The New England journal of medicine
November 3, 2022
Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al.
1,095 citations
A single 25 mg dose of psilocybin, but not 10 mg, reduced depression scores more than a 1 mg control dose over three weeks in adults with treatment-resistant depression. In this phase 2 trial, 233 participants were randomly assigned to 25 mg, 10 mg, or 1 mg of synthetic psilocybin with psychological support. The 25 mg group showed an average 12-point drop on the MADRS depression scale versus a 5.4-point drop in the 1 mg group, a significant difference. The 10 mg group did not differ significantly from control. Response and remission rates at three weeks supported the primary result, but sustained response at 12 weeks was not significantly different.
Journal of Affective Disorders
February 3, 2023
Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al.
168 citations
Three weeks after a single dose, 25 mg of psilocybin, and to a lesser extent 10 mg, improved patient-reported measures of depression severity, anxiety, affect, and functioning in people with treatment-resistant depression. These findings extend the primary results from the largest randomized clinical trial of psilocybin for TRD, highlighting outcomes that matter to patients.
Journal of affective disorders
March 1, 2025
Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al.
35 citations
In treatment-resistant depression, a single dose of 25 mg of psilocybin produced stronger correlations between certain psychedelic experiences and depression improvement three weeks later than lower doses. The intensity of psychedelic effects was dose-related, but scores for different doses overlapped considerably. At the 25 mg dose, dimensions of oceanic boundlessness and visual restructuralization, along with emotional breakthrough, showed the strongest correlations with reduced depression scores. The study does not establish causation and requires replication. The overlap in experience intensity across doses suggests unblinding to dose is less likely. Correlations between psychedelic experience and outcome indicate specificity in psilocybin's mechanism of action.
The international journal of neuropsychopharmacology
June 6, 2025
Naim Zaki, Li Nancy Chen, Rosanne Lane et al.
32 citations
In a long-term extension study (SUSTAIN-3) involving 1,148 adults with treatment-resistant depression, esketamine nasal spray combined with an oral antidepressant was evaluated for safety and efficacy over up to 79 months (median 45.8 months). Common adverse events included headache (36.9%), dizziness (33.9%), and nausea (33.6%). Nine participants died, with causes including COVID-19 and suicide. Depressive symptoms, measured by the MADRS, improved during the initial induction phase (average reduction of 12.8 points) and this improvement was maintained during the optimization/maintenance phase. At the end of maintenance, 49.6% of participants were in remission. No new safety concerns emerged, and depression improvement generally persisted for those continuing treatment.
Journal of psychopharmacology (Oxford, England)
August 1, 2024
James Jonathan Rucker, Claire Roberts, Mathieu Seynaeve et al.
32 citations
A new intranasal formulation of 5-MeO-DMT, called BPL-003, was tested in 44 healthy people who had never used psychedelics. Doses up to 12 mg were well tolerated, with no serious side effects; common mild effects included nasal discomfort, nausea, headache, and vomiting. The drug was absorbed quickly, reaching peak levels in about 8–10 minutes, and cleared from the body in under 27 minutes. Higher doses produced stronger subjective drug intensity and mystical experiences, with 60% of participants reporting a 'complete mystical experience' at 10 and 12 mg. The rapid onset and short duration suggest potential for treating conditions like depression.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
August 1, 2024
Roger S McIntyre, Istvan Bitter, Jozefien Buyze et al.
30 citations
In the ESCAPE-TRD trial, esketamine nasal spray caused treatment-emergent adverse events more often than quetiapine extended release (91.9% versus 78.0%), but these events were typically mild or moderate and transient: 92.0% resolved the same day, and only 4.2% of patients discontinued esketamine due to adverse events compared with 11.0% for quetiapine. The median proportion of days with adverse events was lower with esketamine (11.9% versus 21.3%). Along with greater efficacy, esketamine's tolerability profile supports its use for treatment-resistant depression.
Nature medicine
July 24, 2025
Luke A Jelen, David J Lythgoe, James M Stone et al.
29 citations
Blocking the opioid system with naltrexone reduced both the brain glutamate response and the antidepressant effect of ketamine in adults with major depressive disorder. In a double-blind crossover study of 26 adults, naltrexone before ketamine infusion attenuated the rise in glutamate+glutamine relative to N-acetylaspartate in the anterior cingulate cortex and lessened the drop in depression scores the next day. The opioid system modulates ketamine's acute brain effects and subsequent mood improvement, suggesting interactions between glutamate and opioid systems may inform new depression treatments.
Expert Opinion on Pharmacotherapy
November 10, 2023
Michail Kalfas, Rosie H Taylor, Dimosthenis Tsapekos et al.
