Blocking opioid receptors reduced ketamine’s brain activity and mood benefits.
A new study suggests that part of ketamine’s antidepressant effect may rely on the brain’s opioid system. The finding comes from research involving adults with major depression, where blocking opioid receptors appeared to dampen both a key brain signal and the mood boost usually seen after ketamine treatment.
The work, led by Dr. Luke Jelen of King’s College London, looked at whether the drug naltrexone, often used to block opioid effects, would change how ketamine works in the brain. While ketamine is known for producing a rapid improvement in mood for many people with depression, exactly how it does so is not fully understood.
In this trial, 26 adults with moderate-to-severe depression were given either naltrexone or a placebo before receiving a standard low-dose ketamine infusion. Each participant took part in both conditions several weeks apart. During treatment, brain scans tracked changes in glutamate, a chemical linked to learning, mood, and brain flexibility. Glutamate levels in the anterior cingulate cortex, an area tied to emotion and decision-making, are thought to play a role in ketamine’s benefits.
Results showed that when participants took placebo before ketamine, glutamate levels rose more sharply. When they took naltrexone instead, the increase in glutamate was smaller. This was matched by a weaker improvement in mood the day after treatment, as measured by the Montgomery–Åsberg Depression Rating Scale. The reduction in the antidepressant effect was estimated at about 28%.
The study also hinted at a difference between men and women, with the dampening effect of naltrexone on glutamate activity appearing more marked in male participants. However, the small sample size means this finding needs to be explored further in larger research.
Self-reported mood changes showed a similar trend, with lower improvement seen after naltrexone pretreatment, though these differences did not reach statistical significance.
The results add weight to earlier theories that the opioid system plays some role in ketamine’s mood-lifting action. Past animal studies and smaller human trials have pointed in the same direction, though researchers stress that more work is needed before any changes to treatment are considered.
Dr. Jelen emphasized that this was a small, controlled experiment designed to explore how ketamine works rather than to guide patient care. He noted that people taking naltrexone for other medical reasons should not stop or alter their treatment based on these findings.
Future studies, he said, should be larger and include a true placebo infusion to help clarify how naltrexone affects both ketamine’s real and placebo-driven responses. Adding brain imaging to directly measure opioid receptor activity would also give a clearer picture. Separate analysis by sex is likely to be important, given the differences observed in this study.
Understanding the pathways involved in ketamine’s antidepressant effects could help guide more personalized treatment. If the opioid system is confirmed to be an important part of the process, it might one day influence who is most likely to benefit from ketamine and how it is used alongside other medications.
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Ketamine’s Antidepressant Action May Depend on Opioid System
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