Summary: Researchers discovered the first pharmacological method to prolong the rapid, yet notoriously fleeting, antisuicidal effects of ketamine. While a single ketamine infusion can halt severe suicidal ruminations within hours, the effect traditionally fades after a single week.
By introducing a four-week follow-up regimen of daily, low-dose buprenorphine, scientists successfully sustained greater and longer-lasting reductions in suicidality for over a month. This major breakthrough targets a historically understudied and high-risk patient population, offering a manageable sequence of treatments to buy critical time for long-term psychiatric interventions to take root.
Key Facts
- The Durability Breakthrough: In a double-blind clinical trial of 45 patients with major depressive disorder and suicidal ideation, pairing a single ketamine infusion with a four-week daily regimen of low-dose buprenorphine significantly extended the lifespan of ketamine’s antisuicidal effects.
- Massive Response Gap: At the end of the one-month trial, 78% of patients in the buprenorphine arm remained responsive to the treatment (suicidal ideation scores cut by more than half) compared to just 48% of patients in the placebo group.
- Shattering the Clinical Threshold: Participants began the study with a moderate severity baseline score of 15 on a 38-point suicide ideation scale. After one month, the placebo group hovered at an average score of 8.7 (above the significant clinical threshold of 6), while the buprenorphine group dropped well into safety at an average score of 3.6.
- Divergent Biological Mechanisms: Surprisingly, while buprenorphine dramatically sustained ketamine’s antisuicidal properties, it did not extend the drug’s core antidepressant effects. This stark divergence proves that suicidality and depression possess separate underlying neurobiology and pharmacology.
- The Opioid System Connection: This treatment sequence builds on Stanford’s 2018 discovery that blocking the brain’s opioid receptors halts ketamine’s therapeutic benefits, indicating that ketamine counters psychiatric crisis primarily by activating the endogenous opioid network rather than functioning purely as a glutamate blocker.
Source: Stanford
For people struggling with suicidal ideation, a single infusion of the drug ketamine can rapidly reduce those dark ruminations, usually within a day or two, sometimes within hours. But the effect is also fleeting, lasting about a week before beginning to fade.
Now, Stanford Medicine researchers have discovered a way to prolong the antisuicidal effects of ketamine for at least a month. In a clinical trial of 45 patients with major depressive disorder and suicidal ideation who were treated with a ketamine infusion, those given a four-week follow-up treatment of low-dose buprenorphine, taken daily, experienced greater and longer-lasting reductions in suicidality compared with those given a placebo follow-up treatment. (Neither the patients nor researchers knew who received which follow-up treatment until after the trial.)
“These patients — some of whom have suffered chronically with the idea of dying, of self-harm — within a day get some relief and can build on that relief over a four-week period,” said Alan Schatzberg, MD, the Kenneth T. Norris, Jr. Professor in Psychiatry and Behavioral Sciences and senior author of the study published May 18 in the American Journal of Psychiatry.
Ketamine is a common surgical anesthetic, and buprenorphine is used both as a pain medication and to treat opioid use disorder.
“We have a sequence of treatments that’s doable now if the field wants to adopt it,” Schatzberg said.
The extended reprieve could buy someone enough time to try other therapies, such as conventional antidepressants that can take several weeks to kick in, connect with the right therapist or find other resources.
At the end of one month, 48% of patients who received a placebo after ketamine remained responsive to the treatment, meaning their scores on a standard scale of suicide ideation were less than half of what they were at the start of the trial. Of the patients who received buprenorphine after ketamine, 78% remained responsive.
On average, the patients began the trial with a score of 15 on a 38-point scale for suicide ideation, indicating moderate severity. One month later, those in the placebo arm scored an average of 8.7, hovering above the threshold of 6 for clinically significant suicidal ideation. Those in the buprenorphine arm scored well below that threshold, an average of 3.6.
It is the first pharmacological method shown to extend ketamine’s antisuicidal effects, although it did not appear to extend the drug’s antidepressant effects.
The study allowed patients to continue taking their other medications. Further research is needed to understand the longer term effects of the treatment, including extended or repeat treatments, and whether the method helps with suicidality in less common types of depression, such as that experienced by people with bipolar disorder.
