Conditions: Anxiety Generalized
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 198
Healthy volunteers: no

Brief summary:
This is a Phase 2, multi-center, randomized, double-blind, parallel-group, dose-finding study to assess the effect of 4 doses of MM-120 (25, 50, 100 or 200 μg freebase-equivalent) for the treatment of anxiety symptoms in subjects diagnosed with generalized anxiety disorder (GAD).

Detailed description:
The study will enroll approximately 200 male and female subjects 18 years to \< 75 years of age who meet DSM-5 criteria for GAD and have a minimum HAM-A Total Score of 20. Subjects on contraindicated concomitant medications, supplements or other therapeutics at Screening (Visit 1) will undergo a medication taper prior to advancing to Baseline (Visit 2).

Arms:
arm 1: A substance that is designed to have no therapeutic value. arm 2: A psychoactive substance that mediates effects mainly through an agonist activity in the serotonin 2A receptor (5-HT2A). arm 3: A psychoactive substance that mediates effects mainly through an agonist activity in the serotonin 2A receptor (5-HT2A). arm 4: A psychoactive substance that mediates effects mainly through an agonist activity in the serotonin 2A receptor (5-HT2A). arm 5: A psychoactive substance that mediates effects mainly through an agonist activity in the serotonin 2A receptor (5-HT2A).

Interventions: intervention 1: MM-120 (LSD D-Tartrate) intervention 2: Placebo
Intervention descriptions: intervention 1: A psychoactive substance that mediates effects mainly through an agonist activity in the serotonin 2A receptor (5-HT2A). intervention 2: A substance that is designed to have no therapeutic value.

Protocol document:
SAP_002.pdf: 
MM120 (D-lysergic acid diethylamide [LSD] D-tartrate) 
Clinical Study Report MMED008 
Mind Medicine Inc. 
 Confidential 
NCT05407064
STATISTICAL METHODS ANALYSIS PLAN
Statistical Analysis Plan v1.0 (01 August 2023) 
Addendum to SAP (08 January 2024)
Protocol Number: MMED008
Protocol Version: 6.0
Protocol Date: 26 July 2023


A Phase 2, Multi-center, Randomized, Double-Blind, Parallel-Group, Dose-Finding Study to 
Assess the Effect of Four Doses of MM-120 for the Treatment of Anxiety Symptoms 
Protocol Number: MMED008 
Protocol Version: 6.0 
Protocol Date: 26 July 2023 
STATISTICAL ANALYSIS PLAN 
Version 1.0 




 
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SAP Revisions  
 
Version 1.0 of the SAP was finalized at the time of Protocol version 6.0 (26Jul2023). The 
following table details the changes made to the SAP.    
 
Protocol 
Version # 
Date 
SAP 
Section 
Modification 
Description and Rationale 
1.0 
All 
Initial document 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table of Contents 
SAP REVISIONS ................................................................................................................................................. 3 
1 
INTRODUCTION ............................................................................................................................................. 6 
2 
OBJECTIVES AND ENDPOINTS ........................................................................................................................ 6 
2.1 
OBJECTIVES ...................................................................................................................................................... 6 
2.1.1 
Primary Objective ..................................................................................................................................... 6 
2.1.2 
Secondary Objectives ............................................................................................................................... 6 
2.1.3 
Safety Objectives ...................................................................................................................................... 6 
2.1.4 
Exploratory Objectives ............................................................................................................................. 7 
2.2 
ENDPOINTS ...................................................................................................................................................... 7 
2.2.1 
Primary Endpoint ..................................................................................................................................... 7 
2.2.2 
Secondary Endpoints ................................................................................................................................ 7 
2.2.3 
Exploratory Endpoints .............................................................................................................................. 8 
3 
INVESTIGATIONAL PLAN ................................................................................................................................ 8 
3.1 
STUDY DESIGN .................................................................................................................................................. 8 
3.2 
TREATMENT ..................................................................................................................................................... 8 
3.2.1 
Randomization Scheme and Treatment Arm Assignment ....................................................................... 8 
3.2.2 
Blinding .................................................................................................................................................... 8 
3.2.3 
Dosing Schedule ....................................................................................................................................... 9 
3.2.4 
Subject Compliance .................................................................................................................................. 9 
4 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ......................................................................................... 9 
4.1 
ANALYSIS QUALITY CONTROL PROCEDURES ............................................................................................................ 9 
4.2 
ANALYSIS SETS ................................................................................................................................................ 10 
4.3 
ASSESSMENT WINDOWS .................................................................................................................................. 10 
4.4 
UNSCHEDULED VISITS ...................................................................................................................................... 11 
4.5 
HANDLING OF DROPOUTS OR MISSING DATA ....................................................................................................... 12 
4.6 
MULTIPLE COMPARISONS ................................................................................................................................. 12 
4.7 
DATA DERIVATIONS AND TRANSFORMATIONS ....................................................................................................... 12 
5 
STUDY PATIENTS ......................................................................................................................................... 12 
5.1 
DISPOSITION OF PATIENTS ................................................................................................................................ 12 
5.2 
PROTOCOL DEVIATIONS .................................................................................................................................... 13 
5.3 
DEMOGRAPHIC CHARACTERISTICS....................................................................................................................... 13 
5.4 
BASELINE CHARACTERISTICS .............................................................................................................................. 13 
5.5 
MEDICAL HISTORY........................................................................................................................................... 13 
5.6 
PSYCHIATRIC HISTORY ...................................................................................................................................... 13 
5.7 
PRIOR AND CONCOMITANT MEDICATIONS, PSYCHIATRIC MEDICATIONS AND NON-DRUG TREATMENTS ........................... 13 
5.8 
NEUROPSYCHIATRIC EXAMINATION ..................................................................................................................... 14 
5.9 
DOSING RELEASE CHECKLIST .............................................................................................................................. 14 
6 
EFFICACY ANALYSIS ..................................................................................................................................... 14 
6.1 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS ....................................................................................................... 14 
6.1.1 
Handling of Missing Data and Potentially Biased Values ...................................................................... 15 


 
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6.1.2 
Analysis of Primary Endpoint ................................................................................................................. 15 
6.2 
KEY SECONDARY EFFICACY ENDPOINT AND ANALYSIS ............................................................................................. 18 
6.2.1 
Key Secondary Endpoint ......................................................................................................................... 18 
6.3 
SECONDARY EFFICACY ENDPOINTS AND ANALYSES ................................................................................................. 18 
6.3.1 
Change from Baseline in HAM-A Total Score ......................................................................................... 18 
6.3.2 
Change from Baseline in MADRS Total Score ........................................................................................ 18 
6.3.3 
Change from Baseline in CGI-S ............................................................................................................... 19 
6.3.4 
Post-Baseline CGI-I Assessment ............................................................................................................. 19 
6.3.5 
Change from Baseline in PGI-S ............................................................................................................... 19 
6.3.6 
Post-Baseline PGI-C Assessment ............................................................................................................ 19 
6.3.7 
Change from Baseline in SDS Total Score............................................................................................... 20 
6.3.8 
Change from Baseline in EQ-5D-5L Index Values and VAS ..................................................................... 20 
6.3.9 
Change from Baseline in PSQI Global Score ........................................................................................... 21 
6.3.10 Change from Baseline in ASEX Total Score ............................................................................................ 22 
6.4 
EXPLORATORY ENDPOINTS AND ANALYSES ........................................................................................................... 23 
6.4.1 
HAM-A Response and Remission ........................................................................................................... 23 
6.4.2 
Drug Effect VAS ...................................................................................................................................... 23 
6.4.3 
MEQ30 ................................................................................................................................................... 23 
6.4.4 
5D-ASC ................................................................................................................................................... 24 
6.4.5 
Treatment Assignment/Blinding Question ............................................................................................. 24 
6.5 
SUBGROUP ANALYSES ...................................................................................................................................... 25 
7 
SAFETY ANALYSIS ........................................................................................................................................ 25 
7.1 
EXTENT OF EXPOSURE ...................................................................................................................................... 25 
7.2 
ADVERSE EVENTS ............................................................................................................................................ 26 
7.2.1 
Treatment-emergent Adverse Events .................................................................................................... 26 
7.2.2 
Adverse Event Severity ........................................................................................................................... 26 
7.2.3 
Adverse Event Relationship to Study Medication .................................................................................. 26 
7.2.4 
Serious Adverse Events .......................................................................................................................... 26 
7.2.5 
Adverse Events of Special Interest ......................................................................................................... 26 
7.2.6 
Adverse Event Summaries ...................................................................................................................... 27 
7.3 
CLINICAL LABORATORY ASSESSMENTS ................................................................................................................. 28 
7.4 
VITAL SIGNS ................................................................................................................................................... 30 
7.5 
ECG ............................................................................................................................................................. 30 
7.6 
PHYSICAL EXAMINATION ................................................................................................................................... 30 
7.7 
C-SSRS......................................................................................................................................................... 30 
8 
INTERIM ANALYSIS AND CHANGES FROM PROTOCOL ................................................................................. 31 
9 
SAMPLE SIZE AND POWER CALCULATIONS .................................................................................................. 31 
10 
REFERENCES ................................................................................................................................................ 33 
11 
APPENDICES ................................................................................................................................................ 34 
11.1 
APPENDIX A ................................................................................................................................................... 35 
 
 


 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analysis to be performed for 
the study, MMED008 entitled “A Phase 2, Multi-center, Randomized, Double-Blind, Parallel-
Group, Dose-Finding Study to Assess the Effect of Four Doses of MM-120 for the Treatment of 
Anxiety Symptoms.”  
 has been engaged by Mind 
Medicine, Inc. (the ‘sponsor’) to develop the SAP and carry out the statistical analysis described 
in this SAP, including production of all tables, figures and listings.  This SAP denotes the final 
analysis of the study, and does not include any formal interim analysis.   
2 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objective 
The primary objective of the study is to determine the dose-response signal and assess the dose-
response relationship of 4 doses of MM-120 (25, 50, 100 or 200 µg freebase-equivalent) as 
measured by the change in Hamilton Anxiety Rating Scale (HAM-A) Total Score from Baseline 
to Week 4. 
2.1.2 Secondary Objectives 
The key secondary objective of the study is to determine the dose-response signal and asses the 
dose-response relationship of the 4 doses of MM-120 (25, 50, 100 or 200 µg freebase-equivalent) 
as measured by the change in HAM-A Total Score from Baseline to Week 8.   Other secondary 
objectives are: 
• To determine the dose-response signal and assess the dose-response relationship of the 4 
doses of MM-120 (25, 50, 100 or 200 µg freebase-equivalent) as measured by the change 
in HAM-A Total Score from Baseline to End of Study, 
• To determine whether MM-120 (25, 50, 100 or 200 µg freebase-equivalent) improves 
functionality and quality of life measures in subjects with anxiety symptoms, including 
improvements in the following: 
o Depressive symptoms 
o Anxiety symptoms 
o Functional disability 
o Quality of life 
o Sleep 
o Sexual function 
2.1.3 Safety Objectives 
The safety objectives of the study are to assess the safety and tolerability of the 4 doses of MM-
120 (25, 50, 100 or 200 µg freebase-equivalent) after oral administration in subjects with anxiety 
symptoms. 


 
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2.1.4 Exploratory Objectives 
Exploratory objectives of the study include: 
• To explore dose response on drug effects, altered perception and mystical experience, 
• To explore the effect of MM-120 on direct and indirect health-care resource utilization 
(HCRU) and associated costs (for later analysis, not part of this SAP), 
• To explore whether genetic polymorphisms are related to pharmacodynamics, 
• To assess blind integrity and to examine whether guess rates are associated with outcomes 
such as AEs or mood/anxiety symptoms. 
2.2 
Endpoints 
2.2.1 Primary Endpoint 
The primary endpoint of the study will be the change in HAM-A Total Score from Baseline to 
Week 4. 
2.2.2 Secondary Endpoints 
The key secondary endpoint is change in HAM-A Total Score from Baseline to Week 8.   
Other secondary endpoints are: 
• Change in HAM-A Total Score from Baseline to End of Study 
• Change from Baseline to Day 2 (where applicable), Week 1, Week 2, Week 4, Week 8, 
and End of Study in the following measures: 
- For depressive symptoms 
▪ Montgomery-Asberg Depression Rating Scale (MADRS) 
- For anxiety symptoms 
▪ Clinical Global Impression - Severity (CGI-S) 
▪ Clinical Global Impression – Improvement (CGI-I) 
▪ Patient Global Impression – Severity (PGI-S) 
▪ Patient Global Impression – Change (PGI-C) 
- For functional disability 
▪ Sheehan Disability Scale (SDS) 
- For quality of life 
▪ EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) 
- For sleep 
▪ Pittsburgh Sleep Quality Index (PSQI) 
- For sexual function 
▪ Arizona Sexual Experiences Questionnaire (ASEX) 


 
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2.2.3 Exploratory Endpoints 
Exploratory endpoints for the study are: 
• HAM-A response and remission at Weeks 1, 2, 4, 8 and End of Study 
• Drug Effect Visual Analog Scale (VAS) assessed on Day 2 
• Mystical Experience Questionnaire (MEQ30) assessed on Day 2 
• 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) assessed on Day 2 
• The Treatment Assignment/Blinding Question assessed on Day 2 
3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This Phase 2 study will enroll approximately 180 male and female subjects 18-<75 years of age 
who meet DSM-5 criteria for generalized anxiety disorder (GAD) and have a minimum HAM-A 
Total Score of 20.  Potential subjects who have contraindicated medical or psychiatric conditions 
or who are taking concomitant medications, supplements or other therapeutics that are 
contraindicated that cannot be paused will be excluded from the study. Subjects on contraindicated 
concomitant medications, supplements or other therapeutics at screening will undergo a 
medication taper prior to advancing to Baseline.  Potential study subjects who provide informed 
consent will have eligibility evaluated/confirmed at 3 visits:  Screening, Baseline and Day 
1/Randomization.  Eligible subjects will be randomized in a 1:1:1:1:1 ratio to receive a single dose 
of either investigational drug at 4 dose levels (25, 50, 100 or 200 µg MM-120 freebase-equivalent) 
or placebo in a controlled clinical setting.  After Day 1 subjects will have visits on Day 2, Week 
1, Week 2, Week 4, Week 8 and Week 12. 
3.2 
Treatment 
The study includes 4 dose levels of investigational product (IP):  25, 50, 100, or 200 µg MM-120 
freebase-equivalent as well as a placebo arm. Subjects will receive one dose of study drug.  
3.2.1 Randomization Scheme and Treatment Arm Assignment 
Subjects will be randomized in a 1:1:1:1:1 ratio to one of the 4 dose levels of IP or placebo. 
Randomization will be centrally performed by a Randomization Trial Management System 
(RTMS).  The 5 treatment groups are: 
1. 25 µg (freebase-equivalent) of MM-120 
2. 50 µg (freebase-equivalent) of MM-120 
3. 100 µg (freebase-equivalent) of MM-120 
4. 200 µg (freebase-equivalent) of MM-120 
5. Placebo 
3.2.2 Blinding 
This double-blind trial will use a masking technique to blind subjects and study site personnel to 


 
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the treatment assignment.  The subject, Investigator and Sponsor personnel who are involved in 
the treatment or clinical evaluation of the subjects will be unaware of the treatment group 
assignments.  
An unblinded statistician, who is not involved with the conduct of the trial, will perform 
randomization schema reviews and will be unblinded for the duration of the study.  
At the end of the trial, and after medical/scientific review has been performed and data have been 
declared final and complete, the official final database will be locked and unblinded.  
3.2.3 Dosing Schedule 
Subjects will be administered a single dose of capsules to be taken orally on Day 1.  Each capsule 
contains 25 µg MM-120 freebase-equivalent, or placebo.  Each subject will receive a total of 8 
capsules comprising of a combination of active and/or placebo as follows: 
• The 25-µg arm consists of 1 active capsule + 7 placebo capsules 
• The 50-µg arm consists of 2 active capsule + 6 placebo capsules 
• The 100-µg arm consists of 4 active capsule + 4 placebo capsules 
• The 200-µg arm consists of 8 active capsules 
• The placebo arm consists of 8 placebo capsules 
3.2.4 Subject Compliance 
All subject dosing will occur at the site and be witnessed by the Investigator and/or Dosing Session 
Monitor(s) and the subject will be monitored at all times until release from the clinic.   
4 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
Unless otherwise specified, continuous variables will be summarized by presenting the number of 
non-missing observations, mean, standard deviation, median, 25th and 75th percentiles, minimum, 
and maximum.  Categorical variables will be summarized by presenting the number of subjects 
and percentage for each category.   
Summary results will be provided by treatment group and where appropriate overall for all 
subjects.  All tabulations will be based on pooled data across centers. 
Subject data will be listed, sorted by treatment group, investigative center and subject number. 
When applicable, listings will be sorted by visit and assessment date/time as well.   
Analyses will be performed using SAS for Windows statistical software, version 9.4 or higher 
(SAS, Cary, NC), except where other software may be deemed more appropriate.  
CTI Clinical Trial and Consulting Services (Covington, KY) will perform all efficacy and safety 
statistical analyses. 
4.1 
Analysis Quality Control Procedures 
Once all the source verification is complete, all queries are resolved, and the database has been 
updated appropriately, the database will be locked and made available to CTI Biostatistics for final 


 
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analysis.  
All SAS programs used to create analysis data sets, tables, and listings will be double programmed. 
The SAS outputs will be compared and the programs will be updated until the outputs match.  
4.2 
Analysis Sets 
The following populations will be defined for the purpose of analysis: 
• Randomized Set (RAN) – all subjects who received a randomization number, regardless of 
receiving study drug. Subjects will be analyzed according to the treatment assigned. 
• Safety Set (SAF) – all subjects who received the double-blind study drug.  Subjects will be 
analyzed according to the actual treatment received. 
• Full Analysis Set (FAS) – all randomized subjects with a valid baseline HAM-A 
assessment and at least one valid post-baseline HAM-A assessment. Subjects will be 
analyzed according to the treatment assigned. 
• Per Protocol Set (PPS) - All subjects in the full analysis set who  had no major protocol 
deviations deemed as impacting the primary endpoint.  Subjects will be analyzed according 
to the actual treatment received.     
An impact assessment will be performed prior to the unblinding of the study. The impact 
assessment will determine whether a major protocol deviation impacts the primary endpoint 
thereby leading to the removal of the respective subject(s) from the PPS.   
4.3 
Assessment Windows 
Day 1 of the study will be defined as the date of first administration of study drug.  Study Day will 
be measured relative to Day 1.  Select efficacy endpoints will use analysis visit windows for the 
assigning of efficacy data to visits. Data from all scheduled and unscheduled visits will be included 
in these analyses.  All other endpoints will be summarized/analyzed using the nominal study visit. 
Analysis visit windows are defined for the select efficacy endpoints in the tables below. The data 
point within an analysis visit window that is closest to the target visit day will be assigned to the 
respective analysis visit. In case of ties, the data point associated with the largest study day (i.e.; 
the latest data point) will be assigned to the respective analysis visit. 
 
Table 1 Analysis Visit Windows for HAM-A, MADRS, SDS, EQ-5D-5L, and ASEX 
Analysis Visit 
Target Study Day 
Analysis Visit Window 
Baseline 
1-5 days prior to Day 1 
<= Day 1 
Week 1 
Day 8 
>= Day 2 and <= Day 11 
Week 2 
Day 15 
>= Day 12 and <= Day 21 
Week 4 
Day 29 
>= Day 22 and <= Day 43 
Week 8 
Day 57 
>= Day 44 and <= Day 71 
Week 12 
Day 85 
>= Day 72 


 
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Table 2 Analysis Visit Windows for CGI-S and PGI-S 
Analysis Visit 
Target Study Day 
Analysis Visit Window 
Baseline 
1-5 days prior to Day 1 
<= Day 1 
Day 2 
Day 2 
>= Day 2 and <= Day 4 
Week 1 
Day 8 
>= Day 5 and <= Day 11 
Week 2 
Day 15 
>= Day 12 and <= Day 21 
Week 4 
Day 29 
>= Day 22 and <= Day 43 
Week 8 
Day 57 
>= Day 44 and <= Day 71 
Week 12 
Day 85 
>= Day 72 
 
Table 3 Analysis Visit Windows for CGI-I and PGI-C 
Analysis Visit 
Target Study Day 
Analysis Visit Window 
Day 2 
Day 2 
>= Day 2 and <= Day 4 
Week 1 
Day 8 
>= Day 5 and <= Day 11 
Week 2 
Day 15 
>= Day 12 and <= Day 21 
Week 4 
Day 29 
>= Day 22 and <= Day 43 
Week 8 
Day 57 
>= Day 44 and <= Day 71 
Week 12 
Day 85 
>= Day 72 
 
Table 4 Analysis Visit Windows for PSQI 
Analysis Visit 
Target Study Day 
Analysis Visit Window 
Baseline 
1-5 days prior to Day 1 
<= Day 1 
Week 4 
Day 29 
>= Day 2 and <= Day 43 
Week 8 
Day 57 
>= Day 44 and <= Day 71 
Week 12 
Day 85 
>= Day 72 
 
4.4 
Unscheduled Visits 
Unscheduled visits will be included in select efficacy analyses as noted above and will be presented 
in relevant subject listings.  In certain circumstances laboratory test results from local labs, noted 
as ‘unscheduled’ will replace missing values from the central laboratory tests.  In situations where 
a laboratory blood draw was performed according to the protocol schedule, but the central 
laboratory was unable to produce test results, another blood draw was performed, noted as 


 
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‘unscheduled’, and sent to the local laboratory.  These local laboratory results will be reclassified 
as the visit in question and will be used for analysis. 
4.5 
Handling of Dropouts or Missing Data 
Missing data on demographics, baseline information and safety measures will be treated as 
missing; no imputation is planned.  
Missing or partial dates and times will be imputed for analysis purposes in a manner that imputes 
the most conservative date or time.  Imputation methods for dates and times are described for each 
endpoint where applicable.   
Details of missing data imputation will be specified in the analysis methods for the primary and 
key secondary efficacy endpoints. Subject-completed questionnaires will be considered missing if 
incomplete.  Missing data will not be imputed for analysis of non-key secondary efficacy endpoints 
or safety endpoints.  
4.6 
Multiple Comparisons 
The Multiple Comparison Procedure – Modeling (MCP-Mod) method will be used to assess the 
primary endpoint. Details of the method is provided in Section 6.1 below.   
A hierarchical (i.e., simple fixed sequence testing) testing strategy will be used to protect the 
overall type I error rate when testing the primary efficacy endpoint with the key secondary efficacy 
endpoint. 
No adjustment for multiplicity will be performed for testing the non-key secondary and exploratory 
endpoints.  
4.7 
Data Derivations and Transformations 
The following derivations will be used in this study: 
Study Day:  
• Equal to (date of assessment - date of first dose + 1) for assessments done on or after date 
of first dose 
• Equal to (date of assessment - date of first dose) for assessments before date of first dose 
Baseline Observation: the last non-missing value prior to first study drug administration. 
Duration: end date – start date +1; measured in days. 
Change from Baseline: post-baseline value - baseline value 
Percent Change from Baseline: (post-baseline value - baseline value) / baseline value x 100 
5 
STUDY PATIENTS 
5.1 
Disposition of Patients 
A table of frequency counts of all subjects who are enrolled, randomized, treated, and in each 
analysis population will be provided.  Frequency counts and percentages of subject disposition 
including study completion status and reasons for early termination will be tabulated. A subject 


 
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listing will be provided.  
5.2 
Protocol Deviations 
Distribution of the types of protocol deviations and the number of subjects that deviate from the 
protocol will be tabulated by treatment group for the FAS.  Protocol deviations will also be 
tabulated by severity (e.g., minor or major).  A listing of all deviations will be provided.  
5.3 
Demographic Characteristics 
Descriptive statistics will be used to summarize the demographic characteristics (age, sex at birth, 
self-identified gender, race, ethnicity, and baseline height, weight and BMI) by treatment group 
and overall, for the FAS and PPS populations.  A listing of demographic characteristics will be 
provided.  
5.4 
Baseline Characteristics 
Baseline values of HAM-A Total Score, MADRS Total Score, CGI-S, PGI-S, PSQI Global Score, 
SDS Total Score, and the proportion of subjects with sexual dysfunction according to the ASEX 
Total Score will be summarized for the FAS and PPS populations.  The duration (in days) from 
the time of GAD diagnosis to study drug administration will be reported. A listing of baseline 
characteristics will be provided.  
5.5 
Medical History 
All medical conditions and surgical procedures will be classified by system organ class (SOC) and 
preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) version 
24.1.  The number and percent of subjects with each medical condition and surgical procedure will 
be presented for each SOC and PT by treatment group and overall, for the FAS and PPS 
populations.  A listing of subject medical history will be provided.  
5.6 
Psychiatric History 
All psychiatric conditions will be classified by system organ class (SOC) and preferred term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA) version 24.1.  The number and 
percent of subjects with each psychiatric condition will be presented for each SOC and PT by 
treatment group and overall, for the FAS and PPS populations.  A listing of subject psychiatric 
history will be provided.  
5.7 
Prior and Concomitant Medications, Psychiatric Medications and Non-drug 
Treatments 
Prior and concomitant medications and psychiatric medications taken for GAD will be coded using 
World Health Organization (WHO) drug classifications, version March 2022 B3.  Non-drug 
treatments will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Prior medications are defined as medications that ended prior to the date of first dose of study drug 
administration (Day 1).  Concomitant medications are defined as medications that started at any 
time but ended on or after the date of first dose (Day 1), including those that are ongoing at study 
completion.  In the case of a missing or partial end date, in order to determine whether a medication 
is prior or concomitant, the following conservative imputation rule will be used:  the unknown 


 
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portions of a medication end date will be imputed to the latest possible day or month.  The imputed 
medication date will then be compared with the date of first dose to determine if the medication is 
prior or concomitant.   
The number and percent of subjects using prior medications and concomitant medications will be 
tabulated by Anatomical, Therapeutic, and Chemical (ATC) Level 2 and by preferred name.  Prior 
medications will be summarized separately from concomitant medications and will be reported by 
treatment group and overall, for the FAS and PPS populations.  A subject listing of all prior and 
concomitant medications will be provided. 
Psychiatric medications taken for GAD will be summarized by ATC Level 2 and preferred name 
and presented by treatment group and overall.  Prior psychiatric medications will be summarized 
separately from concomitant psychiatric medications for the FAS and PPS populations.  A subject 
listing of all psychiatric medications taken for GAD will be provided.  
Non-drug treatments will be summarized by system organ class (SOC) and preferred term (PT) by 
treatment group and overall.  Prior non-drug treatments will be summarized separately from 
concomitant non-drug treatments. A subject listing of all non-drug treatments will be provided.  
5.8 
Neuropsychiatric Examination 
The Neuropsychiatric examination will be performed at Baseline, Day 1, and all subsequent visits 
including End of Study.  The examination at Baseline will establish a standard comparison for 
possible acute and lasting effects of the study drug.  A subject listing by visit will be provided. 
5.9 
Dosing Release Checklist 
The Dosing Release Checklist will, at a minimum, be performed approximately 8 and 12 hours 
post-dose to ascertain if the subject  meets DSM-5 criteria for Hallucinogen Intoxication.  Subjects 
will be assessed hourly at 9, 10, and 11 hours post-dose until all release criteria are met. A summary 
of the number and percentage of subjects meeting release criteria at each hourly time point will be 
provided.  A subject listing by time point will be provided.  
6 
EFFICACY ANALYSIS 
All efficacy analyses, primary and secondary, will be carried out on the FAS population.  Where 
noted, additional analyses on the PPS population may be included.  
6.1 
Primary Efficacy Endpoint and Analysis   
The primary efficacy endpoint is change from Baseline to Week 4 in HAM-A Total Score.  The 
MCP-MOD method (Bretz 2005; Pinheiro 2014) will be used to assess the primary endpoint to 
investigate the dose-response relationship for the 4 doses levels of MM-120 versus placebo. The 
analysis of the primary endpoint using MCP-MOD will be performed on the FAS population. A 
sensitivity analysis will be performed on the PPS population.  
The HAM-A consists of 14 items that encompass both psychological and somatic symptoms of 
anxiety.  The HAM-A takes about 20 minutes to administer and will be completed by a central 
rater.  The central rater will assess the extent to which the subject displays each given criterion and 
give a rating on a scale of 0-4, where 4 represents the most severe symptoms.  The HAM-A Total 
Score will be calculated as the sum of the 14 items and will range from 0-56. Higher Total Scores 


 
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indicate increased severity of symptoms.  
6.1.1 Handling of Missing Data and Potentially Biased Values 
Missing data for the primary endpoint will be imputed using a multiple imputation approach 
assuming that the missingness mechanism can be retrieved from observed data.  The imputation 
model will include the treatment group and the longitudinal sequence of HAM-A Total Score.  
Imputations will be performed 20 times using SAS PROC MI with the fully conditional 
specification (FCS) method.  
For intercurrent events (IEs) the following methods will be used: 
• The data recorded after the IE will be set to missing and imputed under a Missing Not at 
Random (MNAR) assumption by borrowing information from the placebo arm subjects 
(reference-based imputation) for the following: 
o Concomitant/prohibited medications that meet the threshold for impact = "Yes" 
during the impact assessment will be considered as the IE. Any observations after 
such an IE will be set to missing and will be imputed using the MNAR assumption. 
• Available data will be used; missing data will be imputed under a Missing at Random 
(MAR) assumption, borrowing information from subjects in the same treatment arm for 
the following: 
o For IEs leading to study discontinuation due to other reasons 
o IEs related to the COVID-19 pandemic. 
For missing data not due to IEs the imputation will be performed based on MAR assumption. 
6.1.2 Analysis of Primary Endpoint 
The following process will be followed to analyze the primary endpoint using the MCP-MOD 
method.   
Step 1  
A test statistic will be derived from the data using an analysis of covariance (ANCOVA) model 
with change from Baseline to Week 4 for the HAM-A Total Score as a response variable, treatment 
arm and Baseline value of HAM-A Total Score as covariates.  Geographic region will be included 
as a covariate if clinical sites outside the US are used; otherwise, it will not be included in the 
model.   Missing or potentially biased values occurring after IEs will be imputed as described in 
Section 6.1.1.    
The ANCOVA model will be repeated for each imputed dataset, which results in a set of least 
squares (LS) mean estimates for all dose groups and the related covariance matrices.  Rubin’s rule 
will be used to combine the multiple sets of LS mean estimates and the related covariance matrices 
to a single set of LS mean estimates of change from Baseline to Week 4 for HAM-A Total Score 
for all dose groups and the related covariance matrix.  The SAS procedure PROC MIANALYZE 
will be used to combine the results from imputed datasets and provide valid statistical inferences.  
A range of possible dose-response relationships will be considered to take model uncertainty into 
account.  The following six candidate dose-response curves, as depicted below in Figure 1, will be 
used to derive the optimal model contrasts for the multiple contrast tests: 


 
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• Sigmoid Emax (ED50, hill): 
o 10, 1 
o 100, 5 
o 100, 10 
o 150, 10 
• Emax (D50 = 100) 
• Linear 
The optimal contrasts derived from the candidate model sets will be applied to the combined 
estimated dose means and covariance matrix to obtain the t-statistics for each candidate model and 
the common critical value C0.05 derived from the reference multivariate t-distribution with the 6x6 
correlation matrix induced by testing the candidate dose-range models with respect to comparing 
all MM-120 doses to the placebo group.   
The null hypothesis will be rejected and the statistical significance of dose-response in change 
from Baseline to Week 4 for HAM-A Total Score will be established if the max (t1, t2, t3, t4, t5, t6) 
≥ C0.05.  


