Views on Using Psychoactive Substances to Self-Manage Functional Neurological Disorder: Online Patient Survey Results.

Objective: Functional neurological disorder (FND) causes a high burden of disability and distress. Although it is a common disorder, there is a pressing need for improved access to evidence-based treatments. With difficulties in finding effective treatment, some people with FND may seek alternative means of symptom relief, such as legal and illicit psychoactive substances, although the prevalence and nature of such self-management strategies are currently unclear. Additionally, psychoactive substances may represent novel treatment research opportunities, particularly for those with suboptimal improvement. The investigators examined the use of self-management techniques, as well as perspectives on novel therapies, in this patient population. Methods: An online survey was created to assess self-management strategies and views on novel treatments for FND, including psychedelic therapy. The survey was accessible for 1 month, and respondents were recruited internationally through social media and patient groups. A total of 1,048 respondents from 16 countries completed the survey. Results: Almost half (46%) of 980 respondents reported having tried legal psychoactive substances for the management of their FND symptoms and, on average, nicotine, alcohol, and cannabidiol were reported as modestly effective. Additionally, 15% of respondents reported having used illicit substances, mostly cannabis, to manage FND, with the majority reporting moderate effectiveness and experiencing no or minimal physical (90%) and psychological (95%) sequelae. Many respondents (46%) reported that they would be willing to try medically supervised psychedelic therapy (with 19% of respondents ambivalent) if it were found to be safe and effective. Conclusions: Many people with FND seek alternative means of symptom management outside usual medical care, including legal and illicit psychoactive substances. Further research exploring novel treatment options, such as psychedelics, in FND may be warranted.

Clinical Outcome Data of Children Treated with Cannabis-Based Medicinal Products for Treatment Resistant Epilepsy-Analysis from the UK Medical Cannabis Registry.

BACKGROUND: There is a paucity of high-quality evidence of the efficacy and safety of cannabis-based medicinal products in treatment of treatment-resistant epilepsy (TRE) in children. METHODS: A case series of children (<18 years old) with TRE from the UK Medical Cannabis Registry was analyzed. Primary outcomes were ≥50% reduction in seizure frequency, changes in the Impact of Pediatric Epilepsy Score (IPES), and incidence of adverse events. RESULTS: Thirty-five patients were included in the analysis. Patients were prescribed during their treatment with the following: CBD isolate oils (n = 19), CBD broad-spectrum oils (n = 17), and CBD/Δ9-THC combination therapy (n = 17). Twenty-three (65.7%) patients achieved a ≥50% reduction in seizure frequency. 94.1% (n = 16) of patients treated with CBD and Δ9-THC observed a ≥50% reduction in seizure frequency compared to 31.6% (n = 6) and 17.6% (n = 3) of patients treated with CBD isolates and broad-spectrum CBD products, respectively (p< 0.001). Twenty-six (74.3%) adverse events were reported by 16 patients (45.7%). The majority of these were mild (n = 12; 34.2%) and moderate (n = 10; 28.6%). CONCLUSION: The results of this study demonstrate a positive signal of improved seizure frequency in children treated with Cannabis-based medicinal products (CBMPs) for TRE. Moreover, the results suggest that CBMPs are well-tolerated in the short term. The limitations mean causation cannot be determined in this open-label, case series.

International online survey of 1048 individuals with functional neurological disorder.

