Ketamine Antidepressant Effects May Rely on Opioid System
New research suggests ketamine’s rapid mood-lifting benefits could be linked to opioid receptor activity in the brain.
A small randomized trial found that blocking the opioid system with naltrexone weakened ketamine’s antidepressant effects and blunted brain glutamate activity, suggesting the opioid system may play a role in ketamine’s rapid mood benefits.
Study Details
Ketamine has gained attention as a rapid-acting antidepressant for treatment-resistant depression. Traditionally, its effects have been linked to a surge in glutamate a brain chemical involved in mood and neural plasticity. However, prior evidence hinted that opioid receptor activation might also contribute.
To explore this, researchers at King’s College London studied 26 adults with moderate-to-severe depression. Each participant received both placebo and naltrexone pretreatment in a crossover design before receiving intravenous ketamine.
Methodology
The study was designed as a randomized, double-blind, crossover trial that enrolled 26 adults with moderate-to-severe depression. Each participant received two different pretreatments, separated by three weeks: a single oral dose of 50 mg naltrexone or a placebo, given one hour before an intravenous ketamine infusion at 0.5 mg/kg. During the first 30 minutes of infusion, researchers measured glutamatergic activity in the anterior cingulate cortex using functional magnetic resonance spectroscopy. Depressive symptoms were assessed both before infusion and 24 hours afterward, when ketamine’s antidepressant effects typically peak, using the Montgomery-Åsberg Depression Rating Scale (MADRS).face
Key Findings
For Patients
This study suggests that ketamine’s antidepressant action may not be explained by glutamate alone. The findings point to a possible role of the brain’s opioid system in shaping how ketamine works. While this is important for understanding how treatments might be tailored in the future, it does not mean patients should stop or alter their current medications. Anyone receiving ketamine therapy or taking opioid blockers such as naltrexone should continue following their clinician’s guidance, since this research is early and not yet practice-changing.
For Clinicians
For healthcare providers, the results highlight the complexity of ketamine’s mechanisms and the need to consider both glutamatergic and opioid systems in future treatment strategies. However, this was a small mechanistic study rather than a definitive clinical trial, so it should not change prescribing practices at present. The study does underscore the importance of monitoring emerging evidence, particularly research that may clarify whether sex differences or concurrent use of opioid antagonists influence treatment outcomes. Larger, controlled trials will be essential to determine how, or if, these findings should inform clinical decision-making.