MLS101 Study in PMDD

The purpose of this trial is to investigate the safety and tolerability of intermittent low-dose MLS101 (psilocybin) 2mg, 4mg, and 8mg versus placebo in participants with PMDD. These doses are less than one third of the doses typically administered in high-dose psilocybin studies.

The study will enroll premenopausal women, ages 18-50 (inclusive) with an existing diagnosis of PMDD and history of having tried at least 1 prior treatment for PMDD. There is an initial Screening/Preparation Period of up to 2-5 weeks. The 16-day Treatment Period will span the luteal phase of 1 menstrual cycle. During this time, participants will receive 6 doses of MLS101 capsules in the clinic approximately every 3 days. After the Treatment Period, there is a Follow-up Period of approximately 1 month.

Participants will be monitored after receiving each dose for at least 8 hours in the clinic and must meet specified criteria before discharge. All participants will be escorted home by a companion or via concierge care service after each dosing session.

Inclusion criteria

• Provides informed consent for participating in the study
• Biologically female participants 18-50 years of age (inclusive) at Screening and premenopausal
• Body mass index (BMI) ≥ 18.5 and < 40.0 kg/m2
• Menstrual cycle duration of 24-35 days (inclusive) reported at Screening
• Menstrual cycles are sufficiently regular to allow estimation of menses onset with reasonable accuracy based on participant's reported history and the Investigator's assessment
• Participant has an existing diagnosis of PMDD and history of at least one prior or current medically-supervised treatment for PMDD
• CGI-S ≥ 4 for late luteal phase PMDD symptom severity and associated impairment at Screening
• Mean VAS score ≥ 50 on any one of the 4 core symptoms of PMDD at Screening, as measured using the first 4 items on the PMTS-VAS
• Participant is using a medically acceptable form of birth control for at least 8 weeks prior to receiving first dose of study drug and agrees to continue using medically acceptable birth control for at least 4 weeks post last dose in the study. Medically acceptable birth control methods include double-barrier methods used with spermicide, copper or low-dose levonorgestrel-releasing IUD, participant has had tubal ligation, participant is in a monogamous relationship with a vasectomized male or with another female, or participant is celibate as part of her lifestyle and will remain so throughout the study. (Note that for this study, oral, subdermal, transdermal, injectable, and vaginal ring hormonal contraceptives are not allowed).
• If a participant is currently taking SSRI treatment, it must have been maintained as a stable monotherapy for at least 3 months prior to Screening with intent to continue unchanged for the duration of the study.