 
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Figure 1  Candidate Dose-response Curves 
 
Step 2 
The response data in each imputed data set, including relevant covariates, will be used to fit the 
models in the candidate set.  The estimated dose-response will be derived by using model 
averaging methods on a subset of candidate models, for which the associated contrast tests are 
statistically significant.  The ≤ 3 models with the largest t-statistics ≥ C0.05 as calculated above will 
be selected as the basis for the model averaging.   
Model averaging will be carried out for each imputed dataset, and the resulting mean efficacy 
estimates, and CIs will be derived using the combination variance that accounts for the uncertainty 
of the imputed data using Rubin’s combination rules.  Comparisons between MM-120 doses and 
placebo will be simultaneously derived for the model averaged estimates together with the CIs 
reflecting the imputation procedure applied.  The model-averaging-based estimates of the mean 
changes from Baseline to Week 4 for HAM-A Total Score within each dose group, and the mean 


 
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differences between MM-120 and placebo and their CIs will then be displayed.  
Target dose selection (e.g., minimum effective dose [MED], EDp) will be based on the model 
change from Baseline to Week 4 for the HAM-A Total Score over the dose range studied.  MED 
is defined as the lowest dose ensuring a clinically relevant and statistically significant 
improvement, MED = min{d ∈ (d1, d5) : f(d)> f(d1) + Δ}, where Δ is the clinical relevance 
threshold. EDp is defined as the lowest dose that gives a certain percentage p of maximum effect 
δmax.  EDp = min{d ∈ (d1, d5) : f(d)> f(d1) + pδmax}.  For this analysis, p will be set to 100%. The 
final choice of the target dose depends on the evaluation of the primary efficacy variable and other 
efficacy variables, as well as safety considerations. 
The above will be repeated using only the model with the largest t-statistic ≥ C0.05. 
6.2 
Key Secondary Efficacy Endpoint and Analysis 
6.2.1 Key Secondary Endpoint 
The key secondary endpoint is change from Baseline to Week 8 in HAM-A Total Score. Analysis 
of this endpoint will follow the same process as the primary endpoint described in Section 6.1.  
The outcome for this endpoint will be considered confirmatory, if in agreement with the primary 
endpoint outcome and provided that the null hypothesis is rejected for the primary outcome.   This 
gatekeeping function of the primary outcome allows for no adjustment of alpha level for 
multiplicity of testing.  
6.3 
Secondary Efficacy Endpoints and Analyses 
All secondary efficacy endpoints will be analyzed on the FAS population.  Additional analyses 
may be performed on the PPS population, where noted.  
6.3.1 Change from Baseline in HAM-A Total Score   
In addition to the primary and key secondary analysis for HAM-A, descriptive statistics will be 
presented for actual values and change from Baseline for scheduled visits.  The change from 
Baseline will be analyzed using an analysis of covariance (ANCOVA) model including change 
from Baseline HAM-A Total Score as dependent variable, the baseline HAM-A Total Score as a 
covariate and treatment group as a fixed effect.  The Least Square Means (LS Means) for each 
treatment group compared to placebo will be reported along with associated 95% CI and p-value.  
The ANCOVA comparisons will be performed for Week 1, Week 2, Week 4, Week 8 and the End 
of Study visit and will be presented for both the FAS and PPS populations.  
A by-subject listing of results by visit, including any unscheduled visits, will be provided.  
6.3.2 Change from Baseline in MADRS Total Score   
The MADRS consists of 10 questions to assess depression severity and change due to treatment.  
The questionnaire will be administered by the central rater after completion of the HAM-A.  Each 
question is scored with a range of 0-6 points, with 0 indicating item is not present or is normal, 
and 6 indicating severe or continuous presence of the symptom.  The Total Score, ranging from 0 
to 60, is calculated by summing the 10 individual scores.  A higher score represents a more severe 
condition.    
Descriptive statistics, including 95% CIs for the mean, will be presented for actual values, change 


 
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and percent change from Baseline for scheduled visits for the FAS.    The change from Baseline 
difference in means between each dose of MM-120 and placebo, 95% CI for the difference and 
corresponding p value from a two-sample t-test will be presented for Week 1, Week 2, Week 4, 
Week 8 and the End of Study visit. A by-subject listing of results by visit, including any 
unscheduled visits, will be provided.  
6.3.3 Change from Baseline in CGI-S 
The CGI-S assesses the subject’s current severity of illness at the time of the assessment, as 
assessed by the clinician and in reference to the clinician’s past experience with patients having 
the same diagnosis.  The CGI-S consists of one investigator-completed rating ranging from 1 
(normal, not at all ill) to 7 (among the most extremely ill patients); a higher score indicates a more 
severe illness. 
Descriptive statistics, including 95% CIs for the mean, will be presented for actual values and 
change from Baseline for scheduled visits.  The change from Baseline difference in means between 
each dose of MM-120 and placebo, 95% CI for the difference and corresponding p value from a 
two-sample t-test will be presented for Day 2, Week 1, Week 2, Week 4, Week 8 and the End of 
Study visit. A by-subject listing of results by visit, including any unscheduled visits, will be 
provided.  
6.3.4 Post-Baseline CGI-I Assessment 
The CGI-I measures the clinician’s assessment of how the subject’s illness has improved or 
worsened relative to baseline.  The CGI-I consists of one investigator-completed rating ranging 
from 1 (very much improved since the initiation of treatment) to 7 (very much worse since the 
initiation of treatment), where a lower score indicates improvement, and a higher score indicates 
worsening.  
Descriptive statistics, including 95% CIs for the mean, will be presented for actual values for 
scheduled visits.  The difference in means between each dose of MM-120 and placebo,  95% CI 
for the difference and corresponding p value from a two-sample t-test will be presented for Day 2, 
Week 1, Week 2, Week 4, Week 8 and the End of Study visit. A by-subject listing of results by 
visit, including any unscheduled visits, will be provided.  
6.3.5 Change from Baseline in PGI-S 
The PGI-S measures disease severity as a patient reported outcome.  The PGI-S consists of one 
subject-completed rating ranging from 1 (none) – 5 (very severe), where a higher score indicates 
a more severe illness.  
Descriptive statistics, including 95% CIs for the mean, will be presented for actual values and 
change from Baseline for scheduled visits.  The change from Baseline difference in means between 
each dose of MM-120 and placebo, 95% CI for the difference and corresponding p-value from a 
two-sample t-test will be presented for Day 2, Week 1, Week 2, Week 4, Week 8 and the End of 
Study visit. A by-subject listing of results by visit, including any unscheduled visits, will be 
provided.  
6.3.6 Post-Baseline PGI-C Assessment 
The PGI-C measures change in clinical status as a patient reported outcome.  The PGI-C consists 


 
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of one subject-completed rating ranging from 1 (much better) – 5 (much worse), where a lower 
score indicates improvement in symptoms and a high score indicates worsening symptoms.  
Descriptive statistics, including 95% CIs for the mean, will be presented for actual values for 
scheduled visits.  The difference in means between each dose of MM-120 and placebo,  95% CI 
for the difference and corresponding p-value from a two-sample t-test will be presented for Day 2, 
Week 1, Week 2, Week 4, Week 8 and the End of Study visit. A by-subject listing of results by 
visit, including any unscheduled visits, will be provided.  
6.3.7 Change from Baseline in SDS Total Score 
The SDS will assess the extent to which 3 major domains (work, social life/leisure activities, and 
family life/home responsibilities) are functionally impaired.  The SDS is a self-reported assessment 
with 5 questions.  The Total Score is derived as the sum of the response to the first 3 questions, 
each ranging from 0 (not at all) to 10 (extremely).  The Total Score ranges from 0-30, where a 
higher score indicates increased functional impairment. The last 2 questions are not included in 
the SDS Total Score.  
Descriptive statistics, including 95% CIs for the mean, for the SDS Total Score will be presented 
for actual values and change from Baseline for scheduled visits.  The change from Baseline 
difference in means between each dose of MM-120 and placebo and 95% CI for the difference 
will be presented for Week 1, Week 2, Week 4, Week 8 and the End of Study visit. A by-subject 
listing of results by visit will be provided for all SDS responses and the Total Score.  
6.3.8 Change from Baseline in EQ-5D-5L Index Values and VAS 
The EQ-5D-5L will assess health outcomes over 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression and the EuroQol visual analog scale (EQ VAS).   Each 
dimension has 5 levels of response scored as: 1 = no problems, 2 = slight problems, 3 = moderate 
problems, 4 = severe problems, and 5 = extreme problems.   The five dimensions are combined to 
create a 5-digit code to represent the subject’s health state.  An EQ-5D-5L index value will be 
calculated by applying a formula that attaches a weight to each level in each dimension, using the 
US standard value set.  The index is calculated by deducting the appropriate weights from 1, the 
value of full health. The resulting index value is a number between 0 (equivalent to dead) and 1 
(full health).  Missing data will not be imputed for analysis.  
The frequency and proportion of subjects reporting each level for each of the 5 dimensions will be 
presented by visit.  Changes over time will be presented using figures to present the frequency and 
proportion of subjects reporting each level for each of the 5 dimensions at baseline and each post-
baseline measurement.  
The EQ-5D-5L index values will be summarized by descriptive statistics, including 95% CIs for 
the mean, for actual values and change from Baseline for scheduled visits.  The change from 
Baseline difference in means between each dose of MM-120 and placebo and 95% CI for the 
difference in means will be presented for Week 4, Week 8 and the End of Study visit.  
The EQ VAS will be summarized by descriptive statistics, including 95% CIs for the mean, for 
actual values and change from Baseline for scheduled visits.  The change from Baseline difference 
in means between each dose of MM-120 and placebo and 95% CI for the difference in means will 
be presented for Week 1, Week 2, Week 4, Week 8 and the End of Study visit. 


 
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A by-subject listing of all EQ-5D-5L measures and the EQ VAS will be presented by visit.  
6.3.9 Change from Baseline in PSQI Global Score 
The PSQI will assess sleep quality and disturbances for the previous month through 19 self-rated 
questions and 5 questions rated by the bed partner or roommate.  The self-rated questions consist 
of 7 components: 
▪ Subjective sleep quality  
• Component 1 Score = Question 6 Score (0-3) 
▪ Sleep latency 
• To calculate Component 2 Score 
1.  Assign score to Question 2 as: 
≤ 15 minutes = 0 
16-30 minutes = 1 
31-60 minutes = 2 
> 60 minutes = 3 
2. Add score from Question 2 to response from Question 5a 
3. Assign this sum as score of: 
0 = 0 
1-2 = 1 
3-4 = 2 
5-6 = 3 
▪ Sleep duration 
• To calculate Component 3 Score, assign score as follows: 
> 7 hours = 0 
6-7 hours = 1 
5-6 hours = 2 
<5 hours = 3 
▪ Habitual sleep efficiency 
• To calculate Component 4 Score 
1. Calculate the number of hours spent in bed (Question 3 minus Question 1) 
2. Calculate Habitual Sleep Efficiency (HSE) as: 
𝐻𝑆𝐸 (%) = 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 ℎ𝑜𝑢𝑟𝑠 𝑠𝑙𝑒𝑝𝑡 {𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒 𝑡𝑜 𝑄𝑢𝑒𝑠𝑡𝑖𝑜𝑛 4}
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 ℎ𝑜𝑢𝑟𝑠 𝑠𝑝𝑒𝑛𝑡 𝑖𝑛 𝑏𝑒𝑑
 × 100   
3. Assign score as follows: 
>85% = 0 
75-84% = 1 
65-74% = 2 
< 65% = 3 
▪ Sleep disturbance 
• To Calculate Component 5 Score: 
1. Add the scores from Questions 5b to 5j 
2. Assign score as follows: 
0 = 0 
1-9 = 1 


 
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10-18 = 2 
19-27 = 3 
▪ Use of sleeping medication 
• Component 6 Score = response to Question 7 
▪ Daytime dysfunction 
• To calculate Component 7 Score 
1. Add responses to Question 8 and Question 9 
2. Assign Score as follows: 
0 = 0 
1-2 = 1 
3-4 = 2 
5-6 = 3 
 
To Calculate the Global PSQI score, add the seven component scores. 
Each self-rated component has a Component Score ranging from 0-3 points, which are summed to 
calculate the Global Score with a range of 0-21.  A Global Score of 0 indicates no difficulty, and 
a score of 21 indicates severe difficulty in all areas.  
Descriptive statistics, including 95% CIs for the mean, for the PSQI Global Score will be presented 
for actual values and change from Baseline for scheduled visits.  The change from Baseline 
difference in means between each dose of MM-120 and placebo and 95% for the difference will 
be presented for Week 4, Week 8 and the End of Study visit. A by-subject listing of results by 
visit, including any unscheduled visits, will be provided for all PSQI responses and the PSQI 
Global Score.  
6.3.10 Change from Baseline in ASEX Total Score 
The ASEX questionnaire measures sexual experience, with categories of sex drive, arousal, 
vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm.  Each of 
the 5 items will be scored from 1-6 and the Total Score will be calculated by summing each 
component.  The total score will range from 5 to 30.  Higher scores indicate the presence of sexual 
dysfunction.  Sexual dysfunction is defined as having a total score ≥ 19, or a score of ≥ 5 on any 
item, or a score of ≥ 4 on three items.   
The number and proportion of subjects with sexual dysfunction will be presented by sex at birth 
and treatment group for each visit.  The observed difference in the rates of sexual dysfunction 
between each dose of MM-120 and placebo, along with the 95% CI for the difference, will be 
presented by sex at birth for Week 1, Week 2, Week 4, Week 8 and the End of Study visit. 
Descriptive statistics, including 95% CIs for the mean, for the ASEX Total Score will be presented 
for actual values and change from Baseline for scheduled visits by sex at birth.  The change from 
Baseline difference in means between each dose of MM-120 and placebo and 95% CI for the 
difference will be presented for Week 1, Week 2, Week 4, Week 8 and the End of Study visit. A 
by-subject listing of results by visit, including sex at birth, will be provided for all ASEX responses 
and the Total Score.  


 
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6.4 
Exploratory Endpoints and Analyses 
The endpoints of Drug Effect VAS, MEQ30 and 5D-ASC will be measured to explore the dose 
response on drug effects, altered perception and mystical experience.  To assess the blind integrity 
and to examine whether guess rates are associated with outcomes such as AEs or mood/anxiety, a 
treatment assignment question will be administered.   
6.4.1 HAM-A Response and Remission 
HAM-A response is defined as a decrease from Baseline by ≥ 50% in HAM-A Total Score in 
response to treatment, and a Total Score of ≤ 7 indicates a remission of symptoms.  The number 
and proportion of subjects with response and with remission will be presented by treatment group 
for Week 1, Week 2, Week 4, Week 8 and the End of Study visit.  The observed difference in the 
rates of response and remission between each dose of MM-120 and placebo, along with the 95% 
CI for the difference, will be presented for each visit. 
6.4.2 Drug Effect VAS 
The Drug Effect VAS will be administered on Day 2 to retrospectively assess the subject’s 
perception of drug effects experienced during the dosing session.  A series of single-item 100 mm 
VAS questions will be used to measure the extent to which the subject experienced each of the 
following: 
• ‘any drug effect’ 
• ‘good drug effect’ 
• ‘bad drug effect’ 
• ‘drug liking’ 
• ‘fear’ 
• ‘nausea’ 
• ‘alteration of vision’ 
• ‘alteration of sense of time’ 
• ‘the boundaries between myself and 
my surroundings seem to blur’ 
Descriptive statistics for each VAS score will be presented for actual values at Day 2.  A by-subject 
listing of results be provided. 
6.4.3 MEQ30 
The MEQ30 will be administered on Day 2 to retrospectively assess the subject’s mystical 
experience during the dosing session.  The MEQ30 includes 30 self-rated questions with 4 
subscales: mystical, positively mood, transcendence of time and space, and ineffability.  Each of 
the 30 questions will be scored from 0 to 5 as: 
0 = none; not at all 
1 = so slight cannot decide 
2 = slight 
3 = moderate 
4 = strong (equivalent in degree to any other strong experience) 
5 = extreme (more than any other time in my life and stronger than 4) 
 
The 4 subscales will be calculated as follows: 
• Transcendence (%) = sum of transcendence questions / 30  


 
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o Transcendence questions are those marked with a ‘T’ on questionnaire: 1, 7, 11, 13, 
19, and 22 
• Positive Mood (%) = sum of positive mood questions / 30 
o Positive Mood questions are those marked with a ‘P’ on questionnaire: 2, 8, 12, 17, 
27, and 30 
• Ineffability (%) = sum of ineffability questions / 15 
o Ineffability questions are those marked with an ‘I’ on questionnaire: 3, 10, and 29 
• Mystical (%) = sum of mystical questions / 75 
o Mystical questions are those unmarked on questionnaire: 4, 5, 6, 9, 14, 15, 16, 18, 
20, 21, 23, 24, 25, 26, and 28 
The MEQ30 Total Score (%) will be calculated by summing all 30 questions and dividing by 150.  
A subject is considered to have had a ‘complete mystical experience’ when ≥60% of the maximum 
possible score is achieved on all 4 factor subscales.  
Descriptive statistics for each of the 4 subscales and for the MEQ30 Total Score will be presented 
for actual values on Day 2.  The number and percentage of subjects defined as having ‘a complete 
mystical experience’ will be provided.  A by-subject listing will be provided for all MEQ30 
responses, the 4 subscales and the MEQ30 Total Score.  
6.4.4 5D-ASC 
The 5D-ASC will be administered on Day 2 to retrospectively assess the subject’s peak alteration 
of consciousness during the dosing session as compared with their normal waking consciousness.  
The 5D-ASC consists of 94 self-rated 100 mm VAS questions with anchors of 0 = ‘no not more 
than usually’ to 100 = ‘yes more than usually’.  The 94 items are combined into 5 subscales.   
1. Oceanic boundlessness – summation of questions 1, 3, 9, 12, 16, 18, 26, 34, 35, 36, 40, 41, 
42, 45, 50, 52, 57, 62, 63, 69, 71, 73, 81, 86, 87, 91, and 94. Maximum value = 2700. 
2. Anxious ego dissolution – summation of questions 6, 8, 21, 27, 32, 38, 43, 44, 46, 47, 53, 
56, 60, 64, 67, 78, 79, 80, 85, 88, and 89. Maximum value = 2100. 
3. Visionary destructuralization – summation of questions 7, 14, 20, 22, 23, 28, 31, 33, 39, 
54, 58, 70, 72, 75, 77, 82, 83, and 90. Maximum value = 1800. 
4. Auditory alterations – summation of questions 4, 5, 11, 13, 19, 25, 30, 48, 49, 55, 65, 66, 
74, 76, 92 and 93. Maximum value = 1600. 
5. Vigilance reduction – summation of questions 2, 10, 15, 17, 24, 29, 37, 51, 59, 61, 68, and 
84. Maximum value = 1200. 
The 5D-ASC Total Score will be calculated as the sum of all the questions.  The maximum value 
for the Total Score is 9400.   
Descriptive statistics for each subscale and the total score will be presented for each treatment arm.  
A figure showing the percent of maximum value for each subscale and total score by treatment 
arm will be provided.  A listing of the 5D-ASC subscales and Total Score will be provided.   
6.4.5 Treatment Assignment/Blinding Question 
On Day 2, subjects will be asked to indicate which sentence they agree with most, using a 5-point 
Likert Scale: 


 
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1 = I am positive I received active drug 
2 = I think I received active drug 
3 = I cannot tell whether I received active drug or placebo 
4 = I think I received placebo 
5 = I am positive I received placebo 
The number and percentage of subjects reporting each level will be presented.  Also, the number 
and percentage of subjects correctly reporting (levels 1 and 2 for active drug or levels 4 and 5 for 
placebo) their treatment assignments will be reported.  A listing will be provided.  
6.5 
Subgroup Analyses 
Descriptive statistics, including 95% CIs for the HAM-A Total Score change from baseline at 
Week 1, Week 2, Week 4, Week 8 and End of Study will be provided by the following subgroups: 
• Baseline HAM-A Total Score: ≤ median baseline value, > median baseline value 
• Age: ≤35 years, > 35 years 
• Sex: male, female 
• Race: white, non-white 
7 
SAFETY ANALYSIS 
Safety assessments include adverse events, laboratory parameters, vital signs, electrocardiograms, 
physical exams and the Columbia Suicide Severity Rating Scale (C-SSRS). All safety summaries 
will be conducted using the safety (SAF) population and will be presented by treatment group. No 
formal hypothesis testing will be performed to compare differences between treatment groups. 
7.1 
Extent of Exposure 
Subjects will be dosed 1 time during this study, consisting of 8 capsules.   Descriptive statistics for 
the total number of capsules taken will be provided by treatment group.    
In addition, the number and percent of subjects (or ‘0’ if no subjects encounter such an event) with 
any of the following special situations for study drug administration will be provided:  
• Medication error or incorrect drug administration 
• Overdose 
• Deliberate abuse 
• Drug interaction 
• Occupational exposure 
• Breastfeeding with suspected infant exposure 
• Drug accountability issue 
A listing of all subject exposure data will be provided.  


 
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7.2 
Adverse Events 
Adverse events (AE) will be collected starting at the time of informed consent until the End of 
Study visit on Week 12.  An AE is defined as any untoward medical occurrence in a clinical trial 
subject.  AEs will be analyzed for subjects in the SAF population.  AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).   
7.2.1 Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as AEs starting during or after 
administration of the first dose of study drug.  A determination of treatment emergence for AEs 
with missing or partial AE start dates and times will use a conservative approach that assumes 
treatment emergence when the true start time or date is unknown.  
7.2.2 Adverse Event Severity 
Severity describes the intensity of a specific adverse event. The Investigator will determine the 
severity of each AE according to the NCI CTCAE v5.0.  AEs will be characterized as ‘mild’, 
‘moderate’, ‘severe’, ‘life-threatening’, or ‘death’.   
7.2.3 Adverse Event Relationship to Study Medication 
The Investigator will assign a relationship to each AE based on his/her determination of whether 
there exists a reasonable possibility that the IP caused or contributed to the AE.  The AE 
relationship will be characterized as ‘not related’, ‘unlikely related’, ‘possibly related’, and 
‘definitely related’.  For analysis purposes, AEs will be summarized by ‘Related’ (including 
‘possibly related’ and ‘definitely related’) and ‘Not Related (‘unlikely related’ and ‘not related’).  
AEs with missing relationship will be considered to be ‘Related’ events.   
7.2.4 Serious Adverse Events 
A serious adverse event (SAE) is defined as an AE that meets at least one of the following criteria: 
• Results in death 
• Is life-threatening 
• Requires hospitalization or prolongation of existing hospitalization  
• Results in a disability/incapacity 
• Congenital anomaly/birth defect 
• Other medically important serious event 
7.2.5 Adverse Events of Special Interest  
Adverse events of special interest (AESI) are defined as a subset of AEs that are suggestive of 
abuse potential and any special situations defined in Section 9.9 of the protocol that have an 
associated AE.  The following MedDRA Preferred Terms will be used to classify AESIs related 
to abuse liability: 
• Euphoria-related terms: Euphoric mood; Elevated mood; Feeling abnormal; Feeling 
drunk; Feeling of relaxation; Dizziness; Thinking abnormal; Hallucination; Inappropriate 




 
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ix. the number and percentage of subjects experiencing a TEAE leading to study withdrawal 
by SOC and PT 
x. the number and percentage of subjects experiencing a TEAE leading to study death by 
SOC and PT 
xi. the number and percentage of subjects experiencing a treatment emergent AESI by SOC 
and PT 
Additionally, two tables, the incidence by severity of TEAE by SOC and PT (ii), and the incidence 
by severity of TESAE by SOC and PT (vi),  will also be presented separately for AEs starting on 
Study Day 1 (dosing day) and for those AEs starting post Study Day 1.  For AEs starting on Day 
1 (dosing day) the duration, in days, will be summarized by descriptive statistics.   
In the overall summary of TEAEs table (i), besides tabulating the number and percentage of 
subjects, the total number of TEAE episodes will also be provided. If a subject has repeated 
episodes of a particular TEAE, all episodes will be counted in the summary table.   
In the remaining summary tables, the incidence of TEAEs will be calculated by dividing the 
number of subjects who have experienced the event by the total number of subjects in the Safety 
Analysis set.  Thus, the incidence of TEAEs is shown in terms of the total number of subjects and 
not in terms of the total number of episodes.  If a subject has repeated episodes of a particular 
TEAE, only the most severe episode, or the episode with the strongest causal relationship to study 
drug, will be counted in the summary tables.  
A subject with more than one type of TEAE in a particular SOC will be counted only once in the 
total of subjects experiencing TEAEs in that particular SOC.  Since a subject could have more than 
one type of TEAE within a particular SOC, the sum of subjects experiencing different TEAEs 
within the SOC could appear larger than the total number of subjects experiencing TEAEs in that 
SOC.  Similarly, a subject who has experienced a TEAE in more than one SOC will be counted 
only once in the total number of subjects experiencing AEs in all SOCs. 
All occurrences of all AEs will be listed for each subject, grouped by treatment group.  The listing 
will contain the following information: treatment group, verbatim term, SOC, PT, severity, 
relationship to study medication, date and day of onset, date and day of resolution, action taken, 
the outcome, and whether the event was an SAE.  Listings will be sorted by subject identification 
number, onset date, SOC, and PT. If the onset date is completely missing, then these events will 
be presented first. If the onset date is missing a month or a day, then these events will be presented 
before any complete dates.  Additional listings of SAEs, AEs leading to Study Withdrawal, and 
Subject Deaths will be provided.  
7.3 
Clinical Laboratory Assessments 
Clinical laboratory tests in chemistry, hematology and urinalysis will be performed throughout the 
study according to the schedule of assessments.  The laboratory will also provide eGFR, calculated 
using the CKD-EPI formula.  Descriptive statistics for actual values and change from Baseline 
values for laboratory tests will be presented for each scheduled measurement.  The number and 
percentage of subjects with values beyond the laboratory normal ranges will be summarized by 
frequency tables and shift tables.  A by-subject listing, including flags for abnormal or out-of-
range values, will be provided.  The laboratory tests to be performed are listed in Table 5. 
 
 


 
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CONFIDENTIAL  
 
Page 29 of 37 
Table 5 
Clinical Laboratory Parameters with Standard Units 
 
Serum Chemistry Panel 
Units 
Hematology and Coagulation 
Units 
Albumin 
g/L 
Hemoglobin 
g/L 
Total protein 
g/L 
Hematocrit 
% 
Alkaline phosphatase 
U/L 
Red blood cell count 
x10^12/L 
ALT 
U/L 
White blood cell count 
x10^9/L 
AST 
U/L 
MCV 
fL 
Bicarbonate 
mmol/L 
MCH 
pg 
Bilirubin, total  
umol/L 
MCHC 
g/L 
Bilirubin, direct 
umol/L 
RDW 
% 
Blood urea nitrogen  
mmol/L 
Platelet count 
x10^9/L 
Calcium 
mmol/L 
MPV 
fL 
Chloride 
mmol/L 
Basophils 
% 
Creatinine 
umol/L 
Eosinophils 
% 
Creatinine clearance  
mL/s 
Lymphocytes 
% 
FSH 
U/L 
Monocytes 
% 
GGT 
U/L 
Neutrophils 
% 
Glucose 
mmol/L 
 
 
Lactate dehydrogenase  
U/L 
Urinalysis 
Units 
Cholesterol 
mmol/L 
Protein 
n/a 
HDL 
mmol/L 
Glucose 
n/a 
LDL 
mmol/L 
Ketones 
n/a 
Triglycerides 
mmol/L 
Bilirubin 
n/a 
Phosphorus 
mmol/L 
pH 
n/a 
Potassium 
mmol/L 
Nitrites 
n/a 
Sodium 
mmol/L 
Specific gravity 
n/a 
TSH  
mU/L 
Urobilinogen 
n/a 
Free T4 
mmol/L 
Leukocyte Esterase 
n/a 
eGFR 
mL/min/1.73m^2 
Microscopic Urine 
 Units 
 
 
Bacteria 
n/a 
 
 
RBC 
n/a 
 
 
WBC 
n/a 
 
 
Epithelial cells 
n/a 
 
 
Casts  
n/a 
 
 
Crystals 
n/a 
 


 
Mind Medicine, Inc. MMED008 Statistical Analysis Plan (Final version 1.0) 
 
CONFIDENTIAL  
 
Page 30 of 37 
7.4 
Vital Signs 
Descriptive statistics for actual values and change from Baseline values for vital signs will be 
presented for each scheduled measurement.  Vital sign parameters include: 
• height (cm, measured only at baseline) 
• weight (kg)  
• BMI (kg/m2) 
• systolic and diastolic blood pressure (mmHg) 
• heart rate (beats per minute) 
• temperature (◦C)  
• respiratory rate (breaths per minute) 
• orthostatic blood pressure (mmHg)  
• standing pulse (bmp) 
Measurements from unscheduled visits will be excluded from the analyses but will be included in 
the data listings.  
7.5 
ECG 
Electrocardiogram (ECG) measures will be collected at screening, Baseline and the Day 2 visit. 
The number and percent of ECG findings of normal; abnormal, not clinically significant; and 
abnormal, clinically significant will be presented for each scheduled measurement. The following 
ECG interval measurements will be summarized by presenting descriptive statistics of actual 
values and change from baseline values at each scheduled visit: 
• PR Interval (ms) 
• QRS Duration (ms) 
• Ventricular Rate (bpm) 
• QT Interval (ms) 
• RR Interval (ms) 
• QTcF Interval (ms) 
Listings will include measurements at each scheduled visit as well as any unscheduled visits. 
7.6 
Physical Examination 
The number and percentage of subjects with physical examination findings of normal and 
abnormal at each visit will be summarized and presented for each body system.  A listing of 
physical examination findings will also be provided. 
7.7 
C-SSRS 
The Columbia-Suicide Severity Rating Scale (C-SSRS) assesses a subject’s suicidal ideation 
(severity and intensity) and behavior.  The C-SSRS has 11 categories: 5 subtypes of suicidal 


 
Mind Medicine, Inc. MMED008 Statistical Analysis Plan (Final version 1.0) 
 
CONFIDENTIAL  
 
Page 31 of 37 
ideation, 5 subtypes of suicidal behavior and 1 subtype of self-injurious behavior without suicidal 
intent.  All responses are binary (yes/no).  
The number and percent of subjects answering ‘Yes’ to each of the 11 categories will be provided 
for each scheduled time point.  No statistical comparisons between treatment groups will be 
performed.  A by-subject data listing will be provided.  
8 
INTERIM ANALYSIS AND CHANGES FROM PROTOCOL 
No formal interim analysis was planned for the study.   
During the conduct of the study, a Sponsor decision was made to perform the analysis of the 
primary endpoint when all enrolled subjects reached their Week 4 visit.   The approximately 180 
subjects will provide adequate power to determine the dose-response relationship as defined in the 
primary objective of the study.  No further subjects will be enrolled, and the study will continue to 
its normal conclusion.   
This ‘Top-Line’ analysis will be the final analysis for the HAM-A primary endpoint at Week 4, 
HAM-A response and remission through Week 4, HAM-A change from baseline through Week 4, 
MADRS change from baseline through Week 4 and CGI-S through Week 4.  Preliminary analysis 
of Subject Disposition, and Adverse Events will be provided as well.  As this will be the final 
analysis for the select efficacy endpoints through Week 4, this is not considered an interim analysis 
and no adjustment to the overall alpha level of the trial is needed. 
At the time of analysis, data for the select efficacy analyses through Week 4 will be cleaned and 
locked in the clinical trial database according to the Data Management Plan.  Supporting data for 
the preliminary analyses will be cleaned and frozen, and a snapshot of the database taken.     
A pre-defined unblinded statistician and programmer, not involved with the conduct of the study, 
will perform this analysis.  The Study team will remain blinded through the completion of the 
study.  The topline results for the primary endpoint will not be available to the Study Team or 
externally until the final subject has completed their last visit assessment. 
The remaining secondary efficacy analyses and final safety analyses will be conducted at the 
completion of the trial. 
9 
SAMPLE SIZE AND POWER CALCULATIONS 
A total sample of 180 subjects, 36 per arm, is required to ensure a mean power >87% for an MCP-
Mod Analysis rejecting the hypothesis of a constant dose-response curve using the multiple 
comparisons procedure (MCP), assuming a null placebo response, a maximum standardized effect 
of 0.6 within the doses range, and a common standard deviation within the dose arms, if a study-
wise one-sided type-1 error rate <0.05 is required.  
The analysis assumes 4 doses of active medication (25, 50, 100 and 200 µg freebase-equivalent) 
and placebo.  The required sample size for each arm is 36 subjects.  
The R package Dose Finding (https://CRAN.R-project.org/package=DoseFinding) has been used 
to estimate the sample size and corresponding power.  The power for each model is estimated as 
shown Table 6. 


 
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Page 32 of 37 
 
Table 6 
Power by Model 
Model 
Power (%) 
Sigmoid Emax (ED50, hill) 
 
10, 1 
84.5 
100, 5 
90.7 
100, 10 
91.0 
150, 10 
89.9 
Emax (D50 = 100) 
83.2 
Linear 
85.0 
 
 
 


 
Mind Medicine, Inc. MMED008 Statistical Analysis Plan (Final version 1.0) 
 
CONFIDENTIAL  
 
Page 33 of 37 
10 REFERENCES 
1. Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in dose-
response studies. Biometrics. 2005;61(3):738-48. 
 
 


 
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11 APPENDICES 
 
 
 
 
 


 
Mind Medicine, Inc. MMED008 Statistical Analysis Plan (Final version 1.0) 
 
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Page 35 of 37 
11.1 Appendix A 
Table 11-1 
MMED008 Schedule of Activities 
 
 










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CONFIDENTIAL 
Page 1 of 7 
A Phase 2, Multi-center, Randomized, Double-Blind, Parallel-Group, Dose-Finding Study to 
Assess the Effect of Four Doses of MM-120 for the Treatment of Anxiety Symptoms 
Protocol Number: MMED008 
Protocol Version: 6.0 
Protocol Date: 26 July 2023 
STATISTICAL ANALYSIS PLAN - ADDENDUM 
Version 1.0 




Mind Medicine, Inc. MMED008  SAP - Addendum (version 1.0)
CONFIDENTIAL 
Page 3 of 7 
SAP Revisions 
Version 1.0 of the SAP was finalized at the time of Protocol version 6.0 (26Jul2023). The 
following table details the changes made to the SAP and/or addendum.    
Protocol 
Version # 
Date 
SAP 
Section 
Modification 
Description and Rationale 
1.0 
All 
Initial document 
Addendum 
All 
Initial Addendum document 
Added safety and efficacy analysis 
after the Primary Efficacy Analysis 
was performed 


 
Mind Medicine, Inc. MMED008  SAP - Addendum (version 1.0) 
 
CONFIDENTIAL  
 
Page 4 of 7 
Table of Contents 
SAP REVISIONS ................................................................................................................................................. 3 
1 
INTRODUCTION ............................................................................................................................................. 5 
2 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ......................................................................................... 5 
2.1 
ANALYSIS QUALITY CONTROL PROCEDURES ............................................................................................................ 5 
2.2 
ANALYSIS SETS .................................................................................................................................................. 5 
2.3 
ASSESSMENT WINDOWS .................................................................................................................................... 5 
2.4 
HANDLING OF DROPOUTS OR MISSING DATA ......................................................................................................... 6 
2.5 
MULTIPLE COMPARISONS ................................................................................................................................... 6 
2.6 
DATA DERIVATIONS AND TRANSFORMATIONS ......................................................................................................... 6 
3 
EFFICACY ANALYSIS ....................................................................................................................................... 6 
3.1 
CHANGE FROM BASELINE IN HAM-A SUBSCALES – SOMATIC ANXIETY AND PSYCHIC ANXIETY ......................................... 6 
4 
SAFETY ANALYSIS .......................................................................................................................................... 6 
4.1 
ADVERSE EVENTS .............................................................................................................................................. 6 
4.1.1 
Treatment-emergent Adverse Events ...................................................................................................... 6 
4.1.2 
Adverse Event Summaries ........................................................................................................................ 7 
 
 




 
Mind Medicine, Inc. MMED008  SAP - Addendum (version 1.0) 
 
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Page 6 of 7 
2.4 
Handling of Dropouts or Missing Data 
Missing data will not be imputed for analysis of non-key secondary efficacy endpoints or safety 
endpoints.  
2.5 
Multiple Comparisons 
No adjustment for multiplicity will be performed for testing the non-key secondary and exploratory 
endpoints.  
2.6 
Data Derivations and Transformations 
Data derivations and transformations defined in the Final SAP version 1.0, dated 01Aug2023 will 
be used for all analyses in this addendum. 
3 
EFFICACY ANALYSIS 
3.1 
Change from Baseline in HAM-A Subscales – Somatic Anxiety and Psychic Anxiety  
Two subscales will be defined from the HAM-A questionnaire.   
Somatic Anxiety is defined as the sum of items 7 – 13 of the HAM-A questionnaire. 
Psychic Anxiety is defined as the sum of items 1 - 6, and item 14 of the HAM-A questionnaire. 
Descriptive statistics will be presented for actual values and change from Baseline for scheduled 
visits for the FAS and PPS analysis populations.  The change from Baseline will be analyzed using 
an analysis of covariance (ANCOVA) model including change from Baseline HAM-A Somatic 
Anxiety, or Psychic Anxiety, score as dependent variable, the baseline HAM-A Somatic Anxiety, 
or Psychic Anxiety, score as a covariate and treatment group as a fixed effect.  The Least Square 
Means (LS Means) for each treatment group compared to placebo will be reported along with 
associated 95% CI and p-value.  The ANCOVA comparisons will be performed for Week 1, Week 
2, Week 4, Week 8 and the End of Study visit and will be presented for both the FAS and PPS 
populations.  
4 
SAFETY ANALYSIS 
All safety summaries will be conducted using the safety (SAF) population and will be presented 
by treatment group. No formal hypothesis testing will be performed to compare differences 
between treatment groups. 
4.1 
Adverse Events 
Adverse events (AE) will be collected starting at the time of informed consent until the End of 
Study visit on Week 12.  An AE is defined as any untoward medical occurrence in a clinical trial 
subject.  AEs will be analyzed for subjects in the SAF population.  AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).   
4.1.1 Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as AEs starting during or after 
administration of the first dose of study drug.  A determination of treatment emergence for AEs 


 
Mind Medicine, Inc. MMED008  SAP - Addendum (version 1.0) 
 
CONFIDENTIAL  
 
Page 7 of 7 
with missing or partial AE start dates and times will use a conservative approach that assumes 
treatment emergence when the true start time or date is unknown.  
4.1.2 Adverse Event Summaries 
AEs (serious and non-serious) occurring after completion of the informed consent process and 
before the end of study, regardless of relationship to study drug, will be included and classified by 
system organ class (SOC) and preferred term (PT) using the Medical Dictionary for Regulatory 
Activities (MedDRA).  
For treatment-emergent AEs (TEAEs) occurring during the entirety of the study, the following 
will be summarized and presented for the SAF set: 
• The incidence of TEAEs occurring on dosing day by PT and severity 
• The incidence of TEAEs occurring post dosing day by PT and severity 
• The incidence of TEAEs occurring on dosing day by PT and relationship 
• The incidence of TEAEs occurring post dosing day by PT and relationship 
• The incidence of TEAEs occurring on dosing day and post dosing day by PT 
The incidence of TEAEs will be calculated by dividing the number of subjects who have 
experienced the event by the total number of subjects in the Safety Analysis set.  Thus, the 
incidence of TEAEs is shown in terms of the total number of subjects and not in terms of the total 
number of episodes.  If a subject has repeated episodes of a particular TEAE, only the most severe 
episode, or the episode with the strongest causal relationship to study drug, will be counted in the 
summary tables for severity and relationship.  
  
