James Rucker’s research while affiliated with South London and Maudsley NHS Foundation Trust and other places

Post-traumatic stress disorder (PTSD) and associated trauma and stressor-related disorders are common and debilitating, presenting significant treatment challenges due to their complex interplay of biological, cognitive, affective, somatic and social factors. Current treatments, while advancing and effective, yield limited efficacy for many individuals, underscoring the need for novel therapeutic approaches. This review explores the multifaceted nature of PTSD, emphasising its intricate predisposing and maintaining factors and explores the potential of psilocybin, a classical psychedelic, as a therapeutic agent. This review synthesises recent literature on the safety, efficacy and proposed mechanisms of action and change of psychedelic therapies for psychiatric conditions associated with traumatic stress, including treatment-resistant depression, end-of-life anxiety and anorexia nervosa. Correspondingly, it proposes a conceptual framework for psilocybin treatment in PTSD, framing the condition as a complex, maladaptive interpretive framework that is both predetermined and over-determined. A clinical narrative illustrates how psilocybin’s unique psychopharmacological properties and catalysed subjective effects may facilitate therapeutic progress by disrupting this rigid and restricting framework. Finally, we offer recommendations for the safe administration of psilocybin for traumatised patients in medical research settings, emphasising the importance of rigorous and trauma-informed protocols and comprehensive patient care.

Background Functional neurological disorder (FND) is a common cause of neurological symptoms including seizures and movement disorders. It can be debilitating, is associated with high health and social care costs, and can have a poor prognosis. Functional magnetic resonance imaging (fMRI) has suggested FND is a multi-network disorder. Converging evidence suggests that other mechanisms including dissociation, interoception, and motor agency may be abnormal in people with FND. Psychedelics are currently under investigation for numerous neuropsychiatric disorders and have been shown to disrupt functional brain networks. Administering psychedelics to people with FND will help us to probe mechanistic theories of the disorder. Protocol In this open-label neuroimaging study, we will administer 25mg oral psilocybin with psychological support to people with chronic FND (target n = 24). Participants will undergo resting-state and task-based (Libet’s clock, a measure of motor agency) fMRI sequences which will be compared in a pre-post manner. Additional mechanistic outcomes including measures of interoception (heartbeat tracking task), somatisation, illness perceptions, suggestibility, and dissociation will be collected. Data on expectancy, preparedness, and subjective experience of the psychedelic experience will also be gathered. Participants will be followed up for three months following psilocybin administration. fMRI changes in networks will be analysed using seed-based approaches, and additional exploratory analysis of resting-state imaging will take place. Discussion The study will help us to probe the mechanisms thought to potentially underpin FND. As the first modern study of psychedelics in FND, it will also help us to understand whether psychedelic administration alongside psychological support might be safe and feasible in this patient population.

Background A third of epilepsy patients fail to enter seizure remission despite optimal therapeutic management. Cannabis‐based medicinal products (CBMPs) have shown promise as a potential therapy. However, a paucity of high‐quality literature regarding CBMPs’ efficacy and safety profile means further investigation is needed. The study aimed to examine changes in epilepsy‐specific and general health‐related quality of life (HRQoL) patient‐reported outcome measures (PROMs) in individuals with treatment‐resistant epilepsy. Methods A case series of patients with epilepsy from the UK Medical Cannabis Registry analyzed changes in Quality of Life in Epilpesy‐31 (QOILE‐31), Single‐Item Sleep Quality Score (SQS), EQ‐5D‐5L, Generalized Anxiety Disorder‐7 (GAD‐7) and Patient Global Impression of Change (PGIC) between baseline, one, three, and six months. Adverse events (AEs) were collected and classified by severity. p < 0.050 was considered statistically significant. Results There were 134 patients included. Improvements were recorded from baseline to one, three, and six months in QOILE‐31 and all HRQoL PROMs (p < 0.050). Forty patients (29.85%) reported a minimal clinically important difference in Quality of Life in Epilepsy‐31 (QOLIE‐31) at six months. There were 18 (13.43%) AEs reported by 5 (3.73%) patients, mainly mild and moderate. Discussion The proportion of patients achieving a clinically significant change is similar to existing CBMPs in epilepsy literature. AE incidence was lower than similar studies although this may be due to the large proportion (67.16%) of individuals who were not cannabis naïve. Conclusion Initiation of CBMPs was associated with an improvement across all PROMs. CBMPs were well tolerated across the cohort. However, randomized controlled trials are needed to help determine causality. Clinical Trial Registration

Setting up a psychedelic study can be a long, arduous, and kafkaesque process. Researchers are faced with a host of challenges in this rapidly-evolving field, necessitating a range of questions that remain largely unstandardised. Many of the complexities inherent to psychedelic research also challenge existing assumptions around, for example, approaches to psychiatric prescribing, the conceptual framing of the placebo effect, and definitions of selfhood. This review paper aims to formalise these unique hurdles by addressing the sociocultural, political, legal, pharmacological, safety, study-design and experiential facets inherent to a psychedelic study. We bring several of the major psychedelic research teams across the United Kingdom, identify continuing areas of debate, and provide a practical, comprehensive, experience-based guide, with recommendations for policymakers and future researchers intending to set up a psychedelic research study or clinical trial.

