JAMA Network Open
May 1, 2020
K. Beck, Guy Hindley, F. Borgan et al.
179 citations
Ketamine administration produces transient psychopathological effects in both healthy volunteers and patients with schizophrenia, with the nature and severity of these effects varying according to experimental factors such as dose, route of administration, and participant characteristics. The meta-analysis quantifies these outcomes, showing that ketamine reliably induces psychotic-like symptoms, dissociation, and cognitive impairments in healthy individuals, while its effects in patients with schizophrenia are more complex and may involve both symptom exacerbation and potential therapeutic benefits depending on the context.
JAMA Network Open
April 10, 2024
Akhila Yerubandi, Catherine Harrington, Joshua Caballero et al.
80 citations
A meta-analysis of six randomized, double-blind clinical trials involving 528 participants (about 51% female, median age 39.8 years) found that therapeutic single doses of psilocybin for depression and anxiety are associated with several acute adverse effects. Compared to placebo or low-dose psilocybin, psilocybin significantly increased the risk of headache (nearly double), nausea (nearly nine times), anxiety (more than double), dizziness (nearly six times), and elevated blood pressure (more than double). Psilocybin was not linked to paranoia or transient thought disorder. The adverse effects were tolerable and resolved within 48 hours, but the authors call for future studies to better manage these effects.
JAMA Network Open
March 6, 2024
Yu Chen, Yu Guo, Han Wu et al.
63 citations
A single intravenous dose of esketamine given during cesarean delivery, followed by 48 hours of patient-controlled analgesia containing esketamine, reduced early postpartum depression symptoms. On day 7 after delivery, 23% of women who received esketamine screened positive for postpartum depression (score of 10 or higher on the Edinburgh Postnatal Depression Scale) compared with 35% in the placebo group. The difference in depression scores between groups was small but statistically significant. However, by days 14, 28, and 42, there were no differences between groups in depression screening rates or score changes. Pain scores were similar between groups except for a small advantage with esketamine during movement at 72 hours. The antidepressive effect may not apply to women with low baseline depression scores.
JAMA Network Open
August 12, 2020
Matthew S. Milak, Rain Rashid, Zhengchao Dong et al.
59 citations
A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder within hours. In this randomized clinical trial of 38 adults, higher ketamine doses and blood levels correlated with greater improvement on the Hamilton Depression Rating Scale 24 hours later. However, the brain's glutamate+glutamine (Glx) response to ketamine mediated this relationship: lower Glx responses predicted better antidepressant effects. GABA levels did not correlate with antidepressant benefit. Adverse effects were linked to blood levels only in men. The findings suggest that ketamine's antidepressant mechanism involves reducing Glx levels in the ventromedial prefrontal cortex.
JAMA Network Open
June 3, 2024
Amy L. Mcguire, I Glenn Cohen, Dominic Sisti et al.
41 citations
A consensus statement from a 2023 meeting of 27 experts identifies 20 points of consensus across five ethical issues for integrating psychedelic medicines into mainstream medical practice: reparations and reciprocity, equity, and respect; informed consent; professional boundaries and physical touch; personal experience; and gatekeeping. The meeting included clinicians, researchers, Indigenous groups, industry, philanthropy, veterans, retreat facilitators, training programs, and bioethicists. The statement focuses on government-approved medical use in the US and abroad, emphasizing that policymakers must address challenges ahead while acknowledging the hopeful moment.
JAMA Network Open
December 5, 2024
Anthony L. Back, Timara K Freeman-Young, Ladybird Morgan et al.
37 citations
A double-blind randomized trial tested psilocybin therapy against niacin in 30 US clinicians (physicians, advanced practice practitioners, and nurses) who developed depression, burnout, or PTSD from frontline COVID-19 pandemic work. Participants had no prepandemic mental health diagnoses but had moderate or severe depression at enrollment. After one medication session, depression symptoms (measured by the Montgomery-Asberg Depression Rating Scale) improved significantly more with psilocybin (mean decrease of 21.33 points) than with niacin (mean decrease of 9.33 points), a difference of 12.00 points. Burnout and PTSD symptoms showed numerically larger improvements with psilocybin, but these differences were not statistically significant. The findings suggest psilocybin therapy can reduce depression in this postpandemic condition.
