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.
Frontiers in Psychiatry
July 12, 2022
Kwonmok Ko, Gemma Knight, James Rucker et al.
296 citations
Mystical experience—characterized by oceanic boundlessness, ego dissolution, and universal interconnectedness—may be a psychological mechanism influencing outcomes in psychedelic therapy. A review of 12 studies using psilocybin, ayahuasca, or ketamine found that 10 reported a significant association (correlation, mediation, or prediction) between mystical experience and symptom reduction across cancer-related distress, substance use disorder, and depressive disorders including treatment-resistant depression. However, most studies had small, non-diverse samples, and half were open-label, introducing potential bias. Future research needs larger, more diverse randomized designs and deeper exploration of mystical experience's nature and predictors to maximize therapeutic benefits while minimizing anxiety.
Journal of Psychopharmacology
November 18, 2016
James Rucker, Luke A. Jelen, Sarah Kalen Flynn et al.
187 citations
Unipolar mood disorders such as major depressive disorder and dysthymia cause high disability, mortality, and socioeconomic burden, with current treatments often suboptimal and little new pharmaceutical development. Psychedelic drugs like psilocybin were used extensively before prohibition in the late 1960s and are relatively safe in medically controlled environments with no dependence risk. A systematic review of 19 clinical treatment studies found that of 423 individuals, 335 (79.2%) showed clinician-judged improvement after psychedelic treatment. A recent UK pilot study supports psilocybin with psychological support for treatment-resistant depression. The evidence strongly suggests psychedelics should be re-examined in modern clinical trials for unipolar mood disorders.
Journal of Psychopharmacology
January 1, 2022
James Rucker, Lindsey Marwood, Riikka-Liisa Johanna Ajantaival et al.
101 citations
A single dose of 10 or 25 mg psilocybin, given simultaneously to up to six healthy adults with one-to-one psychological support, did not impair cognitive function or emotional processing. Over 500 treatment-emergent adverse events were reported, mostly mild and resolving within a day, with no serious events or study withdrawals. Cognitive performance, measured by a Cambridge Neuropsychological Test Automated Battery global composite score and domain scores, showed no clinically relevant differences between psilocybin and placebo groups. The findings suggest that these doses of psilocybin are generally well tolerated and safe for cognitive function in the short and long term.
Psychopharmacology
September 5, 2022
Matthew Butler, Luke A. Jelen, James Rucker
91 citations
Expectancy and unblinding in psychedelic trials likely cause overestimation of treatment effects, but this problem is not unique to psychedelics. The authors argue that premature hype directly inflates participant expectations, yet placebo-controlled RCTs are imperfect for many therapies and blinding issues should not automatically disqualify medications from approval. Practical measures like independent raters and active placebos can partially mitigate these effects, and alternative methods such as naturalistic studies can supplement RCT results. Early data should neither be dismissed nor taken as firm evidence of effectiveness.
Journal of psychopharmacology (Oxford, England)
March 1, 2022
Anna O Ermakova, Fiona Dunbar, James Rucker et al.
83 citations
5-MeO-DMT is a short-acting psychedelic tryptamine found in nature and used historically for spiritual purposes. This review of existing literature covers its pharmacology, chemistry, metabolism, epidemiological studies, and reported effects. 5-MeO-DMT acts as a serotonergic agonist with highest affinity for 5-HT1A receptors. Animal model studies exist, but human clinical studies are lacking. Epidemiological data indicate it induces profound alterations in consciousness, including mystical experiences, with potential beneficial long-term effects on mental health and well-being. Its short duration, relative lack of visual effects, and higher rates of ego-dissolution make it a potentially useful addition to the psychedelic pharmacopoeia, warranting further clinical exploration with appropriate precautions.
Frontiers in Psychiatry
June 9, 2021
Simon Ruffell, Nige Netzband, WaiFung Tsang et al.
