Trials
July 3, 2024
Joshua M Poulin, Gregory E Bigford, Krista L Lanctôt et al.
3 citations
A proposed randomized controlled trial will test whether a single 25 mg dose of psilocybin, compared to a placebo, acutely alters cerebral blood flow and functional brain activity in mood-regulating networks in people with major depressive disorder or persistent depressive disorder. Fifty participants from a mood disorders clinic will be randomly assigned to receive either psilocybin or a placebo, with the placebo group later crossing over to receive psilocybin. The study will use arterial spin labelling and blood oxygenation level-dependent functional MRI to measure brain changes intraday and at three weeks. Clinical outcomes will be tracked with the Montgomery-Åsberg Depression Rating Scale and other scales. The work aims to clarify psilocybin's neuroplastic mechanisms and identify early brain-based predictors of treatment response.
The Journal of clinical psychiatry
July 7, 2025
Angela T H Kwan, Moiz Lakhani, Joshua D Rosenblat et al.
2 citations
In a global pharmacovigilance analysis of adverse event reports from the World Health Organization's VigiBase database, esketamine was associated with higher reporting odds for suicidal ideation compared to lithium (5.13 times) and fluoxetine (3.34 times), while ketamine showed lower reporting odds for suicidal ideation, suicide attempt, and completed suicide relative to both reference drugs. Both drugs had lower reporting odds for suicide attempts and completed suicides. The authors caution that causality cannot be determined from these observational data.
Psychiatry research
July 1, 2026
Erin Artna, Guneet Sandhu, Noah Chisamore et al.
1 citation
Borderline personality disorder (BPD) is a serious mental illness with limited treatment options. Although patients with BPD are often excluded from psychedelic research due to safety concerns about suicide and substance misuse, emerging evidence suggests psychedelics may target core BPD symptoms and common co-occurring mood and anxiety disorders. This narrative review analyzed 22 studies from multiple databases examining ketamine, esketamine, and psilocybin in individuals with BPD. Preliminary evidence indicates these psychedelics may be safe and effective for improving core BPD symptoms and socio-occupational functioning, but more high-quality research focused on BPD-specific outcomes is needed to clarify their potential as a treatment modality.
The Canadian Journal of Psychiatry
March 25, 2025
Noah Chisamore, Erica S Kaczmarek, Zoe Doyle et al.
1 citation
A single 25 mg dose of psilocybin combined with psychotherapy produced clinically significant reductions in depression, anxiety, and suicidality symptoms over two months in people with treatment-resistant depression. Among 27 participants, those who tapered off antidepressant medications before treatment (n = 18) and those not on antidepressants at screening (n = 9) showed comparable improvements, with no significant differences between groups on clinician-rated depression, self-reported depression, anxiety, or suicidality. The intensity of the psychedelic experience was also similar. These results suggest that tapering antidepressants before psilocybin-assisted psychotherapy may not diminish therapeutic benefits, though further research is needed.
Journal of pain and symptom management
August 1, 2026
Stefan Aguiar, Mary Makarious, Orly Lipsitz et al.
In adults with advanced cancer receiving palliative care, intranasal ketamine was associated with clinically meaningful improvements in existential distress, anxiety, symptom burden, and quality of life. Fifteen participants who completed three doses of ketamine showed improvements exceeding established minimal clinically important differences on measures of anxiety, death and dying distress, overall symptoms, and quality of life. Improvements in existential well-being were larger than those in physical symptoms. Changes in depression did not significantly correlate with changes in existential distress outcomes, suggesting ketamine may have independent effects on multiple dimensions of distress in this population.
Journal of psychopharmacology (Oxford, England)
June 24, 2026
Shreya Vasudeva, Gabrielle F M Lovell, Sabrina Wong et al.
Ketamine and its enantiomer esketamine show low risk of abuse, dependence, or misuse when administered under controlled clinical supervision, based on a systematic review of 30 studies (25 clinical and 5 preclinical). Clinical studies found minimal evidence of craving, dose escalation, or illicit use in monitored settings. Preclinical work indicated that (S)-ketamine produces reward-related behaviors, racemic ketamine shows reinforcing effects at higher doses, and (R)-ketamine has minimal reinforcing effects. Abuse risk was identified mainly in case reports lacking proper monitoring. The findings support safe incorporation of ketamine into mood disorder treatment protocols with structured administration and ongoing monitoring.
Expert Opinion on Pharmacotherapy
January 22, 2026
Diana Orsini, Sara D Di Luch, Gabrielle F. M. Lovell et al.
