Low-dose buprenorphine after a ketamine infusion and suicidal thoughts in depression

The question

Ketamine can quickly reduce suicidal thoughts, but the effect fades. Can a low dose of buprenorphine, a medicine that partly activates the brain’s opioid receptors, taken afterwards keep those gains going?

What they did

At one outpatient centre in the United States, 50 adults with major depressive disorder and a score of at least 6 on the Scale for Suicide Ideation (SSI) received a single intravenous ketamine infusion (0.5 mg/kg over 40 minutes), given openly. Starting 48 hours later, they were randomly assigned, with neither participants nor staff knowing who got what, to 4 weeks of sublingual (under the tongue) buprenorphine at 0.2 to 0.8 mg per day or a matching placebo. Suicidal thinking was measured weekly from day 1 to day 31. Recruitment ran from November 2020 to March 2025.

What they found

Forty-five participants completed at least one week of the follow-on treatment. Suicidal ideation scores fell significantly in both groups, but more so with buprenorphine (mean change -11.6, SD=5.8; N=23) than with placebo (mean change -6.3, SD=7; N=22), a difference of moderate-to-large size (Glass delta=0.76, 95% CI 0.11 to 1.39). Statistical modelling showed the groups’ paths over time differed significantly (p<0.001). Depression scores did not differ significantly between the two groups, and no serious treatment-related adverse events were reported.

The fine print

The trial was small and run at a single site, so results may not generalize. Everyone received ketamine openly, without a ketamine placebo comparison, so this tests the add-on only. Follow-up ended at about one month, and depression scores showed no group difference, which makes the specificity of the suicidal-ideation finding harder to interpret. Buprenorphine is an opioid medicine, and longer-term safety was not assessed here. This summary is based on the abstract alone.

What it means

In this small trial, adding a low dose of buprenorphine after a ketamine infusion was linked to a larger and longer-lasting drop in suicidal thinking than placebo, without serious side effects reported. Larger and longer studies are needed before this could be considered an established approach.

Evidence grade: Moderate. A randomized, double-blind, placebo-controlled trial, but small (45 analyzed), at a single centre, with only about a month of follow-up and the ketamine infusion given open-label.

This summary is based on the study’s published abstract.