medRxiv
January 17, 2023
Ryan Yermus, Michael Verbora, Sidney H. Kennedy et al.
2 citations
preprint
Ketamine-Assisted Psychotherapy (KAP) produced large and sustained reductions in depression, anxiety, and PTSD symptoms for up to six months after treatment. In a retrospective trial of 1806 adults with treatment-resistant depression, anxiety, or PTSD, effect sizes at three months ranged from 0.75 to 0.86 and were maintained at six months (0.61 to 0.73). Between 39% and 41% of patients showed case reductions at three months, and 29% to 37% at six months. A minimal clinically important difference was reported by 50% to 75% at three months and 48% to 70% at six months. The treatment involved 4 to 6 guided ketamine sessions with psychotherapy.
medRxiv
January 16, 2026
1 citation
Classical psychedelics such as LSD, psilocybin, and mescaline produce distinct changes in brain complexity and entropy that are not seen with stimulants like MDMA or d-Amphetamine. Using resting-state fMRI data from three placebo-controlled crossover trials with 79 participants across 255 sessions, the study found that psychedelics specifically increased meta-state complexity, short-timescale multiscale entropy, and dynamic conditional correlation entropy. Both drug classes increased Lempel-Ziv and spatial complexity and decreased absolute modularity, but only psychedelics showed these unique complexity and entropy increases. These findings suggest that psychedelic-specific brain signal changes may help distinguish the acute psychedelic state from other psychoactive drug effects and could be relevant to understanding their therapeutic potential.
medRxiv
December 23, 2025
Chiranth Bhagavan, O. Carter, Glenn Nielsen et al.
1 citation
Movement tasks such as walking, reaching, and dexterity tests were feasible for healthy volunteers who took psilocybin doses up to 15 mg. At 20 mg, impairments appeared in tasks that combined movement with cognitive demands, such as the Box and Block Test and Digit Symbol Substitution Test. Nausea (62% of participants) and headache (54%) were the most common adverse events; no serious adverse events occurred. Participants and physiotherapists guessed the dose correctly only about half the time, indicating adequate blinding. These results suggest that psilocybin-assisted physical rehabilitation may be safe and feasible for future trials in people with movement disorders.
medRxiv
September 25, 2025
B Gowthami, Ishita Mehta, Sneha Baiju et al.
1 citation
preprint
Adding esketamine nasal spray to an oral antidepressant improves treatment response, remission, and daily functioning in people with treatment-resistant depression, but it also raises the risk of dissociation and hypertension. A systematic review pooled data from 17 randomized controlled trials involving 10,073 patients. Esketamine plus an antidepressant roughly doubled the odds of achieving a 50% reduction in depressive symptoms and nearly tripled the odds of remission compared to placebo plus an antidepressant. Functional disability scores also improved more with esketamine. However, continuous measures of depression severity showed no statistically significant difference between groups. Safety analysis found that dissociation was about twice as likely and hypertension about 40% more likely with esketamine, while sedation and nausea risks were not significantly elevated.
medRxiv
August 27, 2025
Md. Shahidul Islam, Md Sakib Ibne Salam, Md Nahid Hasan
1 citation
preprint
Unsupervised automatic text summarization was applied to 1,200 user experience reports of LSD, psilocybin, and DMT. Three extractive methods—LexRank, LSA with HDBSCAN clustering, and SBERT with Maximal Marginal Relevance—were compared using a custom scoring function that measures semantic coverage, narrative coherence, and experiential preservation. LexRank achieved the best overall balance, while SBERT excelled in content coverage and experiential depth but lacked coherence. Trade-offs between content richness and narrative fluency varied across substances due to differences in narrative structure. The study suggests that extractive summarization can help make subjective psychedelic reports more clinically useful, though future work should explore abstractive methods and expert adjudication.
medRxiv
June 25, 2025
Devon Stoliker, Fosco Bernasconi, Olaf Blanke et al.
1 citation
preprint
Psilocybin reduces effective connectivity between the right and left anterior insula and between the right anterior insula and right temporoparietal junction in people who report intense out-of-body experiences. These changes parallel disruptions in TPJ–insula circuits observed in clinical and experimental OBEs, particularly in the right hemisphere. The findings highlight how psilocybin-induced disembodiment corresponds to altered causal neural dynamics underlying bodily self-consciousness.
medRxiv
May 27, 2025
Nathan J Wellington, Ana Paula Bouças, Paul Schwenn et al.
