Research Square
February 25, 2026
Sean M. Viña
Lifetime psychedelic use is not independently linked to lower odds of missing needed mental health treatment after accounting for psychological distress. However, among people with higher distress, those who have used psychedelics—especially men—show a smaller increase in missed care compared to non-users. For women, only MDMA use shows a similar buffering effect. The findings indicate that psychedelic exposure does not uniformly improve treatment engagement and that gender differences exist in how distress relates to disengagement from care. Structural inequality may produce diminished benefits for women despite similar distress levels.
Research Square
February 23, 2026
Rotem Petranker, Norman A. S. Farb, Omer A. Syed et al.
Repeated low doses of psilocybin were safe and well tolerated in adults with major depressive disorder but did not show greater antidepressant effects than placebo. In a randomized, double-blind trial, 39 participants received either 2 mg psilocybin or placebo weekly for four weeks. Both groups reported similar reductions in depression scores on the PHQ-9 (psilocybin: -5.4; placebo: -6.0) and other measures. The microdose-first group showed slightly more improvement on a dysfunctional attitudes scale than the placebo-first group. No serious adverse events occurred, and symptom reductions continued during an open-label phase. Trial participation itself contributed to clinically meaningful improvement.
Research Square
February 23, 2026
Sandy R Shultz, Josh Allen, Grace O'Regan et al.
Repeated mild traumatic brain injury in rats produced lasting deficits in mood, social behavior, and pain sensitivity. Delayed treatment with psilocybin (1 mg/kg) reversed several of these effects, including antidepressant-like effects, increased social behavior, and raised pain thresholds. Psilocybin also reduced injury-related increases in microglial density and increased the number and complexity of newborn neurons in the dentate gyrus, suggesting enhanced neuroplasticity. The findings indicate psilocybin may be a promising intervention for persistent symptoms after repeated mild traumatic brain injury.
Research Square
February 17, 2026
Zofia Winczewska, Magdalena Górska-ponikowska, Wiesław Jerzy Cubała
Ketamine at 25 ng/mL increased the viability of mouse hippocampal HT22 neuronal cells exposed to hydrogen peroxide, but only at the highest concentration tested (1000 µM H₂O₂). At that level, cell viability rose from 12% (±1.63%) without ketamine to 38% (±9.12%) with ketamine. This suggests a protective, nonlinear effect that depends on the intensity of oxidative stress, activating only at critical H₂O₂ overload typical of severe depression. The findings indicate a threshold antioxidant mechanism that may contribute to ketamine's antidepressant action and inform future predictive models for individualized treatment.
Research Square
February 12, 2026
Jenessa N Johnston, Greg Jones, Shiyong Peng et al.
Rapid-acting antidepressants such as ketamine and psychedelics share common downstream effects on gene expression in human cortical neurons, despite targeting different initial receptors. Using stem cells from people with treatment-resistant depression and healthy volunteers, neurons were treated with several compounds. After 6 and 24 hours, gene activity was highly correlated across all drugs, converging on pathways related to inflammation, mTORC1 signaling, and cell growth. One compound, HNK, increased gene activity in excitatory neurons and decreased it in inhibitory neurons. These gene changes matched protein changes in spinal fluid from people given ketamine, supporting the model's relevance for studying antidepressant mechanisms.
Research Square
February 11, 2026
Jack Swain, Davis Carter, Leonardo Vando
Among 374 adults with moderate-to-severe PTSD who completed six sessions of at-home, telehealth-supported ketamine-assisted therapy, PTSD symptoms improved substantially. Mean PCL-5 scores dropped from 51.1 at baseline to 28.3 after session 6, a 44.6% reduction. The clinical response rate was 79.7%, and 60.7% achieved remission. Suicidal ideation resolved completely in 75.9% of those who reported it at baseline. Depression and anxiety scores also declined by about half. Side effects occurred in 4.3% of participants. Controlled trials are needed to confirm causality.
Research Square
February 2, 2026
Ziv Ben-Zion, Guy Simon, Teddy Lazebnik
Large language models can be prompted to generate narratives that closely mimic human accounts of psychedelic experiences, but they simulate the form without genuine phenomenology. A dual-metric evaluation compared 3,000 LLM-generated narratives from five models against 1,085 human trip reports. Psychedelic induction prompts increased semantic similarity to human reports from a mean of 0.156 to 0.548 and mystical-experience scores from 0.046 to 0.748. Models produced substance-specific linguistic styles but uniformly high mystical intensity across substances. This dissociation between linguistic mimicry and lack of experiential content raises safety concerns about anthropomorphism and the potential for AI to amplify distress or delusional ideation in vulnerable users.
Research Square
January 12, 2026
Lucas M Wittenkeller, Gary A. Gudelsky, T. John Winhusen et al.