JAMA Network Open
June 3, 2024
Manish Kumar Jha, Samuel T. Wilkinson, Kamini Krishnan et al.
29 citations
In people with treatment-resistant depression who do not have psychosis, intravenous ketamine works as well as electroconvulsive therapy (ECT) overall. Among outpatients with moderately severe or severe depression, ketamine produced greater improvement in depressive symptoms than ECT. In contrast, inpatients with very severe depression improved more with ECT early in treatment, though by the end of the three-week course both treatments were similarly effective. Higher premorbid intelligence and a diagnosis of posttraumatic stress disorder were linked to greater improvement with ECT, but not with ketamine. These findings may help patients and clinicians decide between the two treatments.
JAMA Network Open
January 2, 2024
Asli Korkmaz, Guro Pauck Bernhardsen, Burcu Cirit et al.
24 citations
A yoga breathing and meditation program (Sudarshan Kriya Yoga, SKY) reduced stress, depression, anxiety, and burnout and increased professional fulfillment among physicians compared with stress management education alone. In a randomized trial with 129 physicians from Turkey, Germany, and Dubai, those who practiced SKY for about 30 minutes daily over two months showed significantly lower stress and depression scores at both posttraining and postintervention, and lower anxiety at postintervention, compared with controls. Insomnia also decreased in the SKY group. No effect was found on self-reported medical errors. The findings suggest SKY may be a practical strategy to improve physician wellness and reduce burnout.
JAMA Network Open
July 30, 2025
Fredrik Hieronymus, Evana López, Helena Werin Sjögren et al.
21 citations
In clinical trials for depression, patients given a placebo or control treatment in psilocybin trials showed significantly less improvement in depression ratings than those given control treatments in trials of SSRIs or esketamine. The meta-analysis of 17 trials found that control treatment response rates in SSRI trials were 14 percentage points higher than in psilocybin trials, and in esketamine trials were 23 percentage points higher. Dropout rates were similar for psilocybin and esketamine (5-12% active, 8-11% control) but much lower than for SSRIs (32% active, 35% control). These results suggest that psilocybin's antidepressant efficacy may be overestimated compared to SSRIs and esketamine.
JAMA Network Open
November 4, 2024
Cihan Atila, Isabelle Straumann, Patrick Vizeli et al.
15 citations
A single dose of MDMA (ecstasy) caused acute hyponatremia (low blood sodium) in 31% of 96 healthy participants across four placebo-controlled trials. Hyponatremia occurred in 37% of those with unrestricted fluid intake but in none of the 15 participants whose fluid intake was restricted, suggesting fluid restriction may prevent this complication. The drop in sodium levels correlated with a sharp rise in oxytocin (433% increase) but not with copeptin, a marker of vasopressin. This challenges the long-held belief that MDMA-induced hyponatremia is caused by vasopressin release and instead points to oxytocin mimicking vasopressin's water-retaining effect in the kidneys due to structural similarity.
JAMA Network Open
February 3, 2025
Li Ren, Ting Zhang, Bingyu Zou et al.
13 citations
A single-site randomized clinical trial at a Chinese hospital found that administering a low dose of esketamine during cesarean delivery significantly reduced the incidence of postpartum depression at six weeks. Among 308 women, 10.4% who received esketamine developed postpartum depression compared with 19.5% who received a placebo saline infusion, a relative risk of 0.53. The authors suggest esketamine shows promise for preventing postpartum depression in this setting but call for further research in broader clinical practice.
JAMA Network Open
January 2, 2025
Rachel M Radin, Julie Vacarro, Elena Fromer et al.
11 citations
A brief digital mindfulness meditation program, compared to a waiting list, reduced perceived stress and job strain among employees of a large academic medical center. In a randomized clinical trial with 1458 adults (mostly female, average age 35.5 years), those assigned to 10 minutes of daily meditation for 8 weeks showed moderate to large improvements in stress and secondary outcomes like burnout and work engagement at 8 weeks, and these benefits persisted at 4 months. Greater daily use of the app (5 to 9.9 minutes versus less than 5 minutes) was linked to larger stress reductions. The findings suggest that a scalable digital meditation program can effectively lower stress in the workplace.