 






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Prot_000.pdf: 
 
Confidential 
Page 1 
 
 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
A Phase 2, Multi-center, Randomized, Double-Blind, Parallel-
Group, Dose-Finding Study to Assess the Effect of Four Doses 
of MM-120 for the Treatment of Anxiety Symptoms 
Protocol Number: 
MMED008 
Compound Name: 
MM-120 (D-lysergic acid diethylamide [LSD] D-tartrate) 
Sponsor: 
Mind Medicine, Inc. 
Development Phase: 
2 
Regulatory Agency 
Identifying 
Number(s): 
IND 151069 
Version: 
6.0 
Effective Date: 
26 July 2023 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or 
under control of Mind Medicine, Inc., and is provided to you in confidence as an 
Investigator, potential Investigator or consultant, for review by you, your staff and an 
applicable Institutional Review Board or Independent Ethics Committee. The information is 
only to be used by you in connection with authorized clinical studies of the investigational 
drug described in the protocol. You will not disclose any of the information to others without 
written authorization from Mind Medicine, Inc., except to the extent necessary to obtain 
informed consent from those persons to whom the drug may be administered. 


MM-120 (LSD) 
Mind Medicine, Inc. 
Clinical Study Protocol: MMED008 
 
Version 6.0 
Confidential 
Page 2 
Issued DD Month 2023 
 
SUMMARY OF CHANGES 
Version number: 6.0  
Effective Date: 26 July 2023 
Supersedes MMED008 V5.0 (31 March 2023) 
MMED008 V5.0 was revised. Minor grammatical, wordsmithing, or formatting changes are 
not included in the summary below. New or revised text is shown in bold font, deleted text is 
shown as strike through text. 
Table 1 Emergency 
Contact Information 
Change of Primary Medical Monitor 
From Eric J Christopher to Christopher Perkins 
Synopsis Number of 
Subjects Planned 
4.2. Number of 
Subjects 
Change in Number of Subjects 
Approximately 200180 
Synopsis Study 
Design 
4.1. Overall Study 
Design 
Change in Number of Subjects 
The study will enroll approximately 200 180 male and female subjects 
Synopsis Exclusion 
Criterion #18 
5.1.2 
Exclusion 
Criterion #18 
Clarification added regarding tapering 
…until End of Study. 
Note: See Section 6.10 for details of prohibited concomitant medications, 
supplements and other therapeutics and allowable conditions of use. Exclusion does 
not apply to medications that need to be tapered for inclusion in the study and 
reference is to achieving and maintaining a steady state. 
Synopsis Exclusion 
Criteria #26 g, 26 h, 
26 i 
5.1.2 
Exclusion 
Criteria #26 g, 26 h, 
26 i 
Clarifications added related to blood pressure, heart rate, and orthostatic hypotension 
g. … after an additional approximately 5 minutes relaxationrest. 
h. Heart rate < 45 beats/minute or > 90 beats/minute after an approximately 5-minute 
rest at Screening and Baseline 
NOTE: If the first measurement of a subject’s heart rate is outside the allowable 
range, a second recording is allowed after an additional approximately 5 
minutes rest. 
> 90 beats/minute, a second recording is allowed after an additional approximately 5
minute rest. 
i. … following a change from a supine position to a standing position (measured 
within 1 to 3 minutes of standing); 
Synopsis Endpoints  
3 
Endpoints 
Clarification to timing of assessments 
Change from Baseline to Week 1, Week 2 (where applicable), Week 4… 
Synopsis Statistical 
Methods 
Updated to account for the change in the number of subjects 
A total sample of 200 180 subjects (40 36 per dose arm and 40 36 for the placebo 
arm) is required to ensure a mean power > 9087% for an MCP-Mod analysis rejecting 
the hypothesis… 
Table 2: 
 
MMED008 
Schedule of 
Activities 
Updated to include measurement of weight, height, and BMI at the Screening Visit 
and revised footnote ‘e’ to describe collection of Vital signs 
e 
Vital signs should be performed prior to an ECG and/or a blood draw; Screening 
and Baseline vital signs require sitting, lying, and standing vital signs in order to 
capture orthostatic vitals.   
3. Objectives and 
Endpoints 
Addition of Exploratory Objective and Endpoints 


MM-120 (LSD) 
Mind Medicine, Inc. 
Clinical Study Protocol: MMED008 
 
Version 6.0 
Confidential 
Page 3 
Issued DD Month 2023 
New Exploratory Objective: • To assess response and remission across the 4 
doses of MM-120 (25, 50, 100, or 200 µg freebase-equivalent) as measured by the 
change in HAM-A from Baseline to End of Study 
New Exploratory Endpoints: • HAM-A response (defined as ≥50% reduction in 
HAM-A Total Score) from Baseline to Weeks 1, 2, 4, 8, and End of Study.  
• 
HAM-A remission (defined as HAM-A Total Score of ≤7) at Weeks 1, 2, 4, 8, 
and End of Study 
4.1 Overall Study 
Design 
Qualifications of Dosing Session Monitors clarified 
The lead monitor must be a licensed healthcare provider with graduate-level 
professional training and clinical experience. The lead monitor must be actively 
licensed to practice independently in the state of the study site location. Lead monitor 
acceptable professional credentials are as follows: Clinical or counseling psychologist 
(PhD or PsyD); Psychiatrist or other physician (MD or DO); Master Level Clinician, 
such as of Social Work (Licensed Clinical Social Worker (-LCSW), Licensed 
Clinical Professional Counselor (LCPC), Licensed Marriage and Family 
Therapist (LMFT), or local state equivalent; Advanced Nurse Practitioner 
(NP/APRN) such as a Psychiatric Nurse Practitioner or local state equivalent. 
Masters level Clinician (Licensed Professional Counselor  LPC, Licensed 
Professional Counselor Candidate  LPCC; Licensed Mental Health Counselor  
LMHC, Licensed Marriage Family Therapist  LMFT, Licensed Professional 
Counselor  LPC, Licensed Clinical Professional Counselor  LCPC, Licensed 
Clinical Mental Health Counselor  LCMHC); Psychiatric Nurse Practitioner, Nurse 
Practitioner (NP), Advanced Practice Nurse (APRN) and Physician’s Assistant (PA).   
One of the DSMs must be appropriately trained to monitor vital signs and 
administer the C-SSRS., including orthostatic blood pressure. A site-designated 
licensed physician with prescribing rights or a qualified designee can may serve as 
the backup to either DSM if short breaks are needed. 
5.2.2. 
Nicotine 
Use 
Clarifications regarding the use of nicotine 
Due to the length of Day 1/Dosing Session subjects are not permitted to smoke 
cigarettes/vape during the dosing session. and theDue to the possibility of nicotine 
withdrawal symptoms, 
8.1.4. 
Eligibility 
Assessment 
Clarification related to Vital Signs 
however, of the vital signs taken at Visit 3A will not beonly temperature and blood 
pressure will be used to confirm final eligibility 
8.2.3 
Vital Signs 
Clarifications related to Vital Signs 
Initial vital signsBlood pressure should be taken with the subject seated in a chair 
with back support and arms, feet flat on the floor, arms supported by the arm rest. 
aAfter an approximately 5-minute rest, measure blood pressure, . heart rate, and 
respiration rate. If any of the first measurements are out of range, a second  
measurement can be taken after the subject has been allowed an additional 
approximately 5 minutes of rest. will be obtained after the subject has rested quietly 
in a supine position for approximately 5 minutes.  
At Screening (Visit 1) and Baseline (Visit 2), vital sign measurements will also 
include measure me nt of orthostatic blood pressure. This measurement is taken 
separately from the initial vital signs. For eligibility determinations at these 2 visits, 
the Oo Orthostatic blood pressure should be measured by: allowing the subject to 
rest in a supine position for approximately 5 minutes; the subject then stands; 
and heart rate and blood pressure are measured within in 1 to 3 minutes of 
standing. following a change from a supine position to a standing position (measured 
within 3 minutes of standing). If convenient, orthostatic blood pressure can be 
measured after the subject has been supine for the ECG. 
8.2.4. 
Weight 
Clarifications related to timing of the measurement 
Weight may be estimated during a remote Prescreen session but should be 
physically measured once the subject is on-site to determine eligibility. 


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Body weight may be measured with the subject in street clothing with jacket/coat and 
shoes removed. Weight may be estimated during a remote Prescreen session but 
should be physically measured once the subject is on site to determine eligibility.An 
estimated weight may be used during the optional Prescreen for sites that implement 
remote prescreening activities. 
8.2.5. 
Height 
Clarifications related to timing of the measurement 
Height may be estimated during a remote Prescreen session but should be 
physically measured once the subject is on-site. 
Standing height will be measured without shoes at Screening (Visit 1) only when 
Height may be estimated during a remote Prescreen session but should be physically 
measured once the subject is on-site to determine eligibility.An estimated height 
may be used during the optional Prescreen for sites that implement remote 
prescreening activities. 
9.1. Definition of an 
Adverse Event 
Definition of adverse events updated  
Any change in clinical status , ECGs, routine labs, physical examinations, etc., that is 
considered clinically significant by the PI should be documented. AEs occurring prior 
to randomization should be documented in medical history. AEs occurring after 
randomization should be documented in the AE log. Adverse events include any 
clinically significant changes not present prior to drug administration. , or an already 
present event that worsens either in intensity or frequency following the treatment.   
An AE includes:  
• 
An unexpected worsening, excluding minor fluctuations, in the nature, 
severity, frequency, or duration of a pre-existing condition.  
• 
A new condition detected or diagnosed after investigational product 
administration even though it may have been present prior to the start 
of the study.  
• 
Injury or accidents: If a medical condition is known to have caused the 
injury or accident, the medical condition and the accident should be 
reported as 2 separate medical events (e.g., for a fall secondary to 
dizziness, both “dizziness” and “fall” should be recorded separately).  
• 
An investigational abnormality (e.g., laboratory parameter, vital sign, 
ECG) only if the abnormality which occurs during the conduct of a 
clinical trial. Any change in clinical status, ECGs, routine labs, physical 
examinations, etc., that is considered clinically significant by the 
Investigator based on at least one of the following criteria:  
- 
 Induces clinical signs or symptoms  
- 
 Requires active intervention  
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction.  
• 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of 
either investigational product or a concomitant medication. 
9.3. Adverse Events 
of Special Interest 
Definition of adverse events of special interest updated for clarity 
The AE terms listed below are MedDRA Preferred Terms to be used in classifying 
Adverse Events of Special Interest (AESIs) related to abuse liability when deemed 
appropriate by the PI (or designee): 
• 
Euphoria-related terms: Euphoric mood; Elevated mood; Feeling 
abnormal; Feeling drunk; Feeling of relaxation; Dizziness; Thinking 
abnormal; Hallucination; Inappropriate affect. 
• 
Terms indicative of impaired attention, cognition, and mood: 
Somnolence; Mood disorders and disturbances. 
• 
Dissociative/psychotic terms: Psychosis; Aggression; Confusion and 
disorientation. 
• 
Overdose-/ Misuse-related terms not captured elsewhere: Drug 
tolerance; Habituation; Drug withdrawal syndrome; Substance-related 
disorders. 
• 
Euphoria  
• 
Disassociation 


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• 
Impaired cognition and attention  
• 
Psychomotor effects  
• 
Inappropriate Affect  
• 
Overdose/ Misuse 
Table 8: MMED008 
Analysis Sets 
Updated to account for the change in the number of subjects 
Analysis Set 
Description 
Randomized Set 
(RAN) 
All subjects who received a randomization number, regardless 
of receiving trial medication. Subjects will be analyzed 
according to the treatment assigned. 
Safety Set (SAF) 
All subjects who received the double-blind study drug. 
Subjects will be analyzed according to actual treatment 
received. 
Full Analysis Set 
(FAS) 
All subjects in RAN who were not mis randomizeda.with a 
valid Baseline HAM-A assessment and at least one valid 
post-baseline HAM-A assessment. Subjects will be 
analyzed according to the treatment assigned. Following 
the intent to treat (ITT) principle, subjects are analyzed 
according to the treatment they have been assigned to at the 
randomization. 
Per 
Protocol 
Set 
(PPS) 
All subjects in FAS who took the study medication andhad no 
major protocol deviations deemed as impacting the primary 
endpointa. Subjects will be analyzed according to the actual 
treatment received. 
a 
Mis randomized subjects are those who have not been qualified for 
randomization and who have been inadvertently randomized into the study but have 
not received double blind study drug. 
 
An impact assessment will be performed prior to the unblinding of the 
study. The impact assessment will determine whether a major protocol deviation 
impacts the primary endpoint thereby leading to the removal of the respective 
subject(s) from the PPS.Major protocol deviations are those affecting the primary 
endpoint analyses and will be finalized prior to unblinding treatment codes for 
analyses. 
10.2.1. Patient 
Demographics and 
Other Baseline 
Characteristics 
10.2.2.1 Primary 
Estimand  Step 1 
Removal of geographical area from analysis of demographics 
Summary statistics will be provided by treatment group for demographics and 
baseline characteristics, including sex at birth, self-identified gender, age, race, 
weight, height, BMI, systolic blood pressure, diastolic blood pressure, geographical 
region, medical history… 
The analysis to derive the test statistics is based on an analysis of covariance 
(ANCOVA) model with the change from Baseline to Week 4 for HAM-A Total 
Score as a response variable, treatment (placebo and all MM-120 doses), and 
Baseline value of HAM-A Total Score,  geographical region, 
10.2.2.1 Primary 
Estimand 
Added clarification of how the assessment of impact on the primary endpoint is 
conducted 
• 
Handling of IEs prior to HAM-A assessment at Week 4: 
- 
Intake or change in concomitant medications/therapies which have potential 
confounding effects per the impact assessment. 
- 
Intake of prohibited medications/therapies assessed as “Yes” per the impact 
assessment. 
 
Statistical 
Methods & Analysis 
Correction of typographical error 
• 
Sigmoid Emax (ED50, hill): 
 
10, 10 
 
100, 5 
 
100, 10 


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150, 10 
 
Step 2 
Clarification of analysis population for the primary and key secondary endpoints 
The MCP-Mod analysis will be performed on the PPS FAS population. It will also 
be performed on the PPS as a sensitivity analysis. 
Handling of 
Missing/Potentially 
Biased Values 
Clarifications related to impact assessment 
- 
For intake or change in concomitant medications/therapies that have potential 
confounding effects per the impact assessment; or 
- 
For intake of prohibited medications/therapies assessed as “Yes” per the 
impact assessment. 
10.2.2.2. Sample 
Size Determination 
Sponsor determination that 90% power was not necessary given the inherent power of 
the MCP-Mod analysis. 
A total sample of 200 180 subjects (40 36 per dose arm and 40 36 for the placebo 
arm) is required to ensure a mean power > 9087% for an MCP-Mod Analysis 
The analysis assumes 4 doses of active medication (25, 50, 100, and 200 µg freebase-
equivalent) and placebo. The required sample size for each dose arm is 40 36 
subjects. 
Table 9  Study 
MMED008 Power 
by Model 
Updated based on N of 180 plus correction of typographical error 
Sigmoid Emax (ED50, hill) 
 
Model 
Power (%) 
Sigmoid Emax (ED50, hill) 
 
10, 10 
84.593.2 
100, 5 
90.793.4 
100, 10 
91.087.9 
150, 10 
89.992.6 
Emax (D50 = 100) 
83.286.6 
Linear 
85.088.21 
10.2.2.4. Secondary 
Efficacy Endpoints 
Clarifications to analyses of Secondary Endpoint 
Change from Baseline to Week 1, Week 2 (as applicable), Week 4, Week 8 and End 
of Study (as applicable) in HAM-A, MADRS, CGI-S, CGI-I, PGI-S, PGI-C, SDS, EQ-
5D-5L, PSQI and ASEX will be analyzed descriptively. Continuous outcomes will be 
summarized reporting by dose: n, mean, standard deviation, median, Q1 (25th 
percentile), Q3 (75th percentile), minimum, maximum and 9095% Confidence Interval 
for the mean and for the median. For the active doses similar statistics will be reported 
for the difference from placebo. Categorical measures will be summarized by the 
number and percentage of subjects within each category. 
11.6. 
Safety 
Review 
New Section providing guidance related to safety review of blinded data 
The Sponsor’s Medical Monitor or designee will review blinded safety data 
listings monthly as detailed in the Medical Management Plan (MMP). Safety 
review meetings will review ongoing data for all subjects to identify trends in 
safety parameters. If necessary, the Sponsor will terminate the study if this 
blinded review process identifies significant intolerable safety signals based on 
either individual or aggregate blinded safety information that puts subjects in this 
study at unacceptable risk. 
Appendix 1 
Acceptable Highly 
Effective Methods 
of Contraception 
Correction of typographical error 
• 
Two barrier methods of contraception: condom or and occlusive cap (diaphragm 
or cervical/vault cap) with spermicide 
Appendix 3. Rescue 
Medications 
Clarifications that the study site physician will administer rescue medications 
Rescue medications should only be considered after other alternativesnon-medical 
interventions have been exhausted. Under all circumstances, only the study site-
designated physician will administer rescue medications in this study. The choice 


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of rescue medications are is at the discretion of the Investigatorstudy site 
designated-physician and should be based on subject medical history and local 
standard of care. 
The Investigatorstudy site-designated physician must consider rescue medications 
and if they have been associated with lengthening QTc interval, which can lead to 
syncope, arrhythmia or sudden cardiac arrest. 
 


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SPONSOR SIGNATURE PAGE 
Study Title: A Phase 2, Multi-center, Randomized, Double-Blind, Parallel-Group, Dose-
Finding Study to Assess the Effect of Four Doses of MM-120 for the Treatment of Anxiety 
Symptoms 
Protocol Number: MMED008 
 
This protocol has been approved by Mind Medicine, Inc. The following signatures document 
this approval. 
 
 
 
 
Chief Medical Officer 
 
Date 
 


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INVESTIGATOR STATEMENT 
● I confirm agreement to conduct the study in compliance with the protocol. 
● I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
● I agree to ensure that all associates, colleagues, and employees assisting in the 
conduct of the study understand their obligations and will comply with the study 
protocol. Mechanisms are in place to ensure that site staff receives the appropriate 
training and information throughout the study. 
● I acknowledge that I will be making the application for a DEA Schedule I Researcher 
Registration and be in compliance with all Federal and State laws and regulations. 
 
 
 
Principal Investigator Name (Printed) 
 
Signature 
 
 
 
Date 
 
Site 
 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Sponsor’s Address: 
Mind Medicine, Inc. 
One World Trade Center, Suite 8500 
New York, NY 10007 
Primary Sponsor 
Contact: 
 
Chief Medical Officer 
Mind Medicine, Inc. 
Email:
  
Phone: 
 
Primary Medical 
Monitor: 
 
Senior Medical Director, Clinical Research 
PPD, part of Thermo Fisher Scientific 
Email: 
  
Phone: 
 
Sponsor Medical 
Monitor: 
  
Director Clinical Development 
Mind Medicine, Inc.  
Email: 
  
Phone: 
 
Contact for Serious 
Adverse Events or 
Adverse Events (SAEs 
or AESIs): 
To report an SAE and/or AESI suggestive of abuse potential, 
please contact the 
 main Safety Management email / 
phone / fax (or your applicable country-specific toll-free 
numbers): 
 
Email (preferred method): 
 
 
Phone (back-up method): 
 
 
 
 
 


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TABLE OF CONTENTS 
SUMMARY OF CHANGES ....................................................................................... 2 
SPONSOR SIGNATURE PAGE ................................................................................ 8 
INVESTIGATOR STATEMENT ............................................................................... 9 
PROCEDURES IN CASE OF EMERGENCY ......................................................... 10 
TABLE OF CONTENTS ........................................................................................... 11 
LIST OF TABLES ..................................................................................................... 16 
LIST OF FIGURES ................................................................................................... 16 
LIST OF ABBREVIATIONS .................................................................................... 17 
1. 
SYNOPSIS ............................................................................................. 21 
Schedule of Activities ................................................................................................ 30 
2. 
INTRODUCTION .................................................................................. 33 
2.1. 
Background ............................................................................................. 33 
2.1.1. 
Disease Background and Unmet Need ................................................... 33 
2.1.2. 
Drug Background .................................................................................... 34 
2.2. 
Study Rationale ....................................................................................... 34 
2.2.1. 
Assessment of Efficacy in MMED008 ................................................... 35 
2.2.2. 
Study Population Considerations ............................................................ 36 
2.2.3. 
Summary ................................................................................................. 36 
2.3. 
Dose Rationale ........................................................................................ 37 
2.4. 
Benefit/Risk Assessment ........................................................................ 38 
3. 
OBJECTIVES AND ENDPOINTS ........................................................ 40 
4. 
INVESTIGATIONAL PLAN ................................................................. 42 
4.1. 
Overall Study Design .............................................................................. 42 
4.2. 
Number of Subjects ................................................................................ 44 
4.3. 
End of Study Definition .......................................................................... 44 
5. 
STUDY POPULATION ......................................................................... 45 
5.1. 
Eligibility ................................................................................................ 45 
5.1.1. 
Inclusion Criteria .................................................................................... 45 
5.1.2. 
Exclusion Criteria ................................................................................... 45 
5.2. 
Lifestyle Restrictions .............................................................................. 49 
5.2.1. 
Reproductive Concerns ........................................................................... 49 


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5.2.1.1. 
Additional Information for Female Subjects .......................................... 49 
5.2.1.2. 
Additional Information for Male Subjects .............................................. 50 
5.2.2. 
Nicotine Use ........................................................................................... 50 
5.2.3. 
Non-Medicinal Therapies ....................................................................... 50 
5.3. 
Screen Failures ........................................................................................ 50 
6. 
STUDY DRUG AND CONCOMITANT THERAPY ........................... 52 
6.1. 
Description of Study Drugs .................................................................... 52 
6.2. 
Directions for Administration of Study Drug ......................................... 52 
6.3. 
Randomization ........................................................................................ 52 
6.4. 
Blinding .................................................................................................. 53 
6.4.1. 
Unblinding .............................................................................................. 53 
6.5. 
Dose Modification .................................................................................. 53 
6.6. 
Encapsulation, Packaging and Labeling ................................................. 53 
6.7. 
Handling/Storage/Accountability ........................................................... 54 
6.8. 
Study Drug Compliance ......................................................................... 55 
6.9. 
Study Drug Overdose ............................................................................. 55 
6.10. 
Concomitant Therapies ........................................................................... 55 
6.10.1. 
Prohibited Medications, Supplements and Therapeutics ........................ 55 
 
 
6.10.3. 
Permitted Medications, Supplements and Therapeutics ......................... 58 
6.11. 
Treatment after the End of the Study ...................................................... 58 
7. 
WITHDRAWAL/DISCONTINUATION .............................................. 59 
7.1. 
Discontinuation of Study Drug ............................................................... 59 
7.2. 
Early Withdrawal from the Study ........................................................... 59 
7.3. 
Early Study Termination ......................................................................... 60 
8. 
STUDY ASSESSMENTS AND PROCEDURES .................................. 61 
8.1. 
Administrative Procedures ...................................................................... 61 
8.1.1. 
Informed Consent ................................................................................... 61 
8.1.1.1. 
Prescreen Informed Consent (Optional) ................................................. 61 
8.1.1.2. 
Main Informed Consent .......................................................................... 61 
8.1.1.3. 
Real World Evidence .............................................................................. 62 
8.1.2. 
Demographics ......................................................................................... 63 
8.1.3. 
Prescreen Assessment (Optional) ........................................................... 63 


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8.1.4. 
Eligibility Assessment ............................................................................ 63 
8.1.5. 
Medical/Psychiatric and Medication History ......................................... 64 
8.1.6. 
Medication Taper .................................................................................... 64 
8.1.7. 
Concomitant Medication Review/Collection ......................................... 65 
8.2. 
Clinical Procedures/Assessments ........................................................... 65 
8.2.1. 
Physical Examination ............................................................................. 66 
8.2.2. 
Neuropsychiatric Examination ............................................................... 66 
8.2.3. 
Vital Signs .............................................................................................. 66 
8.2.4. 
Weight ..................................................................................................... 67 
8.2.5. 
Height ..................................................................................................... 67 
8.2.6. 
Body Mass Index .................................................................................... 67 
8.2.7. 
Electrocardiogram ................................................................................... 67 
8.2.8. 
Adverse Event Collection ....................................................................... 67 
8.3. 
Laboratory Procedures/Assessments ...................................................... 68 
8.3.1. 
Biobanking (DNA) Sample .................................................................... 68 
8.3.2. 
Safety Laboratory Assessments and Urinalysis ...................................... 68 
 
 
8.3.4. 
Urine/Serum Pregnancy Tests ................................................................ 70 
8.4. 
Screening and Efficacy Questionnaires .................................................. 71 
8.4.1. 
Mini-International Neuropsychiatric Interview (MINI) ......................... 71 
8.4.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................... 72 
8.4.3. 
Hamilton Anxiety Rating Scale (HAM-A) ............................................. 72 
8.4.4. 
Montgomery-Åsberg Depression Rating Scale (MADRS) .................... 73 
8.4.5. 
Clinical Global Impression – Severity (CGI-S) and Clinical Global 
Impression – Improvement (CGI-I) ........................................................ 74 
8.4.6. 
Patient Global Impression – Severity (PGI-S) and Patient Global 
Impression – Change (PGI-C) ................................................................ 74 
8.4.7. 
Sheehan Disability Scale (SDS) ............................................................. 75 
8.4.8. 
EQ-5D-5L ............................................................................................... 75 
8.4.9. 
Pittsburgh Sleep Quality Index (PSQI) ................................................... 75 
8.4.10. 
Arizona Sexual Experiences Questionnaire (ASEX) ............................. 76 
8.4.11. 
Placebo Response Reduction .................................................................. 76 
8.5. 
Other Patient-Reported Outcomes .......................................................... 76 


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8.5.1. 
Drug Effect VAS .................................................................................... 77 
8.5.2. 
Mystical Experience Questionnaire (MEQ30) ....................................... 77 
8.5.3. 
5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC)
 ................................................................................................................ 77 
8.5.4. 
Treatment Assignment/Blinding Question ............................................. 78 
8.6. 
Dosing Day Activities ............................................................................. 78 
8.6.1. 
Study Drug Dosing ................................................................................. 78 
8.6.2. 
Subject Education / Follow-up Session with Dosing Session Monitors . 79 
8.6.3. 
Subject Observation by Dosing Session Monitors ................................. 79 
8.6.4. 
Subject Release on Dosing Day/ Dosing Release Checklist .................. 79 
9. 
SAFETY CONSIDERATIONS .............................................................. 81 
9.1. 
Definition of an Adverse Event .............................................................. 81 
9.2. 
Definition of a Serious Adverse Event ................................................... 81 
9.3. 
Adverse Events of Special Interest ......................................................... 82 
9.4. 
Adverse Event Detecting and Reporting ................................................ 83 
9.4.1. 
Period for Reporting Adverse Events ..................................................... 84 
9.4.2. 
Reporting Serious Adverse Events and Adverse Events of Special 
Interest Suggestive of Abuse Potential ................................................... 84 
9.5. 
Study Drug Overdose Management ........................................................ 85 
9.6. 
Assigning Causal Relationship to Study Drug ....................................... 85 
9.7. 
Assigning Severity Rating for Adverse Events ...................................... 86 
9.8. 
Urgent Safety Measures .......................................................................... 87 
9.9. 
Special Situations .................................................................................... 87 
9.10. 
Reporting of Pregnancy to the Sponsor .................................................. 88 
10. 
STATISTICAL CONSIDERATIONS ................................................... 89 
10.1. 
Analysis Sets ........................................................................................... 89 
10.2. 
Statistical Analyses ................................................................................. 89 
10.2.1. 
Patient Demographics and Other Baseline Characteristics .................... 89 
10.2.2. 
Efficacy Analyses ................................................................................... 90 
10.2.2.1. 
Primary Estimand ................................................................................... 90 
10.2.2.2. 
Sample Size Determination .................................................................... 93 
10.2.2.3. 
Key Secondary Efficacy Endpoints ........................................................ 94 
10.2.2.4. 
Secondary Efficacy Endpoints ................................................................ 94 


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10.2.3. 
Safety Analyses ...................................................................................... 94 
10.2.3.1. 
Adverse Events ....................................................................................... 94 
10.2.3.2. 
Other Safety Parameters ......................................................................... 95 
10.2.4. 
Other Analyses ........................................................................................ 95 
10.2.4.1. 
Treatments .............................................................................................. 95 
10.2.5. 
Interim Analyses ..................................................................................... 95 
11. 
STUDY GOVERNANCE CONSIDERATIONS ................................... 96 
11.1. 
Financial Disclosure ............................................................................... 96 
11.2. 
Pre-Initiation Visit .................................................................................. 96 
11.3. 
Data Management ................................................................................... 96 
11.4. 
Monitoring .............................................................................................. 96 
11.5. 
Auditing or Inspections ........................................................................... 97 
11.6. 
Safety Review ......................................................................................... 97 
11.7. 
Protocol Modifications ........................................................................... 97 
11.8. 
Study Discontinuation ............................................................................ 98 
11.9. 
Publications ............................................................................................. 98 
11.10. 
Investigator-Specific Responsibilities .................................................... 98 
11.10.1. 
Compliance with Regulations and Ethical Standards ............................. 98 
11.10.2. 
Protocol Compliance .............................................................................. 98 
11.10.3. 
Institutional Review Board/Independent Ethics Committee Requirements
 ................................................................................................................ 99 
11.10.4. 
Obtaining Informed Consent .................................................................. 99 
11.10.5. 
Confidentiality ...................................................................................... 100 
11.10.6. 
Study Files and Retention of Records .................................................. 100 
11.10.7. 
Electronic Case Report Forms .............................................................. 101 
11.10.8. 
Monitoring of Study Drug Accountability ........................................... 101 
11.11. 
Sponsor-Specific Responsibilities ........................................................ 102 
11.11.1. 
Study Report ......................................................................................... 102 
11.11.2. 
Posting of Information on Publicly Available Clinical Trial Registers 102 
REFERENCES ........................................................................................................ 103 
APPENDIX 1. DEFINITION OF WOMEN OF CHILDBEARING POTENTIAL 
AND ACCEPTABLE HIGHLY EFFECTIVE METHODS OF 
CONTRACEPTION ............................................................................. 110 


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APPENDIX 2. CYP2D6 INHIBITORS ................................................................ 112 
APPENDIX 3. RESCUE MEDICATIONS .......................................................... 113 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ............................................................. 10 
Table 2: 
MMED008 Schedule of Activities ......................................................... 30 
Table 3: 
Rationale for Selected MM-120 Doses................................................... 37 
Table 4: 
MMED008 Study Drugs ......................................................................... 52 
Table 5: 
Listing of Prohibited Medications, Supplements and Other Therapies .. 57 
Table 6: 
Required Laboratory Analytes ................................................................ 69 
Table 7: 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute Common Terminology 
Criteria for Adverse Events .................................................................... 86 
Table 8: 
MMED008 Analysis Sets ....................................................................... 89 
Table 9: 
Study MMED008 Power by Model ........................................................ 94 
Table 10: Examples of Rescue Benzodiazepines: Dosing .................................... 113 
Table 11: Examples of Rescue Neuroleptics: Dosing ........................................... 114 
Table 12: Examples of Medications for Nausea ................................................... 114 
 
LIST OF FIGURES 
Figure 1: 
MMED008 Study Schematic .................................................................. 44 
Figure 2: 
Candidate Dose-response Curves ........................................................... 92 
 


