Mindfulness-based Psilocybin Therapy for PTSD

Many patients with PTSD do not respond or have an incomplete response to treatment with currently available medications that are FDA-approved for PTSD, and/or do not respond to psychotherapies for PTSD. The use of psychedelics (e.g. psilocybin) is being investigated as a new approach to improve symptoms in patients with PTSD and depression, however their mechanism of action is still not well understood. Furthermore, while psychedelics are usually administered in the context of psychological support ("psychedelic assisted therapy", PAT) the kinds of support therapy used and possible interactions with drug with therapy effects is not well understood.

This study will investigate the changes in brain activity, connectivity, and microstructural neuroplasticity, assessed using electroencephalography (EEG) / electromyography (EMG) and functional magnetic resonance imaging (fMRI) /diffusion-weighted magnetic resonance imaging (DWI), after administration of one oral dose of 25 mg synthetic Psilocybin delivered in the context of either non-directive psychological support only (the most common approach for PAT) or in combination with psychological support plus an active form of psychotherapy called Mindfulness-based Cognitive Therapy (MBCT).

Up to 30 participants will be enrolled altogether.

The initial phase of this study will be an open label administration of 25 mg synthetic Psilocybin combined with standard "PAT psychological support" plus MBCT in ten participants with PTSD, to allow us to pilot this new intervention package.

In the next phase of the study, we will randomly assign twenty participants with PTSD into two groups: one group receiving 25 mg of synthetic Psilocybin (open label) combined with standard "PAT support" only, and one group receiving 25 mg of synthetic Psilocybin (open label) combined with standard "support" plus active form MBCT psychotherapy. In both groups, psychological support will be provided before, during and after the administration session. The MBCT group will also receive bi-weekly individual MBCT sessions and will be invited to complete daily homework, as per the MBCT protocol.

Assessments performed at Baseline and on Day 2 and Day 28 after administration will include EEG/EMG, MRI, clinician-administered scales (CAPS-5, MADRS, C-SSRS) and self-report questionnaires to assess PTSD, depression and anxiety symptoms, cognitive testing, self-report questionnaires to evaluate the psychedelic effects of synthetic Psilocybin administration, and blood collection for the Gsα-AC biomarker assay.

Inclusion criteria

Participants meeting the following criteria will be included in the study:

• Participant is assigned female or male at birth.
• Participant is aged between 21 to 65 years, inclusive, at Screening. This is to reduce variability in brain function and connectivity in this small pilot study that may be related to age / developmental factors in persons under 21 and over 65.
• Participant has a BMI of 18 to 30 kg/m2, inclusive, at Screening.
• Participant has a diagnosis of PTSD (as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition [DSM-5] established through a clinician interview that includes the Mini-International Neuropsychiatric Interview [MINI]) and the Clinician Administered PTSD Scale for DSM-5 (CAPS-5).
• PTSD severity moderate to severe based on CAPS-5 score ≥25, and with moderate depression MADRS ≥20.
• Participants capable of producing sperm must use a condom during the trial and for 3 months after their dose of trial medication, if their partner is a person of childbearing potential. In addition, their partner of childbearing potential must also use a highly effective method of contraception (i.e., failure rate less than 1% when used consistently and correctly) from dosing until 3 months following dosing. Condoms alone and abstinence are not considered highly effective methods of contraception.
• Participants of childbearing potential must agree to use a highly effective method of contraception (i.e., failure rate less than 1% when used consistently and correctly) in combination with use of a condom by a partner who is capable of producing sperm, during the trial and for 3 months after dosing. Condoms alone and abstinence are not considered highly effective methods of contraception. Such participants must have a negative pregnancy test at Screening and Day 1.
• Participants of non-childbearing potential who are or were capable of producing eggs (ova) must be postmenopausal or permanently sterile following hysterectomy, bilateral salpingectomy or bilateral oophorectomy. Postmenopausal is defined as spontaneous amenorrhea for at least 12 months, and a serum follicle stimulating hormone (FSH) level in the menopausal range, unless the participant is taking hormone replacement therapy or is using hormonal contraception.
• Provision of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

If appropriate, describe why certain populations may be excluded (e.g., non-English speaking individuals for studies involving informed consent).

Exclusion criteria

Participants with the following will be excluded from study participation:

