Missouri medicine
January 1, 2023
Joshua S Siegel, Craig Pearson, Eric J Lenze
592 citations
New treatments for major depressive disorder are moving beyond traditional monoamine-targeting antidepressants toward options like κ-opioid antagonists, ketamine, and neurosteroids. These advances, combined with smartphone-based experience sampling and brain imaging, enable more precise diagnosis and symptom-specific measurement. This convergence heralds 'precision psychiatry'—selecting optimal treatments for individual patients. Anhedonia exemplifies this shift, evolving from a mere depression criterion to a transdiagnostic condition understood neurobiologically and targeted by novel pharmacotherapies. Functional testing of reward circuits in developing κ-opioid antagonists for anhedonia illustrates how other treatments, including psychedelics, may fit into future precision psychiatric care.
Nature
August 1, 2024
Joshua S Siegel, Subha Subramanian, Demetrius Perry et al.
241 citations
A single high dose of psilocybin (25 mg) massively disrupts functional connectivity in the human brain, causing more than threefold greater change than methylphenidate (40 mg). These changes are driven by desynchronization across spatial scales, dissolving network distinctions by reducing correlations within and anticorrelations between networks. The strongest effects occur in the default mode network, which is connected to the anterior hippocampus and is thought to create the sense of space, time, and self. Individual differences in connectivity changes are strongly linked to the subjective psychedelic experience. A persistent decrease in connectivity between the anterior hippocampus and default mode network lasts for weeks, suggesting a neuroanatomical correlate of the therapeutic and proplasticity effects of psychedelics.
Nature medicine
February 6, 2026
Joshua S Siegel, Conor Liston, Ginger E Nicol et al.
10 citations
Classic psychedelics, acting at the serotonin 5-HT2A receptor, alter brain function and consciousness. Research converges on two complementary processes: acute neural desynchronization, which destabilizes entrenched network patterns, and subacute neuroplasticity, which opens a window for psychological and behavioral change. Evidence of therapeutic response across neuropsychiatric indications is reviewed, integrating mechanistic findings. Challenges include discrepancies between preclinical evidence that non-hallucinogenic psychedelic analogs engage putative therapeutic mechanisms and clinical evidence linking subjective experience to therapeutic response, risks of enhanced neuroplasticity, and questions about trial design, scalability, and regulatory approval. The growth of psychedelic science may compel a rethinking of the relationship between subjective experience and biological change in psychiatry.
American journal of psychotherapy
May 6, 2025
David A Bender, Sandeep M Nayak, Joshua S Siegel et al.
7 citations
Practitioners of psychedelic therapy largely view physical touch as an important component of treatment, but they also emphasize strict professional boundaries and the necessity of patient consent. In a survey of 40 practitioners who had overseen an average of 41.4 psychedelic sessions, 70% agreed that therapeutic touch is crucial. However, most deemed specific forms of touch inappropriate: 63% considered bodywork inappropriate, and 98% considered full-body contact inappropriate. Free-response analysis showed 96% supported touching the patient's hand and 58% supported touching the shoulder. Unprompted, 63% of respondents stressed the importance of consent. These views may inform future practice.
The Journal of clinical psychiatry
February 5, 2025
David A Bender, Sandeep M Nayak, Joshua S Siegel et al.
3 citations
Practitioners who oversee psychedelic therapy sessions slightly prefer an 'emotive' approach—one that emphasizes human and spiritual elements—over a 'neuromodulatory' approach that focuses on biological drug effects. A survey of 40 qualified respondents from at least 4 countries, 11 U.S. states, and 16 institutions found no consensus on many psychological support strategies. Four key themes emerged: the importance of trust, the role of spirituality, creating an emotional setting, and conceptualizing negative experiences. Practitioners trained at the Multidisciplinary Association for Psychedelic Studies or the California Institute of Integral Studies showed a significantly stronger emotive preference than those trained elsewhere.
Proceedings of the National Academy of Sciences of the United States of America
June 16, 2026
Adam R Pines, Xue Zhang, John Kochalka et al.
Psychedelic drugs consistently reduce the strength and bottom-up direction of signal flow within the brain's default mode network, according to analyses of four independent datasets spanning humans and mice and three different psychedelic compounds (MDMA, psilocybin, and LSD). This attenuation of cortical propagations is not explained by data quality or previously known effects of psychedelics and is uniquely tied to self-reported outcomes. The findings clarify how psychedelics alter macroscale hierarchical processing in the brain.
The Journal of clinical psychiatry
June 10, 2026
Jacob T Steinle, Suraj Shankar, Joshua S Siegel et al.
After adjusting for preexisting psychiatric conditions, the link between hallucinogen use and psychosis disappears. Among 273,466 people with substance-related hospital admissions, psychosis diagnoses were more common after hallucinogen-related admissions (16.4%) than after other substance admissions (6.6%). However, once clinical characteristics were accounted for, the increased risk became nonsignificant (hazard ratio 0.97). This suggests that observed associations between hallucinogens and psychosis are largely due to underlying mental health vulnerabilities, not a direct causal effect. The findings inform psychedelic policy by indicating that population-level data on hallucinogen safety may reflect preexisting risk factors.
Psychopharmacology
October 27, 2025
David A Bender, Sandeep M Nayak, Joshua S Siegel et al.
Providers administering psychedelic drugs in clinical trials report a range of challenges, including intense dysphoria during sessions (42% of respondents), disappointment with the intervention (25%), and re-engaging with traumatic experiences (17%). An anonymous survey of 40 qualified respondents who oversaw 1656 psychedelic sessions identified 11 distinct themes of challenges. 70% of respondents felt that individuals with PTSD or prior trauma need additional psychological support, and they recommended an average of 9.8 hours of total psychological support for first-time recipients with serious mental illness. These findings highlight the need to incorporate potential adverse experiences into psychological support protocols for clinical trials and future guidelines.