BACKGROUND AND PURPOSE: Functional neurological disorder (FND) is common, and symptoms can be severe. There have been no international large-scale studies of patient experiences of FND. METHODS: A patient questionnaire was created to assess FND patient characteristics, symptom comorbidities and illness perceptions. Respondents were recruited internationally through an open access questionnaire via social media and patient groups over a month-long period. RESULTS: In total, 1048 respondents from 16 countries participated. Mean age was 42 years (86% female). Median FND symptom duration was 5 years, and median time from first symptom to diagnosis was 2 years. Mean number of current symptoms (core FND and associated) was 9.9. Many respondents had associated symptoms, for example fatigue (93%), memory difficulties (80%) and headache (70%). Self-reported psychiatric comorbidities were relatively common (depression, 43%; anxiety, 51%; panic, 20%; and post-traumatic stress disorder, 22%). Most respondents reported that FND had multiple causes, including physical and psychological. CONCLUSIONS: This large survey adds further evidence that people with FND typically have high levels of multiple symptom comorbidity with resultant distress. It also supports the notion that associated physical symptoms are of particular clinical significance in FND patients. Dualistic ideas of FND were not supported by respondents, who generally preferred to conceptualize the disorder as one at the interface of mind and brain. The need for a broad approach to this poorly served patient group is highlighted. Potential selection and response biases due to distribution of the survey online, mostly via FND patient groups, are a key limitation.

Psilocybin and MDMA for the treatment of trauma-related psychopathology.

This review examines the role of trauma in psychiatric morbidity and analogous psychoneurobiological changes. Trauma is a necessary criterion for Post-Traumatic Stress Disorder (PTSD), however, trauma history is highly correlated with a variety of psychiatric conditions. Some evidence suggests that Major Depressive Disorder (MDD) is the most common psychiatric condition that arises following trauma. Approximately 50% of PTSD cases present with co-morbid MDD. Overlapping symptomatology and neurobiology between these conditions underlie the debate over whether these phenomena result from problematic nosology or whether comorbid MDD + PTSD is a distinct phenotype of trauma-related psychopathology. Regardless, similar treatment approaches have been employed historically, with varying success. The drug-assisted psychotherapy treatment model, which combines pharmacological and psychotherapeutic approaches, is currently being trialled as a novel treatment approach in psychiatry. Both psilocybin- and 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have received Food and Drug Administration 'breakthrough therapy' designation for the treatment of resistant MDD and PTSD, respectively. This paper reviews the therapeutic rationale of both psilocybin and MDMA for treating both trauma-related MDD and PTSD.

Historic psychedelic drug trials and the treatment of anxiety disorders.

INTRODUCTION: In this paper, we systematically review literature from 1940 to 2000 relating to the combined use of psychological therapies and psychedelic drugs in the treatment of ICD-10 anxiety disorders. METHODS: The databases Ovid MEDLINE(R), PsycINFO, and Multidisciplinary Association for Psychedelic Studies (MAPS) were searched for case reports and trials involving humans in the treatment of ICD-10 anxiety and related disorders. Twenty-four studies are described; four describe anxiety symptoms in diverse patient groups, 14 studies describe historic diagnoses that usefully correspond with ICD-10 anxiety disorders, six studies pooled results or failed to detail results specific to contemporary ICD-10 anxiety disorders. Two of the 24 studies reported are individual case reports while two of them were inadequate in terms of the reporting of outcome measures. Thus 20 studies were ultimately included in the summary analysis. RESULTS: Three of the 20 studies reviewed described improvements in anxiety by standardized measures (p < .05) and two studies found that this effect was dose related. Of the 20 studies included in the final analysis, 94 of 145 (65%) cases of "psychoneurotic anxiety reaction" as defined by Diagnostic and Statistical Manual of Mental Disorders-I showed improvement that ranged from moderate improvement to full recovery. Despite methodological inadequacies, the results from previous studies are encouraging and should be used to guide and inform further investigation. CONCLUSION: The majority of studies indicate that a combination of psychedelic drug administration and psychological therapy was most beneficial. We found no study suggesting that the pharmacological action of psychedelic drugs in isolation is sufficient.

Interaction between the FTO gene, body mass index and depression: meta-analysis of 13701 individuals.

BackgroundDepression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.AimsTo confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.MethodThe sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.ResultsIn the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (ß = 0.12, P = 2.7 × 10-4) and with the Han/Eskin random effects method (P = 1.4 × 10-7) but not with traditional random effects (ß = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (ß = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10-8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTOConclusionsThis meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.

Copy number variant study of bipolar disorder in Canadian and UK populations implicates synaptic genes.

