Glutide for Ending Methamphetamine
Phase: PHASE2
Conditions: Methamphetamine-dependence
Sponsor: San Francisco Department of Public Health

CONFIDENTIAL 
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16 September 2025 
SAN FRANCISCO DEPARTMENT OF PUBLIC HEALTH 
 
CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
Glutide for Ending Methamphetamine (GEM) 
Sponsor: 
San Francisco Department of Public Health 
25 Van Ness Avenue, Suite 500 
San Francisco, California 94102 
IND No.: 
173445 
Indication: 
Methamphetamine Use Disorder 
Study Director: 
Name: 
Phillip O. Coffin, MD MIA 
Telephone: 
415-437-6282 
E-mail: 
Phillip.coffin@sfdph.org 
 
 
Protocol Version/Date: 
Original:              15 April 2025 
Amendment 1:  16 September 2025 
  
 

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16 September 2025 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................................... 2 
PROTOCOL SYNOPSIS ........................................................................................................................... 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 10 
1. 
INTRODUCTION ........................................................................................................................... 11 
1.1. 
Background ......................................................................................................................................... 11 
1.2. 
Semaglutide ......................................................................................................................................... 12 
1.3. 
Rationale for the Current Study ........................................................................................................ 12 
1.4. 
Rationale for Dose Selection of Semaglutide ................................................................................... 12 
1.5. 
Overall Risk/Benefit Assessment...................................................................................................... 13 
1.6. 
Compliance .......................................................................................................................................... 13 
2. 
OBJECTIVES ................................................................................................................................... 14 
3. 
STUDY DESIGN ............................................................................................................................. 15 
3.1. 
Study Treatment and Duration of Treatment .................................................................................. 15 
4. 
SUBJECT POPULATION .............................................................................................................. 16 
4.1. 
Number of Subjects and Subject Selection ....................................................................................... 16 
4.2. 
Inclusion Criteria ................................................................................................................................ 16 
4.3. 
Exclusion Criteria ................................................................................................................................ 17 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ...................................................................... 19 
5.1. 
Description and Handling of Semaglutide ....................................................................................... 19 
5.1.1. 
Formulation ............................................................................................................................................. 19 
5.1.2. 
Packaging and Labeling .......................................................................................................................... 19 
5.1.3. 
Storage and Handling ............................................................................................................................. 19 
5.1.4. 
Dosage and Administration of Semaglutide .......................................................................................... 20 
Management of Missed Doses ......................................................................................................................... 20 
5.2. 
Prior and Concomitant Medications ................................................................................................. 20 

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16 September 2025 
5.3. 
Study Drug Adherence ........................................................................................................................ 21 
5.4. 
Accountability for Study Drug ........................................................................................................... 21 
5.4.1. 
Investigational Medicinal Product Return or Disposal ........................................................................ 21 
6. 
STUDY PROCEDURES ................................................................................................................. 22 
6.1. 
Subject Enrollment and Treatment Assignment ............................................................................. 22 
6.2. 
Pretreatment Assessments ................................................................................................................ 22 
6.2.1. 
Screening Visits ....................................................................................................................................... 22 
6.2.2. 
Enrollment Visit (week 0) ...................................................................................................................... 22 
6.3. 
Weekly Treatment Visits (weeks 1-3, 5-7, 9-11) ............................................................................. 23 
6.4. 
Monthly Treatment Visits (weeks 4, 8, and 12) ............................................................................... 23 
6.5. 
Post-trial Study Visit (week 20) ........................................................................................................ 24 
6.6. 
Post Treatment Assessments ............................................................................................................ 24 
6.7. 
Survey ................................................................................................................................................... 24 
6.8. 
Assessments for Premature Discontinuation from Study .............................................................. 24 
6.9. 
End of Study ......................................................................................................................................... 24 
6.10. 
Procedures and Specifications .......................................................................................................... 25 
6.10.1. 
Clinical Laboratory Analytes ............................................................................................................. 25 
6.10.2. 
Medical History .................................................................................................................................. 25 
6.10.3. 
Physical Examination ......................................................................................................................... 26 
6.10.4. 
Vital Signs ........................................................................................................................................... 26 
6.10.5. 
Body Mass Index (BMI) ...................................................................................................................... 26 
6.10.6. 
Liver Function .................................................................................................................................... 26 
6.10.7. 
Structured Clinical Interview for DSM-IV (SCID) ............................................................................. 26 
7. 
TOXICITY MANAGEMENT ......................................................................................................... 27 
7.1. 
Subject Stopping Rules ....................................................................................................................... 27 
7.2. 
Study Discontinuation Criteria .......................................................................................................... 27 
7.3. 
Dose Titration Rules ........................................................................................................................... 28 
8. 
ADVERSE EVENTS MANAGEMENT ......................................................................................... 29 
8.1. 
Definition of Adverse Events, Adverse Reactions, and Serious Adverse Events .......................... 29 
8.1.1. 
Adverse Event ......................................................................................................................................... 29 
8.1.2. 
Serious Adverse Events .......................................................................................................................... 30 
8.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or Serious 
Adverse Events ...................................................................................................................................................... 30 

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8.2. 
Assessment of Adverse Events and Serious Adverse Events.......................................................... 30 
8.2.1. 
Assessment of Causality for Study Drug and Procedures .................................................................... 30 
8.3. 
Assessment of Severity ....................................................................................................................... 31 
8.4. 
Investigator Requirements for Reporting Adverse Events and Serious Adverse Events ........... 31 
8.4.1. 
Reporting to UCSF Committee on Human Research (CHR / IRB) ....................................................... 31 
8.4.2. 
Reporting to Data Safety Monitoring Board (DSMB) ........................................................................... 31 
8.4.3. 
Reporting to NIH – National Institute of Drug Abuse (NIDA) .............................................................. 32 
8.5. 
Special Situations Reports ................................................................................................................. 32 
8.5.1. 
Definitions of Special Situations ............................................................................................................ 32 
8.5.2. 
Instructions for Reporting Special Situations ....................................................................................... 32 
9. 
STATISTICAL CONSIDERATIONS ........................................................................................... 34 
9.1 
Analysis Objectives and Endpoints ................................................................................................... 34 
9.1.1 
Analysis Objectives ................................................................................................................................. 34 
9.1.2 
Primary Endpoints .................................................................................................................................. 34 
9.1.3 
Secondary Endpoints .............................................................................................................................. 34 
9.1.4 
Other Endpoints of Interest ................................................................................................................... 35 
9.1.6 
Demographic Data and Baseline Characteristics ............................................................................ 35 
9.2 
Data Analysis ....................................................................................................................................... 35 
9.2.1 
Primary Analysis ..................................................................................................................................... 35 
9.2.2 
Exploratory Analyses .............................................................................................................................. 36 
9.3 
Sample Size .......................................................................................................................................... 37 
10 
RESPONSIBILITIES ................................................................................................................. 38 
10.1 
Investigator Responsibilities ............................................................................................................. 38 
10.1.1 
Good Clinical Practice ........................................................................................................................ 38 
10.1.2 
Institutional Review Board (IRB) Approval ..................................................................................... 38 
10.1.3 
Informed Consent ............................................................................................................................... 38 
10.1.4 
Confidentiality .................................................................................................................................... 38 
10.1.5 
Study Files and Retention of Records ............................................................................................... 38 
10.1.6 
Case Report Forms (CRFs) ................................................................................................................. 39 
10.1.7 
Investigational Medicinal Product Accountability and Return ....................................................... 39 
10.1.8 
Inspections .......................................................................................................................................... 40 
10.1.9 
Protocol Compliance .......................................................................................................................... 40 
10.1.10 
Protocol Modifications ....................................................................................................................... 40 
10.1.11 
Access to Information for Auditing or Inspections .......................................................................... 40 
10.1.12 
Study Discontinuation........................................................................................................................ 40 
11 
APPENDICES ............................................................................................................................. 41 
Appendix 1. 
Study Procedures Table........................................................................................................ 42 
Appendix 2. Suicidality SOP ............................................................................................................................. 43 

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Appendix 3. Description and Dates of Amendments .................................................................................... 45 
 

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PROTOCOL SYNOPSIS 
San Francisco Department of Public Health 
25 Van Ness Ave, Suite 500 
San Francisco CA 94102 
 
 
Study Title: 
Glutide for Ending Methamphetamine (GEM) 
IND Number: 
173445 
Study Centers 
Planned: 
1 site in the United States 
Number of Subjects 
Planned: 
25 subjects 
Target Population: 
Adults with moderate to severe methamphetamine use disorder 
Duration of 
Treatment: 
Subjects will receive study treatment for 12 weeks 
Objectives: 
The primary objectives of this study are as follows: 
1. To determine acceptability, feasibility, and preliminary 
efficacy of weekly injectable semaglutide for adults with 
methamphetamine use disorder (MeUD). 
2. To evaluate safety and tolerability of semaglutide among adults 
with MeUD.  
The exploratory objectives of this study are as follows: 
1. To measure the impact of semaglutide on methamphetamine 
cravings through the Brief Substance Use Craving Scale. 
2. To measure the impact of semaglutide on inflammation related 
to methamphetamine use by measuring hs-CRP, IL-1β, IL-6, and 
TNF-α as the primary biomarkers. 
3. To measure the impact of semaglutide on cognitive function 
through the CogState Battery. 
Study Design: 
Twenty-five subjects will be enrolled in this phase IIa open-label single-
arm trial and will be assigned to the following treatment: 
Semaglutide (Wegovy) administered by clinician via subcutaneous 
injection once weekly for 12 weeks (N=25). 

