According to the National Institute of Mental Health, major depressive disorder (MDD) affected an estimated 7.1% of adults and 13.3% of adolescents in the United States in 2017. Approximately 35.0% and 60.1% of these individuals, respectively, did not receive any type of treatment for their illness. Among those who are prescribed antidepressant medications, an estimated 30% of patients do not show an adequate response to these drugs.2

In efforts to address these high rates of nonresponse to standard depression therapies, researchers continue to explore a wide range of other promising agents, including anti-inflammatory therapies and psilocybin.3,4 In addition, a growing body of research points to the potential benefits of drugs targeting the endogenous opioid system for adjunctive use in MDD treatment. Among various effects on mood regulation, opioid-based therapies have been shown to modulate the negative affective bias and other cognitive deficits that often characterize MDD.

“Opioid receptors are expressed in low, moderate and high densities in each of the brain regions involved in the neural circuitry involved in affective cognition,” wrote the authors of a paper published in April 2020 in Behavioural Pharmacology.2 Mu-opioid receptor activation and kappa-opioid receptor blockade “may modulate activity within these key brain areas and address negative bias by re-balancing amygdala activity.” Researchers are currently exploring the effects and development of such compounds for potential use in patients with treatment-resistant depression.2,5-7

To learn more about the state of research and remaining needs in this area, we interviewed Parnika P. Saxena, MD, psychiatrist at Brockton Neighborhood Health Center in Massachusetts and co-author of a 2019 review on the topic that was published in CNS Drugs, as well as Colleen A. McClung, PhD, professor of psychiatry and clinical and translational science at the University of Pittsburgh Medical Center in Pennsylvania.

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What is known or suspected about the role of opioid receptors in the pathogenesis of MDD?

Dr Saxena: All 3 opioid receptors – mu, delta, and kappa – have demonstrated a role in the pathogenesis of depressive disorders. Opioid receptors are present in reward pathways in different parts of the brain, and dopamine attaches to them which in turn controls hedonic tone, therefore their activation or lack thereof affects dopamine release.

They are also present on serotonin and norepinephric neurons and affect the release of these 2 neurotransmitters as well. Mu and delta agonism induce release of monoamines, and kappa antagonism does the same. Kappa antagonism also blocks upregulation of dynorphin, which leads to increased dopamine release. They also have been hypothesized to affect NMDA (N- methyl d-aspartate) release and subsequently glutamate release, which in turn modulates serotonin release.

Another point of interest: Brains of individuals who completed suicide had a much higher number of mu opioid receptors in the brain due to possible upregulation of the same due to deficiency of an endogenous ligand.2

Dr McClung: Most of the work in this area has been done in animal models, but there have been a few clinical studies. The endogenous opioid system is made up of a family of peptides known as beta-endorphin, the enkephalins, dynorphins, and their receptors. Beta-endorphins, as well as drugs like morphine, bind primarily to mu-opioid receptors. 

Both preclinical and clinical studies suggest that mu-opioid receptor activation can produce antidepressant effects. Furthermore, genetic studies suggest that individuals with lower expression of mu-opioid receptors and a reduced ability to release endogenous opioids may be more vulnerable to depression-related symptoms. 

In contrast, the kappa-opioid receptor, which typically is activated by dynorphins, produces aversive and depressive-like states when stimulated, and blockade of this receptor can produce antidepressant effects in preclinical models. Studies are ongoing to evaluate the possible role of other opiate receptors in mood regulation.  

What are some of the most promising opioid-based therapies being explored for MDD treatment?

