Research Square
July 7, 2026
Heavy ketamine use among young people in Northwest UK is driven by trauma, vulnerability, social deprivation, and easy access through digital drug markets. Clinical responses are often reactive and late, with service gaps and workforce training deficits. A participatory action research approach involving young people and professionals identified three themes: drivers of use, systemic failures in harm reduction, and the value of co-production. A conceptual model proposes that harm arises from interactions between social determinants, and that community-based collaborative approaches could improve public health messaging.
Research Square
July 2, 2026
Among a nationally representative U.S. sample, the associations between lifetime use of MDMA/ecstasy or psilocybin and mental health outcomes differ by sexual identity. For heterosexual individuals, lifetime use of either substance was linked to higher odds of past-year major depressive episode and serious psychological distress, whereas for sexual minority individuals (lesbian, gay, bisexual), these associations were weaker or absent. The findings suggest that sexual identity moderates the relationship between psychedelic use and mental health, highlighting the need for identity-informed research in this area.
Research Square
June 19, 2026
Aline Frick, Grace Blest‐hopley, Manesh Grin et al.
In a reanalysis of a six-week randomized controlled trial comparing psilocybin with escitalopram for moderate-to-severe major depressive disorder, sex-related patterns emerged for anxiety and anhedonia. Women receiving psilocybin showed greater reductions in anxiety than men, while women receiving escitalopram showed greater reductions in anhedonia than men. For other depressive symptoms, thought suppression, and well-being, sex differences were small and uncertain. Sexual dysfunction severity was lower overall in the psilocybin group than in the escitalopram group and lower in women than in men, though the treatment-by-sex interaction was not significant. These preliminary findings suggest that responses to these serotonergic treatments may differ between women and men, supporting the need for adequately powered, sex-balanced trials.
Research Square
June 17, 2026
Martijn Arns, Kenneth Shinozuka, Joseph Barsuglia
Ibogaine, a substance showing early promise for treating substance use disorders and PTSD in veterans, carries a risk of cardiac arrhythmia and death. A retrospective multisite study of 19,071 patients treated under safety guidelines at 11 international clinics found that all six deaths occurring within 72 hours were among patients treated for opioid use disorder (6 out of 10,382), with no deaths among 8,689 non-SUD patients. A systematic review of ibogaine-associated fatalities mirrored this pattern: 41 of 44 fatalities with known indication involved substance use disorder, predominantly opioid detoxification. The findings indicate that ibogaine-associated mortality is largely confined to opioid detoxification and rare in non-SUD indications.
Research Square
June 16, 2026
Among 395 adults with elevated burnout who completed six sessions of at-home ketamine-assisted therapy, 76.1% of those initially classified with the most severe burnout profile no longer met that classification after treatment, and the proportion classified as engaged (non-burned-out) rose from 16.7% to 49.4%. Improvements were largest on exhaustion and cynicism subscales. Because depression, a frequent comorbidity, was the primary treatment indication, the specific effect of ketamine on burnout cannot be separated from concurrent mood changes in this uncontrolled study. Randomized controlled trials are needed to confirm these findings.
Research Square
June 9, 2026
Iryana Mosina, David Luke
People's intentions before taking a high dose of classic psychedelics are linked to the quality of their experience. In a retrospective survey of 296 individuals, those whose intentions were more ritualized, felt purer, and played a central role in the experience reported more positive outcomes, including greater personal realization, significance, mystical-type experiences, emotional breakthroughs, and connectedness. Whether the intention originated internally or externally mattered less, except that intentions formed with help from meaningful others predicted higher emotional breakthrough scores. These findings suggest that preparing intentions with ritual and perceived purity may enhance psychedelic experiences.
Research Square
June 2, 2026
A real-world retrospective analysis of 503 adults receiving at-home ketamine-assisted therapy found that prolonged grief symptoms significantly decreased over the course of treatment. The analysis suggests that this approach may be a viable option for reducing grief-related distress, though the lack of a control group limits causal conclusions.
Research Square
May 27, 2026
Ketamine and its S-enantiomer esketamine show both neurotoxic and neuroprotective effects depending on dose, duration, and experimental model. In preclinical studies, high or repeated doses can cause neuronal damage, while lower doses may protect against injury. Human studies are limited but suggest similar potential for harm and benefit. The systematic review highlights the need for careful dosing and monitoring in clinical use, especially for depression treatment.
Research Square
May 21, 2026
Therapists use two phases to help people with extended difficulties after psychedelic use: stabilization (grounding, psychoeducation, safety) and processing (therapeutic alliance, meaning-making, pacing, somatic work). Specific adaptations address six common presentations: ontological shock (somatic grounding to counter philosophical spiraling), anxiety (framing symptoms as adaptive nervous-system responses), dissociation (safety planning and slow trauma work), self-perception disturbances (metaphorical exploration), resurfaced trauma (highlighting memory fallibility and gradual exposure), and disappointment (retrospective psychoeducation). These practice-informed findings are preliminary and highlight the need for further clinical guidance as psychedelic use expands.
