Expert Opinion on Drug Safety
June 21, 2024
Roger S McIntyre, Rodrigo B. Mansur, Joshua D. Rosenblat et al.
7 citations
Ketamine and esketamine reduce measures of suicidality in people with treatment-resistant depression, but whether they can worsen preexisting suicidality is unclear. Analysis of the FDA Adverse Event Reporting System from 1970 and 2019 through September 2023 found higher reporting odds ratios for suicidal ideation (7.58) and depression suicidal (14.19) with esketamine compared to lithium. In contrast, lower reporting odds ratios for suicide attempt were observed with both ketamine (0.15) and esketamine (0.57). The mixed results across different aspects of suicidality prevent any determination of causal effects, and the lower odds for suicide attempt cannot be interpreted as a direct therapeutic effect.
Therapeutic Advances in Psychopharmacology
September 1, 2025
Stanley Wong, Gray Meckling, Nicholas Fabiano et al.
6 citations
A systematic review and meta-analysis of nine randomized controlled trials involving 593 adults with psychiatric diagnoses found that psilocybin therapy led to a small but significant decrease in suicidal ideation compared to control conditions. No studies reported suicide attempts or deaths. The analysis showed low heterogeneity and no publication bias, though two studies had a high risk of bias. Current evidence is limited by small sample sizes, insufficient follow-up data, and inadequate assessment of blinding.
Psychiatry Research
January 1, 2025
David C J Chen-Li, Rodrigo B. Mansur, Joshua D. Di Vincenzo et al.
6 citations
In a real-world clinic setting, a single ketamine infusion significantly reduced suicidal ideation among 96 adults with treatment-resistant depression, as measured by the Columbia Suicide Severity Rating Scale. The reduction shifted the group average from active toward passive suicidal thoughts. A mediation analysis showed that ketamine's antisuicidal effects are partially independent of its antidepressant effects, suggesting a direct benefit on suicidality beyond mood improvement. The findings support ketamine's effectiveness for suicidal ideation outside controlled clinical trials.
Expert Opinion on Therapeutic Targets
June 1, 2025
Naomi Xiao, Liyang Yin, Kayla M Teopiz et al.
5 citations
Sigma-1 receptors (S1Rs) may be a target and mediator of antidepressant activity. They regulate neurotransmitter release (including monoamines and glutamate), influence intracellular calcium levels, and affect immune inflammatory responses. In August 2022, the FDA approved dextromethorphan-bupropion, the first antidepressant whose hypothesized mechanism includes activity at S1Rs. The review synthesizes preclinical and clinical data on S1R physiology, pathophysiology, and function. Modulating sigma-1 systems is relevant to current FDA-approved treatments for major depressive disorder and may inform future therapeutic development. Whether sigma-1 modulation uniquely targets difficult-to-treat symptoms like anhedonia remains unknown.
Journal of Affective Disorders
April 15, 2026
Gia Han Le, Sabrina Wong, Danica E. Johnson et al.
4 citations
Ketamine and esketamine rapidly reduce depression in people with treatment-resistant depression and bipolar depression, but the synaptic mechanisms behind dosing and durability are unclear. This review of 61 clinical and 17 preclinical studies found that a single 0.5 mg/kg intravenous infusion produces antidepressant effects peaking at 24 hours and fading over 2-3 days. Early neurophysiological changes appear within 3-8 hours, consolidate by 24 hours, and are rarely detected beyond 3 days. Twice-weekly and thrice-weekly dosing produce comparable four-week outcomes, and weekly maintenance reduces relapse risk. Ketamine may open a plasticity window lasting about 2-3 days, and aligning dosing intervals with this window could optimize durability while minimizing drug exposure.
JAMA Psychiatry
April 15, 2026
Diana Orsini, Sabrina Wong, Sara Di Luch et al.
