Expert Opinion on Drug Safety
April 15, 2022
Marcus A. Doyle, Susan Ling, Leanna M.W. Lui et al.
24 citations
Hallucinogen persisting perception disorder (HPPD) is an uncommon but serious condition in which individuals repeatedly experience hallucinations and perceptual disturbances after prior hallucinogen use. As some hallucinogens are being developed to treat mental disorders, understanding HPPD becomes more important. A scoping review of the literature up to July 2021 covered treatments, prevalence, risk factors, and pathophysiology of HPPD. The renewed interest in psychedelics as potential treatments highlights the need to better characterize HPPD's frequency, risk and protective factors, key features, and clinical factors.
The American journal of psychiatry
January 1, 2025
Roger S McIntyre, Angela T H Kwan, Rodrigo B. Mansur et al.
23 citations
Psychedelics show promise for treating difficult-to-treat psychiatric disorders like major depressive disorder, treatment-resistant depression, and posttraumatic stress disorder, with preliminary evidence also supporting efficacy in tobacco and alcohol use disorders. However, concerns exist about the interpretability and translatability of study results due to insufficiently characterized short- and long-term safety, abuse liability, and the essentiality of the psychedelic experience and psychological support. This overview reviews methodological aspects affecting inferences and interpretation of extant psychedelic studies and provides guidance for future research and development critical to study interpretation and clinical implementation.
Annals of Clinical Psychiatry
November 1, 2022
David C J Chen-Li, Leanna M.W. Lui, Joshua D. Rosenblat et al.
22 citations
Postpartum depression (PPD) is a severe mood disorder affecting mothers and children, and there is a need for rapid-acting treatments. This narrative review examined the available literature on ketamine for PPD, searching databases for preclinical studies, clinical trials, and reviews. Four clinical trials were identified. The review suggests that ketamine may be a favorable option due to its antidepressant and analgesic effects, short infusion time, and rapid clearance from the mother's bloodstream. However, evidence is insufficient to support its routine use, highlighting the need for more clinical research.
Journal of Psychiatric Research
August 1, 2024
Noah Chisamore, Danica E. Johnson, Margery J.q. Chen et al.
21 citations
Psilocybin-assisted psychotherapy shows promise for treating depression and distress in life-threatening illnesses, but a systematic review of 28 clinical trial protocols reveals substantial variability and inconsistency in therapeutic approaches beyond the basic framework of preparatory, dosing, and integration sessions. The review found no validated or universally agreed-upon protocol, with frequent lack of clarity in descriptions of therapy models, duration, and number of sessions. Future studies need to define and report psychotherapeutic components more clearly to identify the safest and most effective approaches.
Journal of Affective Disorders
April 1, 2024
Sabrina Wong, Angela T H Kwan, Kayla M Teopiz et al.
19 citations
A systematic review of randomized controlled trials compared the clinical efficacy of psilocybin and esketamine in adults with treatment-resistant depression. 25 mg of psilocybin significantly reduced depressive symptoms at 21 days post-dose, with a number needed to treat (NNT) of 5. Psilocybin-induced nausea had a number needed to harm (NNH) of 5. Fixed doses of esketamine (56 mg and 84 mg) showed significant effects at 28 days post-dose, with NNTs of 7. Esketamine-induced headache, nausea, dizziness, and dissociation had NNHs below 10. The preliminary results may reflect only a small portion of the patient population and require replication and longer-term studies. Both agents showed clinically meaningful NNT estimates and acceptable NNH profiles, underscoring their clinical relevance for treatment-resistant depression.
Journal of Psychopharmacology
October 11, 2020
Roger S McIntyre, Nelson B Rodrigues, Orly Lipsitz et al.
19 citations
Adults with treatment-resistant depression or bipolar disorder who also have high anxiety show greater improvement in depressive and anxiety symptoms after intravenous ketamine treatment than those with low anxiety. Among 209 patients receiving four ketamine infusions, the 94 with anxious-distress had a significantly larger drop in depression scores and a greater reduction in anxiety symptoms after three and four infusions. Both groups experienced a significant decrease in suicidal thoughts. The findings suggest that ketamine may be particularly effective for people with treatment-resistant mood disorders and prominent anxiety.
