Scientific Reports
August 22, 2023
Hannes Kettner, Stephen Ross, Richard J. Zeifman et al.
31 citations
Co-using a low dose of MDMA with psilocybin or LSD is associated with less intense challenging experiences—such as grief and fear—and increased feelings of self-compassion, love, and gratitude, compared to using psilocybin or LSD alone. In a survey of 698 people planning to use these substances, the 27 who also took a low dose of MDMA reported these benefits without a reduction in mystical-type experiences or compassion. Medium-to-high MDMA doses did not show the same effects. The findings suggest MDMA may buffer against some difficult aspects of psychedelic experiences, but the study's small, non-experimental convenience sample limits certainty.
Journal of Psychopharmacology
March 22, 2024
Tommaso Barba, David Erritzøe, Meg J. Spriggs et al.
26 citations
In a clinical trial comparing psilocybin plus psychological support to escitalopram plus psychological support for major depressive disorder, patients who discontinued their SSRI or SNRI medication before receiving psilocybin showed a reduced treatment effect on all depression severity and well-being measures compared with those who were unmedicated at trial entry. Discontinuation did not affect the intensity of the acute psychedelic experience. The findings are exploratory and hypothesis-generating, not confirmatory, and the study did not test SSRI/SNRI continuation. A controlled trial comparing discontinuation versus continuation before psilocybin is needed.
Psychiatry and Clinical Neurosciences
October 1, 2024
Shakila Meshkat, Fatemeh Gholaminezhad, Eric Vermetten et al.
24 citations
A systematic review of 20 studies with 2,959 participants found that psilocybin's effects on cognitive function are mixed. Global cognitive function and processing speed remained mostly unchanged in healthy individuals, while improvements in sustained attention, working memory, and executive function were reported in patients with treatment-resistant depression. Emotional processing and empathy were positively modified, especially in these patients, but cognitive empathy and social cognition were not significantly altered. Cognitive flexibility and creative cognition initially declined but could improve over time. Psilocybin improved semantic associations and associative learning, but effects on episodic and verbal memory were less pronounced than with other cognitive enhancers.
Scientific Reports
February 7, 2024
Tommaso Barba, Hannes Kettner, Caterina Radu et al.
24 citations
Psychedelics may improve sexual functioning and satisfaction days or weeks after use, according to two studies. In a large naturalistic study, people who used psychedelics reported greater pleasure, communication during sex, and satisfaction with their partner and appearance. A controlled clinical trial comparing psilocybin therapy with the SSRI escitalopram for depression found that those given psilocybin reported positive changes in sexual functioning after treatment, while those given escitalopram did not. This is the first quantitative investigation of psychedelics' post-acute effects on sexual functioning, suggesting a potential benefit and a need for further research.
Neuropsychopharmacology
March 8, 2019
M. Madsen, Patrick M. Fisher, Daniel Burmester et al.
21 citations
correction
No Summary
Psychedelic Medicine
October 28, 2022
Bruna Giribaldi, Sandeep M. Nayak, Bilal A. Bari et al.
15 citations
A Bayesian reanalysis of a trial comparing psilocybin (25 mg) to escitalopram (20 mg) over 6 weeks in 59 patients with major depressive disorder found that psilocybin outperformed escitalopram on three of four depression scales, though evidence was not uniformly clinically meaningful. Using skeptical priors that bias results toward zero, the analysis showed strong to extremely strong evidence favoring psilocybin on the BDI-1A, MADRS, and HAMD-17, while evidence on the primary outcome (QIDS SR-16) was indeterminate. For clinically meaningful superiority, evidence was moderate against it for the QIDS SR-16 but moderate to strong for the MADRS and HAMD-17. Psilocybin showed extremely strong evidence of noninferiority to escitalopram across all scales. The findings support further research on psilocybin's relative efficacy.
July 7, 2022
Richard J. Zeifman, Meg J. Spriggs, Hannes Kettner et al.