4 citations
In randomized clinical trials of psychedelic drugs for psychiatric disorders, the drugs' strong subjective effects often reveal which treatment participants or raters think they received, a phenomenon called functional unblinding. A systematic review of 112 trials found that only 29.5% assessed whether blinding was maintained, yet 57.1% cited blinding as a limitation. Blinding failure exceeded 90% in psilocybin, LSD, and ayahuasca studies and 85% in MDMA trials with inert placebos. Ketamine trials rarely assessed blinding but fared better when midazolam was used as an active comparator. No control strategy consistently preserved ideal blinding, raising concerns about the validity of efficacy estimates.
General Hospital Psychiatry
December 9, 2025
Gerasimos Konstantinou, Joshua D. Rosenblat, Sarah Hales et al.
4 citations
Psilocybin-assisted therapy shows promise for treating late-life mental health conditions such as depression, loneliness, and existential distress, where conventional medications often have limited effectiveness and poor tolerability in older adults. The review describes neurobiological mechanisms including serotonergic modulation, enhanced neuroplasticity, and disruption of maladaptive default mode network activity. Clinical trials in general adult populations report sustained improvements in depressive symptoms, existential anxiety, and social connectedness following psilocybin administration. However, older adults are underrepresented in psychedelic research, creating gaps in knowledge about dosing, safety, and long-term outcomes. Age-specific protocols are needed to address pharmacokinetic complexities, cardiovascular risks, drug interactions, and ethical challenges around informed consent in cognitively impaired patients.
Focus (American Psychiatric Publishing)
October 1, 2023
Farhan Fancy, Nelson B Rodrigues, Joshua D. Di Vincenzo et al.
4 citations
Repeated intravenous ketamine infusions significantly reduced depression, suicidal thoughts, and anxiety in patients with treatment-resistant bipolar I/II depression, and improved functioning. In an observational study of 66 patients receiving four infusions over two weeks, depressive symptoms dropped by an average of 6.08 points on the QIDS-SR16 scale. Response rate was 35% and remission rate 20%. Hypomania occurred in only 4.5% of patients, with no mania or psychosis. The findings suggest real-world effectiveness and tolerability of IV ketamine for bipolar depression.
Ther Adv Psychopharmacol
October 16, 2025
Stanley Wong, Brett D. M. Jones, Mathura T. Thiyagarajah et al.
3 citations
A review of nine small clinical trials found that ayahuasca and psilocybin, when used to treat major depressive disorder and treatment-resistant depression, are associated with changes in several biological markers. These include increased serum brain-derived neurotrophic factor, decreased serum C-reactive protein, altered amygdala activation, and changes in functional connectivity between brain regions such as the ventromedial prefrontal cortex, anterior cingulate cortex, and posterior cingulate cortex. These associations suggest potential mechanisms of clinical response, but larger, longer-term studies are needed to confirm these findings.
Journal of Psychopharmacology
July 1, 2025
Ryan M Brudner, Erica Kaczmarek, Marc G Blainey et al.
3 citations
In a small sample of 31 individuals with treatment-resistant major depressive disorder or bipolar II disorder, those who reported more intense mystical experiences after their first dose of psilocybin-assisted psychotherapy showed greater reductions in depressive symptoms two weeks later. This link between mystical experiences and antidepressant benefit was not observed after the second or third psilocybin doses. The findings offer preliminary support for the idea that mystical-type experiences play a therapeutic role in psilocybin-assisted psychotherapy, extending prior work to a clinically complex population with treatment-resistant depression.
Journal of Affective Disorders
December 15, 2024
Sabrina Wong, Gia Han Le, Rodrigo B. Mansur et al.
3 citations
A review of preclinical and clinical studies examined whether ketamine affects metabolic parameters, particularly glucose-insulin homeostasis, in people with major depressive disorder (MDD) and treatment-resistant depression (TRD). In experimental diabetic conditions, ketamine did not disrupt glucose-insulin homeostasis. In adults with MDD, ketamine was associated with GLUT3 transporter upregulation and altered metabolomic signatures. In adults with TRD, ketamine increased brain glucose uptake in the prefrontal cortex. The available evidence suggests ketamine does not adversely affect metabolic parameters, though few clinical studies have evaluated its effects on glucose-insulin homeostasis in MDD. Ketamine appears safe regarding metabolic disturbances commonly seen with other augmentation therapies.
