Archives of General Psychiatry
June 6, 2011
David Erritzøe, Vibe G. Frøkjær, Klaus K. Holst et al.
86 citations
MDMA use, but not hallucinogen use, is linked to changes in the brain's presynaptic serotonin system. Because hallucinogens primarily act on serotonin 2A receptors, the negative association between MDMA use and serotonin transporter (SERT) binding is likely due to MDMA's direct presynaptic effect rather than its serotonin 2A agonistic actions. Cross-sectional data suggest that subcortical, but not cortical, SERT binding may recover after several months of MDMA abstinence.
Journal of Psychopharmacology
October 8, 2020
Dea Siggaard Stenbæk, M. Madsen, Brice Ozenne et al.
81 citations
People with higher levels of serotonin 2A receptor (5-HT2AR) binding in the neocortex before taking psilocybin experienced shorter peak psychedelic intensity and a longer time to return to normal consciousness. Higher pre-drug 5-HT2AR binding also predicted lower scores on a measure of mystical-type experiences. The findings reinforce that individual differences in brain 5-HT2AR levels shape the temporal and subjective features of the psilocybin experience.
Frontiers in Psychiatry
October 20, 2021
Meg J. Spriggs, Hannah Douglass, Rebecca J. Park et al.
78 citations
Anorexia nervosa is a severe psychiatric condition with few approved treatments. This paper describes how individuals with lived experience of anorexia nervosa helped shape a pilot study of psilocybin-assisted therapy through two online focus groups involving eleven people, and presents the protocol for that study at Imperial College London. Twenty female participants aged 21–65 with a body mass index of 15 kg/m² or above will receive three oral doses of psilocybin (up to 25 mg) over six weeks, supported by psychological preparation and integration, with a 12-month remote follow-up.
Neuropharmacology
September 27, 2022
David Nutt, Meg Spriggs, David Erritzøe
77 citations
Psychedelic therapy represents a promising new direction in psychiatry, offering effective treatment where conventional methods have failed and challenging the current diagnosis-specific model by showing transdiagnostic benefits. This has spurred significant investment and the creation of many new pharmaceutical companies researching known psychedelics and developing novel molecules. However, the authors caution that this enthusiasm must be grounded in established facts and current knowledge. They outline a knowledge framework that all innovative researchers in this field should consider to ensure rigorous and responsible scientific progress.
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.
J Psychopharmacol
August 1, 2022
Victoria Amalie Nygart, Lis Marie Pommerencke, Eline Haijen et al.
73 citations
Depressive symptoms decreased two and four weeks after a psychedelic experience in a naturalistic, non-clinical setting. The study tracked a large group of people who planned to use psychedelics outside a lab or clinic, including only those with depressive symptoms at the start. A medicinal motive, prior psychedelic use, drug dose, and having an emotional breakthrough during the experience were all linked to greater symptom reductions. The authors note potential sample and attrition biases and call for further controlled and observational studies to confirm the findings.
Frontiers in Psychiatry
June 29, 2021
Keri Mans, Hannes Kettner, David Erritzøe et al.
65 citations
Psychedelic substances like LSD and psilocybin have regained legitimacy in clinical research. In this naturalistic observational study of volunteers intending to take a psychedelic, well-being was assessed using fourteen measures at four time points: 1 week before and 2 weeks, 4 weeks, and 2 years after the experience (sample sizes 654, 315, 212, and 64, respectively). Changes clustered into three factors: 'Being well,' 'Staying well,' and 'Spirituality.' Repeated measures analysis showed improvements in Being Well and Staying Well in the weeks following the experience, and mixed model analyses indicated these improvements remained statistically significant up to 2 years, despite high attrition. Spirituality did not show significant change.
BJPsych Open
September 1, 2022
Tommaso Barba, Sarah Buehler, Hannes Kettner et al.
