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 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 Psychopharmacology
August 26, 2022
Joost J. Breeksema, Bouwe Kuin, Jeanine Kamphuis et al.
171 citations
A systematic review of 44 clinical studies (34 quantitative, 10 qualitative) involving 598 patients treated with MDMA or serotonergic psychedelics (psilocybin, LSD, ayahuasca) found that treatments were generally well tolerated, though adverse events were often not systematically assessed. Common acute adverse events across diagnoses and compounds included nausea, headaches, and anxiety. Late adverse events included headaches (psilocybin, MDMA), fatigue, low mood, and anxiety (MDMA). One serious adverse event occurred during MDMA administration (increased premature ventricular contractions requiring brief hospitalization); no other events required medical intervention. Qualitative studies suggested that psychologically challenging experiences may be therapeutically beneficial. The authors conclude that adverse events are poorly defined and likely underreported due to study design and sample selection.
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.
The British Journal of Psychiatry
February 1, 2016
Robert A Schoevers, Tharcila V. Chaves, Sonya M. Balukova et al.
80 citations
A review of 88 articles examined how ketamine is given (oral, intravenous, intranasal, subcutaneous) for treatment-resistant depression and chronic pain. The methodological quality of studies on ketamine's antidepressant effects was low for all routes. Doses used for depression were lower than those for pain. Studies on pain suggest that oral ketamine may be acceptable for depression in terms of tolerability and side-effects, but few studies have systematically examined longer-term negative consequences. The authors conclude that rigorous randomized controlled trials are needed to study short- and longer-term depression outcomes and side-effects.
Scientific Reports
February 5, 2024
Alistair Niemeijer, Erwin Krediet, Jeanine Kamphuis et al.
50 citations
Patients with treatment-resistant depression who received psilocybin in a clinical trial described challenges with trust-building and expectation management, the need to navigate intense experiences often guided by music, and a desire for a more comprehensive treatment including multiple psilocybin sessions and sustained therapy. Distrust in mental healthcare generally, but trust in study therapists, was a key subtheme. The findings suggest that optimizing psilocybin treatment for this population requires individualized preparation, investment in trust-building, additional sessions, and access to ongoing psychotherapy with trusted therapists.
Frontiers in Psychiatry
January 1, 2022
Joost J. Breeksema, Alistair Niemeijer, Bouwe Kuin et al.
41 citations
Patients with treatment-resistant depression undergoing oral esketamine treatment often find the experience overwhelming and struggle with whether to let go or maintain control. Their ability to let go is influenced by preparation, emotional support, and the treatment setting. Better preparation, an optimized environment, and psychological support during sessions may improve patients' experiences and outcomes. The study provides recommendations for improving quality of care, including training for nurses and support staff.
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.
Psychopharmacology
July 1, 2023
Joost J. Breeksema, Alistair Niemeijer, Bouwe Kuin et al.
26 citations
The effects of oral esketamine for treatment-resistant depression are highly variable, and psychological distress is common. Patients report perceptual changes, detachment from body and emotions, stillness, mystical-type experiences, and fear. After sessions, many feel hungover and fatigued, while depressive mood is neutralized. Some effects, such as increased openness and detachment, may hold psychotherapeutic potential, but the frequent distress calls for additional patient support throughout treatment.
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 Psychopharmacology
September 12, 2025
Stephan Tap, Kelan Thomas, Tomáš Páleníček et al.
5 citations
Classic psychedelics like psilocybin are being studied for psychiatric disorders. Current protocols typically require patients to stop antidepressants (ADs) for at least two weeks before psychedelic use to avoid serotonin syndrome and preserve efficacy, but discontinuation can worsen depression and increase suicidal ideation. This scoping review of 18 studies found that using ADs alongside classic psychedelics is generally safe and tolerable, with no increased risk of serotonin syndrome, especially with psilocybin. Some studies showed significant improvements in depression and other symptoms. Although some evidence suggests a potential reduction in acute subjective psychedelic effects, this was not consistent. The authors conclude that maintaining ADs may improve patient access and avoid discontinuation risks.
International review of neurobiology
January 1, 2025
Stephan Tap, Tijmen Bostoen, Joost J. Breeksema et al.
4 citations
Patients with life-threatening disease often experience end-of-life distress—physical, psychological, emotional, and spiritual suffering linked to chronic illness and the prospect of death. Palliative care aims to improve quality of life, but current psychological and pharmacological interventions show inconclusive evidence with only short- to moderate effects and often require months to work. Over the past decade, psychedelic-assisted therapy has been investigated for addressing end-of-life distress, producing highly significant and sometimes sustained decreases in depression and death anxiety, along with improvements in meaning, spiritual well-being, optimism, life satisfaction, and attitudes toward disease. This chapter describes end-of-life distress, its prevalence, limitations of palliative interventions, the evidence for psychedelic-assisted therapy, why it may work for these patients, and future directions.
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.
International review of neurobiology
January 1, 2025
Tijmen Bostoen, Stephan Tap, Joost J. Breeksema et al.
1 citation
MDMA-assisted therapy shows substantial and sustained reductions in PTSD symptoms, especially for patients resistant to conventional treatments. Over the past two decades, it has emerged as one of the most promising psychedelic treatments, with the FDA designating it a 'breakthrough therapy' in 2017. However, due to methodological concerns such as unblinding and potential expectancy effects, the FDA decided in 2024 not to approve it for clinical use, requiring additional research. The chapter examines psychological and neurobiological mechanisms of action, methodological challenges, and future directions for psychedelic-assisted therapies for PTSD.