1 citation
preprint
People with post-traumatic stress disorder who had a sustained clinical response to oral ketamine showed distinct baseline differences in DNA methylation and gene expression across 112 genes compared with non-responders. Key biomarkers included DENND5B, ZFY, PDGFRA, CPT1A, AHRR, and others involved in metabolism, cell signaling, neuronal development, immune response, and synaptic plasticity. Non-responders had persistent dysregulation in these pathways, suggesting biological barriers to treatment. Clinically, sustained responders had more severe PTSD at baseline and responded at lower ketamine doses. The findings point toward molecular profiling that could help personalize ketamine therapy for PTSD.
medRxiv
November 1, 2024
1 citation
preprint
A psychedelic formulation combining DMT and harmine, inspired by ayahuasca, blurs the brain's distinction between self and other faces. In a double-blind, placebo-controlled experiment with 31 healthy men, the DMT/harmine combination increased early visual brain responses (P1 amplitude) and disrupted the structural encoding of faces (reduced N170 amplitude) for all face types. It also specifically reduced the brain's later response (P300) to one's own face, making the neural reaction to self-faces more similar to that for familiar or unknown faces. Harmine alone did not produce these effects. The findings suggest psychedelics may reduce attentional focus on self-referential information, potentially explaining feelings of unity and enhanced empathy.
medRxiv
July 12, 2024
Marcel Nogueira, Solimary García-Hernández, Gleicy Sotéro Roberto et al.
1 citation
preprint
Psilocybin mushrooms pose a very low risk of adverse events requiring medical attention in Brazil. Analyzing over 112,000 drug-related reports from 2007 to 2022, only 13 involved psilocybin mushrooms, with no deaths and a hospitalization rate of 46.2% (6 cases), representing just 0.02% of all hospitalizations. By contrast, alcohol accounted for 49.2% of toxic agent reports and 45.0% of hospitalizations, while cocaine was linked to 33.3% of deaths. The findings suggest current drug policy, which classifies psilocybin as high abuse potential, may not reflect its actual public health risk, supporting evidence-based regulatory discussions for clinical and ceremonial use.
medRxiv
February 15, 2023
Victoria di Virgilio, Amir Minerbi, Jenna Fletcher et al.
1 citation
preprint
Veterans who used psychedelic medicines for non-recreational therapeutic purposes reported improvements in medical and mental health conditions, social interaction, spirituality, and overall function. Analysis of 93 comments from 65 civilian or military veterans identified themes including mysticism and spirituality, functional improvement and self-awareness, social connection and cultural impact, and impact on medical and mental health conditions, as well as neutral impressions and difficult experiences. The findings suggest that psychedelic use is associated with multidimensional wellness improvements beyond the absence of disease, reflecting dynamic interactions with personal, psychophysiological, and socio-environmental factors.
medRxiv
January 21, 2022
Latifah Kamal, Major Pauline Godsell, Bryce P. Mulligan et al.
1 citation
preprint
A dashboard system called SENSOR (Standardized Data Entry and Dashboards for Review of Scientific Studies) was developed to improve how scientific literature reviews communicate data. The system was tested on an existing review about clinical applications of psychedelics for mental health issues. Two team members entered 46 study entries, including 3 articles published after the original review to show ease of updating. The dashboard displayed the data in various visual representations. Using a dynamic, graphical display for review studies proved feasible and offers advantages such as standardizing reporting, centralizing datasets, streamlining submissions, improving collaboration, measuring author contributions, and enhancing patient involvement. Limitations include heterogeneity in study design, dosing, indications, and outcome measures.
medRxiv
July 10, 2026
Lada Kohoutová, Jevita Potheegadoo, Léa F Duong Phan Thanh et al.
Hallucinations in Parkinson's disease, from minor to structured, are linked to changes in brain connectivity and cognitive decline. Non-demented patients with minor or structured hallucinations share a common pattern of resting-state functional connectivity that is absent in patients without hallucinations. This pattern involves connections between subcortical areas and visual, attention, and default mode networks, as well as within-cerebellar and within-subcortical connectivity. The pattern is equally expressed in both hallucination groups and is associated with impairments in attention and executive function, as well as increased sensitivity to an experimental procedure that induces presence hallucinations. The findings suggest that altered subcortical-cortical connectivity underlies hallucinations even in their early, minor forms.
medRxiv
July 8, 2026
Paulina Clara Dagnino, Anne Maj van der Velden, Yonatan Sanz Perl et al.