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16 September 2025 
• 
Semaglutide injection dose will follow the product label 
(0.25mg SC weekly for 4 weeks; 0.5mg SC weekly for 4 weeks; 
1.0mg SC weekly for 4 weeks) 
Diagnosis and 
Main Eligibility 
Criteria:  
Adults aged 18 – 65 with moderate to severe MeUD and frequent 
methamphetamine use, BMI ≥ 25kg/m2, with no history of diabetes, 
thyroid disease, significant cardiovascular disease, or moderate to 
severe cocaine or opioid use disorder. 
Reference Section 4.2 and 4.3 of the protocol for detailed Inclusion and 
Exclusion criteria. 
Study 
Procedures/ 
Frequency: 
Screening assessments will be completed across two to four visits 
consisting of two screening visits and up to two run-in visits.  
All subjects will complete the following study visits: screening 1 and 2, 
run-in visit 1 and 2 (as needed), enrollment (week 1), weekly study 
visits (weeks 2-12), with additional procedures at weeks 4, 8, and 12, 
and a post-study follow-up visit at week 20. Additional visits will be 
completed as necessary for emergent adverse events.  
After consent is obtained, screening assessments (split between two 
visits) will include: complete medical history and physical examination, 
mental health and substance use history by Structured Clinical 
Interview for Diagnostic and Statistical Manual of Mental Disorders IV-
TR (SCID), urine testing for methamphetamine and other substances, 
and lab testing including comprehensive metabolic panel (CMP), 
hemoglobin A1c, lipase, amylase, calcitonin, and urine pregnancy test. 
The enrollment visit will include baseline survey, hair sample 
collection, urine drug testing, biomarker testing, study drug 
administration, medical management (MM) counseling for substance 
use, vital signs, and a symptom-driven physical exam. 
Weekly study visits (weeks 2 – 12) will include study drug 
administration, urine testing for methamphetamine, TLFB assessment 
of methamphetamine use, and adverse event assessment with a 
symptom-driven physical exam.  
Monthly visits (occurring at weeks 4, 8) will include safety lab 
assessment, urine testing for methamphetamine and other substances, 
survey, and MM counseling, in addition to all weekly study visit 
procedures.  
The week 12 visit will include all assessments for weekly and monthly 
visits, as well as hair sample collection, biomarker testing, and CogState 
Battery. Study drug will not be administered at the week 12 visit. 
An off-treatment follow-up visit will occur eight weeks post-study 
(week 20) and will include urine drug testing, vital signs, symptom-
drive physical exam, survey, and AE assessment. 

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Test Product, Dose, 
and Mode of 
Administration: 
Semaglutide (Wegovy) is manufactured for subcutaneous 
administration as a single-use pen that delivers 0.25, 0.5, or 1 mg per 
injection in the first 12 weeks of therapy (higher doses are available for 
later in the standard titration process). Study drug will be administered 
by clinician in the abdomen, thigh, or upper arm at each weekly study 
visit according to the following schedule: 0.25mg weekly for 4 weeks, 
0.5mg weekly for 4 weeks, 1.0mg weekly for 4 weeks.  
Reference Therapy, 
Dose, and Mode of 
Administration: 
All participants will receive semaglutide according to the product label. 
Study medication will be stored in our alarm-secured pharmacy 
refrigerator. Medication will be administered by clinician via 
subcutaneous injection at each visit.   
Criteria for 
Evaluation Safety: 
To assess safety, we will closely monitor adverse events through 
clinician interview, vital signs (including weight), and safety labs. We 
will assess for AEs at every visit and complete monthly safety labs. 
Should a participant become pregnant or report a desire to become 
pregnant during the trial, the study drug will be discontinued and the 
event will be reported to the institutional review board (IRB) or Data 
and Safety Monitoring Board (DSMB). 
Efficacy: 
Efficacy will be evaluated using within-person changes in 
methamphetamine concentration in hair and self-reported 
methamphetamine use (co-primary) and weekly urine drug testing for 
methamphetamine (exploratory). 

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Statistical Methods: 
Aim 1: To determine acceptability, feasibility, and preliminary efficacy 
of weekly injectable semaglutide for adults with MeUD, we will 
determine the ratio of eligible to enrolled participants, adherence to 
weekly injections, and willingness to continue therapy at study 
conclusion, as well as the change in methamphetamine concentration in 
hair samples and change in frequency of methamphetamine use by 
time-line followback (TLFB). 
Aim 2: To evaluate safety and tolerability of semaglutide among adults 
with MeUD, we will closely track self-reported and laboratory adverse 
events and the rate of study drug discontinuation due to adverse 
events. 
Other Exploratory Outcomes:  
To explore the effect of the semaglutide on methamphetamine use, we 
will conduct urine drug testing for methamphetamine. We do not 
expect to be powered to detect a significant effect on urine positivity for 
methamphetamine. 
To measure the impact of semaglutide on methamphetamine cravings 
through the Brief Substance Craving Scale. 
To measure the impact of semaglutide on inflammation related to 
methamphetamine we will measure hs-CRP, IL-1β, IL-6, and TNF-α, 
with hs-CRP as the primary biomarker. 
To assess the impact of semaglutide on cognitive function through the 
CogState Battery. 
This study will be conducted in accordance with the guidelines of Good Clinical Practices (GCPs) 
including archiving of essential documents. 

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse event 
ALT 
Alanine transaminase  
AST 
Aspartate aminotransferase (also SGOT) 
BPM 
Beats per minute 
BMI 
Body mass index 
DSMB 
Data safety monitoring board 
DSMP 
Data safety monitoring plan 
CGI 
Clinical Global Impression 
CHR 
Committee on human research 
CI 
Confidence interval 
CRF 
Case report form(s) 
CMP 
Comprehensive metabolic panel  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DAIDS 
Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events 
FDA 
(United States) Food and Drug Administration 
GCP 
Good Clinical Practice (Guidelines) 
Hgb 
Hemoglobin 
hs-CRP 
High-sensitivity C-reactive protein 
IRB 
Institutional review board 
IL-1β 
Interleukin-1 beta 
IL-6 
Interleukin-6 
min 
Minute 
MM 
Medical management 
mmHg 
Millimeters mercury 
ng/mL 
Nanograms per milliliter 
NTIM 
Narrow therapeutic index medication 
PI 
Principal investigator  
SAE 
Serious adverse event 
SD 
Standard deviation 
SF-36 
36 Item Short Form Survey 
STI 
Sexually transmitted infection 
SOP 
Standard operating procedure 
TNF-α 
Tumor necrosis factor-alpha 
UCSF 
University of California, San Francisco 
US 
United States 

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1. 
INTRODUCTION 
1.1. 
Background 
Methamphetamine is highly addictive with serious medical, societal, and economic consequences. 
Methamphetamine use remains more prevalent than many other drugs, including opioids, with 37 
million users of amphetamines worldwide and 2.1 million past-year users in the U.S. alone in 2021. 
At least half of people who regularly use methamphetamine have MeUD. U.S. methamphetamine 
poisoning deaths have steadily risen in recent years, from 1,887 in 2011 to 32,537 in 2021. San 
Francisco has witnessed a marked increase in methamphetamine mortality.  
  
Methamphetamine use is also a driving force in transmission of infectious diseases, particularly 
HIV. Multiple studies across diverse populations (adolescents, heterosexual men and women, men 
who have sex with men (MSM), and people who inject drugs) have found methamphetamine use to 
be independently associated with a variety of high-risk behaviors, including condomless 
intercourse, multiple sex partners, increased duration of sex, anonymous partners, and exchanging 
money or drugs for sex. Longitudinal studies have also observed that methamphetamine use was 
independently associated with greater risk for HIV seroconversion. Because methamphetamine use 
is associated with high-risk sexual behavior, HIV seroconversion, STI incidence, and drug-resistant 
HIV, data strongly support that methamphetamine use plays an important role in perpetuating the 
U.S. HIV epidemic.  
 
Notwithstanding persistent efforts to identify a pharmacotherapy for MeUD, there remain no 
approved medications – and mixed results with existing candidates. While some behavioral 
interventions report reduced methamphetamine use, behavioral interventions alone have limited 
effectiveness and may benefit from the addition of pharmacologic agents, similar to the 
management of heroin, nicotine, and alcohol use disorders, and other chronic conditions such as 
depression and diabetes. Studies of multiple agents, including tricyclic antidepressants, serotonin 
re-uptake inhibitors, and antipsychotics, as well as dextroamphetamine, modafinil, and other 
psychostimulants, have been disappointing. Methylphenidate has mixed results. Bupropion is 
commonly used in clinical practice, although trials are less promising. Our center had success twice 
with mirtazapine, with methamphetamine use reductions of 30-50%. However, none of these 
therapies is likely to be sufficient on its own and agents using novel mechanisms of action are 
needed.  
  
Many investigators have come to believe that a combination pharmacotherapy that impacts 
multiple neurotransmitter systems will be needed to reduce methamphetamine use. There is an 
urgent need to identify novel classes with potential benefits that could be combined with other 
medications. Multiple reports suggest that glucagon-like peptide 1 (GLP-1) receptor agonists will be 
effective for multiple addictive disorders.  
 
