Open-label Study to Assess the Safety and Efficacy of Psilocybin With Psychotherapy in Adult Participants With Fibromyalgia

The pressing need for effective fibromyalgia (FM) treatments, the known safety of psilocybin therapy, and the mechanistic plausibility for potential benefit provide a backdrop for investigating psilocybin therapy as a treatment for FM. The primary objective of this study is to evaluate the clinical benefit of oral psilocybin in concert with psychotherapy to treat chronic pain symptoms in patients with FM.

Fibromyalgia is a chronic syndrome of widespread musculoskeletal pain that often manifests with a cluster of co-occurring symptoms, including sleep disturbances, fatigue, cognitive dysfunction, and mood problems including anxiety and depression. Recent studies have provided evidence of altered central pain pathways. Current management of FM typically takes a multidimensional approach including behavioral therapy, exercise, and medication. However, current medications provide only modest benefit and carry significant side effect burden, leading many people with FM to seek other alternatives.

Psilocybin therapy (psilocybin delivered in concert with psychotherapy) may be a potentially safe and effective treatment for symptoms associated with FM. Indeed, psilocybin therapy has shown positive effects in treating cancer-related psychiatric distress, depression and anxiety, treatment-resistant depression, and nicotine or alcohol addiction. The United States Food and Drug Administration (FDA) has granted a Breakthrough Therapy designation for psilocybin in treatment-resistant depression and major depressive disorder. Psilocybin therapy is generally safe and well-tolerated when conducted under controlled conditions. While no clinical studies have explored psychedelic effects among people with FM, a recent review outlined potential mechanisms through which psychedelics could alleviate chronic pain symptoms.

Eligibility Criteria:
Inclusion Criteria

Participants are eligible to be included in the study only if all of the following criteria apply:

Age

- Participant must be 25 to 64 years of age, inclusive, at the time of signing the informed consent form.

Type of Participant and Disease Characteristics

* Participant must meet "criteria for FM per the 2016 FM survey criteria."
* Concurrent psychotherapy is allowed if the type and frequency of the therapy has been stable for at least 2 months prior to screening and is expected to remain stable during participation in the study.
* Participant must be a non-smoker (tobacco).
* Participant must be medically stable as determined by screening for medical problems via a personal interview and/or, a medical questionnaire, and an ECG, within 1 month of starting active intervention (performed during screening).
* Participant must agree to consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea, cola) that he/she consumes on a usual morning, before arriving at the research unit on the mornings of psilocybin session days. If the participant does not routinely consume caffeinated beverages, he/she must agree to not do so on psilocybin session days.
* Participant must agree to refrain from using any psychoactive drugs, including alcoholic beverages and nicotine, within 24 hours before and after each psilocybin administration. The exception is caffeine.
* Participant must agree to not take sildenafil (Viagra®), tadalafil, or similar medications within 72 hours before and after each psilocybin administration.
* Participant must agree to not take any pro re nata (PRN) medications on the mornings of psilocybin sessions.
* Participant must agree that for 7 days before each psilocybin session, he/she will refrain from taking any nonprescription medication, cannabis, nutritional supplement, or herbal supplement except when approved by the Principal Investigator. Exceptions will be evaluated by the Principal Investigator and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals.
* Participant must have at least a high school level of education or equivalent (e.g., General Educational Development \[GED\] Test).

Sex and Contraceptive/Barrier Requirements

* Contraceptive use by women and men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

  1. Females of reproductive potential must agree to use effective birth control for the duration of active intervention (defined as the time from the Baseline \[deep phenotyping\] visit until the EOT \[deep phenotyping\] visit).
  2. Sexually active male participants and/or their female partners must agree to use effective birth control for the duration of active intervention (defined as the time from the Baseline \[deep phenotyping\] visit until the EOT \[deep phenotyping\] visit) of the male participant. Male participants must also agree not to donate sperm for the duration of active intervention.

     Informed Consent
* Participant has provided informed consent as described in Appendix 1, Section 10.1.3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

* Participant has had (within the past 1 year) a cardiovascular condition such as coronary artery disease, stroke, angina, uncontrolled hypertension, a clinically significant ECG abnormality (e.g., atrial fibrillation), prolonged QTc interval (i.e., QTc \> 450 msec), artificial heart valve, or transient ischemic attack.
* Participant has epilepsy with a history of seizures.
* Participant has insulin-dependent diabetes.
* Participant is taking an oral hypoglycemic agent and has a history of hypoglycemia.
* Participant has active auto-immune disease (e.g., lupus, rheumatoid arthritis).
* Participant has a current or past history of meeting Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria for schizophrenia spectrum or other psychotic disorders (except substance/medication-induced or due to another medical condition), or bipolar I or II disorder measured via SCID-5 and SCID-5-PD.
* Participant has a current or past history (within 1 year) of meeting DSM-5 criteria for a moderate or severe alcohol, tobacco, or other drug use disorder (excluding caffeine) measured via relevant questions from the SCID-5.
* Participant has a history of a medically significant suicide attempt.

Prior/Concomitant Therapy

* Participant is taking psychoactive prescription medication (e.g., opioids, tramadol, benzodiazepines) on a regular basis (i.e., more than 2 times a week).
* Participant is currently taking an antidepressant. Participants will also be required to refrain from using antidepressant medications through the completion of primary outcome assessments. Note: if a participant self-initiates a medication taper with the consent and support of their physician, they can re-screen after the appropriate time period.
* Participant is currently taking bupropion or antidepressants other than selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs).
* Participant is currently taking on a regular (e.g., daily) basis any medications having a primary centrally-acting serotonergic effect, including monoamine oxidase inhibitors (MAOIs). For individuals who have intermittent or PRN use of such medications, psilocybin sessions will not be conducted until at least 5 half-lives of the agent have elapsed after the last dose.
* Participant tests above 0.02% blood alcohol content on breath alcohol testing and/or positive for cocaine, methamphetamine, or opioids on urine drug testing.
* Participant has a psychiatric condition judged to be incompatible with establishment of rapport or safe exposure to psilocybin.

Prior/Concurrent Clinical Study Experience

- Participant is currently in another clinical trial.

Diagnostic assessments

* Participant has a significant suicide risk as defined by:

  1. suicidal ideation as endorsed on items 4 or 5 on the C-SSRS within the past year at Screening or at Baseline; or
  2. suicidal behaviors within the past year; or
  3. clinical assessment of significant suicidal risk during participant interviews
* Participant has severe depression as measured through PHQ-8 at Screening.

Other Exclusions

* Participant is pregnant (as indicated by a positive urine pregnancy test assessed at Screening and before each psilocybin session) or nursing.
* Participant is a WOCBP and sexually active, or a man and sexually active, and not practicing an effective means of birth control.
* Participant has a confirmed first- or second-degree relative with schizophrenia spectrum or other psychotic disorders (except substance/medication-induced or due to another medical condition), or bipolar I or II disorder.