In people with major depressive disorder, mindfulness-based cognitive therapy (MBCT) plus treatment as usual, compared to treatment as usual alone, alters whole-brain dynamics in ways that may reduce rumination. Using a novel method called complex harmonics decomposition on fMRI data from 80 patients, the study identified low-dimensional spatiotemporal manifolds that capture both local and long-range brain interactions. After MBCT, during rumination, brain regions involved in bodily and interoceptive processing became more consistently integrated across these manifolds. The latent configurations shifted with clinical and behavioral improvements, and the brain showed greater flexibility within the reduced space. These changes may reflect reduced 'stickiness' of ruminative thinking patterns following mindfulness training.
medRxiv
July 4, 2026
Marco Zierhut, Max Alt, Inge Maria Hahne et al.
Combining intranasal oxytocin with mindfulness-based group therapy may improve negative symptoms in schizophrenia spectrum disorders. In a pilot study, 47 participants received either oxytocin or placebo before four therapy sessions. Only the oxytocin group showed significant reductions in negative symptoms from baseline to post-intervention and at a 4-week follow-up, with small between-group effects favoring oxytocin at follow-up. No serious adverse events occurred. The findings support further large-scale trials.
medRxiv
June 23, 2026
Paulina Clara Dagnino, Anne Maj van der Velden, Henricus G. Ruhé et al.
In people with major depressive disorder, mindfulness-based cognitive therapy (MBCT) plus treatment as usual, compared to treatment as usual alone, increased the hierarchical organization of brain activity during rumination but not at rest. Greater hierarchy—meaning more directional information flow and less recurrent looping—was linked to improvements in clinical and behavioral outcomes. This shift away from self-reinforcing negative mental loops toward more differentiated cognitive and bodily cycles may help explain how MBCT interrupts ruminative thought patterns. Hierarchical brain dynamics could serve as a treatment-sensitive marker and potential mechanism of therapeutic change in MBCT for depression.
medRxiv
June 22, 2026
Roi Basch, Maya Cohen, Leehe Peled‐avron
Serotonin-boosting treatments, such as SSRIs and psychedelics, consistently reduce repetitive negative thoughts like rumination, worry, and obsessions, but do not reliably improve performance on lab tests of cognitive flexibility. A meta-analysis of 2,030 participants across 45 effect sizes found that acute tryptophan depletion did not impair cognitive flexibility, and serotonin elevation did not enhance it. However, serotonin elevation produced a medium-to-large reduction in pathological perseverative thinking. The effect was stronger in samples with more female participants, and psilocybin showed a marginally larger reduction than SSRIs. The findings suggest serotonin's role in emotional and cognitive rigidity is distinct from its effects on objective executive function.
medRxiv
June 1, 2026
In a survey of 295 adults with musculoskeletal pain attending a hospital orthopaedic clinic, most perceived psilocybin as moderately to highly effective for pain (76%) and expressed moderate-to-high willingness to try microdoses (58%) or macrodoses (53%) of psilocybin for pain. Prior non-therapeutic psychedelic use was the strongest predictor of willingness to try a macrodose (B=3.16) or microdose (B=2.82), while pain severity had a small but significant effect. Only 3% had discussed psychedelics with a healthcare provider, and health risks were the primary concern (33%). The findings suggest neutral-to-positive perceptions, with gaps in patient knowledge and health concerns as key barriers to address in future trials.
medRxiv
February 19, 2026
Amanda Gow, Emily Shih, Ryan Reid et al.
Under Oregon's regulated psilocybin program, adults who consumed an average of 27.8 mg of psilocybin showed significant improvements in depression, anxiety, and well-being 30 days after a session, including those concurrently using psychiatric medication. Of 88 participants (median age 43, 52% male, 64.8% with prior psychedelic experience), two reported symptoms of hallucinogen persisting perception disorder one day after the session, but none at 30 days. The findings suggest that legal psilocybin services can produce clinically meaningful mental health benefits.
medRxiv
December 1, 2025
Tatiana Aboulafia Brakha, Albert Buchard, Cédric Mabilais et al.