Anecdotal reports find that those treated with GLP-1 agents for diabetes have reduced interest in 
compulsive behaviors including drinking alcohol, smoking, skin picking, etc. There have been 
several trials so far addressing alcohol and tobacco use with older GLP-1 agonists, showing mixed 
results to-date. Among patients with alcohol use disorder, exenatide, a first-generation GLP-1 
agonist, reduced cue reactivity and – among obese participants – total alcohol intake and heavy 
drinking days. A phase II trial of semaglutide, a second-generation agent thought to be more potent, 
among adults with alcohol use disorder began in 2022 (NCT05520775). 
  

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GLP-1 agonists, particularly semaglutide, hold substantial promise for treating MeUD. GLP-1 
increases insulin secretion, decreases glucagon secretion, delays gastric emptying, and increases 
satiety, making it ideal for managing diabetes. These agents work in part by substantially 
diminishing food cravings – and craving for methamphetamine is a central component of MeUD, 
with reductions in craving often predicting success in therapeutic trials and relapse after 
abstinence. As the most potent agent for weight loss, with availability in weekly injections (in 
contrast to liraglutide which is administered daily), semaglutide holds the most promise among 
GLP-1 agonists for influencing MeUD, a disorder characterized by poor medication adherence (and 
thus benefiting from weekly administrations). Moreover, while reductions in methamphetamine 
use, as well as available off-label MeUD therapies like mirtazapine, are associated with unwanted 
weight gain that may deter some patients from remaining abstinent, semaglutide is associated with 
weight loss, which may help to avoid unwanted weight gain in appropriate subjects (i.e., those with 
preexisting elevated body mass index [BMI]). Finally, GLP-1 agonists have also been shown to be 
cardioprotective and neuroprotective, potentially helping to address the two main pathways of 
methamphetamine toxicity.   
   
1.2. 
Semaglutide 
Semaglutide is a polypeptide that contains a linear sequence of 31 amino acids joined together by 
peptide linkages. It is an agonist of glucagon-like peptide-1 receptors (GLP-1 AR). Its molecular 
weight is 4114 g/mol. It has the molecular formula of C187H291N45O59. 
The proposed product is a clear, colorless solution of 2mg/1.5 mL semaglutide, which is meant for 
self-administration subcutaneously via pre-filled, disposable, single-patient use pen that delivers 
0.25 mg, 0.5 mg, or 1 mg per injection. Doses of 1.7 mg and 2.4 mg are also available but will not be 
used in this trial. Semaglutide will be administered per product label and by a clinician. 
1.3. 
Rationale for the Current Study 
Given the prevalence and negative health outcomes associated with methamphetamine use, there is 
urgent need to identify effective treatments for MeUD. GLP-1 agonists, particularly semaglutide, 
show promise for treating MeUD by reducing cravings. Research is needed to evaluate the 
acceptability, feasibility, and effectiveness of semaglutide (Wegovy) for reducing 
methamphetamine use among adults with MeUD. 
1.4. 
Rationale for Dose Selection of Semaglutide 
We will be following the package insert guidelines for administration of semaglutide (Wegovy). We 
plan to use semaglutide in injection form as opposed to oral tablet form due to MeUD being 
characterized by poor medication adherence (and thus participants may benefit from weekly 
injections over daily oral administration). We will limit duration to 12 weeks in an effort to identify 
a signal of potential benefit, to be followed by more intensive studies if go/no-go criteria are met. 
Thus, this trial will achieve a maximum dose of 1mg per week. If no signs of reduced 
methamphetamine use are seen at this dose, a higher dose is unlikely to achieve the “response” 
required for medications to treat MeUD (current standard is 3 out of 4 final urines negative for 
methamphetamine). 

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1.5. 
Overall Risk/Benefit Assessment 
Semaglutide is a US Food and Drug Administration (FDA)-approved drug with substantial promise 
for treating methamphetamine use disorder. Semaglutide is widely used and well-tolerated, 
although gastrointestinal symptoms are common and can be severe. The most common adverse 
events, which generally resolve with time, are nausea, vomiting, abdominal pain, constipation and 
diarrhea. Long-term therapy has been associated with the rare side effect of gastroparesis, as well 
as acute pancreatitis and hepatobiliary disease. In the setting of severe gastrointestinal symptoms, 
kidney dysfunction has been reported, likely due to dehydration. Worsening of diabetic retinopathy 
has also been reported. In animal studies, some GLP-1 agonists have been associated with thyroid 
tumors, although humans have a minimal concentration of GLP-1 receptors in thyroid tissue and 
thus may not be at risk. One notable early concern was suicidal ideation, however, in a real-world 
cohort of >1.5 million patients with type 2 diabetes the hazard ratio for suicidal ideation among 
patients on semaglutide compared to non-GLP-1 diabetes medications was 0.27 (0.20-0.60) across 
age, sex, and ethnicity. In this study, adverse events and safety lab results will be consistently 
monitored, and treatment will be discontinued as needed. 
The potential risks to participants described above are reasonable given the urgent need to identify 
new, effective treatments for MeUD. Because millions of people use methamphetamine in the US, 
half of whom suffer from MeUD, the potential impacts for society are significant. Effective 
treatments for MeUD can potentially decrease methamphetamine toxicity deaths, reduce the spread 
of HIV and other STIs, and reduce healthcare utilization costs. Methamphetamine use often 
adversely impacts physical and psychological health, so the risks of semaglutide in comparison are 
low. 
The study will be evaluated on an ongoing basis by a Data Safety Monitoring Board. 
1.6. 
Compliance 
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), and all 
applicable regulatory requirements. 

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2. 
OBJECTIVES 
The primary objectives of this study are as follows: 
• 
To determine acceptability, feasibility, and preliminary efficacy of weekly injectable 
semaglutide for adults with MeUD, we will determine the ratio of eligible to enrolled 
participants, adherence to weekly injections, and willingness to continue therapy at study 
conclusion, as well as the change in hair concentrations of methamphetamine from 
enrollment to week 12 of treatment, and the change in self-reported methamphetamine use 
from the 4 weeks preceding enrollment to the final 4 weeks of treatment. 
• 
To evaluate safety and tolerability of semaglutide among adults with MeUD, we will closely 
track self-reported and laboratory adverse events and the rate of study drug 
discontinuation due to adverse events. 
The exploratory objectives of this study are as follows: 
• 
To measure the impact of semaglutide on methamphetamine cravings through the Brief 
Substance Use Craving Scale. 
• 
To measure the impact of semaglutide on inflammation related to methamphetamine use by 
measuring hs-CRP as the primary biomarker. 
• 
To measure the impact of semaglutide therapy on cognitive function through the CogState 
Battery.  

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16 September 2025 
3. 
STUDY DESIGN 
3.1. 
Study Treatment and Duration of Treatment 
This is an open-label single-arm pilot trial to evaluate the efficacy of semaglutide in reducing 
methamphetamine use among adults with methamphetamine use disorder. Twenty-five subjects 
will be enrolled and receive semaglutide at increasing doses over a total of 12 weeks (0.25mg for 4 
weeks, 0.5mg for 4 weeks, and 1.0mg for 4 weeks).  

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4. 
SUBJECT POPULATION 
4.1. 
Number of Subjects and Subject Selection 
Twenty-five (25) subjects will be enrolled in this study.  
4.2. 
Inclusion Criteria 
Subjects must meet all the following inclusion criteria to be eligible for participation in this study: 
(1) Ability to provide informed consent before any study-related activity, willing to comply with all 
study procedures, and be available for the duration of the study, 
(2) Age 18 – 65 years inclusive, 
(3) Moderate to severe Methamphetamine Use Disorder by SCID, 
(4) Self-reported methamphetamine use ≥15 days out of the past 30, 
(5) Methamphetamine-positive urine during screening and run-in period, 
(6) Interested in stopping or reducing meth use, 
(7) BMI ≥ 25kg/m2,  
(8) Have at least 1 centimeter of scalp hair,  
(9) Agree (if the participant is of child-bearing potential) to use effective contraceptive methods, 
unless all of the participant’s male partner(s) is/are surgically sterile (underwent vasectomy). 
Acceptable contraceptives include oral contraceptives, contraceptive sponge, patch, double 
barrier (diaphragm/spermicidal or condom/spermicidal), intrauterine contraceptive system, 
etonogestrel implant, medroxyprogesterone acetate contraceptive injection, complete 
abstinence from sexual intercourse, and/or hormonal vaginal ring. Contraceptive measures sold 
for emergency use after unprotected sex are not acceptable methods for routine use.  Women of 
child-bearing potential must provide negative urine pregnancy test prior to randomization. 
Note: A woman is considered fertile (of childbearing potential) following menarche and until 
becoming postmenopausal unless permanently sterile. Women in the following categories are 
not considered of childbearing potential: premenarcheal, premenopausal female with one of the 
following: documented hysterectomy, documented bilateral salpingectomy, documented 
bilateral oophorectomy.  Postmenopausal female is defined as no menses for 12 months 
without an alternative medical cause. Females on hormone replacement therapy (HRT) and 
whose menopausal status is in doubt will be required to use one of the non-hormonal highly 
effective contraception methods if they wish to continue their HRT during the trial. 
(10) 
Be able to provide the names of at least 2 persons who can consistently locate their 
whereabouts. 

