medRxiv
September 29, 2019
Lorenzo Pasquini, Fernanda Palhano-Fontes, Draulio B. Araujo
24 citations
preprint
One day after a single session with the psychedelic ayahuasca, connectivity within and between brain networks that support interoception, emotion, and self-related thought is altered compared to placebo. In a randomized trial with 22 participants receiving ayahuasca and 21 receiving placebo, the ayahuasca group showed increased connectivity within the salience network, decreased connectivity within the default mode network, and increased connectivity between these two networks. Primary sensory networks were not affected. These connectivity changes correlated with acute subjective effects such as altered body awareness, volition, and affect. The findings suggest that ayahuasca induces subacute functional reorganization of higher-order cognitive brain networks.
medRxiv
December 11, 2022
Hannah Hartland, Kimia Mahdavi, L. Jelen et al.
22 citations
Ketamine reduces anxiety symptoms within 12 hours of administration, and the effect lasts for 1 to 2 weeks. A systematic review and meta-analysis of 14 randomized controlled trials found significant reductions in anxiety scores compared to placebo at acute (less than 12 hours), subacute (24 hours), and sustained (7–14 days) time points. Improvements in anxiety and depression symptoms were correlated at 24 hours and at 7–14 days. The relationship between peak dissociation and anxiety improvement was not significant. Most studies had a high risk of bias.
medRxiv
July 3, 2023
Drummond E-Wen Mcculloch, Anders S. Olsen, Brice Ozenne et al.
20 citations
preprint
Psychedelics like psilocybin are thought to increase brain entropy, but previous findings have not been replicated. In 28 healthy participants with 121 fMRI scans taken before and after psilocybin, brain entropy was measured alongside plasma psilocin levels, serotonin 2A receptor occupancy, and subjective drug intensity. Shannon entropy of path-length and instantaneous correlation distributions showed significant positive associations with drug effects, while sample entropy showed divergent associations depending on time-scale. However, 8 of 13 entropy metrics showed no significant effects, and the metrics correlated poorly with each other. The results suggest a nuanced acute effect of psilocybin on brain entropy and highlight specific metrics that may mediate clinical effects.
medRxiv
June 1, 2023
Andreas Halman, Geraldine Kong, Jerome Sarris et al.
17 citations
preprint
Classic psychedelics—LSD, psilocybin, mescaline, and DMT—are powerful psychoactive substances, but little is known about how they interact with other psychoactive drugs. This systematic review screened 8,487 records and identified 50 studies from 34 reports published before April 20, 2023, covering 31 studies on LSD, 11 on psilocybin, 4 on mescaline, 3 on DMT, and 1 on ayahuasca. The findings show that combining these psychedelics with antidepressants, antipsychotics, anxiolytics, mood stabilizers, or recreational drugs can attenuate, potentiate, or produce no change in effects. Except for a few case reports, no serious adverse drug events were reported.
medRxiv
August 24, 2023
Subha Subramanian, Demetrius Perry, Caterina Gratton et al.
14 citations
preprint
Psilocybin disrupts connectivity across cortical networks and subcortical structures, producing more than three-fold greater acute changes in functional networks than methylphenidate. These changes are driven by desynchronization of brain activity across spatial scales, strongest in the default mode network (DMN), which is connected to the anterior hippocampus and thought to create our sense of self. Performing a perceptual task reduces psilocybin-induced network changes, suggesting a neurobiological basis for grounding during psychedelic therapy. Psilocybin induces a persistent decrease in functional connectivity between the anterior hippocampus and cortex (and DMN in particular), lasting for weeks but normalizing after six months. This persistent suppression of hippocampal-DMN connectivity represents a candidate neuroanatomical and mechanistic correlate for psilocybin's pro-plasticity and anti-depressant effects.
medRxiv
December 12, 2019
Ron Shore, Paul Ioudovski, Craig Goldie et al.