Exclusion criteria

• Currently meets DSM-5 criteria for MDD, GAD, Panic Disorder, OCD, Anorexia, Bulimia, Binge Eating Disorder, Borderline Personality Disorder, or Anti-Social Personality Disorder, based on M.I.N.I.
• History of meeting DSM-5 criteria for Major Depressive Episode within the past 6 months from Screening
• History of meeting DSM-5 criteria for Panic Disorder, OCD, Anorexia, Bulimia, Binge Eating Disorder, Anti-Social Personality Disorder, or Borderline Personality Disorder within 24 months from Screening
• History of meeting DSM-5 criteria for Substance or Alcohol Use Disorder in the last 2 years at Screening (Note: mild recreational cannabis use in the judgment of the Investigator, that does not meet criteria for moderate or severe Substance Use Disorder, is not exclusionary)
• Lifetime history of any psychosis or mania not attributable to substance use
• First degree relative with schizophrenia, schizoaffective disorder or bipolar I disorder
• Confirmed to be in perimenopause, or diagnosis of Polycystic Ovary Syndrome based on ACOG/Rotterdam criteria, or diagnosis of symptomatic uterine fibroids
• PMDD symptoms attributable to, or exacerbated by, hormonal contraceptives/treatments
• Participant plans to start any new treatment for PMDD, or to stop any ongoing SSRI treatment during the study
• Use of any herbal or supplement with known serotonin-enhancing properties (e.g. St. John's Wort, L-tryptophan, 5-hydroxytryptophan) within the past 3 months at Screening
• Use of any hormonal contraceptive that works primarily by suppression of ovulation, for the past month at Screening. Therefore, use of oral, subdermal, transdermal, injectable, and vaginal ring hormonal contraceptives is excluded. (However, copper IUDs and hormonal IUDs that release low-dose levonorgestrel are acceptable.)
• Use of any non-SSRI antidepressant, antipsychotic, or anticonvulsant within the past 3 months
• Exposure to a neurosteroid, whether marketed or in a clinical trial, during the past 12 months
• Requires ongoing pharmacologic treatment for Attention-deficit/hyperactivity disorder (ADHD)
• Suicidal ideation with intent and plan, suicide attempt, or psychiatric hospitalization during the past 12 months, or an answer of "yes" to Question 4 or 5 on the Baseline/Screening version of the Columbia-Suicide Severity Rating Scale (C-SSRS)
• Use of a classic (serotonergic) psychedelic in any form and at any dose in the past 6 months
• Participation in another psychiatric clinical trial during the past 6 months, or a clinical trial of any other medical intervention during the past 3 months, at Screening
• Estimated glomerular filtration rate (eGFR) below the limit of normal range (< 60 mL/min/1.73m2)
• Alanine transaminase (ALT) or aspartate transaminase (AST) > 1.5 x upper limit of normal (ULN)
• Total bilirubin > 1.5 x ULN (unless the participant has predominantly unconjugated hyperbilirubinemia in the absence of other liver function test [LFT] abnormalities including elevated Direct [conjugated] Bilirubin)
• History or presence of clinically significant cardiovascular disease including valvulopathies, cardiac valve abnormalities; or clinically significant heart murmurs, and/or screening echocardiogram, as determined by the Investigator
• History of or presence of pulmonary hypertension
• Abnormal and clinically significant ECG measurements at Screening (calculated as the average of 3 individual 12-lead ECG measurements) indicating a second- or third- degree atrioventricular block, or one or more of the following:

• QRS ≥ 120 msec
• QTcF > 470 msec
• PR interval > 220 msec
• Known personal or family history of congenital long QT syndrome or sudden death
• Supine resting bradycardia (pulse < 45 bpm) or a supine resting tachycardia (pulse > 100 bpm) at Screening or Day 1
• History of orthostatic hypotension or postural orthostatic tachycardic syndrome, multiple syncopes, or unresolved/ongoing clinically significant hypotensive episodes or symptoms of fainting, dizziness, or light-headedness
• History or presence of a neurological or neurodegenerative disorder such Alzheimer's disease or Parkinson's disease, transient ischemic attack, stroke, seizure disorder, or behavioral disturbances resulting from other neurological disorders. (Note: occurrence of childhood febrile seizure is not exclusionary.)
• Any evidence of current or previous clinically significant disease, e.g., clinically relevant hepatic impairment; clinically relevant renal impairment; diabetes mellitus, thyroid disorder (uncontrolled hypo- or hyperthyroidism), or other endocrine disease; cardiovascular disease (e.g., uncontrolled coronary artery disease, uncontrolled hypertension, uncontrolled hypercholesterolemia); uncontrolled gastrointestinal disease (e.g., active peptic ulcer; uncontrolled hematological disease; uncontrolled autoimmune disorders, or other which may impact or confound the results of the study according to the judgment of the Investigator or Sponsor Medical Monitor (MM)
• Any medical condition possibly affecting drug absorption (e.g., previous surgery on the gastrointestinal tract [including removal of parts of the stomach, bowel, liver, gall bladder, or pancreas], or history of bariatric surgery). History of cholecystectomy ≥ 1 year prior to Screening would be allowable.
• Positive results at Screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV)
• Donation or loss of 500 mL or more of plasma or whole blood within 30 days of Screening
• Participant who, for any reason, is deemed by the Investigator to be inappropriate for this study; or has any chronic or acute medical condition which would confound or interfere with the evaluation of the safety, tolerability, or PK of the investigational product; or is unable to comply with the study protocol

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