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4.3. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study: 
(1) Uncontrolled hypertension or systolic BP >160 mmHg and/or diastolic BP >90 mmHg, averaged 
from three measurements, 
(2) Resting heart rate greater than 100 bpm at baseline, on at least two measurements,  
(3) Diabetes (type 1 or 2), hemoglobin A1c ≥ 6.5 at screening, or history of diabetic ketoacidosis, 
(4) History or current hypoglycemia (blood glucose <70 mg/dL), 
(5) History of malignant neoplasms within the past 5 years prior to screening. Basal and squamous 
cell skin cancer and any carcinoma in-situ are allowed. 
(6) History of heart failure or severe gastrointestinal disease (including acute or chronic 
pancreatitis, any gastric emptying disorder, gallbladder disease; any gastric resection), 
(7) Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 
2B, 
(8) Impaired renal function (estimated GFR <60 ml/min), 
(9) Lipase, amylase, direct (conjugated) bilirubin, or alkaline phosphatase (ALP) 1.5 times the 
upper limit of normal, or ALT or AST more than 2.5 times the upper limit of normal,  
(10) Calcitonin value equal to or above 50 ng/L, 
(11) History of retinopathy, 
(12) Women who are currently pregnant, or plan to become pregnant, or lactating, or of 
childbearing potential and are not using medically accepted forms of contraception (see inclusion 
criterion 9 regarding medically accepted forms of contraception). 
(13) Acute or chronic illnesses likely to result in hospitalization or death during trial participation, 
(14) Plan to have all hair removed or chemically treat hair during study, 
Psychiatric/Substance Use Exclusions: 
(1) Moderate to severe opioid, cocaine, or alcohol use disorder, 
(2) Current non-drug-induced psychotic disorder by Structured Clinical Interview for DSM 
Disorders (SCID), 
(3) History of a suicide attempt or past 30-day suicidal ideation, 

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16 September 2025 
(4) Have any psychiatric illness or condition which in the opinion of the PI and/or the Study 
Physician would preclude safe and/or successful completion of the study, 
Weight-related exclusions: 
(1) Uncontrolled thyroid disease, 
Medication-related exclusions: 
(1) Past 30 day use of sulfonylureas, insulin and insulin products, or medication used for weight 
management (e.g., orlistat, naltrexone-bupropion, liraglutide, semaglutide, tirzepatide, 
phentermine, topiramate, benzphetamine, diethylpropion, phendimetrazine). 
(2) Prior use of or known hypersensitivity to any GLP-1 agonist, 
(3) Any otherwise not specified concomitant medication that could compromise participant safety 
or treatment in the opinion of the Study Physician and/or the PIs, 
General exclusions: 
(1) Current, anticipated, or pending enrollment in another addiction treatment program and/or 
research study that could potentially affect participant safety and/or the study data/design as 
determined by the Principal Investigator and/or Study Physician. 
(2) Planning to leave the area during the trial, 
(3) Surgery scheduled during the trial, except for minor surgical procedures that, in the opinion of 
the PI and/or the Study Physician, will not require general anesthesia with the risk of aspiration, 
(4) Unable to communicate (read, write, and speak) fluently in English, 
OR 
(5) Any other condition that, in the PI’s judgment, interferes with safe study participation or 
adherence to study procedures. 

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5. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
5.1. 
Description and Handling of Semaglutide 
5.1.1. 
Formulation 
The proposed formulations include semaglutide in a pre-filled, disposable, single-patient-use pen. 
Each single-use disposable pen injector delivers a discrete dose of: 0.25 mg, 0.5 mg, or 1 mg of 
semaglutide per pen. 
Active ingredient: semaglutide 
Inactive ingredients: disodium phosphate dihydrate, sodium chloride, and water for injection. 
5.1.2. 
Packaging and Labeling 
Semaglutide injection is supplied as a clear, colorless solution that contains a dose of either 0.25mg, 
0.5mg, or 1mg of semaglutide in a pre-filled, disposable, single-patient-use pen injector with an 
integrated needle. It is supplied in cartons containing 4 pre-filled pen injectors in the following 
packaging configurations:  
Pre-filled pen dose (cartons of 
4 pens) 
Dose concentration 
NDC 
0.25 mg 
0.25 mg/0.5 mL 
0169-4525-14 
0.5 mg 
0.5 mg/0.5 mL 
0169-4505-14 
1 mg 
1 mg/0.5 mL 
0169-4505-14 
All study drug administered to study participants shall be provided in containers labeled to meet all 
applicable requirements of the FDA and/or other local regulations as applicable. 
5.1.3. 
Storage and Handling 
Prior to first use, study drug will be stored in our pharmacy refrigerator between 36F to 46F (2C to 
8C). After first use of the pen, study drug will be stored for up to 56 days at controlled room 
temperature (59F to 86F; 15C to 30C) or in a refrigerator between 36F to 46F (2C to 8C). When 
stored at controlled room temperature, the study drug will be stored away from excessive heat, 
light, and moisture. 
After each injection, the pen injector will be discarded in a sharps container. 
All drug products will be stored in a securely locked area, accessible only to authorized site 
personnel. Consideration will be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions will be followed to avoid direct 
eye contact or exposure through inhalation when handling study drug. 

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16 September 2025 
5.1.4. 
Dosage and Administration of Semaglutide  
Study drug is to be administered subcutaneously to the abdomen, thigh, or upper arm. The 
participant will be able to select the body area. If administering in the same body region, the 
administering clinician will use a different injection site. 
Study drug will be administered at any time of day, with or without meals. The day of weekly 
administration can be changed if necessary, as long as the time between two doses is at least 2 days 
(>48 hours).  
If a dose is missed, study drug will be administered as soon as possible at the previously used dose 
unless 3 or more doses have been missed. If 3 or more doses have been missed, the next dose will 
be administered as soon as possible according to the below table. 
Management of Missed Doses 
Last Dose 
Missed 
1 or 2 missed 
doses 
3 or 4 missed 
doses 
5 or more 
missed doses 
0.25 mg 
0.25 mg 
0.25 mg 
0.25 mg 
0.5 mg 
0.5 mg 
0.25 mg 
0.25 mg 
1 mg 
1 mg 
0.5 mg 
0.25 mg 
 
5.2. 
Prior and Concomitant Medications 
Concomitant medications taken within 30 days prior to screening will be recorded in the source 
documents and case report form(s) (CRFs). 
Table 1. 
Concomitant Medications Disallowed or to be used with Caution 
Drug Class 
Agents Disallowed 
Use with Caution 
sulfonylureas 
Any 
 
cholecystokinetic 
sincalide 
 
Weight control medications 
Any other GLP-1 agonists 
 
insulin 
Any insulin products 
 

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16 September 2025 
Dipeptidyl peptidase 4 inhibitors 
Any 
 
 
5.3. 
Study Drug Adherence 
Subjects will be administered study drug by a clinician using the pre-packaged single dose pens 
provided by the manufacturer. Other trials of injectable medication for methamphetamine use 
disorder at this study site have shown high adherence rates.  
5.4. 
Accountability for Study Drug 
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug pens. This includes acknowledgement of receipt of each shipment of study drug (quantity and 
condition). 
Semaglutide accountability records will: 
• 
Record the date received, quantity, and dosage of study drug shipments received 
• 
Record the date of administration, deidentified subject ID number, amount administered, where 
administered, pen lot number, and expiration date of every study drug administration 
5.4.1. 
Investigational Medicinal Product Return or Disposal 
Please refer to Section 10.1.7 for Investigational Medicinal Product Accountability. 

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16 September 2025 
6. 
STUDY PROCEDURES 
The investigator will document any deviation from protocol procedures and notify appropriate 
regulatory authorities (e.g., IRB, DSMB, and NIH). 
6.1. 
Subject Enrollment and Treatment Assignment 
Screening will occur at screening visits 1 and 2 and up to two run-in visits. On-treatment visits will 
occur weekly from enrollment (week 0) through week 11.  
Every effort will be made for all participants to complete all study visits, regardless of continuation 
of study drug. 
6.2. 
Pretreatment Assessments 
6.2.1. 
Screening Visits  
Subjects will be screened for the determination of eligibility for participation in the study. Subjects 
meeting all of the inclusion criteria and none of the exclusion criteria will return to the clinic within 
30 days after screening for enrollment in the study. 
After consent is obtained, screening assessments (split between two visits) will include a physical 
exam, complete medical history (including collection of any current medications), mental health 
and substance use history by SCID and C-SSRS, urine testing for methamphetamine and other 
substances, and lab testing. Labs completed during screening include CMP, hemoglobin A1c, lipase, 
amylase, calcitonin, TSH (as needed) and urine pregnancy test. 
Two additional “run-in visits” before enrollment will be completed as necessary in order to 
complete all screening assessments and, if needed, assess participant ability to adhere to the study 
schedule. 
Participants will be compensated $25 for each screening and run-in visit. 
6.2.2. 
Enrollment Visit (week 0) 
At the enrollment visit, the participant will meet with the clinician to review and confirm eligibility 
criteria and suicidality screen (C-SSRS), will provide urine, hair, and blood samples (for biomarker 
testing), receive their first study drug injection, and receive medical management counseling for 
substance use, medication adherence, and side effect prevention and management. Vital signs 
(including weight) and a symptom-driven physical exam will be completed. Participants will also 
complete their baseline survey. 
Baseline surveys will be completed by participants at enrollment, including assessment of reported 
days/episodes of other substance use (TLFB), injecting and sexual risk behaviors, substance use 
treatment outside the study, impulsivity, cravings, demographics, cumulative methamphetamine 
exposure, psychological symptoms, severity of methamphetamine dependence, and physical and 
psychiatric health (SF-36, CGI).  

