Systematic review · 2026
Does ketamine's antidepressant effect work partly through the opioid system?
- Original title
- Is the antidepressant efficacy of ketamine and esketamine mediated via opioid mechanisms?
- Authors
- Lu A, Xu H, Le GH, et al.
- Journal
- European psychiatry : the journal of the Association of European Psychiatrists, 2026
- Molecules
- Ketamine, Esketamine
- Conditions
- Treatment-resistant depression, Depression
- Participants
- 790
- Evidence grade
- Low
- Source
- Read the original paper
The question
Ketamine and esketamine can lift depression quickly. This review asked whether the body’s opioid system plays a role in that antidepressant effect, rather than glutamate signalling alone.
What they did
Researchers searched four research databases (PubMed, Cochrane Library, Embase and PsycINFO) from their earliest records to 27 September 2025. They looked for any study, in people or animals, that tested whether the opioid system is involved in ketamine’s or esketamine’s antidepressant action. They found 16 studies: 12 clinical studies covering 790 people, and 4 animal studies. Clinical designs ranged from randomized controlled trials to case reports, before-and-after studies and observational cohorts.
What they found
The results did not line up. Naltrexone, a drug that blocks opioid receptors, weakened ketamine’s antidepressant effect in three studies, but four studies found no such weakening and one reported mixed evidence. Three studies looked at genetic markers for opioid receptor subtypes (OPRM1 and OPRD1) and the results were inconclusive. Opioid use was not linked to how well people responded to ketamine. Only one of the 16 studies looked at esketamine.
The fine print
This is a small evidence base with very mixed study designs, including case reports and animal models, so the findings cannot be pooled into a single reliable estimate. Only one study examined esketamine, and few studies directly measured opioid receptor subtypes. The review does not report how long participants were followed or the size of individual trials. This summary is based on the abstract only.
What it means
The opioid system may play some part in how ketamine eases depression, but current evidence suggests it is more of a context-dependent modifier than the main driver. The question remains open and needs better-designed studies.
Evidence grade: Low. A systematic review that pools a small, mixed set of studies — including case reports, pre-post studies and animal research — with inconsistent findings.
This summary is based on the study’s published abstract.