Frontiers in Pharmacology
March 31, 2022
Roberta Murphy, Roberta Murphy, Hannes Kettner et al.
229 citations
In a trial comparing psilocybin-assisted therapy to escitalopram for moderate-to-severe depression, a stronger therapeutic alliance with the therapist predicted greater emotional breakthrough and mystical-type experiences during psilocybin sessions, and these experiences in turn predicted larger reductions in depression symptoms six weeks after treatment. Emotional breakthrough during the first session strengthened the alliance before the second session, while a weaker alliance before the second session directly predicted higher depression scores at the endpoint, independent of the acute psychedelic experience. The findings suggest the therapeutic relationship plays a key role in shaping both the quality of the psychedelic experience and clinical outcomes.
Proceedings of the National Academy of Sciences of the United States of America
March 28, 2023
Christopher Timmermann, Leor Roseman, Sharad Haridas et al.
217 citations
Intravenous DMT, a potent psychedelic and serotonin 2A receptor agonist, profoundly alters brain function in healthy volunteers. In a placebo-controlled study with 20 participants, multimodal neuroimaging (EEG-fMRI) showed that DMT robustly increases global functional connectivity, disrupts and desegregates brain networks, and compresses the principal cortical gradient. These changes overlapped with brain regions rich in serotonin 2A receptors and associated with human-specific psychological functions. EEG and fMRI measures correlated, linking neurophysiological changes to network-level effects. The findings indicate DMT predominantly acts on the brain's transmodal association cortex, the evolutionarily recent area tied to advanced cognition and high 5-HT2A receptor density.
Psychological medicine
June 1, 2024
Balázs Szigeti, Brandon Weiss, Fernando E Rosas et al.
74 citations
In a double-blind trial comparing escitalopram and COMP360 psilocybin for major depressive disorder, patients held higher expectations for psilocybin than for escitalopram. Higher pre-trial expectancy for escitalopram predicted better outcomes with escitalopram, but expectancy for psilocybin did not predict response to psilocybin. Pre-treatment trait suggestibility was linked to therapeutic response in the psilocybin arm but not the escitalopram arm. These findings suggest that psychedelic therapy may be less influenced by expectancy biases than previously thought, and that highly suggestible individuals may be especially responsive to psilocybin treatment.
European journal of drug metabolism and pharmacokinetics
May 1, 2023
Meghan Good, Zelah Joel, Tiffanie Benway et al.
54 citations
DMT, a psychedelic compound being developed for major depressive disorder, is rapidly cleared from the body with a mean elimination half-life of 9 to 12 minutes. In vitro experiments showed that blocking monoamine oxidase A and certain cytochrome P450 enzymes (CYP2D6 and, to a lesser extent, CYP2C19) slowed DMT's clearance. The drug has low lipophilicity and low plasma protein binding, meaning a high proportion is available for distribution and metabolism, consistent with its very fast clinical pharmacokinetics. In a phase I trial, 24 healthy adults received single escalating intravenous infusions of DMT (9–21.5 mg freebase) over 10 minutes. All doses were safe and well tolerated, and peak plasma concentrations did not relate to body weight or BMI. These results support developing novel DMT infusion regimens for treating major depressive disorder.
EClinicalMedicine
September 23, 2024
David Erritzoe, Tommaso Barba, Kyle T Greenway et al.
46 citations
In a clinical trial, psilocybin therapy showed comparable effectiveness to a common SSRI antidepressant for treating depression, with both treatments leading to significant reductions in depressive symptoms over a follow-up period. The findings suggest psilocybin may offer a viable alternative to standard antidepressant medication, though the study's design and sample size limit the strength of conclusions.
Molecular psychiatry
September 1, 2023
Matthew B Wall, Rebecca Harding, Rayyan Zafar et al.
39 citations
Psychedelic therapy shows promise for treating depression, addiction, PTSD, and other psychiatric disorders. Classic serotonergic psychedelics like psilocybin and LSD act primarily at the 5-HT2A receptor, while ketamine, MDMA, and ibogaine also show potential. Modern neuroimaging techniques, especially PET and MRI, now allow precise measurement of brain effects. Key knowledge gaps remain: the link between acute drug effects and long-term clinical outcomes, detailed characterization of 5-HT2A receptor effects, and the role of neuroplasticity. Future studies combining PET with 5-HT2A-selective ligands like [11C]Cimbi-36 and MRI could bridge molecular, functional, and clinical understanding.
