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.
Research Square
September 20, 2022
Jakub Vohryzek, Joana Cabral, Louis-David Lord et al.
10 citations
Psilocybin therapy for depression shows promise, but how it works is unclear. By comparing responders (those with >50% reduction in symptoms) to non-responders after 10mg and 25mg doses, whole-brain modeling identified specific brain regions whose dynamics shift from a depressive to a healthy state. These regions overlap with maps of serotonin 5-HT2A and 5-HT1A receptors, which psilocin—the active metabolite of psilocybin—activates. The findings provide causal evidence linking serotonergic transmission and recovery from depression via psilocybin.
Research Square
October 26, 2022
Rubén Herzog, Pedro A. M. Mediano, Fernando E. Rosas et al.
6 citations
Psychedelic drugs like LSD, which activate serotonin 2A receptors, dramatically alter subjective experience and offer a window into the neurobiology of consciousness. A key signature of these drugs is increased entropy—or randomness—in spontaneous brain activity, but why this occurs was unclear. Using a computational model of serotonin's effects on the whole brain, researchers reproduced the entropy increase seen in living brains, providing the first model-based explanation. Entropy rose across all brain regions but was most pronounced in visual and occipital areas. Surprisingly, this pattern was not tied to the density of serotonin receptors but instead linked to the brain's structural connectivity network. The findings clarify how psychedelics reconfigure brain activity.
Research Square
June 7, 2024
Målin Schmidt, Anne Hoffrichter, Mahnaz Davoudi et al.
5 citations
Psilocin, the psychoactive metabolite of psilocybin, triggers a cascade of neuroplastic changes in human cortical neurons derived from stem cells. It reduces cell-surface 5-HT2A receptors, increases BDNF abundance, alters gene expression toward plasticity, enhances neuronal complexity and synaptic protein levels, and boosts excitability and network activity. These findings suggest psilocin induces a state of enhanced neuronal plasticity that may underlie its therapeutic effects in neuropsychiatric disorders involving synaptic dysfunction.
Research Square
March 8, 2024
Hannes Kettner, Leor Roseman, Adam Gazzaley et al.
5 citations
Older adults (age 60+) who participated in a guided psychedelic group retreat showed significant improvements in well-being, with larger gains among those with a prior psychiatric diagnosis. Compared to younger adults, older adults experienced weaker acute psychedelic effects, and these effects did not predict well-being changes. Instead, a sense of communitas—the relational or social connection during the group session—predicted well-being improvements in older adults, suggesting that the social context of psychedelic therapy may be especially important for this age group.
Research Square
July 6, 2022
Giovana Gonçalves Gallo, Daniela Fernandez Curado, Mayra Pires Alves Machado et al.
4 citations
A mindfulness-based intervention improved symptoms of stress, depression, and insomnia among university students. In a randomized trial, 136 students were assigned to either an MBI group or a wait-list control. After the intervention, the MBI group showed significant reductions in stress, depression, and insomnia, but no effect was found for trait anxiety. The findings suggest that MBIs can reduce important mental health symptoms in university populations and may help prevent the development of mental disorders.
Research Square
October 15, 2024
Alexandra R. Gordon, Brennan M. Carrithers, Broc A. Pagni et al.
3 citations
Among individuals who reported a personality disorder diagnosis, psychedelic use was associated with improvements in mental health outcomes. In two observational studies, participants showed reductions in anxiety and depression symptoms lasting up to 2-3 months, with moderate to large effect sizes. Suicidal ideation decreased, and no participants moved to high risk of suicidal behavior after use. A small proportion experienced clinically significant worsening of anxiety (up to 8.2%) or depression (up to 7.1%). Transient increases in cognitive flexibility and sustained increases in cognitive reappraisal were observed, with the latter linked to reduced anxiety and depression. The findings are limited by small sample sizes and self-reported data.
Research Square
August 8, 2024
Danilo Bzdok, Robin Carhart-Harris, Chloe Savignac et al.
3 citations
Large language models can design, annotate, and evaluate experience dimensions from psychedelic reports, producing over 2 million automatic ratings that discriminate the unique mental effects of 30 psychoactive substances. This approach offers a bottom-up complement to legacy questionnaires for measuring changes in subjective awareness.
Research Square
February 22, 2024
Martha N. Havenith, Max Leidenberger, Jelena Brasanac et al.
3 citations
Circular breathwork, which involves deliberate hyperventilation, can induce altered states of consciousness (ASCs) comparable to those produced by psychedelics, without the legal, medical, or financial barriers. A reduction in end-tidal CO2 pressure due to hyperventilation is instrumental in catalyzing these ASCs. The depth of the ASCs predicted psychological and physiological follow-on effects, including improved well-being and a reduction of depressive symptoms. Two popular forms of breathwork—Holotropic Breathwork® and Consciously-Connected breathwork—produced highly similar physiological, experiential, and psychological outcomes. These findings outline physiological boundary conditions for ASCs in a non-pharmacological context and suggest breathwork's potential as an accessible psychotherapeutic tool.
Research Square
July 20, 2023
Orr Shahar, Alexander Botvinnik, Amit Shwartz et al.