13 citations
preprint
The Relaxed Beliefs Under pSychedelics (REBUS) model suggests that psychedelics reduce the strength of deeply held beliefs. In a preliminary test of this idea, 11 healthy adults received a low (1 mg) and a high (25 mg) dose of psilocybin four weeks apart. Confidence in negative self-beliefs decreased after the high dose but not after the low dose. Greater brain signal entropy and stronger subjective effects during the high dose correlated with larger decreases in negative belief confidence, both during the session and four weeks later. Reduced confidence in negative beliefs was strongly linked to improved well-being at the four-week follow-up. These findings provide initial psychological support for the REBUS model, though replication in larger and clinical samples is needed.
April 12, 2023
Rebecka Bremler, Nancy Katati, Parvinder Shergill et al.
12 citations
preprint
Negative psychological responses to psychedelics, lasting at least 72 hours, are real and can include new psychiatric diagnoses or worsened symptoms, particularly anxiety. In a sample of 32 individuals who reported such experiences, 37.5% received a new psychiatric diagnosis after psychedelic use, and 87% experienced new or worsened anxiety. In-depth interviews with 15 of the most severe cases suggested that contributing factors include unsafe environments, unpleasant acute experiences, prior psychological vulnerabilities, high or unknown drug doses, and young age. The study's small, self-selected sample means these findings cannot estimate how common such harms are.
Journal of Psychedelic Studies
December 8, 2023
Brandon Weiss, Chelsea Sleep, Nicholas M. Beller et al.
11 citations
People who use psychedelics tend to be more open and extraverted and less neurotic than non-users, and non-users interested in trying psychedelics are more open and neurotic than uninterested non-users. An online survey of 218 psychedelic users, 104 interested non-users, and 104 uninterested non-users identified 52 themes of perceived personality change attributed to the most intense psychedelic experience, which clustered into eight factors: Unitive Spiritual, Gratitude Absorption, Purpose Freedom, Compassion Understanding, Emotional Stability, Openness Perspective, Connection to Self, and Neuroticism Caution. The findings suggest that personality traits influence who uses psychedelics, and that setting and drug type moderate different types of personality changes.
Research Square
May 20, 2021
Richard E. Daws, Christopher Timmerman, Bruna Giribaldi et al.
11 citations
Across two clinical trials, psilocybin therapy produced robust antidepressant effects that were linked to a decrease in brain network modularity measured by resting-state fMRI. In an open-label study of 16 adults with treatment-resistant depression, Beck Depression Inventory scores dropped sharply at one week and six months, and the reduction in network modularity one day after treatment correlated with clinical improvement at six months. In a double-blind randomized trial of 43 adults with major depressive disorder, the psilocybin arm showed superior antidepressant effects at two and six weeks compared with escitalopram, and improvements correlated with decreased modularity. These convergent findings suggest that psilocybin therapy may work by reducing the brain's network modularity.
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.
medRxiv
June 3, 2023
Matthew B. Wall, Lysia Demetriou, Bruna Giribaldi et al.
7 citations
preprint
Psilocybin therapy for major depressive disorder may work through a different brain mechanism than the SSRI escitalopram. In a trial comparing two groups—one receiving two 25 mg psilocybin doses plus daily placebo, the other receiving daily escitalopram plus two inactive 1 mg psilocybin doses—brain responses to emotional faces were measured with fMRI before and after six weeks of treatment. The escitalopram group showed significantly reduced brain activity in response to fear, happy, and neutral faces, including a specific reduction in amygdala response to fear faces. The psilocybin group showed no such reduction and even a slight increase in brain responsiveness, despite large improvements in depressive symptoms. Reduced emotional responsiveness may be a biomarker of SSRIs' antidepressant action not shared by psilocybin therapy.
Frontiers in Psychology
June 6, 2025
William Roseby, Hannes Kettner, Leor Roseman et al.