JAMA Network Open
April 1, 2025
Xue Zhang, Laura M Hack, Claire Bertrand et al.
10 citations
In a double-blind, placebo-controlled trial, 16 adults with subthreshold PTSD symptoms and early life trauma but no current psychiatric disorders were given 120 mg of MDMA or placebo. Participants were split into two groups based on baseline brain activity in the amygdala in response to nonconscious threat cues: those with high amygdala reactivity (NTNA+) and those with low reactivity (NTNA-). MDMA, compared with placebo, reduced activity in the amygdala and subgenual anterior cingulate cortex (sgACC), increased connectivity between the sgACC and amygdala, and increased liking of threatening facial expressions, but only in the NTNA+ subgroup. These findings suggest that baseline neural circuit profiles can identify who may benefit most from MDMA therapy and point to possible biomarkers for personalized treatment.
JAMA Network Open
May 1, 2023
R. Price, M. Wallace, S. Mathew et al.
9 citations
Automated self-association training may extend the antidepressant effect of a single ketamine infusion beyond one month in people with treatment-resistant depression. This secondary analysis of a randomized clinical trial tested whether a computerized task designed to strengthen positive self-associations could prolong the benefits of ketamine. The results suggest that combining ketamine with this training could help maintain mood improvement for a longer period than ketamine alone.
JAMA Network Open
April 1, 2025
Jenna Matsukubo, Sarah Dickson, Jennifer Xiao et al.
7 citations
As of May 2024, 57 psilocybin dispensaries operated in Canada, located in 15 of 42 major cities (35.7%) and concentrated in Ontario and British Columbia. Most stores (61.4%) were part of a chain, 91.2% had an online presence, and all sold dried mushrooms, with many also offering microdosing capsules, chocolates, and gummies. 65.2% sold products mimicking popular food brands. Among stores with websites, 86.4% claimed mental health benefits such as alleviating anxiety, yet warnings about driving, pregnancy, or history of psychosis were rare (9.1%, 13.6%, and 31.8% respectively). The findings suggest a need for greater regulatory measures to protect the public.
JAMA Network Open
March 10, 2026
Mw Johnson, Gideon P. Naudé, Peter S. Hendricks et al.
6 citations
A single high dose of psilocybin combined with cognitive behavioral therapy (CBT) led to significantly higher long-term smoking abstinence rates than nicotine patch treatment plus CBT. At six months, 40.5% of participants who received psilocybin had biochemically verified prolonged abstinence, compared to 10.0% of those using the nicotine patch. No serious adverse events were attributed to either treatment. The pilot trial randomized 82 psychiatrically healthy adult smokers and used an intention-to-treat analysis. The findings suggest psilocybin-assisted therapy may be a promising intervention for tobacco smoking cessation.
JAMA Network Open
January 2, 2026
Gianluca Andri Florineth, Isabell Klima, Anna Laura Boeker et al.
5 citations
In a systematic review and meta-analysis of 12 controlled clinical trials involving 733 adults with depressive symptoms, psychedelic-assisted therapy (PAT) with psilocybin or LSD produced a large overall reduction in depressive symptoms compared to control conditions. More hours of preparation therapy before the psychedelic session were significantly linked to greater symptom reduction. However, the number of post-dosing integration therapy hours, total therapy sessions, and longer follow-up periods were not associated with better outcomes. Most studies had high risk of bias due to ineffective blinding. The findings suggest that preparation therapy may be a key component in optimizing PAT outcomes, but further research is needed.
JAMA Network Open
July 1, 2025
Sarah-Catherine Rodan, Sarah Maguire, Noah Meez et al.
5 citations
In a large international survey of over 6,600 adults with eating disorders or disordered eating, cannabis and psychedelics were rated as most helpful for improving eating disorder symptoms, while prescription antidepressants were seen as beneficial for overall mental health but not for eating disorder symptoms, except for fluoxetine in bulimia nervosa and lisdexamfetamine in binge-eating disorder. Alcohol, nicotine, and tobacco were rated as most harmful. The findings suggest that cannabis and psychedelics may alleviate eating disorder symptoms, supporting further research into these substances as potential treatments.
