Summary: Researchers have identified the first pharmacological approach that meaningfully extends ketamine’s rapid but short-lived antisuicidal benefit. A single ketamine infusion can sharply reduce severe suicidal thoughts within hours, yet that relief typically subsides after about a week. The new strategy adds a four-week course of daily, very low-dose buprenorphine to sustain ketamine’s antisuicidal effect for at least a month.
In a randomized, double-blind clinical trial, patients with major depressive disorder and active suicidal ideation received one ketamine infusion followed 48 hours later by either a daily sublingual low-dose buprenorphine lozenge or a matched placebo for four weeks. The buprenorphine follow-up significantly prolonged reductions in suicidal thinking compared with placebo, offering a practicable treatment sequence that could create a safer window for longer-term therapies to take effect.
Key Facts
- Durability breakthrough: In a double-blind trial of 45 evaluable patients with major depressive disorder and suicidal ideation, a single ketamine infusion followed by four weeks of daily low-dose buprenorphine significantly extended the antisuicidal benefit compared with ketamine plus placebo.
- Large difference in response: After one month, 78% of participants in the buprenorphine arm remained treatment-responsive (suicidal ideation scores reduced by more than half) versus 48% in the placebo arm.
- Clinically meaningful change: Participants entered the trial with an average 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 dropped to an average of 3.6 (below the threshold).
- Different effects on depression and suicidality: Buprenorphine prolonged ketamine’s antisuicidal effects but did not significantly extend its antidepressant effects, supporting the idea that suicidality and depressive symptoms can be driven by distinct neurobiological mechanisms.
- Opioid-system involvement: This regimen builds on prior Stanford findings that ketamine’s therapeutic impact depends in part on the brain’s endogenous opioid system. Buprenorphine’s action at opioid receptors likely helps maintain the protective effect initiated by ketamine.
Source: Stanford
Background: Ketamine, used as an anesthetic and in lower doses for rapid psychiatric relief, can quickly reduce suicidal ideation—often within hours—but its benefits typically fade within a week. Buprenorphine, an opioid partial agonist commonly used for pain and opioid use disorder, was tested here at microdoses (well below standard pain or replacement therapy doses) as a follow-on treatment to sustain ketamine’s effect.
The trial enrolled adults experiencing a major depressive episode lasting at least eight weeks who continued to have clinically significant suicidal ideation despite prior treatment. All participants received a single 40-minute intravenous ketamine infusion (0.5 mg/kg). Beginning 48 hours later, they self-administered a daily sublingual lozenge of either buprenorphine (ramped from 0.2 mg/day to 0.8 mg/day over four weeks) or placebo. Participants could remain on their usual psychiatric medications during the study.
Excluded from trials
Suicidal patients are often underrepresented in clinical research because investigators exclude individuals with active suicidality for safety and ethical reasons. That exclusion has left a critical evidence gap: few therapies have been studied specifically for suicidal ideation, and no medications are currently FDA-approved for suicidal ideation in major depressive disorder. The Stanford team intentionally designed a trial for this high-risk, understudied population.
While ketamine is increasingly used off-label to rapidly reduce suicidal thoughts, repeated intravenous ketamine carries risks—dissociation, transient cardiovascular effects, potential for dependence, and practical barriers such as cost and clinic access. A short, low-dose buprenorphine regimen after a single ketamine infusion may offer a safer, more scalable way to extend antisuicidal protection without repeated ketamine infusions.
Better in combination?
The mechanisms behind ketamine’s rapid clinical benefits are still under study. Initial theories focused on glutamate receptor antagonism, but Stanford research in 2018 showed ketamine’s effects can be blocked by naltrexone, an opioid receptor antagonist, suggesting ketamine activates endogenous opioid pathways as part of its therapeutic action. Buprenorphine, which also modulates opioid receptors, was therefore a rational candidate to prolong ketamine’s benefit.
Earlier work showed modest reductions in suicidality with four weeks of low-dose buprenorphine alone. The current trial tested whether buprenorphine could extend the stronger, faster antisuicidal effect that ketamine provides.
Inescapable negativity
The study included patients with long-standing suicidal thinking that had not responded to standard therapies. One participant described years of treatment-resistant suicidal ideation and how a ketamine infusion produced rapid relief that, when followed by buprenorphine, allowed him to regain hope and function. Personal accounts from participants illustrate how a rapid reduction in suicidal thinking can create an opportunity to engage in longer-term care.