6 citations
Psychedelics like psilocybin strongly increase the sense that life has meaning, based on three different studies: a clinical trial for depression, a healthy volunteer study, and naturalistic retreats. The 'presence of meaning' rose substantially after a psychedelic experience, while the 'search for meaning' dropped only slightly. These meaning enhancements were moderately linked to improvements in mental health, such as greater wellbeing and reduced depression. Mystical, ego dissolution, and emotional breakthrough experiences were associated with increased meaning, though the strength varied by context. The evidence converges to show a robust, lasting positive effect of psychedelics on meaning in life, with context influencing outcomes.
Neuroscience Applied
December 2, 2024
Kate Godfrey, Brandon Weiss, Joseph Peill et al.
5 citations
A single high dose of psilocybin (25 mg) given to healthy volunteers who had never used psychedelics reduced neuroticism one month later, consistent with prior research. The reduction was linked to how meaningful the experience felt and to the dread of ego dissolution during the drug's acute effects. Personality was measured with the Big Five Inventory and Big Five Aspect Scale; acute effects were tracked with the Altered States of Consciousness questionnaire and Psychological Insight Scale. Electroencephalography measured alpha power and Lempel-Ziv complexity. The findings suggest that acute psychedelic states can catalyze lasting personality changes in a beneficial direction, with implications for therapy and understanding personality.
Molecular Psychiatry
April 26, 2025
Rebecca Harding, Neomi Singer, Talma Hendler et al.
4 citations
Psilocybin therapy reduces anhedonia more than the SSRI escitalopram in major depressive disorder, yet escitalopram dampens emotional responses to musical surprises while psilocybin therapy preserves them. Escitalopram increases brain activity in memory and emotion regions during musical surprises, whereas psilocybin therapy decreases activity in the ventromedial prefrontal cortex and angular gyrus and increases sensory region activation. These contrasting neural and behavioral effects suggest fundamentally different treatment mechanisms: psilocybin may maintain subjective responses by reducing the salience of prediction errors or strengthening hedonic expectations, while escitalopram may weaken hedonic priors.
Frontiers in Psychiatry
August 6, 2025
Grace Blest‐hopley, Giuseppe Pasculli, Simon Ruffell et al.
3 citations
Veterans with traumatic brain injuries who participated in psilocybin retreats showed improvements in PTSD, depression, and anxiety symptoms four weeks afterward. PTSD scores decreased by 50%, depression scores by 65%, and anxiety scores by 28%. Electroencephalography measurements revealed decreased delta and theta brainwave power in frontal and temporal regions, along with enhanced coherence in alpha and beta bands, suggesting improved cognitive control, emotional processing, and neural communication. The preliminary findings provide a rationale for larger controlled studies.
Journal of Clinical Medicine
February 20, 2025
Shakila Meshkat, Taha Malik, Jennifer Swainson et al.
3 citations
A systematic review examined whether psychedelic therapies can rapidly reduce suicide risk. Four randomized controlled trials reported significant reductions in suicidal ideation with psilocybin (three studies) and MDMA-assisted therapy (one study), with effect sizes (Cohen's d) ranging from 0.52 to 1.25 and no safety issues. Five additional randomized trials also showed reductions. Among 24 non-randomized and cross-sectional studies, results were mixed: psilocybin reduced suicidal ideation (odds ratios 0.40–0.75), MDMA-assisted therapy for PTSD showed a pooled effect of d = 0.61, while LSD was associated with increased odds of suicidality (odds ratios 1.15–2.08). DMT studies showed no significant effects. The evidence remains inconclusive, underscoring the need for further trials.
June 30, 2022
Matthew B. Wall, Rebecca Harding, Rayyan Zafar et al.
3 citations
preprint
Psychedelic therapy shows potential for treating psychiatric disorders like depression, addiction, and PTSD. Classic serotonergic psychedelics such as psilocybin, LSD, DMT, and 5-MeO-DMT are the main focus, along with ketamine, MDMA, and ibogaine. The concurrent use of advanced neuroimaging methods, particularly PET and MRI, has allowed precise assessment of brain effects, benefiting the development of these treatments. The text identifies gaps in knowledge that future multimodal imaging studies could address, providing a stronger foundation for psychedelic therapy.