Dr Saxena: Methadone, buprenorphine, tramadol, and dextromethorphan have all demonstrated antidepressant effects, however buprenorphine has been the most effective and widely studied. It is unique due to its strong antagonism of kappa-opioid receptor, which not only contributes to antidepressant effectiveness but also has virtually no reward potential, thus making it a much safer choice. A recent study that combined buprenorphine with samidorphan – which blocked any reward potential – showed beneficial effects in treatment-resistant depression, especially at a dose of 2mg per day.8

Tramadol strongly inhibits serotonin and norepinephrine, and multiple case studies have demonstrated its effectiveness in treating treatment-resistant depression as well as obsessive-compulsive disorder.3

Dr McClung: Buprenorphine has been studied in a range of clinical trials for MDD. It is a mu-opioid receptor partial agonist and therefore offers potential advantages compared with a full mu-opioid agonist in terms of safety. Buprenorphine also acts as a kappa-opioid receptor antagonist, and some of its activity as an antidepressant may be mediated through blockade of this receptor. Though clinical studies are limited, in general they find substantial clinical improvements in patients with treatment-resistant depression, including patients who did not respond to electroconvulsive therapy.

What are believed to be some of the unique benefits of these agents compared to existing therapies for MDD?

Dr Saxena: Despite diligent use of medications, a significant percentage of depressed individuals struggle with treatment-resistant depression. Opioidergic agents have shown response in individuals who have failed to respond to conventional treatments. Also, most antidepressant treatments used today have at least a 4-6 week time of action, and in older adults this stretches to 8 weeks. By contrast, buprenorphine has shown results within 1 week, thus causing a dramatic reduction in patient distress and reducing risk of suicidal ideation.9

Dr McClung: Some studies suggest that drugs which target the opiate system may produce rapid antidepressant effects compared to SSRIs, for example, which take weeks to produce a response. Multiple studies have utilized intravenous infusions of synthetic endorphin peptide preparations or synthetic opioids in the treatment of MDD.  In general, the majority of subjects in these clinical trials displayed improvements in depressive symptoms within hours of treatment. Buprenorphine treatment can also produce a rapid antidepressant response, and as mentioned above, may be therapeutic in individuals with otherwise treatment-resistant depression.   

What should be the focus of future research in this area?

Dr Saxena: The risk of abuse due to activation of reward potential has been associated with these medications, and buprenorphine-samidorphan was the first opioidergic antidepressant with a significant body of data with respect to safety and efficacy. Further work should focus on the creation of opioidergic agents that are safe and non-abusable to allow for their re-entrance in the pharmacopoeia.

Dr McClung: The obvious downside of using these types of treatments is the potential for dependence, overdose, and addiction. Current work is examining the efficacy of targeting other, non-mu opioid receptors for treatment of MDD. There may also be the potential to simultaneously give a mu-opioid agonist and antagonist, or some other combination of drugs, which will reduce the potential for dependence and addiction. More knowledge of the downstream signaling cascades in response to receptor activation at a variety of doses will also help researchers develop more targeted therapies with very specific effects. 


  1. National Institute of Mental Health. Major depression. Updated February 2019. Accessed October 27, 2020.
  2. Varastehmoradi B, Wegener G, Sanchez C, Smith KL. Opioid system modulation of cognitive affective bias: implications for the treatment of mood disorders. Behav Pharmacol. 2020;31(2&3):122-135. doi: 10.1097/FBP.0000000000000559
  3. Rodriguez T. Anti-inflammatory treatments for MDD: update and expert interview. Psychiatry Advisor. Published January 15, 2020. Accessed October 27, 2020.
  4. Rodriguez T. A new center at Johns Hopkins builds the case for psychedelic research. Psychiatry Advisor. Published November 4, 2019. Accessed October 27, 2020
  5. Peciña M, Karp JF, Mathew S, Todtenkopf MS, Ehrich EW, Zubieta JK. Endogenous opioid system dysregulation in depression: implications for new therapeutic approachesMol Psychiatry. 2019;24(4):576-587. doi: 10.1038/s41380-018-0117-2
  6. Browne CA, Lucki I. Targeting opioid dysregulation in depression for the development of novel therapeutics. Pharmacol Ther. 2019;201:51-76. doi: 10.1016/j.pharmthera.2019.04.009
  7. Saxena PP, Bodkin JA. Opioidergic agents as antidepressants: rationale and promise. CNS Drugs. 2019;33(1):9-16. doi: 10.1007/s40263-018-0584-7
  8. Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry. 2016;173(5):499-508. doi: 10.1176/appi.ajp.2015.15070921
  9. Bodkin, JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995;15(1):49-57