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LIST OF ABBREVIATIONS 
Term 
Description 
5D-ASC 
5-Dimensional Altered States of Consciousness Rating Scale 
5-HTP 
5 hydroxytryptophan 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ASEX 
Arizona Sexual Experiences Questionnaire 
AST 
aspartate aminotransferase 
AV 
atrioventricular 
BMI 
body mass index 
BP 
blood pressure 
CBD 
cannabidiol 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CIS 
carcinoma in situ 
COVID-19 
coronavirus disease 2019 
C-SSRS 
Columbia-Suicidality Severity Rating Scale 
C-SSRS – SLV 
Columbia-Suicide Severity Rating Scale – Since Last Visit 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBS 
deep brain stimulation 
DEA 
Drug Enforcement Agency 
DMT 
dimethyltryptamine 
DSM 
Dosing Session Monitor 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECT 
electroconvulsive therapy 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOS 
End of Study 
EQ-5D-5L 
EuroQol-5 Dimentions-5 Levels 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration (United States) 
FSH 
follicle-stimulating hormone 
GABA 
gamma-aminobutyric acid 


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Term 
Description 
GAD 
generalized anxiety disorder 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GRAS 
generally recognized as safe 
HAM-A 
Hamilton Anxiety Rating Scale 
HCRU 
health-care resource utilization 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IE 
intercurrent event 
IEC 
Institutional Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
IWRS 
integrated web response system 
LDL 
low-density lipoprotein 
LS 
least-squares 
LSD 
D-lysergic acid diethylamide 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MAOI 
monoamine oxidase inhibitor 
MAR 
Missing at Random 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCP 
multiple comparisons procedure 
MCP-Mod 
Multiple Comparison Procedure-Modelling 
MCV 
mean corpuscular volume 
MDMA 
3,4-methylenedioxymethamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEQ30 
Mystical Experience Questionnaire 
MI 
myocardial infarction 
MINI 
Mini-International Neuropsychiatric Interview 
MM-120 
Mind Medicine, Inc. compound code for D-lysergic acid diethylamide D-tartrate 
MMP 
Medical Management Plan 
MNAR 
Missing Not at Random 
MPV 
mean platelet volume 


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Term 
Description 
NCI 
National Cancer Institute 
NDA 
new drug application 
AESI 
adverse events of special interest 
PGI 
Patient Global Impression 
PGI-C 
Patient Global Impression – Change 
PGI-S 
Patient Global Impression – Severity 
PIND 
pre-investigational new drug (application) 
PPS 
Per Protocol Set 
PRO 
patient-reported outcome 
PSQI 
Pittsburgh Sleep Quality Index 
Q1 
25th percentile 
Q3 
75th percentile 
QTcF 
QT interval corrected using Fridericia’s formula 
RAN 
Randomized Analysis Set 
RDW 
red cell distribution width 
SAE 
serious adverse event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SDS 
Sheehan Disability Scale 
SNDRI 
serotonin–norepinephrine–dopamine reuptake inhibitor 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SRC 
Safety Review Committee 
SSRI 
selective serotonin reuptake inhibitor 
T4 
thyroxine 
TCA 
tricyclic antidepressant 
TdP 
Torsades de pointes 
THC 
tetrahydrocannabinol 
TIA 
transient ischemic attack 
TMS 
transcranial magnetic stimulation 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States (of America) 
VAS 
visual analogue scale 
VNS 
vagus nerve stimulation 
WD 
withdrawal 
WHO 
World Health Organization 


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Term 
Description 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
WOCBP 
women of childbearing potential 
β-HCG 
beta human chorionic gonadotropin 


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1. 
SYNOPSIS 
Study Title 
A Phase 2, Multi-center, Randomized, Double-Blind, Parallel-Group, Dose-
Finding Study to Assess the Effect of Four Doses of MM-120 for the 
Treatment of Anxiety Symptoms 
Protocol Number 
MMED008 
Study Center 
Location(s) 
United States 
Number of Study 
Centers Planned 
Approximately 20 
Study Phase 
2 
Target Population 
Adults with clinically significant symptoms of anxiety (as defined by a 
Hamilton Anxiety Rating Scale [HAM-A] Total Score of 20 or greater) who 
meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
(DSM-5) criteria for generalized anxiety disorder (GAD) 
Number of 
Subjects Planned 
Approximately 180 
Study Objectives 
Primary Objectives 
• To determine the dose-response signal and assess the dose-response 
relationship of 4 doses of MM-120 (25, 50, 100, or 200 µg freebase-
equivalent) as measured by the change in HAM-A Total Score from 
Baseline to Week 4 
 
Key Secondary Objective 
• To determine the dose-response signal and assess the dose-response 
relationship of 4 doses of MM-120 (25, 50, 100, or 200 µg freebase-
equivalent) as measured by the change in HAM-A Total Score from 
Baseline to Week 8 
 
Secondary Objectives 
• To determine the dose-response signal and assess the dose-response 
relationship of 4 doses of MM-120 (25, 50, 100, or 200 µg freebase-
equivalent) as measured by the change in HAM-A Total Score from 
Baseline to End of Study 
• To determine whether MM-120 (25, 50, 100, or 200 µg freebase-
equivalent) improves functionality and quality of life measures in subjects 
with anxiety symptoms, including improvements in the following: 
o Depressive symptoms 
o Anxiety symptoms 
o Functional disability 
o Quality of life 
o Sleep 
o Sexual function 


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Safety Objective 
• To assess the safety and tolerability of MM-120 (25, 50, 100, or 200 µg 
freebase-equivalent) after oral administration in subjects with anxiety 
symptoms 
Study Design 
This is a Phase 2, multi-center, randomized, double-blind, parallel-group, 
dose-finding study to assess the effect of 4 doses of MM-120 (25, 50, 100, or 
200 µg freebase-equivalent) for the treatment of anxiety symptoms in subjects 
diagnosed with GAD. 
The study will enroll approximately 180 male and female subjects 18 years to 
< 75 years of age at Screening who meet DSM-5 criteria for GAD and have a 
minimum HAM-A Total Score of 20. Potential subjects who have 
contraindicated medical or psychiatric conditions or who are taking 
concomitant medications, supplements or other therapeutics that are 
contraindicated (e.g., due to drug-drug interaction potential, or anxiolytic or 
antidepressant function) that cannot be paused will be excluded from the 
study. Subjects on contraindicated concomitant medications, supplements or 
other therapeutics at Screening (Visit 1) will undergo a medication taper prior 
to advancing to Baseline (Visit 2); for subjects on prescribed medications to 
treat anxiety, depression or other mood disorders, the medication taper will be 
overseen by a psychiatrist based on acceptable local practice standards. 
Potential study subjects who provide informed consent will have eligibility 
evaluated/confirmed at 3 visits: 1) Screening (Visit 1); 2) Baseline (Visit 2), 
and 3) Day 1/Randomization (Visit 3A). To streamline eligibility 
determinations, sites also have the option of implementing a ‘Prescreen’ prior 
to Visit 1. 
Randomization will occur following the final assessment of eligibility on 
Day 1/Randomization (Visit 3A). Eligible subjects will be randomized in a 
1:1:1:1:1 ratio to receive a single dose of either investigational drug (25, 50, 
100 or 200 µg MM-120 freebase-equivalent) or placebo in a controlled 
clinical setting, which will be administered during the Dosing Session 
(Visit 3B) on Day 1. 
Prior to Day 1/Randomization & Dosing Session (Visits 3A & 3B), subjects 
will be given preparatory education about the planned intervention. 
Throughout the Dosing Session (Visit 3B) on Day 1, subjects will be 
supported by a team of appropriately trained and qualified Dosing Session 
Monitors who will be in the room with the subject at all times. A site-
designated licensed physician will be available or on call and be able to reach 
the clinical site within 15 minutes in the event of a physiological or 
psychiatric emergency; events requiring intervention should be discussed with 
the Sponsor as soon as the situation permits, but implementation of the 
intervention should not be delayed. The Subject Education and Safety 
Management Framework for this study is included in the Dosing Session 
Monitor Manual, which provides detailed information for education prior to 
Day 1/Dosing Session (Visit 3B), Dosing Session safety monitoring and 
management procedures, Dosing Session Monitor qualifications, and 
requirements that must be met in order to release the subject from the clinic at 
the end of the Dosing Session (Visit 3B). 


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After Day 1/Randomization & Dosing Session (Visits 3A & 3B), subjects will 
have scheduled visits on Day 2 (Visit 4), Week 1 (Visit 5), Week 2 (Visit 6), 
Week 4 (Visit 7), Week 8 (Visit 8) and Week 12 (Visit 9). 
Eligibility Criteria 
Inclusion Criteria 
1. Age ≥ 18 to < 75 years at Screening (Visit 1) 
2. Body weight of ≥ 50 kg 
3. Body mass index [BMI] ≥ 18 to ≤ 38 mg/kg2 
4. Diagnosis of DSM-5 generalized anxiety disorder based upon clinical 
assessment and confirmed by the Mini-International Neuropsychiatric 
Interview (MINI) 
5. HAM-A Total Score ≥ 20 at Screening (Visit 1) and Baseline (Visit 2) 
6. Ability and willingness to provide written, informed consent prior to 
initiation of any study-related procedures and to adhere to all study 
requirements 
NOTE: The subject (i.e., not a legally authorized representative) must be 
cognitively able to understand the requirements of the study and provide 
the informed consent. 
7. Acceptable overall medical condition to be safely enrolled into and to 
complete the study, at the discretion of the Investigator 
8. Ability to swallow capsules 
 
Exclusion Criteria 
1. Women of childbearing potential (WOCBP) (persons physiologically 
capable of becoming pregnant) who are unwilling or unable to use a 
highly effective method of contraception, as defined in Appendix 1, for 
the duration of the study, OR 
Men physiologically capable of fathering a child who are sexually active 
with WOCBP but are unwilling or unable to use barrier contraception 
(e.g., condom with or without spermicidal cream or jelly) for the duration 
of the study  
NOTE: See Appendix 1 for definitions of WOCBP and highly effective 
methods of contraception and for information about unacceptable 
methods of contraception. 
NOTE: Abstinence is not considered an acceptable form of birth control 
for WOCBP. 
2. Women who are currently pregnant or breastfeeding or plan to become 
pregnant or breastfeed during the study 
3. Sperm or egg donation during the study 
4. Prior history (lifetime diagnosis) or known first-degree relative 
(i.e., mother/father/full siblings) with a lifetime diagnosis of 
schizophrenia spectrum, or other psychotic disorders or bipolar disorder 
(bipolar I, bipolar II or cyclothymic disorder) 
5. Lifetime diagnosis of Posttraumatic Stress Disorder 


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6. Other current psychiatric disorders that, in the opinion of the Investigator, 
may confound the results of the study (e.g., major depressive disorder, 
obsessive-compulsive disorder, dysthymic disorder, panic disorder, 
dissociative disorder, anorexia nervosa or bulimia nervosa) 
7. Current untreated clinically significant sleep disorder that, in the opinion 
of the Investigator, may confound the results of the study 
(e.g., obstructive sleep apnea, narcolepsy) 
8. Significant loss of hearing or vision that, in the opinion of the 
Investigator, may confound the results of the study or interfere with the 
ability of Dosing Session Monitor(s) or other site staff to provide 
adequate oversight to the subject during the Day 1/Dosing Session 
(Visit 3B) 
9. History of alcohol or substance use disorder within 
 prior to 
Screening (Visit 1) (includes diagnosis of alcohol or drug use disorder per 
the MINI) 
NOTE: Current use or a history of use of nicotine-containing products is 
not excluded.  
10. 
 
 
 
 
 
 
11. 
 
 
 
 
 
 
 
12. Greater than 
 
including microdosing. Any instance of psychedelic use in the 
 
 including microdosing (including use as part of a clinical trial) 
13. History of illicit substance use in the past 
 
of any illicit substance (does not include cannabis)  
- 
Illicit drug use includes any use of cocaine, crack, heroin/ opioids, or 
methamphetamine. This does not include misuse of over the counter 
drugs.   
14. History of ketamine use including: ketamine therapy within the 
 
before screening (including as part of a clinical trial); illicit use of 
ketamine 
; or use of ketamine for treatment 
of an excluded condition (see exclusion criteria #4, #5, #6)  


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15. 
 
 
 
 
 
 
 
 
 
 
16. Current use at Baseline (Visit 2) or Day 1/Randomization (Visit 3A) of 
any prescribed psychotropic medication 
Note: See Section 6.10 for details of prohibited concomitant medications, 
supplements and other therapeutics and allowable conditions of use. 
17. Unwillingness or inability to discontinue prohibited concomitant 
medications, supplements or other therapeutics (prescription or over-the-
counter) 
Note: See Section 6.10 for details of prohibited concomitant medications, 
supplements and other therapeutics and allowable conditions of use; see 
Section 8.1.6 for information on medication tapering. 
18. Any form of medicinal therapy should be 
 to 
screening with no plan to start, stop or alter the use of any prescribed 
medications, supplements or other therapeutics from Baseline (Visit 2) 
until End of Study 
Note: See Section 6.10 for details of prohibited concomitant medications, 
supplements and other therapeutics and allowable conditions of use. 
Exclusion does not apply to medications that need to be tapered for 
inclusion in the study and reference is to achieving and maintaining a 
steady state 
19. Any form of non-medicinal therapy should be 
 to 
screening with no plan to start, stop or alter the use of psychotherapy, 
acupuncture, hypnosis, or other similar therapy from the time of 
providing informed consent until End of Study 
20. Plan to start, stop or alter the use of nicotine-containing products from the 
time of providing informed consent until End of Study 
NOTE: Current use or a history of use of nicotine-containing products is 
not excluded.  
21. Treatment with deep brain stimulation (DBS), vagus nerve stimulation 
(VNS), electroconvulsive therapy (ECT) or transcranial magnetic 
stimulation (TMS) within 3 months prior to Screening (Visit 1) or a plan 
to receive treatment with any of these from the time of providing 
informed consent until End of Study 
22. Acute infection and/or antibiotic treatment within 30 days prior to 
Baseline 


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23. Any chronic infection, including human immunodeficiency virus (HIV), 
hepatitis B, or hepatitis C, unless the subject is asymptomatic and is 
expected to remain asymptomatic during the study and, in the opinion of 
the Investigator, the infection is unlikely to confound the results of the 
study 
24. Has had a major trauma or surgery in the 3 months prior to Screening 
(Visit 1) or any time between Screening and Day 1/Randomization 
(Visit 3A), has surgery scheduled to occur during the study or has had 
open biopsy within 3 months prior to Screening (Visit 1) 
25. History of malignancy or treatment of malignancy within 2 years prior to 
Screening (Visit 1) (excluding resected basal cell or squamous cell 
carcinoma of the skin or carcinoma in situ [CIS] cervix that has been 
resolved without further treatment) 
26. Any of the following cardiovascular conditions or findings: 
a. Hemodynamically significant uncorrected cardiac valve disease or 
hypertrophic/restrictive cardiomyopathy 
b. Any cardiovascular event requiring hospitalization within 12 months 
prior to Screening (Visit 1) (e.g., stroke, myocardial infarction [MI]) 
c. A diagnosis of congenital or long QT syndrome, or personal history of 
syncope or family history of arrhythmia, a first degree relative with 
sudden or unexplained death at a young age (under 40 years). 
d. History of uncorrected life-threatening arrhythmia or any unstable 
rhythm, ventricular, supraventricular or atrial arrhythmia with a rapid 
rate, unless treated with a reliable measure to prevent recurrence 
(e.g., implantable cardioverter defibrillator or catheter ablation), including 
second- or third-degree atrioventricular (AV) block or sinus node disease 
if not successfully treated with a pacemaker or ablation 
e. History of cardiovascular disease, including but not limited to coronary 
artery disease, cardiac hypertrophy, cardiac ischemia, congestive heart 
failure, myocardial infarction (within 1 year prior to Screening [Visit 1]), 
angina pectoris (within 1 year prior to Screening [Visit 1]), coronary 
artery bypass graft or artificial heart valve (within 1 year prior to 
Screening [Visit 1]), stroke, transient ischemic attack (TIA) or any other 
clinically significant arrhythmia 
f. Uncontrolled hypertension  
g. Blood pressure (BP) outside the range of 90-140 mmHg systolic BP or 
50-90 mmHg diastolic BP after an approximately 5 minutes of rest. 
NOTE: If the first measurement of a subject’s BP is outside the allowable 
range, a second recording is allowed after an additional approximately 
5 minutes rest. 
h. Heart rate < 45 beats/minute or > 90 beats/minute after an 
approximately 5-minute rest at Screening and Baseline 
NOTE: If the first measurement of a subject’s heart rate is outside the 
allowable range, a second recording is allowed after an additional 
approximately 5 minutes rest. 


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i. Orthostatic hypotension at Screening (Visit 1) or Baseline (Visit 2), 
defined as a decrease of more than 20 mmHg in systolic BP or 10 mmHg 
in diastolic BP, or both, following a change from a supine position to a 
standing position (measured within 1 to 3 minutes of standing); or 
orthostatic intolerance (e.g., developing symptoms upon standing). 
NOTE: If the first measurement of a subject’s change in BP exceeds the 
allowable decrease, a second recording is allowed after an additional 
approximately 5-minute supine rest. 
j. Any clinically significant abnormal electrocardiogram (ECG) finding 
(e.g., atrial fibrillation) at Screening (Visit 1) or Baseline (Visit 2), as 
determined by the Investigator or study site designated physician or, if 
needed, in consultation with a cardiologist. 
k. Resting QT interval corrected using Fridericia’s formula (QTcF) 
≥ 450 msec (male) or ≥ 460 msec (female) at Baseline (Visit 2) or 
inability to determine QTcF 
l. Presence of risk factors for Torsades de pointes (TdP), including long 
QT syndrome, uncontrolled hypokalemia or hypomagnesemia, history of 
cardiac failure, history of clinically significant/symptomatic bradycardia, 
family history of idiopathic sudden death or congenital long QT 
syndrome, or concomitant use of a torsadogenic medication that cannot 
be discontinued prior to Baseline (Visit 2) 
27. Have evidence of clinically significant hepatic disorder (e.g., alanine 
aminotransferase [ALT] or aspartate aminotransferase [AST] > 2.0x 
upper limit of normal [ULN]) 
28. Moderate-to-severe renal impairment, indicated by an estimated 
glomerular filtration rate (eGFR) of < 50 mL/min/1.73 m2 at Screening 
(Visit 1), based on the Cockroft-Gault formula 
29. Use of any other investigational drugs, devices, therapies or other 
advanced therapies that, in the opinion of the Investigator, may confound 
the study results (e.g., stem cell transplantation, gene therapy) within 
30 days prior to Screening (Visit 1). Participation in observational trials 
must be approved by the Sponsor. 
30. Presence or history of neurological (e.g., seizures except febrile resolved 
before age 5) or psychiatric disorder(s) or any illness (including clinically 
significant diseases of the renal, hepatic, gastrointestinal, cardiovascular 
or musculoskeletal system or clinically significant immunological, 
endocrine, or metabolic diseases) that, in the opinion of the Investigator, 
may pose additional risk to the subject from participation in the study or 
may confound the results of the study 
31. Any other condition, therapy, laboratory abnormality, or other 
circumstance that, in the opinion of the Investigator, may pose additional 
risk to the subject from participation in the study, may interfere with the 
subject’s ability to comply with study procedures, may make participation 
in the study not in the subject’s best interest or may confound the results 
of the study 


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32. Prior history or ongoing neuropsychiatric signs or symptoms associated 
with COVID-19 such as development of, or current disorder, during or 
after a covid infection including anxiety, memory loss, confusion, 
depression, delirium, agitation, or psychosis 
33. 
 
 
Study Treatment 
Subjects will be randomized 1:1:1:1:1 to receive a single dose of one of the 
following blinded treatments: 
• 25 µg (freebase-equivalent) of MM-120 (n ≈ 36) 
• 50 µg (freebase-equivalent) of MM-120 (n ≈ 36) 
• 100 µg (freebase-equivalent) of MM-120 (n ≈ 36) 
• 200 µg (freebase-equivalent) of MM-120 (n ≈ 36) 
• Placebo (n ≈ 36) 
All treatments will be administered orally. All subjects will receive a total of 
8 capsules (combination of capsules containing MM-120 and/or placebo 
capsules, depending on their randomized dose), which are to be taken 
together as the subject’s single dose of study drug. 
Duration of 
Treatment 
Subjects will receive a single dose of study drug during the trial. 
The trial duration will be up to approximately 17 weeks, over the following 
study periods: Screening Period, lasting up to 30 days; Baseline & Dosing 
Period, lasting up to 5 days; and Follow-Up Period, lasting approximately 12 
weeks. There are 9 scheduled in-clinic visits across these 3 study periods. 
The total duration of the study conduct (first subject first visit to last subject 
last visit) is expected to be approximately 18 months. 
Endpoints/ 
Outcome Measures 
Primary Endpoint 
• Change in HAM-A Total Score from Baseline to Week 4 
Key Secondary Endpoint 
• Change in HAM-A Total Score from Baseline to Week 8 


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Secondary Endpoints 
• Change in HAM-A Total Score from Baseline to End of Study 
• Change from Baseline to Week 1, Week 2 (where applicable), Week 4, 
Week 8, and End of Study in score for the following measures: 
o Montgomery-Åsberg Depression Rating Scale (MADRS) 
o Clinical Global Impression – Severity (CGI-S) Scale 
o Clinical Global Impression – Improvement (CGI-I) Scale 
o Patient Global Impression – Severity (PGI-S) Scale 
o Patient Global Impression – Change (PGI-C) Scale 
o Sheehan Disability Scale (SDS) 
o EuroQol-5 Dimentions-5 Levels (EQ-5D-5L) 
o Pittsburgh Sleep Quality Index (PSQI) 
o Arizona Sexual Experiences Questionnaire (ASEX) 
Safety Endpoints 
Safety will be evaluated based on the following measure/assessments: 
• Adverse events 
• Vital signs (heart rate, blood pressure, respiration rate, temperature) 
• 12-lead safety ECG 
• Physical examination 
• C-SSRS 
• Safety laboratory evaluation 
Statistical Methods 
This study will utilize the Multiple Comparison Procedure-Modelling (MCP-
Mod) approach to analyze the primary outcome measure (Bretz 2005, 
Pinheiro 2014). The MCP-Mod is a hybrid approach that combines 
hypothesis testing and modeling in a structured manner to analyze Phase 2 
dose-finding studies to find suitable dose(s) for confirmatory Phase 3 trials. 
A total sample of 180 subjects (36 per dose arm and 36 for the placebo arm) 
is required to ensure a mean power > 87% for an MCP-Mod analysis rejecting 
the hypothesis of a constant dose-response curve using the multiple 
comparisons procedure (MCP), assuming a null placebo response, a 
maximum standardized effect of 0.6 within the doses range, and a common 
standard deviation within the dose arms, if a study-wise one-sided type-1 
error rate < 0.05 is required. The analysis assumes 4 doses of active 
medication (MM-120 25, 50, 100, and 200 µg freebase-equivalent) and 
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2. 
INTRODUCTION 
2.1. 
Background 
Mind Medicine, Inc. is developing D-lysergic acid diethylamide (LSD) D-tartrate (MM-120) 
for the treatment of anxiety symptoms. MM-120 / LSD is a synthetic tryptamine belonging to 
the group of classic, or serotonergic, hallucinogens (“psychedelics”). 
There is an extensive body of literature on the nonclinical pharmacology/toxicology, clinical 
safety and efficacy and clinical pharmacology of LSD. LSD has previously been administered 
to hundreds of human subjects in recently conducted (i.e., since 2008) controlled clinical trials. 
These trials have demonstrated that LSD has an attractive safety profile and have provided 
preliminary evidence of efficacy in the target patient population when administered in 
controlled settings. 
2.1.1. 
Disease Background and Unmet Need 
There is a high unmet need to find new treatment options for patients with clinically significant 
anxiety, and it is an active area of research. Patients with anxiety disorders often experience 
substantial physical and emotional discomfort, functional impairment and reduced work 
productivity (Erickson 2009; Waghorn 2005), as well as increased rates of substance use and 
medical illnesses (Kariuki-Nyuthe & Stein 2015). With a 12-month prevalence rate of 18% in 
the United States (US), anxiety disorders are the most common psychiatric disorders, and there 
remains a significant need for novel treatments (Kessler 2005). Indeed, the course of anxiety 
disorders is often relapsing and chronic, with most patients remaining symptomatic decades 
after their initial diagnosis (Kessler 2001). The chronic and disabling nature of anxiety 
disorders is associated with substantial economic and social costs related to premature 
mortality, 
unemployment 
and 
reduced 
productivity 
(Bandelow & Michaelis 2015; 
Issakidis & Andrews 2004). 
There are a number of medications approved to treat generalized anxiety disorder (GAD) – the 
target patient population for this study – but for many patients, they have unfavorable side 
effect profiles, contraindications or are ineffective. Withdrawal symptoms and undesirable 
adverse effects, including insomnia, nausea, nervousness and sexual dysfunction are common 
with long‐term use of these agents (Gartlehner 2011). A meta-analysis of 21 placebo-
controlled GAD trials from the world literature observed only modest treatment benefit from 
active medications: overall effect size (Cohen’s d) = 0.39 (Hidalgo 2007). For adults with 
GAD, comparative effect sizes of the different agents were as follows: 0.5 for pregabalin, 0.45 
for antihistamines, 0.42 for serotonin-norepinephrine reuptake inhibitors (SNRIs), 0.38 for 
benzodiazepines, 0.36 for selective serotonin reuptake inhibitors (SSRIs) and 0.17 for 
azapirones (buspirone). The practice of treating GAD patients with antidepressant treatments 
is fairly common, likely because patients with anxiety frequently have concurrent depressive 
symptoms. Gamma-aminobutyric acid (GABA) agonists, sedative-hypnotic drugs and 
antipsychotics have also been used off label for relief of insomnia or other common symptoms 
of anxiety disorders, but these drugs provide only symptomatic relief instead of disease 
modification. 


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2.1.2. 
Drug Background 
LSD is a prototypical classic hallucinogen (reviewed in Nichols 2004; Passie 2008). The 
administration of LSD to humans was first reported in 1943 by Albert Hofmann 
(Hofmann 1979), after which Sandoz manufactured LSD (Delysid®) and distributed it for 
experimental use (Sessa 2011). In the 1950s to 1970s, LSD was initially used as an 
experimental tool to study psychotic-like states and model psychosis (“psychotomimetic”) 
(Bercel 1956; Koelle 1958) and as an adjunct in “psycholytic (substance-assisted) 
psychotherapy”. LSD became one of the best studied substances with several thousands of 
early scientific reports (reviewed in Hintzen & Passie 2010; Nichols 2004; Nichols 2016; 
Passie 2008). LSD has also been investigated for the treatment of alcoholism 
(Krebs & Johansen 2012), addiction (Savage 1973), anxiety associated with terminal illness 
(Gasser 2014; Grof 1973; Pahnke 1969), depression (Passie 2008) and different manifestations 
of headache (Schindler 2015; Sewell 2006). 
Although regulatory restrictions implemented in the 1970s limited its distribution and led to a 
dearth of clinical research, the use of LSD for personal and recreational purposes continued. 
Among US residents, an estimated 32 million and 23 million people, respectively, reported 
using a hallucinogen and LSD at least once in their lifetime, based on data from a 2010 US 
population survey of individuals aged 12 years and older (Krebs & Johansen 2013a). Another 
report – based on 2015 results of repeated ongoing cross-sectional surveys of high school 
graduating classes since 1976 – estimated the adjusted lifetime usage of hallucinogens to range 
from 12-21% for younger groups (ages 21-30 years) and 26-30% for older groups (ages 35-50 
years); in the same study, prevalence of LSD use was also reported for the younger age groups, 
which had an adjusted lifetime usage ranging from 8-10% (Johnston 2016). In Europe, the 
estimated prevalence for lifetime usage of LSD is lower than the US and varies by country, 
with most countries reporting a prevalence in the range of 1-5%, both among young adults (age 
15-34 years) and all adults (age 15-64 years) (EMCDDA 2021). Thus, a significant proportion 
of the western society is familiar with the effects of hallucinogens, including LSD. 
LSD is not associated with compulsive drug seeking (addiction), and there are relatively few 
medical emergencies and adverse effect (Nichols 2016). Use of LSD or psilocybin is not 
associated with mental health problems and may even be protective (Johansen & Krebs 2015; 
Krebs & Johansen 2013b). In a safe setting, no drug-related severe adverse effects have been 
observed after administration of LSD in healthy participants (Carhart-Harris 2015; Carhart-
Harris 2016a; Dolder 2016; Gasser 2014; Schmid 2015). Beginning in 2008, the medical value 
of classic serotonergic hallucinogens has again been studied in several clinical trials 
(Baumeister 2014; 
Bogenschutz 2015; 
Davenport 2016; 
Gasser 2014; 
Gasser 2015; 
Grob 2011; Johnson 2014; Johnson 2017; Kupferschmidt 2014). 
2.2. 
Study Rationale 
Although there are a number of medications approved to treat anxiety disorders, for many 
patients, as noted in Section 2.1, anxiolytics (and antidepressants, which are sometimes 
prescribed off label for anxiety) may have unfavorable side effect profiles, contraindications 
or are ineffective. Thus, there remains a significant need for novel therapeutic approaches in 
treating anxiety disorders. 


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Classic serotonergic psychedelics such as LSD and psilocybin have shown promise in treating 
anxiety and depression (Carhart-Harris 2016b; Gasser 2014; Griffiths 2016; Grob 2011; 
Ross 2016). The potential clinical utility of LSD is complemented by a relatively safe 
physiologically profile  that is further enhanced by the fact that a single administration may 
have both rapid-acting and long-lasting clinical effect.  
Restrictions on LSD distribution and its subsequent illegalization led to a dearth of clinical 
research of LSD; however, following a four-decade hiatus, there has been a recent resurgence 
in clinical research studies of LSD. In the period since 2008, 12 clinical trials enrolling more 
than 200 subjects have been conducted investigating the safety, pharmacodynamics, 
pharmacokinetics and clinical activity of LSD. Evidence from both legacy and modern 
investigator-initiated studies support the safe use of LSD in controlled clinical settings, and 
preliminary evidence suggests a potential for clinical benefit in a variety of target indications 
and patient populations, including anxiety disorders. Robust clinical trial data are needed to 
confirm the clinical utility of LSD in treating anxiety disorders. 
Given that there are many patients with anxiety disorders, including GAD, who do not reach 
their treatment goals with currently approved therapies, there remains an unmet need for new 
GAD therapies with a favorable safety, tolerability and efficacy profile. This randomized, 
double-blind, placebo-controlled study is designed to evaluate the safety, tolerability and 
efficacy of 4 doses of MM-120 compared to placebo in subjects with GAD. Specifically, it will 
examine the impact of single-dose treatment with MM-120 on anxiety symptoms as well as on 
other measures of function and quality of life. 
2.2.1. 
Assessment of Efficacy in MMED008 
The primary outcome measure for this study is the Hamilton Anxiety Rating Scale (HAM-A); 
a validated anxiety rating scale that has been used extensively in clinical trials (including 
numerous FDA registration trials) to assess anxiety symptoms across a range of psychiatric 
diagnoses (Ansseau 1996; Constantin 2020; Greiner 2020; Stein 2015; Stein 2018). It has been 
widely used as the standard primary outcome in randomized controlled trials as an indicator of 
the effectiveness of pharmacological and psychologic interventions against anxiety in a variety 
of patient populations (Alaka 2014; Goodman 2005; Hartford 2007; Rynn 2008). The change 
in HAM-A score from baseline to post-treatment was used as the primary efficacy endpoint 
supporting approval of venlafaxine, paroxetine, escitalopram and duloxetine. 
The HAM-A has been used as a standard reliable and valid tool for measuring treatment 
response in clinical trials with an indication of generalized anxiety disorder (GAD). 
Specifically, studies have shown that the HAM-A has inter-rater reliability (measured by 
interclass correlation) ranging from 0.74-0.98, as well as appropriate test-retest reliability 
(interclass correlation = 0.86) and validity (against the Covi Anxiety Scale, Spearman 
correlation = 0.63) (Bruss 1994; Maier 1988). 
Based on the myriad of patient populations that are sensitive to the HAM-A, the long history 
of use in new drug application enabling clinical trials and established validity, the HAM-A 
scale is fit-for-purpose to assess anxiety symptoms in subjects with GAD. 


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2.2.2. 
Study Population Considerations 
Eligibility for this study is based in part on a minimum HAM-A Total Score of 20. This is to 
target enrollment to a population of subjects who have significant anxiety that is sensitive to 
measurement by the HAM-A. A HAM-A Total Score of 17 and above has been consistently 
used as a cut-off for inclusion in clinical trials for GAD medications (Allgulander 2004; 
Lenze 2005; Llorca 2002; Rickels 2003; Sheehan & Sheehan 2008; Wan 2006). Additionally, 
to ensure that only subjects with relatively stable anxiety severity are enrolled, the HAM-A is 
completed at Screening (Visit 1) and Baseline (Visit 2) and the Total Score from both 
assessments must be at least 20 points; this exclusion criterion will help prevent enrolling 
subjects with transient anxiety related to daily stressors. These measures together will ensure 
that the study population consists of subjects with clinically significant anxiety that is sensitive 
to measurement by the HAM-A. 
The sensitivity of the HAM-A to changes in the target patient population and disorder is also 
supported by results from past studies of other investigational drugs of the psychedelic drug 
class. In particular, Griffiths and colleagues found significant reductions in HAM-A scores 
following administration of psilocybin in cancer patients with distress (diagnoses included 
adjustment disorders, MDD, GAD and others) (Griffiths 2016). Following a single high dose 
of psilocybin, HAM-A scores in this study decreased from 25.73 (SD: 1.11) to 8.48 (1.16) at 
approximately 5 weeks post-dose, a reduction of approximately 67%. 
The primary endpoint for the current study is change in HAM-A Total Score from Baseline to 
Week 4. Preliminary evidence suggests that LSD (along with other psychedelic therapies such 
as psilocybin) are rapid-acting, and that acute responses to treatment are predictive of 
intermediate and longer-term outcomes (Gasser 2014; Griffiths 2016; Ross 2016). To assess 
the durability of effect, the key secondary endpoint of change in HAM-A Total Score from 
Baseline to Week 8 will be used. 
Bonson et al. found that chronic administration of antidepressants – including serotonergic 
antidepressants, monoamine oxidase inhibitors (MAOIs) and lithium – substantially attenuated 
the subjective effects of self-administered LSD, as evaluated using a standardized 
questionnaire (Bonson 1996a; Bonson & Murphy 1996b). Thus, in this study, subjects will be 
required to taper off any prohibited anxiolytics, antidepressants or other medications, 
supplements or therapeutics used to treat anxiety, depression or other mood disorders prior to 
randomization into the study. 
2.2.3. 
Summary 
The use of LSD for anxiety in prior studies has yielded encouraging safety, tolerability and 
efficacious results. However, additional data from randomized, controlled clinical trials are 
needed. Given that there are GAD patients who do not reach their treatment goals with 
currently approved therapies, there remains an unmet need for new therapeutic approaches 
with favorable safety, tolerability, and efficacy profiles. The current study is designed to 
provide new data on the use of LSD in the treatment of anxiety symptoms in subjects with 
GAD. 