28 citations
Psychedelic therapy is transforming treatment for treatment-resistant depression (TRD) by increasing benefits and reducing risks. Psilocybin shows promise as a potential game-changer, with initial evidence indicating a rapid antidepressant effect that lasts at least three months for some responders. However, more rigorous, double-blind, comparator-controlled trials with adequate statistical power are needed to understand how psychedelics work and their long-term effects in TRD. Psychedelics may also benefit other psychiatric conditions like bipolar depression and post-traumatic stress disorder.
The British Journal of Psychiatry
May 20, 2024
David Nutt, Ilana Crome, Allan H Young
18 citations
Australia has reclassified psilocybin and MDMA from prohibited substances to prescription medicines for treatment-resistant depression and post-traumatic stress disorder, respectively. The feature examines the rationale behind these regulatory changes, the potential benefits and difficulties they present to psychiatric practice, and how mental health professionals and healthcare systems can adapt to integrate these treatments.
BMC Psychiatry
January 2, 2024
Minna Chang, Mario F Juruena, Allan H Young
16 citations
Ketamine, a promising antidepressant for treatment-resistant depression, can cause ulcerative cystitis—a bladder condition with lower urinary tract symptoms and potential kidney damage seen in over 25% of regular recreational users. This condition, known as ketamine-induced cystitis (KIC), had not been reported in therapeutic use until now. A 28-year-old woman developed KIC symptoms after starting ketamine for depression, confirmed by urine tests. Early diagnosis and stopping ketamine can improve symptoms and prevent further harm. This is the first reported case of KIC in a patient receiving treatment-dose ketamine for depression.
Neuropsychiatric disease and treatment
January 1, 2023
Allan H Young, Mohamed Abdelghani, Mario F Juruena et al.
10 citations
Treatment-resistant depression (TRD) imposes severe burdens on patients, health services, and society, yet has lacked viable treatment options. An advisory panel of psychiatrists and clinical researchers experienced in managing TRD developed best practice statements on using esketamine nasal spray, one of the first TRD treatments licensed in 30 years. The panel agreed on recommendations for setting up and running an efficient esketamine clinic, emphasizing logistical planning, patient education to prevent discontinuation, and checklists for safe appointments. Expanding treatment options like esketamine nasal spray is likely key to improving long-term outcomes for this underserved population.
The lancet. Psychiatry
June 1, 2025
Thorsten Barnhofer, Barnaby D Dunn, Clara Strauss et al.
9 citations
About half of patients with depression who complete the UK National Health Service Talking Therapies stepped care pathway still have symptoms. A randomized trial tested whether adding mindfulness-based cognitive therapy (MBCT) via videoconference to treatment as usual improves outcomes for these patients. At 34 weeks, the MBCT group had significantly lower depression scores than the treatment-as-usual group (adjusted difference -2.49 points on the PHQ-9). The MBCT group also had slightly lower healthcare costs and higher quality-of-life scores, with a 99% chance of being cost-effective at the £20,000 per QALY threshold. No serious adverse events occurred. MBCT is an effective and scalable further-line treatment for depression that does not remit after psychological therapy.
The British journal of psychiatry : the journal of mental science
February 1, 2025
Allan H Young, Pierre-Michel Llorca, Andrea Fagiolini et al.
7 citations
In people with treatment-resistant depression, esketamine nasal spray outperformed quetiapine extended release across multiple measures. Sensitivity analyses using different definitions of remission and relapse consistently favored esketamine, with relative risks for the primary endpoint ranging from 1.462 to 1.737 and for the key secondary endpoint from 1.417 to 1.838. Esketamine also shortened time to first remission by 71% and confirmed remission by 66%. The robustness of the original ESCAPE-TRD trial findings was confirmed.
BJPsych open
May 10, 2024
Luke A Jelen, Rupert McShane, Allan H Young
7 citations
Ketamine shows promise for treatment-resistant depression, but its use requires careful management through evidence-based guidelines. The editorial emphasizes the need for comprehensive protocols to oversee both licensed and off-licence ketamine formulations, referencing recent efforts to develop such guidelines in New Zealand. It advocates for national registries to monitor ketamine therapy, ensuring responsible and effective treatment for depression.
Journal of psychopharmacology (Oxford, England)
June 30, 2025
Jess Kerr-Gaffney, Anna Tröger, Alice Caulfield et al.
