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
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
October 15, 2024
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
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
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
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 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
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
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
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.
Research Square
December 28, 2023
Joshua M. Poulin, Gregory E. Bigford, Krista L. Lanctôt et al.
1 citation
About one third of people with depression do not fully respond to standard treatments, and psilocybin may offer a rapid-acting alternative. This registered trial will randomize 36 adults with major depressive or persistent depressive disorder to receive either 25 mg psilocybin or an active placebo (100 mg niacin), then cross over three weeks later so that all participants receive psilocybin. Using serial neuroimaging, the study will test whether psilocybin acutely alters cerebral blood flow and functional brain activity in mood-related networks compared to placebo, and whether those changes persist subacutely. Clinical scales and serum biomarkers will also be collected to explore relationships with treatment response.
Research Square
March 14, 2023
1 citation
A single session of mindfulness meditation, whether 10 or 20 minutes, increases state mindfulness more than listening to a National Geographic article. Ten minutes of meditation was sufficient to produce this effect, and extending the session to 20 minutes did not yield additional gains. For people with lower trait mindfulness, meditation boosted state mindfulness more than the control. Among those with high trait mindfulness, a 20-minute session led to greater reductions in state anxiety than a 10-minute session. The minimal dose-response relationships suggest that 10 and 20 minutes of meditation improve state mindfulness to a similar degree.
Research Square
August 17, 2022
Sam Friedman, Galen Ballentine
1 citation
Machine learning applied to 11,816 publicly available drug testimonials reveals distinct subjective experiences linked to specific substances. Using BERT, a transformer model, the study predicted 28 dimensions of sentiment across narratives, validated by psychiatrist annotations. Canonical correlation analysis connected 52 drugs' receptor affinities with word usage, uncovering 11 latent receptor-experience factors mapped to a 3D cortical atlas. Results distinguished lucid from mundane phenomena: MDMA was linked to "Love," DMT and 5-MeO-DMT to "Mystical Experiences," and other tryptamines to "Surprise," "Curiosity," and "Realization." These models could potentially guide real-time biofeedback in therapeutic sessions.
Research Square
Ulrich Gergs, Hannes Jacob, Pauline Braekow et al.
1 citation
LSD increases the force and rate of heart muscle contraction by activating H2-histamine receptors in humans, and also acts as a partial agonist at 5-HT4 serotonin receptors in mice. In human atrial tissue from heart surgery patients, LSD's contractile effects were blocked by cimetidine, an H2-receptor antagonist. These findings clarify the cardiac effects of LSD, which is being studied again for psychiatric uses.
Research Square
July 9, 2026
For people with treatment-resistant depression, intranasal esketamine significantly reduced depressive symptoms during an initial four-week induction phase. After induction, two different maintenance schedules—one with a front-loaded pattern and one with a spaced interval-extension pattern—were compared. No significant differences in depressive symptom trajectories were observed between the two schedules over the maintenance period. By the end of maintenance, response rates were 35.3% on the clinician-rated scale and 26.0% on the self-report scale; remission rates were 31.4% and 38.0%, respectively. These results suggest that maintenance dosing intervals may be scheduled flexibly without loss of efficacy, though the retrospective, observational design and small sample size warrant caution.