8 citations
preprint
A scoping review of psilocybin-assisted therapy for addiction, depression, anxiety, and post-traumatic stress disorder identified 40 publications, including 9 clinical trials with 169 participants. Trials used a peak-psychedelic model with eyeshades, music, and medium to high psilocybin doses. No serious adverse effects occurred; mild effects included transient anxiety, nausea, and headaches. The trials demonstrated safety, tolerability, and preliminary efficacy for obsessive-compulsive disorder, substance use disorder, treatment-resistant unipolar depression, anxiety or depression in life-threatening cancer patients, and demoralization among long-term AIDS survivors. The literature is early and exploratory, with only 5 randomized controlled trials, small homogeneous samples, blinding difficulties, and confounding psychological support. Further research with diverse patients and varied dosing is needed.
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.
medRxiv
April 7, 2021
David E. Gard, Mollie Pleet, Ellen Bradley et al.
7 citations
preprint
Psilocybin, the active ingredient in hallucinogenic mushrooms, can rapidly and durably improve depression symptoms, but its safety in people with bipolar disorder is unknown because they have been excluded from clinical trials. The authors reviewed 17 published case histories and found potential risk for activating a manic episode, warranting caution. However, the lack of systematic data or common case examples indicating risk suggests that a cautious trial using modern methods, focused on those at lowest risk for mania (e.g., bipolar 2 disorder), is needed given depression's impact on this population.
medRxiv
September 11, 2024
M. Nikolič, Pedro A. M. Mediano, Tom Froese et al.
6 citations
preprint
Psilocybin, a classic psychedelic, alters perception, cognition, and emotion by activating 5-HT2A receptors and reducing serotonin reuptake. In a placebo-controlled crossover study with 20 healthy individuals, electroencephalography tracked brain activity changes over 24 hours after oral psilocybin (0.26 mg/kg). Acutely, absolute power decreased in alpha and beta bands but increased in delta and gamma frequencies; alpha power decreased occipitally between 1 and 3 hours, and beta decreased frontally at 3 hours. Global functional connectivity in the alpha band dropped acutely, while Lempel-Ziv complexity increased at 1 and 1.5 hours.
medRxiv
November 1, 2022
Natasha L. Mason, Attila Szabó, Kim P. C. Kuypers et al.
6 citations
preprint
Psilocybin immediately reduced concentrations of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), while other inflammatory markers (interleukin-1α, IL-1β, IL-6, and C-reactive protein) remained unchanged. Seven days later, TNF-α returned to baseline, but IL-6 and CRP were persistently reduced in the psilocybin group. Changes in immune profile were linked to acute neurometabolic activity: reductions in TNF-α were associated with lower hippocampal glutamate concentrations. Greater reductions in IL-6 and CRP at seven days correlated with persisting positive mood and social effects. Psilocybin also blunted the cortisol response to a psychosocial stressor compared to placebo.
medRxiv
January 4, 2024
Marcelo Falchi-Carvalho, Handersson Barros, Raynara Bolcont et al.
5 citations
preprint
A single-day session of vaporized DMT, a psychedelic compound found in ayahuasca, rapidly reduced depression symptoms in six patients with treatment-resistant depression. Depression scores on two standard rating scales dropped substantially by day one and remained lower for one month. By day seven, 83% of patients responded to treatment and 67% achieved remission; at one month, 67% maintained response and 50% maintained remission. The non-invasive, short-acting nature of DMT may make psychedelic treatments more accessible in interventional psychiatry.
medRxiv
September 9, 2022
Devon Stoliker, Katrin H. Preller, Leonardo Novelli et al.