Psychological medicine
January 1, 2024
Brandon Weiss, Induni Ginige, Lu Shannon et al.
38 citations
In a trial comparing psilocybin therapy with the antidepressant escitalopram for moderate-to-severe major depressive disorder, both treatments led to personality changes in a direction consistent with improved mental health. Psilocybin was linked to decreases in neuroticism, introversion, disagreeableness, and impulsivity, and increases in absorption, conscientiousness, and openness at six weeks, with some changes lasting six months. Escitalopram was linked to decreases in neuroticism, disagreeableness, and impulsivity, and increases in openness at six weeks, with neuroticism remaining decreased at six months. No significant differences between the two treatments were observed, except that patients' pre-trial positive expectations for escitalopram moderated personality changes after that treatment, but not after psilocybin.
Scientific Reports
February 7, 2024
Christopher Timmermann, Richard J Zeifman, David Erritzoe et al.
37 citations
Intravenous DMT, a fast-acting psychedelic, improved depression scores in healthy volunteers one to two weeks after administration. In a placebo-controlled comparison (13 participants) and a prospective dataset (17 participants), depression severity decreased significantly. Reductions in trait neuroticism appeared only in the placebo-controlled sample. Changes in depression and anxiety correlated with the intensity of acute peak experiences, suggesting that DMT may reduce depressive symptoms by inducing such experiences. The short half-life and flexible dosing of intravenous DMT make it a practical candidate for psychedelic medicine, though further research in clinical samples is needed.
Scientific reports
June 9, 2023
Brandon Weiss, Aleksandra Wingert, David Erritzoe et al.
32 citations
Ayahuasca ceremonies commonly trigger reexperiencing of adverse life events, with women more likely to reexperience sexual assault, veterans more likely to reexperience combat trauma, and individuals with PTSD showing higher prevalence of reexperiencing. Reexperiencing was associated with cognitive reappraisal, psychological flexibility, and discomfort during ceremonies. Participants who reexperienced adverse events showed greater reductions in trait neuroticism after ceremonies. The study tracked 33 military veterans and 306 non-veterans across three timepoints at ayahuasca centers in South and Central America.
Scientific reports
January 29, 2025
Richard J Zeifman, Meg J Spriggs, Hannes Kettner et al.
26 citations
A preliminary test of the REBUS model found that a high dose of psilocybin (25 mg) reduced confidence in negative self-beliefs in 11 healthy individuals, both during the acute experience and four weeks later. Greater brain signal entropy and stronger subjective effects under psilocybin correlated with larger decreases in negative self-belief confidence. Decreases in negative self-belief confidence were linked to increases in well-being. The findings provide initial evidence that relaxing and revising negative self-beliefs may underlie psilocybin's positive psychological effects, with increased neuronal entropy as a possible mechanism. Replication in larger clinical samples is needed.
International Journal of Mental Health and Addiction
March 7, 2024
Brandon Weiss, Leor Roseman, Bruna Giribaldi et al.
26 citations
Acute psychological experiences, particularly mystical experience and ego dissolution, partially account for how psilocybin therapy improves depression compared to escitalopram. In a phase 2 trial of patients with moderate-to-severe major depressive disorder, mystical experience and ego dissolution uniquely mediated the effect of treatment on depressive response. Higher levels of mystical experience, emotional breakthrough, and intense music-listening responses were also linked to greater antidepressant improvement. These findings suggest that acute psychological experiences play a causal mechanistic role in psilocybin therapy for depression.
Psychiatry Research
July 23, 2023
Otto Simonsson, Per Carlbring, Robin Carhart-Harris et al.
24 citations
In a meta-analysis of three psilocybin trials for depression involving 102 participants, clinically significant symptom worsening occurred for a minority of those receiving psilocybin or escitalopram (about 10%) and for a majority of those in the waitlist condition (63.6%). The psilocybin arm showed a lower likelihood of symptom worsening compared to waitlist and no difference compared to escitalopram. The authors note the limitation of a relatively small sample size.
Journal of Psychopharmacology
April 25, 2023
Brandon Weiss, David Erritzoe, Bruna Giribaldi et al.
