A Promising, Yet Controversial, Approach to Treating Depression


Mounting evidence shows the endogenous opioid system is a potential therapeutic target for mood disorders, yet questions remain.


The currently available treatment options for depressive disorders have limitations and many sufferers are left with either residual symptoms (treatment refractory depression), or worse-a syndrome of lack of response, or treatment-resistant depression (TRD).1 There is a need to expand the currently available options and recently, after having been the standard of care in the 19th century, the opioid system has re-emerged as a potential therapeutic target for mood disorders.2

There is evidence from neurobiological studies that opioid receptors are densely distributed in cortical areas involved in stress response, as well as subcortical areas involved in emotion regulation.3 Clinically, the kappa opioid receptors in particular have been shown to have antidepressant effect when blocked and have led to dysphoric reactions when activated, while mu receptor blockade has not had any effect.4,5

As a result, use of ketamine/esketamine, which may exert its action through binding to the kappa receptors, has rapidly grown in the field of psychiatry due to its rapid antidepressant effect.6,7 Likewise, buprenorphine, in addition to acting as a partial agonist at mu receptors and an antagonist at delta, also binds to kappa receptors where it acts as the strongest human receptor antagonist.8

In our review of the literature, we evaluated the state of science pertaining to the potential of buprenorphine to serve such an antidepressant role.9 A total of 12 studies emerged reporting positive outcomes. Overall, we found that low-dose buprenorphine has successfully been utilized as augmentation of pharmacotherapy for depression with an effect size comparable, if not greater than, most currently adopted augmentation strategies.9

The two most striking randomized controlled trials included in our review are from 2016.10,11 In a study by Fava and colleagues,10 a combination of buprenorphine and a specific mu receptor antagonist, samidorphan, in 1:1 doses of 2-2mg and 8-8mg (buprenorphine-samidorphan combination) were used in 142 patients with TRD as augmentation. A significant antidepressant effect was noted at four weeks of treatment with both doses; however, this effect was much greater with the lower doses.

In the second noteworthy study, Yovell and colleagues11 used ultra-low doses of buprenorphine (0.1 mg to 0.44 mg/day) in 40 severely suicidal patients without substance use disorders and found a drastic improvement in mood and a robust and rapid resolution of suicidal ideation.

This presents a very promising approach to the treatment of TRD. At such low doses, buprenorphine has a fairly benign safety profile and is well tolerated.

In both studies, withdrawal was not noted on discontinuation; however, these trials were all time-limited in duration. Of consideration, buprenorphine is a Schedule III controlled substance and long term-use can certainly lead to risks or misuse, abuse, and diversion.

Clinical bottom line

The endogenous opioid system presents yet another therapeutic target with mounting evidence of its involvement in mood disorders. Significant evidence supports an antidepressant effect of low dose (<= 2 mg) buprenorphine in individuals with TRD. Before this becomes widely implemented clinically, however, further prospective randomized controlled trials should be undertaken.


Dr Stanciu is Assistant Professor of Psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH.He is Addiction Section Editor for Psychiatric Times. The author reports no conflicts of interest concerning the subject matter of this article.


1. American Psychiatric Association. 2010. Practice guideline for the treatment of patients with major depressive disorder (3rd Ed). https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Accessed March 12, 2020.

2. Carlezon WA, Beguin C, Knoll AT, et al. Kappa-opioid ligands in the study and treatment of mood disorders. Pharmacol Ther. 2009;123, 334-343.

3. Lutz PE, Kieffer BL. Opioid Receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36(3):195-206

4. Falcon E, Browne CA, Leon RM, et al. Antidepressant-like effects of buprenorphine are mediated by kappa opioid receptors. Neuropsychopharmacology. 2016; 41:2344-2351.

5. Terenius L, Wahlstrom, JA, Bigelow GE, et al. Naloxone (Narcan) treatment in depression: clinical observations and effects on CSF endorphins and monoamine metabolites. Psychopharmacology (Berl). 1977;54:31-33.

6. Williams NR, Heifets BD, Blasey C, et al. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. Am J Psychiatry. 2018;175:1205-1215. https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2018.18020138. Accessed March 12, 2020.

7. Vilevielle T, Mion G. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013;19:370-380.

8. Cowan A. Buprenorphine: the basic pharmacology revisited. J Addict Med. 2007;1:68-72.

9. Stanciu CN, Glass OM, Penders MT. Use of Buprenorphine in treatment of refractory depression – A review of current literature. Asian J Psychiatry. 2017;26:94-98.

10. Fava M, Memisoglu A, Thase, ME, et al. Opioid modulation with nuprenorphine-samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry. 2016;173, 5 499-508.

11. Yovell Y, Bar G, Mehsiah, M, et al. Ultra-low dose buprenorphine as a time limited treatment for severe suicidal ideation: a randomized controlled trial. Am J Psychiatry. 2016;173:491-498.

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