JAMA Network Open
May 7, 2026
Peter S. Hendricks, Sara N Lappan, Richard C. Shelton et al.
4 citations
A single 25 mg dose of psilocybin, combined with psychotherapy, led to a higher percentage of cocaine-abstinent days, a greater likelihood of complete abstinence, and a longer time before the first cocaine lapse over 180 days compared with an active placebo (100 mg diphenhydramine) in a randomized, quadruple-blind trial. Among 40 participants with cocaine use disorder, 33 were men, 33 were Black, and most had low income. Psilocybin appeared safe, with no serious adverse events, and may offer a treatment for cocaine use disorder in underrepresented populations.
JAMA Network Open
April 1, 2025
Paul R. Hutson
2 citations
No Summary
JAMA Network Open
June 1, 2026
Martin Walter, Christine Zu Eulenburg, Ani Damyanova et al.
1 citation
A novel oral prolonged-release ketamine tablet, KET01, produced minimal dissociative and cardiovascular side effects compared to intranasal esketamine, which caused significant dissociation. In a phase 2 trial for treatment-resistant depression, the primary endpoint at 21 days was not met; the difference in Montgomery-Åsberg Depression Rating Scale (MADRS) score for 240 mg/day KET01 versus placebo was -1.82 points, not statistically significant. However, early reductions in depression scores were observed at 7 hours and at days 4 and 7. The antidepressant properties and tolerability support further development of KET01 for at-home use.
JAMA Network Open
May 15, 2026
Hampus Yngwe, Pontus Plavén-sigray, Carl Johan Ekman et al.
1 citation
A single 25 mg dose of psilocybin, combined with psychotherapeutic support, produced rapid antidepressant effects in people with moderate to severe recurrent major depressive disorder. Depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale, improved significantly more in the psilocybin group than in the placebo group by day 8, with benefits lasting through day 42 but not at one year. Self-reported depressive symptoms showed improvement as early as day 2 and persisted for over three months. The treatment was generally well tolerated, though two participants experienced persistent severe anxiety requiring medical attention. These findings suggest psilocybin may offer a rapid and relatively durable antidepressant effect.
JAMA Network Open
January 2, 2026
Moshe Berchansky, A Eden Evins, Bryn Evohr et al.
1 citation
A brain-imaging technique called resting-state functional near-infrared spectroscopy (fNIRS) detected THC-induced impairment more accurately and with far fewer false positives than standard behavioral field sobriety tests (FSTs). In a double-blind, randomized crossover trial, 183 regular cannabis users (average age 25, half female) received either a single oral dose of synthetic THC or a placebo. fNIRS scans of the prefrontal cortex, taken at rest and during a working-memory task, were used to train machine-learning models to identify clinically determined intoxication. The fNIRS classifier achieved 90% accuracy and a 5% false-positive rate, compared with 69% accuracy and a 34% false-positive rate for FSTs. The findings suggest that resting-state fNIRS may provide a more reliable, objective method for detecting cannabis-related driving impairment.
JAMA Network Open
September 11, 2025
Richard B. van Breemen, Daniel Simchuk, Bjorn Fritzsche et al.
1 citation
Unregulated psilocybin mushroom edibles contain a range of active constituents beyond psilocybin and psilocin, including baeocystin, norbaeocystin, and aeruginascin, with variable concentrations across products. The analysis of these edibles reveals inconsistent labeling and dosing, posing potential risks for consumers.
JAMA Network Open
May 1, 2026
C Austin Zamarripa, Spencer Lin, Mckenna Klausner et al.
Combining cannabis edibles with alcohol worsens driving impairment more than either substance alone. In a controlled experiment with 25 healthy adults who reported prior co-use, driving performance was significantly impaired under most active drug conditions, including 25 mg THC with alcohol at 0.05% breath alcohol concentration. The legal alcohol intoxication limit of 0.08% may be too high when cannabis has also been consumed. Standard field sobriety tests often failed to detect impairment that was evident in driving measures. The findings suggest a need for better impairment detection and policies that account for co-use.