Ketamine is unlike any other antidepressant, yet understanding why has remained a challenge.
A new study from King’s College London shows that ketamine’s antidepressant effects rely in part on the brain’s opioid system. When opioid receptors were blocked, both brain chemistry and symptom improvement were dampened.
The paper was published in Nature Medicine.
How ketamine works
Ketamine can lift depression in hours, even in people who’ve failed to respond to other treatments. Yet despite growing use in clinics, no one fully understands how it works.
Most theories focus on glutamate, a brain chemical involved in learning and memory. Ketamine blocks N-methyl-D-aspartate (NMDA) receptors, leading to a short-term glutamate surge that may help reset brain circuits. However, some studies suggest another player is involved: the brain’s opioid system.
In rodents, ketamine’s effects seem to depend on opioid receptors. A few small human studies found that the antidepressant effect was reduced when these receptors were blocked. Although these studies were limited, they didn’t track brain chemistry, and their results were mixed.
“Ketamine often makes the news for negative reasons,” said lead author Dr. Luke Jelen, a psychiatrist and a clinical lecturer in psychiatry at King’s College London. “However, at a low dose, ketamine shows enormous potential to offer relief from the symptoms of depression.”
The new study tested whether ketamine’s impact on glutamate is changed when the opioid system is blocked, and whether that changes how well it relieves symptoms of depression.
“Understanding whether the opioid system is involved in ketamine’s antidepressant effects is a really important question, given how much we still don’t know about how ketamine works,” Jelen added.
Testing the opioid system’s role in depression treatment
To test how the opioid system influences ketamine’s effects, Jelen and the team ran a randomized, double-blind crossover study in 26 adults with major depressive disorder. Each participant received two ketamine infusions: one was preceded by a placebo, the other by naltrexone, a drug that blocks opioid receptors.
The team used a brain scanning technique called proton functional magnetic resonance spectroscopy to measure levels of glutamate and glutamine, combined as Glx, in the anterior cingulate cortex – a region involved in emotion regulation. Depression symptoms were rated before and one day after each infusion, using both clinician and self-report tools.
When ketamine was given after the placebo, Glx levels rose sharply; however, this increase was dampened when ketamine followed naltrexone, and the antidepressant effect also dropped. MADRS scores fell by 14.65 points after placebo-plus-ketamine, although only by 10.5 points when naltrexone was used – roughly a 28% difference.
MADRS (Montgomery–Åsberg Depression Rating Scale)
A clinician-administered questionnaire that is used to assess the severity of depression symptoms. Scores range from 0 to 60, with higher scores indicating more severe depression.
The dampening was also more pronounced in male participants. Self-reported improvements followed a similar pattern, although the differences were smaller.
There were no changes in dissociative side effects.
What do these results mean for future ketamine use?
“Our study shows that the opioid system is involved and offers insight into how it contributes to ketamine’s effects,” said Jelen.
Blocking opioid receptors reduced both glutamate activity and antidepressant response, suggesting that ketamine’s effects are not driven by glutamate alone, but by a more complex interaction between glutamatergic and opioid systems.
“The brain’s different neurochemical systems work together to produce our experiences and behavior, so it is no surprise that the opiate system may have a role in ketamine’s antidepressant effect,” said corresponding author Dr. Mitul Mehta, a professor of neuroimaging and psychopharmacology at King’s College London.
If opioid involvement varies between individuals, by biology, sex or treatment history, it could help explain why some people respond to ketamine and others do not. Personalized approaches that take these differences into account may improve outcomes.
However, the study had no ketamine-free placebo condition, and therefore, it cannot rule out all non-specific effects. The sample size was relatively small, particularly for exploring sex-based differences, and while 3T MRI allowed tracking of glutamate changes, it couldn’t fully separate glutamate from glutamine or account for all measurement variability.
Future work should use higher-field scanners, larger and more diverse samples and direct imaging of opioid receptors.
“Understanding more about how ketamine works can lead to treatment being personalized for different people, which is vital for creating safe and effective treatments,” Mehta added.
Reference: Jelen LA, Lythgoe DJ, Stone JM, Young AH, Mehta MA. Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study. Nat Med. 2025. doi: 10.1038/s41591-025-03800-w
This article is a rework of a press release issued by King’s College London. Material has been edited for length and content.