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.
CNS Drugs
August 17, 2020
Joost J Breeksema, Alistair R Niemeijer, Erwin Krediet et al.
217 citations
This review argues that qualitative research on psychedelic treatments can reveal unique features of different substances and uncover implications for treating specific psychiatric disorders that quantitative methods might miss. By examining subjective experiences, such studies can help tailor therapies to particular conditions and substances, offering insights into how psilocybin, LSD, or other compounds produce distinct psychological effects. The authors suggest that incorporating qualitative findings into clinical practice could enhance treatment precision and patient outcomes, highlighting the value of exploring personal narratives and emotional processes in psychedelic therapy.
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 lancet. Psychiatry
January 1, 2025
Carolina Seybert, Nina Schimmers, Lucio Silva et al.
26 citations
Reporting on the psychological intervention component of psychedelic-assisted psychotherapy is mostly incomplete and inconsistent across studies, limiting replicability and clinical translation. A systematic review of 45 original studies on psilocybin, MDMA, LSD, or ayahuasca for mental disorders found that descriptions of psychotherapy varied widely and completeness of information was generally low, based on an adapted Template for Intervention Description and Replication checklist. Studies involving MDMA showed more homogeneous psychotherapy and more procedural details. Improved reporting on psychological interventions would support replicability, generalisability, and accurate interpretation of research, as well as enhance feasibility and safety of future clinical research and real-world implementation.
Molecular psychiatry
September 1, 2024
Sanne Y Smith-Apeldoorn, Jolien K E Veraart, Jeanine Kamphuis et al.
23 citations
A randomized placebo-controlled trial tested whether a fixed low dose of oral esketamine (30 mg three times daily) could reduce depression severity in patients with treatment-resistant depression. Over six weeks, the drug showed no benefit compared to placebo on the Hamilton Depression Rating Scale. Dizziness and sleep hallucinations were more common with esketamine. In an open-label extension phase where doses were individually titrated up to 3.0 mg/kg twice weekly, depressive symptoms decreased substantially. The findings suggest that fixed low-dose oral esketamine is ineffective, but individually adjusted higher doses may hold promise for treatment-resistant depression.
Psychiatry research
March 1, 2025
Juliana Lima Constantino, Martijn Godschalk, Jens H van Dalfsen et al.
14 citations
About half of people with treatment-resistant depression do not respond to (es)ketamine, despite its known efficacy. This systematic review of 44 studies examined whether demographic or clinical traits predict who will respond or remit after (es)ketamine treatment. Overall, most demographic and clinical variables showed no consistent predictive value. Preliminary evidence linked better response to anhedonia, sleep disturbances, childhood physical abuse, obesity, openness, better episodic memory and visual learning, poorer neurocognitive performance, slower processing speed, and lower attention, while melancholic depression, benzodiazepine use, and metabolic syndrome were linked to worse response. These associations need replication, but suggest (es)ketamine may benefit patients with characteristics often considered hard to treat.
Neuroscience and biobehavioral reviews
September 1, 2024
Jesca E De Jager, Rutger Boesjes, Gijs H J Roelandt et al.
13 citations
Electroconvulsive shocks (ECS) and ketamine are fast-acting antidepressant treatments whose shared neurobiological mechanisms are explored in this systematic review of animal models of depression. Both interventions consistently increase hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) levels. They also positively affect glutamatergic neurotransmission, astrocyte and neuronal morphology, synaptic density, vasculature, and functional plasticity. Restoration of neuroplasticity may be a common mechanism underlying their antidepressant efficacy. Fewer studies have examined these processes after ECS. Understanding these shared fundamental mechanisms could help develop novel therapeutic approaches for severe depression.
Journal of psychopharmacology (Oxford, England)
April 25, 2025
Jolien Ke Veraart, Sanne Y Smith-Apeldoorn, Annemarie van der Meij et al.