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2.3. 
Dose Rationale 
Based on literature review, LSD has been safely administered in over 1000 subjects in studies 
with various levels of control and at doses up to 800 µg, including more than 200 subjects 
across 12 trials conducted since 2008. To date, however, full interrogation of the dose-response 
curve for LSD has not been established, and no prior dose-finding study has been completed 
for MM-120. The doses of 25, 50, 100 and 200 µg MM-120 (freebase-equivalent) used in the 
current study have been selected based on preliminary evidence of safety and clinical effect 
from prior, published studies of LSD. Dose increases from 100 µg to 200 µg have been 
associated with an increase in “bad drug effect” while not resulting in increased “overall or 
good drug effect” (Holze 2021a), but doses within this range (and above) have been 
demonstrated to be safe. 
The minimal recognizable (“threshold”) dose of LSD in humans (i.e., the dose at which 
psychoactive effects are perceivable by patients on average) is reported to be approximately 
10-25 µg (Bershad 2019; Holze 2021b; Hutten 2020) and doses above 50-75 µg typically 
produce an altered state of consciousness (including enhanced capacity for introspection, 
altered psychological functioning and perceptual changes such as illusions, pseudo-
hallucinations, synesthesia and alterations of thinking and time experience) (Holze, 2020; 
Holze 2021a; Passie 2008). Under supportive supervised conditions (i.e., appropriate set and 
setting) and at doses up to 200 µg LSD freebase-equivalent, adverse drug reactions were 
typically mild and resolved within a day. Transient anxiety, short-lived headaches, nausea and 
mild increases in heart rate and blood pressure were the most commonly reported adverse 
events (AEs). 
The 4 individual dose levels of MM-120 in the current study have been selected to assess both: 
1) the dose-response relationship over a wide dose range that has been previously shown to be 
safe in clinical trials; and 2) the functional mechanism of action, specifically the extent to 
which psychedelic effects mediate clinical outcomes. The rationale for each dose level is 
provided in Table 3. 
Table 3: 
Rationale for Selected MM-120 Doses 
Dose 
of MM-120 
(µg) 
(Freebase-equivalent) 
Rationale 
0 
Placebo control – an inactive placebo is the most appropriate control for the 
Multiple Comparison Procedure-Modelling (MCP-Mod) statistical approach to 
be used in the current study and for characterization of dose-response 
25 
Threshold dose – minimum dose at which psychoactive effects are perceivable 
by patients on average 
50 
Dose that is above threshold but unlikely to result in significant “psychedelic 
effects” 
100 
Lower of two doses that reliably results in a “psychedelic effect” while 
minimizing “bad drug effect” 
200 
Higher of two doses that reliably results in a “psychedelic effect” 
Thus, the 4 doses of MM-120 administered in the current study are expected to have a dose-
dependent response. Based on historical data in other patient populations, higher doses are 
expected to be associated with perceptual alterations including visual and auditory disturbances 


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(including hallucinations), emotional volatility and a dose-dependent autonomic stimulation 
(transient tachycardia, hypertension and pupillary dilation). The autonomic effects of LSD are 
typically mild and transient and rarely require intervention. The Sponsor concluded that no 
further dose increase beyond 200 µg (freebase-equivalent) would be required for predicted 
changes on HAM-A. 
2.4. 
Benefit/Risk Assessment 
Clinical data on the use of LSD in patients with anxiety disorder are limited. This is the first 
trial of oral MM-120, currently in development, in subjects with GAD, and thus, its safety 
profile for this patient population is unknown. Although to date there are no completed clinical 
trials with oral MM-120, expected safety signals of perceptual and autonomic effects may be 
detected and are considered as potential risks for oral MM-120 use. 
The pharmacologic and toxicologic effects of LSD in various animal species has been 
extensively studied; published reports support the conclusion that LSD has a relatively benign 
safety profile (refer to the MM-120 Investigator’s Brochure for details of nonclinical study 
findings). Monkeys (M. mulatta) have been injected with intravenous (IV) doses as high as 
1 mg/kg without any lasting somatic effects (Evarts 1956). Although dose at first signs of 
toxicity is difficult to determine from the published literature, signs of toxicity described were 
at high mg/kg exposures in animal species whereas the current study uses µg doses (200 µg 
freebase-equivalent is the highest dose evaluated in the current study). The clinical relevance 
of these findings from the animal literature is not known. 
Available human findings from historical published literature suggest that MM-120 or its 
active metabolites are not likely to cause clinically significant perceptual or physical adverse 
effects in a controlled clinical trial setting. LSD has been safely administered in controlled 
clinical trials to over 1000 persons aged 18-75 years, in doses ranging 5-800 µg. The most 
common adverse effects of LSD administration include visual and auditory disturbances 
(including hallucinations), emotional volatility and autonomic stimulation (transient 
tachycardia, hypertension and pupillary dilation). The autonomic effects of LSD are typically 
mild and transient and rarely require intervention. Physiological adverse reactions to LSD have 
been reported in common media in instances of illicit use outside of a controlled clinical 
setting; however, in a controlled clinical setting, adequate screening procedures, patient 
monitoring and psychological intervention (when warranted) have resulted in a low incidence 
of physiological AEs. Rare instances of serious adverse reactions (psychosis and seizure) have 
been reportedly precipitated by use of LSD in a clinical setting, but in these cases, the subjects 
had one or more pre-existing diagnoses or risk factors. 
LSD is not associated with dependence. Hallucinogens are not self-administered by animals, 
and there is no human LSD dependence syndrome (Passie 2008). Patients with current 
substance use or a history 
 
 of other illicit substances are not included in 
the study. 
Most available clinical research data on the use of LSD for relief of anxiety symptoms has 
been in the context of anxiety associated with life-threatening illness (Gasser 2014; Grof 1973; 
Pahnke 1969). However, findings from these studies have showed positive trends in reducing 


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anxiety, including the observation in one study of sustained benefits at a 12-month follow-up 
after finishing LSD psychotherapy (Gasser 2015). Subjects with GAD participating in this 
study may benefit from improvements to their well-being and functional ability. 
Multiple procedures have been included in this study to enhance subject safety. Subjects will 
undergo repeated eligibility assessments at Screening (Visit 1), Baseline (Visit 2), and prior to 
dosing on Day 1 (Visit 3A) to ensure the subject is fit to receive study drug. Additionally, 
based on the pharmacological profile of LSD, which includes alterations of perception and 
consciousness and the potential for development of acute anxiety, subjects will be continuously 
monitored during the Dosing Session for psychological and physiological well-being. Two 
Dosing Session Monitors will support the subject, and subjects will be under their observation 
at all times during the Dosing Session (either both in the session room, or one in the session 
room and one via live remote monitoring on site in a separate room). Additionally, based on 
the known autonomic effects of MM-120, serial measurement of vital signs (heart rate and 
blood pressure) will be collected throughout the Dosing Session. A detailed Dosing Session 
Monitor Manual and Participant Education Session Manual has been developed to provide 
subjects across clinical sites with consistent education about what to expect and consistent, 
continual monitoring during the Dosing Session. 
Overall, the benefit-risk profile of LSD at doses up to 200 µg (freebase-equivalent) is favorable 
and supports development based on its prior safe clinical use in over 1000 subjects, well-
characterized pharmacokinetics, pharmacodynamics and manageable transient physiological 
and psychological effects. Inclusion of the 4 planned doses in this Phase 2 dose-finding study 
(see Section 2.3) will enable optimal dose selection for Phase 3 clinical trials, aid in 
interpretation of study results in the context of potential functional unblinding and will enable 
further characterization of the mechanism of action of MM-120 (i.e., whether psychedelic 
effects are necessary for clinical benefit). 
Refer to the MM-120 Investigator’s Brochure for additional risk-benefit information. 


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3. 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS/OUTCOME MEASURES 
Primary 
• To determine the dose-response signal and 
assess the dose-response relationship of 
4 doses of MM-120 (25, 50, 100, or 200 µg 
freebase-equivalent) as measured by the 
change in HAM-A Total Score from 
Baseline to Week 4 
• Change in HAM-A Total Score from 
Baseline to Week 4 
Key Secondary 
• To determine the dose-response signal and 
assess the dose-response relationship of 
4 doses of MM-120 (25, 50, 100, or 200 µg 
freebase-equivalent) as measured by the 
change in HAM-A Total Score from 
Baseline to Week 8 
• Change in HAM-A Total Score from 
Baseline to Week 8 
Secondary 
• To determine the dose-response signal and 
assess the dose-response relationship of 
4 doses of MM-120 (25, 50, 100, or 200 µg 
freebase-equivalent) as measured by the 
change in HAM-A Total Score from 
Baseline to End of Study 
• Change in HAM-A Total Score from 
Baseline to End of Study 
• To determine whether MM-120 (25, 50, 
100, or 200 µg freebase-equivalent) 
improves functionality and quality of life 
measures in subjects with anxiety 
symptoms, including improvements in the 
following: 
• Change from Baseline to Week 1, Week 2 
(where applicable), Week 4, Week 8, and 
End of Study in score for the following 
measures: 
o Depressive symptoms 
o MADRS 
o Anxiety symptoms 
o CGI-S 
o CGI-I 
o PGI-S 
o PGI-C 
o Functional disability 
o SDS 
o Quality of life 
o EQ-5D-5L 
o Sleep 
o PSQI 
o Sexual function 
o ASEX 


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OBJECTIVES 
ENDPOINTS/OUTCOME MEASURES 
Safety 
• To assess the safety and tolerability of MM-
120 (25, 50, 100, or 200 µg freebase-
equivalent) after oral administration in 
subjects with anxiety symptoms 
• Adverse events 
• Vital signs (heart rate, blood pressure, 
respiration rate, temperature) 
• 12-lead safety ECG 
• Physical examination 
• C-SSRS 
• Safety laboratory evaluation 
Exploratory 
• To assess response and remission across the 
4 doses of MM-120 (25, 50, 100, or 200 µg 
freebase-equivalent) as measured by the 
change in HAM-A from Baseline to End of 
Study 
• HAM-A response (defined as ≥50% 
reduction in HAM-A Total Score) from 
Baseline to Weeks 1, 2, 4, 8, and End of 
Study.  
• HAM-A remission (defined as HAM-A 
Total Score of ≤7) at Weeks 1, 2, 4, 8, and 
End of Study 
• To explore dose response on drug effects, 
altered perception and mystical experience 
• Score at Day 2 on the following 
questionnaires: 
o Drug Effect VAS 
o MEQ30 
o 5D-ASC 
• To explore the effect of MM-120 on direct 
and indirect health-care resource utilization 
(HCRU) and associated costs 
• For later pharmacoeconomic analysis, the 
use of healthcare resources 
 
• To explore whether genetic polymorphisms 
are related to pharmacodynamics 
• Pharmacogenomic sample 
• To assess blind integrity and to examine 
whether guess rates are associated with 
outcomes such as AEs or mood/anxiety 
symptoms 
• Score at Day 2 on Treatment 
Assignment/Blinding Question 
 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a Phase 2 multi-center, randomized, double-blind, placebo-controlled, parallel-group, 
dose-finding clinical study that will assess the effect of 4 doses of MM-120 (25, 50, 100 or 
200 µg freebase-equivalent) in comparison to placebo on anxiety symptoms in subjects 
diagnosed with GAD. 
The study will enroll approximately 180 male and female subjects 18 years to < 75 years of 
age at Screening who meet DSM-5 criteria for GAD and have a minimum HAM-A Total Score 
of 20. Potential subjects who have contraindicated medical or psychiatric conditions or who 
are taking concomitant medications, supplements or other therapeutics that are contraindicated 
(e.g., due to drug-drug interaction potential, or anxiolytic or antidepressant function) that 
cannot be paused will be excluded from the study. Subjects on contraindicated concomitant 
medications, supplements or other therapeutics at Screening (Visit 1) will undergo a 
medication taper prior to advancing to Baseline (Visit 2); for subjects on prescribed 
medications to treat anxiety, depression or other mood disorders, the medication taper will be 
overseen by the study site designated physician based on acceptable local practice standards. 
Prescreening of potential study subjects to determine initial eligibility is a common strategy in 
the recruitment process. Sites will be provided with an IRB approved prescreening template 
which must be IRB approved for subjects to provide consent. The Prescreen process will 
determine if they are excluded based on the eligibility criteria before proceeding further. The 
Prescreening option is being offered to reduce unnecessary burdens on sites and potential study 
subjects and to further assess the subject’s eligibility. 
Potential study subjects who provide informed consent beyond the Prescreen stage will have 
eligibility evaluated/confirmed at 3 visits: 1) Screening (Visit 1); 2) Baseline (Visit 2), and 
3) Day 1/Randomization (Visit 3A). Randomization will occur following the final assessment 
of eligibility on Day 1/Randomization (Visit 3A). Eligible subjects will be randomized in a 
1:1:1:1:1 ratio to receive a single dose of either investigational drug (25, 50, 100 or 200 µg 
MM-120 freebase-equivalent) or placebo in a controlled clinical setting, which will be 
administered during the Dosing Session (Visit 3B) on Day 1. 
Prior to Day 1/Randomization & Dosing Session (Visits 3A & 3B), subjects will be given 
preparatory education about the planned intervention. 
Throughout the Dosing Session (Visit 3B) on Day 1, subjects will be supported by a team of 
appropriately trained and qualified Dosing Session Monitors. There will be two qualified 
monitors monitoring the subject at all times, and a site-designated licensed physician must be 
available or on call and be able to reach the clinical site within 15 minutes in the event of a 
physiological or psychiatric emergency; events requiring intervention should be discussed with 
the Sponsor as soon as the situation permits, but implementation of the intervention should not 
be delayed. The Participant Education Session Manual for this study is included in the Dosing 
Session Monitor Manual, which provides detailed information for education prior to 
Day 1/Dosing Session (Visit 3B), Dosing Session safety monitoring and management 


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procedures, Dosing Session Monitor qualifications, and requirements that must be met in order 
to release the subject from the clinic at the end of the Dosing Session (Visit 3B). 
At least one of the Dosing Session Monitors will be identified and qualified to serve as a ‘lead 
monitor.’ The lead monitor must be a licensed healthcare provider with graduate-level 
professional training and clinical experience. The lead monitor must be actively licensed to 
practice independently in the state of the study site location. Lead monitor acceptable 
professional credentials are as follows: Clinical or counseling psychologist (PhD or PsyD); 
Psychiatrist or other physician (MD or DO); Master Level Clinician, such as Licensed Clinical 
Social Worker (LCSW), Licensed Clinical Professional Counselor (LCPC), Licensed Marriage 
and Family Therapist (LMFT), or local state equivalent; Advanced Nurse Practitioner 
(NP/APRN) such as a Psychiatric Nurse Practitioner or local state equivalent.   
The secondary monitor must have a bachelor’s degree and at least one year of clinical 
experience in a mental health care setting. One of the DSMs must be appropriately trained to 
monitor vital signs and administer the C-SSRS. A site-designated licensed physician with 
prescribing rights or a qualified designee may serve as the backup to either DSM if short breaks 
are needed. This licensed physician must meet the criteria to be a lead monitor if they plan to 
step in as back up dosing session monitor to alleviate the lead or secondary monitor. 
After Day 1/Randomization & Dosing Session (Visits 3A & 3B), subjects will have scheduled 
visits on Day 2 (Visit 4), Week 1 (Visit 5), Week 2 (Visit 6), Week 4 (Visit 7), Week 8 
(Visit 8) and Week 12 (Visit 9). In the event that a subject withdraws early from the study (i.e., 
prior to Week 12), they should return to the clinic to complete an Early Withdrawal visit (same 
assessments/procedures as Week 12 [Visit 9]) or if the subject is at the site at the time of early 
withdrawal, all applicable activities scheduled for the final study visit should be performed at 
the time of discontinuation. 
At Week 4 (the study’s primary endpoint), the efficacy of MM-120 in treating anxiety 
symptoms will be evaluated as the change from Baseline in the HAM-A Total Score. HAM-A 
and several additional questionnaires will be administered throughout the study, as outlined in 
the Schedule of Activities (Table 2), to further evaluate efficacy and/or the subjects’ 
experiences taking study drug. 
Subjects will be assessed for safety and tolerability throughout the study by monitoring the 
type, frequency, and severity of AEs, vital signs, ECG findings, and clinical laboratory 
assessments. 
Figure 1 presents the design schema, and the study procedures/assessments at each visit are 
outlined in the Schedule of Activities (Table 2). 


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Figure 1: 
MMED008 Study Schematic 
 
EOS = End of Study; HAM-A = The Hamilton Anxiety Rating Scale 
Note: Doses of MM-120 are freebase-equivalent. 
 
4.2. 
Number of Subjects 
The target sample size for this study is approximately 180 subjects. 
4.3. 
End of Study Definition 
End of Study is defined as the date when the last subject has either completed the last study 
visit, has discontinued from the study, or is lost to follow-up (i.e., the site/Investigator is unable 
to contact the subject). 


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5. 
STUDY POPULATION 
5.1. 
Eligibility 
5.1.1. 
Inclusion Criteria 
An individual will be eligible for participation in this study only if all the following inclusion 
criteria are met: 
1. Age ≥ 18 to < 75 years at Screening (Visit 1) 
2. Body weight of ≥ 50 kg 
3. Body mass index [BMI] ≥ 18 to ≤ 38 mg/kg2 
4. Diagnosis of DSM-5 generalized anxiety disorder based upon clinical assessment and 
confirmed by the Mini-International Neuropsychiatric Interview (MINI) 
5. HAM-A Total Score ≥ 20 at Screening (Visit 1) and Baseline (Visit 2) 
6. Ability and willingness to provide written, informed consent prior to initiation of any 
study-related 
procedures 
and 
to 
adhere 
to 
all 
study 
requirements 
NOTE: The subject (i.e., not a legally authorized representative) must be cognitively able 
to understand the requirements of the study and provide the informed consent. 
7. Acceptable overall medical condition to be safely enrolled into and to complete the study, 
at the discretion of the Investigator 
8. Ability to swallow capsules 
5.1.2. 
Exclusion Criteria 
An individual will be excluded from participation in this study if any of the following exclusion 
criteria apply: 
1. Women of childbearing potential (WOCBP) (persons physiologically capable of becoming 
pregnant) who are unwilling or unable to use a highly effective method of contraception, 
as 
defined 
in 
Appendix 1, 
for 
the 
duration 
of 
the 
study, 
OR 
Men physiologically capable of fathering a child who are sexually active with WOCBP but 
are unwilling or unable to use barrier contraception (e.g., condom with or without 
spermicidal 
cream 
or 
jelly) 
for 
the 
duration 
of 
the 
study  
NOTE: See Appendix 1 for definitions of WOCBP and highly effective methods of 
contraception and for information about unacceptable methods of contraception. 
NOTE: Abstinence is not considered an acceptable form of birth control for WOCBP. 
2. Women who are currently pregnant or breastfeeding or plan to become pregnant or 
breastfeed during the study 
3. Sperm or egg donation during the study 
4. Prior history (lifetime diagnosis) or known first-degree relative (i.e., mother/father/full 
siblings) with a lifetime diagnosis of schizophrenia spectrum, or other psychotic disorder 
or bipolar disorder (bipolar I, bipolar II or cyclothymic disorder) 
5. Lifetime diagnosis of Posttraumatic Stress Disorder 
6. Other current psychiatric disorders that, in the opinion of the Investigator, may confound 
the results of the study (e.g., major depressive disorder, obsessive-compulsive disorder, 


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dysthymic disorder, panic disorder, dissociative disorder, anorexia nervosa or bulimia 
nervosa) 
7. Current untreated clinically significant sleep disorder that, in the opinion of the 
Investigator, may confound the results of the study (e.g., obstructive sleep apnea, 
narcolepsy) 
8. Significant loss of hearing or vision that, in the opinion of the Investigator, may confound 
the results of the study or interfere with the ability of Dosing Session Monitor(s) or other 
site staff to provide adequate oversight to the subject during the Day 1/Dosing Session 
(Visit 3B) 
9. History of alcohol or substance use disorder within 12 months prior to Screening (Visit 1) 
(includes 
diagnosis 
of 
alcohol 
or 
drug 
use 
disorder 
per 
the 
MINI)  
NOTE: Current use or a history of use of nicotine-containing products is not excluded.  
10. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12. Greater than 
 of psychedelics use in the 
, including microdosing.  
Any instance of psychedelic use including microdosing in the 
 (including use 
as part of a clinical trial). 
13. History of illicit substance use in the 
 
  
 
 
   
14. History of ketamine use including: ketamine therapy within the 
 before 
screening (including as part of a clinical trial); illicit use of ketamine 
 
; or use of ketamine for treatment of an excluded condition (see exclusion criteria 
#4, #5, #6)  
15. 
 
 
 
 
 
 
 
 
 


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16. Current use at Baseline (Visit 2) or Day 1/Randomization (Visit 3A) of any prescribed 
psychotropic medication 
Note: See Section 6.10 for details of prohibited concomitant medications, supplements and 
other therapeutics and allowable conditions of use. 
17. Unwillingness or inability to discontinue prohibited concomitant medications, 
supplements or other therapeutics (prescription or over-the-counter) 
Note: See Section 6.10 for details of prohibited concomitant medications, supplements 
and other therapeutics and allowable conditions of use; see Section 8.1.6 for information 
on medication tapering. 
18. Any form of medicinal therapy 
 to screening with no plan 
to start, stop or alter the use of any prescribed medications, supplements, or other 
therapeutics from Baseline (Visit 2) until End of Study. Note: See Section 6.10 for details 
of prohibited concomitant medications, supplements and other therapeutics and 
allowable conditions of use. Exclusion does not apply to medications that need to be 
tapered for inclusion in the study and reference is to achieving and maintaining a steady 
state. 
19. Any form of non-medicinal therapy should be 
 to Screening with no 
plan to start, stop, or alter the use of psychotherapy, acupuncture, hypnosis, or other similar 
therapy from the time of providing informed consent until the End of Study 
20. Plan to start, stop or alter the use of nicotine-containing products from the time of 
providing informed consent until End of Study 
NOTE: Current use or a history of use of nicotine-containing products is not excluded. 
21. Treatment with deep brain stimulation (DBS), vagus nerve stimulation (VNS), 
electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) within 3 
months prior to Screening (Visit 1) or a plan to receive treatment with any of these from 
the time of providing informed consent until End of Study 
22. Acute infection and/or antibiotic treatment within 30 days prior to Baseline 
23. Any chronic infection, including human immunodeficiency virus (HIV), hepatitis B, or 
hepatitis C, unless the subject is asymptomatic and is expected to remain asymptomatic 
during the study and, in the opinion of the Investigator, the infection is unlikely to confound 
the results of the study 
24. Has had a major trauma or surgery in the 3 months prior to Screening (Visit 1) or any time 
between Screening and Day 1/Randomization (Visit 3A), has surgery scheduled to occur 
during the study or has had open biopsy within 3 months prior to Screening (Visit 1) 
25. History of malignancy or treatment of malignancy within 2 years prior to Screening 
(Visit 1) (excluding resected basal cell or squamous cell carcinoma of the skin or 
carcinoma in situ [CIS] cervix that has been resolved without further treatment) 
26. Any of the following cardiovascular conditions or findings: 
a. Hemodynamically 
significant 
uncorrected 
cardiac 
valve 
disease 
or 
hypertrophic/restrictive cardiomyopathy 
b. Any cardiovascular event requiring hospitalization within 12 months prior to Screening 
(Visit 1) (e.g., stroke, myocardial infarction [MI]) 
c. A diagnosis of congenital or long QT syndrome, or personal history of syncope or 
family history of arrhythmia, a first degree relative with sudden or unexplained death 
at a young age (under 40 years). 


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d. History of uncorrected life-threatening arrhythmia or any unstable rhythm, ventricular, 
supraventricular or atrial arrhythmia with a rapid rate, unless treated with a reliable 
measure to prevent recurrence (e.g., implantable cardioverter defibrillator or catheter 
ablation), including second- or third-degree atrioventricular (AV) block or sinus node 
disease if not successfully treated with a pacemaker or ablation 
e. History of cardiovascular disease, including but not limited to coronary artery disease, 
cardiac hypertrophy, cardiac ischemia, congestive heart failure, myocardial infarction 
(within 1 year prior to Screening [Visit 1]), angina pectoris (within 1 year prior to 
Screening [Visit 1]), coronary artery bypass graft or artificial heart valve (within 1 year 
prior to Screening [Visit 1]), stroke, transient ischemic attack (TIA) or any other 
clinically significant arrhythmia 
f. Uncontrolled hypertension 
g. Blood pressure (BP) outside the range of 90-140 mmHg systolic BP or 50-90 mmHg 
diastolic BP after an approximately 5 minutes of rest 
NOTE: If the first measurement of a subject’s BP is outside the allowable range, a 
second recording is allowed after an additional approximately 5 minutes rest. 
h. Heart rate <45 beats/minute or >90 beats/minute after an approximately 5-minute 
supine rest at Screening and Baseline 
NOTE: If the first measurement of a subject’s heart rate is outside the allowable range, a 
second recording is allowed after an additional approximately 5 minutes rest. 
i. Orthostatic hypotension at Screening (Visit 1) or Baseline (Visit 2), defined as a 
decrease of more than 20 mmHg in systolic BP or 10 mmHg in diastolic BP, or both, 
following a change from a supine position to a standing position (measured within 
1 to 3 minutes of standing); or orthostatic intolerance (e.g., developing symptoms upon 
standing). 
NOTE: If the first measurement of a subject’s change in BP exceeds the allowable 
decrease, a second recording is allowed after an additional approximately 5-minute 
supine rest. 
j. Any clinically significant abnormal electrocardiogram (ECG) finding (e.g., atrial 
fibrillation) at Screening (Visit 1) or Baseline (Visit 2), as determined by the 
Investigator or study site designated physician or, if needed, in consultation with a 
cardiologist 
k. Resting QT interval corrected using Fridericia’s formula (QTcF) ≥ 450 msec (male) or 
≥ 460 msec (female) at Baseline (Visit 2) or inability to determine QTcF 
l. Presence of risk factors for Torsades de pointes (TdP), including long QT syndrome, 
uncontrolled hypokalemia or hypomagnesemia, history of cardiac failure, history of 
clinically significant/symptomatic bradycardia, family history of idiopathic sudden 
death or congenital long QT syndrome, or concomitant use of a torsadogenic 
medication that cannot be discontinued prior to Baseline (Visit 2) 
27. Have evidence of clinically significant hepatic disorder (e.g., alanine aminotransferase 
[ALT] or aspartate aminotransferase [AST] >2.0x upper limit of normal [ULN]) 
28. Moderate-to-severe renal impairment, indicated by an estimated glomerular filtration rate 
(eGFR) of < 50 mL/min/1.73 m2 at Screening (Visit 1), based on the Cockroft-Gault 
formula 


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29. Use of any other investigational drugs, devices, therapies or other advanced therapies that, 
in the opinion of the Investigator, may confound the study results (e.g., stem cell 
transplantation, gene therapy) within 30 days prior to Screening (Visit 1). Participation in 
observational trials must be approved by the Sponsor. 
30. Presence or history of neurological (e.g., seizures except febrile resolved before age 5) or 
psychiatric disorder(s) or any illness (including clinically significant diseases of the renal, 
hepatic, gastrointestinal, cardiovascular or musculoskeletal system or clinically significant 
immunological, endocrine, or metabolic diseases) that, in the opinion of the Investigator, 
may pose additional risk to the subject from participation in the study or may confound the 
results of the study 
31. Any other condition, therapy, laboratory abnormality, or other circumstance that, in the 
opinion of the Investigator, may pose additional risk to the subject from participation in 
the study, may interfere with the subject’s ability to comply with study procedures, may 
make participation in the study not in the subject’s best interest or may confound the results 
of the study 
32. Prior history or ongoing neuropsychiatric signs or symptoms associated with COVID-19 
such as development of, or current disorder, during or after a covid infection including 
anxiety, memory loss, confusion, depression, delirium, agitation, or psychosis 
33. 
 
 
5.2. 
Lifestyle Restrictions 
5.2.1. 
Reproductive Concerns 
There are mixed results from preclinical studies evaluating reproductive toxicity, chromosomal 
aberration and mutagenic studies (refer to the MM-120 Investigator’s Brochure for details). 
Thus, to participate in this study, women of childbearing potential (WOCBP) (i.e., 
physiologically capable of becoming pregnant) must agree to use a highly effective method of 
contraception for the duration of the study, and non-sterilized men who are sexually active 
with a WOCBP must agree to use barrier contraception (e.g., condom with or without 
spermicidal cream or jelly). Subjects who do not agree to these conditions are not eligible to 
participate in the study.  
Appendix 1 provides definitions of WOCBP, and highly effective methods of contraception as 
well as information about unacceptable methods of contraception. Subjects will be provided 
with information on methods of contraception as part of the informed consent process and by 
signing the consent form confirm that they understand the requirements for avoidance of 
pregnancy in the subject or the subject’s sexual partner during the course of the study. 
5.2.1.1. 
Additional Information for Female Subjects 
WOCBP may participate in the study only if they have a negative urine pregnancy test result 
at Screening [Visit 1] and Day 1/Randomization [Visit 3A]), and a non-positive serum 
pregnancy test on Baseline [Visit 2], (see Section 8.3.4). 
Subjects who are planning to donate eggs during the study period are excluded. If a subject is 
capable of producing egg and withdraws early from the study, they should be advised not to 


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donate eggs for at least 30 days after they received the single dose of study drug at 
Day 1/Dosing Session (Visit 3B). 
Subjects who are currently or planning to become pregnant or breastfeed during the study 
period are excluded. If a subject who is physiological capable of becoming pregnant withdraws 
early from the study, they should be advised to continue use of a highly effective method of 
birth control for at least 30 days after they received the single dose of study drug at 
Day 1/Dosing Session (Visit 3B). 
Because this is a single-dose study, if a subject becomes pregnant after Day 1/Dosing Session 
(Visit 3B), they are not required to withdraw from the study. The subject will be monitored for 
the outcome of the pregnancy, and reporting will occur as described in Section 9.10. 
5.2.1.2. 
Additional Information for Male Subjects 
Male subjects defined as subjects capable of producing sperm should be encouraged to advise 
any person of childbearing potential who are their sexual partners to use a highly effective 
method of contraception in addition to the subject’s use of barrier contraception. A female 
condom and male condom should not be used together. 
Subjects who are planning to donate sperm during the study period are excluded. If a subject 
is capable of producing sperm and withdraws early from the study, they should be advised not 
to donate sperm for at least 30 days after they received the single dose of study drug at 
Day 1/Dosing Session (Visit 3B). Additionally, male subjects who withdrawal early from the 
study should continue use of barrier contraception for a minimum of 30 days.  
5.2.2. 
Nicotine Use 
As changes in the consumption of nicotine may impact anxiety symptoms and/or mood, 
subjects should avoid starting, stopping or altering the use of these products from the time of 
providing informed consent until the End of Study. Due to the length of Day 1/Dosing Session, 
subjects are not permitted to smoke cigarettes/vape during the dosing session. Due to the 
possibility of nicotine withdrawal symptoms, subjects who are current users of nicotine 
products will be permitted to use nicotine replacement gum or patches. The dose and frequency 
of the nicotine replacement products will be determined by the subject’s current level of 
dependence in accordance with the product’s prescribing information. 
5.2.3. 
Non-Medicinal Therapies 
Any form of non-medicinal therapy should be stable 3 months prior to screening with no plans 
to start, stop or alter the use of non-medicinal therapies/activities (e.g., psychotherapy, 
acupuncture, hypnosis, or other similar therapy) from the time of providing informed consent 
until End of Study. 
Non-medicinal therapies will be recorded in the eCRF, beginning at the time of ICF signing 
until End of Study (Week 12 [Visit 9] or Early Withdrawal). 
5.3. 
Screen Failures 
Screen failures are subjects who consent to participate in the clinical study but are never 
randomized. 


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Subjects excluded during screening should promptly be reported as a screen failure in the 
electronic data capture (EDC) system.  
Subjects excluded during screening may be rescreened once in consultation with the Sponsor’s 
Medical Monitor, when the reason for meeting an exclusion is likely to resolve (e.g., the subject 
had an exclusionary acute infection that is resolving, transient lab abnormalities, or a 
medication taper is taking longer than 30 days). Subjects who do not meet criteria for inclusion 
at screening or baseline on the HAM-A score are not permitted to rescreen. If a subject is 
rescreened, the subject must be reconsented to participate in the study, and all screening 
procedures should be repeated (unless the Investigator and Sponsor’s Medical Monitor agree 
with re-using one or more original screening results).  


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6. 
STUDY DRUG AND CONCOMITANT THERAPY 
6.1. 
Description of Study Drugs 
For the purposes of this protocol, the term “investigational drug” refers to MM-120 (25, 50, 
100 or 200 µg freebase-equivalent); the terms “study treatment” and “study drug” are 
interchangeable and refer to either MM-120 or matching placebo. 
All study drugs will be supplied as a solid dosage form (capsules). Table 4 provides a 
description of the study drugs. 
Table 4: 
MMED008 Study Drugs 
Study 
Drug 
Total Dosea 
(Freebase-
equivalent) 
Frequency; Route of Administration;  
Product Description 
Use 
MM-120 
25, 50, 100 or 
200 µg 
Single dose; oral; capsule containing 25 µg MM-120 
(D-LSD D-tartrate) freebase-equivalent blended with 
“generally recognized as safe” (GRAS) excipients 
Investigational 
product 
Placebo 
Not applicable 
Single dose; oral; capsule containing GRAS 
excipients 
Blinding 
a 
Each subject will receive a total of 8 capsules (combination of active and/or placebo) to provide their 
randomly assigned total dose as follows: 
Subjects randomized to a total dose of 25 µg receive 1 active capsule + 7 placebo capsules. 
Subjects randomized to a total dose of 50 µg receive 2 active capsules + 6 placebo capsules. 
Subjects randomized to a total dose of 100 µg receive 4 active capsules + 4 placebo capsules. 
Subjects randomized to a total dose of 200 µg receive 8 active capsules. 
Subjects randomized to placebo receive 8 placebo capsules. 
6.2. 
Directions for Administration of Study Drug 
Study drug (MM-120 25, 50, 100 or 200 µg freebase-equivalent or placebo) will be 
administered under blinded conditions. To maintain the blind, all subjects will receive a total 
of 8 capsules, which will be a combination of active capsules each containing 25 µg MM-120 
freebase-equivalent and/or placebo capsules, depending on the subject’s randomized dose (see 
Table 4). All 8 capsules will be taken together as the subject’s single dose of study drug. 
Administration of study drug will occur only during Day 1/Dosing Session (Visit 3B), as 
specified in the Schedule of Activities (Table 2). 
Subjects will take the 8 study drug capsules orally with ad libitum water. Subjects will only 
have 15 minutes to swallow all 8 capsules. Administration of study drug will be witnessed by 
the Investigator and/or Dosing Session Monitor(s), and the subject will subsequently be 
monitored at all times until released from the clinic by the study site designated physician, as 
detailed in the Dosing Session Monitor Manual.  
6.3. 
Randomization  
Once final eligibility is confirmed at Day 1/Randomization (Visit 3A), subjects will be 
randomized centrally. The assigned randomization number will be used to identify the study 
drug to be dispensed to the subject and will be entered into the EDC system. 


