Ketamine drops suicidal ideation fast, and buprenorphine keeps it down
STUDY: Tucciarone JM et al, Am J Psychiatry 2026
STUDY TYPE: Randomized, double-blind, placebo-controlled trial
FUNDING: American Foundation for Suicide Prevention, Pritzker Foundation, NIDA, NIH
Background
What sustains ketamine’s rapid benefits? Here’s the score so far:
- Lithium failed in a small trial, despite success in sustaining ECT’s benefits
- D-cycloserine, which shares ketamine’s glutamatergic effects, showed promise
- Another glutamatergic, riluzole, failed
- Psychotherapy (CBT) succeeds
Ketamine also has opioid effects, so this trial tested the partial opioid agonist buprenorphine, FDA-approved for opioid use disorder and chronic pain. In 2019, buprenorphine came close to FDA-approval in major depression, where it showed rapid antisuicide effects, but the trials had flaws.
The Study
Although buprenorphine is often combined with naloxone, an opioid blocker that prevents misuse, here they tested it alone. The dose was much 10-times lower than that used for opioid use disorder.
- 50 adults with major depressive disorder and significant suicidal ideation (Suicidal Ideation scale (SSI) ≥ 6), most with treatment-resistant depression.
- All received a single intravenous ketamine infusion (0.5 mg/kg over 40 minutes), then 48 hours later were randomized to sublingual buprenorphine (0.2–0.8 mg/day, titrated weekly) or placebo for 4 weeks.
- Double-blind; most (45) completed at least one week of follow-on treatment.
Results
Ketamine alone dropped suicidal ideation scores by 60% within 48 hours. After that, the groups diverged. Over 4 weeks, the buprenorphine group fell from a mean suicide (SSI) score of 15 to 3.6, while the placebo group leveled off at 8.7 (a NNT of 3).
The mood benefits were less dramatic but still statistically significant. At day 31, 78% of the buprenorphine group met response criteria versus 48% in the placebo group. Depression scores improved in both groups but didn’t differ significantly between them.
When buprenorphine stopped, suicidal ideation ticked back up slightly but didn’t return to baseline. Opioid withdrawal scores stayed in the minimal range.
Unblinding
66% on buprenorphine guessed correctly compared to 32% on placebo (that’s similar to the unblinding in antidepressant trials, and much better than ketamine trials).
Side Effects
Dizziness (22%), oral burning (17%), nausea (13%), and constipation (13%) in the buprenorphine group. No serious adverse events.
Limitations
Small sample (45 analyzable subjects), single center, mostly white participants. The trial wasn’t powered to determine whether ketamine response predicts buprenorphine response. Patients who guessed their treatment assignment may have influenced outcomes.
Practice Implications
- This protocol reduces ketamine exposure, reducing the need for in-office treatment: one ketamine infusion, then sublingual buprenorphine starting at 0.2 mg/day and titrated to 0.6–0.8 mg/day over four weeks. Screen carefully for opioid use disorder and get a urine drug screen first.
- The results are preliminary and suggest a short-term strategy for acutely suicidal patients. Don’t interpret this study as a long-term strategy for depression. The mood effects were not as robust, and long term use of opioids can cause tolerance and, as this VA study suggests, higher suicidality risks upon cessation.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