A large body of evidence from clinical trials and real-world studies supports the antidepressant effects of intravenous ketamine and intranasal esketamine. Larger studies have provided reassuring safety data, including for long-term treatment. Alternative routes of administration show promise for scalability, but their efficacy relative to intravenous ketamine remains unclear. Preliminary data suggest ketamine may also be effective for bipolar disorders, personality disorders, posttraumatic stress, and obsessive-compulsive disorder. Further research is needed to optimize protocols, such as combining ketamine with other interventions. Challenges include functional unblinding, expectancy-related bias, and treatment costs.
General hospital psychiatry
January 1, 2026
Gabrielle F M Lovell, Shreya Vasudeva, Diana K Orsini et al.
Ketamine, an anesthetic also used for mood and anxiety disorders, may cause mild, temporary elevations in liver enzymes, but serious liver damage appears rare. A systematic review of 13 studies (5 randomized trials, 3 observational studies, and 5 case reports) involving 1,017 patients—mostly with major depressive disorder or bipolar disorder—found 75 mild liver enzyme elevations across trials, with only a few cases of impaired liver function. No cases met Hy's Law criteria for severe drug-induced liver injury. Case reports described more severe liver issues that improved with dose reduction or stopping treatment. Routine liver monitoring during ketamine treatment remains advisable.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
February 1, 2025
Danica E Johnson, Nelson B Rodrigues, Sydney Weisz et al.
Depression with co-occurring posttraumatic stress disorder (PTSD) leads to more severe symptoms and poorer response to standard treatments. In a retrospective analysis of 134 patients with treatment-resistant depression, four ketamine infusions (0.5-0.75 mg/kg) reduced depressive symptoms equally in those with and without comorbid PTSD; no significant group-by-time interaction was found. PTSD symptoms also significantly improved across all symptom clusters, with moderate to large effect sizes. Ketamine shows promise as an effective intervention for this hard-to-treat population, though future randomized trials should explore factors driving improvement and long-term outcomes.
The lancet. Psychiatry
May 1, 2026
Joseph J Taylor, Balázs Szigeti, Noah D Silverberg et al.
Placebo effects remain a major paradox in medical research, with more data available from placebo-controlled trials than on any treatment, yet little deep analysis of how they are measured, appraised, and interpreted. This review shifts focus from clinical practice to clinical trials, examining established and emerging approaches for managing placebo effects in randomized controlled trials. It highlights three key challenges in contemporary psychiatric research: blinding and expectancy in psychedelic trials, large placebo responses in interventional psychiatry trials (device or procedure-based treatments), and the implications of overlapping neurobiological mechanisms between placebo effects and psychiatric treatments.
CNS drugs
October 1, 2023
Dania Akbar, Taeho Greg Rhee, Felicia Ceban et al.
A systematic review of five studies found that AXS-05, a combination of dextromethorphan and bupropion, rapidly reduces depression severity in adults with major depressive disorder who do not respond to standard antidepressants. Depressive symptoms measured on the MADRS scale decreased significantly compared to placebo as early as one week and compared to an active control at two weeks. The treatment effect was maintained for up to 12 months, with an average 23-point reduction from baseline. The therapy was well-tolerated with only transient side effects. These results support the role of glutamatergic and sigma-1 signaling pathways in depression.
Journal of affective disorders
December 1, 2022
Anastasia Levinta, Shakila Meshkat, Roger S McIntyre et al.
Ketamine rapidly reduces depressive symptoms in people with treatment-resistant depression, but its effectiveness may diminish as the number of prior failed treatments increases. A systematic review of 18 randomized controlled trials found that ketamine and esketamine worked at both lower and higher stages of treatment resistance, yet effect sizes and duration of benefits were greater in studies involving patients with fewer prior antidepressant failures. Variability in how studies defined treatment resistance and measured outcomes prevented clear comparisons of efficacy across different resistance stages. The authors conclude that while ketamine remains broadly effective, more failed treatment trials may reduce its efficacy, and participant-level data are needed to clarify the relationship between resistance level and response.
Journal of affective disorders
October 15, 2022
Isak Joneborg, Yena Lee, Joshua D Di Vincenzo et al.
A systematic review of five randomized-controlled trials found that ketamine-assisted psychotherapy (KAP) had a significant positive effect on primary outcome measures for adults with substance use disorders and treatment-resistant depression, but the data is mixed. The single trial examining KAP for treatment-resistant depression found no benefit. The review notes a lack of large, replicated clinical trials and no studies actively examining mechanisms of action. Evidence suggests temporary neural changes caused by ketamine, such as NMDAR inhibition and increased synaptic neuroplasticity, may affect treatment outcomes. Preliminary findings also suggest adjunct psychotherapy, changes in perspective, and spirituality may play a role.