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There are 5 treatment groups to which subjects will be randomized in a 1:1:1:1:1 ratio: 
• Arm A: 25 µg (freebase-equivalent) of MM-120 (n ≈ 36) 
• Arm B: 50 µg (freebase-equivalent) of MM-120 (n ≈ 36) 
• Arm C: 100 µg (freebase-equivalent) of MM-120 (n ≈ 36) 
• Arm D: 200 µg (freebase-equivalent) of MM-120 (n ≈ 36) 
• Arm E: Placebo (n ≈ 36). 
6.4. 
Blinding 
A double-blind/masking technique will be used. All doses of MM-120 and placebo will be 
packaged identically so that treatment blind/masking is maintained. The subject, the 
Investigator, and Sponsor personnel or delegate(s) who are involved in the treatment or clinical 
evaluation of the subjects will be unaware of the treatment group assignments. 
At the end of the study and after medical/scientific review has been performed and data have 
been declared final and complete, the official, final database will be frozen and unblinded. The 
Sponsor will be granted access to the frozen and unblinded database in order to analyze the 
data. 
6.4.1. 
Unblinding 
In the event of a medical emergency where knowledge of subject’s study drug assignment is 
necessary per the medical judgment of the Investigator, the Investigator may break the blind 
using the randomization system. If possible, the Sponsor’s Medical Monitor should be notified 
before the Investigator breaks the blind to discuss the case. If not possible, the Sponsor’s 
Medical Monitor should be notified as soon as possible after breaking a treatment code. The 
unblinding must be clearly justified and explained by a comment in the source documentation, 
along with the date on which the code was broken and the identity of the person authorizing 
the unblinding. 
Only the Investigator or delegate should be unblinded to the subject’s code. Site personnel and 
Sponsor personnel directly associated with the conduct of the study should not be unblinded. 
Additionally, the Sponsor’s delegate may unblind the treatment for an individual subject’s 
serious adverse event (SAE) if needed to fulfill expedited regulatory reporting requirements, 
or the Safety Review Committee (SRC) may have access to the treatment code, if needed. 
6.5. 
Dose Modification 
This is a single-dose study. No dose modifications by the Investigator are permitted. 
6.6. 
Encapsulation, Packaging and Labeling 
Study drug must be stored under the conditions specified on the label and remain in the original 
container until dispensed. 


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6.7. 
Handling/Storage/Accountability 
The process for each site to abide by the security controls detailed by the Drug Enforcement 
Agency (DEA) surrounding Schedule I drugs is described in the DEA Site Security Agreement. 
The Investigator is responsible for ensuring compliance at the site with all procedures outlined 
in the DEA Site Security Agreement. 
Additionally, details of drug handling, storage and accountability will be included in the 
Pharmacy Manual, which will provide information on tamper-proof dispensing, the maximum 
time period allowed between removal of drug from secured storage until dosing, tracking, 
control and return via reverse distributor, and prevention of unauthorized access. 
Study drug should be stored in a secure (recommended double-locked and bolted to the 
floor/wall), limited-access location. Sites will ensure proper perimeter and internal physical 
security is in place to prevent any diversion or theft of study drugs. 
At any time from the site’s receipt of study drug until the final collection of study data, drug 
accountability discrepancies will be monitored as follows:  
• The site will conduct drug accountability by site delegated team member and 
readily retrievable. 
• Any time the site identifies a discrepancy or possible diversion, the Sponsor must 
be notified promptly. For any discrepancy that triggers a drug accountability check, 
the Investigator or designee must resolve it promptly and will complete the eCRF 
page and ensure state, federal and ethics committee reporting is accomplished. The 
triggering drug accountability discrepancies are as follows:  
− Compliance issues where 1 or more subjects’ masked supplies are used more 
than the expected use, according to the drug accountability calculations 
− Missing masked supply capsule(s) 
− Evidence of tampering 
The Investigator is required to indicate the level of certainty of the classification and enter this 
into the subject’s eCRF for the trial. The Sponsor or their designee will review and confirm 
classified triggered cases and detail conclusions and recommendations (see Section 9.9 on 
Special Situations). 
The Investigator is responsible for ensuring accurate records are kept of the study drug received 
from the Sponsor or designee, the amount dispensed to the subjects and the amount remaining 
at the conclusion of the trial. Receipt and dispensing of study medication must be recorded by 
an authorized person at the study site. 
Study drug may not be used for any purpose other than that stated in the protocol. DEA storage 
and dispensing procedures must be strictly followed to prevent the illegal distribution and/or 
abuse of study drug by subjects or site staff (i.e., diversion). In addition, study subjects must 
be administered study drug under the supervision of the study drug dispenser and dosing 
session monitors. 


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Each site will have a practitioner who is a Schedule I license holder. 
6.8. 
Study Drug Compliance 
All subjects will be dosed at the site and will receive study drug directly from the Investigator 
or designee under medical supervision; the study drug administration will be witnessed by the 
Investigator and/or Dosing Session Monitor(s). The date and time of study drug administration 
at the site will be recorded in the source documents and the eCRF. 
The randomized study drug and study subject identification will be confirmed at the time of 
administration by a member of the study site staff other than the person administering the study 
drug. The study site personnel administering the dose will examine the subject’s mouth and 
hands to ensure that the study drug was ingested. 
6.9. 
Study Drug Overdose 
Refer to Section 9.5 for the definition of overdose and overdose management and refer to 
Section 9.9 for information on overdose reporting. 
6.10. 
Concomitant Therapies 
All medications, therapies and supplements taken by the subject during the course of the study 
will be recorded. Upon entry into the study, subjects will be instructed to report the possible 
need for any prescription or nonprescription medications, therapies and supplements 
immediately (and before use) to the Investigator. 
Subjects should remain on a stable regimen of all allowable medications from Baseline 
(Visit 2) until End of Study and will be excluded from the study if they plan to initiate, stop, 
or alter concomitant medication use during this time. 
Medications and supplements to treat anxiety, depression or other mood disorders will be 
tapered prior to Baseline (Visit 2) (see Section 8.1.6 for information on medication tapering). 
As subject safety is paramount, any treatments considered necessary for the subject’s welfare 
may be given during the study at the discretion of the Investigator. If the permissibility of the 
drug treatment is questionable, the Sponsor’s Medical Monitor must be consulted. 
6.10.1. 
Prohibited Medications, Supplements and Therapeutics 
The use of medications, supplements and other therapeutics (over-the-counter or prescribed) 
for treating anxiety, depression or mood disorders are prohibited from Baseline (Visit 2) until 
End of Study (except if needed during Day 1/Dosing Session [Visit 3B], as noted in Table 5. 
Additionally, the use of other substances, supplements, etc. that may confound the results of 
the study are prohibited from Baseline (Visit 2) until End of Study (e.g., cannabis, cannabidiol 
[CBD], ginkgo biloba). 
Subjects must also avoid starting, stopping or altering non-medicinal therapies from the time 
of providing informed consent until End of Study, as described in Section 5.2.3. 
Any prohibited substance(s) being taken at the time of Screening (Visit 1) should be tapered 
prior to at Baseline (Visit 2), if safe for the subject, in the opinion of the Investigator; tapering 


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will be done with oversight from the study site designated physician and in accordance with 
information provided in Section 8.1.6. 
Table 5 provides a listing of specific restrictions for concomitant therapy use during the course 
of this study, with any necessary washout periods or allowable conditions described. This table 
provides examples; however, it is not a comprehensive list of all restricted medications, 
supplements and other therapeutics. Consult the Sponsor’s Medical Monitor or designee if 
there is any uncertainty regarding a subject’s use of a particular drug, drug class, supplement 
or other therapeutic. 
Subjects on prohibited medications, supplements or other therapeutics at the time of Screening 
(Visit 1) may taper off that substance (see Section 8.1.6) and participate in the study if the 
required washout conditions have been met. For prescribed medications to treat anxiety, 
depression or other mood disorders, the medication taper will be overseen by the study site 
designated physician based on acceptable local practice standards. 
The final decision to continue or discontinue any medications/supplements/therapeutics that 
the subject is taking rests with the subject, the study site designated physician and/or the 
subject's primary care provider. However, the decision to have the subject receive study drug 
requires the mutual agreement of the Investigator, the Sponsor and the subject. 


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Table 5: 
Listing of Prohibited Medications, Supplements and Other Therapies 
Drug Class or Drug Name 
Washout 
Conditions/ 
Prohibition Perioda 
Allowable Conditions 
Benzodiazepines 
Last dose must have been taken 
at least 5 half-lives prior to 
Day 1/Randomization 
(Visit 3A) 
To treat anxiety during 
Day 1/Dosing 
Session 
(Visit 3B), 
at 
Investigator’s discretionb 
Lithium 
Last dose must have been taken 
at least 7 days prior to 
Day 1/Randomization 
(Visit 3A) 
None 
Monoamine oxidase inhibitors (MAOIs)c 
Last dose must have been taken 
at least 3 weeks prior to 
Day 1/Randomization 
(Visit 3A) 
None 
Antipsychotics – traditional 
Last dose must have been taken 
at least 5 half-lives prior to 
Day 1/Randomization 
(Visit 3A) 
None 
Antipsychotics – atypical 
Atypical agents (e.g., bupropion, mirtazapine) 
Barbiturates 
Selective serotonin reuptake inhibitors (SSRIs). 
NOTE: fluoxetine washout is 35 days 
Serotonin-norepinephrine reuptake inhibitors 
(SNRIs) 
Serotonin–norepinephrine–dopamine 
reuptake 
inhibitors (SNDRIs) 
Serotonin 
modulators 
(e.g., vortioxetine, 
trazodone) 
Tricyclic antidepressants (TCAs) 
Stimulant (e.g., methylphenidate hydrochloride) 
Cannabisd 
Prohibited from Baseline (Visit 
2) through End of Study 
None 
Other medications, supplements, or therapeutics 
that affect serotonergic function (e.g., efavirenz, 
Kava, ginkgo biloba, St. John’s Wort, 5-
hydroxytryptophan 
[5-HTP], 
ayahuasca, 
dimethyltryptamine [DMT]) 
Last dose must have been taken 
at least 5 half-lives prior to 
Day 1/Randomization 
(Visit 3A) 
None 
Note: This table is not a comprehensive list of all restricted medications or supplements. Consult the Sponsor’s 
Medical Monitor or designee with any questions about specific medications, supplements or therapeutics. 
a 
Subjects on prohibited medications, supplements or other therapeutics at the time of Screening may taper off 
that substance(s) prior to Baseline (Visit 2) (see Section 8.1.6) and will be eligible to participate in the study 
if the required washout conditions have been met. Investigator must consider the half-life of active 
metabolites. 
b 
Benzodiazepines should only be offered and administered if non-pharmacological interventions 
(e.g., reassurance, verbal communication) do not adequately address severe anxiety during the Dosing 
Session. 
c 
Although the half-life of MAOIs is typically 1.5-4 hours (eliminated quickly), the irreversible inhibition of 
monoamine oxidase may persist for 2-3 weeks due to the requirement for de novo synthesis of new enzyme, 
which is a relatively slow process. Therefore, washout for any MAOI should be conservatively 3 weeks. 


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d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.10.3. 
Permitted Medications, Supplements and Therapeutics 
Consult the Sponsor’s Medical Monitor or designee if there is any uncertainty regarding a 
subject’s use of a particular drug, drug class, supplement or other therapeutic. 
6.11. 
Treatment after the End of the Study 
Subjects will not receive any additional treatment with study drug from the Sponsor after 
completing the study. The Investigator is responsible for ensuring that consideration has been 
given to the post-study care of the subject’s mental health and physical health. Sites must refer 
subjects for ongoing psychiatric care at the end of the study. 


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7. 
WITHDRAWAL/DISCONTINUATION 
7.1. 
Discontinuation of Study Drug 
This is a single-dose study, and thus, discontinuation of study drug is not applicable. 
7.2. 
Early Withdrawal from the Study 
Subjects may withdraw consent at any time for any reason or be withdrawn from the study at 
the discretion of the Investigator should any untoward effect occur. A subject may be 
withdrawn by the Investigator or the Sponsor if enrollment into the study is inappropriate, the 
protocol is violated or for administrative and/or other safety reasons. The subject may be 
discontinued from further study participation after discussion between the Investigator and the 
Sponsor’s Medical Monitor (or designee) if the subject requires therapy with any excluded 
medication (see Section 6.10.1). Every effort should be made to establish and document the 
possible reason(s) for withdrawal. 
A subject must be discontinued from the study for any of the following reasons: 
• The subject withdraws consent. 
• The subject has a medical condition or personal circumstance that precludes the 
subject from attending future study visits, does not allow the subject to adhere to 
the requirements of the protocol or, in the opinion of the Investigator and/or 
Sponsor, places the subject at unnecessary risk through continued participation in 
the trial. 
When a subject discontinues/withdraws prior to study completion (i.e., prior to Week 12 
[Visit 9]), he/she should return to the clinic to complete an Early Withdrawal visit (same 
assessments/procedures as Week 12 [Visit 9]) or if the subject is at the site at the time of early 
withdrawal, all applicable activities scheduled for the final study visit should be performed at 
the time of discontinuation. The Sponsor’s Medical Monitor or designee should be notified 
within 24 hours if the withdrawal is due to an SAE and within 7 days if the withdrawal is due 
to another reason. 
Any AEs that are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 9. 
Once a subject is discontinued, the subject shall not be allowed to enroll again. 
As this is a single-dose study, if a subject becomes pregnant after Day 1/Dosing Session 
(Visit 3B), they are not required to withdraw from the study. The subject will be monitored for 
the pregnancy outcome, and reporting will occur as described in Section 9.10. 
Sites must refer subjects withdrawn early for ongoing psychiatric care. 
Lost to Follow Up 
Should a subject fail to attend a required study visit, the site should attempt to contact the 
subject and re-schedule the missed visit as soon as possible. The site should also counsel the 


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subject on the importance of maintaining the assigned visit schedule and ascertain whether or 
not the subject wishes to and/or should continue in the study based on previous non-
compliance. In cases where the subject does not return for the rescheduled visit or cannot be 
reached to reschedule the missed visit, the site should make every effort to regain contact with 
the subject (3 documented telephone calls and, if necessary, a certified letter to the subject’s 
last known mailing address) so that they can appropriately be withdrawn from the study with 
a primary reason of “Lost to Follow-up”. Efforts to establish the possible reason for 
discontinuation should be documented. 
7.3. 
Early Study Termination 
The study may be terminated early if the extent (incidence and/or severity) of emerging 
effects/clinical endpoints is such that the risk/benefit ratio to the study population as a whole 
is unacceptable. In addition, further recruitment in the study overall or at a particular study 
site may be stopped due to insufficient compliance with the protocol, Good Clinical Practice 
(GCP) and/or other applicable regulatory requirements, due to procedure-related problems or 
if the number of discontinuations for administrative reasons is too high. Sites must refer 
subjects for ongoing psychiatric care if the study is terminated early. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
The Schedule of Activities (Table 2) summarizes the study assessments/procedures to be 
performed at each visit. Individual assessments and procedures are described below. 
It may be necessary to perform these procedures at unscheduled time points if deemed 
clinically necessary by the Investigator. Furthermore, additional evaluations/testing may be 
deemed necessary by the Investigator and/or the Sponsor for reasons related to subject safety. 
In some cases, such evaluation/testing may be potentially sensitive in nature (e.g., testing for 
human immunodeficiency virus [HIV], hepatitis C virus [HCV], etc.), and thus local 
regulations may require that additional informed consent be obtained from the subject. In these 
cases, such evaluations/testing will be performed in accordance with those regulations. 
Sites may begin using the optional Prescreen assessments described within this protocol upon 
all regulatory approvals and Part 1 site activation. 
Changes that may be implemented, if needed, due to the coronavirus disease 2019 (COVID-19) 
pandemic are described in Section 9.8. 
8.1. 
Administrative Procedures 
8.1.1. 
Informed Consent 
For this study, the subject must be cognitively able to understand the requirements of the study 
and provide the informed consent to participate in the study; use of a legally authorized 
representative to provide consent to participate is not allowed. 
Informed consent forms (ICFs), any subsequently revised written ICFs, and any written 
information provided to the subject must receive Institutional Review Board 
(IRB)/Institutional Ethics Committee (IEC) approval in advance of use. The subject should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the study. The communication of this 
information will be provided and documented via a revised main ICF or addendum to the 
original ICF that captures the subject’s dated signature. 
The ICFs will adhere to IRB/IEC requirements, applicable laws and regulations and Sponsor 
requirements. 
8.1.1.1. 
Prescreen Informed Consent (Optional) 
Informed consent must be obtained from each potential subject prior to the collection of any 
information about them during the Prescreen process. Prescreen consent may be obtained via 
a signed consent form or verbal consent over the phone per the standard practice of the 
individual site. 
8.1.1.2. 
Main Informed Consent 
Documented consent must be obtained from each potential subject prior to participating in 
study procedures. The subject will be given sufficient time to read the ICF(s) and the 
opportunity to ask questions. Consent must be documented by the subject’s dated signature on 


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the ICF(s) along with the dated signature of the person conducting the consent discussion. The 
ICF(s) that is/are used must be approved by both the sponsor and by the reviewing IRB.  
A copy of the signed and dated ICF(s) should be given to the subject before participation in 
the study. 
Subjects will be asked to inform their care provider(s) that they are considering taking part in 
the study to ensure that the subject’s care providers are able to appropriately monitor the 
subject during the study including during any required tapering of prohibited concomitant 
medications. 
8.1.1.3. 
Real World Evidence 
At the beginning of the study participants will be invited to opt into a service which can link 
existing health data with the participant to enrich data collected in the study. In order to link 
traditional study data to Real World Data (RWD), a common, universal ID (herein named a 
“token”) that is unique to each study subject, persistent, and also available in real-world 
datasets will be used. A token is a universal, de-identified key that can be used to reference 
participants across datasets, created based on elements of patient personal identifying 
information (PII) using privacy-preserving technology from vendor 
 The key features 
below make tokens a secure and consistent mechanism for linking real world healthcare data 
sources at the patient level while preserving the privacy of trial participants. 
• Tokens are irreversible and blinded: Hashing by 
 technology destroys 
the input PII, which makes tokens de-identified. The input PII cannot be 
backward-engineered from the output token. 
• Tokens are unique: Each token is unique to the input PII, avoiding false matches.  
• Tokens are consistent: The same set of input PII will always create the same 
tokens. Tokens created in any dataset are compatible and can be matched to one 
another.  
• Tokens are compliant with trial regulation: A participant’s PII never leaves the 
site. 
• Multiple tokens derived from different PII elements are created for each subject to 
enable accurate matching (avoiding false positives and limiting false negatives). 
At the time trial participants are screened for enrollment into the study, participants will be 
offered the consent for tokenization and linking of their clinical trial data. Outside of 
tokenization and linking of their clinical trial data, no additional study procedures beyond what 
is outlined in this study protocol, would be completed as result of their participation. 
Participation in tokenization is optional and participants who decline to participate in the 
tokenization process will still be able to participate in the study. The trial participant’s 
tokenized data will be available for linking to other future data indefinitely or until they 
withdraw their consent for future data linking. The participant will be instructed of the 
withdrawal consent process with information provided in the ICF. 


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8.1.2. 
Demographics 
The following demographics will be recorded: year of birth, self-identified gender, sex at birth, 
race and ethnicity. 
For the purposes of demographics, both sex at birth (e.g., male, female) and self-identified 
gender (e.g., male, female, non-binary) should be recorded. This is because normal ranges for 
some clinical laboratory and ECG parameters, scoring from some questionnaires and the ability 
to become pregnant are based on a binary male/female designation while other parameters such 
as baseline symptom scores for anxiety and depression are expected to correlate to gender 
identity. Further, selected dosing session monitors should be aligned with gender identity and 
not sex at birth. 
8.1.3. 
Prescreen Assessment (Optional) 
Per the Schedule of Activities (Table 2) limited activities are planned for the optional 
Prescreen. Verbal consent must be collected before any Prescreen information is collected (see 
Section 8.1.1.1). Sites that choose to participate in the optional Prescreen will be provided a 
checklist with detailed instructions including prompts for collecting demography, an 
abbreviated Medical History and Concomitant medication review. Sex at birth, age, weight 
and height will be collected (an estimate of weight and height can be made for a phone screen), 
and BMI will be determined via calculation. The MINI can also be administered by qualified 
site personnel at the Prescreen. 
Note: Information captured during the Prescreening assessments will not be captured in the 
EDC. 
8.1.4. 
Eligibility Assessment 
All inclusion criteria (listed in Section 5.1.1) and exclusion criteria (listed in Section 5.1.2) 
will be reviewed by the Investigator or qualified designee at Screening (Visit 1), Baseline 
(Visit 2) and Day 1/Randomization (Visit 3A), prior to randomizing the subject, to ensure that 
the subject qualifies for the study, however, of the vital signs taken at Visit 3A only 
temperature and blood pressure will be used to confirm final eligibility against 
inclusion/exclusion criteria. 
All inclusion criteria must be met and none of the exclusion criteria may apply for the potential 
subject to be eligible to participate in the study. No eligibility waivers (or other protocol 
waivers) will be granted. 
Subjects found ineligible during review of inclusion/exclusion at any of these visits will not 
proceed through the remaining screening process, except in cases of rescreening as described 
in Section 5.3. 
Eligibility at Visit 3a/Randomization includes: 
1. Review medical, psychiatric, and medication history 
2. Vital signs (BP, HR, RR, temperature) within 1 hour of dose administration; 
Temperature and blood pressure (only) will be used to determine eligibility at 
Visit 3a. Systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg 


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(confirmed by 3 separate readings) will make the participant ineligible for 
dosing. Temperature over 37.78°C (100°F) would be indicative of an acute illness 
and would make the subject ineligible for dosing.  
3. 
  
 
 
 
 
  
• A positive pregnancy test will make the participant ineligible for dosing.  
4. C-SSRS-SLV version  
• Active suicidal ideation will make the participant ineligible for dosing as 
evidenced by a “Yes” in response to C-SSRS suicidal ideation question 4 or 5  
8.1.5. 
Medical/Psychiatric and Medication History 
Medical/psychiatric and medication history will be assessed during Screening (Visit 1) and 
recorded in the eCRF. However, if information about the subject’s medical/psychiatric and 
medication history is learned during the course of the study, this will also be recorded in the 
eCRF, even if this history is learned after Screening (Visit 1). 
The medical/psychiatric history will be obtained by the Investigator or qualified designee. 
Medical/psychiatric history will include all chronic, past and ongoing conditions, regardless of 
the year diagnosed. To confirm eligibility criteria, the medical/psychiatric history will include, 
but is not limited to, a review of the following: suicidal ideation or behaviors; neurological or 
psychiatric disorder(s); family history of relevant psychiatric and medical concerns; major 
traumas; surgeries; any clinically significant diseases of the renal, hepatic, gastrointestinal, 
cardiovascular, or musculoskeletal system; clinically significant immunological, endocrine, or 
metabolic diseases; infection with HIV, hepatitis B and hepatitis C. Sites should make an effort 
to obtain medical and/ or psychiatric records for subjects. 
All therapies (prescription or over-the-counter medications, including vaccines, supplements; 
non-pharmacologic therapies such as electrical stimulation, acupuncture), other than the study 
intervention will be assessed as part of the subject’s medical and medication history. 
Medication history will include a description of the type of therapy, duration of use, dosing 
regimen, route of administration, and reason for use. Sites should make an effort to obtain 
pharmacy records for subjects.  
8.1.6. 
Medication Taper 
Medication tapers will be required for any subject on a prohibited medication for the following 
reasons: 
• to eliminate potential confounding efficacy in the statistical analysis, 
• to mitigate the risk of serotonin syndrome, and 
• to eliminate the pharmacologic effects of potent 2D6 inhibitors. 


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The study site designated physician must monitor study subjects throughout the taper and 
through the end of the study or early termination. 
Any prohibited anxiolytics, antidepressants or other medications, supplements or therapeutics 
(over-the-counter or prescribed) used to treat anxiety, depression or other mood disorders, as 
well as any other substances, supplements etc. that may confound the results of the study (as 
described in Section 6.10.1) will be tapered prior to Baseline (Visit 2). Subjects on such 
prohibited medications/substances at the time of Screening (Visit 1) will undergo a medication 
taper prior to advancing to Baseline (Visit 2), if safe for the subject, in the opinion of the 
Investigator. Medication tapering will be done with oversight from the study site designated 
physician; for subjects on prescribed medications to treat anxiety, depression or other mood 
disorders, the medication taper will be overseen by the study site designated physician based 
on acceptable local practice standards. 
The last dose of the substance being tapered must have been taken no closer to Baseline 
(Visit 2) or Day 1/Randomization (Visit 3A) than indicated by the prohibition period described 
in Table 5. If the medication taper is anticipated to require more time than is available in the 
subject’s remaining screening period, the subject will need to be screen-failed, and will need 
to rescreen. 
Confirmation of eligibility is required at Baseline (Visit 2) and Day 1/Randomization 
(Visit 3A), including confirmation of a negative urine dipstick drug screen at these 2 visits and 
confirmation that the subject is no longer taking any prohibited medications/substances. 
Additionally, subjects must also avoid starting, stopping or altering non-medicinal 
therapies/activities from the time of providing informed consent until End of Study, as 
described in Section 5.2.3. 
Note: It is not permitted to stop/taper medications being used to treat excluded conditions. 
8.1.7. 
Concomitant Medication Review/Collection 
Concomitant therapies will be recorded throughout the study, beginning at the time of ICF 
signing until End of Study (Week 12 [Visit 9] or Early Withdrawal). 
Medications taken at Baseline (Visit 2) or any time after, including those between visits 
regardless of whether the subject is on the medication at the time of the site visit, will be 
recorded in the concomitant medication eCRF. Medications stopped prior to Baseline (Visit 2) 
are recorded in the medication history eCRF.  
Non-medicinal therapies/activities (see Section 5.2.3) will also be recorded throughout the 
study, beginning at the time of ICF signing until End of Study (Week 12 [Visit 9] or Early 
Withdrawal). 
8.2. 
Clinical Procedures/Assessments 
Refer to the DSMM, SoA and Lab manual for specific information procedures/assessments, 
including any required order for conducting them and any particular timing between them that 
must be followed. 


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8.2.1. 
Physical Examination 
The site-designated licensed physician (MD/DO) will conduct a comprehensive physical exam 
at Screening (Visit 1), Day 2 (Visit 4) and End of Study (Week 12 [Visit 9] or Early 
Withdrawal). The comprehensive physical examination should be based on local standard of 
care for a general physical and include general assessments: general appearance, head, eyes, 
ears, nose, throat, lungs, abdomen, heart, skin and extremities. 
Although physical exams are not required at all visits, additional physical exams may be 
conducted if medically indicated in the opinion of the Investigator. Any physical exam finding 
judged by the Investigator to be a clinically significant change from the screening assessment 
should be entered as an AE and monitored to resolution in accordance with safety procedures 
described in Section 9. 
8.2.2. 
Neuropsychiatric Examination 
The site-designated licensed physician (MD/DO) will conduct the Neuropsychiatric Exam at 
Baseline (Visit 2), Day 1/Randomization (Visit 3B) and all subsequent visits including End of 
Study (Week 12 [Visit 9] or Early Withdrawal). The Neuropsychiatric Exam performed at 
Baseline (Visit 2) establishes a standard comparison for possible effects of the study drug, thus 
the site-designated licensed physician who completes the baseline exam should complete 
dosing session day Dosing Release Checklists. The exam will monitor for mental status and 
sensory motor abnormalities. Any abnormal findings should be documented in accordance 
with the protocol as described in Section 8.2.8 and 9. 
Note: At Visit 3B, the Neuropsychiatric Exam is included as part of the Dosing Release 
Checklist and need not be repeated. 
8.2.3. 
Vital Signs 
For any visits which includes an ECG and/or blood draw, vital signs should be measured prior 
to those tests.  
Vital signs measured will include blood pressure, heart rate, respiration rate, and temperature 
(oral or tympanic). Continuous HR/BP monitoring devices and temperature guns are not 
permitted.  
Initial vital signs should be taken with the subject seated in a chair with back support and arms, 
feet flat on the floor, and arms supported by the arm rest. After an approximately 5-minute 
rest, measure blood pressure, heart rate, and respiration rate. If any of the first measurements 
are out of range, a second measurement can be taken after the subject has been allowed an 
additional approximately 5 minutes of rest.  
At Screening (Visit 1) and Baseline (Visit 2), measure orthostatic blood pressure. This 
measurement is taken separately from the initial vital signs. Orthostatic blood pressure should 
be measured by: allowing the subject to rest in a supine position for approximately 5 minutes; 
the subject then stands; and heart rate and blood pressure are measured within in 1 to 3 minutes 
of standing. If convenient, orthostatic blood pressure can be measured after the subject has 
been supine for the ECG. 


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On Day 1/Randomization (Visit 3A), the pre-dose vital signs (blood pressure, heart rate, 
respiration rate, and temperature) should be measured within 1 hour (± 15 min) prior to study 
drug dosing. The only vital signs taken at Visit 3A used to confirm final eligibility against 
inclusion/exclusion criteria are blood pressure and temperature (see Section 8.1.4 ). 
On Day 1/Dosing Session (Visit 3B), following administration of study drug, vital signs (blood 
pressure, heart rate, respiration rate, and temperature) will be monitored at 0.5, 1, 1.5, 2, 4, 6, 
8, 10, and 12 hours post-dose. The time of vital sign assessments should be recorded in the 
study database. In situations in which the post-dose assessment of individual vital signs as 
specified in this section does not occur before the next post-dose vital signs assessment 
timepoint, the next temporal assessment should be recorded at the protocol-specified post-dose 
time. For example, if the 1.5-hour post-dose assessment does not occur before the 2-hour 
assessment, the 1.5-hour assessment should be skipped and recorded as missing, and the 2-
hour assessment would proceed as specified in this section.  
8.2.4. 
Weight 
Weight may be estimated during a remote Prescreen session but should be physically measured 
once the subject is on-site to determine eligibility. 
Body weight may be measured with the subject in street clothing with jacket/coat and shoes 
removed. 
8.2.5. 
Height 
Height may be estimated during a remote Prescreen session but should be physically measured 
once the subject is on-site. Standing height will be measured without shoes at Screening 
(Visit 1) only when subject is on-site to determine eligibility.  
8.2.6. 
Body Mass Index 
BMI will be calculated using the subject’s weight and height recorded at Screening (Visit 1). 
BMI calculated during the optional Prescreen may be estimated and can be used to aid 
eligibility determinations, but the recorded value must come from Screening (Visit 1). 
8.2.7. 
Electrocardiogram 
For any visits in which there is an ECG and blood draw, the ECG should be performed prior 
to the blood draw. 
ECG should be performed after 5 minutes of rest in a semi-recumbent position. A qualified 
designee at the investigative site is responsible for interpreting the ECG, and if needed, in 
consultation with a cardiologist. If an ECG finding is identified as abnormal and is a clinically 
significant change from the baseline assessment, then the finding should be entered as an AE 
and monitored to resolution in accordance with safety procedures described in Section 9. 
8.2.8. 
Adverse Event Collection 
AE collection (of all spontaneously-reported events or events described by the subject in 
response to site staff queries) will occur from the time informed consent (main consent) is 
given until completion of the study and will be recorded at each visit. 


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Events occurring between signing of the ICF and dosing with study drug at Day 1/Dosing 
Session (Visit 3B) will be recorded on the medical history page of the eCRF (see also 
Section 9.4.1). Events occurring from the time study drug is administered through End of Study 
(Week 12 [Visit 9] or Early Withdrawal) will be recorded on the AE page of the eCRF. 
The Investigator or site staff is responsible for detecting, documenting, and reporting events 
that meet the definition of an AE, SAE or adverse event of special interest (AESI) suggestive 
of abuse potential. See Section 9 for details on AE definitions and reporting. 
8.3. 
Laboratory Procedures/Assessments 
8.3.1. 
Biobanking (DNA) Sample 
For subjects who consent to provide a sample pharmacogenomic (DNA) sample, a single blood 
sample for biobanking will be collected from each subject during the study and stored for future 
analyses. It is preferable to collect the sample at Day 1/Randomization (Visit 3A); however, 
the sample may be collected at any time after this visit through End of Study (Week 12 [Visit 9] 
or Early Withdrawal). The blood sample should not be collected from the subject during 
Day 1/Randomization (Visit 3B) after being dosed with study drug. 
All analyses of the biobanked samples will be conducted by the Sponsor’s designee. 
Information regarding the handling/shipping of specimens will be provided in the Laboratory 
Manual. 
8.3.2. 
Safety Laboratory Assessments and Urinalysis 
A central laboratory will perform all safety clinical laboratory assessments (blood chemistry 
panel and hematology) and urinalysis. (Note that the urine dipstick drug screen and pregnancy 
testing will be done locally; see Section 8.3.3 and Section 8.3.4, respectively). Additional 
testing may be required by the Sponsor based on emerging safety data. All protocol-required 
laboratory assessments must be conducted in accordance with the Laboratory Manual and the 
Schedule of Activities (Table 2). 
Safety clinical laboratory assessments and urinalysis tests to be performed by the central 
laboratory are listed in Table 6. The central laboratory will also provide estimated glomerular 
filtration rate (eGFR), calculated using the Cockroft-Gault formula. 