24 citations
A reanalysis of data from a trial comparing psilocybin therapy (PT) to escitalopram (ET) for major depressive disorder found that 14 of 16 outcome measures favored PT, but the QIDS-SR-16 did not. The QIDS-SR-16 showed higher variance, imprecision from compound items and sum-scoring, vague response options, and lack of focus on a core depression factor. When the trial data were examined at item, facet, and factor levels, results suggested PT was superior in reducing depressed mood, anhedonia, a core depression factor, and specific symptoms like sexual dysfunction. This raises concerns about relying on individual scales that miss depression's multidimensional structure.
Scientific reports
July 17, 2024
Sara de la Salle, Hannes Kettner, Julien Thibault Lévesque et al.
21 citations
A prospective longitudinal survey of eight Canadians with cancer who received legal psilocybin-assisted psychotherapy under Section 56 exemptions found significant improvements in anxiety, depression, pain, fear of COVID-19, quality of life, and spiritual well-being two weeks after the session. Attitudes toward death, medical assistance in dying, and desire for hastened death remained unchanged. Most participants found the sessions highly meaningful, though one reported a substantial decrease in well-being. These preliminary data suggest that real-world psilocybin-assisted psychotherapy can produce psychiatric benefits similar to those in clinical trials, but limited enrollment and negative experiences indicate a need for formal real-world evaluation programs.
Neuroscience of consciousness
January 1, 2025
Christopher Timmermann, James W Sanders, David Reydellet et al.
19 citations
The psychedelic 5-MeO-DMT can, in its most extreme cases, produce a complete absence of self-experience and other perceptual content while preserving a quality of aroused, waking awareness. In an exploratory observational study in naturalistic ceremonial settings, micro-phenomenological interviews, questionnaires, and EEG recordings revealed a dynamic progression of effects, including variable disruptions of bodily and narrative self, reduced phenomenal distinctions, and visual imagery. EEG showed global alpha and posterior beta power reductions, suggesting inhibition of top-down brain models. The findings indicate 5-MeO-DMT's potential as a pharmacological model for deconstructed consciousness, though retrospective questionnaires have limitations.
Comprehensive psychiatry
July 1, 2025
Luca Pellegrini, Naomi A Fineberg, Sorcha O'Connor et al.
17 citations
A 10 mg dose of psilocybin produced a rapid, moderate-to-large reduction in compulsive symptoms in people with obsessive-compulsive disorder (OCD), lasting up to one week after dosing. In a blinded pharmacological challenge study, 18 adults with at least moderate OCD received a 1 mg and then a 10 mg dose of oral psilocybin, separated by four weeks. One week after the 10 mg dose, scores on the compulsion subscale of the Yale-Brown Obsessive Compulsive Scale showed a significant improvement compared to the 1 mg dose (Cohen's d = 0.74). No effect on depression was detected. The drug was well tolerated with no serious adverse events.
American Journal of Psychiatry
May 7, 2025
Matthew B Wall, Lysia Demetriou, Bruna Giribaldi et al.
16 citations
Psilocybin therapy greatly improved depressive symptoms but had only a small effect on how the brain responds to emotional stimuli. This contrasts with SSRIs, which often reduce emotional responsiveness alongside their antidepressant action. The findings suggest that psychedelic therapy may work through different neural mechanisms than conventional antidepressants.
Journal of Psychopharmacology
April 12, 2024
Joseph Peill, Miriam Marguilho, David Erritzoe et al.
16 citations
In a double-blind randomized controlled trial, 59 patients with depression received either a high (25 mg) or placebo (1 mg) dose of psilocybin. Those given the high dose reported stronger perceived 'inner healing' effects, and within that group, higher inner healer scores predicted greater improvement in depressive symptoms two weeks later. The findings suggest that the concept of an intrinsic healing mechanism activated by psychedelics merits further scientific investigation, though the idea remains scientifically nascent.
Frontiers in psychiatry
January 1, 2023
Ellen James, David Erritzoe, Tiffanie Benway et al.
16 citations
A phase 1 trial tested escalating intravenous doses of the psychedelic DMT (SPL026) in healthy volunteers who had never used psychedelics, to find a safe, tolerable dose for a future trial in people with major depressive disorder. Participants were randomly assigned to placebo or one of four doses (9, 12, 17, or 21.5 mg). The drug was well tolerated with no serious adverse events. Higher blood levels of DMT correlated with stronger ratings of mystical experience, ego dissolution, and intensity, though these trends need confirmation in larger studies. Based on safety and pharmacodynamic results, 21.5 mg given as a two-phase infusion was chosen for the patient trial.
