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 5^th 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