Genome-wide single nucleotide polymorphism (SNP) data from 936 bipolar disorder (BD) individuals and 940 psychiatrically healthy comparison individuals of North European descent were analyzed for copy number variation (CNV). Using multiple CNV calling algorithms, and validating using in vitro molecular analyses, we identified CNVs implicating several candidate genes that encode synaptic proteins, such as DLG1, DLG2, DPP6, NRXN1, NRXN2, NRXN3, SHANK2, and EPHA5, as well as the neuronal splicing regulator RBFOX1 (A2BP1), and neuronal cell adhesion molecule CHL1. We have also identified recurrent CNVs on 15q13.3 and 16p11.2-regions previously reported as risk loci for neuropsychiatric disorders. In addition, we performed CNV analysis of individuals from 215 BD trios and identified de novo CNVs involving the NRXN1 and DRD5 genes. Our study provides further evidence of the occasional involvement of genomic mutations in the etiology of BD, however, there is no evidence of an increased burden of CNVs in BD. Further, the identification of CNVs at multiple members of the neurexin gene family in BD individuals, supports the role of synaptic disruption in the etiology of BD.

Evidence versus expectancy: the development of psilocybin therapy.

SUMMARY: Although the development of psilocybin therapy has come as a surprise to many, modern research with the drug has been ongoing for 25 years. Psilocybin therapy is composed of psilocybin dosing sessions embedded within a wider process of psychoeducation, psychological support and integration. Early phase clinical trial evidence is promising, particularly for treatment-resistant depression. However, masking probably fails and expectancy effects may be a part of the mechanism of change. Disambiguating between drug and expectancy effects is a necessary part of the development process, yet this is difficult if masking fails. Hitherto, masking and expectancy have not been routinely measured in psilocybin or other medication trials. Doing so represents an opportunity for research and may influence psychiatry more widely. In this opinion piece I summarise the clinical development process of psilocybin therapy thus far, discussing the hope, the hype, the challenges and the opportunities along the way.

The development of psilocybin therapy for treatment-resistant depression: an update.

Psilocybin is a classic psychedelic drug that has attracted increasing research interest over the past 10 years as a possible treatment for mood, anxiety and related conditions. Initial phase 2 clinical trials of psilocybin given alongside psychological support for major depression and treatment-resistant depression (TRD) demonstrated encouraging signs of basic safety, further confirmed by a large study in groups of healthy volunteers. The first international multi-centre randomised controlled trial was published in 2022, with signs of efficacy for the 25 mg dose condition in people with TRD when compared with an active placebo. Phase 3 trials in TRD are scheduled to start in 2023. Early evidence suggests that single doses of psilocybin given with psychological support induce rapid improvement in depressive symptoms that endure for some weeks. We therefore provide a timely update to psychiatrists on what psilocybin therapy is, what it is not, and the current state of the evidence-base.

A cohort study comparing the effects of medical cannabis for anxiety patients with and without comorbid sleep disturbance.

BACKGROUND: Research on cannabis-based medicinal products (CBMPs) in anxiety remains inconclusive due to a paucity of high-quality evidence. Studies indicate a bidirectional relationship between generalized anxiety disorder (GAD) and sleep disruption, but it is unclear how this affects CBMP treatment outcomes. This study aims to compare the patient-reported outcome measures (PROMs) of patients prescribed CBMPs for GAD, with and without impaired sleep. METHODS: Changes in PROMs were recorded from baseline to 1, 3, 6, and 12 months between those with impaired or unimpaired sleep. Multivariate logistic regression was applied to compare factors associated with a clinically significant improvement in GAD-7 at 12 months. Secondary outcomes included adverse event incidence and frequency. RESULTS: Of the 302 patients that fit the inclusion criteria, mean GAD-7, single-item sleep quality, and EQ-5D-5L index values improved at all time points (p < 0.001). A relationship between sleep impairment and clinically significant changes in GAD-7 at 1 and 3 months was identified (p ≤ 0.01). On multivariate regression, only baseline GAD severity was associated with an increased likelihood of observing a clinically significant improvement in anxiety (p < 0.001). Seven hundred and seven (234%) adverse events were reported by 55 (18.21%) participants. CONCLUSIONS: This study observed an association between CBMP treatment and improvements in anxiety in patients with GAD. While patients with comorbid sleep disruption had greater improvements in anxiety, the differences were not maintained in a multivariate analysis. Baseline anxiety severity may be a predictor for CBMP treatment outcomes.