• Cardiovascular disease, including coronary artery disease (CAD) and congestive heart failure (CHF). This is an FDA requirement.
• Current or previously diagnosis of schizophrenia spectrum or other psychotic disorders, including schizophrenia, schizoaffective disorder, schizotypal disorder, schizophreniform disorder or brief psychotic disorder; current or previous history of bipolar disorder, or current personality disorder (as determined by MINI at Screening). This is an FDA requirement.
• Clinically significant risk of suicidality, as determined through a comprehensive psychiatric interview that incorporates the Columbia Suicide Severity Rating Scale (CSSRS); a score of 4 or higher on the suicidal ideation subscale of C-SSRS (past 6 months) or any suicidal behaviour (lifetime), would be exclusionary.
• History of substance use disorder within the 12 months, as assessed by a structured clinical interview (Mini International Neuropsychiatric Interview [MINI], Version 7.0.2) or determined by self-report, or intake of >21 units of alcohol weekly, and the inability to refrain from alcohol use from 48 hours before Screening and each scheduled visit until discharge from the study site. One unit is equivalent to a 285 mL glass of full-strength beer or 1 (30 mL) measure of spirits or 1 glass (100 mL) of wine.
• Currently receiving a monoamine oxidase inhibitor, tricyclic antidepressant, other non-SSRI or non-SNRI antidepressants (e.g. bupropion, mirtazapine, etc), an antipsychotic or a mood stabilizer.
• Exposure to psilocybin, or any other psychedelics, such as ayahuasca, mescaline, LSD or peyote more than 10 times in the last 10 years, or any psychedelic use within 6 months prior to Screening.
• Use of psychotropic medicine/supplement (or medicine/supplement that would interact with psilocybin) including buspirone and venlafaxine, during the 28 days before dosing. Participants may take a stable chronic dose of other SSRI antidepressant medication(s) and/or sedatives/hypnotics. The Investigator and study team may review medication on a case-by-case basis to determine if its use would compromise participant safety or interfere with study procedures or data interpretation.
• Family history of schizophrenia or schizoaffective disorder (first degree relatives), or bipolar disorder type 1 (first degree relatives).
• Clinically relevant history of abnormal physical health interfering with the study as determined by medical history and physical examinations obtained during Screening as judged by the Investigator (including [but not limited to], neurological, endocrine, cardiovascular, respiratory, gastrointestinal (including dyspepsia or gastroesophageal reflux disease), hepatic, or renal disorder).
• Participant has a presence or relevant history of any of the following medical conditions: organic brain disorders (e.g., epilepsy, seizure, intracranial hypertension, intracranial bleed and aneurysmal disease, brain tumor or other medical conditions associated with seizures or convulsions).
• Diagnosis of hypertension or arrhythmia.
• Clinically relevant abnormal heart rate (resting supine heart rate >100 bpm) or blood pressure (resting supine systolic blood pressure (SBP) above 140 mmHg or diastolic blood pressure (DBP) above 90 mmHg) at screening. Screening supine SBP, DBP and heart rate for evaluation will be the average of 3 readings obtained after at least 5 minutes rest. Participants with abnormal vital signs which are out of range and deemed clinically significant by the Investigator at Day 1, following triplicate readings.
• Presence of clinically significant ECG abnormalities at the Screening visit, as defined by medical judgement.
• QT interval corrected for heart rate using Fridericia's formula (QTcF) >450 msec at Screening, following triplicate ECG readings.
• Hypothyroidism and/or current abnormal thyroid function tests. In case of uncertain or questionable screening thyroid function test results, the TSH test may be repeated once during screening. The TSH test must be reviewed to ensure that it is within normal limits before randomizing a participant into the study.
• Clinically relevant abnormal laboratory results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis), 12-lead ECG and vital signs, or physical findings at Screening. In case of uncertain or questionable results, tests performed during Screening may be repeated once to confirm eligibility or judged to be clinically irrelevant.
• Other eligibility considerations (i.e., participant personal circumstances, behavior, and/or any current problem that might interfere with participation or that is incompatible with establishment of rapport or safe exposure to psilocin), as judged by the Investigator.
• History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion (ADME) of the study drug.
• Any other concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study as outlined in this Protocol, or that would, in the opinion of the Investigator, pose an unacceptable risk to the participant in this study.
• Participant is not fluent in English. Participants must be fluent in English because the consent form as well as all assessments are written and will be administered/communicated in English.
• Aspartate aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT) or total bilirubin levels ≥1.5 x the upper limit of normal (ULN) at Screening. These laboratory evaluations may be repeated once at the discretion of the Investigator. If the repeat test is within the reference range, the participant may be included if the Investigator considers that the previous finding will not introduce additional risk factors.
• Positive urine test for drugs of abuse or alcohol breath test at Screening or Day 1. A positive test for cannabinoids (e.g., marijuana) at Screening may not exclude a participant if after discussion with and evaluation by the Investigator, the participant agrees not to use any marijuana or other cannabinoid products during the study, and if allowed to participate, the participant must test negative for cannabinoids on Day 1.
• Participant who consumes excessive amounts of caffeine (e.g., coffee, tea, caffeinated sodas) or (methyl) xanthines (e.g., chocolate) based on the Investigator's determination and discretion.
• The participant has participated in a clinical study and has received a medication or a new chemical entity within 3 months prior to dosing of current study medication.
• Known sensitivity to psilocybin, psilocin and/or any excipients present in the formulation.
• Participant is taking or has taken any drugs known to inhibit monoamine oxidase within 28 days prior to study drug administration.
• Participant is taking or has taken OTC doses of 5-hydroxytryptophan or St John's Wort within 28 days prior to study drug administration.
• Strenuous exercise within 48 hours prior to each visit, and while at the study site.
• Participants capable of producing sperm who will not abstain from sperm donation between first dosing and 3 months after final dosing.
• Participants of childbearing potential who are pregnant, breastfeeding or planning to conceive. This is an FDA requirement.