A review of 165 ongoing clinical trials using classic psychedelics reveals that most are early-phase, U.S.-based studies for depression. Psychedelics are typically administered once, with designs either open-label single-arm or parallel-assignment quadruple-blinded active-placebo. Only six trials explicitly report blinding effectiveness, and 33 different placebos are used as controls. The review identifies a need for proper placebo selection and improved participant masking to address unanswered questions in the field.
Research Square
January 5, 2026
Noor Tasnim, Alana Hutchinson, Daphne Gyamfi et al.
Flow, a state of deep immersion linked to better performance and well-being, was studied in professional Memphis Jookin' dancers. Six dancers reported high levels of flow and greater interoceptive awareness than people trained in other mind-body practices. Two dancers wore EEG caps; one showed theta-band activity during dance across several brain regions, including the posterior cingulate and supplementary motor area. Resting-state functional connectivity increased after dance across theta, alpha, beta, and gamma bands. The findings suggest street dance elicits robust flow states with distinct patterns of brain activity and connectivity, highlighting dance as an embodied practice relevant for health.
Research Square
December 22, 2025
Negar Fani, Alexa Kondas, Vishwadeep Ahluwalia et al.
Sternal vibration paired with mindfulness meditation improved body awareness and increased neurite density in the corticospinal tract in trauma-exposed adults with elevated dissociative symptoms. In a study of 116 participants, those who received sternal vibration (n=60) showed significant improvements in body awareness and increased neurite density index in the left cerebral peduncle compared to those without vibration (n=56). Increased neurite density in the left and right corticospinal tracts was also observed. Decreased body dissociation correlated with increased neurite density only in the vibration group. The findings suggest sternal vibration as a low-cost neurostimulation method that may enhance interoception through neuroplastic changes.
Research Square
December 18, 2025
Alejo Acuña, Federico Billeri, Valentino Totaro et al.
A single dose of ibogaine, an atypical psychedelic, reinstated juvenile-like experience-dependent plasticity in the adult mouse visual cortex. Adult mice given ibogaine and then subjected to four days of monocular deprivation showed reduced visual acuity in the deprived eye and decreased dendritic spine density in the binocular visual cortex, effects not seen in vehicle-treated mice. Ibogaine alone did not alter these measures. The plasticity enhancement was accompanied by reductions in perineuronal nets, parvalbumin-positive interneurons, and inhibitory synaptic puncta density, suggesting ibogaine removes structural and inhibitory brakes on plasticity. These findings indicate ibogaine's therapeutic actions may stem from reopening windows of heightened cortical adaptability.
Research Square
December 17, 2025
Camarin E. Rolle, Nolan Williams, Afik Faerman et al.
A single dose of magnesium-ibogaine produced large and lasting reductions in disability, posttraumatic stress disorder, depression, and anxiety symptoms over 12 months in male U.S. Special Operations Veterans with a history of traumatic brain injury. Of 30 treated participants, 25 completed the full year of follow-up. Effect sizes at 12 months were very large (Cohen's d ≥ 2.18). The estimated probability of sustained remission at one year was 84% for PTSD, 66% for depression, and 61% for anxiety. These results suggest ibogaine may offer durable clinical benefits for TBI-related psychiatric and functional problems, though randomized controlled trials are needed to confirm the findings.
Research Square
December 1, 2025
Albert Buchard, Federico Seragnoli, Michel Sabé et al.
Early maladaptive schemas (EMS) are common in people seeking psychedelic-assisted psychotherapy and are strongly linked to baseline depression and anxiety. In 192 adults assessed for EMS and 74 patients followed through psilocybin- or LSD-assisted therapy, baseline schema burden—especially around failure and defectiveness—was tied to cognitive-depressive symptoms. However, schema burden did not predict the quality of the acute psychedelic experience or moderate overall symptom improvement. Patients experienced significant reductions in depression and anxiety with each session, but these changes depended on initial symptom severity, not their schema profile. Treatment effects were similar for psilocybin and LSD. The findings indicate that EMS are useful for identifying cognitive-emotional themes, such as core beliefs about failure, to address during psychotherapeutic integration, rather than for patient selection or outcome prediction.
Research Square
November 17, 2025
Sergio Pérez 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
Xuming Zhu, Xiaoyong Wei, Qianyu Guo et al.
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 T. 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
Patrick A. McConnell, Jackson Raffety, Andrew Li et al.
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
July 4, 2025
Erika Blair, David Chester
People often rely on others to help manage their emotions, a process called interpersonal emotion regulation (IER), while mindfulness involves turning inward to regulate emotions. A longitudinal study of 469 undergraduates across three waves, each about 20 days apart, examined how these strategies relate to each other and to aggression. Contrary to predictions, individuals who were generally more mindful engaged in less IER over time. However, when participants were more mindful than their own average, they subsequently used more IER. Neither mindfulness nor IER consistently predicted aggressive behavior. The inverse relationship between these effective regulatory approaches raises questions about trade-offs between their costs and benefits.