UK medical students' self-reported knowledge and harm assessment of psychedelics and their application in clinical research: a cross-sectional study.

OBJECTIVE: To capture UK medical students' self-reported knowledge and harm assessment of psychedelics and to explore the factors associated with support for changing the legal status of psychedelics to facilitate further clinical research. DESIGN: Cross-sectional, anonymous online survey of UK medical students using a non-random sampling method. SETTING: UK medical schools recognised by the General Medical Council. PARTICIPANTS: 132 medical students who had spent an average of 3.8 years (SD=1.4; range: 1-6) in medical school. RESULTS: Most students (83%) reported that they were aware of psychedelic research and only four participants (3%) said that they were not interested in learning more about this type of research. Although medical students' harm assessment of psychedelics closely aligned with that of experts, only 17% of students felt well-educated on psychedelic research. Teachings on psychedelics were only rarely encountered in their curriculum (psilocybin: 14.1 (SD=19.9), scale: 0 (never) to 100 (very often)). Time spent at medical schools was not associated with more knowledge about psychedelics (r=0.12, p=0.129). On average, this sample of medical students showed strong support for changing the legal status of psychedelics to facilitate further research into their potential clinical applications (psilocybin: 80.2 (SD=24.8), scale: 0 (strongly oppose) to 100 (strongly support)). Regression modelling indicated that greater knowledge of psychedelics (p<0.001), lower estimated harm scores (p<0.001), more time spent in medical school (p=0.024) and lower perceived effectiveness of non-pharmacological mental health treatments (p=0.044) were associated with greater support for legal status change. CONCLUSIONS: Our findings reveal a significant interest among UK medical students to learn more about psychedelic research and a strong support for further psychedelic research. Future studies are needed to examine how medical education could be refined to adequately prepare medical students for a changing healthcare landscape in which psychedelic-assisted therapy could soon be implemented in clinical practice.

Trauma-Informed Care in Psychedelic Therapy Research: A Qualitative Literature Review of Evidence-Based Psychotherapy Interventions in PTSD and Psychedelic Therapy Across Conditions.

Introduction: Post-traumatic stress disorder (PTSD) is associated with significant patient burden. While pharmacotherapies and evidence-based psychotherapy interventions (EBPI) are effective, studies consistently highlight inadequate outcomes and high treatment dropout. Psychedelic therapy (PT) has shown preliminary promise across difficult-to-treat conditions, including MDMA-assisted therapy for PTSD, however trials of classical psychedelics in PTSD are lacking. Understanding patients' experiences of EBPI could help promote safety in PT. Aim: To systematically review qualitative research on patients' subjective experience of EBPI for PTSD, and of PT, and examine areas of overlap and divergence between them. Methods: Systematic literature searches for studies published between 2010 and 2023 were conducted on OVID, PubMed, Web of Science, and PsycInfo. Included were original studies in English that presented qualitative data of patient experiences of EBPI in PTSD, or PT for any indication. Extracted data from included studies were analysed using thematic synthesis. Syntheses were completed separately for EBPI and PT, before similarities and differences between the therapies were identified. Results: 40 research articles were included for review: 26 studies on EBPI for PTSD, and 14 studies on PT. EBPI studied were CBT, EMDR, CPT and PE. Psychedelic compounds studied were psilocybin, ibogaine, LSD, MDMA and ketamine, for treatment of substance use disorders, anxiety relating to physical illness, depression, and PTSD. Core themes from patient experiences of EBPI: 1) patient burden in PTSD treatment; 2) readiness; 3) key mechanisms of change; 4) psychological safety and trust. Themes identified in the review of PT: 1) indirect trauma processing; 2) reorganisation of self-narratives via processes of relatedness and identification; 3) key treatment characteristics. Conclusion: This study suggests overlap between patients' experience of EBPI and PT in terms of key mechanisms of change, the importance of psychological safety and readiness to engage in treatment. Trauma-informed care paradigms and practices may improve safety and acceptability of PT research.

