Research Square
November 17, 2025
Sergio R. Perez Rosal, Sonya C. Faber
Natural variation in psilocybin content across mushroom samples makes consistent dosing difficult in research and retreat settings. In an observational report, psilocybin content was chemically analyzed rather than inferred from weight, revealing large variability across samples. Eleven individuals participated in a 7-day psilocybin retreat, receiving two doses of psilocybin-containing mushrooms. Standardization based on measured psilocybin concentration allowed for dose adjustments, including a planned increase of the second dose to approximately twice the first to compensate for known acute tolerance effects. This method provides a model for responsible natural product use in community or retreat settings and can inform future translational research.
Research Square
November 11, 2025
The 95% effective dose (ED95) of esketamine for reducing preoperative anxiety in children aged 1–4 years is 0.86 mg/kg, and for children aged 4–6 years it is 0.43 mg/kg, indicating that older children require a lower dose. The study included 80 children undergoing elective general anesthesia, divided into two age groups. Doses were adjusted using a biased coin design, and isotonic regression with bootstrapping calculated the ED95 and 95% confidence intervals. The ED95 values are clinically relevant for covering 95% of patients.
Research Square
November 5, 2025
Joseph la Torre, Step Cheung, Ariana Kam et al.
In a study with 236 participants, the largest sample to date, researchers asked open-ended questions to people in an ibogaine-assisted treatment program in Mexico. Common themes emerged: emotional amplification, life review, perceptual and sensory changes, visionary states, and a sense that ibogaine has its own character or agency. The findings provide a detailed, empirically grounded portrait of ibogaine's subjective effects and show its capacity to evoke structured, meaningful, and potentially transformative states of consciousness. The study's strengths include its large sample, rapid data collection, a safe clinical setting, careful participant preparation, and open-ended questions that captured the full range of experiences.
Research Square
October 10, 2025
Gitte M. Knudsen, Annette Johansen, Pontus Plavén‐sigray et al.
A single dose of psilocybin increases synaptic density in the frontal cortex and hippocampus of healthy individuals, but the magnitude of this effect depends on the environment in which the experience occurs. Participants who took psilocybin in a therapeutic-like room reported more intense mystical-type experiences, longer-lasting psychological benefits, and showed greater increases in synaptic density compared to those dosed inside an MRI scanner. These findings indicate that psilocybin's neuroplastic effects are modulated by environmental context, with implications for psychedelic-assisted therapies.
Research Square
October 7, 2025
Małgorzata Domżalska, Joanna Kwiatkowska, Iwona Cichoń et al.
In a mouse model of depression using chronic social defeat stress, a single dose of either ketamine or psilocybin reversed social avoidance behavior within 24 hours, with effects lasting up to 14 days. By contrast, the SSRI fluoxetine showed no effect after a single dose or after 7 days of daily treatment; antidepressant-like effects appeared only after 14 days of continuous administration. These rapid and sustained effects of ketamine and psilocybin mirror clinical patterns and highlight their potential as fast-acting alternatives to conventional antidepressants like fluoxetine.
Research Square
October 3, 2025
Psychedelic compounds alter gene expression in the brain, and this study maps those changes across species. The gene activity patterns linked to psychedelic action are associated with the 5HT2A receptor, specific cortical layers of the brain, and human accelerated regions—genetic sequences that evolved rapidly in humans and are thought to be important for brain evolution. These findings suggest that psychedelic-induced gene expression may tap into evolutionarily recent and layer-specific brain circuitry.
Research Square
September 26, 2025
Soria López, Cinto Segalàs, Eva Real et al.
In eight adults with treatment-resistant obsessive-compulsive disorder and major depression, adding intranasal esketamine to their existing treatment for 12 weeks reduced depressive symptoms by 48.8% and obsessive-compulsive symptoms by 30.4%. Four participants (50%) showed a depression response, with two (25%) achieving remission; three (37.5%) met the response criterion for OCD. The findings suggest esketamine may have dual benefits for both conditions, but controlled trials are needed to confirm these preliminary results.