57 citations
Psilocybin, but not the antidepressant escitalopram, reduced rumination and thought suppression in people with major depressive disorder six weeks after treatment. In a randomized trial of 59 participants, only those given psilocybin showed significant decreases in both maladaptive coping strategies. Among treatment responders, thought suppression decreased exclusively in psilocybin responders, while rumination decreased in both psilocybin and escitalopram responders. Reductions in rumination and thought suppression correlated with ego dissolution and psychological insight during psilocybin sessions, suggesting distinct therapeutic mechanisms for the two treatments.
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.
J Psychopharmacol
April 22, 2021
Robin L Carhart-Harris, Anne C Wagner, Manish Agrawal et al.
54 citations
Psychedelic therapy is experiencing a resurgence due to favorable regulations, policy changes, and positive trial results, but current confirmatory trials may not fully address safety and best practice. The authors recommend supplementing these trials with pragmatic trials, real-world data initiatives, and digital health solutions to discover optimal and personalized treatment protocols. These steps aim to develop safe, effective, and cost-efficient psychedelic therapy, which is susceptible to hype and regulatory challenges given its history.
J Psychopharmacol
March 4, 2024
Alessia Marrocu, Hannes Kettner, Brandon Weiss et al.
51 citations
About 16% of people who used psychedelics in naturalistic settings showed a clinically meaningful decline in psychological well-being four weeks later. Those with a prior diagnosis of a personality disorder were disproportionately affected: 31% were negative responders, and multivariate regression indicated a greater than four-fold elevated risk of adverse psychological responses. The findings suggest that personality disorders may represent an elevated risk for psychedelic use, and that psychological support and a good therapeutic alliance may be especially important for this population.
Neuropsychopharmacology
February 14, 2017
Ishan C Walpola, Timothy Nest, Leor Roseman et al.
50 citations
MDMA (100 mg) reduces functional connectivity between the right insula and the salience network in the brain, indicating a disintegration of this network. This decrease in connectivity correlates with higher baseline trait anxiety and more intense acute experiences of altered bodily sensations under the drug. The findings suggest that insular disintegration is a neurobiological signature of the MDMA experience, linking the drug's effects on brain activity to individual differences in anxiety and bodily awareness.
Frontiers in Psychology
November 25, 2021
Brandon Weiss, Victoria Amalie Nygart, Lis Marie Pommerencke et al.
47 citations
In an online volunteer sample, naturalistic use of psychedelic compounds was associated with reductions in Neuroticism and increases in Agreeableness and perceived social connectedness over four weeks. These changes covaried, suggesting shared emotion-regulation processes. Preliminary evidence pointed to a specific decrease in critical and quarrelsome interpersonal style, a component of Agreeableness. Baseline levels of Neuroticism, perspective taking, and social connectedness tentatively amplified adaptive changes in those respective traits. Demographic characteristics, social setting, and acute subjective factors showed limited moderating effects. The findings suggest psychedelics might help address interpersonal aspects of personality pathology and loneliness.
EClinicalMedicine
September 23, 2024
David Erritzøe, 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.
Journal of psychopharmacology (Oxford, England)
January 1, 2024
Lisa X Luan, Emma Eckernäs, Michael Ashton et al.
41 citations
A novel method of administering the psychedelic DMT via a bolus injection followed by a constant-rate infusion safely extends the experience to 30 minutes in a stable and tolerable fashion. In eleven healthy volunteers, subjective effects plateaued into a steady state while plasma DMT concentrations continued to rise, indicating acute psychological tolerance. Anxiety ratings remained low and heart rate habituated within 15 minutes, demonstrating psychological and physiological safety. This continuous intravenous administration method lays groundwork for further basic and clinical research into DMT's potential for treating mental health conditions and studying consciousness.
Human Psychopharmacology Clinical and Experimental
June 14, 2012
Cecilie Löe Licht, M.v. Christoffersen, Mads Okholm et al.
40 citations
Among 98 Danish users of MDMA (Ecstasy) and hallucinogens, simultaneous use of multiple psychoactive substances was common. Participants had tried an average of 12.6 substances in their lifetime. MDMA was frequently combined with amphetamines (69%), hallucinogens (56%), and cocaine (47%). Alcohol and cannabis were used before, during, and after MDMA, LSD, and psilocybin, while amphetamines were typically taken before these drugs. Users preferred specific combinations to enhance or counteract effects. At their last recalled use, MDMA was taken with an average of 2.1 other substances in 32 different combinations.
