Low-dose psilocybin in short-lasting unilateral neuralgiform headache attacks: results from an open-label phase Ib ascending dose study.

BACKGROUND: Short-lasting unilateral neuralgiform headache attacks (SUNHA) are trigeminal autonomic cephalalgias that feature intense and recurrent paroxysms of pain and autonomic symptoms. Many patients are left with debilitating symptoms despite best-available treatment. Psychedelics, such as the serotonin 2A partial agonist psilocybin, have shown promise in related disorders such as migraine and cluster headache. In this open-label phase Ib ascending dose study, we aimed to assess the effects of low-dose oral psilocybin with psychological support in six to 12 patients with chronic SUNHA. Study objectives were to determine effects on cognition, as well as safety, tolerability, and effects on headache severity and frequency. METHODS: Oral psilocybin in ascending doses of 5, 7.5, and 10 mg (one dose per session; three dosing sessions in total) were administered. Cognition was assessed via the Cambridge Neuropsychological Tests Automated Battery. Headache attacks were assessed via headache diaries and the six-item Headache Impact Test (HIT-6). Subjective dose intensity was assessed via the five-Dimensional Altered States of Consciousness Questionnaire (5D-ASC). The study was terminated early due to recruitment difficulties; four patients were enrolled, three of whom were study completers. Post hoc, we undertook a thematic analysis of the applicable free-text clinical trial notes from the dosing and subsequent visits (n = 22). An inductive method was employed to establish emergent themes. RESULTS: No significant adverse events were recorded. We were unable to collect data as planned on cognitive function during the acute experience due to high ratings of subjective dose intensity (mean 5D-ASC scores 37.8-45.7). The impact of the headaches remained severe throughout the duration of the trial (HIT-6 mean scores 64.3-65.7). There were limited effects on headache duration and severity based on the diaries; however, mean daily attack frequency decreased by >50% in two participants at final follow-up (22.9 to 11.0 and 56.4 to 28.0, respectively). Completing participants and their clinicians recorded "much" (two participants) or "minimal" improvements (one participant) at final follow-up via the Clinical Global Impression rating scale. Thematic analysis indicated that psychological insights were key features of participants' experience; these insights included re-configured relationships to their headache pain. CONCLUSION: The study met with recruitment difficulties and cognition could not be assessed during the acute experience due to subjective dose intensity, likely mediated in part by expectancy effects. The clinical results provide no conclusive evidence for the use of psilocybin in SUNHA. We suggest that accounting for psychological factors in chronic SUNHA may be an important facet of treatment.

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.

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.

Perspectives on psychedelic treatment and research in eating disorders: a web-based questionnaire study of people with eating disorders.

Approximately 1.25 million people in the UK suffer from an eating disorder, yet the treatment options show limited efficacy, warranting the need for novel approaches. This study aimed to investigate the perspectives of people with eating disorders on the use of complementary therapies and psychedelic research and treatment. Two hundred participants with eating disorders took part in this web survey study. The majority of participants (70%) had used a complementary treatment to manage their eating disorder. Participants believed that psychedelic research was worthwhile in the context of a moderate level of concern. The most popular solutions to meet these concerns included providing education around psychedelics and their effects and use in psychiatry and experiencing endorsement from professionals in the area. Moreover, participant responses emphasized the need for a safe, monitored environment and the patient-therapist rapport in the context of psychedelic treatment. The findings are explored concerning future trials of psychedelics as a treatment for eating disorders.

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.

Psychedelic treatment of functional neurological disorder: a systematic review.

Functional neurological disorder (FND), formerly known as conversion disorder, causes a high burden of disability and distress, and is amongst the most commonly encountered conditions in neurology clinics and neuropsychiatric services, yet the therapeutic evidence base is somewhat limited. There has been recent interest in the therapeutic potential of psychedelics such as psilocybin and lysergic acid diethylamide (LSD), and in recent studies psychedelics have shown promise in treating a range of neuropsychiatric conditions. Modification of neural circuits associated with self-representation is thought to underlie some of this effect, and as some contemporary theories of FND focus on aberrant somatic self-representation, psychedelics may therefore represent an unexplored treatment option for FND. We systematically reviewed studies involving the use of psychedelics in FND. Nine studies published between 1954 and 1967, with a total of 26 patients, were identified. Due to restriction of licencing of psychedelic drugs since this period, no modern studies were identified. In most cases, patients received a course of psychotherapy with variable adjunctive administration of psychedelics (in a combination known as 'psycholytic therapy'), with protocols varying between studies. Of those treated, 69% (n = 18) were found to have made at least some recovery on heterogeneous and subjective clinician-rated criteria. Adverse events were mostly mild and transient; however, at least one patient terminated the study due to distressing effects. All included studies were of low quality, often lacking control groups and valid outcome measures. Although no conclusions on efficacy may be drawn from these data, further research may help to determine whether psychedelics offer a feasible, safe and effective treatment for FND.

Clinical factors associated with progression to dementia in people with late-life depression: a cohort study of patients in secondary care.

OBJECTIVES: Depression can be a prodromal feature or a risk factor for dementia. We aimed to investigate which clinical factors in patients with late-life depression are associated with a higher risk of developing dementia and a more rapid conversion. DESIGN: Retrospective cohort study. SETTING: South London and Maudsley NHS Foundation Trust (SLaM) secondary mental healthcare services. PARTICIPANTS: The SLaM Clinical Record Interactive Search was used to retrieve anonymised data on 3659 patients aged 65 years or older who had received a diagnosis of depression in mental health services and had been followed up for at least 3 months. OUTCOME MEASURES: Predictors of development of incident dementia were investigated, including demographic factors, health status rated on the Health of the National Outcome scale for older people (HoNOS65+), depression recurrence and treatments including psychotropic drugs and cognitive behavioural therapy (CBT). RESULTS: In total, 806 (22.0%) patients developed dementia over a mean follow-up time of 2.7 years. Significant predictors of receiving a dementia diagnosis in fully adjusted models and after accounting for multiple comparisons were older age (adjusted HR=1.04, 95% CI 1.03 to 1.06 per year difference from sample mean) and the HoNOS65+ subscale measuring cognitive problems (HR=4.72, 95% CI 3.67 to 6.06 for scores in the problematic range). Recurrent depressive disorder or past depression (HR=0.65, 95% CI 0.55 to 0.77) and the receipt of CBT (HR=0.73 95% CI 0.61 to 0.87) were associated with a lower dementia risk. Over time, hazards related to age increased and hazards related to cognitive problems decreased. CONCLUSIONS: In older adults with depression, a higher risk of being subsequently diagnosed with dementia was predicted by higher age, new onset depression, severity of cognitive symptoms and not receiving CBT. Further exploration is needed to determine whether the latter risk factors are responsive to interventions.