5 citations
preprint
A double-blind, placebo-controlled study of 24 healthy adults found that psilocybin, the active compound in magic mushrooms, alters visual brain connectivity in ways consistent with preclinical models. Under psilocybin, early visual and higher visual-association regions showed increased self-inhibition, while top-down feedback from association areas to earlier visual regions was enhanced. These connectivity changes were linked to decreased sensitivity to neural inputs and the perception of eyes-closed visual imagery. The findings suggest that psilocybin-induced visual imagery arises from reduced bottom-up gain and strengthened top-down influences, informing basic and clinical understanding of visual perception.
medRxiv
July 10, 2022
M. Madsen, Anja Sofie Petersen, Dea Siggaard Stenbæk et al.
5 citations
preprint
In a small open-label clinical trial, three low-to-moderate doses of psilocybin reduced attack frequency by an average of 30% from baseline to follow-up in patients with chronic cluster headache. One patient experienced 21 weeks of complete remission. The treatment was well-tolerated with no serious adverse reactions. Changes in hypothalamic-diencephalic functional connectivity correlated negatively with the relative reduction in attack frequency, suggesting this neural pathway is involved in treatment response. Further studies are needed to confirm safety and prophylactic efficacy.
medRxiv
September 9, 2022
Devon Stoliker, Leonardo Novelli, Franz X. Vollenweider et al.
4 citations
preprint
Psilocybin reduces the brain's top-down control from resting state networks to the amygdala, which is involved in emotion appraisal and regulation. In a randomized, double-blind, placebo-controlled trial of 24 healthy adults given 0.215 mg/kg psilocybin, effective connectivity decreased from the default mode network and salience network to the amygdala, and within the DMN and SN, while connectivity within the central executive network increased. These changes were linked to altered emotion and meaning under the drug, suggesting that attenuation of the amygdala signal may serve as a biomarker for psilocybin's therapeutic effects in conditions like addiction and depression.
medRxiv
December 17, 2021
Anders S. Olsen, Anders Lykkebo-Valløe, Brice Ozenne et al.
4 citations
preprint
After a psychedelic dose of psilocybin, the occurrence and duration of two brain states involving lateral frontoparietal and medial fronto-parietal-cingulate coherence decrease, while a fully connected brain state increases. These changes are associated with both the level of psilocin in the blood and the intensity of the subjective drug experience. The findings suggest that the acute perceptual effects of psilocybin may arise from a shift away from specific frontoparietal connectivity motifs toward a more uniform connectivity structure. The study also proposes an improved method for modeling brain states from dynamic functional connectivity data.
medRxiv
W. M. Green, S.b. Raut, F.l.j. James et al.
4 citations
preprint
MDMA-assisted psychotherapy improves dissociation, depression, and functional impairment in people with post-traumatic stress disorder (PTSD), but does not improve sleep quality. A systematic review and meta-analysis of randomized controlled trials found that the therapy reduces core PTSD symptoms and enhances quality of life. The evidence is limited by small sample sizes in available trials, but supports further development of MDMA-assisted psychotherapy for PTSD.
medRxiv
April 6, 2025
Lucas M Wittenkeller, Gary A. Gudelsky, John T. Winhusen et al.
3 citations
preprint
Psychedelics are being tested as treatments for substance use disorders, building on their promise for depression. A scoping review of clinical trials and publications identifies a potential new mechanism: restoring dopamine homeostasis. This process may reduce drug-seeking behavior and support abstinence, complementing previously known effects. The neurobiological basis of psychedelics' therapeutic action remains incompletely understood, but this dopamine-related pathway offers a novel target for treating addiction.
medRxiv
January 1, 2025
Benjamin R Lewis, John Hendrick, Kevin Byrne et al.
3 citations
preprint
Adding a single 25 mg dose of psilocybin to an 8-week mindfulness-based stress reduction (MBSR) program reduced depression and burnout symptoms more than MBSR alone in frontline physicians and nurses who worked during the COVID-19 pandemic. In a randomized trial with 25 participants, those receiving psilocybin-assisted therapy plus MBSR showed larger decreases in depressive symptoms at two weeks and six months, and greater improvements in burnout, demoralization, and connectedness. No serious adverse events occurred; only mild to moderate side effects were reported. The findings suggest that combining psilocybin with mindfulness training may be a promising treatment for depression and burnout in healthcare workers.
medRxiv
August 28, 2024
3 citations
preprint
Most meditators who use psychedelics perceive them as beneficial for their meditation practice. Among 863 regular meditators (practicing at least three times weekly for the past year) who also used psychedelics, machine learning identified four factors most likely to predict this positive perception: greater frequency of psychedelic use, setting intentions before use, higher agreeableness, and having used N,N-Dimethyltryptamine (DMT). The model explained about 27% of the variance. The findings suggest that intentional and personality factors may shape how psychedelics influence meditation, but causality remains unestablished.
medRxiv
May 26, 2023
Tobias P. Whelan, Eileen Daly, Nicolaas A.j. Puts et al.
