Low-Dose Buprenorphine Following Ketamine Treatment for Suicidal Ideation in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial.
Jason M Tucciarone, Igor D. Bandeira, Christine Blasey, Ian H. Kratter, Jarrod Ehrie, Jennifer Keller, Heather Pankow, Maureen Chang, Jessica Hawkins, Audrey G. Evers, Rebecca A. Bernert, Charles DeBattista, Henry Truong, Carolyn I. Rodríguez, Boris D. Heifets, Alan F. Schatzberg
The American journal of psychiatry June 1, 2026 DOI: 10.1176/appi.ajp.20250840 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Double-blind Open-label Peer reviewed |
|---|---|
| Sample size | 50 |
| Population | Adults with major depressive disorder and a Scale for Suicide Ideation total score ≥6 |
| Interventions | Intravenous ketamine Sublingual buprenorphine |
| Dose | 0.2 to 0.8 mg/day |
| Duration | 4-week follow-on treatment, assessed weekly from day 1 through day 31 |
| Topics | Depression Esketamine Ketamine |
| Keywords | Bipolar disorder Buprenorphine Ketamine/esketamine Suicide prevention |
| Citations | 5 |
| Key findings | Low-dose sublingual buprenorphine significantly sustained and enhanced the antisuicidal effects of ketamine compared to placebo in adults with major depressive disorder. |
Abstract
Ketamine rapidly reduces suicidal ideation in major depressive disorder (MDD), but its effects are transient. Preclinical and clinical studies suggest that ketamine's antidepressant and antisuicidal effects may be partly mediated by mu-opioid receptor (MOR) modulation. The authors investigated the efficacy and safety of low-dose sublingual buprenorphine, a partial MOR agonist, as a follow-on treatment to prolong the effects of intravenous ketamine. This was a randomized, double-blind, placebo-controlled trial conducted at a single outpatient center in the United States. Adults with MDD and a total score ≥6 on the Scale for Suicide Ideation (SSI) were randomly assigned in a 1:1 ratio to receive either sublingual buprenorphine (0.2 to 0.8 mg/day) or a matched placebo for 4 weeks, beginning 48 hours after a single open-label intravenous ketamine infusion (0.5 mg/kg over 40 minutes). The primary outcome was the change in SSI total score, assessed weekly from day 1 through day 31. From November 2020 to March 2025, 50 participants (68% female) received ketamine, of whom 45 completed at least 1 week of follow-on treatment. Both groups showed significant reductions in SSI total scores, with greater improvement in the buprenorphine group (mean change, -11.6, SD=5.8; N=23) than the placebo group (mean change, -6.3, SD=7; N=22) (Glass delta=0.76, 95% CI=0.11, 1.39). Mixed-effects modeling showed a significant time-by-treatment interaction (p<0.001). Depression scores did not differ significantly between groups. No serious treatment-related adverse events occurred. This randomized controlled trial provides the first evidence that a pharmacological intervention, buprenorphine, significantly sustains and enhances the antisuicidal effects of ketamine in MDD. These findings offer a potentially scalable and safe therapeutic option for a population at risk of suicide.
Comparable studies
Other randomized controlled trials on ketamine for depression, most cited first.