JAMA psychiatry
March 1, 2019
Gihyun Yoon, I. Petrakis, J. Krystal
152 citations
Naltrexone pretreatment does not interfere with the antidepressant effects of ketamine. In the study, participants who received naltrexone before ketamine treatment showed similar reductions in depressive symptoms as those who received a placebo before ketamine. The findings suggest that ketamine's antidepressant action does not depend on the opioid system, contrary to some previous theories.
JAMA psychiatry
October 19, 2022
T. Rhee, S. Shim, B. Forester et al.
139 citations
A systematic review and meta-analysis of six clinical trials involving 340 patients with major depressive episodes found that electroconvulsive therapy (ECT) was more effective than ketamine for reducing depression severity in the acute phase, with a standardized mean difference of -0.69 favoring ECT. No significant differences were observed between the two treatments for cognition, memory, or serious adverse events. Ketamine carried lower risks of headache and muscle pain, while ECT carried lower risks of blurred vision, vertigo, diplopia, and dissociative symptoms. The findings suggest ECT may be superior, but treatment decisions should be individualized.
JAMA psychiatry
July 1, 2023
Roman Palitsky, Deanna M Kaplan, Caroline Peacock et al.
86 citations
Spiritual, existential, religious, and theological components are important in psychedelic-assisted therapy, but they have not been systematically integrated into clinical practice. Research shows that spiritually integrated psychotherapies are effective and produce additional benefits on spiritually relevant outcomes, which are particularly relevant to psychedelic therapy. Established standards in spiritually integrated psychotherapy can be applied to psychedelic-assisted therapy. Integrating these topics is needed for culturally competent, evidence-based treatment aligned with high clinical standards, and neglecting them may undermine treatment success and increase risks for patients.
JAMA psychiatry
September 28, 2022
H. Bottemanne, O. Morlaàs, A. Claret et al.
59 citations
In patients with treatment-resistant depression, a single ketamine infusion shifted belief updating toward a more optimistic bias within 4 hours. This early cognitive change was characterized by stronger asymmetrical reinforcement learning and, after one week of treatment, mediated the clinical antidepressant effect. The findings offer new insights into how fast-acting antidepressants alter cognition, which could be harnessed to promote lasting clinical improvement and treatment responsiveness.
JAMA psychiatry
May 1, 2025
Nathan T M Huneke, Guilherme Fusetto Veronesi, Matthew Garner et al.
50 citations
Expectancy effects—participants' beliefs about treatment—can bias the results of psychiatric randomized clinical trials by compromising blinding integrity and inflating effect sizes. This narrative review is the first to examine the interplay between expectancy, unblinding, and treatment outcomes in such trials. Evidence from experimental and clinical studies shows that expectation shapes placebo and active treatment responses. Meta-analytic data from psychedelic and anxiety disorder research indicate that unblinding due to perceived efficacy or side effects can alter effect sizes. The authors recommend collecting expectancy data and monitoring blinding integrity, and they propose developing objective outcome measures less susceptible to expectancy effects to improve trial reliability.
JAMA psychiatry
July 2, 2025
Adam Janik, Xin Qiu, Rosanne Lane et al.
40 citations
In adults with treatment-resistant depression who had not responded to at least two prior oral antidepressants, esketamine nasal spray taken alone (without an oral antidepressant) reduced depressive symptoms more than a placebo. Over four weeks, both a 56 mg and an 84 mg dose of esketamine produced significantly greater improvements on the Montgomery-Åsberg Depression Rating Scale than placebo, with effects apparent as early as 24 hours after the first dose. Common side effects included nausea, dissociation, dizziness, and headache. The findings suggest that esketamine monotherapy could offer a new treatment option for patients who cannot tolerate or do not respond to oral antidepressants.
JAMA psychiatry
April 1, 2024
Nina A Cooperman, Shou-En Lu, Adam W Hanley et al.
39 citations
Adding a telehealth mindfulness-based program called Mindfulness-Oriented Recovery Enhancement (MORE) to standard methadone treatment reduced the risk of returning to drug use by 42% and the risk of dropping out of methadone treatment by 59% over 16 weeks among people with opioid use disorder and chronic pain. Participants receiving MORE also had fewer days of drug use, better methadone adherence, and greater reductions in pain and depression than those receiving standard care alone. Anxiety did not differ significantly between groups. The findings suggest that telehealth MORE is a feasible and effective supplement to methadone treatment.
JAMA psychiatry
January 1, 2024
Claire A Walsh, Lauren Gorfinkel, Dvora Shmulewitz et al.
24 citations
From 2008 to 2019, past-year LSD use increased more among US adults with major depression (from 0.5% to 1.8%) than among those without depression (from 0.2% to 0.8%), a difference-in-difference of 0.8 percentage points. The increase was especially pronounced in adults aged 18–34 with depression and in those with annual household incomes below $75,000. The findings suggest that growing clinical interest in hallucinogens may be accompanied by rising nonmedical LSD use among people with depression, particularly younger adults and those with lower incomes. Clinicians are advised to discuss harm reduction and potential benefits with patients who use LSD in unsupervised settings.
JAMA psychiatry
February 1, 2025
Daniel T Myran, Michael Pugliese, Jennifer Xiao et al.
23 citations
People who had an emergency department visit involving hallucinogen use were more likely to be diagnosed with a schizophrenia spectrum disorder within three years compared with the general population (3.99% vs 0.15%). After accounting for other substance use and mental health conditions, the risk remained elevated: they were about 3.5 times as likely as the general population, 4.7 times as likely as those with an alcohol-related ED visit, and 1.5 times as likely as those with a cannabis-related ED visit. The rate of hallucinogen-related ED visits rose 86% between 2013 and 2021.