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Table 6: 
Required Laboratory Analytes 
Serum Chemistry Panel 
Hematology 
Urinalysis 
● Albumin 
● Total protein 
● Alkaline phosphatase 
● ALT 
● AST 
● Bicarbonate 
● Bilirubin, total  
● Bilirubin, direct (if total bilirubin is > ULN) 
● Blood urea nitrogen or urea 
● Calcium 
● Chloride 
● Creatinine 
● Creatinine clearance 
● FSHa (Scr only; confirm postmenopausal) 
● GGT 
● Glucose 
● Lactate dehydrogenase 
● Lipid 
panel 
(cholesterol, 
HDL, 
LDL, 
triglycerides) 
● Phosphorus 
● Potassium 
● Sodium 
● TSH with reflex to free T4b 
Complete 
blood 
count, 
including: 
● Hemoglobin 
● Hematocrit 
● RBC indices 
o MCV 
o MCH 
o MCHC 
o RDW 
● Platelet count 
● MPV 
● Red blood cell count 
● White 
blood 
cell 
count 
 
Differential 
count, 
including: 
● Basophils 
● Eosinophils 
● Lymphocytes 
● Monocytes 
● Neutrophils 
● Protein 
● Glucose 
● Ketones 
● Bilirubin 
● pH 
● Nitrites 
● Specific gravity 
● Urobilinogen 
● Leukocytes 
● Microscopic (if 
positive for bacteria, 
leukocyte esterase, 
blood, protein or 
nitrites) 
● Red cell count 
● White cell count 
● Epithelial cells 
● Casts and crystals 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; FSH: follicle-stimulating hormone; 
GGT: gamma-glutamyl transferase; HDL: high-density lipoprotein; LDL: low-density lipoprotein; MCH: mean 
corpuscular hemoglobin; MCHC: mean corpuscular hemoglobin concentration; MCV: mean corpuscular volume; 
MPV: mean platelet volume; T4: thyroxine; RBC: red blood cell; RDW: red cell distribution width; TSH: thyroid-
stimulating hormone; ULN: upper limit of normal 
a 
FSH: Performed only at Screening (Visit 1) if needed to confirm a subject’s post-menopausal status 
(> 40 mIU/mL) 
b 
TSH and FT4: Performed only at Screening (Visit 1) 
 
All laboratory tests considered clinically significant by the Investigator should be documented 
as AEs and repeated until the value returns to baseline or are no longer considered clinically 
significant by the Investigator or Sponsor’s Medical Monitor or designee. 
Information regarding the collection, processing and shipping of laboratory assessments is 
provided in the Laboratory Manual. 
PI/Sub-I (if an MD/DO) or study site designated physician should review all lab values for 
clinical significance.  


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8.3.4. 
Urine/Serum Pregnancy Tests 
As outlined in the Schedule of Activities (Table 2), all WOCBP will require a urine pregnancy 
test (performed at the site) at Screening (Visit 1) and a serum pregnancy test at Baseline (Visit 
2). A negative β-HCG test result is required at Screening (urine) and a non-positive result is 
required at Baseline (serum); otherwise, the subject is not eligible to enroll or participate 
further in the study. Urine pregnancy tests (performed at the site) will be repeated at Day 
1/Randomization (Visit 3A), Week 1 (Visit 5) and all subsequent follow-up visits including 
End of Study (Week 12 [Visit 9] or Early Withdrawal). 
The results of each urine/serum pregnancy test will be recorded in the eCRF. 
A pregnancy test is not required for persons of non-childbearing potential, defined as women 
meeting any of the following conditions (see also Appendix 1): 
• Has undergone total hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, or bilateral tubal ligation at least 2 months prior to Screening 
• Has a congenitally absent uterus 
• Is postmenopausal, confirmed as being age > 45 years with one of the following: 
− At least 1 year without menses prior to Screening 
− 6 months to < 1 year without menses prior to Screening and serum follicle-
stimulating hormone [FSH] levels > 40 mIU/mL at Screening.  


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All persons who become pregnant or men with a female sexual partner who becomes pregnant 
during the study after Day 1 will be monitored for the pregnancy outcome, and reporting will 
occur as described in Section 9.10. 
8.4. 
Screening and Efficacy Questionnaires 
Questionnaires will be administered according to the timing/frequency indicated in the 
Schedule of Activities (Table 2). Information about the questionnaires is briefly summarized 
below. 
The following instruments can be administered for sites that implement the optional Prescreen: 
• MINI (see Section 8.4.1) 
The following instruments will be administered during the screening process only: 
• MINI (see Section 8.4.1) 
• C-SSRS – Baseline/Screening Version (see Section 8.4.2) 
• Placebo Script Review (see Section 8.4.11) 
Additionally, the following instruments will be administered during the study to assess 
functionality and quality of life: 
• HAM-A, performed by central rater (see Section 8.4.3) 
• MADRS, performed by central rater (see Section 8.4.4) 
• C-SSRS – SLV Version (see Section 8.4.2) 
• CGI-S and CGI-I (see Section 8.4.5) 
• PGI-S and PGI-C (see Section 8.4.6) 
• SDS (see Section 8.4.7) 
• EQ-5D-5L (see Section 8.4.8) 
• PSQI (see Section 8.4.9) 
• ASEX (see Section 8.4.10) 
8.4.1. 
Mini-International Neuropsychiatric Interview (MINI) 
The MINI will be administered at Screening (Visit 1) to help determine subject eligibility. The 
psychiatric interview using the MINI will be conducted by a certified site rater. DSMs may 
administer the MINI if qualified.  
The MINI is a short structured diagnostic interview for the major psychiatric disorders in 
DSM‐III‐R, DSM‐IV and DSM‐5 and ICD‐10. It was originally developed for the major 
psychiatric disorders in DSM‐IV and ICD‐10 to meet the need for a short, accurate structured 
psychiatric interview in various settings, including for multi-center clinical trials 
(Sheehan 1998). The standard MINI assesses the 17 most common disorders in mental health. 
It takes approximately 15 minutes to administer. 


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Note: The MINI will be used by sites that implement the optional Prescreen. The MINI must 
be repeated at Screening to confirm diagnosis. 
8.4.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be used to assess the subject’s suicidal ideation (severity and intensity) and 
behavior during screening and throughout the study. The C-SSRS Baseline/Screening Version 
will be administered by the Investigator or designee at Screening (Visit 1) and will use recall 
periods of lifetime and over the past 3 months. The C-SSRS – SLV Version will be used at all 
other visits where the C-SSRS is to be administered, as described in the Schedule of Activities 
(Table 2). 
For both versions, if the subject provides a “Yes” response in the Suicidal Behavior sections 
of the C-SSRS for Actual Attempt, Interrupted Attempt or Aborted Attempt, the site should 
inquire about the approximate date when the event occurred and record this in the source 
document and eCRF. 
The C-SSRS is a validated outcome assessment tool that evaluates suicidal ideation or behavior 
defined within 11 categories (5 subtypes of suicidal ideation, 5 subtypes of suicidal behavior, 
and 1 subtype of self-injurious behavior without suicidal intent) with binary responses (yes/no) 
(Posner 2011). 
Any positive findings or changes in the subject’s suicidal ideation/behavior that are revealed 
by the subject’s responses to the C-SSRS should be handled in accordance with local standard 
of care and at the Investigator’s discretion. The Investigator may consult with the Sponsor’s 
Medical Monitor on any questions related to treatment and/or follow-up of such findings. 
The C-SSRS may be administered by certified site raters. DSMs may administer the C-SSRS 
if qualified.  
8.4.3. 
Hamilton Anxiety Rating Scale (HAM-A) 
The HAM-A is being used as the primary outcome measure for this study for the evaluation of 
anxiety symptoms. It will be administered to determine eligibility at Screening (Visit 1) and 
Baseline (Visit 2) and will be administered at additional visits as described in the Schedule of 
Activities (Table 2). The HAM-A takes approximately 20 minutes to administer. 
The HAM-A will be completed by a central rater (see further details below). The HAM-A 
consists of the following 14 items that encompass both psychological and somatic symptoms 
of anxiety: 
• Anxious mood 
• Tension 
• Fears 
• Insomnia 
• Intellectual 
• Depressed mood 


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• Somatic (muscular) 
• Somatic (sensory) 
• Cardiovascular symptoms 
• Respiratory symptoms 
• Gastrointestinal symptoms 
• Genitourinary symptoms 
• Autonomic symptoms 
• Behavior at interview (general) 
The central rater must be appropriately trained/qualified to administer the HAM-A. The central 
rater will assess the extent to which the subject displays each given criterion and give a rating 
on a scale of 0-4, where 4 represents the most severe symptoms. 
A central rater located remotely from the site will be used to administer and score the HAM-A. 
As much as possible, the HAM-A should be administered at approximately the same time of 
the day across each of the individual subject’s study visits. Following completion of the HAM-
A, the central rater will administer the MADRS (see Section 8.4.4). 
At the site, the evaluations must be conducted with the subject in a private room with the door 
closed; no study site staff should be in the room during the assessment.  
The central raters will also complete a safety report risk assessment, and if any concerns are 
identified (e.g., possible suicide, homicide, abuse), the central rater will report this information 
to the site. If any such safety risks are identified, the Investigator is required to follow-up, 
including management and further reporting as needed, and will promptly notify the Sponsor’s 
Medical Monitor. 
Additionally, if the subject spontaneously reports any potential AEs to the central rater during 
an assessment, the central rater will notify the site after the interview session has concluded. It 
is the site’s responsibility to determine whether this event qualifies as an AE, SAE or AESI 
suggestive of abuse potential and to report the event as described in Section 9.  
If the central rater feels that there is an emergent risk to the safety of the subject, or to a third 
party, the site will be contacted immediately by the central rater to intervene in the subject 
assessment room. The central rater shall remain on the teleconference call with the subject 
until appropriate personnel from the clinical trial site arrive. The central rater will forward the 
complete report to the site. The Investigator retains responsibility for compliance with 
reporting requirements and to warn third parties of potentially harmful conduct by the subject. 
8.4.4. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS will be administered during the study at the visits indicated in the Schedule of 
Activities (Table 2). The MADRS takes approximately 15-20 minutes to administer. 
An appropriately trained/qualified central rater located remotely from the site will be used to 
administer and score the MADRS, as was described for the HAM-A (see Section 8.4.3, 


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including plans for completing a safety report risk assessment, reporting AE, SAE, and/or 
AESIs suggestive of abuse potential to the site, and immediately contacting the site in case of 
any emergent risk to the subject’s safety). As much as possible, the MADRS should be 
administered at approximately the same time of the day across each of the individual subject’s 
study visits. The MADRS will be administered by the central rater after completion of the 
HAM-A. 
The MADRS is used to assess depression severity and to detect changes due to antidepressant 
treatment (Montgomery & Åsberg 1979). This questionnaire includes 10 clinician-completed 
items. 
Each of the 10 questions is scored with a range of 0-6 points. An item score of 0 indicates item 
not present or normal, while an item score of 6 indicates severe or continuous presence of the 
symptoms. The total possible score is 60, and higher scores represent a more severe condition. 
A decrease in score by ≥ 50% indicates a response to treatment, and an actual score of ≤ 10 
indicates a remission of symptoms. 
8.4.5. 
Clinical Global Impression – Severity (CGI-S) and Clinical Global 
Impression – Improvement (CGI-I) 
The Clinical Global Impression (CGI) scales will be administered during the study at the visits 
indicated in the Schedule of Activities (Table 2). Sites should make every effort to maintain 
the same rater for the same subject for the CGI-S/I. The CGI-S/I rater may not function as a 
DSM or the study site designated physician as they may be functionally unblinded on dosing 
session day. 
CGI-S: The CGI-S scale will be used to assess the subject’s current severity of illness at the 
time of the assessment relative to the clinician's past experience with patients who have the 
same diagnosis (Guy 1976). The CGI-S comprises 1 Investigator-completed (or trained rater-
completed) item with 7 possible ratings (1-7 points), where a higher score indicates more 
severe illness. 
CGI-I: The CGI-I scale will be used to measure the clinician’s assessment of how much the 
subject’s illness has improved or worsened relative to Baseline (Visit 2). The CGI-I comprises 
1 Investigator-completed (or trained rater-completed) item with 7 possible ratings (1-7 points), 
where a lower score indicates improvement, and a higher score indicates worsening. 
8.4.6. 
Patient Global Impression – Severity (PGI-S) and Patient Global 
Impression – Change (PGI-C) 
The Patient Global Impression (PGI) scales will be administered during the study at the visits 
indicated in the Schedule of Activities (Table 2). The PGI-S/C are patient reported outcome 
measures.  
The PGI scale is the patient-reported outcome counterpart to the CGI scale (Guy 1976), which 
was published in 1976 by the National Institute of Mental Health. The PGI is adapted to the 
patient population and can be used to measure disease severity (PGI-S) or change in clinical 
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The PGI-S and PGI-C each comprise 1 subject-completed item with 5 possible ratings (1-5). 
In the case of PGI-S, a higher score indicates more severe illness. In the case of PGI-C, a lower 
score indicates change for the better (improvement in symptoms) and a higher score change 
for the worse (worsening symptoms). 
8.4.7. 
Sheehan Disability Scale (SDS) 
The SDS will be administered during the study at the visits indicated in the Schedule of 
Activities (Table 2). The SDS is a patient reported outcome measure.  
The SDS is a composite of 3 self-rated items designed to measure the extent to which 3 major 
domains in the patient’s life (work, social life/leisure activities and family life/home 
responsibilities) are functionally impaired by psychiatric or medical symptoms 
(Sheehan & Sheehan 2008). 
The SDS will be used to assess the extent to which these 3 major domains in the subject’s life 
are functionally impaired. 
8.4.8. 
EQ-5D-5L 
The EQ-5D-5L will be administered during the study at the visits indicated in the Schedule of 
Activities (Table 2). The EQ-5D is a patient reported outcome measure.  
The EQ-5D has been developed by the EuroQol Group and can be used to evaluate health 
outcomes over a wide range of health conditions and treatments (Herdman 2011). The EQ-5D 
consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). 
The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression. In the EQ-5D-5L version, each dimension has 5 levels of 
responses: no problems, slight problems, moderate problems, severe problems, and extreme 
problems. 
The EQ VAS records the subject’s self-rated health on a 20-cm vertical VAS, with endpoints 
labeled as “the best health you can imagine” and “the worst health you can imagine”. 
8.4.9. 
Pittsburgh Sleep Quality Index (PSQI) 
The PSQI will be administered during the study at the visits indicated in the Schedule of 
Activities (Table 2). The PSQI is a patient reported outcome measure.  
The PSQI assesses sleep quality and disturbances over the preceding month (Buysse 1989). 
This questionnaire includes 19 self-rated questions and 5 questions rated by the bed partner or 
roommate (if available). 
Responses to the 19 self-rated questions are included in the PSQI scoring, with the items 
combined to score the following 7 components: 
• Subjective sleep quality 
• Sleep latency 
• Sleep duration 


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• Habitual sleep efficiency 
• Sleep disturbance 
• Use of sleeping medication 
• Daytime dysfunction. 
Each of the 7 components has a Component Score with a range of 0-3 points. The 7 Component 
Scores are added to yield a single Global Score, with a range of 1-21 points. A Global Score 
of 0 indicates no difficulty, while a Global Score of 21 indicates severe difficulty in all areas. 
8.4.10. 
Arizona Sexual Experiences Questionnaire (ASEX) 
The ASEX will be administered during the study at the visits indicated in the Schedule of 
Activities (Table 2). The ASEX is a patient reported outcome measure.  
The ASEX is a 5-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile 
erection, ability to reach orgasm, and satisfaction from orgasm over the past week 
(McGahuey 2000).  
Possible total scores on the ASEX range of 5-30, with a higher score indicating more sexual 
dysfunction.  
8.4.11. 
Placebo Response Reduction 
A brief web-based script must be reviewed by the subject and the site personnel immediately 
before administering study assessments.  
The purpose is to provide site staff and subjects straightforward information that will neutralize 
the typically excessive expectations that drive high placebo responses in clinical studies. 
Placebo Response Reduction (PRR) training teaches the subject about the appropriate 
expectations of personal benefit while participating in a clinical trial (Erpelding 2020; 
Evans 2021).  
The script is being implemented at 3 visits as follows; Baseline/Visit 2, Week 4/Visit 7 
(primary endpoint), and Week 8/Visit 8 (key secondary endpoint) to reduce placebo response, 
and to balance subject and site burden. 
8.5. 
Other Patient-Reported Outcomes 
Other patient-reported outcomes (PROs) will be administered according to the 
timing/frequency indicated in the Schedule of Activities (Table 2). Information about these 
instruments is briefly summarized below. 
The following instruments will be administered during the study to explore dose response on 
drug effects, altered perception and mystical experience: 
• Drug Effect VAS (see Section 8.5.1) 
• MEQ30 (see Section 8.5.2) 
• 5D-ASC (see Section 8.5.3) 


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Additionally, the following instrument will be administered during the study to explore 
whether functional unblinding of study drug may have occurred: 
• Treatment assignment/blinding question (see Section 8.5.4) 
8.5.1. 
Drug Effect VAS 
The Drug Effect VAS will be administered the day after dosing, at Day 2 (Visit 4), to 
retrospectively assess the subject’s perception of drug effects experienced during 
Day 1/Dosing Session (Visit 3B). The Drug Effect VAS is a patient-reported outcome 
measure. A series of single-item VASs will be used to measure the extent to which the subject 
experienced each of the following: “any drug effect”, “good drug effect”, “bad drug effect”, 
“drug liking”, “fear”, “nausea”, “alteration of vision”, “alteration of sense of time”, and “the 
boundaries between myself and my surroundings seem to blur”. 
8.5.2. 
Mystical Experience Questionnaire (MEQ30) 
The MEQ30 will be administered the day after dosing, at Day 2 (Visit 4), to retrospectively 
assess the subject’s mystical experience during Day 1/Dosing Session (Visit 3B). The MEQ30 
is patient-reported outcome measure. 
The MEQ30 is a psychometrically validated instrument that includes 30 self-rated questions 
(Barrett 2015; Liechti 2017). The 30 items are combined into the following 4 subscales: 
• Mystical (unity, noetic quality, sacredness) 
• Positive mood 
• Transcendence of time and space 
• Ineffability 
Each of the 4 subscales contributes to the MEQ30 total score, which has a range of 
0-150 points. The MEQ30 total score is computed by taking the average response to all items 
and reported as a percentage. Subject is considered to have had a “complete mystical 
experience” when ≥ 60% of the maximum possible score is achieved on all 4 factor subscales. 
8.5.3. 
5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) 
The 5D-ASC will be administered the day after dosing, at Day 2 (Visit 4), to retrospectively 
assess the subject’s peak alteration of consciousness during Day 1/Dosing Session (Visit 3B) 
as compared with their normal waking consciousness. 5D-ASC is a patient-reported outcome 
measure. 
The 5D-ASC includes 94 self-rated items (visual analog scales). It is well-validated and has 
been used to characterize the acute subjective effects of LSD in experimental studies 
(Liechti 2017). The 94 items are combined into the following 5 subscales/dimensions 
(Dittrich 1998) with 11 lower-order scales defined for the first 3 subscales/dimension by 
Studerus et al. (Studerus 2010): 


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• Oceanic boundlessness (derealization and depersonalization associated with 
positive emotional states, ranging from heightened mood to euphoric exaltation); 
subscales within this dimension include: 
− Experience of unity 
− Spiritual experience 
− Blissful state 
− Insightfulness 
• Anxious ego dissolution (ego disintegration and loss of self-control phenomena 
associated with anxiety); subscales within this dimension include: 
− Disembodiment 
− Impaired control of cognition  
− Anxiety 
• Visionary restructuralization; subscales within this dimension include:  
− Complex imagery 
− Elementary imagery 
− Audio-visual synesthesia 
− Changed meaning of percepts 
• Auditory alterations  
• Vigilance reduction. 
8.5.4. 
Treatment Assignment/Blinding Question 
On Day 2 (Visit 4), a 5-point Likert scale will be used to evaluate each subject’s assessment 
of whether they received active study drug or placebo during Day 1/Dosing Session (Visit 3B). 
The treatment assignment question is a patient-reported outcome measure. Subjects will be 
asked to indicate which of the following statements they agree with the most: 
• 
 I am positive I received active drug 
• 
 I think I received active drug 
• 
 I cannot tell whether I received active drug or placebo 
• 
 I think I received placebo 
• 
 I am positive I received placebo. 
8.6. 
Dosing Day Activities 
8.6.1. 
Study Drug Dosing 
Study drug will be taken as a witnessed dose as outlined in Section 6.2 and described in detail 
in the Dosing Session Monitor Manual. 


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8.6.2. 
Subject Education / Follow-up Session with Dosing Session Monitors 
Refer to the Dosing Session Monitor Manual for details on the subject education that will be 
provided at 2 visits prior to dosing (i.e., at Baseline [Visit 2] and Day 1/Randomization 
[Visit 3A]) and for details on the follow-up sessions conducted at 3 visits following dosing 
(i.e., at Day 2 [Visit 4], Week 1 [Visit 5], and Week 2 [Visit 6]). 
8.6.3. 
Subject Observation by Dosing Session Monitors 
Following study drug administration on Day 1/Dosing Session (Visit 3B) until subject release 
from the clinic, subjects will be supported by two appropriately trained and qualified Dosing 
Session Monitors (DSMs) and will be under the observation of two DSMs at all times (both 
DSMs should be in the session room, however, one DSM can be in the session room and one 
in a separate room on site via live remote monitoring during breaks only). At least one of the 
Dosing Session Monitors will be identified and qualified to serve as a ‘lead monitor.’ A site-
designated licensed physician must be available or on call and be able to reach the clinical site 
within 15 minutes in the event of a physiological or psychiatric emergency; events requiring 
intervention should be discussed with the Sponsor as soon as the situation permits, but 
implementation of the intervention should not be delayed.  
The site-designated licensed physician with prescribing rights or a qualified designee can serve 
as the backup to either DSM if short breaks are needed. This licensed physician, or qualified 
designee, must meet the criteria to be a lead monitor.  
Refer to the Dosing Session Monitor Manual for details on monitoring the subject from dosing 
of study drug until the subject is released from the clinic. 
8.6.4. 
Subject Release on Dosing Day/ Dosing Release Checklist 
Study subjects will be kept under continuous observation for a minimum of 12 hours following 
investigational drug administration.  
Beginning approximately 8 hours after drug administration, the Dosing Release Checklist will 
be performed by the site-designated licensed physician (MD/DO) to evaluate the subject’s 
psychological and physiological status. This will include an evaluation to ascertain that the 
subject no longer meets DSM-5 criteria for Hallucinogen Intoxication. Subjects should be 
assessed for release criteria starting at 8 hours (±10 minutes) post-administration and 
subsequently assessed at approximately 9, 10, 11 and 12 hours (±10 minutes) post-dose. The 
Dosing Session Release Checklist should be administered hourly (±10 minutes) until all release 
criteria are met. At a minimum, the Dosing Release Checklist will be completed at 8- and 12-
hours post-dose. If the subject does not meet criteria for release at 12 hours post-dose, the 
Dosing Session Release Checklist should be repeated approximately every hour (±10 minutes) 
until all criteria are met and the subject is deemed eligible for release. Subjects will be kept 
under continuous observation until their release is deemed safe by the site-designated licensed 
physician.  
In order to be eligible for release, subjects MUST: 
• Self-report readiness for release (i.e., physical and mental readiness, and 
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• Be deemed eligible for safe release in the medical judgment of the study site-
designated licensed physician as determined by the Dosing Release Checklist  
• No active suicidal ideation or behavior as determined by the C-SSRS 
And must NOT:  
• Meet DSM-5 criteria for Hallucinogen Intoxication  
• Display clinically significant psychomotor depression, activation or other signs or 
symptoms 
• Display clinically significant abnormal mental status  
Refer to the Dosing Session Monitor Manual and Dosing Release Checklist for further details 
on requirements that must be met in order for the subject to be released from the clinic at the 
end of Day 1/Dosing Session (Visit 3B).  


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9. 
SAFETY CONSIDERATIONS 
9.1. 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a research subject, whether or not considered 
drug related which occurs during the conduct of a clinical trial. Any change in clinical 
status that is considered clinically significant by the PI should be documented. AEs 
occurring prior to randomization should be documented in medical history. AEs occurring 
after randomization should be documented in the AE log. Adverse events include any 
clinically significant changes not present prior to drug administration.  
An AE includes:  
• An unexpected worsening, excluding minor fluctuations, in the nature, severity, 
frequency, or duration of a pre-existing condition.  
• A new condition detected or diagnosed after investigational product 
administration even though it may have been present prior to the start of the 
study.  
• Injury or accidents: If a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as 2 separate 
medical events (e.g., for a fall secondary to dizziness, both “dizziness” and “fall” 
should be recorded separately).  
• An investigational abnormality (e.g., laboratory parameter, vital sign, ECG) only 
if the abnormality which occurs during the conduct of a clinical trial. Any change 
in clinical status, ECGs, routine labs, physical examinations, etc., that is 
considered clinically significant by the Investigator based on at least one of the 
following criteria;  
− Induces clinical signs or symptoms  
− Requires active intervention  
• Signs, symptoms, or the clinical sequelae of a suspected interaction.  
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication. 
All observed and subject reported AEs and SAEs will be recorded from time of 
randomization until the end of study. SAEs will be reported per FDA guidelines. 
9.2. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose: 
a. Results in death; 
b. Is life-threatening; 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event 
in which the subject was at risk of death at the time of the event. It does not refer 
to an event, which hypothetically might have caused death, if it were more severe. 
c. Requires hospitalization or prolongation of existing hospitalization; 


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NOTE: In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or out-patient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in disability/incapacity; 
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which 
may interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. Is a congenital anomaly/birth defect; 
f. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
9.3. 
Adverse Events of Special Interest  
AESIs are a subset of AEs that are suggestive of abuse potential (including Central Nervous 
System-related and drug abuse-related) and any special situations defined in Section 9.9 that 
have an associated AE or drug accountability discrepancy (see Section 6.7). 
The AE terms listed below are MedDRA Preferred Terms to be used in classifying Adverse 
Events of Special Interest (AESIs) related to abuse liability when deemed appropriate by 
the PI (or designee): 
• Euphoria-related terms: Euphoric mood; Elevated mood; Feeling abnormal; 
Feeling drunk; Feeling of relaxation; Dizziness; Thinking abnormal; 
Hallucination; Inappropriate affect. 
• Terms indicative of impaired attention, cognition, and mood: Somnolence; Mood 
disorders and disturbances. 
• Dissociative/psychotic terms: Psychosis; Aggression; Confusion and 
disorientation. 
• Overdose-/ Misuse-related terms not captured elsewhere: Drug tolerance; 
Habituation; Drug withdrawal syndrome; Substance-related disorders. 


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9.4. 
Adverse Event Detecting and Reporting 
The Investigator and site staff are responsible for detecting, documenting and reporting events 
that meet the definition of an AE, SAE or AESI suggestive of abuse potential. 
The reporting of SAE and/or AESIs suggestive of abuse potential to regulatory authorities by 
the Sponsor is a requirement and each authority has a timetable for reporting these events based 
upon established criteria. Likewise, it is the responsibility of the Investigator to report SAE 
and/or AESIs suggestive of abuse potential to their local IRB/IEC. 
Care will be taken not to introduce bias when detecting AEs, SAEs and/or AESIs suggestive 
of abuse potential. Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. Appropriate questions include: 
• “How are you feeling?” 
• “Have you had any (other) medical problems since your last visit/contact?” 
• “Have you taken any new medicines since your last visit/contact? 
Any abnormal exam finding(s) at Screening and Baseline should be entered once as medical 
history and as a physical exam finding (if applicable). The finding will only be considered an 
AE if there is a clinically significant change in signs or symptoms during the study, as judged 
by the Investigator. A medical history finding that worsens after randomization should be 
recorded as an AE. The term should match the recorded finding that has worsened. 
The subject’s responses in clinician reported outcome measures will not be used as a primary 
means to collect AEs, however any AEs indicated in these instruments should be queried by 
the study site personnel and the study monitors and recorded. Should the Investigator or site 
staff become aware of a potential AE through the information collected with these instruments, 
proper follow-up with the subject for medical evaluation should be undertaken. Through this 
follow-up, if it is determined that an AE not previously reported has been identified, normal 
reporting requirements should be applied. 
All subjects who experience an AE will be evaluated at appropriate time intervals until the 
event resolves or has stabilized or become chronic. At the conclusion of the study, the 
Investigator and medical monitor will assess unresolved AEs and determine if additional 
follow-up is warranted. 
All AEs, whether or not related to the study drug treatment, must be fully and completely 
documented on the adverse event case report form and in the subject’s source documents. In 
addition, any AE resulting in permanent treatment discontinuation must be recorded on the 
appropriate case report form as well as documented in the subject’s source documents. AE 
terms should include a diagnosis, as available, in preference to listing the individual signs and 
symptoms. If the diagnosis is not known, the Investigator should record each sign and symptom 
as an individual AE. 
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Overdose and pregnancy in the subject or subject’s partner will be reported as described in 
Section 9.9 and Section 9.10, respectively. 
9.4.1. 
Period for Reporting Adverse Events 
AE collection will occur from the time informed consent is given until completion of the study 
and will be recorded at each visit. 
Any event occurring between signing of the ICF and dosing with study drug at Day 1/Dosing 
Session (Visit 3B) will be recorded as medical history in the eCRF and in the subject’s clinical 
record for any subject who continues to meet eligibility criteria and proceeds to dosing with 
study drug. 
Adverse events collected from the time study drug is administered through End of Study 
(Week 12 [Visit 9] or Early Withdrawal) will be recorded on the AE page of the eCRF. SAEs 
and/or AESIs suggestive of abuse potential will be collected from the signing of the informed 
consent form until the Week 12 (or Early Discontinuation) visit. SAEs and/or AESIs 
suggestive of abuse potential reported to the Investigator after the safety reporting period 
should be reported to the Sponsor if the Investigator assesses the event as related to the study 
drug treatment. 
Reporting instructions for SAEs and/or AESIs suggestive of abuse potential are provided in 
Section 9.4.2. 
9.4.2. 
Reporting Serious Adverse Events and Adverse Events of Special Interest 
Suggestive of Abuse Potential 
All SAE and/or AESIs suggestive of abuse potential must be reported within 24 hours of the 
study site personnel’s knowledge of the event, regardless of the Investigator’s assessment of 
the relationship of the event to study drug. The events will be entered into the EDC and the 
narrative section provided in the drug safety database. 
The minimum criteria for SAE and/ or AESI suggestive of abuse potential reporting are as 
follows: the event or outcome meets the definition of an SAE and/ or AESI suggestive of abuse 
potential (see Section 9.2 and Section 9.3); the event happens to an identifiable study subject; 
and the event is reported by an identifiable and qualified reporter (usually the Investigator or 
other qualified study site personnel). 
A follow-up report to an SAE and/ or AESI suggestive of abuse potential should be prepared 
if any relevant change in the condition of the study subject occurs after the initial report. The 
follow-up report should be documented as an update to the initial report. 
If the subject died, the report should include the cause of death as the event term (with death 
as the outcome) and whether or not the event leading to death was related to study drug, as 
well as the autopsy findings if available. 
Do not delay reporting a suspected SAE and/ or AESI suggestive of abuse potential in order to 
obtain additional information. Any additional information, if collected, can be reported as a 
follow-up to the initial report. All SAE and/ or AESI suggestive of abuse potential will be 
followed until resolution, until the event has stabilized, and/or reached a new baseline. All SAE 


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and/ or AESI suggestive of abuse potential continuing at the completion of the study must be 
assessed or followed to determine outcome. 
SAE and/ or AESI suggestive of abuse potential that occur after End of Study (i.e., after 
Week 12 [Visit 9] or Early Withdrawal) should be reported if the Investigator feels that there 
is a reasonable possibility for the event to have been caused by the subject’s participation in 
the study. The Investigator does not need to actively monitor subjects once the study has ended. 
9.5. 
Study Drug Overdose Management 
An overdose is defined as a known deliberate or accidental administration of a study drug, to 
or by a study subject, at a dose above that assigned to that individual subject according to the 
study protocol.  
The Sponsor’s Medical Monitor or designee must be contacted in the event of any study drug 
overdose. 
For this study, any dose of more than 1 dose (i.e., 8 capsules) of study drug is an overdose. 
There is no known antidote for an overdose. 
In the event of an overdose, the Investigator or treating physician should: 
• Contact the Sponsor’s Medical Monitor or designee immediately. 
• Closely monitor the subject for adverse events and laboratory abnormalities. 
• Report all overdose events as a Special Situation (see Section 9.9). 
• If possible, obtain a plasma sample for pharmacokinetic analysis within 2 days 
from the date of the last dose of study drug if requested by the Sponsor’s Medical 
Monitor or designee (determined on a case-by-case basis). 
• Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF. 
The Investigator, in consultation with the Sponsor’s Medical Monitor or designee, will make 
decisions regarding subject status, based on the clinical evaluation of the subject. 
9.6. 
Assigning Causal Relationship to Study Drug 
The reasonable possibility of the relationship of an adverse event to study drug is to be assessed 
with careful medical consideration at the time of evaluation of an adverse event. The following 
definitions are to be used for the relationship of the adverse event to study drug: 
• Related: A clinical event, including laboratory test abnormality, with a temporal 
relationship to study drug administration that makes a causal relationship 
plausible, unlikely attributed to concurrent disease or other drugs or chemicals, 
and that follows a clinically reasonable response on readministration (rechallenge) 
or withdrawal (dechallenge), although information on drug withdrawal may be 
lacking or unclear. 


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Note: Re-administration/rechallenge is not applicable for this single-dose study; 
but the terminology has been left in the definition for completeness. 
• Not related: A clinical event, including laboratory test abnormality, with a 
temporal relationship to study drug administration that makes a causal relationship 
improbable and/or in which other drugs, chemicals, or underlying disease provide 
a plausible explanation. 
All adverse events, whether or not related to study drug, must be fully and completely 
documented on the adverse event page of the eCRF and in the subject’s clinical record. In the 
event a subject is withdrawn from the study because of an adverse event, it must be recorded 
on the eCRF as such. 
9.7. 
Assigning Severity Rating for Adverse Events 
Severity describes the intensity of a specific event (as in mild, moderate, or severe myocardial 
infarction); the event itself, however, may be of relatively minor medical significance, such as 
a severe headache. This is not the same as “serious”, which is based on subject/event outcome 
or action taken. 
The Investigator must determine the severity of each adverse event according to the NCI 
CTCAE, version 5.0. For terms not specified within the CTCAE, the criteria in Table 7 should 
be used to determine the severity grade. 
Table 7: 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute Common Terminology 
Criteria for Adverse Events 
Grade 
Criteria 
1 
Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily livinga 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
livingb 
4 
Life threatening consequences; urgent intervention indicated 
5 
Death related to adverse event 
Note: The described grading is based on the National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
a 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b 
Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
Adverse event severity should be recorded in the appropriate section of the adverse event case 
report form and in the subject’s source documents. 