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 Erritzøe 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.
Psychopharmacology (Berl)
November 4, 2021
Joanna Kuć, Hannes Kettner, Fernando Rosas et al.
37 citations
People who use cannabis at the same time as a classic psychedelic report more intense subjective effects, with higher cannabis doses linked to stronger mystical, visual, and ego-dissolution experiences. The relationship between cannabis dose and challenging experiences followed a U-shaped pattern, while emotional breakthrough showed no connection to cannabis dose. The findings suggest an interaction between cannabis and psychedelics, but the study's design cannot establish cause or clinical implications.
J Psychopharmacol
June 15, 2020
Anna Borissova, Bart Ferguson, Matthew B Wall et al.
37 citations
MDMA did not increase prosocial behavior in a controlled laboratory setting, despite raising blood levels of the drug and self-reported feelings of closeness and euphoria. In a double-blind, placebo-controlled experiment with 20 healthy volunteers, MDMA (100 mg) failed to significantly change task-based measures of empathy, trust, or cooperative behavior compared to placebo. Bayesian analyses supported the conclusion that MDMA and placebo had equivalent effects on empathy and cooperation. The drug also did not alter mood three days after administration. These findings suggest that the acute prosocial effects of MDMA observed in naturalistic or therapeutic contexts may not replicate under controlled experimental conditions.
Sci Rep
July 26, 2023
Balázs Szigeti, David Nutt, Robin Carhart-Harris et al.
33 citations
Blinding in medical trials aims to evenly distribute expectancy effects between treatment groups, but it often fails. Using computational modeling, this work shows that weak blinding combined with positive treatment expectancy creates an 'activated expectancy bias' (AEB), which can inflate treatment effect estimates and produce false positive results. The authors introduce the Correct Guess Rate Curve (CGRC) to estimate outcomes of a perfectly blinded trial from imperfectly blinded data. Re-analyzing a self-blinding psychedelic microdose trial dataset, they find that observed placebo-microdose differences are susceptible to AEB and may be false positives, suggesting microdosing acts as an active placebo. The findings highlight the distinction between trials with a placebo control group and genuinely placebo-controlled trials.
Neuroscience & Biobehavioral Reviews
April 4, 2025
Claudio Agnorelli, Kate Godfrey, Gabriela Sawicka et al.
32 citations
Classic psychedelics (LSD, psilocybin, N,N-DMT) and non-classic psychedelics (ketamine, MDMA) enhance neuroplasticity—the nervous system's ability to adapt—through molecular, structural, and functional changes. Animal studies indicate these drugs induce meta-plasticity (heightened sensitivity to environmental stimuli) and hyper-plasticity (re-opening developmental windows for long-term structural changes), with implications for mood and behavior. Translating these findings to humans faces challenges due to limitations in current imaging techniques, but promising new directions include novel PET radioligands, non-invasive brain stimulation, and multimodal approaches. This review informs the development of targeted interventions for neuropsychiatric disorders.
Frontiers in Psychiatry
September 19, 2023
Nicolas Garel, Jessica Drury, Julien Thibault Lévesque et al.
32 citations
A biopsychosocial approach to ketamine for treatment-resistant depression, called the Montreal model, pairs ketamine infusions with structured psychiatric care and psychotherapy. Developed over six years in public healthcare settings, the model conceptualizes ketamine as a brief intervention that creates windows of opportunity for enhanced care and psychological growth. It combines six ketamine infusions with psychedelic-inspired nonpharmacological adjuncts, including preparative and integrative psychological support. The model aims to bridge biomedical and psychedelic perspectives, offering a standardized yet flexible approach for severe, real-world patients. Further research is needed to assess its effectiveness and hypothesized psychological mechanisms.
Scientific reports
June 9, 2023
Brandon Weiss, Aleksandra Wingert, David Erritzøe 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.