CNS Drugs
November 17, 2021
Susan Ling, Felicia Ceban, Leanna M.W. Lui et al.
123 citations
Psilocybin, a naturally occurring psychoactive alkaloid found in Psilocybe mushrooms, acts as a non-selective agonist at many serotonin receptors, particularly the 5-HT2A receptor. Its antidepressant and psychedelic effects are thought to involve modulation of the serotonergic system, with downstream changes in gene expression, and indirect effects on dopaminergic and glutamatergic systems. Psilocybin also alters neural circuitry in brain regions implicated in depression, including the default mode network and amygdala. This review synthesizes current understanding of the receptor pharmacology and neuronal mechanisms underlying psilocybin's psychedelic and putative antidepressant properties.
Journal of Psychiatric Research
July 1, 2021
Ashley N. Siegel, Shakila Meshkat, Katie Benitah et al.
101 citations
A review of clinical trials registered on clinicaltrials.gov as of December 3, 2020, shows that 70 studies are evaluating psychedelics (excluding ketamine) for psychiatric disorders. Most studies focus on MDMA (45.7%) and psilocybin (41.4%), with fewer investigating ayahuasca, LSD, ibogaine, salvia divinorum, 5-MeO-DMT, and DMT fumarate. MDMA and psilocybin are primarily studied for PTSD and major depressive disorder; LSD for depression, anxiety, and severe somatic disorders; ibogaine for substance use disorders; and 5-MeO-DMT and DMT for major depressive disorder. Only 21 of the 70 studies had published results; most are ongoing.
Expert Opinion on Emerging Drugs
January 2, 2021
Amna Majeed, Jiaqi Xiong, Kayla M Teopiz et al.
48 citations
A review of preclinical and clinical studies indicates that dextromethorphan (DXM) is well tolerated and shows clinically significant antidepressant effects; DXM combined with bupropion has demonstrated replicated and relatively rapid onset efficacy in adults with major depressive disorder (MDD). Preliminary reports also suggest efficacy in adults with bipolar depression. The combination represents a pharmacokinetic and pharmacodynamic synergy that may account for its rapid action. The authors consider DXM/bupropion a safe, well tolerated, and efficacious treatment option for adults with MDD, and highlight the relevance of glutamate as a treatment target. Priority questions include whether it is uniquely effective across discrete domains of psychopathology and whether it can improve patient-reported outcomes.
Journal of Affective Disorders
July 1, 2024
Cameron N Calder, Angela T H Kwan, Kayla M Teopiz et al.
31 citations
Ketamine is effective for adults with treatment-resistant depression. A systematic review of 21 placebo-controlled randomized trials with 2042 participants calculated the number needed to treat (NNT) for racemic ketamine: 7 at 4 hours, 3 from one day to one week, and 9 at four weeks. Esketamine had an NNT of 2 at one day and 11 at four weeks. Numbers needed to harm indicated low risk. The NNTs under 10 across observation intervals are considered highly clinically meaningful for this difficult-to-treat disorder. Limitations include potential functional unblinding and selective reporting bias.
Current Psychiatry Reports
April 1, 2024
John L. Havlik, Syed Wahid, Kayla M Teopiz et al.
30 citations
Treatment-resistant depression (TRD) has historically had very limited options, but recent advances have expanded knowledge of effective interventions. Psychotherapy can help as an add-on but not alone. Adjunctive non-antidepressant drugs like buprenorphine and antipsychotics show little recent support; side effects and high discontinuation rates may outweigh benefits. Strong recent evidence supports interventional approaches: electroconvulsive therapy, ketamine/esketamine, and transcranial magnetic stimulation. Research on TRD should use internationally defined inclusion criteria for generalizable results.
Journal of Sleep Research
June 16, 2021
Nelson B Rodrigues, Roger S McIntyre, Orly Lipsitz et al.
28 citations
Sleep disturbances are common in treatment-resistant depression (TRD). Intravenous (IV) ketamine improved sleep symptoms, which partially mediated its antidepressant and anti-suicidal effects. In 323 adults with TRD receiving four IV ketamine infusions, self-reported improvements in insomnia, night-time restlessness, hypersomnia, early morning waking, and total sleep partially explained reductions in depression severity. Insomnia, night-time restlessness, early morning waking, and total sleep improvements also mediated reductions in suicidal ideation. Each point improvement in total sleep score was associated with 3.29 times higher odds of achieving response or remission (95% confidence interval 2.00–5.41).
Journal of Affective Disorders
June 15, 2024
Gia Han Le, Sabrina Wong, Sebastian Badulescu et al.
25 citations
A systematic review examined how serotonergic psychedelics (psilocybin, LSD) and ketamine affect brain wave patterns measured by EEG and MEG in people with major depressive disorder, treatment-resistant depression, and healthy controls. Ketamine and psychedelics both increase theta power in depressed individuals. In healthy controls and depressed persons, both drug classes decrease alpha, beta, and delta power. Ketamine also increases gamma power in both groups. Theta power specifically rises in those with major depressive disorder when given psychedelics. The studies varied in patient populations, dosing, and measurement devices. The findings support disease models involving altered network connectivity and may guide future treatment discovery.
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 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 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.
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.
Journal of Affective Disorders
August 1, 2025
Morgan C H Cheng, Christine E. Dri, Hana Ballum et al.
12 citations
Ketamine and esketamine produce rapid antidepressant effects in major depressive disorder and treatment-resistant depression, but their impact on patient-reported quality of life has been unclear. A systematic review of five studies found that both agents improve quality of life measures on scales such as the WHOQOL-BREF, Assessment of Quality of Life 8D, and EuroQol-5 Dimension-5 Layers, with statistically significant results. However, the studies had an overall moderate risk of bias and varied in the quality-of-life scales used and study duration. Further research should examine effects on specific quality-of-life domains.
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.
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.
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.
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.
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.
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.
Acta Psychiatrica Scandinavica
December 1, 2025
Liyang Yin, A. Imamog ̄lu, Gia Han Le et al.
3 citations
Intravenous ketamine may be efficacious in treating posttraumatic stress disorder (PTSD). A systematic review of seven randomized controlled trials involving 323 participants found that ketamine meaningfully improved PTSD symptoms in two trials, as measured by the Clinician-Administered PTSD Scale for DSM-5 and the Impact of Event Scale-Revised. Multi-infusion schedules achieved greater clinical outcomes than single-dose schedules. Preliminary evidence suggests repeated lower doses (0.2 mg/kg) were more efficacious in sustaining treatment effects than standard doses (0.5 mg/kg). Symptom improvement was associated with top-down inhibition of the amygdala originating in the ventromedial prefrontal cortex.
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.