Expert Opinion on Drug Safety
May 3, 2022
Danica Nogo, Hana Nazal, Yuetong Song et al.
17 citations
Ketamine is an established treatment for treatment-resistant depression, but long-term adverse effects from repeated doses are not well characterized. Animal models and studies of people with substance use disorder who use high daily doses of ketamine show clear neurotoxic effects, including potential brain lesions. No studies have specifically evaluated the effects of the lower, infrequent sub-anesthetic doses typically prescribed for depression. It is difficult to separate ketamine's direct effects from other factors like comorbidities and dose differences. It remains unknown whether repeated sub-anesthetic dosing in adults with depression causes brain lesions or other neuropathologies. Practitioners should remain vigilant, recognizing that depression itself is linked to neurodegenerative processes.
CNS Spectrums
December 10, 2020
Nelson B Rodrigues, Ashley N. Siegel, Orly Lipsitz et al.
17 citations
Intravenous (IV) ketamine effectively reduces symptoms of depression, suicidal ideation, anxiety, and anhedonia in adults with treatment-resistant depression, regardless of whether they have previously undergone neurostimulation. In a retrospective analysis of 238 patients, those without prior neurostimulation experienced an average 6.4-point reduction on a depression severity scale, while those with a history of neurostimulation showed a 4.3-point reduction. No significant differences emerged between the groups, indicating that IV ketamine benefits even highly intractable patients.
CNS Drugs
October 1, 2022
Niloufar Pouyan, Zahra Halvaei Khankahdani, Farnaz Younesi Sisi et al.
16 citations
A systematic review of psilocybin research organized by the Research Domain Criteria (RDoC) framework found that psilocybin has beneficial effects across multiple domains, particularly on positive valence systems, negative valence systems, and social processes. Short-term (23 assessments) and long-term (15 assessments) benefits were reported for positive valence systems. For the negative valence system, 12 outcome measures indicated increased fear, 19 showed no significant effect, and 7 parameters indicated lowered sustained threat over the long term. Thirty-four outcome measures revealed short-term alterations in social systems, including enhanced perception and understanding of others and affiliation. Cognitive systems findings mostly reported dyscognitive effects. Seven studies suggested transdiagnostic effects.
Psychiatry Research
April 25, 2022
Hartej Gill, Parnian Puramat, Pankti Patel et al.
16 citations
Psilocybin shows promise as a treatment for major depressive disorder (MDD), potentially offering an alternative to conventional therapies. A systematic review of neuroimaging studies found that psilocybin administration decreased amygdala activity and reduced depressive symptoms in two studies involving MDD participants. In healthy populations, changes in functional connectivity and activation of prefrontal limbic structures, particularly the ventral medial prefrontal cortex and amygdala, were observed. However, high methodological heterogeneity across the thirteen included studies—ten in healthy populations and three in MDD participants—limits conclusions. Longitudinal research is needed to clarify psilocybin's long-term effects and sustained therapeutic potential for MDD.
Journal of Clinical Psychopharmacology
Nicole Ledwos, Joshua D. Rosenblat, Daniel M. Blumberger et al.
16 citations
A critical appraisal of clinical trials on serotonergic psychedelics for major depressive disorder and end-of-life distress finds that current evidence is low-level due to methodological limitations. Small randomized trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy to an active comparator, with similar preliminary positive effects for single-dose ayahuasca in treatment-resistant depression and lysergic acid diethylamide for end-of-life distress. Adverse events were mild and transient. However, small homogenous samples, expectancy bias, functional unblinding, and lack of standardized psychotherapy limit all studies. Psychedelics should remain experimental interventions used within clinical trials.
Journal of Affective Disorders
October 15, 2024
Angela T H Kwan, Joshua D. Rosenblat, Rodrigo B. Mansur et al.