JAMA psychiatry
January 1, 2023
Brian D Kiluk, Bethea A Kleykamp, Sandra D Comer et al.
22 citations
A review sponsored by a public-private partnership addresses clinical trial design for new opioid use disorder (OUD) treatments that target systems other than the μ-opioid receptor. The authors present consensus recommendations for evaluating novel therapies such as cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics. Key design elements include specifying the treatment stage (e.g., early abstinence, long-term recovery), defining the treatment's role (adjunctive or independent), selecting patient-informed primary outcomes that assess opioid use patterns, retention, and quality of life, and monitoring adverse events like relapse or overdose, especially when patients are not on maintenance opioid agonist or antagonist medications. Incorporating input from people with lived experience is urged to accelerate development and uptake of effective therapeutics.
JAMA psychiatry
April 2, 2025
Antonio Del Casale, Sara Spirito, Jan Francesco Arena et al.
17 citations
Among adults with treatment-resistant depression, combining esketamine with an SNRI was associated with lower all-cause mortality (5.3% vs 9.1%), fewer hospitalizations (0.1% vs 0.2%), and fewer depression relapses (14.8% vs 21.2%) compared to combining esketamine with an SSRI. However, the esketamine plus SSRI group had a slightly lower incidence of suicide attempts (0.3% vs 0.5%). Overall rates of these outcomes were low in both groups. The findings come from a large real-world analysis of electronic medical records from over 90 health care centers across 20 countries.
JAMA psychiatry
June 1, 2025
Lorenz Mueller, Joyce Santos de Jesus, Yasmin Schmid et al.
14 citations
Repeated low doses of LSD (20 μg twice weekly for six weeks) did not reduce ADHD symptoms more than placebo in adults with moderate-to-severe ADHD. In a double-blind randomized trial with 53 participants, the LSD group showed an average 7.1-point improvement on the ADHD symptom scale, while the placebo group improved by 8.9 points—a difference that was not statistically significant. The treatment was physically safe and psychologically well tolerated. The findings suggest that microdosing LSD, despite popular interest, offers no advantage over placebo for ADHD symptom relief.
JAMA psychiatry
October 22, 2025
A. Jelovac, Cathal Mccaffrey, Masashi Terao et al.
13 citations
Repeated intravenous ketamine infusions are no more effective than a placebo (midazolam) for reducing depressive symptoms in inpatients with moderate to severe depression. In a randomized clinical trial, there was no statistically significant difference between the ketamine and midazolam groups on the primary outcome of depression severity at the end of treatment. No significant differences were found on secondary measures of efficacy, cognition, economic outcomes, or quality of life. These results do not support a superior antidepressant effect for serial intravenous ketamine as an addition to usual inpatient care.
JAMA psychiatry
March 1, 2025
Michelle Matvey, D Parker Kelley, Ellen R Bradley et al.
12 citations
In psychedelic clinical trials, participants often cannot be masked to whether they received the active drug or placebo, because the drug's effects are so noticeable. This can bias outcomes because participants' expectations influence their responses. One proposed solution is to modify the informed consent process to obscure some details of the study design, which has been used in several recent trials. However, this approach raises serious ethical concerns. The authors review the use of such modifications in trials from 2000 to 2024, discuss the regulatory landscape, and suggest ways to reduce risks. They conclude that modified consent may improve trial interpretability but has not been explicitly tested and may not be appropriate in all cases.
JAMA psychiatry
May 1, 2026
Amanda Jones, Jennifer Warner-Schmidt, Hannah Kwak et al.
6 citations
In a phase 2 randomized clinical trial, TSND-201 (methylone) reduced PTSD symptoms more than placebo in adults aged 18 to 65. Over 10 weeks, 65 participants received either TSND-201 or placebo in four weekly oral sessions. The drug group showed a significantly greater improvement in the primary measure of PTSD severity (CAPS-5) than placebo, with a difference of about 10 points. Secondary measures of PTSD-related distress, disability, and depression also improved more with the drug. Common side effects included headache, nausea, and increased blood pressure. The results suggest TSND-201 is a well-tolerated, rapid-acting treatment for PTSD.
JAMA psychiatry
July 1, 2026
Sung Ryul Shim, Hye Su Jeong, Tanner J Bommersbach et al.
1 citation
A systematic review and meta-analysis of 26 randomized clinical trials with 1,166 patients experiencing a major depressive episode found that intravenous ketamine infusions significantly reduce suicidal and depressive symptoms in the acute phase. A single ketamine infusion lowered suicidal symptoms at 24 hours and at 1 month, and repeated infusions produced similar reductions. Depressive symptoms decreased significantly from 4 hours through 1 week after a single infusion and after repeated infusions. Serious adverse events were unrelated to the interventions, and other side effects were transient. Longer-term outcomes remain unclear.
JAMA psychiatry
June 1, 2026
Ben Deverett, Duan Li, Theresa R Lii et al.
1 citation
Ketamine produces distinct brain-wave patterns that may be linked to its therapeutic effects. General anesthesia selectively blocks one of these patterns—theta oscillations—while leaving another pattern, beta-gamma oscillations, intact. In 52 participants, ketamine given during anesthesia preserved beta-gamma power increases but eliminated the characteristic theta augmentation seen during awake administration. This suggests that different neurophysiologic effects of ketamine can be separated, offering a way to investigate which brain-wave changes underlie its antidepressant, analgesic, or dissociative properties.