New evidence suggests brain’s opioid system helps mediate ketamine’s antidepressant effects

A new study published in Nature Medicine provides more evidence that ketamine’s rapid antidepressant effects may be partially dependent on the brain’s opioid system. The researchers found that blocking opioid receptors with the drug naltrexone reduced both the brain’s glutamate response and the clinical antidepressant effects typically seen after ketamine infusion. These findings offer new insights into how ketamine works and could help guide more personalized treatments for depression in the future.

Ketamine is best known as a fast-acting antidepressant that can relieve symptoms within hours, even for people who have not responded to traditional medications. It has become a focus of major interest in psychiatry due to its ability to improve mood rapidly, especially in severe and treatment-resistant depression. But exactly how ketamine works remains an open question.

Most research has focused on ketamine’s ability to influence glutamate, the brain’s main excitatory neurotransmitter. Ketamine blocks certain receptors that usually inhibit brain activity. By doing so, it triggers a burst of glutamate release that is thought to spark changes in neural circuits related to mood regulation. These effects include increased synaptic plasticity and the growth of new connections between neurons.

However, some researchers have begun to question whether the glutamate pathway tells the whole story. Preclinical studies have suggested that the body’s opioid system—normally associated with pain relief and pleasure—might also play a role. For example, animal studies have shown that ketamine’s antidepressant-like effects are reduced when opioid receptors are blocked. Clinical studies have been limited but hint in a similar direction.

This new study was designed to test whether the opioid system helps shape the brain’s glutamate response to ketamine, and whether this interaction matters for mood improvement.

“Ketamine is a fast-acting antidepressant, including for people who have not responded to other treatments, but the brain mechanisms behind these rapid effects are not fully understood. Most work has focused on glutamatergic signalling; however emerging evidence suggests the brain’s opioid system may also contribute. We set out to test whether blocking opioid receptors would alter ketamine’s acute glutamatergic and clinical effects in individuals with depression,” said study author Luke Jelen, a clinical lecturer in psychiatry at King’s College London.

The study involved 26 adults with moderate to severe depression who had not responded well to at least one prior antidepressant treatment. Each participant took part in two sessions, spaced several weeks apart.

In both sessions, participants received an intravenous infusion of ketamine while lying in an MRI scanner. In one session, they received a placebo pill before the infusion. In the other, they were given a 50 milligram dose of naltrexone—an opioid receptor blocker used to treat opioid and alcohol use disorders. The study was double-blind, meaning neither the participants nor the researchers knew which pill was given during each session.

The researchers used a technique called functional magnetic resonance spectroscopy to monitor real-time changes in glutamatergic activity in a part of the brain called the anterior cingulate cortex. This region has been linked to mood regulation and is often studied in depression research. The researchers also assessed depression symptoms before and after each session using several rating scales, including the clinician-rated Montgomery–Åsberg Depression Rating Scale.

When participants received ketamine after the placebo pill, their brains showed the expected increase in glutamatergic activity. This was measured as an increase in the ratio of glutamate and glutamine to a reference metabolite called total N-acetylaspartate. Participants also experienced a substantial improvement in depressive symptoms the day after the infusion.

However, when participants were pretreated with naltrexone, the picture changed. The increase in brain glutamatergic activity during the ketamine infusion was significantly reduced. At the same time, the antidepressant effect of ketamine—while still present—was blunted. On the primary depression scale, scores improved less than in the placebo condition, and the effect size was moderate. In contrast, self-reported measures of mood and pleasure did not show a statistically significant difference between the two conditions.

These findings suggest that ketamine’s rapid effects on mood may rely, at least in part, on a dynamic interaction between the brain’s glutamate and opioid systems. One possibility is that blocking the opioid system reduces the amount of glutamate released, or interferes with how glutamate supports the brain’s ability to adapt and reorganize in response to treatment.

The imaging data pointed to changes in brain chemistry that occurred within the first half hour of the ketamine infusion, a time window that aligns with prior research showing peak changes in glutamate levels. While this study focused on a single dose of racemic ketamine, other research has suggested that the S-enantiomer of ketamine, which has higher affinity for opioid receptors, may play a stronger role in the drug’s antidepressant effects.

“In 26 adults with major depressive disorder, taking 50 mg oral naltrexone (opioid antagonist) before a standard ketamine infusion (0.5 mg/kg over 40 min) reduced both the acute ketamine-induced increase in glutamatergic activity in the anterior cingulate (a brain region involved in mood regulation) and the next-day improvement on a clinician-rated depression scale,” Jelen told PsyPost. “This suggests the opioid system helps mediate ketamine’s acute antidepressant response.”

“Importantly, ketamine is not classified as an opioid and does not bind to opioid receptors with high affinity like morphine or heroin. Instead, these findings point to a dynamic interaction between glutamatergic and opioid systems which may work together to support ketamine’s rapid action.”

The authors caution that their study was small and focused on brain chemistry rather than long-term treatment outcomes. Because of its crossover design, each participant served as their own control, but the number of participants was still limited. While the reduction in glutamate activity and mood improvement was statistically significant when naltrexone was used, the findings should be replicated in larger and more diverse samples.

Another open question is whether these effects differ between males and females. Although the study was not designed to test sex differences, exploratory analyses suggested that the interaction between ketamine and the opioid system may be more pronounced in male participants.

“We observed a possible sex-related effect: the naltrexone-related dampening of glutamatergic activity appeared more pronounced in males than females,” Jelen said. “This analysis was exploratory and the study was not powered to test sex differences, so it requires confirmation, although it aligns with some preclinical reports.”

In the long run, this line of research may help identify who is most likely to benefit from ketamine treatment and under what conditions. If certain people rely more on the opioid system for the antidepressant effects of ketamine, clinicians may need to account for this when planning treatment. For example, people taking opioid blockers like naltrexone or those with altered opioid signaling might experience weaker benefits.

“Next, we need a larger well-powered trial that includes a placebo-infusion arm, adds PET imaging to quantify opioid-receptor engagement, and pre-specifies sex-stratified analyses,” Jelen explained. “Examining repeated dosing and longer follow-up will show whether these acute effects translate to clinical outcomes. Ultimately, understanding ketamine’s mechanisms should help us personalize treatment- identifying who benefits, under what conditions, and how to do so safely.”

The study, “Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study,” was authored by Luke A. Jelen, David J. Lythgoe, James M. Stone, Allan H. Young, and Mitul A. Mehta.