UNDERSTANDING AND HARNESSING THE OPIOID EFFECTS OF KETAMINE

Ketamine has become a more commonly used agent for refractory depressed patients, primarily via intravenous infusion of racemic agent or the intranasally administered esketamine enantiomer. The drug has been largely thought to act via NMDA receptor antagonism; however, our group has argued that the rapid antidepressant effects are mediated through mu-opioid receptor (MOR) agonism. In the first part of the talk, we review the reasoning beyond our hypothesis and describe our study (Williams N et al Am J Psychiatry 2018) in which naltrexone or placebo was administered 40 minutes prior to an intravenous ketamine infusion at 0.5mg /kg in a double-blind, random order, crossover design separated by 2-9 weeks. We observed significant reduction in depression in the ketamine plus placebo group that was attenuated by pre-administration of naltrexone. Subsequent to this human experiment, there have been some 9 reports that demonstrated in rodents that the behavioral effects of ketamine were blocked by pre-administration of naltrexone. Our human experiment has recently been replicated by Luke Jelen and colleagues and published in Nature Medicine (2025). By combining the basic naltrexone versus placebo protocol with fMRI, it appeared that the opioid effect preceded the NMDA antagonism and accounted for the rapid antidepressant effect. In the pre-clinical studies one key issue has remained unanswered: namely, is the MOR effect of ketamine due to it relatively weak MOR agonism (similar to its degree of NMDA antagonism) or does it reflect a release of endogenous opioids such as b-endorphin? Using a beta endorphin antibody, Pittenger’s group (Translational Psychiatry 2024) replicated the naltrexone blockade of ketamine’s behavioral effects in rodents, suggesting the drug’s MOR effects may largely reflect mu opioid release. The effect of ketamine on MOR may explain why other NMDA antagonists (such as memantine) have not been shown to have antidepressant properties. We have hypothesized that the antidepressant and anti-suicide effects of ketamine could be extended by low doses of buprenorphine, an MOR partial agonist used to treat opioid use disorder. Yovell et al (Am J Psychiatry 2016) reported that over 4 weeks. low doses of buprenorphine (0.4-0.8mg per day) in hospitalized borderline personality or unipolar depressed patients reduced suicidal ideation significantly more than did placebo; however, patients still demonstrated considerable suicidal severity. We repeated (Tucciarone J et al, SoBP Annual Meeting 2025) the four week low dose buprenorphine trial after giving an open label infusion of ketamine and in unipolar suicidal patients and observed not only significant differences between drug and placebo in reduction of suicidal ideation but overall lower post treatment suicidal ideation than was seen in the Yovell et al study. These data point to potential harnessing of opioid activity to reduce suicidality. After the four weeks, the patients’ buprenorphine or placebo was stopped and they were followed blindly to medication treatment for 2 weeks. Transient worsening of suicide and depression ratings was observed in the patients who stopped buprenorphine as compared to placebo. Physical signs or symptoms of opioid withdrawal were not observed. Further studies are needed to understand how long to treat patients with buprenorphine and to determine the optimal withdrawal protocol.

References

Williams NR, Heifets BD, Blasey C, et al. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. Am J Psychiatry, 2018;175(12):1205-1215. Jelen LA, Lythgoe DJ, Stone JM, et al. Effect of naltrexone pretreatment on ketamineinduced glutamatergic activity and symptoms of depression: a randomized crossover study. Nature Medicine, 2025;31:2958–2966.