Journal of Psychopharmacology
November 14, 2022
Meg J Spriggs, Bruna Giribaldi, Taylor Lyons et al.
15 citations
A fixed 25 mg dose of psilocybin produces similar acute psychedelic effects and improvements in well-being regardless of body mass index (BMI). Pooling data from three therapeutic studies, results support the null hypothesis that BMI does not predict overall intensity of the altered state, mystical experiences, perceptual changes, or emotional breakthroughs. There was weak evidence that lower BMI participants reported greater 'dread of ego dissolution,' but BMI did not meaningfully add to predictions beyond age, sex, and study. Mystical-type experiences and emotional breakthroughs strongly predicted well-being improvements, but BMI did not. These findings suggest body weight-adjusted dosing may be unnecessary, supporting fixed dosing to reduce practical and financial burdens on psychedelic therapy scalability.
Nordic Journal of Psychiatry
July 20, 2017
David Erritzoe, William A. Richards
14 citations
Psychedelic therapies are being re-evaluated for treating conditions like major depression, cancer-related anxiety and depression, and alcohol use disorder. The research examines their effects and safety, suggesting potential benefits for these psychopathologies.
Frontiers in Psychiatry
June 4, 2024
Julia Bornemann, James B Close, Kirran Ahmad et al.
11 citations
Psilocybin-assisted therapy may help treat fibromyalgia, a chronic widespread pain condition with limited treatment options. A protocol describes a mechanistic study with 20 participants who will attend 8 visits over 8 weeks, including two dosing sessions where psilocybin is given at least once, with doses up to 25 mg. The primary focus is on brain mechanisms, measured via electroencephalography during the acute psychedelic state and magnetic resonance imaging before and after treatment. Primary outcomes are Lempel-Ziv complexity from EEG and experiential avoidance via questionnaire. Secondary measures include pain, physical and mental function, and additional neuroimaging. Results aim to clarify how psilocybin-therapy works in the brain and inform a future randomized controlled trial.
The British Journal of Psychiatry
June 18, 2025
Kyle T Greenway, Nicolas Garel, Lê-Anh L Dinh-Williams et al.
8 citations
In a clinical trial of ketamine combined with psychotherapy for severe treatment-resistant depression, 32 participants received six ketamine infusions with psychological support, either with or without music. Both groups showed large and sustained reductions in depression, anxiety, and suicidality at four weeks, fully maintained at eight-week follow-up. The ketamine experiences were highly emotional and mystical, comparable to those seen with psilocybin. Converging analyses suggested that mystical-like experiences contributed to the immediate and lasting antidepressant effects. Music did not enhance outcomes or psychedelic experiences.
Journal of psychopharmacology (Oxford, England)
June 10, 2025
Torsten Passie, Anja Loizaga-Velder, Alicia Danforth et al.
4 citations
A consensus-based model curriculum for education and training in substance-assisted psychotherapy (SAP) covers theoretical topics and practical components including apprenticeship observation, ongoing clinical supervision, and self-experience for trainees. The model, developed by authors with extensive SAP experience, also addresses peer and conventional supervision, respect for intercultural differences, and teachings about indigenous use of related substances. It is largely adapted to western industrialized countries with established graduate-level psychotherapy training. The curriculum may be valuable for psychedelic researchers, those training therapists for research studies, and those preparing for clinical work outside research settings.
Meghan Good, Tiffanie Benway, Zelah Joel et al.
4 citations
DMT (N,N-dimethyltryptamine) is being developed as a treatment for major depressive disorder. In a phase I trial, 24 healthy adults received escalating intravenous doses of DMT fumarate (SPL026) that were safe and well-tolerated. DMT exposure increased proportionally with dose over the 9–21.5 mg range. Peak plasma concentration occurred at about 10 minutes, and the mean elimination half-life was 9–12 minutes. In vitro experiments showed that DMT is cleared by monoamine oxidase A (MAO-A) and modified by the enzymes CYP2D6 and CYP2C19. The unbound fraction of DMT in plasma was approximately 70%. These findings support the development of DMT infusion regimens for treating major depressive disorder.