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16 September 2025 
Participants will be compensated $50 for completing the enrollment visit and an additional $25 for 
providing hair samples. 
6.3. 
Weekly Treatment Visits (weeks 1-3, 5-7, 9-11) 
Following enrollment, participants will be seen weekly for study drug administration, urine 
collection for methamphetamine testing, TLFB assessment, and MM counseling. Vital signs and a 
symptom-driven physical exam will also be completed, and the participant will be assessed for AEs. 
More frequent monitoring may be performed for symptomatic participants. 
We will plan to monitor participants on narrow therapeutic index medications (NTIMs). Clinicians 
will inquire about when participants take medications and if they are experiencing emesis, monitor 
problems related to gastric emptying, look for signs of sub-therapeutic effect absorption, and 
ensure that participants are successfully taking medications. 
Counseling will involve a manualized version of the MM brief counseling platform in individual 20-
minute sessions from trained study staff.  
Study drug will be administered by the clinician at weekly visits according to the following 
schedule: 0.25mg weekly for weeks 1-4; 0.5mg weekly for weeks 5-8; 1.0mg weekly for weeks 9-12. 
Participants will be compensated $25 for weekly visits.  
 
6.4. 
Monthly Treatment Visits (weeks 4, 8, and 12) 
Monthly visits at weeks 4 and 8 will be the same as the weekly visits with the addition of the 
following:  
Participants will complete surveys which will assess reported days/episodes of other substance 
use, injecting and sexual risk behaviors, substance use treatment outside the study, impulsivity, 
cravings, symptoms, and severity of methamphetamine dependence.  
Safety labs completed at monthly visits will include CMP, lipase, amylase, urine pregnancy test, and 
others as-needed for AE management. 
Participants will be administered the C-SSRS. 
The final treatment study visit at week 12 will be the same as the monthly visits with the following 
additions: 
Participants will also provide hair for methamphetamine testing and blood samples for biomarker 
testing. The survey for week 12 will include additional sections that will assess the participant’s 
willingness to continue therapy, participant satisfaction with the trial, perception of whether the 
trial helped reduce methamphetamine use, and the CogState Battery for assessment of cognitive 
function. 
Study medication will not be administered at week 12. 

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16 September 2025 
Participants will be compensated $50 for week 4 and 8 visits. Participants will be compensated $75 
for the final study visit and an additional $25 for providing hair samples. Participants will be 
compensated an additional $50 for each 4-week period in which all study visits were attended.  
6.5. 
Post-trial Study Visit (week 20) 
A post-trial visit will be conducted at week 20, 8 weeks after the final weekly study visit. At this 
visit, participants will undergo vital sign collection, urine drug testing, TLFB assessment, C-SSRS, 
and evaluation for resolution of any open AEs. 
Participants will be compensated $30 for the post-trial visit. 
6.6. 
Post Treatment Assessments  
Following the completion of study drug treatment at week 12, participants will be seen on an as-
needed basis to assess adverse events. This assessment may include a symptom-driven physical 
exam, collection of vital signs, and safety labs as-needed.  
These additional visits will be compensated at $20. 
6.7. 
Survey 
Surveys will be completed by participants at enrollment and monthly (weeks 4, 8, and 12) visits, 
and the post-treatment visit (week 20) to assess substance use (reported days/episodes of other 
substance use), injection and sexual risk behaviors, substance use treatment, craving, impulsivity, 
and cognitive function. 
At enrollment, the survey will additionally collect demographics and assess cumulative 
methamphetamine exposure (“gram-year history”). 
At week 12, the survey will additionally assess the participant’s willingness to continue therapy, 
participant satisfaction with the trial, and perception of whether the trial helped reduce 
methamphetamine use. 
6.8. 
Assessments for Premature Discontinuation from Study 
Every effort will be made to continue participants in the study, even if discontinued from or 
otherwise not taking study drug, or if attending visits sporadically. Participants will only be 
formally discontinued from the study if they elect to do so. 
6.9. 
End of Study 
Subjects are considered to have completed the study after the week 20 visit, regardless of 
treatment duration and early termination from study drug.  
The final study visit will include a survey assessment of satisfaction with the study procedures. 

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16 September 2025 
6.10. 
Procedures and Specifications 
6.10.1. 
Clinical Laboratory Analytes 
Hematology: Hemoglobin A1c 
Biomarkers: hs-CRP, IL-1β, IL-6, TNF-α 
Chemistry: CMP (sodium, potassium, chloride, carbon dioxide, blood urea nitrogen creatinine, 
glucose, total bilirubin, total protein, albumin, calcium, ALP, AST, and eGFR), lipase, amylase, 
calcitonin. 
Pregnancy Test: Urine b-hCG 
Urine Drug Testing: qualitative urine testing for methamphetamine and 10 other substances with 
the iSCREEN Urine Test Drug Screen Dip Card 
Hair testing. Hair collection involves taping the tips (for hair>1cm) and cutting 50-100 strands 
close to the scalp into aluminum foil for storage in a dark space until batch shipment for processing. 
Analysis of hair samples will be done by the UCSF Hair Analytical Laboratory with liquid 
chromatography tandem mass spectrometry (LC/MS). Hair samples are washed twice with 2 mL of 
water followed by washing twice with 2 mL of acetone (vortex mixed for 1 min). After removal of 
the solvent, samples are completely dried at ambient temperature. Samples are then cut into small 
pieces (approximately 1–2 mm) with scissors and weighed to ~10 mg in test tubes. 
Methamphetamine is extracted with 1 mL of methanol including deuterated methamphetamine (as 
an internal standard) in a 37˚C shaking water bath overnight (>12 hours). Extracted samples are 
evaporated to dryness under N2 gas atmosphere and then reconstituted with 200 µL of 20% 
acetonitrile. Methamphetamine levels are determined by liquid chromatography tandem mass 
spectrometry (LC/MS/MS) using a Micromass Quattro Ultima and Shimadzu HPLC system equipped 
with a Phenomenex Synergi Polar-RP column (4.6 x 150 mm, 4 μm particle size), a mobile phase 
system consisting of acetonitrile:water:trifluoro acetic acid (20:80:0.05), and mass spectrometric 
detection with positive ionization by electrospray ionization and mass scanning by multiple 
reaction monitoring ([M+H]+ transitions of 150/119 (Q1/Q3) m/z for methamphetamine and 
159/125 m/z for deuterated methamphetamine). The standard curve range of methamphetamine 
by LC/MS/MS analysis is 0.00800 nanograms (ng)/mg (lower limit) to 3.20 ng/mg of hair. Because 
of variable inter-subject methamphetamine levels in hair (with variation based on hair melanin 
concentration, among other factors), we will assess the within-person change in cumulative 
methamphetamine hair levels (ng/mL) pre- vs. post-intervention. Dr. Gandhi and colleagues have 
demonstrated high levels of acceptability (>95%) of hair collection, as the sampling is done from 
the back of the head with quantity of hairs collected (<50 strands) less than the average amount of 
hair lost in the course of a normal day.  Participants without scalp hair will not be included. 
6.10.2. 
Medical History 
A complete medical history will be taken for each participant during screening, including details of 
ongoing or past illnesses, health conditions, and allergies. Mental health and substance use history 
will be collected via SCID. The medical history will also include review of prior and concomitant 
medications and family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 
2B.  

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16 September 2025 
6.10.3. 
Physical Examination 
A full physical examination will be completed during screening and will include source 
documentation of general appearance, and the following body systems: Head, neck, eyes, ears, nose, 
throat, mouth and tongue; respiratory; cardiovascular; lymph nodes; abdomen; skin, hair, nails; 
musculoskeletal; neurological.  
A symptom-driven physical exam will be completed at enrollment, weekly study visits, and at any 
required follow-up visits to assess AEs.  
6.10.4. 
Vital Signs 
Vital sign collection will include measurement of resting blood pressure, pulse, respiratory rate, 
temperature, and weight. Height will be collected during screening only.  
Blood pressure will be measured using the following standardized process: 
• 
Subject will sit with feet flat on the floor and measurement arm supported so that the midpoint 
of the manometer cuff is at heart level. 
• 
Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery. 
• 
Measure and record the blood pressure to the nearest 2 mm Hg mark on the manometer or to 
the nearest whole number on an automatic device. 
6.10.5. 
Body Mass Index (BMI) 
BMI will be calculated by the following equation. 
BMI = weight (pounds) * 703 or 
weight in kilograms 
 
(height in inches)2 
 
(height in meters)2 
6.10.6. 
Liver Function 
Liver function will be evaluated by AST and ALT levels, relative to laboratory range. 
 
6.10.7. 
Structured Clinical Interview for DSM-IV (SCID) 
The SCID will be utilized during screening to diagnose methamphetamine use disorder, cocaine or 
opioid use disorder and to ensure the absence of exclusionary psychiatric disorders. 

