Journal of affective disorders
September 1, 2024
Angela T H Kwan, Joshua D Rosenblat, Rodrigo B Mansur et al.
8 citations
Ketamine and esketamine are effective for treatment-resistant depression and may help people with substance use disorder or alcohol use disorder when paired with behavioral therapy. However, concerns exist about their own abuse potential. Analyzing reports from the FDA Adverse Event Reporting System, ketamine showed significantly increased reporting odds for alcohol abuse, substance dependence, substance use disorder, substance abuse, drug dependence, drug use disorder, and drug abuse. In contrast, esketamine showed significantly reduced reporting odds for substance abuse, drug dependence, and drug abuse. Mixed results across different substance-related outcomes suggest possible beneficial effects, but causal links cannot be established due to data limitations.
Psychiatry Research
May 8, 2025
Noah Chisamore, Lee Phan, Roger S McIntyre et al.
7 citations
A review of pre-clinical and clinical studies on non-hallucinatory psychedelics (NHPs) for mood and anxiety disorders found five animal studies showing antidepressant-like effects, assessed via forced swim test and open field test, without the head-twitch response that indicates hallucination. One case report described a patient who inadvertently combined trazodone and psilocybin and experienced potent antidepressant effects without psychedelic effects. These preliminary findings suggest that antidepressant benefits of psychedelics may be separable from hallucinatory effects, providing impetus for rigorous clinical trials in humans.
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.
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.
Translational psychiatry
August 6, 2024
Chengyu Wang, Xiaofeng Lan, Weijian Liu et al.
6 citations
Non-improvement after four ketamine infusions, or three consecutive non-improvements after three infusions, reliably predicts overall non-response to a six-dose course of intravenous ketamine for depression. Among 135 individuals with major depressive or bipolar disorder in a current depressive episode, sensitivities for predicting non-response exceeded 90% using these early non-improvement criteria. Those who did not improve by these points showed no significant reduction in depressive symptoms from subsequent infusions. The findings suggest that early non-improvement can guide clinicians to discontinue treatment, avoiding ineffective continued dosing.
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.
CNS spectrums
November 20, 2024
Angela T H Kwan, Moiz Lakhani, Gurkaran Singh et al.
4 citations
Ketamine shows potential for treating PTSD, OCD, and alcohol use disorders beyond its established use for depression. A systematic review and meta-analysis of 44 studies found that ketamine significantly reduced PTSD symptoms measured by the PCL-5 (average decrease of 28 points) and CAPS-5 (average decrease of 14 points), and OCD symptoms measured by the Y-BOCS (average decrease of 8 points). For alcohol use disorders, ketamine treatment was associated with reduced urge to drink, higher abstinence rates, and longer time to relapse. However, the small number of randomized controlled trials highlights the need for more research on ketamine's short- and long-term benefits and risks for these conditions.
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.
CNS spectrums
August 12, 2025
Gia Han Le, Sabrina Wong, Stavroula Bargiota et al.
3 citations
G protein-coupled receptors (GPCRs) are involved in many bodily processes. Traditional drug classification divides ligands into agonists or antagonists. Biased agonism is a newer concept where a drug selectively activates one intracellular signaling pathway over another, such as G protein versus β-arrestin pathways. This narrative review of literature up to April 2025 describes distinct mechanisms of antagonism and agonism beyond conventional models. Biased agonism has shown potential for greater efficacy, as with the incretin receptor agonist tirzepatide, and improved safety, as with certain serotonergic psychedelics and opioids. Preclinical evidence suggests biased agonism could improve psychiatric and neurological treatments by differentially activating pathways, pending clinical validation.
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 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.
Journal of affective disorders
July 23, 2025
Joyce Xu Hao Jin, Heidi Ka Ying Lo, Iris Wai Tung Tsui et al.
2 citations
In people with major depressive disorder (MDD) and bipolar disorder (BD), positive psychological traits such as mindfulness and grit interact with negative affect to influence positive mental health. Over two weeks, 29 people with MDD, 29 with BD, and 30 healthy controls reported their negative affect, pleasure attainment, and meaning in life five times daily. Lower negative affect strengthened the link between mindfulness and meaning in life in the MDD group but not in the BD or control group. Higher grit reduced the harmful effect of negative affect on pleasure attainment in the BD group but not in the other groups. These findings highlight complex relationships between positive traits and mental health in mood disorders.
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.
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.
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.
Clinical neuropharmacology
June 19, 2026
Isabela Heroiu, Gia Han Le, Maria-Christina Sioufi et al.
Ketamine, an N-methyl-D-aspartate receptor antagonist, consistently and significantly reduced obsessive-compulsive disorder symptom severity by up to 50% to 60% across five studies, though the duration of effects ranged from a few hours to six weeks. Ketamine was generally well tolerated. The review included three randomized controlled trials and two open-label trials with variable routes of administration (intravenous, intramuscular, and oral) and dosing frequencies. Further research is needed to optimize ketamine treatment for sustained symptom reduction.
Journal of affective disorders
April 1, 2026
Kayla M Teopiz, Gia Han Le, Sabrina Wong et al.
A systematic review of 13 preclinical studies and 1 human study found that dextromethorphan (DXM), a glutamatergic modulator with antidepressant properties, attenuates reward-seeking behavior in rats, as measured by conditioned place preference and behavioral sensitization. In the single human study involving 20 healthy participants, self-reported drug-liking for DXM (400 mg/70 kg) was significantly lower compared to psilocybin (20 mg and 30 mg) 7 hours after dosing. The review highlights a paucity of human studies and suggests that future research should investigate DXM's effects on reward function using validated paradigms in people with anhedonia.
Pharmacopsychiatry
February 5, 2026
Tianyi Xu, Sabrina Wong, Gia Han Le et al.
Lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine activate the 5-hydroxytryptamine 2B receptor, a pathway known to cause drug-induced valvular heart disease. This systematic review of 17 studies found no research on psilocybin, dimethyltryptamine, or mescaline. Both lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine show high or moderate affinity for this receptor and promote signaling linked to fibrotic changes in heart valve tissue. In vivo studies confirm serotonin-induced valvulopathy, and chronic 3,4-methylenedioxymethamphetamine use has been associated with valve abnormalities in humans. No clinical cases of lysergic acid diethylamide-induced valvulopathy have been reported, but preclinical data suggest potential for fibrotic signaling under sustained exposure. Preliminary evidence supports the need for cardiac safety monitoring in psychedelic research.
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.
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.
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.