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 the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) 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 was supported by the Medical Research Council, the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre and the NIHR King’s Clinical Research Facility.

Led by King’s College London and published in Nature Medicine, the study 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 IoPPN 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 IoPPN King’s College London and Theme Lead for Experimental Medicine and Novel Therapeutics at the NIHR Maudsley BRC 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."

Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study.  Jelen, L.A., Lythgoe, D.J., Stone, J.M. et al. was published in Nature Medicine (2025). https://doi.org/10.1038/s41591-025-03800-w