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16 September 2025 
7. 
TOXICITY MANAGEMENT 
7.1. 
Subject Stopping Rules 
Due to a clinical or laboratory event, administration of study drug may be reduced or discontinued. 
If study drug is stopped due to toxicity, it will not be restarted.  
Subjects who meet any of the following criteria must stop study drug: 
• 
Weight loss during treatment to a BMI < 19 kg/m2. 
• 
Any Grade 3 or greater rash associated with constitutional symptoms. 
• 
Any Grade 3 or greater adverse event possibly, probably, or definitely related to the study drug 
will result in a pause of the study drug and prompt evaluation. If the AE is determined to be not 
related to the study drug and symptoms resolve, we may restart study drug with close 
monitoring. 
• 
Subject reports persistent, severe vomiting or diarrhea, that may lead to severe dehydration 
and acute kidney injury. 
• 
Any serious adverse event that the PI, DSMB, IRB, NIDA, or FDA advises should result in 
discontinuation of study drug. 
• 
Toxicity that, in the judgment of the investigator, compromises the ability to continue study-
specific procedures or is considered to not be in the subject’s best interest. 
• 
Subject becomes pregnant or reports a desire to become pregnant. 
• 
Subject requests to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason. 
• 
Subject has a persistent increased heart rate >20 bpm from baseline, as measured on at least 2 
consecutive visits.1 
• 
Subject reports suicidal ideation or behavior on C-SSRS. 
If a subject meets discontinuation criteria during treatment, every effort will be made to continue 
all previously planned visits with the subject, minimizing data loss.  
7.2. 
Study Discontinuation Criteria 
The study will be discontinued in the following instances: 
 
1 Use of methamphetamine will increase heart rate, thus a single elevated value will not result in immediate 
discontinuation of study drug.  

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16 September 2025 
• 
If >35% of participants discontinue study drug due to adverse events, or less if study 
stoppage is determined appropriate in consultation with the PI, biostatistician, DSMB, IRB, 
or FDA. 
• 
Discontinuation of the study for any reason at the request of a regulatory agency, DSMB, or 
IRB, with appropriate justification. 
The study will be paused in the following instances: 
• 
If an SAE occurs at least possibly related to the study medication, enrollment will be paused 
pending DSMB review. 
 
7.3. 
Dose Titration Rules 
Study drug dose titration may be paused or reversed in the following circumstances: 
• 
Weight loss occurs in excess of participant goals  
• 
Study drug-related clinical or laboratory adverse events occur that study clinician and study 
pharmacist determine may be reduced by pausing or reducing study drug dose 
 
 
 

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8. 
ADVERSE EVENTS MANAGEMENT  
8.1. 
Definition of Adverse Events, Adverse Reactions, and Serious Adverse Events 
8.1.1. 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject administered 
a pharmaceutical medicinal product, which does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. AEs may also include pre- or post-treatment complications that occur as a result 
of protocol specified procedures, lack of efficacy, overdose, substance use, or occupational 
exposure. Preexisting events that increase in severity or change in nature during or as a 
consequence of participation in the clinical study will also be considered AEs. 
An expected adverse event is an AE that may be reasonably anticipated to occur as a result of the 
study procedures or study participation or is part of the normal disease process or progression. 
An unexpected adverse event is defined as being unexpected if the event exceeds the nature, 
severity, or frequency described in the current University of California San Francisco (UCSF) IRB 
application including the protocol, consent form and investigator brochure, when applicable. An 
unexpected AE also includes any AE that meets the following criteria: 
• 
Results in subject withdrawal from study participation 
• 
Due to an overdose of study medication 
• 
Due to a deviation from IRB-approved study protocol 
An AE does not include the following: 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; the condition that leads to the procedure may be an adverse event and must be 
reported. 
• 
Pre-existing diseases or conditions or laboratory abnormalities present or detected during or 
before screening that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions) 
• 
Overdose without clinical sequelae (see Section 8.5) 
• 
Any medical condition or clinically significant laboratory abnormality with an onset date before 
enrollment and not related to a protocol-associated procedure is not an AE. It is considered to 
be pre-existing and should be documented on the medical history. 
• 
Substance use or admission to substance use treatment 

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16 September 2025 
• 
Incarceration 
8.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an event that results in the following: 
• 
Death 
• 
Life-threatening event (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 that hypothetically might have caused death if it were more severe.) 
• 
In-patient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect or cancer 
• 
A medically important event or reaction: such events may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the subject or may require intervention 
to prevent one of the other outcomes constituting SAEs. Medical and scientific judgment must 
be exercised to determine whether such an event is reportable under expedited reporting rules. 
Examples of medically important events include intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements. 
• 
Event that changes the risk/benefit ratio of the study 
8.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. However, 
laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that require medical 
or surgical intervention or lead to investigational medical product (IMP) interruption, modification, 
or discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments that are associated with signs and/or symptoms will be 
recorded as an AE or SAE if they meet the definition of an AE or SAE as described in 
Sections 8.1.1 and 8.1.2. If the laboratory abnormality is part of a syndrome, record the syndrome 
or diagnosis (e.g., anemia), not the laboratory result (i.e., decreased hemoglobin). 
8.2. 
Assessment of Adverse Events and Serious Adverse Events 
The investigator or qualified sub-investigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information and 
assessments. 
8.2.1. 
Assessment of Causality for Study Drug and Procedures 
The investigator or qualified sub-investigator is responsible for assessing the relationship to study 
procedures or medications using clinical judgment and the following considerations: 

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16 September 2025 
• 
Unrelated: Evidence exists that the adverse event has an etiology other than semaglutide or a 
study procedure. For SAEs, an alternative causality must be provided (e.g., pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication). 
• 
Probably not: Adverse event has improbable time relationship to intake of Wegovy or study 
procedure, and attribution with disease or other drugs is likely. 
• 
Possibly: Adverse event has reasonable time relationship to intake of Wegovy or study 
procedure, and attribution with disease or other drugs is possible. 
• 
Probably: Adverse event has reasonable time relationship to intake of Wegovy or study 
procedure, and attribution with disease or other drugs is unlikely. 
• 
Definitely: There is reasonable probability that the event may have been caused by Wegovy or 
a study procedure. 
Ineffective treatment should not be considered as causally related in the context of AE reporting. 
8.3. 
Assessment of Severity  
Severity should be recorded and graded according to the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events (DAIDS) Version 2.1 July 2017.2  
8.4. 
Investigator Requirements for Reporting Adverse Events and Serious Adverse 
Events 
8.4.1. 
Reporting to UCSF Committee on Human Research (CHR / IRB) 
All AEs that are possibly, probably, or definitely related, and either serious and unexpected, or 
serious and more frequent or severe than anticipated, must be reported within 5-working-days of 
PI awareness using the Adverse Event Reporting Form on the UCSF IRB website (iRIS).  
8.4.2. 
Reporting to Data Safety Monitoring Board (DSMB) 
Reporting to Data Safety Monitoring Board (DSMB) 
All SAEs and unexpected AEs meeting reportable criteria in the Data Safety Monitoring Plan (DSMP) 
must be reported within 10-working-days of PI awareness. A summary letter must include detailed 
accounts of the following: 
• 
Summary of SAE 
• 
Resolution 
• 
Study Drug 
• 
Attribution 
 
2 DAIDS is frequently used for the assessment of AEs for substance use disorder treatment trials, specifically those 
involving methamphetamine, and is the preferred AE guidance instrument of the DSMB. 

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16 September 2025 
• 
Notification 
8.4.3. 
Reporting to NIH – National Institute of Drug Abuse (NIDA) 
All SAEs meeting reportable criteria in the DSMP must be reported within 10-working-days of PI 
awareness to NIH. If SAE is fatal, it must be reported within 2-working-days of PI awareness. 
8.5. 
Special Situations Reports 
8.5.1. 
Definitions of Special Situations 
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE. 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.  
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject. 
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information. 
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended dose 
as per protocol or in the product labelling (as it applies to the daily dose of the subject in question). 
In cases of a discrepancy in drug accountability, overdose will be established only when it is clear 
that the subject has taken the excess dose(s). Overdose cannot be established when the subject 
cannot account for the discrepancy except in cases in which the investigator has reason to suspect 
that the subject has taken the additional dose(s). 
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product. 
8.5.2. 
Instructions for Reporting Special Situations 
8.5.2.1. 
Instructions for Reporting Pregnancies 
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons. 
Should a participant become pregnant or report a desire to become pregnant during the trial, study 
drug will be discontinued and the event reported to IRB/DSMB. 
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) will be reported within 10 working days as 
an SAE. The underlying medical reason for this procedure should be recorded as the AE term. 
A spontaneous abortion is always considered to be an SAE. Furthermore, any SAE occurring as an 
adverse pregnancy outcome post study will be reported to the IRB and DSMB. 

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16 September 2025 
8.5.2.2. 
Reporting Other Special Situations 
All other special situations will be reported as AEs or SAEs and reported accordingly.  