Assessment of Clinical Outcomes in Patients With Osteoarthritis: Analysis From the UK Medical Cannabis Registry.

Osteoarthritis accounts for 0.6% of disability-adjusted life years globally. There is a paucity of research focused on cannabis-based medicinal products (CBMPs) for osteoarthritic chronic pain management. This study aims to assess changes in validated patient-reported outcome measures (PROMs) and CBMP clinical safety in patients with osteoarthritis. A prospective case series from the UK Medical Cannabis Registry was analyzed. Primary outcomes were changes in the Brief Pain Inventory (BPI), McGill Pain Questionnaire (MPQ2), EQ-5D-5L, Generalized Anxiety Disorder-7 (GAD-7) questionnaire, and Single-Item Sleep Quality Scale (SQS) at 1-, 3-, 6-, and 12-month follow-ups from baseline. Common Terminology Criteria for Adverse Events v.4.0 was used for adverse event (AE) analysis. Statistical significance was defined as p < 0.050. Seventy-seven patients met inclusion criteria. CBMP initiation correlated with BPI pain severity (p = 0.004), pain interference (p = 0.005), and MPQ2 (p = 0.017) improvements at all follow-ups compared to baseline. There were improvements in the EQ-5D-5L index (p = 0.026), SQS (p < 0.001), and GAD-7 (p = 0.038) up to 6 and 3 months, respectively. Seventeen participants (22.08%) recorded 76 mild AEs (34.86%), 104 moderate AEs (47.71%), and 38 severe AEs (17.43%). Though causality cannot be assumed in this observational study, results support development of randomized control trials for osteoarthritis pain management with CBMPs.

UK Medical Cannabis Registry: Assessment of clinical outcomes in patients with insomnia.

INTRODUCTION: The primary aim of this study was to assess changes in sleep-specific health-related quality of life (HRQoL) for those prescribed cannabis-based medicinal products (CBMPs) for insomnia. METHODS: A case series of UK patients with insomnia was analyzed. Primary outcomes were changes in the Single-Item Sleep-Quality Scale (SQS), Generalized Anxiety Disorder-7 (GAD-7), and EQ-5D-5L at up to 6 months from baseline. Statistical significance was identified as a p value < .050. RESULTS: 61 patients were included in the analysis. There was an improvement in the SQS from baseline at 1, 3, and 6 months (p < .001). There were also improvements in the EQ-5D-5L Index value and GAD-7 at 1, 3, and 6 months (p < .050). There were 28 (45.9%) adverse events recorded by 8 patients (13.1%). There were no life-threatening/disabling adverse events. CONCLUSION: Patients with insomnia experienced an improvement in sleep quality following the initiation of CBMPs in this medium-term analysis. Fewer than 15% of participants reported one or more adverse events. However, due to the limitations of the study design, further investigation is required before definitive conclusions can be drawn on the efficacy of CBMPs in treating insomnia.

Phase 1, placebo-controlled, single ascending dose trial to evaluate the safety, pharmacokinetics and effect on altered states of consciousness of intranasal BPL-003 (5-methoxy-N,N-dimethyltryptamine benzoate) in healthy participants.