13 citations
Ketamine and esketamine are increasingly prescribed for treatment-resistant mood disorders and suicide risk, but ketamine is also misused. Analyzing reports in the World Health Organization pharmacovigilance database up to January 2024, ketamine showed elevated reporting odds ratios for alcohol abuse (3.24), substance dependence (12.48), substance use disorder (170.44), substance abuse (2.94), drug dependence (2.88), drug use disorder (11.54), and drug abuse (2.85). Esketamine had reduced odds for substance abuse (0.41), drug dependence (0.083), and drug abuse (0.052), and no increased odds for any alcohol or substance misuse parameter. These associations do not establish causation.
Eur Neuropsychopharmacol
November 7, 2025
Mikkel Højlund, Helin Y. Kafali, Begüm Kırmızı et al.
12 citations
A living systematic review with meta-analysis examined the efficacy, safety, and all-cause discontinuation of serotonergic psychedelics and MDMA for treating mental disorders. The review found that these substances show promise in reducing symptoms of conditions such as depression, anxiety, and post-traumatic stress disorder, with some evidence supporting their therapeutic potential. However, the authors note that the overall quality of evidence is limited by small sample sizes, short follow-up periods, and methodological concerns. Safety profiles varied, with most adverse events being mild to moderate, though serious adverse events were reported in some studies. The review emphasizes the need for larger, more rigorous trials to confirm these findings.
Journal of Affective Disorders
July 18, 2025
Mary E. Kittur, Mingyao Liu, Brett D. M. Jones et al.
12 citations
Psilocybin therapy shows promise for rapid and lasting clinical benefits when paired with psychological support, but the field lacks standardized therapeutic guidelines. A systematic review of 22 recent trials across conditions like depression, substance use, and obsessive-compulsive disorders found broad consistency in the structure of therapy sessions—before, during, and after psilocybin administration. However, trials varied widely in therapeutic intensity, diagnostic adaptations, and use of evidence-based psychotherapies. Fewer than half reported standardization measures such as manualized procedures, specific training, or adherence monitoring. These gaps undermine replicability and generalizability, and until support protocols are clearly defined, mechanistic understanding and clinical adoption will remain limited.
Journal of psychopharmacology (Oxford, England)
April 1, 2024
Nelson B Rodrigues, David C J Chen-Li, Joshua D. Di Vincenzo et al.
12 citations
Ketamine is a rapid antidepressant for people with treatment-resistant depression, but no reliable predictors of response have been identified. This study examined whether variants in the Val66Met and CYP2B6 genes predicted treatment outcomes in 85 participants with major depressive disorder who received four intravenous ketamine infusions. Participants showed significant overall reductions in depression, suicide, and anxiety, with 25% meeting response criteria and 15% meeting remission criteria. However, neither Val66Met nor CYP2B6 genotypes significantly predicted changes in depressive symptoms, suicidality, anxiety, or dissociation. The findings suggest that single-gene predictors are unlikely to be useful and that a broader genetic approach may be needed.
Journal of Affective Disorders
April 1, 2025
Angela T H Kwan, Moiz Lakhani, Kayla M Teopiz et al.
11 citations
An analysis of the FDA Adverse Event Reporting System found that reports of hepatobiliary disorders differ between ketamine and esketamine. Compared to acetaminophen, ketamine was associated with disproportionately lower reporting of hepatitis, liver injury, drug-induced liver injury, hepatic failure, and acute hepatic failure, but disproportionately higher reporting of hepatic function abnormalities and hepatic cytolysis. For esketamine, there was no disproportionate reporting of most hepatobiliary toxicities relative to acetaminophen, except for disproportionately higher reporting of hepatic failure. The authors recommend periodic monitoring of liver function tests and clinical surveillance for signs of hepatobiliary disease in individuals receiving chronic ketamine or esketamine, though causality has not been established.
Journal of Psychopharmacology
October 3, 2024
Charles Q. Choi, Danica E. Johnson, David C J Chen-Li et al.