3 citations
preprint
Clinical trials for drugs targeting core autism features have failed, despite evidence linking various neurochemical systems to brain function in autism. The field has relied on association studies, but the only way to directly establish a neurotransmitter's role in a brain function is to experimentally change it and observe a shift. There is little direct experimental evidence on how neurochemical systems modulate information processing in the living human brain, limiting translation from animal studies. The authors introduce a "shiftability" paradigm to bridge this gap, using psilocybin as a pharmacological probe of the serotonin system in vivo. They present the protocol for 'PSILAUT', a study testing whether the serotonin system functions differently in autistic and non-autistic adults.
medRxiv
April 19, 2023
Jennifer Bennett, Michael D. Blough, Ian Mitchell et al.
3 citations
preprint
In a Phase I trial, 14 healthy individuals received 25 mg of psilocybin extract. Transient, clinically insignificant rises in blood pressure and heart rate occurred, returning to normal as drug effects waned; all participants had normal two-month follow-ups. Mean peak systolic and diastolic blood pressures during the session were 145.93 (SD = 19.01) and 93.93 (SD = 9.75), a significant increase from baseline but tolerated by a healthy cardiovascular system. Focused screening protocols are suggested to balance safety and accessibility. Secondary outcomes showed a statistically significant decrease in QIDS-SR16 depression scores from baseline (M = 3.50, SD = 2.35) to eight-week follow-up (M = 1.86, SD = 0.86), and MEQ-30 scores indicated full mystical experiences.
medRxiv
May 29, 2025
Paul B. Fitzgerald, Sara Webb, Nigel Christopher Denning et al.
2 citations
preprint
A single dose of psilocybin, but not MDMA, produced short-term psychological changes in healthy adults: reduced neuroticism, increased extraversion, and improvements in mindfulness and connectedness one week after dosing. Psilocybin also induced stronger mystical experiences than MDMA, and the magnitude of those experiences correlated with changes in connectedness and mindfulness, though not with personality changes. Participants preferred larger group settings for MDMA than for psilocybin. The findings suggest that psilocybin's psychological effects may be mediated by mystical-type experiences.
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.
medRxiv
September 10, 2024
2 citations
preprint
Dissociative states—disruptions in awareness and perception—occur across many psychiatric disorders and can be experimentally induced. This meta-analysis of 123 studies (6,692 individuals) measured state dissociation using a standard scale. At baseline, the largest effects were in dissociative and complex subtypes of post-traumatic stress disorder (PTSD-DC). In controlled experiments, mirror-gazing and several drugs (especially ketamine and cannabis) produced dissociation levels as high as or higher than baseline PTSD-DC. Effect sizes varied widely but were not consistently linked to study methods. The findings confirm that dissociation can be reliably modeled in the lab, with implications for measuring side effects and predicting outcomes in drug-based treatments.
medRxiv
August 26, 2024
Tereza Klučková, Filip Tylš, Vojtěch Viktorin et al.
2 citations
preprint
In healthy volunteers, two doses of psilocybin (0.26 mg/kg) given at least 56 days apart produced moderate acute psychedelic effects that were mostly pleasant or fluctuating, with only one unpleasant experience. All sessions ended in a positive or neutral state. Psilocybin led to sustained positive effects across all domains of the Persisting Effects Questionnaire, with negligible negative effects. Contrary to expectations, dread of ego dissolution was not linked to negative long-term outcomes. Peak experiences culminating in positive mood were associated with positive lasting effects, while the type of experience (pleasant or mixed) did not correlate with the intensity or direction of the lasting effect. Results were independent of previous psychedelic experience, sex, or study setting.