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9. 
STATISTICAL CONSIDERATIONS  
9.1 Analysis Objectives and Endpoints 
9.1.1 Analysis Objectives 
The primary objectives of this study are as follows: 
• 
To determine acceptability and feasibility of weekly injectable semaglutide for adults with 
methamphetamine use disorder (MeUD). 
• 
To evaluate safety and tolerability of semaglutide among adults with MeUD.  
The exploratory objectives of this study are as follows: 
• 
To measure the perceived effect of the semaglutide on methamphetamine use, self-reported 
methamphetamine use (TLFB), and urine drug testing for methamphetamine metabolites. 
• 
To measure the impact of semaglutide on methamphetamine cravings through the Brief 
Substance Use Craving Scale. 
• 
To measure the impact of semaglutide on inflammation related to methamphetamine use by 
measuring hs-CRP as the primary biomarker. 
• 
To measure the impact of semaglutide therapy on cognitive function through the CogState 
Battery. 
9.1.2 Primary Endpoints 
• 
Eligibility to enrollment ratio 
• 
Adherence to weekly medication injections 
• 
Willingness to continue therapy at study conclusion 
• 
Rate of study drug discontinuation due to adverse events  
• 
Proportion with a pre-post reduction in concentration of methamphetamine in hair samples 
(enrollment vs. week 12 visit)  
9.1.3 Secondary Endpoints 
Secondary endpoints include the following: 
• 
Adverse events 
• 
Self-reported days of methamphetamine use by TLFB  
• 
Urine drug testing (negative vs. positive for methamphetamine) 
• 
Participant satisfaction with trial and participant perception of whether participation 
helped reduce methamphetamine use 

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16 September 2025 
• 
Biomarkers (hs-CRP, IL-1β, IL-6, TNF-α) 
• 
Cognitive function (CogState Battery) 
• 
Number of persons pre-screened, screened, and enrolled 
• 
Scheduled visits attended, overall retention 
9.1.4 Other Endpoints of Interest 
• 
Reported days/episodes of other substance use (opioids, alcohol, cocaine, marijuana, 
ecstasy, etc.)   
• 
Sexual HIV risk behaviors 
• 
Substance use treatment (outside study) 
• 
Impulsivity (measured via BART and the STIMP scales)  
• 
Participant methamphetamine cravings (measured via Brief Substance Use Craving Scale 
(BSCS) and Visual Analog Scale Craving Scores) 
9.1.5 Analysis Conventions 
All individual subject data will be listed as measured. All statistical summaries and analyses will be 
performed using STATA software. The study drug in this study is semaglutide. Last dose of study 
drug refers to the last dose of semaglutide and will be used in the definition of treatment-emergent 
AEs and laboratory abnormalities as well as the efficacy endpoints at various post-treatment time 
points. An as-treated analysis will also be conducted. 
9.1.6 Demographic Data and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using standard descriptive methods 
by treatment group and overall.  Demographic data will include sex at birth, self-identified gender, 
self-identified race/ethnicity, and age. 
Baseline characteristic data will include BMI and additional endpoints as necessary. 
9.2 Data Analysis 
9.2.1 Primary Analysis 
Specific Aim 1: To determine the feasibility and acceptability of treating adults with MeUD with 
semaglutide, we will determine the ratio of eligible to enrolled participants, adherence to weekly 
injections, and willingness to continue therapy at study conclusion. To evaluate preliminary effect 
on methamphetamine use based on hair testing and TLFB, we will conduct within-person 
comparisons of the four weeks prior to enrollment to the final four weeks of medication treatment. 
Hair samples in people who use methamphetamine daily are reported to be 80-360ng/mg of hair, 
although results vary by study. In a study matching hair sampling to self-reported use, 0.25-4 
grams/day (mean 1.2, median 0.9; SD 1.2) corresponded to 0.38-53.15ng/mg of hair (mean 6.10, 
median 2.12; SD 9.56). We will have 80% power to detect that 75% have lower levels at week 12 
than their baseline sample as opposed to the 50% which would be expected with no change in use. 

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16 September 2025 
We will also calculate a Pearson’s coefficient correlating changes in methamphetamine 
concentration in hair with changes in TLFB. 
Go/No-go criteria: We will proceed with the next phase of the trial if (1) enrollment of 25 
individuals is achieved with at least 20 completing treatment, (2) adherence to weekly study 
medication injection is ≥70% of available injections, and (3) no medication-related SAEs are 
reported.  
Specific Aim 2: To evaluate safety and tolerability of semaglutide among adults with MeUD. We 
will focus primarily on the rate of discontinuation of study drug due to AEs. The rate of 
discontinuation of semaglutide in trials varies, based both on the length of the trial and 
comorbidities. For patients with comorbidities, discontinuation rate ranges from 15% at 26 weeks 
to 20% at 100 weeks. When converted to a rate, discontinuation due to AEs in obesity trials ranged 
from 7.2258 to 10.3259 per 100 person-years, although discontinuation tends to occur mostly in 
the early months of trials due to AEs that often resolve during treatment. We will also classify AEs 
as any AE that results in stopping study medication (either by study stopping rules [i.e., excessive 
weight loss, grade 3 rash, grade 3 or greater event associated with study drug, or any event 
PI/IRB/DSMB/FDA/NIH advise should result in stoppage] or participant decision), specific 
common AEs (reported by more than 2% of study participants in both groups), AEs for general 
organ system categories, and AEs potentially related to study drug use. For laboratory values 
(including creatinine, lipase, and amylase) and other continuous variable safety outcomes, means 
and standard deviations (or median and inter-quartile range, for right-skewed distributions) will be 
presented, in combination with the proportions with values outside the normal range. Binary AE 
measures will be analyzed using exact methods, since they are expected to be uncommon, while 
continuous safety outcome variables will be analyzed using regression models. Expected adverse 
event outcomes are primarily gastrointestinal (~75-85%; including abdominal pain [6- 20%], 
constipation [3-24%], diarrhea [9-30%], nausea [16-44%], vomiting [5-24%], fatigue [11%], 
headache [15%]; with less common events including increased ALT [3%], and acute pancreatitis or 
gastroparesis [<1%]). 
Minimum Detectable Effects (MDE): We expect a discontinuation rate due to adverse events of 7-10 
per 100 person-years, most of which occur in the early months, thus representing at least 3% of 
participants discontinuing the medication during the 12-week trial. Based on our small sample size, 
we will have 80% power to rule out a 12-week discontinuation rate of 9% overall and 11% on the 
semaglutide arm. 
9.2.2 Exploratory Analyses 
As-treated analyses. In the primary intent-to-treat (ITT) analyses, outcomes will be included in the 
analysis without regard to adherence to treatment. We will also conduct an as-treated analysis, 
using cumulative adherence, calculated as the number of dosing events. Restricted cubic spline 
terms for adherence in this model will account for non-linearity  
   
Impact on craving and other outcomes. As the impact of GLP-1 agonists may be through reduced 
craving, we will specifically assess craving through the Brief Substance Use Craving Scale (3 items). 
We will calculate the composite score (0-27 points) and anticipate a median score of 12+/-4 at 
baseline. Assuming a moderate correlation (rho=0.70) over time, we will have 80% power to detect 
a difference of 0.34 standard deviations (SD). We will conduct similar analyses for impulsivity. 
  

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16 September 2025 
Evaluation of biomarkers. We will assess hs-CRP, IL-1β, IL-6, and TNF-α, with hs-CRP of primary 
interest because it is readily available for clinical use. Among people with MeUD, mean CRP is 
3.50mg/L (SD 2.50). For this, assuming moderate correlation, we have 80% power to difference of 
0.34 SD. 
 
Cognition. The CogState Battery has 5 tasks, scored separately, assessing verbal learning and 
memory, working memory, spatial working memory, problem solving, and social cognition. As an 
example of the analytic approach, the International Shopping List (ISL) task is used to reflect verbal 
learning and memory. In a study of a MeUD treatment intervention, ISL scores rose in the treatment 
arm from 19 to 26 out of 40, SD 2.5. We will have 80% power to detect a difference of 1.1 points on 
a two-sided 0.05 level test. 
 
9.2.3 Additional Outcomes 
Additional analyses. We will also conduct as-treated analyses, analyze for effects of study 
participation and treatment effects in participants who decline substance use counseling, and 
analyze data by consecutive weeks of meth-abstinence. 
9.3 Sample Size 
Sample size justification:   
To determine the feasibility and acceptability of treating adults with MeUD with semaglutide, we will 
determine the ratio of eligible to enrolled participants, adherence to weekly injections, and 
willingness to continue therapy at study conclusion. To evaluate preliminary effect on 
methamphetamine use based on hair testing and TLFB, we will conduct within-person comparisons 
of the four weeks prior to enrollment to the final four weeks of medication treatment.  
 
The pilot will be considered a success, and plans for a Phase IIb trial will commence, if the following 
criteria are met: 
(1) the ratio of enrolled:eligible, adherence to weekly injections, and willingness to continue 
therapy exceed 70%; and 
(2) hair testing or TLFB show reduced methamphetamine use in the final 4 weeks of the trial 
compared to 4 weeks preceding enrollment. 
 
Hair samples in people who use methamphetamine daily are reported to be 80-360ng/mg of hair, 
although results vary by study. In a study matching hair sampling to self-reported use, 0.25-4 
grams/day (mean 1.2, median 0.9; SD 1.2) corresponded to 0.38-53.15ng/mg of hair (mean 6.10, 
median 2.12; SD 9.56). We will have 80% power to detect that 75% have lower levels at week 12 than 
their baseline sample as opposed to the 50% which would be expected with no change in use. of 
methamphetamine use. We will also calculate a Pearson’s coefficient correlating changes in 
methamphetamine concentration in hair with changes in TLFB. 
 

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10 RESPONSIBILITIES 
10.1 
Investigator Responsibilities 
10.1.1 Good Clinical Practice 
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 Harmonization (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. 
10.1.2 Institutional Review Board (IRB) Approval 
The investigator will submit this protocol, informed consent form, and any accompanying material 
to be provided to the subject (such as advertisements, subject information sheets, or descriptions of 
the study used to obtain informed consent) to an IRB. The investigator will not begin any study 
subject activities until approval from the IRB has been documented and provided as a letter to the 
investigator. 
Before implementation, the investigator will submit to and receive documented approval from the 
IRB any modifications made to the protocol or any accompanying material to be provided to the 
subject after initial IRB approval, with the exception of those necessary to reduce immediate risk to 
study subjects. 
10.1.3 Informed Consent 
Study staff are responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and potential 
risks of the study and before undertaking any study-related procedures. The investigator will use 
the most current IRB-approved consent form for documenting written informed consent. Each 
informed consent will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person conducting the consent discussion, and also by an 
impartial witness as required by IRB or by local requirements.  
10.1.4 Confidentiality 
The investigator will assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Laboratory specimens will be labeled in such a 
way as to protect subject identity while allowing the results to be recorded to the proper subject. 
Refer to specific laboratory instructions. Subject data will be processed in accordance with all 
applicable regulations. 
10.1.5 Study Files and Retention of Records 
The investigator will 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, and (2) subject 
clinical source documents. 