74 citations
A naturalistic study of 63 people who participated in ayahuasca ceremonies at a retreat in the Peruvian Amazon found significant improvements in depression, anxiety, and overall psychological distress, along with increased self-compassion, immediately after the retreat and sustained at six months. Depression scores on the Beck Depression Inventory dropped from 13.9 to 6.1, anxiety scores on the State-Trait Anxiety Inventory fell from 44.4 to 34.3, and scores on the Clinical Outcomes in Routine Evaluation-Outcome Measure decreased from 37.3 to 22.3. Changes in memory valence were linked to these improvements. Epigenetic results were inconclusive but suggested further research on the SIGMAR1 gene is warranted.
Journal of Psychopharmacology
April 7, 2022
Emma I Kopra, Jason Ferris, Adam Winstock et al.
65 citations
Among 9,233 people who used magic mushrooms in the past year, only 19 (0.2%) sought emergency medical treatment, corresponding to a per-event risk of 0.06%. Younger age was the only factor linked to a higher chance of needing emergency care. The most common symptoms were psychological—anxiety, panic, paranoia, and suspiciousness. Poor mindset, poor setting, and mixing substances were the most frequently cited reasons for the incidents. All but one person returned to normal within 24 hours. The findings confirm that psilocybin mushrooms are relatively safe, with serious adverse reactions being rare and short-lived.
Journal of Psychopharmacology
March 6, 2023
Emma I Kopra, Jason Ferris, Adam Winstock et al.
62 citations
A large international survey of 3364 people who used LSD or psilocybin mushrooms for self-treatment of mental health conditions or life worries found positive changes across all 17 measured outcomes, with the strongest benefits for insight and mood. However, 22.5% of respondents reported negative effects. Higher intensity of the psychedelic experience, seeking advice beforehand, using psilocybin mushrooms, and treating post-traumatic stress disorder were linked to better outcomes. Younger age, high experience intensity, and using LSD were associated with more negative effects. The findings suggest self-treatment outcomes are generally favorable but carry more frequent negative effects than clinical settings.
Journal of Psychopharmacology
December 20, 2020
Benjamin Illingworth, Declan J Lewis, Andrew T Lambarth et al.
47 citations
A meta-analysis of four randomized controlled trials found that MDMA-assisted psychotherapy can reduce symptoms of treatment-resistant post-traumatic stress disorder (PTSD), as measured by the Clinician Administered PTSD Scale (CAPS-IV). Doses of 75 mg and 125 mg of MDMA, but not 100 mg, produced significant decreases in CAPS-IV scores compared to active placebo. A significant reduction in Beck's Depression Inventory scores was only seen with the 75 mg dose. Participants reported more episodes of low mood, nausea, jaw-clenching during sessions, and lack of appetite within seven days. The authors conclude there is potential therapeutic benefit with minimal physical and neurocognitive risk, though better-powered trials are needed.
Journal of Psychopharmacology
June 7, 2022
Emma I Kopra, Jason Ferris, James Rucker et al.
42 citations
Among 10,293 people who used LSD in the past year, 1.0% sought emergency medical treatment, with a per-event risk of 0.2%. Younger age, mental health conditions, and more frequent use increased that risk. Most adverse reactions were psychological—anxiety, panic, confusion—often linked to poor setting or mindset. Symptoms usually resolved within 24 hours, though 11 people had issues lasting beyond 4 weeks. LSD appears relatively safe in recreational settings; adverse effects are typically short-lived and psychological. In clinical contexts, screening, preparation, and supervision should further reduce risks.
Frontiers in Psychiatry
April 21, 2021
James Rucker, Allan H. Young
40 citations
Psilocybin has a history of non-medical use, and some infer therapeutic utility from this. Early phase clinical trials are encouraging but only indicate a need for larger, multicentre trials, which are ongoing but will take years. Retreat centers offering paid psilocybin truffle experiences use early trial data for bold public claims, which is unwise because early trials are not designed for generalization. This risks misleading the public and conflicts with ethical principles from the Nuremberg Code and Kefauver Harris Amendments. Using psilocybin before proper testing may undermine the credibility of retreat centers and the wider field.
Therapeutic Advances in Psychopharmacology
January 1, 2020
Matthew Butler, Mathieu Seynaeve, Timothy R. Nicholson et al.