Excluded from trials
“Suicidality is a big problem, and we don’t have good therapies,” said Jason Tucciarone, MD, PhD, assistant professor of psychiatry and behavioral sciences and co-lead author of the study.
“Studying treatments specifically for suicidal symptoms is critical because therapies that help depression do not always adequately address suicidality,” said Igor Bandeira, MD, PhD, postdoctoral scholar in psychiatry and behavioral sciences and the other co-lead author of the study.
Currently, there are no drugs approved by the U.S. Food and Drug Administration for suicidal ideation in major depressive disorder, in part because of a lack of studies.
“As a population, folks who have prominent suicidality are understudied. A lot of times they’re excluded from trials for risk purposes, so targeting this patient population is tricky and not widely done,” Tucciarone said. “But it’s one of the reasons, of course, that we wanted to do it.”
In recent years, ketamine infusions have been increasingly used off-label as a rapid treatment for depression and suicidal ideation. But repeated use of intravenous ketamine carries risks, said Tucciarone, citing its dissociative effects (feeling detached from one’s body or surroundings), increased blood pressure and heart rate, possible dependency, as well as the cost and inconvenience.
(A form of ketamine as a nasal spray is now FDA-approved as a treatment for major depression.)
Better in combination?
Moreover, ketamine’s mechanisms are still not well understood.
In 2018, Stanford Medicine researchers made a breakthrough when they showed that ketamine’s antidepressant effects could be inhibited by naltrexone — an opioid receptor blocker designed to treat opioid use disorder.
“People had assumed that ketamine’s ability to block a receptor for a neurotransmitter called glutamate was largely responsible for its rapid antidepressant effect, but we questioned that, mainly because other glutamate antagonists are not particularly good antidepressants,” Schatzberg said.
Instead, ketamine counters depression, at least in part, by activating the brain’s opioid system.
In 2015, researchers in Israel had found that four weeks of low-dose buprenorphine, which also acts on opioid receptors, could gradually reduce suicidal ideation in hospitalized patients with mental health disorders, including depression and borderline personality disorder. The effect was statistically significant but mild, and most patients remained clinically suicidal.
Schatzberg’s team wondered if they could combine the extended effects of buprenorphine with the more powerful, but short-lived, effects of ketamine.
“Despite considerable research efforts, attempts to extend the durability of ketamine’s effects have largely been unsuccessful until now,” Bandeira said.
Inescapable negativity
For nearly his entire adult life, Logan, 33, a graduate student in chemistry in the Bay Area, has dealt with depression and suicidal thoughts. Despite years of psychotherapy, a growing list of antidepressant medications and even hospitalization, the conviction that his life was not worth living returned again and again. (Logan is a pseudonym.)
“It’s just something that, for a while, seemed kind of inescapable, and it never really responded well to treatment,” he said.
In the fall of 2024, a particularly serious episode brought him to the edge. “I had to dam up this tsunami of self-hate every day to go to classes, and I would release it anytime I wasn’t having to do work. I was doing what I could to stay functional, but there was a lot of time spent on negativity,” he said.
He was barely sleeping. His therapist, whom he was seeing three times a week, considered admitting him to inpatient care.
“I had a plan and I had means,” he said. “I reached a point where I figured, either I actually attempt suicide or I find something else, because what I’m doing isn’t working.”
In desperation, he applied to a handful of clinical trials he found online — Stanford Medicine was the first institution to respond.
The study participants were adults experiencing a major depressive episode that had lasted at least eight weeks and not responded well to standard antidepressants. They could continue their usual medications during the trial.
All participants received a 40-minute ketamine infusion; 48 hours later, they began taking a daily lozenge that contained either buprenorphine or placebo. The buprenorphine dose increased from 0.2 mg per day the first week to 0.8 mg per day the fourth week — about 5% to 10% of the dosage used for pain management or opioid replacement therapy.
Profound effects
For weeks, Logan looked forward to Nov. 13, the date of his ketamine infusion. The experience itself was strange, somewhat out-of-body, like parts of his mind were being taken offline for maintenance.
