Connection Found Between Opioid Network and Ketamine's Antidepressant Capabilities
A new study, conducted by researchers at King's College London, has shed light on the pathways involved in ketamine's antidepressant effects, potentially paving the way for more personalized treatment for major depression.
The study, which involved 26 adults with moderate-to-severe depression, used brain scans to track changes in glutamate levels, a chemical linked to learning, mood, and brain flexibility. Each participant received a standard low-dose ketamine infusion, either with a placebo or naltrexone (a drug that blocks opioid effects).
The results of the study suggest that part of ketamine's antidepressant effect may be due to the brain's opioid system. When participants took naltrexone before ketamine, the increase in glutamate was smaller. This was particularly evident in male participants, with the dampening effect of naltrexone on glutamate activity appearing more marked in men. This was matched by a weaker improvement in mood the day after treatment.
Dr. Jelen, the lead researcher, emphasised that the study was a small, controlled experiment aimed at understanding how ketamine works, not for guiding patient care. The study did not suggest any changes to current treatment based on its findings. However, if the opioid system is confirmed to be an important part of the process, it might influence who is most likely to benefit from ketamine and how it is used alongside other medications.
The study's findings further support the theory that the opioid system plays a role in ketamine's mood-lifting action. Past animal studies and smaller human trials have also pointed towards the same direction. However, future studies should be larger, include a true placebo infusion, and use brain imaging to directly measure opioid receptor activity to confirm these findings.
It's important to note that the reduction in the antidepressant effect was estimated at about 28%. People taking naltrexone for other medical reasons should not stop or alter their treatment based on these findings.
In conclusion, the latest evidence strongly supports that activation of the brain’s opioid system contributes to ketamine’s acute antidepressant effects in major depression, though this may vary with clinical context. Further research is needed to clarify how naltrexone affects both ketamine's real and placebo-driven responses, and to explore the nuances of the opioid system's exact role in different patient populations and co-morbidities.
[1] Jelen, et al. (2025). Opioid system involvement in ketamine's antidepressant effects: A magnetic resonance spectroscopy study. Neuropsychopharmacology. [2] Jelen, et al. (2025). Ketamine's antidepressant efficacy and glutamatergic brain response are reduced by opioid receptor blockade. Nature Medicine. [3] Jelen, et al. (2025). Opioid receptor activity is essential for ketamine's rapid reduction of depressive symptoms. Molecular Psychiatry. [4] Smith, et al. (2025). Comparable antidepressant outcomes with ketamine and naltrexone versus ketamine alone in patients with major depressive disorder and alcohol use disorder. Journal of Affective Disorders. [5] Jelen, et al. (2025). The opioid system's role in ketamine's antidepressant effects: A systematic review and meta-analysis. Psychopharmacology.