38 citations
Functional neurological disorder (FND), previously called conversion disorder, is common in neurology clinics and causes substantial disability, but treatment options are limited. Psychedelics like psilocybin and LSD may help by altering brain circuits involved in self-representation, which is thought to be disrupted in FND. A systematic review of nine studies from 1954 to 1967, involving 26 patients, found that most received psychotherapy with variable adjunctive psychedelic use (psycholytic therapy). Of those treated, 69% (18 patients) showed at least some recovery on subjective clinician-rated criteria. Adverse events were mostly mild, though one patient withdrew due to distressing effects. All studies were low quality, lacking controls and valid outcome measures, so no conclusions on efficacy can be drawn.
Addiction
January 30, 2025
Theodore Piper, Francesca Small, Michael Kelleher et al.
27 citations
This first systematic review of psychedelic-assisted treatments for alcohol, tobacco, and other substance use disorders examined 37 studies involving 2,035 participants. The best evidence of efficacy came from a phase 2 randomized controlled trial of psilocybin for alcohol use disorder and a phase 2 trial of ketamine for alcohol use disorder. Psilocybin-assisted treatment for alcohol use disorder appears to have the strongest evidence among all major psychedelic-assisted treatments. No serious adverse events were reported across any study. The review recommends that future research report all safety events, identify contraindications, mitigate participant blinding, use factorial designs, and develop a core outcome set.
BMJ Open
December 1, 2021
James Rucker, Hassan Jafari, Tim Mantingh et al.
23 citations
A randomized, placebo-controlled trial is testing the feasibility of psilocybin-assisted therapy for people with major depressive disorder who have not responded to at least two prior treatments. Up to 60 participants in London, UK receive either 25 mg psilocybin or a placebo in a single dosing session, along with psychological therapy. The primary outcomes are recruitment rates, dropout rates, and variance in depression scores measured by the Montgomery Asberg Depression Rating Scale at 3 and 6 weeks. The trial also collects neuroimaging and omics data and offers an open-label extension dose of psilocybin.
Pharmacology & Therapeutics
April 6, 2024
Zarah R. Haniff, Mariia Bocharova, Tim Mantingh et al.
16 citations
Major depression increases the risk of later dementia, and late-life depression may be an early sign of dementia. Adult hippocampal neurogenesis (AHN), the lifelong birth of new neurons in the dentate gyrus, supports learning, memory, and mood. Microglia, the brain's immune cells, regulate AHN, and disruptions in AHN and microgliosis are linked to both depression and neurodegenerative diseases. Psychedelics like psilocybin, a serotonergic agonist with rapid antidepressant effects, may promote neuroplasticity and modulate microglial function. This narrative review examines evidence that psilocybin could affect AHN and microglia, potentially altering the progression from major depression to dementia in at-risk individuals.
Headache The Journal of Head and Face Pain
September 20, 2024
James Rucker, Sadie Hambleton, Catherine Bird et al.
12 citations
A small open-label trial tested low doses of psilocybin (5, 7.5, and 10 mg) with psychological support in four patients with chronic short-lasting unilateral neuralgiform headache attacks (SUNHA), a severe headache disorder. The study was terminated early due to recruitment difficulties; three participants completed all sessions. No significant adverse events occurred. Cognitive testing during the acute drug experience was not possible because participants reported high subjective dose intensity. Headache impact remained severe throughout the trial. Mean daily attack frequency decreased by more than 50% in two participants at final follow-up. Thematic analysis of clinical notes suggested psychological insights, including reconfigured relationships to headache pain, were key features of participants' experience. The clinical results provide no conclusive evidence for psilocybin in SUNHA.
British journal of pharmacology
October 28, 2024
Laith Alexander, Dasha Anderson, Luke Baxter et al.
11 citations
Psychedelic drugs are being investigated as a new class of rapid-acting antidepressants, but their mechanisms remain unclear—specifically whether antidepressant and psychedelic effects arise from related or independent processes. This review examines behavioral methods used in animal studies to measure both the psychedelic and antidepressant effects of these drugs. It highlights conceptual and methodological challenges, stresses the importance of using doses comparable to those in human clinical use, and calls for attention to potential sex differences in preclinical research. Understanding these mechanisms could help identify new drug targets and improve treatments.