Profound effects
Across the trial, ketamine produced quick reductions in both depressive symptoms and suicidal ideation. Adding daily low-dose buprenorphine sustained and amplified reductions in suicidal thinking throughout the four-week treatment and into a two-week follow-up period. When buprenorphine stopped, suicidal thoughts rose modestly on average but generally remained below the clinically significant threshold at six weeks. Withdrawal effects were minimal and no serious treatment-related adverse events were reported.
Importantly, the buprenorphine extension did not significantly change overall depression scores compared with placebo, highlighting a separation between mechanisms that reduce suicidal ideation and those that relieve core depressive symptoms.
A life worth living
For participants who received both ketamine and buprenorphine, the combined effect provided a meaningful period of reduced suicidal thinking that permitted engagement with psychotherapies, medication adjustments, or other supports. Some patients reported transformative benefits, including renewed motivation to seek ongoing care and improved quality of life during and after the trial.
The investigators stress the need for larger studies to replicate these results, explore longer or repeat buprenorphine courses, and determine whether the sequence helps suicidality in other forms of depression, such as bipolar depression.
A researcher from Mariner Pharmacy contributed to the study.
Funding: The trial 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: While ketamine was initially thought to act primarily as a glutamate receptor antagonist, evidence indicates part of its rapid antisuicidal and antidepressant effect involves activation of the brain’s endogenous opioid system. Buprenorphine, even at very low doses, acts on the same opioid receptors and appears to sustain the protective opioid-mediated response that ketamine triggers, extending the period of reduced suicidal ideation.
A: Most conventional antidepressants require weeks to produce clinical benefit, which can leave acutely suicidal patients at high risk during that waiting period. Ketamine offers rapid reduction in suicidal thinking; a brief buprenorphine follow-up can buy time—often several weeks—so patients can access psychotherapy, adjust maintenance medications, or arrange additional supports.
A: Clinical trials often exclude people with active, prominent suicidality for safety and ethical reasons, leaving this population understudied. Designing trials that safely include high-risk individuals is challenging but essential; this study intentionally targeted an excluded population to evaluate treatments that directly address suicidal ideation.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by editorial staff.
- Additional context was added by the publication’s 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, Igor D. Bandeira, Christine Blasey, Ian H. Kratter, Jarrod Ehrie, Jennifer Keller, Heather Pankow, Maureen Chang, Jessica Hawkins, Audrey G. Evers, Rebecca Bernert, Charles DeBattista, Henry Truong, Carolyn I. Rodriguez, Boris D. Heifets, and Alan F. Schatzberg. 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 produces rapid reductions in suicidal ideation in major depressive disorder (MDD), but those effects are usually short-lived. Preclinical and clinical evidence suggests that modulation of mu-opioid receptors may contribute to ketamine’s benefits. This trial tested whether low-dose sublingual buprenorphine, a partial mu-opioid receptor agonist, can safely extend the antisuicidal effects of a single intravenous ketamine infusion.
Methods:
This single-center, randomized, double-blind, placebo-controlled trial enrolled adults with MDD and a Scale for Suicide Ideation (SSI) total score ≥6. Participants received a single open-label IV ketamine infusion (0.5 mg/kg over 40 minutes). Starting 48 hours later, they were randomized 1:1 to sublingual buprenorphine (0.2–0.8 mg/day) or matched placebo for four weeks. The primary outcome was weekly change in SSI total score from day 1 through day 31.
Results:
Between November 2020 and March 2025, 50 participants received ketamine and 45 completed at least one week of the follow-on treatment. Both groups showed significant SSI reductions, with a larger mean decrease in the buprenorphine group (mean change −11.6, SD 5.8; N=23) versus placebo (mean change −6.3, SD 7; N=22). Mixed-effects models showed a significant time-by-treatment interaction (p < 0.001). Depression measures did not differ significantly between groups. No serious treatment-related adverse events were reported.
Conclusions:
This randomized controlled trial offers the first evidence that a pharmacological follow-on—low-dose buprenorphine—can safely and significantly sustain and enhance the antisuicidal effects initiated by ketamine in patients with MDD. The findings suggest a potentially scalable approach to reduce short-term suicide risk while patients transition to longer-term treatments, but replication in larger samples and longer follow-up is needed.