11 citations
Posttraumatic stress disorder (PTSD) can develop after a traumatic event, causing intrusive re-experiencing, mood and cognitive changes, and altered arousal. Few treatments help patients who cannot access or do not benefit from conventional psychotherapy or pharmacotherapy. This review examines the neurobiology of PTSD and psilocybin's mechanism of action, suggesting that psilocybin may be an underexplored treatment option based on pharmacodynamic and psychoanalytic principles, though further research is needed.
Journal of Psychoactive Drugs
August 24, 2023
Stanley Wong, An Yi Yu, Nicholas Fabiano et al.
11 citations
Interest in psychedelic therapies for mental and substance use disorders has grown, but evidence for non-psilocybin serotonergic psychedelics remains limited. A scoping review of mescaline, ibogaine, ayahuasca, DMT, and LSD identified 77 studies: 43 on LSD, 24 on ayahuasca, and 5 each on DMT, ibogaine, and mescaline. Reported benefits included improved mood, anxiety, insight, reduced substance use, better relationships, and fewer vegetative symptoms. Adverse effects were psychological, neurological, physical, and gastrointestinal; serious events like homicide and suicide appeared in LSD studies. The review concludes there is only low-level evidence supporting the safety and efficacy of these substances for mental and substance use disorders.
Psychiatry Research
January 1, 2022
Joshua D. Di Vincenzo, Orly Lipsitz, Nelson B Rodrigues et al.
11 citations
A small proportion of people with treatment-resistant depression experience clinically significant worsening of symptoms during a course of intravenous ketamine, but the rate is very low—between 1.83% and 5.49% across infusion time points—and similar to that seen with conventional antidepressants. In a retrospective analysis of 164 adults (142 with unipolar depression and 22 with bipolar depression) who received four ketamine infusions over two weeks, no individuals with bipolar depression reported worsening. The findings suggest that symptomatic worsening with ketamine is uncommon, though the study's uncontrolled, single-center design limits certainty.
CNS Spectrums
October 31, 2024
Sabrina Wong, Gia Han Le, Angela T H Kwan et al.
10 citations
A systematic review and meta-analysis of seven randomized controlled trials found that a single dose of esketamine given around childbirth significantly reduced the incidence of postpartum depression (PPD). Within one week of delivery, the odds of a PPD diagnosis were 70% lower for those who received esketamine compared to a control; between four and six weeks postpartum, the odds were 67% lower. The results suggest that esketamine may have preventive antidepressant effects during the postpartum period, with implications for both the mechanisms and clinical treatment of PPD.
CMAJ
March 2, 2025
Daniel T. Myran, Jennifer Xiao, Nicholas Fabiano et al.
8 citations
People who had an emergency department visit or hospital admission involving hallucinogen use in Ontario, Canada, between 2006 and 2022 had a 2.6-fold higher risk of death from any cause within five years compared with the general population. Among 7953 individuals with such acute care, 6.1% died within five years versus 0.6% in the matched general population. Elevated risks were also seen for death from unintentional drug poisoning, suicide, respiratory disease, and cancer. These associations persisted even after excluding people with other mental or substance use disorders.
Psychedelic Medicine
November 18, 2024
Shakila Meshkat, Erica Kaczmarek, Zoe Doyle et al.
8 citations
In a small subgroup analysis of four adults with treatment-resistant depression associated with bipolar II disorder, two 25 mg doses of psilocybin combined with psychotherapy were associated with reductions in depressive symptoms. The average depression score on the Montgomery–Åsberg Depression Rating Scale dropped from 32.5 at baseline to 20.3 two weeks after the first dose, and to 19 two weeks after the second dose; at six months the average score was 21.3. Mania ratings remained stable, and no mania, hypomania, or psychosis occurred. The authors suggest psilocybin may improve depressive symptoms in bipolar II disorder but call for larger studies to confirm the findings.
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.
Current Treatment Options in Psychiatry
April 26, 2024
Noah Chisamore, Erica Kaczmarek, Gia Han Le et al.
8 citations
No Summary
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.