Research Square
September 25, 2025
David Greguš, Jaroslav Hlinka, Filip Tylš et al.
Individual differences in how people respond to psilocybin are linked to the structural organization of the cingulate cortex. A previous finding that thickness of a specific cingulate region predicted emotional responses was not replicated. Instead, a broader anterior-to-posterior gradient of cingulate thickness predicted the overall intensity of the psychedelic experience, and general cingulate thickness was associated with the balance between anxiety and visionary states. These results suggest that patterns of cortical thickness across the cingulate, rather than a single region, may serve as a neuroanatomical marker for predicting psychedelic response, with potential implications for personalized dosing in therapy.
Research Square
September 17, 2025
Gisela Lima, Carla Soares, Marta Teixeira et al.
Reward processing involves learning, liking, and wanting, and its disruption in mesolimbic and mesocortical pathways underlies many disorders. In a within-subject pharmacoimaging study with 11 healthy participants experienced with psychedelics, inhaled N,N-dimethyltryptamine (DMT) altered connectivity within the mesocorticolimbic circuitry. Connectivity decreased between the right nucleus accumbens and left ventral tegmental area, while it increased between the right nucleus accumbens and anterior cingulate cortex, and between the medial prefrontal cortex and anterior cingulate cortex. These changes correlated with shifts in volition and perception. The findings suggest DMT may have therapeutic potential for disorders affecting reward processing.
Research Square
September 12, 2025
Christina Chwyl, Angelica Spata, Will Lucas et al.
Psilocybin and MDMA produce greater self-transcendent and mystical experiences than cannabis, even after accounting for contextual factors like personality and motivations, but the substance effects are small. Psychological factors—especially surrendering to the experience and having spiritual or prosocial motivations—are much stronger predictors, accounting for up to 58% of the variance in these experiences, compared to 10% or less for the substance alone. The findings suggest that mindset matters more than the specific molecule for producing self-transcendent and mystical experiences.
Research Square
July 25, 2025
Vítor Bruno, Lídia Emmanuela Wiazowski Spelta, Matheus Lujan Pereira et al.
Ayahuasca, a psychedelic brew used in indigenous rituals, reduced the reinstatement of cocaine-induced conditioned place preference in C57Bl/6 mice, suggesting potential for treating cocaine use disorder. While ayahuasca itself produced rewarding effects at the highest dose tested (15 mg DMT/kg), these were weaker than those of cocaine (10 mg/kg). Treatment with ayahuasca (12.5 or 15 mg DMT/kg) after cocaine conditioning and before a cocaine challenge effectively prevented the reactivation of drug-associated contextual preference. The findings indicate therapeutic value for ayahuasca in cocaine use disorder, though research in humans remains limited.
Research Square
May 6, 2025
Psychedelics like 5-MeO-DMT induce a dissociated state of arousal in mice, combining features of waking and sleep. In freely moving adult male mice, chronic neocortical recordings and pupillometry showed that the drug triggered prominent slow oscillations in the cortex and marked pupil dilation while the animals remained awake and moving. REM sleep was initially suppressed but overcompensated in the following 48 hours. This dissociated brain state, mixing waking and sleep characteristics, may underlie psychedelic effects such as dream-like hallucinations and reopening of the critical period for plasticity.
Research Square
May 6, 2025
Zitong Wang, Brett Robbins, R. L. Zhuang et al.
In an animal model of treatment-resistant depression, psilocybin produced a significant and lasting reduction in behavioral despair and cognitive impairment. The compound increased thyroid-stimulating hormone levels without altering the hypothalamic-pituitary-adrenal axis, countering stress-induced TSH reductions that may serve as a proxy marker of therapeutic response. Changes in cannabinoid receptor type I after psilocybin administration suggest possible modulation of the endocannabinoid system, though causal links remain unconfirmed. These findings highlight psilocybin's potential to treat treatment-resistant depression through targeting previously unexplored biological pathways.