3 citations
Psilocybin-containing mushroom extract (PME) produces more potent and prolonged effects on synaptic plasticity in the mouse brain than chemically synthesized psilocybin alone. In male C57Bl/6j mice, both PME and psilocybin triggered similar head twitch responses, but PME increased four synaptic proteins (GAP43, PSD95, synaptophysin, SV2A) across all brain areas studied after 11 days, whereas psilocybin only increased two proteins in the hippocampus and amygdala. Metabolomic analysis of the prefrontal cortex showed a gradient of metabolic changes from vehicle to psilocybin to PME, with declines in purines linked to oxidative stress and energy production. The findings suggest that additional compounds in the mushroom extract may enhance psilocybin's effects on brain plasticity.
Research Square
November 5, 2025
Sarah E. Mennenga, Toni J. Hanson, Moira G. Semple et al.
2 citations
Psilocybin reverses age-related behavioral and epigenetic alterations in aged mice. Male and female C57BL/6 mice (11 months old) received two doses of psilocybin (1mg/kg) or saline one week apart. Psilocybin improved learning and memory in females and reduced depressive-like behavior across sexes. Genome-wide DNA methylation profiling in the prefrontal cortex and hippocampus revealed widespread, sex- and region-specific effects, with the right hippocampus of females showing the most extensive gene-level changes. Differentially methylated loci were enriched for pathways related to synaptic organization, axon guidance, and neuroimmune signaling.
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.
Research Square
August 21, 2025
Guy Simon, Nir Tadmor, Michael Skragge et al.
2 citations
A mixed-methods study of 608 individuals who experienced lasting psychological difficulties after using psychedelics found that 41.8% linked those difficulties to early childhood trauma. Those with trauma links were older, more often female, more likely to have a prior mental-illness diagnosis, and more likely to use psychedelics in guided settings. They reported more emotional but fewer perceptual difficulties. Interviews with 18 participants revealed four themes: direct trauma re-experiencing (39%, some with no prior memory), symbolic/somatic re-embodiment (22%), fragmentation and confusion (50%), and varied outcomes: predominantly positive integration (50%), mixed effects (28%), or re-traumatization (22%). Uncertainty about memory accuracy contributed to ongoing distress. The findings underscore the need for trauma-informed approaches in psychedelic use.
Research Square
August 5, 2025
Christina Chwyl, Odin S. Elvenes, Andrew S. R. Kleven et al.
2 citations
Therapists who support clients after psychedelic experiences report ten key challenges, including unearthing trauma, destabilization or psychological crisis, re-adjusting to daily life with new insights and heightened sensitivity, relational harms from boundary violations, confusion about chaotic experiences, identity and worldview crises, feeling overwhelmed by needed changes, relationship disruption, disappointment after high hopes, and using psychedelics as escape. Based on interviews with 20 licensed mental health professionals (90% white, 70% cisgender women, modal integration clients 25–30), findings suggest that effective integration begins in preparation, involves setting realistic expectations, creating safe therapeutic environments, bolstering coping and social support, using trauma processing techniques, facilitating client-led meaning-making, and supporting gradual, values-guided life changes.
Research Square
May 13, 2025
Eirini K. Argyri, Joy Krecké, Oliver Robinson et al.
2 citations
Professionals who support people after psychedelic experiences identify six common extended difficulties: existential struggle and ontological shock, anxiety and panic, self-perception issues, dissociative symptoms, resurfacing of repressed trauma, and disappointment from unmet expectations. Recommended support strategies include trauma-informed individual psychotherapy, grounding and mindfulness techniques, peer and community support, meaning-making and narrative reconstruction, and sometimes short-term psychiatric medication. Psychiatrists emphasize medical stabilization, while psychotherapists and coaches focus on existential meaning-making and emotional processing. The findings suggest that trauma-informed, cross-disciplinary approaches are needed for psychedelic integration as use expands.
Research Square
November 18, 2024
Chloé Pronovost-Morgan, Kyle T. Greenway, Leor Roseman
2 citations
A large international Delphi consensus study with 89 experts from 17 countries developed guidelines for reporting the setting in psychedelic clinical trials. The process identified 770 potential setting variables, synthesized into 49 items, and refined through four rounds of surveys and debates. Thirty extra-pharmacological variables reached consensus as important or very important for reporting, forming the ReSPCT guidelines. These cover physical environment, dosing session procedure, therapeutic framework and protocol, and subjective experiences. The findings reveal significant ambiguities in current conceptualizations of set and setting, and the guidelines aim to improve methodological rigor in psychedelic research.
Research Square
September 19, 2024
Maria Maiarù, Tatum Askey, Daniel Allen-Ross et al.
2 citations
A single dose of psilocybin produced a sustained reduction in pain sensitivity in a mouse model of chronic neuropathic pain. Additionally, this single dose dramatically increased the pain-relieving effect of gabapentin, a common neuropathic pain medication. These findings suggest that psilocybin may induce lasting changes in neural network processing that enhance the effectiveness of existing treatments.