AIMS: To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BPL-003, a novel intranasal benzoate salt formulation of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), in healthy participants. METHODS: In all, 44 psychedelic-naïve participants enrolled in the double-blind, placebo-controlled single ascending dose study (1-12 mg BPL-003). Concentrations of 5-MeO-DMT and its pharmacologically active metabolite, bufotenine, were determined in plasma and urine. PD endpoints included subjective drug intensity (SDI) rating, the Mystical Experience Questionnaire (MEQ-30) and the Ego Dissolution Inventory (EDI). RESULTS: BPL-003 was well tolerated at doses up to 12 mg. There were no serious adverse events (AEs), and most AEs were mild; the most common being nasal discomfort, nausea, headache and vomiting. 5-MeO-DMT was rapidly absorbed and eliminated; the median time to peak plasma concentration was approximately 8-10 min and the mean terminal elimination half-life was <27 min. 5-MeO-DMT systemic exposure increased approximately dose-proportionally, while plasma bufotenine concentrations and urinary excretion of 5-MeO-DMT and bufotenine were negligible. The intensity of the SDI ratings was associated with plasma 5-MeO-DMT concentrations. MEQ-30 and EDI scores generally increased with the BPL-003 dose; 60% of participants had a 'complete mystical experience' at 10 and 12 mg doses. Profound and highly emotional consciousness-altering effects were observed with BPL-003, with a rapid onset and short-lasting duration. CONCLUSION: The novel intranasal formulation of BPL-003 was well tolerated with dose-proportional increases in PK and PD effects. The short duration of action and induction of mystical experiences suggest clinical potential, warranting further trials. CLINICAL TRIAL REGISTRATION: NCT05347849.

A rapid narrative review of the clinical evolution of psychedelic treatment in clinical trials.

Pre-prohibition psychedelic research with complex psychiatric patients generated a wealth of treatment methodologies and practices, providing invaluable clinical insights pertaining to the medical administration of psychedelics in various mental health diagnoses. Building upon these early studies, which lack the rigor and research tools available today, contemporary psychedelic research has focused on investigating the safety and efficacy of psychedelics in randomized controlled trials via psychometric measures and symptom assessments. Both then and now, the treatment context and the role of clinicians in psychedelic treatment has been recognized as an essential feature for positive patient outcomes. To broaden the knowledge base of modern psychedelic research and support the training of clinicians conducting medically supervised psychedelic research studies, this paper provides a review of pre-prohibition clinical research narratives pertaining to the phenomenology of psychedelic treatment and the role of the non-pharmacological treatment factors in the patient experience. Lastly, this paper explores a range of clinician perspectives and psychological interventions employed in pre-prohibition psychedelic research to inform future research directions and best practice guidelines.

Clinical outcome analysis of patients with multiple sclerosis - Analysis from the UK Medical Cannabis Registry.

INTRODUCTION: Whilst disease-modifying therapies are the cornerstone for treatment of multiple sclerosis (MS), there is a need to develop novel therapeutics for the symptomatic sequalae of the disease. Cannabis-based medicinal products (CBMPs) have been suggested as a potential therapy for the associated pain, spasticity, and mental health disorders. However, there is a paucity of clinical evidence on CBMPs in MS. The aim of this study is to assess changes in MS-specific and general health-related quality of life (HRQoL) outcomes alongside adverse event incidence in patients prescribed CBMPs for MS from the UK Medical Cannabis Registry (UKMCR). METHOD: Patients prescribed CBMPs for MS symptoms for longer than one month were identified from the UKMCR. The primary outcomes were changes from baseline in MS Quality of Life-54 (MSQoL-54), Generalised Anxiety Disorder-7 (GAD-7), Single-Item Sleep Quality Scale (SQS), and EQ-5D-5L scales at one month, three months and six months. p < 0.050 was defined as statistically significant. RESULTS: 141 patients met the inclusion criteria for the study. There was an improvement in the following subscales of the MSQoL-54 at 6 months: change in health scale, cognitive function, mental health composition, physical health, role limitations due to physical limitation and due to emotional problems, as well as social and sexual function (p < 0.050). There were also improvements in the EQ-5D-5L index value, GAD-7 and SQS (p < 0.050). 146 (103.55 %) adverse events were reported in total. Most were considered mild (n = 47; 33.33 %) and moderate (n = 72; 51.06 %). CONCLUSIONS: This preliminary analysis demonstrates a possible association with improved general health-related quality of life in those prescribed CBMPs for MS. Moreover, the results suggest that CBMPs are well-tolerated in the first 6 months of treatment. However, this must be interpreted with caution considering the limitations of the observational study design.