6 citations
Ketamine, a rapid-acting treatment for depression and other psychiatric conditions, has raised safety concerns because chronic recreational use can damage the bladder and urinary tract. This systematic review of 27 clinical studies, mostly in people with depression, found that 0% to 24.5% of patients receiving ketamine reported urological symptoms, which were usually mild or moderate. Objective measures of bladder and kidney function showed no significant changes from before to after treatment. The evidence suggests that therapeutic ketamine does not appear to increase the risk of urological problems, but most studies were short-term and did not systematically monitor symptoms, so more long-term research is needed.
Journal of psychopharmacology (Oxford, England)
June 20, 2025
Mutahira Qureshi, Daniel Silman, Romayne Gadelrab et al.
3 citations
A single dose of immediate-release oral ketamine (40–240 mg) was safe and generally well-tolerated in healthy adults, with no unexpected safety signals or discontinuations due to side effects. Eighty mild or moderate treatment-emergent adverse events occurred after ketamine doses, most commonly dissociation, dizziness, and headache, while only five occurred after placebo. Dissociation events increased with higher doses. Ketamine and its metabolites showed dose-proportional pharmacokinetics. Transient mood and dissociation changes appeared one hour after dosing and resolved within about four hours. These results support further investigation of oral ketamine capsules for treatment-resistant depression.
Journal of affective disorders
August 1, 2026
Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al.
2 citations
In people with treatment-resistant depression receiving 25 mg psilocybin with monitoring and support, the therapeutic alliance before dosing had only weak correlations with improvement in depression scores at three weeks. Stronger correlations were seen with the intensity of the psychedelic experience itself, particularly emotional breakthrough and visual restructuring. Path analysis suggested that therapeutic alliance helped facilitate the psychedelic experience, but it was the psychedelic experience—not the alliance—that had stronger direct effects on clinical outcomes. The alliance's direct effect on antidepressant response was limited or absent.
The American journal of psychiatry
June 1, 2026
Luke A Jelen, Owen O'Daly, Fernando O Zelaya et al.
2 citations
Ketamine increased blood flow in specific brain regions (subgenual, pregenual, and dorsal anterior cingulate cortices) in adults with major depressive disorder, and this effect was not blocked by the opioid blocker naltrexone. However, naltrexone did disrupt the relationships between blood flow changes and both acute subjective effects and antidepressant response. The blood flow changes aligned with patterns of opioid and glutamate receptor distribution, suggesting that ketamine's effects involve interactions among multiple neurotransmitter systems.
Frontiers in psychiatry
January 1, 2023
Simon G D Ruffell, Nige Netzband, WaiFung Tsang et al.
1 citation
correction
This is a correction notice for a previously published article. It provides no new findings, arguments, or data.
Journal of psychopharmacology (Oxford, England)
May 29, 2026
Elliot Hampsey, Kirsty Martin, Michail Kalfas et al.
A systematic review of 32 trials in healthy adults found that LSD and psilocybin show dose-proportional peak concentrations (Cmax), while DMT's oral and intravenous formulations differ in ways that may be clinically significant. LSD was the most studied psychedelic, followed by DMT and psilocybin; mescaline appeared in only two trials. Single studies examined intravenous LSD, intravenous psilocybin, inhaled 5-MEO-DMT, and intranasal 5-MEO-DMT. Variations in absorption, distribution, and elimination among the compounds may have important implications for clinical and research settings.
The International Journal of Neuropsychopharmacology
May 5, 2026
Hiroyuki Uchida, Gabriella Gobbi, Joseph Zohar et al.
Between 2013 and 2026, neuropsychopharmacology advanced from stagnation to momentum, producing several first-in-class treatments: rapid-acting drugs for treatment-resistant depression (intranasal esketamine), psychedelic-assisted therapy for PTSD and depression, neuroactive steroid GABA-A receptor positive allosteric modulators (brexanolone, zuranolone) for postpartum depression, non-dopaminergic muscarinic agonists (xanomeline-trospium) for schizophrenia, orexin receptor antagonists for insomnia, and anti-amyloid monoclonal antibodies (lecanemab, donanemab) for early Alzheimer's disease.
Journal of psychopharmacology (Oxford, England)
April 16, 2026
Minna Chang, Allan H Young, Mario F Juruena
Both electroconvulsive therapy (ECT) and ketamine show sustained therapeutic potential for treatment-resistant depression, with ECT possibly associated with longer remission. Higher doses, more frequent administration, and maintenance ECT or ketamine appear to prolong remission, and continuing oral antidepressants may extend it further. This systematic review of 13 studies found no direct head-to-head comparisons of time-to-relapse between the two treatments that met inclusion criteria, preventing formal statistical analysis. The review excluded studies involving psychotic depression, limiting generalizability to those populations.