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9.8. 
Urgent Safety Measures 
All arrangements described in this section apply only to the extent that protocol requirements 
cannot be met because of restrictions due to a crisis, such as the COVID-19 pandemic. Study 
center visits should take place to the extent possible and usual protocol requirements adopted 
for all subjects as soon as the crisis-related limitations permit. 
Exceptional measures taken in response to a crisis (e.g., COVID-19) and their impact on study 
results, such as tests done in a local laboratory, will be explained, assessed and reported in the 
clinical study report following ICH E3 guidance. 
In case any visit described in the Schedule of Activities (Table 2) cannot be conducted at the 
study center within the visit window due to restrictions related to COVID-19 or another such 
crisis, a telephone visit, home visit and/or video (central rater) call should be arranged. 
The telephone visit should include all protocol assessments that can be performed remotely 
and should take place within the original visit window. The decision to replace the site visit 
with an alternate contact method will be made on a case by case basis with the Study Sponsor. 
In addition to the remote visit, the Investigator should make reasonable efforts to complete the 
following assessments/procedures as soon as possible (if applicable to the study visit): 
• Concomitant medication review/collection 
• Vital signs (blood pressure, heart rate, respiration rate, temperature) 
• 12-lead safety ECG 
• Adverse event collection 
• Chemistry and hematology 
• Urine drug screening 
• Urine pregnancy test (if applicable) 
• HAM-A (central rater) 
• C-SSRS – SLV Version 
9.9. 
 Special Situations 
Special situations with study drug are defined as the following:  
• Medication error or incorrect drug administration  
• Overdose (exceeds the protocol-specified maximum; see Section 9.5 for the 
definition of overdose) 
• Deliberate abuse 
• Deliberate misuse 
• Drug interaction  
• Occupational exposure 


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• Breastfeeding with suspected infant exposure 
• Drug accountability issue (e.g., diversion) if linked to an AE (see Section 6.7) 
If any of these special situations with study drug occur, they will be reported on the special 
situations with study drug eCRF page, even if there is no accompanying AE. All clinical 
manifestations in relation to these special situations (as defined above) will be reported as an 
SAEs or AESIs at the same time using the corresponding section of the eCRF. 
For example, if a medication error or interaction occurred, the Investigator will assess whether 
to consider an AE to have occurred, and if so, will assign the possible relationship to the study 
drug. 
Additional information may be requested by the site including all AE information and all 
triggering drug accountability discrepancies. 
9.10. 
Reporting of Pregnancy to the Sponsor 
For all WOCBP, urine dipstick pregnancy testing will be done locally as described in 
Section 8.3.4 and outlined in the Schedule of Activities (Table 2). If any subject becomes 
pregnant prior to Day 1/Randomization (Visit 3A), the subject is not eligible to be randomized 
in the study. 
As this is a single-dose study, if a subject becomes pregnant during the study after 
Day 1/Dosing Session (Visit 3B), she is not required to withdraw from the study. 
If a female sexual partner of a male subject becomes pregnant (by the male subject) within 
28 days after Day 1/Dosing Session (Visit 3B), and if the subject agrees, the subject’s pregnant 
partner should be notified and requested to sign a Release of Information form, permitting 
transfer of information regarding the pregnancy and outcome to the Sponsor. 
The Investigator must inform the subject of their right to receive treatment information. If the 
pregnant subject (or pregnant female partner of the subject) chooses to receive unblinded 
treatment information, the individual blind should be broken, and the treatment assignment 
provided to the subject/subject’s partner. The study team will remain blinded to the subject’s 
(partner’s) treatment assignment. If she agrees, the Investigator should notify the subject’s 
(partner’s) primary care physician of the pregnancy and provide details of the subject’s 
participation in the study and treatment (blinded or unblinded, as applicable). 
Pregnancy is to be reported to the Sponsor within 24 hours of awareness by the study site 
personnel, using the pregnancy reporting forms and the contact information in Section 9.4.2. 
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result, neonatal data, etc. should be included in this 
information, as available. 
The Investigator will follow the medical status of the mother, as well as the fetus, and will 
report the outcome to the Sponsor. 


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10. 
STATISTICAL CONSIDERATIONS 
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor. 
A general description of the statistical methods to be used to analyze the efficacy and safety 
data is outlined below. Specific details will be provided in the MMED008 Statistical Analysis 
Plan (SAP) that will be finalized prior to unblinding of the study. The treatment code will be 
opened after the study database has been locked. 
This study will utilize the Multiple Comparison Procedure-Modelling (MCP-Mod) approach 
to analyze the primary outcome measure. The MCP-Mod is a hybrid approach that combines 
hypothesis testing and modeling in a structured manner to analyze Phase 2 dose-ranging 
studies to find suitable dose(s) for confirmatory Phase 3 trials. 
10.1. 
Analysis Sets 
The following analysis sets will be defined for the statistical analysis. Subjects without valid 
written study informed consent will be excluded from all analysis sets. 
Table 8: 
MMED008 Analysis Sets 
Analysis Set 
Description 
Randomized Set (RAN) 
All subjects who received a randomization number, regardless of receiving trial 
medication. Subjects will be analyzed according to the treatment assigned. 
Safety Set (SAF) 
All subjects who received the double-blind study drug. Subjects will be analyzed 
according to actual treatment received. 
Full Analysis Set (FAS) 
All subjects in RAN with a valid Baseline HAM-A assessment and at least one 
valid post-baseline HAM-A assessment. Subjects will be analyzed according to the 
treatment assigned. 
Per Protocol Set (PPS) 
All subjects in FAS who had no major protocol deviations deemed as impacting 
the primary endpointa. Subjects will be analyzed according to the actual treatment 
received. 
a 
An impact assessment will be performed prior to the unblinding of the study. The impact assessment will 
determine whether a major protocol deviation impacts the primary endpoint thereby leading to the removal 
of the respective subject(s) from the PPS. 
10.2. 
Statistical Analyses 
10.2.1. 
Patient Demographics and Other Baseline Characteristics 
Summary statistics will be provided by treatment group for demographics and baseline 
characteristics, including sex at birth, self-identified gender, age, race, weight, height, BMI, 
systolic blood pressure, diastolic blood pressure, medical history, baseline values for HAM-A 
Total Score, PSQI, MADRS, CGI-I, CGI-S, PGI-S and ASEX. These summaries will be 
performed for the FAS and PPS populations.  
Continuous variables will be summarized using n, mean, standard deviation (SD), median, Q1 
(25th percentile), Q3 (75th percentile), minimum, and maximum. Categorical variables will be 
summarized using frequency and percentage. 


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10.2.2. 
Efficacy Analyses 
10.2.2.1. Primary Estimand 
The primary estimand quantifies the treatment effect of MM-120 at 4 weeks post-dose 
administration while accounting for intercurrent events (IEs) with potential confounding 
effects and IEs leading to study discontinuation prior to the 4-week assessment. 
The following attributes describe the primary estimand: 
• Population: As defined by the Inclusion/Exclusion criteria 
• Endpoint: Change from Baseline to Week 4 in HAM-A Total Score 
• Treatment of interest /the randomized treatment: 4 doses of MM-120 (25, 50, 100, 
or 200 µg free-base equivalent) or placebo as a single-dose treatment. 
• Handling of IEs prior to HAM-A assessment at Week 4: 
− Intake or change in concomitant medications/therapies which have potential 
confounding effects per the impact assessment. 
− Intake of prohibited medications/therapies assessed as “Yes” per the impact 
assessment. 
Policy strategy: Available data recorded after the IE will be set to missing; 
such missing data will be imputed/substituted under a Missing Not at Random 
(MNAR) assumption by borrowing information from the placebo arm subjects 
(reference-based imputation). 
− IEs leading to study discontinuation due to other reasons. 
− IEs related to the COVID-19 pandemic 
Policy strategy: Available data will be used; missing data will be imputed 
under a Missing at Random (MAR) assumption, borrowing information from 
subjects in the same treatment arm. 
• Summary measure: Identification of the dose-response curve and estimation of the 
target dose 
Statistical Methods & Analysis 
The MCP-Mod methodology (Bretz 2005; Pinheiro 2014) will be employed to assess the 
primary objective: to investigate the dose-response relationship for different doses of MM-120 
versus placebo in change from Baseline in HAM-A Total Score at Week 4. An overview of 
the steps for the MCP-Mod methodology is given below. 
Step 1 
The analysis to derive the test statistics is based on an analysis of covariance (ANCOVA) 
model with the change from Baseline to Week 4 for HAM-A Total Score as a response 
variable, treatment (placebo and all MM-120 doses), and Baseline value of HAM-A Total 
Score. Centers will be pooled according to country and region as appropriate and as defined in 
the SAP prior to unblinding.  


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Missing or potentially biased data will be imputed as described in the following section on 
Handling of Missing/Potentially Biased Values. To account for the imputation uncertainty, this 
ANCOVA model will be repeated for each imputed dataset, which results in a set of least-
squares (LS) mean estimates for all dose groups and the related covariance matrices. Rubin’s 
rule will be used to combine the multiple sets of LS mean estimates and the related covariance 
matrices to a single set of LS mean estimates of change from Baseline to Week 4 for HAM-A 
Total Score for all dose groups and the related covariance matrix. 
A range of possible dose-response relationships will be considered to take model uncertainty 
into account (see Figure 2). The following six candidate dose-response curves will be used to 
derive the optimal model contrasts for the multiple contrast tests: 
• Sigmoid Emax (ED50, hill): 
− 10, 1 
− 100, 5 
− 100, 10 
− 150, 10 
• Emax (D50 = 100) 
• Linear 
The optimal contrasts derived from the candidate model sets will be applied to the combined 
estimated dose means and covariance matrix to obtain the t-statistics for each candidate model 
and the common critical value C0.05 derived from the reference multivariate t-distribution with 
the 6x6 correlation matrix induced by testing the candidate dose-range models with respect to 
comparing all MM-120 doses to the placebo group.  
The null hypothesis will be rejected and the statistical significance of dose-response in change 
from Baseline to Week 4 for HAM-A Total Score will be established if the max (t1, t2, t3, 
…, t6) ≥ C0.05.  


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Figure 2: 
Candidate Dose-response Curves 
 
Step 2 
The response data in each imputed data set, including relevant covariates, will be used to fit 
the models in the candidate set. The estimated dose-response will be derived by using model 
averaging methods on a subset of candidate models, for which the associated contrast tests are 
statistically significant. The ≤ 3 models with the largest t-statistics ≥ C0.05 as calculated above 
will be selected as the basis for the model averaging.  
Model averaging will be carried out for each imputed data set, and the resulting mean efficacy 
estimates, and confidence intervals will be derived using the combination variance that 
accounts for the uncertainty of the imputed data using Rubin’s combination rules. Comparisons 
between MM-120 doses and placebo will be simultaneously derived for the model averaged 
estimates together with confidence intervals reflecting the imputation procedure applied. The 


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model-averaging-based estimates of the mean changes from Baseline to Week 4 for HAM-A 
Total Score within each dose group, and the mean differences between MM-120 and placebo 
and their confidence intervals will then be displayed.  
Target dose selection will be based on the model change from Baseline to Week 4 for HAM-A 
Total Score over the dose range studied.  
Detailed information about the algorithms including multiple imputation will be specified in 
the SAP that will be finalized prior to unblinding. 
The MCP-Mod analysis will be performed on the FAS population. It will also be performed 
on the PPS as a sensitivity analysis. 
Handling of Missing/Potentially Biased Values 
Missing data will be imputed using a multiple imputation approach assuming that the 
missingness mechanism can be retrieved from observed data. The imputation model will 
include the longitudinal sequence of HAM-A Total Score. 
For IEs, handling will depend on the IE causing the missing or potentially biased value as 
follows:  
• The data recorded after the IE will be imputed/substituted under an MNAR 
assumption by borrowing information from the placebo arm subjects (reference-
based imputation) for the following: 
− For intake or change in concomitant medications/therapies that have potential 
confounding effects per the impact assessment; or 
− For intake of prohibited medications/therapies assessed as “Yes” per the 
impact assessment. 
• Missing data will be imputed under a MAR assumption, borrowing information 
from subjects in the same treatment arm for the following: 
− For IEs leading to study discontinuation due to other reasons than the above, 
including IEs related to the COVID-19 pandemic. 
Centers will be pooled according to country and region as appropriate and as defined in the 
SAP prior to unblinding. 
The full detailed information about the multiple imputation algorithms will be specified in the 
SAP. 
10.2.2.2. Sample Size Determination 
A total sample of 180 subjects (36 per dose arm and 36 for the placebo arm) is required to 
ensure a mean power >87% for an MCP-Mod Analysis rejecting the hypothesis of a constant 
dose-response curve using the multiple comparisons procedure (MCP), assuming a null 
placebo response, a maximum standardized effect of 0.6 within the doses range, and a common 


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standard deviation within the dose arms, if a study-wise one-sided type-1 error rate < 0.05 is 
required. 
The analysis assumes 4 doses of active medication (25, 50, 100, and 200 µg freebase-
equivalent) and placebo. The required sample size for each dose arm is 36 subjects. 
The R package Dose Finding (https://CRAN.R-project.org/package=DoseFinding) has been 
used to estimate the sample size and the corresponding power. The power for each model is 
estimated as shown in Table 9. 
Table 9: 
Study MMED008 Power by Model 
Model 
Power (%) 
Sigmoid Emax (ED50, hill) 
 
10, 1 
84.5 
100, 5 
90.7 
100, 10 
91.0 
150, 10 
89.9 
Emax (D50 = 100) 
83.2 
Linear 
85.0 
 
10.2.2.3. Key Secondary Efficacy Endpoints 
The change from Baseline to Week 8 in HAM-A Total Score will be analyzed using the same 
process as the primary endpoint. The outcome will be considered confirmatory, if in agreement 
with the primary endpoint outcome and provided that the null hypothesis is rejected for the 
primary outcome. This gatekeeping function of the primary outcome allows to avoid any 
adjustment for multiplicity of testing. 
10.2.2.4. Secondary Efficacy Endpoints 
Change from Baseline to Week 1, Week 2 (as applicable), Week 4, Week 8 and End of Study 
(as applicable) in HAM-A, MADRS, CGI-S, CGI-I, PGI-S, PGI-C, SDS, EQ-5D-5L, PSQI 
and ASEX will be analyzed descriptively. Continuous outcomes will be summarized by: n, 
mean, standard deviation, median, Q1 (25th percentile), Q3 (75th percentile), minimum, 
maximum and 95% Confidence Interval for the mean. For the active doses similar statistics 
will be reported for the difference from placebo. Categorical measures will be summarized by 
the number and percentage of subjects within each category. 
10.2.3. 
Safety Analyses 
No statistical inference on safety parameters is planned. 
10.2.3.1. Adverse Events 
The verbatim terms used in the eCRF by Investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent 
adverse events are adverse events with onset after the treatment phase or that are a consequence 


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of a pre-existing condition that has worsened since baseline. All reported adverse events will 
be included in the analysis. For each adverse event, the percentage of subjects who experience 
at least 1 occurrence of the given event will be summarized by intervention group. In addition, 
comparisons between treatment groups will be provided as appropriate. 
Summaries, listings, datasets, or subject narratives will be provided, as appropriate, for those 
subjects who die, or who experience an important medical event, SAE, and/or AESI suggestive 
of abuse potential. 
10.2.3.2. Other Safety Parameters 
Other safety outcomes, including vital signs, ECG parameters and abnormalities, C-SSRS 
scores, and laboratory parameter values, will be reported by treatment arm. All safety data 
(scheduled and unscheduled) will be presented in the data listings. Continuous variables will 
be summarized using descriptive statistics (n, mean, SD, minimum, median, and maximum) 
by treatment/dose group at relevant timepoints. Categorical variables will be summarized in 
frequency tables (frequency and proportion) by treatment/dose group at relevant timepoints. 
Graphical presentations will be used as appropriate. 
Where applicable, data will be summarized for the absolute value at each scheduled assessment 
and for the corresponding change from baseline. For clinical laboratory tests, listings of values 
for each subject will be presented with abnormal or out-of-range values flagged. The 
percentage of subjects with values beyond clinically important limits will be summarized by 
frequency tables and shift tables. 
Treatment-emergent ECG abnormalities will be summarized similarly to AEs. 
10.2.4. 
Other Analyses 
10.2.4.1. Treatments 
A summary of subjects receiving or not receiving the single-dose treatment will be provided 
overall. 
10.2.5. 
Interim Analyses 
No interim analyses are planned. 


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11. 
STUDY GOVERNANCE CONSIDERATIONS 
11.1. 
Financial Disclosure 
Financial disclosure requirements are outlined by the United States Code of Federal 
Regulations Title 21, Part 54 (21 CFR 54), Financial Disclosure by Clinical Investigators. It is 
the Sponsor's responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the Investigator's and sub-Investigator's 
responsibility to comply with any such request. 
This is a “covered clinical study”, defined under 21 CFR 54 as “any study of a drug or device 
in humans submitted in a marketing application or reclassification petition subject to this part 
that the applicant or FDA relies on to establish that the product is effective (including studies 
that show equivalence to an effective product) or any study in which a single Investigator 
makes a significant contribution to the demonstration of safety.” As such, all Investigators and 
sub-Investigators must provide documentation of their financial interest or arrangements with 
the Sponsor or proprietary interests in the drug being studied. This documentation must be 
provided before participation of the Investigator and any sub-Investigator. The Investigator 
and sub-Investigator agree to notify the Sponsor of any change in reportable interests during 
the study and for 1 year following completion of the study. 
11.2. 
Pre-Initiation Visit 
Sponsor personnel or designee(s) may visit the study site as necessary prior to initiation of the 
study to review information about the study drug, protocol requirements, eCRFs, monitoring 
requirements, and reporting of adverse events with the site personnel. 
11.3. 
Data Management 
Subject data will be entered into a Sponsor-approved electronic database and combined with 
data from other sources in validated datasets then transmitted electronically to the Sponsor or 
designee. 
Management of clinical data will be performed in accordance with applicable Sponsor-
approved standards and data cleaning procedures to ensure data integrity (e.g., errors will be 
corrected, and inconsistencies clarified). 
Adverse events and concomitant medications terms will be coded using the MedDRA and the 
World Health Organization Drug Dictionary Enhanced (WHO-DDE), respectively. 
The Investigator will retain original source documents and the Sponsor will receive eCRF-
required data as electronic datasets. Subject initials will not be collected or transmitted to the 
Sponsor. 
11.4. 
Monitoring 
This study will be monitored by the Sponsor (or designee) in accordance with current GCP 
regulations. By signing this protocol, the Investigator grants permission to the Sponsor (or 
designee) and appropriate regulatory authorities to conduct on-site monitoring of all 
appropriate study documentation. In order to verify the accuracy of data collected in the eCRF, 


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the monitor will require direct access to original source documents (e.g., patient records, 
patient charts, and laboratory reports). 
During the review of these documents, the anonymity of the subject will be respected with 
strict adherence to professional standards of confidentiality. A study monitor will contact and 
visit the site regularly and will be allowed, on request at a mutually acceptable time, to inspect 
the various records of the study. It will be the study monitor’s responsibility to inspect the 
eCRF at regular intervals throughout the study, to verify the adherence to the protocol and the 
completeness, correctness, and accuracy of all eCRF entries, and to meet with the Investigator 
to discuss study progress and compliance with the protocol and GCP. The study monitor should 
have access to laboratory test results and any other source records and data needed to verify 
the entries on the eCRF. The Investigator agrees to cooperate with the study monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved. 
11.5. 
Auditing or Inspections 
Representatives of regulatory authorities, health authorities, the Sponsor or IRBs/IECs may 
conduct inspections or audits of the clinical study. If the Investigator is notified of an inspection 
by a regulatory authority, the Investigator agrees to notify the Sponsor immediately. By signing 
this protocol, the Investigator agrees to provide to appropriately qualified personnel from such 
groups, access to records, facilities and personnel for the effective conduct of any inspection 
or audit. 
11.6. 
Safety Review  
The Sponsor’s Medical Monitor or designee will review blinded safety data listings monthly 
as detailed in the Medical Management Plan (MMP). Safety review meetings will review 
ongoing data for all subjects to identify trends in safety parameters. If necessary, the Sponsor 
will terminate the study if this blinded review process identifies significant intolerable safety 
signals based on either individual or aggregate blinded safety information that puts subjects in 
this study at unacceptable risk. 
11.7. 
Protocol Modifications 
Protocol modifications, except those made by the Investigator when intended to reduce 
immediate risk to subjects, may be made only by the Sponsor. All protocol modifications must 
be submitted to the IRB/IEC in accordance with local requirements. Approval must be obtained 
before changes can be implemented. The Investigator must not deviate from the protocol 
without first obtaining approval from the Sponsor and the IRB/IEC, if required. In medical 
emergencies, the Investigator will use medical judgment and will remove the subject from 
immediate hazard, then notify the Sponsor (or designee) and the IRB/IEC immediately 
regarding the type of emergency and the course of action taken. The Investigator must notify 
the Sponsor (or designee) of any inadvertent protocol deviations upon their discovery and 
document the deviations appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the informed consent form will be amended and approved by the IRB/IEC, 
and all subjects on treatment will again provide informed consent. 


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11.8. 
Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time. Should this be necessary, the 
Sponsor will arrange discontinuation procedures and notify the appropriate regulatory 
authority(ies) and IRBs/IECs. In terminating the study, the Sponsor and the Investigator will 
ensure that adequate consideration is given to the protection of the study subjects’ interests. 
11.9. 
Publications 
After conclusion of the study and without prior written approval from the Sponsor, 
Investigators in this study may communicate, orally present, or publish in scientific journals 
or other scholarly media only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with 
the consent of the Sponsor in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 5 years. 
No such communication, presentation or publication will include the Sponsor’s confidential 
information (see Section 11.10.5). 
The Investigator will submit to the Sponsor any proposed publication or presentation along 
with the respective target scientific journal or presentation forum at least 30 days before 
submission of the publication or presentation. The Investigator will comply with Sponsor 
requests to delete references to its confidential information (other than the study results) in any 
paper or presentation and agrees to withhold publication or presentation for an additional 
60 days in order to obtain patent protection if deemed necessary. 
11.10. 
Investigator-Specific Responsibilities 
11.10.1. 
Compliance with Regulations and Ethical Standards 
The Investigator will ensure that this study is conducted in accordance with the principles of 
the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws 
and regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. For studies conducted under a United States investigational 
new drug application, the Investigator will ensure that the basic principles of “Good Clinical 
Practice,” as outlined in 21 Code of Federal Regulations (CFR 312), subpart D, 
“Responsibilities of Sponsors and Investigators”, 21 CFR, part 50, 1998, and 21 CFR, part 56, 
1998, are adhered to. These standards are consistent with the requirements of the European 
Community Directive 2001/20/EC. 
The Investigator will also comply with financial disclosure requirements as described in 
Section 11.1. 
11.10.2. 
Protocol Compliance 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 


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11.10.3. 
Institutional Review Board/Independent Ethics Committee Requirements 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure and any 
other relevant materials, including accompanying material to be provided to the subject 
(e.g., advertisements, patient information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the Investigator to an IRB/IEC. Approval from the 
IRB/IEC must be obtained before starting the study and should be documented in a letter to 
the Investigator specifying the following: 
• Protocol number 
• Protocol version 
• Protocol date 
• Documents reviewed 
• Date on which the committee met and granted the approval. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs, AESIs suggestive of abuse potential or other 
significant safety findings as required by procedures established by the IRB/IEC. 
11.10.4. 
Obtaining Informed Consent 
The Investigator (or Investigator’s designee) is responsible for obtaining informed consent 
from each study subject. To help the individual make an informed decision about participating, 
the Investigator (or designee) shall discuss with the potential subject the purpose of the 
research, procedures, risks, benefits, alternative options to participating, confidentiality, how 
to contact study personnel and the subject’s rights. Potential subjects must be informed that 
their participation is voluntary and must be given ample time to ask the Investigator questions 
and obtain clarifications regarding the study prior to providing consent. 
The Investigator must utilize an IRB/IEC-approved informed consent form for documenting 
written informed consent that contains all elements required by national, state, local and 
institutional regulations or requirements. Each informed consent form will be appropriately 
signed and dated by the subject and the person obtaining consent. 
As described in Section 11.6, subjects must be re-consented to participate in the study if a 
protocol amendment is made that substantially alters the study design or the potential risks or 
burden to subjects. 


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11.10.5. 
Confidentiality 
The Investigator must ensure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject number, date of birth, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the Sponsor, IRB/IEC or laboratory. The Investigator must keep a screening log 
showing codes, names and addresses for all subjects screened and for all subjects enrolled in 
the study. 
The Investigator agrees that all information received from the Sponsor, including but not 
limited to the protocol, Investigator’s Brochure, eCRFs and other study forms, the 
investigational drug and any other study information, remain the sole and exclusive property 
of the Sponsor during the conduct of the study and thereafter. This information is not to be 
disclosed to any third party (except employees or agents directly involved in the conduct of 
the study or as required by law) without prior written consent from the Sponsor. The 
Investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain. 
11.10.6. 
Study Files and Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These documents 
should be classified into at least the following two categories: 
1. Investigator’s study file. The Investigator’s study file will contain the Investigator’s 
Brochure, protocol/amendments, IRB/IEC and governmental approval with 
correspondence, informed consent forms, drug records, staff curriculum vitae, 
authorization and training forms and other appropriate documents and correspondence. 
2. Subject clinical source documents. The required source data should include the 
following for each subject: 
• Subject identification (name, date of birth, gender) 
• Documentation that the subject meets eligibility criteria (e.g., history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion 
criteria) 
• Participation in the study (including study number) 
• Study discussed and date of informed consent 
• Dates of all visits 
• Documentation that protocol-specific procedures were performed 
• Results of efficacy parameters, as required by the protocol 
• Dosing date of study drug 
• Record of all adverse events and other safety parameters (start and end date, and 
causality and intensity as assigned by the Investigator) 
• Concomitant medication (including start and end date) 


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• Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the Investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (i.e., United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH region; 
or, if no application is filed or if the application is not approved for such indication, until 2 
years after the investigation is discontinued and regulatory authorities have been notified. 
Investigators may be required to retain documents longer if required by applicable regulatory 
requirements, by local regulations or by an agreement with the Sponsor. The Investigator must 
notify the Sponsor before destroying any clinical study records. 
Clinical study documentation includes the Investigator’s Brochure, signed protocol and 
amendments, signed informed consents, notification of serious adverse events and related 
reports, any dispensing and accountability logs, shipping records of study drug and study-
related materials, documentation of financial aspects of the study, insurance statement, signed 
agreement between the involved parties, dated and documented IRB/IEC approval, approval 
of regulatory authorities as applicable, decoding procedures for blinded studies, curriculum 
vitae and all training records of study site personnel and all correspondence pertaining to the 
conduct of the study. 
Should the Investigator wish to assign the study records to another party or move them to 
another location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the Investigator and the 
Sponsor to store these in sealed containers outside of the site so that they can be returned sealed 
to the Investigator in case of a regulatory audit. When source documents are required for the 
continued care of the subject, appropriate copies should be made for storage outside of the site. 
11.10.7. 
Electronic Case Report Forms 
For each subject enrolled, an eCRF must be completed and signed by the Investigator or sub-
Investigator (as appropriate) listed on Food and Drug Administration Form 1572 and/or other 
appropriate local health authority documents within a reasonable time period after data 
collection. This also applies to records for those subjects who fail to complete the study (even 
during a pre-randomization screening period if an eCRF was initiated). If a subject withdraws 
from the study, the reason must be noted on the eCRF. If a subject is withdrawn from the study 
because of a treatment-limiting adverse event, thorough efforts should be made to clearly 
document the outcome. 
11.10.8. 
Monitoring of Study Drug Accountability 
The Investigator or approved Investigator’s designee (e.g., pharmacist) is responsible for 
ensuring adequate accountability (including dates and lot numbers) of all used and unused 
study drug (active and placebos). This includes acknowledgment of receipt of each shipment 
of study drug (quantity and condition), subject dispensing records and returned or destroyed 
study drug. Dispensing records will document quantities received from the Sponsor and 
quantities dispensed to subjects, including lot number, date dispensed, Subject Identification 
Number and the initials of the person dispensing the medication. 


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At study initiation, the study monitor will evaluate the site’s standard operating procedure for 
study drug disposal/destruction in order to ensure that it complies with the Sponsor’s 
requirements. Study drug may be returned or destroyed on an ongoing basis during the study 
if appropriate. At the end of the study, following final study drug inventory reconciliation by 
the monitor, the study site will dispose of and/or destroy all unused study drug supplies, 
including empty containers, according to these procedures. If the site cannot meet the 
Sponsor’s requirements for disposal, arrangements will be made between the site and the 
Sponsor (or designee) for destruction or return of unused study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by 
the study monitor over the course of the study. 
11.11. 
Sponsor-Specific Responsibilities 
11.11.1. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies). The 
Sponsor will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may 
be prepared in certain cases. 
11.11.2. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of subjects begins. Results will be posted as required. 


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APPENDIX 1. DEFINITION OF WOMEN OF CHILDBEARING 
POTENTIAL AND ACCEPTABLE HIGHLY 
EFFECTIVE METHODS OF CONTRACEPTION 
Definition of Women of Childbearing Potential (WOCBP) 
A woman of childbearing potential (WOCBP) is defined as a person who is physiologically 
capable of becoming pregnant. 
Subjects are considered to be not of childbearing potential if they meet at least one of the 
following conditions: 
• Has undergone total hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, or bilateral tubal ligation at least 2 months prior to Screening  
• Has a congenitally absent uterus 
• Is postmenopausal, confirmed as being age > 45 years with one of the following: 
− At least 1 year without menses prior to Screening 
− 6 months to < 1 year without menses prior to Screening and serum FSH levels 
> 40 mIU/mL at Screening. 
Acceptable Highly Effective Methods of Contraception 
Highly effective birth control methods are methods that can achieve a failure rate of less than 
1% per year when used consistently and correctly. The following highly effective methods of 
contraception are acceptable for use by WOCBP: 
• Oral, injected or implanted hormonal methods of contraception 
− Combined estrogen and progestogen hormonal contraception (oral, 
intravaginal, transdermal) associated with inhibition of ovulation; these should 
be initiated at least 3 months prior to Screening 
− Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation; these should be initiated at least 
3 months prior to Screening 
• Established intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS) (in place for at least 2 months prior to Screening) 
• Surgical sterilization verified by either medical records (requires a medical 
release) or a progress note prior to randomization (hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy, bilateral tubal ligation or vasectomy at 
least 2 months prior to Screening) 
• Sexual activity is limited to a male partner who has undergone effective surgical 
sterilization provided that partner is the sole sexual partner of the female study 
subject 
• Sexual activity is limited to same sex partner 


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• Two barrier methods of contraception: condom and occlusive cap (diaphragm or 
cervical/vault cap) with spermicide 
Unacceptable Methods of Contraception 
Abstinence, periodic abstinence (calendar, “symptothermal,” and post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only and lactational amenorrhea method are not 
acceptable methods of contraception. A female condom and male condom should not be used 
together. 


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APPENDIX 3. RESCUE MEDICATIONS 
Rescue medications should only be considered after non-medical interventions have been 
exhausted. Under all circumstances, only the study site-designated physician will administer 
rescue medications in this study. The choice of rescue medications is at the discretion of the 
study site-designated physician and should be based on subject medical history and local 
standard of care. 
The unique pharmacologic properties of individual rescue medications (e.g., rapidity of onset, 
persistence of active drug or metabolite in the body) should be considered for rescue and 
considered along with a subject’s sex, age, weight and/or comorbidities. 
The study site-designated physician must consider rescue medications and if they have been 
associated with lengthening QTc interval, which can lead to syncope, arrhythmia or sudden 
cardiac arrest. 
Other Considerations: 
• Adjustment of doses for non-smokers versus moderate to heavy smokers. 
• Concurrent use of IM and IV benzodiazepines and neuroleptics, individually or 
concomitantly, is not recommended outside of an emergency setting because of the 
need to monitor (e.g., a respiratory depression). 
• If a rescue medication is considered, monitoring parameters include mental 
status/alertness, vital signs, neuropsychiatric signs and symptoms, delirium, fever, 
muscle rigidity, and/or autonomic instability, and risk of falling. Follow-up with 
ECG as needed. 
Examples of acceptable rescue medications including benzodiazepines, neuroleptics, and 
antiemetics are shown in Table 10, Table 11, and Table 12. These tables are not meant to be 
exhaustive. 
Table 10: 
Examples of Rescue Benzodiazepines: Dosing  
Drug 
Adult oral doses (mg) 
Alprazolam 
0.5 to 6 
Clonazepam 
0.5 to 4 
Diazepam 
4 to 40 
Lorazepam immediate release 
0.5 to 6 
0.5 to 4 (hypnotic) 
 


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Table 11: 
Examples of Rescue Neuroleptics: Dosing  
Agent 
Initial oral dose range 
(mg) 
Adjustment of oral dose in older subjects 
Olanzapine 
5 to 10 
1.25 to 2.5 mg 
Quetiapine 
50 (immediate release) 
300 (extended release) 
25 to 50 mg 
Risperidone 
1 to 2 
0.25 to 0.5 mg 
 
Table 12: 
Examples of Medications for Nausea  
Nausea is a known and tolerable effect of this compound. Supportive solutions are the best 
first line treatment, please refer to DSMM.  
 
Drug 
Dosing 
Benzodiazepines 
Refer to Table 10 for appropriate doses 
Ondansetron 
8 mg q12 hr 
Promethazine 
25 mg q12 hr 
 


Signature Page for VV-CLIN-000052 v1.0
Signature Page for VV-CLIN-000052 v1.0
Approval Task Task
Verdict: Approved
27-Jul-2023 18:02:00 GMT+0000