Assessment of Psilocybin's Impact on Neural Correlates of Cognitive Control in Psychogenic Non-Epileptic Seizures: A Single-Arm, Open-Label Pilot Study

Trial ID: 2023-509679-17-00
Protocol: NIMAO/2022-2/IC-01
Sponsor: Centre Hospitalier Universitaire De Nimes

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Diseases & Conditions

Seizure Psychogenic seizure

Objectives

The primary objective of this study is to assess the effect of **psilocybin** on the activity of brain regions associated with cognitive control during an emotional Go-No Go task in patients with **psychogenic non-epileptic seizures** (CNEP). This is clinically relevant as it aims to explore potential therapeutic effects of psilocybin on cognitive control, which may contribute to improved management of CNEP.

Secondary objectives include:

Evaluating the effect of psilocybin on the resting activity of regions involved in cognitive control and the default mode network (DMN) using functional brain MRI.
Assessing the effect of psilocybin on cognitive control abilities during emotional and neutral Go-No Go tasks by analyzing error rate and response latency.
Evaluating the effect of psilocybin on the frequency and functional impact of CNEP up to 3 months post-administration.
Assessing the effect of psilocybin on dissociative symptoms using the DES scale and psychic tolerance using the 5D-ASC scale up to 3 months post-administration.

Participants

The clinical trial involves participants diagnosed with **psychogenic non-epileptic seizures** (PNES). The study population includes both male and female adults aged 18 to under 60 years, who are in good physical health and free from unstable medical conditions. Participants are required to be euthymic according to the MINI questionnaire and may continue their SSRI or SNRI antidepressant therapy during the trial. The trial does not involve a vulnerable population. Participants must have a confirmed diagnosis of PNES by video-EEG, evolving for more than three months, and meeting DSM-5 criteria. They should have a normal brain MRI during the initial evaluation and be available for a six-month follow-up. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the effect of a single dose of **psilocybine** on neural correlates of cognitive control in patients with **psychogenic non-epileptic seizures** (CNEP). This study is a single-arm, open-label pilot trial, conducted in a prospective, monocentric manner with longitudinal follow-up. The trial is categorized as a Phase 4 study and is not considered low intervention. The primary objective is to assess changes in brain activity associated with cognitive control using functional brain MRI during an emotional Go-No Go task. The trial will also evaluate secondary endpoints, including changes in brain activity on resting-state MRI and the frequency of CNEP episodes.

Participants will be involved in the study for a total duration of approximately six months. The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as a confirmed diagnosis of CNEP, normal brain MRI, and good physical health. Participants must be adults aged 18 to 59 years, able to speak and understand French, and available for the entire follow-up period. The study will exclude individuals with unstable medical conditions or significant impairments in liver function, among other criteria.

The sequence of study visits includes an initial screening visit, followed by a baseline assessment three days before psilocybine administration (D-3). The administration of psilocybine will occur on day zero (D0), with subsequent follow-up visits scheduled for five days post-administration (D+5), one month (M1), and three months (M3) after administration. The end-of-study visit will coincide with the final follow-up assessment. During these visits, various assessments will be conducted, including functional brain MRI, cognitive tasks, and questionnaires to evaluate changes in dissociative symptoms and consciousness states.

Participants are expected to adhere to the study schedule and complete all required assessments. Conditions that may lead to early termination from the study include the development of any exclusion criteria, withdrawal of consent, or any adverse events that compromise participant safety. The trial is anticipated to start recruitment in April 2024 and conclude by October 2025.

Treatment

The clinical trial involves the administration of **psilocybine** as the experimental medication. Psilocybine is provided in the form of a capsule intended for **oral use**. Each capsule contains a dosage of 25 mg of psilocybine. The administration of the medication is a single dose, with no repeated dosing scheduled. The maximum treatment period is limited to one day, ensuring that participants receive only one dose throughout the study. The chemical origin of psilocybine is confirmed, and it is not formulated for pediatric use. The product is manufactured by CHU DE NÎMES and is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is designed as a single-arm, open-label pilot study, focusing solely on the effects of psilocybine. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The primary objective is to evaluate the effect of psilocybine on neural correlates of cognitive control in patients with psychogenic nonepileptic seizures (CNEP) using functional brain MRI during an emotional Go-No Go task.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of a single dose of **psilocybin** on patients with psychogenic nonepileptic seizures (CNEP). The primary endpoint involves the quantification of changes in the activity of the cognitive control network using functional brain MRI during an emotional Go-No Go task. This assessment will be conducted before (D-3) and after (D+5) the administration of psilocybin.

