are a leading cause of post-traumatic stress disorder, anxiety, depression and suicide among veterans. Few treatments have been effective at diminishing the long-term effects of TBI, leaving many veterans feeling hopeless.
Now, Stanford Medicine researchers have discovered that the plant-based psychoactive drug ibogaine, when combined with magnesium to protect the heart, safely and effectively reduces PTSD, anxiety and depression and improves functioning in veterans with TBI.
In a study to be published July 24, 2025, in Nature Mental Health, Williams and his team analyzed electroencephalography and MRI scans collected from a cohort of 30 veterans to uncover the neural mechanisms underlying the cognitive improvements. They found, for example, that veterans who improved in executive function after ibogaine treatment tended to show an increase in a type of brain wave known as theta rhythms. They also found that veterans with lowered PTSD symptoms after treatment tended to show a reduction in the complexity of brain activity in the cortex.
The researchers speculate that stronger theta rhythms may encourage neuroplasticity and cognitive flexibility, while less complex cortical activity may lower the heightened stress response seen in PTSD. Brain activity patterns before treatment could also be used to identify patients who would benefit most from ibogaine therapy.
“No other drug has ever been able to alleviate the functional and neuropsychiatric symptoms of traumatic brain injury,” said Nolan Williams, MD, an associate professor of psychiatry and behavioral sciences. “The results are dramatic, and we intend to study this compound further.”
The new study expands on a study published online Jan. 5, 2024, in Nature Medicine.
Alternatives
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.
Hundreds of thousands of troops serving in Afghanistan and Iraq have sustained TBIs in recent decades, and these injuries are suspected of playing a role in the high rates of depression and suicide seen among military veterans. With mainstream treatment options not fully effective for some veterans, researchers have sought therapeutic alternatives.
Ibogaine is a naturally occurring compound found in the roots of the African shrub 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., but 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.”
Capturing ‘before and after’
For the study published in January of 2024, Williams and his colleagues at Stanford Medicine teamed up with VETS, Inc., a foundation that helps facilitate psychedelic-assisted therapies for veterans. With support from VETS, 30 special operations veterans 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 researchers gauged the participants’ levels of PTSD, anxiety, depression and functioning 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 ibogaine. The veterans then returned to Stanford Medicine for post-treatment assessments.
“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.”
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.
Life-changing results
On average, treatment with ibogaine immediately led to significant improvements in functioning, PTSD, depression and anxiety. Moreover, those 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. Formal cognitive testing also revealed improvements in participants' concentration, information processing, memory and impulsivity.
“I wasn’t willing to admit I was dealing with any TBI challenges. I just thought I’d had my bell rung a few times — until the day I forgot my wife’s name,” said Craig, a 52-year-old study participant from Colorado who served 27 years in the U.S. Navy. “Since [ibogaine treatment], my cognitive function has been fully restored. This has resulted in advancement at work and vastly improved my ability to talk to my children and wife.”
“Before the treatment, I was living life in a blizzard with zero visibility and a cold, hopeless, listless feeling,” said Sean, a 51-year-old veteran from Arizona with six combat deployments who participated in the study and says ibogaine saved his life. “After ibogaine, the storm lifted.”
Importantly, there were no serious side effects of ibogaine and no instances of the heart problems that have occasionally been linked to ibogaine. During treatment, veterans reported only typical symptoms such as headaches and nausea.
Lessons for PTSD, depression and anxiety
The researchers hope to launch future studies to further understand how the drug might be used to treat TBI. In fact, based in part on the promising results of the team’s ibogaine studies, Texas recently approved a $50 million initiative to fund clinical trials of ibogaine. The initiative — one of the largest government investments in psychedelic therapy — will provide matching state funds to private investments in ibogaine trials that may lead to FDA approval.
Williams believes ibogaine’s drastic effects on TBI suggest that it holds broader therapeutic potential for other neuropsychiatric conditions. “In addition to treating TBI, I think this may emerge as a broader neuro-rehab drug,” Williams said. “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.”
The study was independently funded by philanthropic gifts from Steve and Genevieve Jurvetson. Stanford Medicine received no funding from VETS, Inc. or Ambio.
Journal
Nature Mental Health
Method of Research
Observational study
Subject of Research
People
Article Title
Magnesium–ibogaine therapy effects on cortical oscillations and neural complexity in veterans with traumatic brain injury
Article Publication Date
24-Jul-2025
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