6 citations
Oral esketamine, taken twice weekly for six weeks at doses from 0.5 to 3 mg/kg, reduced depressive symptom severity in adults with severe treatment-resistant depression who had not benefited from an average of 8.1 prior antidepressant trials and, in 63% of cases, electroconvulsive therapy. Hamilton Depression Rating Scale scores dropped from 21.2 to 15.8. Nearly half of participants achieved a clinically meaningful improvement, 26.8% responded, and 15.6% remitted. Side effects were common but well tolerated, with a 7.6% dropout rate and no significant urinary or cognitive adverse effects. Treatment continued beyond six weeks in 45.9% of participants to maintain gains.
Progress in neuro-psychopharmacology & biological psychiatry
January 10, 2025
Juliana Lima Constantino, Jens H van Dalfsen, Sara Massetti et al.
6 citations
A systematic review of nine studies found that psilocybin consistently decreases interleukin-6, C-reactive protein, and eosinophils, and increases cortisol, prolactin, oxytocin, thyroid-stimulating hormone, adrenocorticotropic hormone, brain-derived neurotrophic factor, and free fatty acids in healthy participants. These biomarker changes align with preclinical evidence and suggest psilocybin may have beneficial effects on biological processes involved in major depressive disorder. However, results are preliminary due to the small number of studies and exclusive use of healthy volunteers. Further research with clinical populations, larger samples, and longer follow-up is needed before drawing firm conclusions.
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.
European journal of pharmacology
July 5, 2025
Jolien K E Veraart, Sanne Y Smith-Apeldoorn, Jeanine Kamphuis et al.
2 citations
Oral esketamine shows low and variable bioavailability, complicating its use as an antidepressant. In 17 patients with treatment-resistant depression given oral esketamine twice weekly for six weeks with a titration approach, esketamine and noresketamine serum levels were measured 30 and 60 minutes after administration. No association was found between changes in depressive symptoms and any pharmacokinetic outcomes, including serum levels of esketamine, noresketamine, their sum, or ratios. High inter-individual variability in pharmacokinetics was observed. The small sample and flexible-dose regimen limit conclusions. Clinical response may not correspond to esketamine pharmacokinetics, suggesting individually-based titration according to clinical effects is optimal.
Pharmaceuticals (Basel, Switzerland)
April 25, 2025
Jolien K E Veraart, Cornelis F Vos, Nieko C Punt et al.
2 citations
In patients with treatment-resistant depression receiving oral esketamine for six weeks, plasma concentrations of esketamine and noresketamine on day 39 were 59% and 35% lower than predicted by a pharmacokinetic model. This suggests that auto-induction of drug-metabolizing enzymes CYP3A4 and CYP2B6 occurs, which may explain the diminished therapeutic effects and side effects observed with long-term use. Identifying auto-induction as a mechanism of tolerance could have important clinical implications for maintaining efficacy.
Journal of affective disorders
September 15, 2026
Rutger Boesjes, Claudia Oosterveld, Jeanine Kamphuis et al.
1 citation
Ketamine and its enantiomers show rapid antidepressant effects for major depressive disorder and bipolar disorder, but responses vary widely. This systematic review of 26 studies (1694 participants) found that ketamine treatment is linked to improved subjective sleep quality. Preliminary evidence suggests that baseline sleep disturbances and early sleep improvements may predict antidepressant response. Some studies also indicate beneficial effects on objective sleep and circadian rhythmicity, but this finding is tentative due to few published articles. The authors call for more research on objective circadian measures and potential synergy with chronotherapies.
Psychiatry research
March 1, 2026
Gijsbrecht H J Roelandt, Jurriaan F M Strous, Radboud M Marijnissen et al.
1 citation
A single open-label dose of 75 mg intranasal racemic ketamine was tested in 12 acutely suicidal patients in an emergency setting, regardless of underlying diagnosis. The treatment was generally feasible, well-tolerated, and safe. Scores for suicidal ideation and depression showed a downward trend one day after treatment, but this effect declined by day seven. One patient developed ketamine misuse several weeks after participation. No definitive conclusions about efficacy could be drawn from this pilot study.
International journal of methods in psychiatric research
December 1, 2025
Jurriaan F M Strous, Gijs H J Roelandt, Jens H van Dalfsen et al.
