Psychedelic science in post-COVID-19 psychiatry

The extracted text does not report a formal systematic search strategy or predefined methods typical of a systematic review. Instead, the paper functions as a narrative overview that integrates preclinical findings, human imaging and electrophysiology studies, open-label and small clinical trials, large academic programme reports, and descriptions of ongoing randomised controlled trials. Evidence discussed includes preclinical pharmacology and neuroplasticity studies, small experimental imaging studies in healthy volunteers, open-label clinical studies in treatment-resistant depression (TRD), long-term safety monitoring from a single institution, and descriptions of phase 2b and exploratory clinical trials (COMP001, COMP003) and a double-blind trial at Imperial College (Psilodep-RCT). Where trial protocols are presented in the extracted text, key design elements are summarised: COMP001 is described as a double-blind phase 2b randomised controlled trial in antidepressant-free TRD with a Dublin site; Psilodep-RCT is a double-blind comparison of psilocybin therapy versus escitalopram; COMP003 is described as an exploratory open-label study enrolling up to 20 participants with moderate depression who remain on selective serotonin reuptake inhibitors (SSRIs), receiving a single 25 mg oral dose of psilocybin with psychological support. The paper also outlines pragmatic trial adaptations for conducting studies safely during COVID-19 (symptom checks, temperature monitoring, testing, enhanced hygiene, personal protective equipment and remote visits where appropriate).

The overview presents a heterogeneous body of evidence suggesting potential therapeutic effects of psilocybin across several domains, while emphasising that high-quality long-term data are limited. Preclinical studies reported that serotonergic psychedelics, including psilocybin, can promote hippocampal neurogenesis, dendritic spine growth and synaptogenesis in the prefrontal cortex. Mechanistically, psychedelics are said to act via agonism at the 5-HT2A receptor, producing dose-dependent alterations in consciousness and transient reorganisation of large-scale brain networks implicated in self-representation and cognitive flexibility. Human neurochemical and imaging findings cited include a magnetic resonance spectroscopy study reporting increased glutamate in the medial prefrontal cortex after psilocybin, and a small (n=15) study from Johns Hopkins that found acute reductions in claustrum activity and altered connectivity between the claustrum, the default mode network and frontoparietal control networks. An open-label pilot of 12 healthy volunteers reported reduced negative affect and reduced amygdala responses to emotional stimuli at 1 week after psilocybin, with those measures returning toward baseline by 1 month; both 1-week and 1-month time points showed global increases in functional connectivity. By contrast, an open-label study of 19 people with TRD reported increased amygdala responses to emotional faces and decreased ventromedial prefrontal cortex–right amygdala connectivity one day after psilocybin, highlighting heterogeneity across populations and study designs. Clinical-trial activity and feasibility data are described: the COMPASS phase 2b trial (COMP001) is under way with a Dublin centre to evaluate safety, efficacy and dose optimisation in antidepressant-free TRD. A separate exploratory open-label COMPASS study (COMP003) will recruit approximately 20 participants with moderate depression of 3 months to 2 years' duration who have failed at least two pharmacological treatments and who remain on SSRIs; participants will receive a single 25 mg oral dose of psilocybin with psychological support. The Imperial College Psilodep-RCT (NCT03429075) is presented as a double-blind trial comparing psilocybin therapy with the SSRI escitalopram, with results awaited. Safety, tolerability and acceptability data reported in the text are limited but noteworthy: recreational psychedelic use in a large public sample rose from 0.55% in 2015 to 0.86% in 2018. The Global Drug Survey (2019) indicated that only 18% of respondents who had never used psychedelics would accept psilocybin therapy for depression or PTSD, rising to 59% among those with prior psychedelic experience; primary fears related to ‘‘brain damage’’ and ‘‘bad trips’’. Longitudinal safety monitoring at Johns Hopkins across 250 volunteers and 380 sessions reportedly found no major psychological issues and 0.9% experienced minor transient psychological problems. The authors note sparse data on rare outcomes such as hallucinogen-persisting perception disorder (HPPD) and identify potential clinical risk markers (personal or family history of anxiety, pre-drug tinnitus, floaters or concentration problems). Pharmacological interactions are mentioned: 5-HT2A antagonists such as ketanserin block psilocybin's therapeutic effects experimentally, and buspirone (a partial 5-HT1A agonist) may exert inhibitory effects; however, concomitant SSRI use in TRD has not been empirically studied and is a stated rationale for COMP003.

Kelly and colleagues interpret the assembled evidence as indicating that psilocybin therapy is a promising transdiagnostic approach, particularly for internalising disorders characterised by rigid cognitive and behavioural patterns. They argue that psilocybin's capacity to transiently alter large-scale network dynamics and increase neuroplasticity may be harnessed, together with psychological support, to reconfigure maladaptive habits and enhance therapeutic change. The paper advocates for a precision-personalised approach, noting substantial individual variability in response, high relapse rates in psychiatric disorders and clear contraindications (notably psychotic and manic conditions). The authors are careful to highlight limitations and uncertainties: much of the human evidence comes from small open-label studies and experimental imaging work, animal models have intrinsic limitations in modelling complex subjective effects, and robust long-term safety data are lacking. They emphasise the need to resolve questions about psilocybin's interaction with SSRIs and to await the outcomes of larger randomised trials (COMP001, COMP003, Psilodep-RCT) to address safety, efficacy and dose optimisation. Practical implications for conducting trials during the COVID-19 era are discussed, with recommended mitigation measures to protect participants and staff and to permit continuing research. Overall, the authors conclude that, despite the early stage of development and the challenges posed by the pandemic, psilocybin therapy could play an important therapeutic role in post-COVID-19 clinical psychiatry if forthcoming trials confirm safety and efficacy. The extracted text also notes that COMP001 and COMP003 have ethical approval from the Cork Clinical Research Ethics Committee.