European Neuropsychopharmacology
January 1, 2019
M. Madsen, Daniel Burmester, Dea Siggaard Stenbæk et al.
3 citations
No Summary
Research Square
August 22, 2025
Richard J. Zeifman, George Danias, Gabrielle Agin-Liebes et al.
2 citations
Psychedelics can acutely induce mystical experiences and elevated positive mood, which may contribute to the potential benefits of psychedelic therapy. However, there remains limited understanding of the occurrence and importance of specific positive emotional experiences within psychedelic therapy. Therefore, we examined the effects of psychedelics on positive emotional experiences and their association with improvements in mental health. Methods: Study 1 was an observational study of naturalistic psychedelic use. Study 2 used data from a clinical trial that compared psilocybin with escitalopram in individuals with major depressive disorder.
medRxiv
March 21, 2025
Jessica S. Henry, Bruna Giribaldi, David Nutt et al.
2 citations
preprint
In a randomized controlled trial of 59 patients with major depressive disorder, two high-dose psilocybin therapy sessions produced large increases in optimism and improvements in dysfunctional attitudes related to achievement, dependency, and self-control after six weeks. By contrast, a six-week daily course of escitalopram produced no change in optimism and only improved dysfunctional attitudes in the achievement domain. Psilocybin therapy was superior to escitalopram in remediating negative cognitive biases in depression.
arXiv (Cornell University)
November 29, 2024
Claudio Agnorelli, Meg J. Spriggs, Kate Godfrey et al.
2 citations
Classic psychedelics (LSD, psilocybin, N,N-DMT) and non-classic psychedelics (ketamine, MDMA) enhance neuroplasticity, the nervous system's ability to adapt. Animal studies indicate these drugs induce meta-plasticity, heightening sensitivity to environmental stimuli, and hyper-plasticity, reopening developmental windows for long-term structural changes that affect mood and behavior. Translating these findings to humans is challenged by limitations in current imaging techniques, but emerging approaches like novel PET radioligands, non-invasive brain stimulation, and multimodal methods offer promising directions. This review informs development of targeted interventions for neuropsychiatric disorders and advances understanding of psychedelics' therapeutic potential.
bioRxiv (Cold Spring Harbor Laboratory)
June 16, 2026
Paulina Clara Dagnino, Irene Acero-Pousa, Gorka Zamora‐lópez et al.
1 citation
Psilocybin and the conventional antidepressant escitalopram produce opposite changes in the brain's hierarchical non-equilibrium dynamics when treating major depressive disorder. Using resting-state fMRI before and after treatment, researchers built whole-brain models and measured how much each patient's brain activity deviated from the fluctuation-dissipation theorem. Baseline measures distinguished treatment responders from non-responders within each group. The deviation from the fluctuation-dissipation theorem may serve as a marker to differentiate the brain effects of psilocybin and escitalopram, contributing to understanding how these treatments work for depression.
Psychological Medicine
July 19, 2023
Brandon Weiss, Induni Ginige, Lu Shannon et al.
1 citation
No Summary
ChemRxiv
February 7, 2023
Vito F. Palmisano, Claudio Agnorelli, David Erritzøe et al.
1 citation
Classic psychedelics target the 5-HT2A serotonin receptor, but their precise mode of action remains unclear. Computational modeling of the receptor's orthosteric binding pocket for several psychedelics—including serotonin, LSD, DMT, and a photoswitchable analog (AzoDMT)—revealed two nearly equivalent binding poses. LSD and serotonin preferred the canonical crystallized pose, whereas DMT and 4-OH-DMT slightly favored a newly identified pose. The cis form of AzoDMT was the most stable, and its azobenzene domain interacted with the same residue (L229) responsible for LSD's extracellular loop closure. These simulations clarify drug–protein interactions and may aid development of new psychedelic compounds.