Research Square
April 28, 2025
Yi Wang, Tianjie Li, Erin S. Reynolds et al.
An enzyme called PcncAAAD, a noncanonical aromatic L-amino acid decarboxylase, is activated by calcium through a specific mechanism. Using computer simulations and lab experiments, researchers identified two calcium-binding sites: site A, at the junction of two enzyme domains, primarily drives activation, while site B within a unique tail domain stabilizes the enzyme's structure. Calcium binding at site A stabilizes a 'lid-rim' structure that maintains the substrate-binding pocket. Mutations disrupting site A or this lid-rim severely distort the active site and reduce or eliminate enzyme activity. These findings clarify how calcium activates this enzyme and may aid in designing enzymes to produce aromatic amino acid derivatives.
Research Square
April 16, 2025
Among 100 cancer patients undergoing radiation therapy, 43% expressed interest in psychedelic-assisted therapy (PAT), 31% opposed it, and 26% were unsure. Interest was higher among those with prior mood disorders, prior recreational psychedelic use, younger age, and male sex. Patients experiencing more depression, worse spiritual well-being, greater demoralization, poorer quality of life, and more pain were more likely to be receptive. The main reason for hesitancy, cited by 43% of those not interested or unsure, was a lack of information. The findings suggest substantial patient openness to PAT, with education needed to address informational barriers.
Research Square
March 5, 2025
Chronic stress during adolescence can shrink neurons in the brain's somatosensory cortex, a region involved in depression. In a study of juvenile monkeys, those isolated to induce chronic stress had significantly smaller neurons than those living in a family group. However, monkeys given the traditional psychoactive brew ayahuasca before and during isolation had neuron volumes similar to the family group, suggesting the brew may protect against stress-induced cortical atrophy. Trends also hinted at preserved cortical structure in the ayahuasca-treated group, though differences in neuron density and overall cortical volume were not statistically confirmed. The findings point to ayahuasca's potential to mitigate stress-related brain changes and support further research into its therapeutic use for adolescent depression.
Research Square
September 26, 2024
Shona G. Allohverdi, Milad Soltanzadeh, André Schmidt et al.
Ketamine and psilocybin affect sensory learning in the brain through different neural mechanisms. By combining computational modeling with EEG data from a previous study, researchers analyzed how these drugs alter the brain's processing of prediction errors during an auditory task. Ketamine produced a larger reduction in sensory precision from 207 to 316 milliseconds after sounds, peaking at 277 milliseconds in frontal central brain regions, while psilocybin showed no significant effect on this measure. Both drugs reduced belief precision between 160 to 184 milliseconds, peaking at 172 milliseconds. For higher-level volatility prediction errors, ketamine reduced expression while psilocybin had no effect at 312 milliseconds. These distinct effects could inform tailored therapies for major depressive disorder.
Research Square
September 18, 2024
Shane Mageean, Anderson Daniel, Sara Tai
Cancer patients often suffer significant psychological distress, and current treatments often fall short. Psilocybin combined with psychotherapy may help, but oncologists, who are key gatekeepers to patient care, have not been well studied. Interviews with nine oncologists in England revealed five themes: their current approaches to distress, attitudes toward psychedelics, the need for quality research, service design, and distress across different patient backgrounds. Oncologists are open to psilocybin-assisted therapy but have concerns about safety and drug interactions with cancer treatments. Future research should explore these issues and include diverse patient groups.
Research Square
August 15, 2024
Around 4% to 8% of Polish adults, or about 2 million people, have tried classic psychedelics like psilocybin or LSD at least once. Men were more likely than women to use these substances, with the largest group of users aged 25–34 and living in urban areas. Curiosity was the most common reason for trying them, and users typically described the experience as a mix of pleasant and unpleasant sensations. Many participants held negative views of psychedelics and psychedelic-assisted therapy, but those with prior psychedelic experience had more positive attitudes.
Research Square
February 22, 2024
Bettina Habelt, Dzmitry Afanasenkau, Cindy Schwarz et al.