Research Square
December 28, 2023
Margareth Nogueira, Daiane C Ferreira Golbert, Richardson Menezes et al.
2 citations
A single high dose of the short-acting psychedelic 5-MeO-DMT alters gene expression in specific brain regions of mice, including the anterior cingulate cortex, basolateral amygdala, ventral hippocampus CA1 region, and dentate gyrus. The compound changed mRNA levels of immediate early genes Arc and Zif268 in several regions and increased TRIP8b expression in the ventral hippocampus after five days. Behaviorally, treated mice showed mixed anxiety-reducing and anxiety-increasing effects in standard tests. However, when pre-treated mice were subjected to acute stress, they had lower corticosterone levels and robust anxiety-reducing effects. These findings suggest molecular actions of 5-MeO-DMT related to its potential anxiolytic effects.
Research Square
April 28, 2022
David Wyndham Lawrence, Robin Carhart-Harris, Roland R. Griffiths et al.
2 citations
An analysis of 3,778 inhaled DMT experiences posted to Reddit over a decade found that entity encounters occurred in 45.5% of experiences, most commonly with a feminine phenotype (24.2%), aliens (16.3%), deities (13.8%), and jesters (6.5%). Interactions were predominantly positive (34.9%) or pedagogical (32.4%). Common visual phenomena included fractals and vivid colors, while somatic effects like auditory ringing were frequent. Mystical features and reduced fear of death were reported, with 6.1% of experiences described as profoundly beautiful. Challenging responses were less common.
Research Square
January 6, 2022
Hadley Rahrig, David R. Vago, Matthew A. Passarelli et al.
2 citations
Mindfulness training increases resting-state functional connectivity between the salience network and the default mode network, specifically between the left middle cingulate and the posterior cingulate cortex. This finding supports the idea that mindfulness enhances flexible control of internally-oriented attention. The meta-analysis included 12 studies with 226 mindfulness participants and 204 controls. The effect was small but significant, and there was no evidence of publication bias.
Research Square
April 8, 2026
Oliver Robinson, David Luke, Jules Evans et al.
1 citation
In a large global online survey of 6,476 people who have used psychedelics, nearly half (48.3%) reported at least one difficulty lasting 24 hours or more, and 9.9% experienced difficulties for over a year. The most common difficulties were existential struggle (36.6%), depression (34%), and derealization (29.4%). Existential struggle was rated as the most severe difficulty but also the one most linked to healing. Clinically relevant disruptive difficulties lasting at least a month and disrupting daily life were reported by 8% of participants and were associated with younger age, lower income, lack of family support, lower emotional stability, higher pre-existing anxiety or depression, and using psychedelics to treat mental health conditions. The findings highlight the need for education on risks and benefits, safety guidelines, and support services.
Research Square
November 25, 2025
Nai‐kong V. Cheung
1 citation
A brief oral regimen combining dextromethorphan with fluoxetine, sometimes plus piracetam or bupropion, produced rapid and lasting remission in four patients with hard-to-treat trauma-related disorders, including somatic PTSD, bereavement-related PTSD, adolescent depression, and complex PTSD with bipolar II and borderline features. Within days to weeks, intrusive memories, rumination, somatic pain, and disability sharply declined, with no dissociation, hypertension, or mania. The findings extend the ketamine/Auvelity treatment framework to trauma-spectrum illnesses and support controlled trials of low-cost NMDA–AMPA modulators for PTSD prevention and treatment.
Research Square
July 27, 2025
Klemens Egger, Robert Bozsak, Helena Aicher et al.
1 citation
In healthy volunteers, acute administration of N,N-dimethyltryptamine (DMT) combined with harmine produces global increases in brain glucose metabolism, as measured by [¹⁸F]FDG-PET. This suggests that the compound combination broadly energizes brain activity rather than acting on isolated regions. The findings indicate a neurobiological basis for the altered states of consciousness and mood enhancement reported with these psychoactive compounds, supporting further investigation into their therapeutic potential.
Research Square
February 13, 2025
Ayanna K. Bell, Bianca R. Watt, Arturo S. Lopez Flores et al.
1 citation
Practice manuals and clinical guidelines for psychedelic-assisted therapy (PAT) show varying alignment with the American Psychological Association's 2017 Multicultural Guidelines, but none offer teachable instructions for delivering culturally responsive care. This gap points to a need for more comprehensive training of PAT facilitators to ensure equitable treatment for diverse populations.
Research Square
August 23, 2024
Mathias E. Jensen, Dea Siggaard Stenbæk, Catharina Messell et al.
1 citation
A single 25 mg dose of psilocybin, given with preparation and integration sessions, reduced alcohol consumption in ten adults with severe alcohol use disorder. Heavy drinking days dropped by 37.5 percentage points over 12 weeks, and drinks per day decreased by 3.4 units. Participants also reported rapid and lasting reductions in craving and increased self-efficacy. Blood levels of the active metabolite psilocin varied widely between individuals, peaking from 14 to 59 µg per liter. The open-label study, which lacked a placebo group, suggests that even a single psilocybin session may be safe and effective, but larger randomized controlled trials are needed.