Summary: Researchers have identified the first pharmacological strategy to extend the rapid but typically short-lived antisuicidal effects of ketamine. A single ketamine infusion can sharply reduce severe suicidal thoughts within hours, yet that relief commonly wanes after about a week. This new approach uses a daily, low-dose course of buprenorphine for four weeks after ketamine to maintain and prolong reductions in suicidal ideation.
In a randomized, double-blind clinical trial of adults with major depressive disorder (MDD) and active suicidal ideation, adding a four-week regimen of sublingual, low-dose buprenorphine after a single ketamine infusion produced larger and more durable decreases in suicidal thinking than placebo. The treatment sequence offers a practical option to stabilize patients during high-risk periods while clinicians arrange longer-term psychiatric care.
Key Facts
- Durability breakthrough: In a double-blind trial of 45 participants who entered treatment after a single ketamine infusion, daily low-dose buprenorphine for four weeks significantly extended ketamine’s antisuicidal benefits.
- High response rate: After one month, 78% of patients who received buprenorphine remained responsive (a greater than 50% reduction in suicide ideation scores) versus 48% in the placebo group.
- Clinically meaningful change: Participants began with a mean score of 15 on a 38-point suicide ideation scale (moderate severity). After one month the placebo group averaged 8.7 (above the clinical threshold of 6), while the buprenorphine group averaged 3.6 (well below that threshold).
- Separate mechanisms: Buprenorphine prolonged ketamine’s antisuicidal effect but did not extend its antidepressant effect, reinforcing evidence that suicidality and depressive symptoms can have distinct neurobiological and pharmacological pathways.
- Opioid system involvement: The sequence builds on prior findings that ketamine’s rapid effects depend in part on the brain’s endogenous opioid system; buprenorphine targets those same opioid receptors at very low doses to sustain benefit.
Source: Stanford
Ketamine, widely used as an anesthetic and increasingly used off-label for acute depression and suicidal ideation, often produces dramatic, rapid relief from suicidal thoughts within hours to days. However, without follow-up treatment, that relief usually fades within about a week. This trial tested whether low-dose buprenorphine, a partial opioid receptor agonist used for pain and opioid use disorder, could maintain ketamine’s antisuicidal effect for a longer period.
The trial enrolled adults in a major depressive episode lasting at least eight weeks who had not responded adequately to standard antidepressants and who had a minimum score indicating active suicidal ideation. All participants received a single 40-minute intravenous ketamine infusion (0.5 mg/kg). Forty-eight hours later they began daily sublingual lozenges either containing buprenorphine or placebo for four weeks. Buprenorphine was titrated from 0.2 mg/day in week one to 0.8 mg/day in week four—roughly 5%–10% of typical pain-management or opioid-replacement doses. Participants were followed for two additional weeks after stopping the study medication to monitor mood, suicidal ideation, and any withdrawal symptoms.
Excluded from trials
Patients with prominent suicidality have often been excluded from clinical trials for ethical and safety reasons, leaving a gap in evidence for treatments that directly target suicidal thoughts. The investigators intentionally enrolled this understudied, high-risk group to evaluate an intervention specifically aimed at reducing suicidal ideation. There are currently no FDA-approved drugs for suicidal ideation in MDD, in part because most trials avoid this population.
Better in combination?
Previous work from the same research center showed that blocking opioid receptors with naltrexone reduced ketamine’s therapeutic benefit, suggesting ketamine’s rapid effects depend partly on endogenous opioid signaling rather than only glutamate antagonism. Earlier studies also reported modest reductions in suicidal ideation with low-dose buprenorphine alone, but most patients in those studies remained clinically suicidal. Combining ketamine’s powerful rapid effect with buprenorphine’s opioid-targeted support produced a stronger and more durable response in this trial.
Inescapable negativity
The trial included participants who had endured chronic suicidal thinking despite therapy, multiple medications, or hospitalization. One participant described a persistent “tsunami” of self-hatred and had reached a crisis point before entering the study. For many enrolled patients, the ketamine infusion produced immediate relief from suicidal impulses, and the buprenorphine follow-up helped preserve that relief over weeks, enabling engagement with other treatments and supports.