Current treatments for alcohol use disorder (AUD) are often ineffective due to large variability in individual responses and high relapse rates. A precision medicine approach using biomarkers of prefrontal control mechanisms—which are severely disrupted in AUD, reducing inhibitory control and promoting compulsive behavior and relapse—may improve outcomes. In a rat model of alcohol addiction and relapse, a biocompatible neuroprosthesis measured prefrontal neural function during abstinence. Alcohol-dependent rats showed reduced amplitudes of P1N1 and N1P2 event-related potential components and attenuated event-related oscillatory activity. Treatment with psilocybin (a 5-HT2AR agonist) or LY379268 (an mGluR2 agonist) restored these impairments. Psilocybin also counteracted a dominance in higher beta frequencies indicative of hyperarousal prone to relapse. These findings identify prefrontal markers of relapse and treatment response, particularly for psychedelic drugs.
Research Square
January 12, 2024
Erik Kaadt, Rolf Søkilde, Hanne D. Hansen et al.
A single dose of psilocybin alters the expression of specific microRNAs (miRNAs) in the prefrontal cortex and hippocampus of pigs, brain regions central to depression. One day after administration, 12 miRNAs were dysregulated in the prefrontal cortex and 2 in the hippocampus; after one week, only 4 dysregulated miRNAs remained in the hippocampus. Nine of the 18 identified miRNAs have been previously linked to depression. Two miRNAs, miR-212-3p and miR-107, showed robust acute regulation in the prefrontal cortex and are known to exert anti-inflammatory effects, mirroring previously reported effects of psilocybin. These results suggest psilocybin may exert its molecular effects through miRNA regulation.
Research Square
December 13, 2023
David K. Sjöström, Emma Claesdotter‐knutsson, Petri Kajonius
In a national Swedish sample, people who have used psychedelics at least once report lower depression scores (effect size d = -0.29) but substantially more drug use (d = 1.27) compared to matched non-users. The largest personality difference is openness to experience (d = 1.72), and the lower depression in users is partly explained by lower neuroticism. The findings suggest that personality traits, especially neuroticism and openness, help account for both the mental health differences and the higher drug use seen in psychedelic users.
Research Square
November 20, 2023
Ottone Baccaredda Boy, Giuseppe Pierpaolo Merola, Andrea Patti et al.
Adolescents reported more severe psychotic symptoms on the Positive and Negative Syndrome Scale than adults, while no significant difference was found in cannabis exposure or Aberrant Salience Inventory scores. A hierarchical pattern emerged among adult subgroups, with psychotic patients scoring higher than other psychiatric and neurological patients. The findings suggest that aberrant salience, and to a lesser degree cannabis use, may contribute to psychotic symptom severity, particularly during more at-risk developmental phases. The role of cannabis in this relationship remains unclear.
Research Square
June 27, 2023
Louise Hecker, Kosuke Kato, Jennifer Kleinhenz et al.
Psilocybin, the psychoactive substance in hallucinogenic mushrooms, has shown therapeutic effects in over 136 clinical studies for psychiatric, neurodegenerative, and chronic pain conditions, though its molecular mechanisms remain unclear. This study tested whether psilocybin affects cellular aging using a human cell model of replicative senescence. Continuous treatment with psilocybin caused a dose-dependent reduction in cell-cycle arrest markers, increased DNA replication and proliferation markers, lowered senescence-associated secretory phenotype (SASP), and decreased oxidative stress, without killing senescent cells. These results provide the first experimental evidence that psilocybin may slow cellular senescence, suggesting potential as a geroprotective agent for age-related diseases.
Research Square
May 5, 2023
During the coronavirus pandemic, pre-hospital emergency staff who practiced mindfulness were more likely to experience flow states, a sense of full immersion and engagement in their work. This connection was explained by two factors: psychological capital (a positive psychological state including hope, efficacy, resilience, and optimism) and coping competence (the ability to manage stressful situations). The findings suggest that mindfulness supports well-being and optimal functioning in high-stress healthcare roles by strengthening these personal resources.