“I was experiencing the things that were happening to me and not focusing on how much I hated myself. And once the infusion was over, it was like, ‘Oh, I don’t have to be hating myself all the time,’” he said. “The change coming out of it immediately was profound.”
Right afterward, he still felt depressed but no longer suicidal. The depression lifted over the next couple of weeks and by the end of the trial, he felt “almost ecstatic.”
After the four-week treatment period, the researchers monitored the patients for another two weeks for any withdrawal symptoms as well as their mood and suicidality.
When the researchers unblinded the data, the clear separation between buprenorphine and placebo surprised them.
“I didn’t fully expect it, because most drug studies against placebo don’t really work out,” Schatzberg said. “I hoped it would be a good treatment sequence, but I didn’t quite expect that we could get as strong an effect as we did.”
As expected, the ketamine had done the heavy lifting in rapidly reducing both depression symptoms and suicidality. But those who received buprenorphine continued to score significantly lower on suicidal ideation for the duration of the trial and beyond.
When participants stopped taking buprenorphine at the end of four weeks, their suicidal ideation scores rose slightly on average, but even at six weeks remained below 6 — the threshold for clinically significant suicidal ideation. Withdrawal symptoms were minimal.
“People had reductions in suicidal ideations with just ketamine and placebo, but the magnitude was much greater when we added the buprenorphine,” Tucciarone said. “The main point is that we can enhance and prolong the antisuicidal effect by giving buprenorphine.”
Notably to the researchers, buprenorphine did not significantly enhance ketamine’s antidepressant effects, hinting at multiple underlying mechanisms.
“There is divergence between the antisuicide effect, to some extent, and the antidepressant effect of ketamine. It is somewhat separate — suggesting there’s a different biology and a different pharmacology,” Schatzberg said.
The researchers don’t fully understand how the drug combination works, nor do they know if continued buprenorphine treatment could keep suicidal thoughts at bay longer. They hope to replicate the findings in a larger clinical trial.
A life worth living
For Logan, who was in the buprenorphine group, the therapeutic effects were both temporary and life changing. After the trial, his mood gradually returned to his baseline. Last fall, he experienced another episode of depression and suicidal thoughts brought on by a painful medical condition. He sought out ketamine treatment, which likely saved his life, he said.
At times he felt like he couldn’t live with the medical condition, but there was no tsunami of self-hate.
“Even when I was severely depressed, back in October and November of last year, I still felt like there’s a person in here that deserves saving,” he said.
“And that’s been the biggest outcome for me for the trial — I was able to take this thing that had been a part of me since I was a teenager and just kind of throw it out. I don’t really need that anymore.”
A researcher from Mariner Pharmacy contributed to the work.
Funding: The study received funding from 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: For years, scientists assumed ketamine worked strictly by blocking a brain chemical called glutamate. However, Stanford researchers shattered that theory when they discovered that ketamine actually triggers the brain’s internal opioid system to rapidly stop self-hate and suicidal urges. Because buprenorphine safely targets those exact same opioid receptors at a fraction of standard pain doses, it acts like a timed-release fuel stabilizer, keeping the brain’s protective pathways active long after the ketamine wears off.
A: Traditional antidepressants are designed for long-term maintenance and typically take several weeks or even months to begin working. For a patient experiencing an active, acute crisis accompanied by a plan and means of self-harm, a multi-week waiting period can be a fatal design flaw. Ketamine acts like a massive fire extinguisher, quelling the immediate cognitive tsunami within hours, while the buprenorphine follow-up buys a solid month of safety so patients can connect with therapists and long-term resources.
A: It stems from an ongoing paradox in clinical research ethics. Pharmaceutical companies and academic institutions routinely exclude patients with active, prominent suicidality from clinical trials due to the massive medical and legal risks involved if an experimental treatment fails. By deliberately choosing to design a trial specifically around this understudied, excluded population, the Stanford team has opened up a brand-new medical paradigm for individuals who traditionally have had nowhere else to turn.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this psychopharmacology research news
Author: Nina Bai
Source: Stanford
Contact: Nina Bai – Stanford
Image: The image is 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 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.
Methods:
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.
Results:
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.
Conclusions:
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.
