A recent study published in the Journal of Affective Disorders has found that chronic opioid use may interfere with the brain’s ability to generate a placebo antidepressant response, but does not seem to reduce the effectiveness of ketamine. In a reanalysis of data from a 2023 trial, researchers found that patients on prescription opioids experienced less relief from depression when given a placebo—but showed a normal response when given ketamine. These findings point to a possible interaction between opioid medications and the brain’s natural mood regulation systems, and may help researchers better understand how both drugs and expectations influence mental health outcomes.
The motivation behind this study came from an unexpected observation. In a recent trial, researchers investigated whether ketamine could still produce antidepressant effects even when its psychoactive effects were eliminated by general anesthesia. Surprisingly, patients who received placebo during surgery experienced improvements in depression nearly equal to those who received ketamine.
“In 2023, we published a surprising result from a study about the antidepressant effect of ketamine. In that study, we attempted to ‘take the trip out’ of ketamine by administering it to depressed patients who were receiving general anesthesia for surgery,” explained study author Boris D. Heifets, an associate professor of anesthesiology, perioperative and pain medicine at the Stanford University School of Medicine and co-director of the Exploratory Therapeutics Laboratory.
“That study was designed to be truly blind, in the sense that participants wouldn’t know which treatment they received (a rarity in studies with psychedelic-class drugs), and designed to test the idea that ketamine might have antidepressant effects independent of its acute psychoactive effects (the ‘trip’).”
“We found that patients who got ketamine under anesthesia did very well (>50% treatment response, ~30% remission from depression). We also found that the placebo group did similarly well – in fact, there was no difference between ketamine and placebo, which some took to mean that ketamine is no better than placebo.
“To me and Theresa Lii, the lead author of both, we thought the most interesting result was the massive placebo effect – which suggested that when you drive large expectations (as is often done in psychedelic studies), but never have a ‘moment of betrayal’ where participants discover they got placebo, you can achieve powerful and perhaps lasting antidepressant effects. This new study, published last month, is a reanalysis of our data from 2023 and takes a much closer look at the placebo effect.”
Opioids, such as morphine and oxycodone, activate the brain’s opioid receptors and are commonly used to treat chronic pain. Ketamine, originally developed as an anesthetic, has gained attention in recent years for its rapid antidepressant effects. Both opioids and ketamine appear to influence mood through pathways involving the brain’s endogenous opioid system—a network that helps regulate pain, pleasure, and emotional responses. Past research has suggested that this system also plays a role in placebo responses, including those seen in antidepressant trials.
Because chronic opioid use can alter the sensitivity of the opioid system, the researchers wondered whether such use might reduce the placebo response in depressed individuals. To test this idea, Heifets and his colleagues reexamined data from their 2023 study involving 40 adults with major depressive disorder who were undergoing routine surgery under general anesthesia. Half of the participants received a single intravenous dose of ketamine, while the other half received a saline placebo. The researchers then assessed depression symptoms using the Montgomery–Åsberg Depression Rating Scale (MADRS) over the two weeks following treatment.
In this new analysis, participants were categorized based on whether they were using prescription opioid medications at the time of screening. Of the 40 participants, 16 were opioid users. Importantly, people taking high opioid doses or medications that act differently on opioid receptors were excluded. Pain levels before and after surgery were measured to ensure that any mood changes were not simply due to differences in physical discomfort.
The analysis revealed that patients who were taking opioids at the start of the study experienced less improvement in depression symptoms after receiving placebo. On average, their MADRS scores dropped much less than those of non-opioid users, indicating a weaker placebo response. In contrast, among patients who received ketamine, there was no meaningful difference in depression outcomes between opioid users and non-users.
The findings indicate that “long term opioid use may interfere with the placebo antidepressant response,” Heifets told PsyPost. “Endogenous opioids (like ‘endorphins’) are known to play a role in the placebo analgesia response, but so far there isn’t much known about the placebo antidepressant response. This study suggests that these different types of placebo response may share a mechanism.”