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.
Journal of Affective Disorders
September 16, 2025
Sami George Sabbah, Sophie Li, Sabrina Wong et al.
2 citations
Psilocybin is linked to dynamic and temporally distinct neuroplastic changes that are associated with clinical improvement in depression. However, many studies reused overlapping datasets, had high exploratory flexibility, and risk of bias, which limits the generalizability of the results. Future research should use independent datasets, pre-registered imaging endpoints, and longitudinal designs to better understand the mechanisms of psychedelic therapy for depression.
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 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.
Nature Mental Health
October 14, 2024
Danica E. Johnson, Joshua D. Rosenblat
1 citation
No Summary
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.
Clinical Pharmacology & Therapeutics
May 28, 2026
Gia Han Le, Sabrina Wong, Danica E. Johnson et al.
The serotonin 5-HT2B receptor sits at a crossroads between potential antidepressant effects in the brain and serious heart valve risks when activated peripherally. This narrative review of preclinical and clinical literature finds that peripheral activation of 5-HT2B receptors causes valvular heart disease through cell proliferation and scarring, as seen with older drugs like fenfluramine and some dopamine agonists. In the brain, the receptor's effects are mixed: astrocytic activation may support metabolism and plasticity, while neuronal blockade can normalize dopamine and glutamate activity. Several approved antidepressant adjuncts (aripiprazole, brexpiprazole, cariprazine) antagonize this receptor without observed heart valve problems. The authors propose developing centrally selective, periphery-sparing 5-HT2B antagonists for treatment-resistant depression, with early cardiac monitoring to ensure safety.
Discover Mental Health
March 7, 2026
Nicholas Fabiano, Brendon Stubbs, David W. Lawrence et al.
More than half of people with major depressive disorder do not respond to standard treatments, prompting interest in alternatives such as exercise and psychedelics. This commentary examines how these two approaches might work together. Biologically, psychedelics briefly boost brain-derived neurotrophic factor (BDNF) signaling, while exercise provides sustained BDNF elevation; psychedelics enhance neuroplasticity mainly in the cortex, whereas exercise promotes hippocampal neurogenesis; both increase serotonin release. Psychologically, psychedelics may help people adopt exercise habits, and exercise may improve emotional resilience, potentially deepening the psychedelic experience. The authors suggest that these complementary mechanisms warrant future research on their combined efficacy, tolerability, safety, and neurobiology.
Journal of Affective Disorders
February 12, 2026
Erica Kaczmarek, Nelson Rodriguez, Noah Chisamore et al.
Anhedonia, a core symptom of depression that often resists standard treatments, may be reduced by psilocybin-assisted psychotherapy (PAP). In a secondary analysis of a randomized, waitlist-controlled trial, 30 adults with treatment-resistant depression (major depressive disorder or bipolar II disorder) received one 25 mg dose of oral psilocybin plus psychotherapy. Anhedonia severity, measured by the Snaith-Hamilton Pleasure Scale, decreased significantly at the 2-week primary endpoint, with clinically meaningful improvements persisting at 3 and 6 months. The analysis adjusted for sex and age. These preliminary results suggest PAP could be a promising intervention for anhedonia in treatment-resistant depression, though larger placebo-controlled trials are needed to confirm the findings and clarify underlying mechanisms.
Expert Opinion on Pharmacotherapy
January 22, 2026
Diana Orsini, Sara 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 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.
Progress in Neuro-psychopharmacology and Biological Psychiatry
November 22, 2025
Shakila Meshkat, Noah Chisamore, Zoe Doyle et al.
A single dose of psilocybin was linked to small, temporary gains in processing speed and executive function in people with treatment-resistant depression. These cognitive improvements seemed unrelated to mood changes but did not consistently surpass the improvements expected from simply retaking the tests. The findings underscore the need for larger, controlled studies to determine whether psilocybin genuinely enhances cognition or if the observed changes stem from practice effects or mood shifts.