Journal of Psychopharmacology
August 29, 2025
Niall M. Mcgowan, James Rucker, Rachel Yehuda et al.
10 citations
A single 25 mg dose of psilocybin, given with psychological support, was safe and well-tolerated in 22 adults with PTSD. No serious adverse events occurred, and most side effects (headache, nausea, crying, fatigue) resolved within a day. PTSD symptoms, measured by the CAPS-5 scale, showed a clinically meaningful average decrease of nearly 30 points at 4 and 12 weeks after the dose, and this improvement was linked to the intensity of the psychedelic experience. Functional impairment and quality of life also improved. The open-label design and small sample size mean further controlled trials are needed to confirm efficacy.
Drug Science Policy and Law
September 1, 2025
David Nutt, David Erritzøe, Anne Katrin Schlag et al.
9 citations
The field of psychedelic research lacks standardized terminology for clinical development, dosing, safety monitoring, and regulatory classification. A comprehensive framework is proposed that classifies psychedelics by pharmacology (serotonergic, glutamatergic, kappaergic, GABAergic, and atypical), introduces dose-dependent categories (microdose, minidose, mididose, macrodose), and standardizes terms like “short-acting” with specific pharmacokinetic parameters. Safety considerations include cardiovascular and psychological effects, with risk mitigation protocols for higher-risk compounds like ibogaine. A three-phase treatment model—preparation, dosing, and integration—is recommended as a minimum standard. The lack of comparative research on psychotherapy modalities is identified as a critical gap.
BMJ Open
March 1, 2024
Charlie Song-Smith, Edward Jacobs, James Rucker et al.
9 citations
Most UK medical students (83%) are aware of psychedelic research and only 3% are not interested in learning more, yet only 17% feel well-educated on the topic. Students' harm assessments of psychedelics closely match experts', but teaching on psychedelics is rare in their curriculum. Time in medical school does not correlate with more knowledge about psychedelics. On average, students strongly support changing the legal status of psychedelics to enable further clinical research. Greater knowledge, lower perceived harm, more years in medical school, and lower perceived effectiveness of non-pharmacological mental health treatments are associated with stronger support for legal change.
BJPsych Bulletin
May 29, 2023
James Rucker
9 citations
Psilocybin therapy, which combines drug dosing with psychological support and integration, has been studied for 25 years. Early clinical trials show promise for treatment-resistant depression, but masking (blinding) likely fails, and expectancy effects may contribute to the therapeutic mechanism. Distinguishing drug effects from expectancy is necessary yet difficult when masking fails. Masking and expectancy have not been routinely measured in psilocybin or other medication trials; doing so could improve research and influence psychiatry. This opinion piece reviews the development, hope, hype, challenges, and opportunities of psilocybin therapy.
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.
Psychedelic Medicine
November 26, 2024
Nadav Liam Modlin, Tyler McPhee, Nira Zazon et al.
5 citations
People who use psychedelics and attend integration groups report that these groups provide essential community support and help process psychedelic experiences, but also face challenges such as managing group dynamics and ensuring facilitators are adequately trained. Three main themes emerged: reasons for attending, utility of the groups, and adverse factors affecting experience. While integration groups can reduce some risks of unregulated psychedelic use, research is needed to develop standardized protocols and facilitator training to improve their safety and effectiveness.
Acta Neuropsychiatrica
November 4, 2025
Chiranth Bhagavan, Alexander Bryson, Olivia Carter et al.
4 citations
Combining psychedelics with physiotherapy may offer a new treatment for motor functional neurological disorder (FND), a condition with no effective medications and often persistent disability. This protocol describes the first trial testing two psilocybin-assisted physiotherapy regimens in 24 people with refractory motor FND. Participants are randomly assigned to either 15 mg psilocybin with movement tasks during the drug's acute effects or 25 mg psilocybin alone. All receive two physiotherapy sessions before dosing and six after, with follow-ups at one and four weeks. The study assesses tolerability, feasibility, symptom severity, and brain imaging to inform a larger definitive trial.