Background and aims This is the first systematic review of the extant literature on all major psychedelic‐assisted treatment for alcohol use disorder (AUD), tobacco use disorder (TUD) and other substance use disorders (SUD). We aimed to summarise the evidence for efficacy of psychedelic‐assisted treatment for AUD, TUD, and SUD; to evaluate its quality; and to offer recommendations for research. Methods This was a prospectively registered narrative systematic review of open‐label, randomised controlled trials (RCT), and observational studies of d‐lysergic acid diethylamide (LSD), mescaline, psilocybin, ayahuasca, ketamine, ibogaine and 3,4‐methylenedioxymethamphetamine (MDMA). Eligible studies had SUD outcome measures including craving, substance use, relapse, and remission. Study quality was evaluated using the Cochrane Collaboration Risk of Bias (RoB), and Cochrane Collaboration RoB in Non‐randomised Studies of Interventions tool. Certainty of evidence for RCTs was judged using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. Findings 37 studies (2035 participants) were reviewed: LSD (14; n = 1047); mescaline (1; n = 7); psilocybin (4; n = 135); ayahuasca (3; n = 101); ketamine (10; n = 579); ibogaine (5; n = 166); and MDMA (1; n = 14). There were no serious adverse events reported in any study. A two‐centre, placebo‐controlled, phase 2 superiority RCT of psilocybin for AUD, and a two‐centre, double‐blind, four‐arm, placebo‐controlled phase 2 RCT of ketamine for AUD yielded the best evidence of efficacy. Progression support to a phase 3 trials was secured from an open‐label phase 2 study of psilocybin for TUD and nine phase 2 RCTs of ketamine for AUD, cannabis use disorder, cocaine use disorder, and opioid use disorder (all nine with high‐RoB and low‐GRADE evidence certainty). Conclusions Psilocybin‐assisted treatment for alcohol use disorder appears to have the best evidence of efficacy among all major psychedelic‐assisted treatments for alcohol, tobacco, and other substance use disorders. Future research of psychedelic‐assisted treatment should report all safety events; screen for person‐level characteristics indicating that psychedelic‐assisted substance use disorders treatment is contraindicated; strive to mitigate blinding of participants to interventions; use factorial designs for drug and psychotherapy randomised controlled trials; and build consensus for a field‐specific Core Outcome Set.

Background Psychedelic drugs are a focus of interest in the treatment of depression and other disorders but there are longstanding concerns about possible adverse psychiatric consequences. Because the relevant literature is largely informal, the seriousness of these risks is difficult to evaluate. Methods Searches were made for case reports of schizophrenia-spectrum, affective or other psychiatric disorders after use of psychedelic drugs. Case reports of flashbacks were also searched for. Individuals with recent use of other drugs (apart from cannabis and alcohol) and/or a previous history of major psychiatric disorder were excluded. Symptoms were tabulated using the Syndrome Check List of the Present State Examination (PSE-9). Results We found 17 case reports of schizophrenia spectrum disorder, 17 of affective disorder (depression, mania, or both), 3 cases of anxiety, 1 of depersonalization, and 1 of unclassifiable illness. The states could develop after a single use of the drug (5/17 schizophrenia; 6/17 affective disorder), and duration was highly variable. Recovery was the rule in cases of affective disorder but not in schizophrenia spectrum disorder. Twelve of 29 cases of flashbacks showed psychiatric symptomatology definitely outlasting the attacks, mainly anxiety (5 cases) and depression (8 cases). Flashback symptoms resolved within twelve months in approximately half of the cases but in a few persisted for years. Conclusions Reliable descriptions of schizophrenia spectrum disorder and major affective disorder after psychedelic drug use disorder exist but are relatively uncommon. Flashbacks are sometimes but not always associated with psychiatric symptomatology, mainly anxiety or depression.

Psychedelic drugs have seen a resurgence in interest as a next generation of psychiatric medicines with potential as rapid‐acting antidepressants (RAADs). Despite promising early clinical trials, the mechanisms which underlie the effects of psychedelics are poorly understood. For example, key questions such as whether antidepressant and psychedelic effects involve related or independent mechanisms are unresolved. Preclinical studies in relevant animal models are key to understanding the pharmacology of psychedelics and translating these findings to explain efficacy and safety in patients. Understanding the mechanisms of action associated with the behavioural effects of psychedelic drugs can also support the identification of novel drug targets and more effective treatments. Here we review the behavioural approaches currently used to quantify the psychedelic and antidepressant effects of psychedelic drugs. We discuss conceptual and methodological issues, the importance of using clinically relevant doses and the need to consider possible sex differences in preclinical psychedelic studies.