To strengthen their findings, the researchers ran several sensitivity tests. They used an alternative self-report depression measure known as the Hospital Anxiety and Depression Scale (HADS), which includes both mood and anxiety items and is commonly used in hospital settings. Results from the HADS supported the initial finding: the dampening effect of opioid use on the placebo response became more pronounced over time, while no such effect was seen with ketamine.
Importantly, the team ruled out pain as a possible explanation for their findings. There was very little correlation between patients’ reported pain levels and their depression symptoms after treatment. Even though opioid users did tend to report more postoperative pain, this did not explain their reduced placebo response.
So why would opioid use weaken the brain’s response to placebo, but not to ketamine? One possibility is that chronic exposure to opioid medications might desensitize or disrupt the body’s natural opioid system. Since this system is thought to play a role in the placebo effect, such changes could reduce a person’s ability to experience mood improvements from positive expectations alone. Ketamine, on the other hand, may work through mechanisms that bypass or even reverse these opioid-related changes, restoring the brain’s sensitivity to mood-regulating signals.
“The ‘placebo effect’ is a complex and powerful response with a biological mechanism,” Heifets said. “Ketamine may act by ‘resetting’ placebo sensitivity. We and others have proposed that psychedelic-class drugs, like ketamine, might work through the same biological pathways that placebo uses. As you can imagine, that would make it difficult to untangle what is “placebo” and what is ‘drug effect” in a psychedelic trial – this question has been a major challenge for studies involving drugs like psilocybin and MDMA.”
The researchers acknowledged some limitations. This was a post hoc analysis, meaning the study was not originally designed to examine opioid effects specifically. The sample size was small, with just 7 opioid users in the placebo group and 9 in the ketamine group, increasing the chance of statistical noise. The researchers also did not have precise data on how closely participants followed their prescribed opioid regimens, or when they last took their medication before the study.
“This was a reanalysis of a small study,” Heifets noted. “It is far from proof of the ideas we are putting forward, but it does support some new thinking about how psychedelic-class drugs work, and how strong placebo effects work.”
Despite these limitations, the findings raise important questions about how common medications like opioids may interfere with both drug-based and placebo-based treatments for depression. Many individuals with depression are also prescribed opioids, and yet this overlap has received relatively little attention in clinical research. If opioids suppress the brain’s natural placebo responses, they could unknowingly dampen the effectiveness of both experimental treatments and standard care.
The authors suggest that future research should directly investigate how opioid exposure—both short- and long-term—interacts with treatment outcomes in antidepressant trials. They also propose that tools like opioid antagonists (which block opioid receptors) could be used to probe the brain’s placebo pathways and better understand how expectations, neurochemistry, and treatment responses are connected.
These findings also have implications for the design of clinical trials, especially in the emerging field of psychedelic therapy. Traditional double-blind studies often struggle to separate drug effects from expectation effects when mind-altering substances like ketamine or psilocybin are examined. If placebo responses themselves can be harnessed and modulated through biological systems, this could open the door to more personalized and effective treatments—even ones that don’t rely solely on pharmacology.
“One of the major challenges for studying psychedelic therapies is that the classic ‘randomized double blind trial’ does not really work well – participants usually know what they got, and attempts to confuse participants about what they received could actually work against one of the nominal goals of psychedelic therapy, which involves gaining insight into one’s condition and one’s self,” Heifets explained. “We think that understanding the mechanism of placebo will give us insight into how to maximize the potential benefits of psychedelics.”
The study, “Opioids diminish the placebo antidepressant response: Observational post hoc findings from a randomized controlled ketamine trial,” was authored by Theresa R. Lii, Josephine R. Flohr, Robin L. Okada, Lisa J. Cianfichi, Laura M. Hack, Alan F. Schatzberg, and Boris D. Heifets.