1 citation
A single 75 mg intranasal dose of ketamine reduces acute suicidal thoughts more than a 4 mg dose of the active placebo midazolam, measured 180 minutes after administration. The double-blind randomized trial includes 100 patients presenting with acute suicidality regardless of psychiatric diagnosis. The primary outcome is the change in suicidal ideation using the Beck Scale for Suicide Ideation. Secondary outcomes assess depression severity, tolerability, and biological markers. The study design addresses patient selection, ketamine formulation, clinical management, and follow-up timing.
The journal of ECT
January 21, 2025
Daniël T Coerts, Jolien K E Veraart, Jeanine Kamphuis et al.
1 citation
In eight patients with treatment-resistant depression, repeated oral esketamine was tested as a replacement for maintenance electroconvulsive therapy (M-ECT). Over six weeks, esketamine doses were gradually increased up to 3.0 mg/kg twice weekly. Depression severity remained stable or improved in five patients, while three worsened and resumed M-ECT. Among five patients with available scores, all showed improvement on the Outcome Questionnaire 45. Four patients continue to receive oral esketamine. Oral esketamine may offer a suitable, patient-friendly alternative to M-ECT, though controlled trials are needed to confirm long-term safety and efficacy.
Journal of psychiatric research
June 12, 2026
Juliana Lima Constantino, Tobias Stephan Freimann, Jens H van Dalfsen et al.
Oral esketamine can be an effective and well-tolerated treatment for treatment-resistant depression (TRD), but about half of those treated do not respond. This study tested whether sociodemographic and clinical features, including depressive symptoms and treatment resistance, could predict how much depressive symptoms would improve in 131 TRD patients receiving individually adjusted oral esketamine doses (0.5 mg/kg to 3 mg/kg) twice weekly for six weeks. Machine learning models—linear regression, elastic net, and random forest—failed to predict symptom change above chance. The findings suggest that oral esketamine may work similarly across the TRD population, regardless of treatment-resistance levels.
The pharmacogenomics journal
April 24, 2026
Daniël T Coerts, Sanne Y Smith-Apeldoorn, Jérôme C Oude Nijhuis et al.
A genetic variation in the CYP2B6 enzyme, known as 516 G > T, is linked to higher blood levels of oral esketamine four hours after dosing in people with treatment-resistant depression. In a small sample of 18 participants from a placebo-controlled trial, carriers of the variant had median esketamine levels of 5.1 µg/L, compared to 2.1 µg/L in non-carriers. No significant associations were found for two other genetic variants, CYP3A4*22 and CYP3A5*3, but the numbers of carriers were very small. Larger studies are needed to clarify their effects.
Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology
August 31, 2025
Cagdas Türkmen, Rutger Boesjes, Anne-Fleur Zandbergen et al.
In adults with treatment-resistant depression, intranasal esketamine added to an antidepressant does not change the likelihood of experiencing insomnia as a side effect compared with placebo. Across seven randomized trials involving 1,311 patients, insomnia was reported by 7.3% of those receiving esketamine and 6.7% of those receiving placebo, a difference that was not statistically significant. This finding contrasts with earlier reports that esketamine improves insomnia symptoms, possibly because adverse-event reporting does not capture gradual improvements in sleep for patients who often have insomnia at the start of treatment.
Journal of affective disorders
July 16, 2026
Sara Massetti, Sanne Y Smith-Apeldoorn, Jolien K E Veraart et al.
Ketamine and its enantiomer esketamine are effective in only 30-35% of patients with treatment-resistant depression. Increased serum brain-derived neurotrophic factor (BDNF) after a single intravenous dose has been proposed as a biomarker of antidepressant response, but effects under different treatment schedules are unclear. In a randomized, placebo-controlled trial of six-week, low-dose, oral esketamine (90 mg/day, three 30 mg intakes), depression severity and serum BDNF were measured in 54 patients at baseline, end of treatment, and after a four-week washout. BDNF levels did not significantly differ between esketamine and placebo groups during treatment or washout. An increase in BDNF occurred regardless of treatment condition.