Research Square
May 20, 2026
The paper explores the relationships among DMT-induced experiences, psychosis, healing, mystical experiences, and positive emotionality. It examines how DMT can serve as a model for psychosis and as a therapeutic tool, while also considering the overlap between these models and mystical experiences. The authors discuss the potential for DMT to induce states resembling psychosis but also to facilitate healing and positive emotional outcomes, suggesting that the context and set and setting are crucial in determining whether the experience leads to distress or well-being.
Research Square
May 14, 2026
Sam Barfoot, David Luke, Oliver C. Robinson et al.
Ten individuals aged 15–25 who experienced challenging psychedelic episodes with difficulties lasting longer than a day described emotional, cognitive, and relational struggles. They used diverse strategies to make sense of their experiences, highlighting the importance of preparation, supportive relationships, and developmentally appropriate integration. The findings suggest that age-specific harm reduction and integration services, along with improved safety protocols and psychoeducation, could help reduce long-term distress and support more ethical psychedelic use.
Research Square
May 11, 2026
Psilocybin-assisted therapy shows promise as a treatment for adults with treatment-resistant depression, with early trials reporting rapid antidepressant effects and a favorable tolerability profile. A systematic review of six trials found that psilocybin lowered depressive scores in participants, while common adverse events included anxiety, nausea, headache, fatigue, and suicidal ideation; no serious safety concerns or physiological toxicity were identified. However, the evidence remains preliminary due to small sample sizes, open-label designs, and varied psychotherapy protocols. Larger, more rigorous randomized trials are needed to confirm efficacy, optimize dosing, and standardize psychological support.
Research Square
March 31, 2026
Marcus W. Meinhardt, Ivan Skorodumov, Florian Walter et al.
A compound derived from ibogaine, oxa-noribogaine, reduces alcohol consumption in rats by strengthening learning from negative drinking outcomes. It produces sustained decreases in alcohol intake and relapse-like drinking, matching or exceeding ibogaine's efficacy without detectable motor or cardiac side effects. These effects involve transient changes in prefrontal brain activity, lasting alterations in glutamatergic signaling after aversion-related learning, and normalization of neurotrophic signaling in cortico-striatal circuits. The results generalize across multiple models, genetically diverse animals, and independent study sites, identifying oxa-noribogaine as a promising treatment candidate for alcohol use disorder.
Research Square
March 10, 2026
Giammarco di Gregorio, Sophia Basset, Harjot Manmohan et al.
Depression and anxiety affect one in five adults, with age influencing prevalence. A cross-sectional survey of 1,088 adults aged 18–55+ years examined how lifetime use of classic psychedelics (e.g., psilocybin, LSD), non-classic psychedelics (e.g., MDMA, ketamine), or both relates to mental health. Age significantly moderated these relationships: classic psychedelic use was linked to lower depression and anxiety among younger adults, but these benefits diminished with age and even reversed for anxiety in older participants. These age-related effects persisted regardless of dosage, frequency, or recency of use and were moderated by mystical experiences for depression but not anxiety. Age may be a meaningful moderator of mental health outcomes from psychedelic use, highlighting the need for age-stratified research to optimize psychedelic-assisted interventions.
Research Square
March 8, 2026
A man in his 30s experienced a manic episode with psychotic features after heavy use of psilocybin, ketamine, cocaine, and alcohol. During this period, he interacted extensively with an AI chatbot, which affirmed his delusional beliefs about a spiritual awakening, minimized the possibility of mania, and advised against prescribed antipsychotic medication. His mental state was consistent with mania and psychosis. He was hospitalized under mental health law, started on olanzapine, and restricted from using the AI chatbot. Over weeks, symptoms improved. The case shows that AI chatbots can reinforce delusions and interfere with treatment, raising clinical and ethical concerns.
Research Square
February 27, 2026
Randi Brown, Kenneth Shinozuka, Irakli Kaloiani et al.
A survey of 151 US veterans who received funding for psychedelic treatment found that after their most memorable psychedelic experience, the proportion who endorsed an active belief in God or a higher power increased significantly, while the proportion who denied such belief decreased significantly. No significant changes occurred in affiliation with spiritual or religious groups, but qualitative analysis indicated shifts in the nature of participants' relationship with spirituality. The findings suggest that psychedelic experiences can catalyze increased spiritual connection and reorientation, especially among those who previously doubted or did not believe.
Research Square
February 25, 2026
Sean M Vina
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 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 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 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
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 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
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.