Profound effects
Quantitatively, both groups showed significant reductions in suicide ideation scores after ketamine, but the buprenorphine group improved more (mean change −11.6, SD 5.8) than the placebo group (mean change −6.3, SD 7), with a moderate-to-large effect size (Glass delta = 0.76) and a significant time-by-treatment interaction. Depression scores fell after ketamine in both groups but did not differ significantly between them, indicating the prolonged antisuicidal benefit was not simply a continuation of antidepressant effects. No serious treatment-related adverse events were reported, and withdrawal symptoms after stopping buprenorphine were minimal.
When patients completed the four-week buprenorphine course, suicidal ideation scores rose slightly but, on average, remained below the clinical threshold at six weeks. The results suggest a feasible, short-term treatment sequence to reduce imminent suicide risk while providing a bridge to longer-term therapies that require more time to take effect.
A life worth living
For some participants the combination proved transformative. One patient who received buprenorphine described a dramatic reduction in suicidal urges and a renewed sense that life was worth saving. While benefits waned over time for some, the sequence provided critical stabilization and an opportunity to pursue ongoing care.
Researchers emphasize the need for larger trials to confirm these findings, test longer or repeated buprenorphine courses, and determine whether the approach helps suicidality in other forms of depression, such as bipolar depression.
A contributor from Mariner Pharmacy assisted with the work.
Funding: The study was supported by the American Foundation for Suicide Prevention, the Pritzker Foundation, and the National Institutes of Health (grants K08-DA055157 and UL1TR003142-01).
Key Questions Answered:
A: Evidence indicates ketamine’s rapid reduction of suicidal ideation relies in part on activation of the brain’s endogenous opioid system rather than solely on glutamate blockade. Low-dose buprenorphine targets the same opioid receptors and appears to sustain those protective neural pathways after ketamine, acting like a stabilizer that prolongs antisuicidal effects.
A: Traditional antidepressants typically take weeks to become effective, which leaves patients in acute crisis vulnerable. Ketamine can provide rapid reduction in suicidal thinking within hours, and a short buprenorphine course can extend that window of safety so patients can access psychotherapy, medication adjustments, and other supports that need more time to work.
A: Many clinical trials exclude patients with active suicidal ideation because of ethical and safety concerns, limiting evidence for treatments that directly target suicidality. This trial deliberately enrolled such patients, helping fill a critical research gap and demonstrating a new therapeutic pathway for a high-risk, understudied population.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper was reviewed in full.
- Additional context was added by editorial staff.
About this psychopharmacology research news
Author: Nina Bai
Source: Stanford
Contact: Nina Bai – Stanford
Image: Image credited to Neuroscience News
Original Research: Open access. “Low-Dose Buprenorphine Following Ketamine Treatment for Suicidal Ideation in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial” by Jason M. Tucciarone et al., American Journal of Psychiatry. DOI: 10.1176/appi.ajp.20250840
Abstract
Low-Dose Buprenorphine Following Ketamine Treatment for Suicidal Ideation in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial
Objective:
Ketamine rapidly reduces suicidal ideation in MDD but its benefits are transient. Preclinical and clinical data suggest ketamine’s effects may involve modulation of mu-opioid receptors (MOR). This trial tested whether low-dose sublingual buprenorphine, a partial MOR agonist, could safely prolong the antisuicidal effects of intravenous ketamine.
Methods:
In a single-center, randomized, double-blind, placebo-controlled trial, adults with MDD and a Scale for Suicide Ideation (SSI) total score ≥6 received a single open-label ketamine infusion (0.5 mg/kg over 40 minutes). Beginning 48 hours later, participants were randomized 1:1 to sublingual buprenorphine (0.2–0.8 mg/day) or matched placebo for four weeks. The primary outcome was change in SSI total score assessed weekly through day 31.
Results:
Between November 2020 and March 2025, 50 participants received ketamine and 45 completed at least one week of follow-on treatment. Both groups experienced significant SSI reductions, with greater improvement in the buprenorphine group (mean change −11.6, SD=5.8; N=23) than in the placebo group (mean change −6.3, SD=7; N=22). 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 were reported.
Conclusions:
This randomized controlled trial provides the first pharmacological evidence that low-dose buprenorphine can significantly sustain and enhance ketamine’s antisuicidal effects in MDD. The sequence may offer a scalable, short-term intervention to reduce suicide risk while patients access longer-term psychiatric care.