preprint
In a real-world clinical setting, a single dose of LSD (100 µg) or psilocybin (25 mg) combined with psychotherapy significantly reduced depression and anxiety symptoms in 115 adults with treatment-resistant disorders. Symptoms were measured one to three months after treatment, with no serious adverse events. Patients also showed reduced rumination, self-blame, and catastrophizing, along with increased positive refocusing and reappraisal. Both substances produced comparable clinical benefits despite different subjective effect profiles. The findings suggest that psychedelic-assisted psychotherapy is feasible and effective in routine specialized care.
medRxiv
November 17, 2025
Georgia Ioakimidis-Macdougall, John Gardner, Paul Liknaitzky
preprint
A single 25 mg dose of psilocybin, given with psychological support in a clinical setting, helped 14 mental health professionals develop a greater embodied understanding of therapeutic principles and processes. Participants reported increases in empathy, attunement, and emotion regulation—qualities that underpin therapeutic alliance and promote trust and safety. While no harms were reported, participants noted two potential risks: the experience could feel destabilizing, and therapists might project their own experience onto clients, narrowing interpretative range. Participants indicated that such training is necessary but not sufficient for high-quality psychedelic-assisted therapy. Findings support including an optional psychedelic experiential component for clinicians with prior training and reflective capacity.
medRxiv
August 28, 2025
Franziska Stadler, Johan Saelens, Ioline D. Henter et al.
preprint
An international online study of 759 people examined how psychedelic drug use affects cognitive performance and mental health in the short and long term. Participants completed tasks measuring working memory, selective attention, and visual/spatial perception, plus questionnaires on mental health and quality of life. Recent users showed significantly lower accuracy on all cognitive tasks and reported more depressive and dissociative symptoms. Lifetime users had the highest task accuracy without slower reaction times, and their use was not linked to long-term cognitive decline. However, lifetime users scored lower on psychological and social quality of life domains, suggesting possible long-term psychosocial effects.
medRxiv
August 16, 2025
S. Parker Singleton, Brooke L. Sevchik, Analiese Lahey et al.
preprint
Psilocybin-assisted therapy produces substantial reductions in depressive symptoms compared to control conditions, according to a systematic review and meta-analysis of 12 randomized controlled trials with 711 participants. The pooled effect size was large (Hedges' g = –0.91), and effects appeared rapidly and remained consistent over several weeks. However, many studies had small sample sizes or risk of bias, and waitlist-controlled or crossover designs contributed heterogeneity. The review provides a living open data resource that will be updated as new evidence emerges.
medRxiv
August 7, 2025
Ben Deverett, Duan Li, Theresa R. Lii et al.
preprint
Ketamine produces dissociative, analgesic, and antidepressant effects, but it is unclear whether its underlying neurophysiological signatures can be separated. In this observational cohort study, 52 participants (healthy volunteers, elective surgery patients, and patients with depression) received a subanesthetic infusion of ketamine or placebo, with or without general anesthesia. When ketamine was given under general anesthesia, its characteristic low-frequency brain wave augmentation was absent, while high-frequency power modulation was preserved. This selective modulation suggests a method for investigating the distinct roles of high- and low-frequency neural activity in ketamine's behavioral effects.
medRxiv
July 29, 2025
Artemis Zavaliangos‐petropulu, Ginny Ghang, Toni Boltz et al.
preprint
Treatment-resistant depression affects 30-50% of people with major depressive disorder. Electroconvulsive therapy and ketamine can relieve it, but how they work is unclear. This transcriptome analysis of peripheral blood from 37 people receiving electroconvulsive therapy, 60 receiving ketamine, and 35 non-depressed controls found no longitudinal changes in gene expression for either treatment after correcting for multiple comparisons. In the ketamine group, one gene (IGKV1-9) differed between remitters and non-remitters at baseline. In the electroconvulsive therapy group, six co-regulated gene modules differed at baseline between patients and controls. Pre-treatment gene expression differences may have predictive value, but larger studies are needed.
medRxiv
February 21, 2025
Alene Sze Jing Yong, Sue Brennan, Suzie Bratuskins et al.
preprint
Australia's Therapeutic Goods Administration rescheduled MDMA in July 2023, allowing its prescription for PTSD outside clinical trials. This manuscript outlines the development of an Australian Clinical Practice Guideline on MDMA-assisted psychotherapy for PTSD, using the GRADE process to weigh benefits and harms against other treatments. A multidisciplinary Guideline Development Group, supported by stakeholder and expert groups, will consider evidence certainty, patient values, resources, equity, acceptability, and feasibility. The guideline will be published on MAGICapp and in peer-reviewed outlets, with a companion guide for people with PTSD and their carers.