Secondary endpoints include several measures: changes in brain activity on resting-state functional brain MRI of the cognitive control network and the Default-Mode Network (DMN), both assessed before (D-3) and after (D+5) psilocybin administration. Additionally, the number of errors and response latency during both emotional and neutral Go-No Go tasks will be collected at the same time points. The frequency of CNEP will be measured using a seizure diary for the 6 weeks before and after psilocybin administration. Changes in the CGI-CNEP scale will be evaluated before (D-3) and after (D+5, M1, and M3) psilocybin administration, with scoring by a neurologist and psychiatrist. Dissociative symptomatology will be measured using the DES scale before (D-45, D-3) and after (D+5, M1, and M3) psilocybin administration. The 5D-ASC (5-Dimensional Altered States of Consciousness Questionnaire) will be administered at D0, then D+5, M1, and M3 following psilocybin administration.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Euthymic patient according to the MINI questionnaire.
Patient able to speak and understand French.
Diagnosis of CNEP confirmed by video-EEG, evolving for more than 3 months and meeting DSM-5 criteria.
Normal brain MRI during initial evaluation as part of routine care
Patient who has signed the consent form.
Patient affiliated or beneficiary of a health insurance plan.
Adult patient (≥18 years) and under 60 years of age (<).
Patient available for 6-month follow-up.
Good physical health and absence of unstable medical pathology. These pathologies include cardiovascular comorbidities: history of stroke, myocardial infarction, heart failure, arrhythmia, uncontrolled hypertension (greater than 165/95 mmHg at screening); organic epileptic syndrome and active neurological comorbidities; endocrine pathologies (dysthyroidism and adrenal insufficiency, type I diabetes or insulin-requiring type II diabetes, history of severe hypoglycemia requiring hospital treatment); significant impairment of liver function; glaucoma; symptomatic prostate hypertrophy or bladder neck obstruction.
Patients receiving SSRI (Selective Serotonin Reuptake Inhibitor) or SNRI (Serotonin and Noradrenaline Reuptake Inhibitor) antidepressant therapy may continue to do so for the duration of the trial, without modification. Other psychotropic treatments will not be interrupted.

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Exclusion Criteria

Severe risk of suicide in the opinion of the clinician.
Medical conditions that would preclude safe participation in the trial; for example: Significant impairment of liver function, coronary artery disease, history of arrhythmia, heart failure, uncontrolled hypertension (greater than 165/95 mmHg at screening), history of stroke, severe asthma, hyperthyroidism, narrow angle glaucoma, uncontrolled type I or type II diabetes or a history of ketoacidosis, hyperglycaemic coma or severe hypoglycaemia with loss of consciousness.
Women who are pregnant or breastfeeding, or who intend to become pregnant during the study.
Insufficient contraception.
Contraindications to magnetic resonance imaging.
Allergy, hypersensitivity or other adverse reaction to previous use of psilocybin or other hallucinogens.
Use of hallucinogenic substances (excluding cannabis) more than 10 times in the course of a lifetime or in the last two months, irrespective of frequency.
Use of medication likely to interfere with the effects of psychedelics.
Regular consumption of alcoholic beverages (>20 drinks/week).
Patient participating in an interventional drug study.
Patients in a period of exclusion determined by another study.
High risk of adverse emotional or behavioural reaction according to the investigator's clinical assessment (e.g. severe personality disorder, antisocial behaviour, severe current stressors, lack of significant social support).
Patient under court protection, guardianship or curatorship.
Patient unable to give consent.
Patients for whom it is impossible to provide informed information.
Active dependence on a substance according to the MINI questionnaire (excluding tobacco).
Psychotropic treatment (anxiolytics, antipsychotics, hypnotics) modified in the last month.
Patient suffering from intellectual disability.
Lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder or psychosis not otherwise specified.
Family history of schizophrenia, schizoaffective disorder or type 1 bipolar disorder in first- or second-degree relatives.
Any unstable disease or physical condition determined by history or laboratory tests (ECG, blood tests at inclusion). These conditions include cardiovascular co-morbidities: history of stroke, myocardial infarction, heart failure, arrhythmia, uncontrolled hypertension (greater than 165/95 mmHg at screening; organic epileptic syndrome and active neurological comorbidities; endocrine pathologies (dysthyroidism and adrenal insufficiency, type I diabetes or insulin-requiring type II diabetes, history of severe hypoglycaemia requiring hospital treatment); significant impairment of liver function; glaucoma; symptomatic prostatic hypertrophy or bladder neck obstruction.
Presence of neurological co-morbidities.
Patient on antidepressant treatment other than SSRIs or SNRIs. (Antidepressant treatments other than SSRIs or SNRIs are prohibited in the trial. Patients receiving antidepressant treatment of a different class (MAOIs, tricyclics, tetracyclics), alone or in combination, will not be included in the study).