Open-Label Dose-Ranging Study of Oral SM-001 in Healthy Adults

Study Overview
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Brief Summary
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Phase I safety and dose finding study of a standardized Ayahuasca analog (SM-001) in healthy adult volunteers

Detailed Description
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The Investigational New Drug SM-001 is formulated as a hot water decoction of two clonal cultivars of the Peruvian plants, Banisteriopsis caapi (BC) and Psychotria viridis (PV). It represents a modern formulation of an ancient Amazonian botanical medicine, ayahuasca (vine of the soul) that is used by many native South American indigenous and mestizo groups for both religious and medicinal purposes. This initial Phase 1 study is to be conducted as an open label, dose-ranging safety assessment of a single dose of SM-001 taken orally by healthy adult volunteers. Twelve adult men and women, ages 25-65 years, will be consecutively assigned to one of three dose levels, 4 subjects per group (2 M; 2 F). In the presence of the Clinical Investigator(s), each subject will receive a single dose of SM-001, administered at the Clinical Study Site as a liquid at one of three dose levels: 0.25, 0.5, or1.5 ml SM-001 per kg body weight. To assess systemic exposure to SM-001, plasma levels of the four biomarkers, dimethyltryptamine, harmine, tetrahydroharmine, and harmaline will be measured. Blood samples will be drawn at baseline, HR 0 (pre-Study Drug dose), and then at HR 1, 2, 4, 8, and 24 post dose. Subjects will return to the Clinical Study Site at Study Day 28 for a final in-person assessment.

Official Title
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Open-Label Dose-Ranging Study of Oral SM-001 in Healthy Adults

Conditions
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Major Depression, Post Traumatic Stress Disorder

Intervention / Treatment
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* Drug: SM-001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adults: men and women ages 25-65 years of age Previous experience with a psychedelic drug Vital Signs within normal limits for temperature (oral), respiratory rate, heart rate Normal blood pressure (for age) in the absence of antihypertensive drugs Normal complete blood count and differential, platelets, coagulation ((PT/PTT) Liver function tests ≤ 1.5X upper limits of normal Renal function (BUN, serum Creatinine) - within normal limits Able to understand and willing to comply with Study Protocol requirements. Willing to abstain from alcohol for at least 72 hours prior to and following Study Day 0 No use of recreational drugs for at least 14 days prior to Study Day 0. Women who are not pregnant or lactating. Exclusion Criteria (None can apply): Body Mass Index > 30 or < 20 Systemic condition that includes, but is not limited to: hematological, immunological, hepatic, renal, cardiac, neurological conditions that is under current treatment or causes abnormal physical or laboratory parameters. History of seizures History of drug or alcohol abuse History of psychiatric disorder or history of significant trauma, as defined by DSM- V. Use of SSRIs, MAO inhibitors, or other psychoactive compounds either pharmaceutical drugs or botanical in origin (i.e., 5-HTP, St John's Wort) Any condition which, in the opinion of the Investigators, would preclude the use of the test article or the successful completion of the study.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Subjects will be consecutively accrued to one of three study groups, starting at the lowest dose, Level 1 (low dose), and proceeding to the next higher dose level. Each subject will receive one dose of the Study Drug orally at the Clinical Study Site, according to their assigned dose Level. Dose levels vary by volume: Level 1: 0.5 mL/kg (low; 50% of usual dose) N=4 (2M/2F) Level 2: 1 ml/kg (medium; 100% of usual dose) N=4 (2M/2F) Level 3: 2 ml/kg (high; 200% of usual dose) N=4 (2M/2F)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Open label Phase I safety & dose finding study: low dose group<br>4 study participants will receive a low oral dose (0.5 mL/Kg) of SM-001 | Drug: SM-001<br>* The Investigational New Drug SM-001 is formulated as a hot water decoction of two proprietary clonal cultivars of the Peruvian plants, Banisteriopsis caapi (BC) and Psychotria viridis (PV).<br>* Other names: Ayahuasca;|
| Active Comparator: Open label Phase I safety & dose finding study: medium dose group<br>4 study participants will receive a medium oral dose (1.0 mL/Kg) of SM-001 | Drug: SM-001<br>* The Investigational New Drug SM-001 is formulated as a hot water decoction of two proprietary clonal cultivars of the Peruvian plants, Banisteriopsis caapi (BC) and Psychotria viridis (PV).<br>* Other names: Ayahuasca;|
| Active Comparator: Open label Phase I safety & dose finding study: high dose group<br>4 study participants will receive a high oral dose (2.0 mL/Kg) of SM-001 | Drug: SM-001<br>* The Investigational New Drug SM-001 is formulated as a hot water decoction of two proprietary clonal cultivars of the Peruvian plants, Banisteriopsis caapi (BC) and Psychotria viridis (PV).<br>* Other names: Ayahuasca;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Objective | To evaluate safety and tolerability of SM-001 in healthy adults following a single oral dose, at one of three different dose levels. The Incidence of Treatment-Emergent Adverse Events will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE). Percentage of participants with at least one safety event [Time Frame: Baseline up to Day 28 ] Safety will be evaluated by the monitoring of adverse events (AEs), vital signs, blood pressure, heart rate, pulse oximetry, electrocardiogram (ECG) evaluations, clinical laboratory assessments and physical examination findings. | 1-28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Short-term psychological impact | To assess short-term psychological impact of a single dose of SM-001 at three different dose levels in healthy adults by asking each study subject to complete a questionnaire called the Hallucinogenic Rating Scale 24 hours after the single experimental drug session. This is an 85 item questionnaire with each item rated 0-4 with a maximum score of 340. A higher score correlates with a more intense psychological experience. | 24 hours after single drug session | 
| Longer-term psychological impact | To assess longer-term psychological impact of a single dose of SM-001 at three different dose levels in healthy adults by asking each study subject to complete a questionnaire called the Persisting Effects Questionnaire 7 days following the single experimental drug session. The Persisting Effects Questionnaire includes 140 of the items that are rated on a 6-point scale (0=none, not at all; 1=so slight cannot decide; 2=slight; 3=moderate; 4=strong; 5=extreme, more than ever before in your life and stronger than 4). | Day 7 after a single drug session | 
| Bioavailability of SM-001 | To determine the blood, urine and feces levels of plant alkaloids including dimethyltryptamine, harmine, tetrahydroharmine and harmaline in ng/mL following a single oral dose of SM-001. | Day 1-2 | 
| Effects of a single dose of SM-001 on blood levels of brain derived nerve growth factor | Brain Derived Neurotrophic Factor will be quantitated (ng/mL) is each study subject's blood on the day before and the day after the SM-001 drug session. | Day 1-28 | 
| Effects of a single dose of SM-001 on blood cortisol blood levels | Cortisol levels in each study subject's blood will be measured (mg/mL) | Day 1 - 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Banisteriopsis caapi, Psychotria viridis, ayahuasca, ethnomedicine, N,N-dimethyltryptamine (DMT), harmine (HAR), harmaline, tetrahydroharmine