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The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB and 
governmental approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
The required source data should include sequential notes containing at least the following 
information for each subject: 
• 
Subject identification (name, date of birth, gender); 
• 
Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria); 
• 
Documentation of the reason(s) a consented subject is not enrolled 
• 
Participation in 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; 
• 
Start and end date (including dose regimen) of study drug, including dates of dispensing; 
• 
Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity); 
• 
Concomitant medication (including start and end date, dose if relevant; dose changes); 
• 
Date of study completion and reason for early discontinuation, if it occurs. 
10.1.6 Case Report Forms (CRFs) 
For each subject consented, a CRF will be completed by an authorized study staff member whose 
training for this function is documented according to study procedures. CRF should be completed 
on the day of the subject visit to enable the sponsor to perform central monitoring of safety data. 
Prior to database lock (or any interim time points as described in the clinical data management 
plan), study staff will confirm that the forms have been reviewed, and that the entries accurately 
reflect the information in the source documents. The CRF will capture the data required per the 
protocol schedule of events and procedures.   
10.1.7 Investigational Medicinal Product Accountability and Return 
Used (empty or partially empty) and unused study drug supplies will be destroyed on site 
according to appropriate standard operating procedure (SOP).  
If study drug is destroyed on site, the investigator must maintain accurate records for all study drug 
destroyed. Records must show the identification and quantity of each unit destroyed, the method of 

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destruction, and the person who disposed of the study drug. Upon study completion, copies of the 
study drug accountability records must be filed at the site.  
10.1.8 Inspections 
The investigator will make available all source documents and other records for this trial to IRBs or 
to regulatory authority or health authority inspectors. 
10.1.9 Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.1.10 
 Protocol Modifications 
Protocol modifications may be made by the investigator. The investigator must submit all protocol 
modifications to the IRB in accordance with local requirements and receive documented IRB 
approval before modifications can be implemented. 
10.1.11 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities may conduct inspections or audits of the clinical study. 
The investigator agrees to provide to representatives of a regulatory agency access to records, 
facilities, and personnel for the effective conduct of any inspection or audit. 
10.1.12 
Study Discontinuation 
The investigator reserves the right to terminate the study at any time. Should this be necessary, the 
investigator will arrange discontinuation procedures and notify the appropriate regulatory 
authority(ies) and IRB. In terminating the study, the investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. 
 
 

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11 APPENDICES 
Appendix 1. Study Procedures Table 
 
Appendix 2. Suicidality SOP 
 
Appendix 3: Description and Dates of Amendments 
 

 
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Appendix 1. 
Study Procedures Table 
Table 3: Study Procedures Summary  
 
Screening 
(2 visits) 
Run-in 
(≤2 visits) 
Enrollment 
(week 0) 
Weekly 
(weeks 1-3, 
5-7, 9-11) 
Weeks 4, 8 Week 12 
FU- 
week 20 
PRN 
Visits 
Informed consent  
X 
 
 
 
 
 
 
 
Urine drug test  
X 
X 
X 
X 
X 
X 
X 
 
Medical history  
X 
 
 
 
 
 
 
 
Physical exam   
X 
 
 
 
 
 
 
 
Vital signs (incl. weight)  
X 
 
X 
X 
X 
X 
X 
X 
Suicidality screen (C-SSRS) 
X 
 
X 
 
X 
X 
X 
 
Study drug administration 
 
 
X 
X 
X 
 
 
 
Interview/survey  
 
 
X 
 
X 
X 
X 
 
Symptom-driven physical 
exam  
 
 
X 
X 
X 
X 
X 
X 
Med. Mgmt. Counseling  
 
 
X 
X 
X 
X 
 
 
AE Assessment  
 
 
X 
X 
X 
X 
X 
X 
Hair sampling  
 
 
X 
 
 
X 
 
 
Safety labs  
X* 
 
 
 
X** 
X** 
 
X 
Biomarker testing  
 
 
X 
 
 
X 
 
 
 
*Baseline safety labs include: comprehensive metabolic panel (CMP), hemoglobin A1c, lipase, amylase, calcitonin, and urine pregnancy test. TSH will be 
conducted as needed. 
**Follow-up safety labs limited to CMP, lipase, amylase, urine pregnancy test, and as-needed labs for clinical adverse event assessment. 
 
 
 
 
 
 
 
 

 
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Appendix 2. Suicidality SOP 
 
Version: 
2.0 
Review: 
Annually 
Pages: 
2 
Author: 
John Walker, Finn Black 
Approved By: 
Phillip Coffin 
Effective Date: 
07/23/24 
 
Location: 
25 Van Ness Avenue, Suite 500 
San Francisco, CA 94102 
Subject: 
Urgent/Emergency Care Procedures 
Function: 
Provides guidelines for managing medical and psychiatric 
emergencies during visits with research participants. 
Distribution: 
S:\Prevention\Research\ Clinician\SOPs and 
S:\Prevention\Research\Psychiatric Emergency 
 
When to use this protocol: This protocol applies to all study visits (in office or remote) with a research participant when there is a suspected 
psychiatric emergency. 
 
General safety protocols for participant study visits: 
 
1. Have emergency resources available: During each study visit, study staff should have contact information available for the study 
clinicians (John Walker and Finn Black) and medical director (Phillip Coffin) including office and cell phone numbers, and crisis services 
numbers in case of a psychiatric or medical emergency. 
2. Have participant emergency contacts available: The participant’s physical address, phone number, and emergency contacts for the 
participant should be confirmed and updated as described in the study protocol. 
 
Psychiatric emergencies: 
 
When to use this protocol: This protocol applies to all visits with a research participant when there is a suspected psychiatric emergency. 
Psychiatric emergencies include situations where a person is in immediate danger of harming themselves or other people, or situations where a 
person is unable to meet their basic survival needs due to their mental health. 
 
1. Initial assessment: Research associates (RAs) are not required to assess participants beyond asking the mental health questions included 
as part of study procedures. RAs should notify a research clinician in any of the following situations: 
a. Participant discloses current suicidal or homicidal thoughts and has a plan to act on these thoughts. 

 
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16 September 2025 
 
b. Participant is acutely psychotic and there is concern the participant may come to harm or harm others if allowed to leave the 
premises. 
c. RA is concerned that participant is unable to meet their basic survival needs due to mental illness (e.g., participant is unable to 
seek shelter or eat). 
2. Call for assistance: The participant should be thanked for sharing this information and told that this situation will best be addressed by a 
licensed study clinician who will meet with the participant or join the Zoom call if the visit is remote. 
a. The research associate will stay on Zoom with video on and call the study clinician. If the study clinician is available, the zoom 
link will be shared via email with the clinician so the clinician can join the call. 
b. If a study clinician is not available within 10 minutes, the medical director, Phillip Coffin [cell (917) 882-7344] should be called. 
c. If licensed study staff are unavailable, the RA should call the SFDPH Mobile Crisis Team at (415) 970-4000. 
3. Clinician assessment: A licensed study clinician will assess the situation in conjunction with the medical director, if available, and 
determine course of action: 
a. Participant is at serious, imminent risk of harm to self or others: 
i. Clinician can call to consult with the SFDPH Mobile Crisis team at (415) 970-4000 OR arrange for transportation to 
Psychiatric Emergency Services (PES) at ZSFGH [(628) 206-8125] or DORE Urgent Care Clinic [(415) 553-3100]. 
Transportation to PES or DORE should be by EMS (by calling 911 and explaining the situation) or the Mobile Crisis 
Team. 
ii. If transfer to PES or DORE Urgent Care Clinic is needed, clinician should stay with the participant until a warm hand off 
of the participant to EMS or Mobile Crisis takes place. 
b. Participant is not at serious, imminent risk of harm to self or others but does require urgent mental health services: 
i. Participant has established mental health care: 
1. The participant will be encouraged to contact their mental health provider. A staff member will help to facilitate 
contacting the provider if the participant requires assistance. 
2. The clinician will obtain a consent for release of information if the participant would like the clinician to contact 
or confer with their mental health provider directly. 
3. Provide participant with crisis resources wallet card. 
ii. Participant requires linkage to mental health care: 
1. Give participant the 24 hour S.F. Behavioral Health Mental Health Access Line [(415) 255-3737 or (888) 246-
3333] and the Suicide Prevention Lifeline (1-800-273-8255). Participants who prefer text can use the Crisis Text 
Line (text HOME to 741741). 
2. Refer participant to same-day care through Westside Crisis (415-355-0311 X1220 at 245 11th Street, drop-in 
hours M–F 7:30am-3pm, participants need to arrive at 7am to be seen the same day for Medi-
Cal/Medicare/uninsured patients). 
3. Provide participant with crisis resources wallet card. 
 

 
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Appendix 3. Description and Dates of Amendments 
Amendment 1:  
In this amendment we made revisions to the inclusion and exclusion criteria based on feedback from NIDA during their review 
process. 
Addition of measures in the survey assessment (CGI, SF-36), and TSH to safety labs.