Journal of Affective Disorders
November 1, 2020
R. Mcintyre, Isabelle P. Carvalho, L. Lui et al.
186 citations
Ketamine is a rapid and effective treatment for adults with treatment-resistant depression, but different formulations and routes of delivery vary in effect size. A meta-analysis of studies found that intranasal ketamine or esketamine had a large effect on depression symptoms at 24 hours and again at 7-20 days. Intravenous ketamine or esketamine showed a large but not statistically significant effect at 2-6 days. Oral ketamine had a moderate effect at 21-28 days. No conclusions about which formulation or route is best could be drawn because direct comparisons are lacking. More studies with larger samples are needed, especially for oral ketamine.
Journal of Psychiatric Research
December 11, 2020
Jiaqi Xiong, Orly Lipsitz, D. Chen-Li et al.
122 citations
A meta-analysis of nine randomized controlled trials (197 participants) found that a single dose of intravenous ketamine or intranasal esketamine is associated with large reductions in suicidal thoughts at 2, 4, and 24 hours after administration. The pooled effect size for intravenous racemic ketamine at 24 hours was 1.035, and for intranasal esketamine it was 1.309. No trials of intramuscular, oral, or sublingual ketamine reported anti-suicidal ideation effects suitable for quantitative analysis. The authors suggest that further studies are needed to evaluate these other routes of delivery and to compare formulations.
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.
Neuroscience and Biobehavioral Reviews
November 23, 2020
H. Gill, Barjot Gill, Nelson B Rodrigues et al.
92 citations
About 40% of people with major depressive disorder have cognitive impairments, and those with treatment-resistant depression (TRD) often show such deficits. Ketamine, a rapid-acting antidepressant, may help. A systematic review of five studies found that a single low-dose intravenous infusion (0.5 mg/kg) did not worsen cognitive function. Some studies reported improvements in working memory and visual learning after ketamine treatment, while gains in processing speed and verbal learning occurred only in anxious TRD patients. The evidence suggests ketamine may have pro-cognitive effects in TRD, but more research is needed.
Expert Review of Neurotherapeutics
September 21, 2020
Hartej Gill, Barjot Gill, David Chen‐li et al.
62 citations
Psychedelics like psilocybin and MDMA show promise as a new type of therapy for mental health disorders. Evidence suggests they may work with just one dose, produce rapid effects, and be effective for treatment-resistant conditions, possibly serving as a standalone treatment. More clinical trials are needed to test their safety, tolerability, and effectiveness in real-world patient populations.
Journal of Psychiatric Research
March 1, 2021
Joshua D. Di Vincenzo, Ashley N. Siegel, Orly Lipsitz et al.
59 citations
Most antidepressant medication trials have focused on adults aged 18-65, leaving gaps in knowledge about older and younger populations. Ketamine shows promise for treatment-resistant depression, but its effects in adolescents and older adults are not well understood. This systematic review of 13 studies found that ketamine produced rapid antidepressant effects (within two weeks) in ten studies, with better results from larger, repeated doses and in open-label rather than blinded settings. Two case reports in adolescents noted rapid anti-suicidal effects. Ketamine appeared safe and well-tolerated in these age groups. However, the small number of studies, high heterogeneity, and generally low quality prevent firm conclusions, and rigorous randomized controlled trials are still needed.
Expert Opinion on Drug Safety
June 15, 2020
Nelson B Rodrigues, R. Mcintyre, Orly Lipsitz et al.
50 citations
Intravenous ketamine is safe and well-tolerated in community-based clinics for treatment-resistant depression. Among 203 patients, fewer than 5% withdrew due to tolerability concerns. Blood pressure increased significantly during infusion, with 44.3% meeting criteria for treatment-emergent hypertension (≥165/100 mmHg), and 12% of those with hypertension required medication. Common adverse events were drowsiness (56.4%), dizziness (45.2%), dissociation (35.6%), and nausea (13.3%). Dissociation severity lessened after the first infusion then plateaued. No patients developed psychosis, mania, or new onset suicidality.
Psychiatry Research
October 1, 2021
Tuyen T. Le, Joshua D. Di Vincenzo, K. Teopiz et al.
26 citations
Psychotic depression, a severe form of major depression with hallucinations or delusions, affects 0.35-1% of people over a lifetime. Current treatments, such as antidepressants combined with antipsychotics or electroconvulsive therapy, often lead to relapse and side effects like tardive dyskinesia. Some case studies suggest ketamine may improve both mood and psychotic symptoms in treatment-resistant patients, but its safety is debated because ketamine can induce psychotomimetic effects. Most clinical trials have excluded these patients, so it remains unknown whether ketamine would worsen psychosis. Future research should include people with psychotic features to determine ketamine's safety and effectiveness.
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
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.
Journal of Affective Disorders
March 1, 2021
R. Mcintyre, Nelson B Rodrigues, Orly Lipsitz et al.
10 citations
The McIntyre and Rosenblat Rapid Response Scale (MARRRS) is a brief self-report measure of depression symptom severity that is sensitive to change with the rapid-acting antidepressant ketamine. In 64 adults with treatment-resistant depression receiving intravenous ketamine, the MARRRS showed high internal consistency and strong convergent validity with the established 16-Item Quick Inventory Depressive Symptoms Self-Report. The scale detected symptom changes across four infusions and loaded onto two factors: dysphoria and psychic anxiety. The findings suggest that outcome measures validated for rapid-acting treatments are needed to inform treatment progress and decisions.
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.
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.
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.
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.
Advances in Therapy
April 30, 2021
Eric P. Mcmullen, Yena Lee, Orly Lipsitz et al.
Ketamine can rapidly improve symptoms in adults with treatment-resistant depression, but its effects often last only a median of 2–4 weeks. This systematic review examined strategies to prolong ketamine's acute antidepressant effects. After searching PubMed/MEDLINE, 22 studies were included: 10 randomized controlled trials, 8 open-label trials, 1 retrospective chart review, and 3 case reports. No treatment modality—including pharmacological interventions, psychotherapies, electroconvulsive therapy, or transcranial magnetic stimulation—significantly prolonged the effects of intravenous ketamine, except for repeat-dose IV ketamine itself. Maintenance esketamine is effective in responders. More multimodality strategies are needed.
Journal of Affective Disorders
December 29, 2020
Nelson B Rodrigues, R. Mcintyre, Orly Lipsitz et al.
A 6-item short form of the Clinician-Administered Dissociative States Scale (CADSS-6) strongly correlates with the full 23-item version in patients with treatment-resistant depression receiving IV ketamine. Using retrospective data from 260 patients split into two groups, the CADSS-6 was derived from items most sensitive to ketamine-induced dissociation. Correlations between the short and full scale ranged from 0.91 to 0.95 across four infusions. The CADSS-6 offers a brief clinical assessment for dissociation, though it remains unvalidated in this population and requires prospective validation.