Adaptive Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Single Ascending Doses of Kratom in Healthy, Nondependent, Adult Recreational Polydrug Users With Opioid Experience
Phase: PHASE1
Conditions: Safety, Pharmacokinetics, Pharmacodynamics
Sponsor: Altasciences Company Inc.

Adaptive Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of 
Single Ascending Doses of Kratom in Healthy, Nondependent, Adult Recreational 
Polydrug Users with Opioid Experience 
 
 
CinicalTrials.gov ID: NCT06072170 
Protocol Number: 75F40121C00199 (FDU-P4-117) 
Protocol: Version 1.0, 05-JUN-2023 

 
 
 
Adaptive Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of 
Single Ascending Doses of Kratom in Healthy, Nondependent, Adult Recreational 
Polydrug Users with Opioid Experience 
Protocol Number: 
75F40121C00199 
Altasciences Project Number: 
FDU-P4-117 
Investigational Product: 
Kratom 500 mg capsules 
Phase of Development: 
1 
Sponsor: 
Food and Drug Administration (FDA), USA 
10903 New Hampshire Ave. 
Silver Spring MD, 20903 
COMPLIANCE 
The study will be conducted in accordance with standards of Good Clinical Practice, as defined by the 
International Council for Harmonisation and all applicable federal and local regulations. 
Protocol Version 
Date 
1.0 
(Original) 
June 05, 2023 
 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for review to Investigator(s) 
and to the appropriate Independent Ethics Committee (IEC) or Institutional Review Board (IRB). It may not be 
used, divulged, published or otherwise disclosed without the written authorization from Altasciences or the 
sponsor. 

Protocol No: 75F40121C00199 
Altasciences Project Number: FDU-P4-117 
 
Version 1.0, 05-JUN-2023 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................................ 2 
LIST OF IN-TEXT TABLES ..................................................................................................................................... 5 
STUDY SYNOPSIS ..................................................................................................................................................... 6 
STUDY ADMINISTRATIVE STRUCTURE ......................................................................................................... 10 
1. 
INTRODUCTION .............................................................................................................................................. 11 
1.1. Study Rationale ............................................................................................................................................. 11 
1.2. Background ................................................................................................................................................... 11 
1.3. Rationale for Dose Selection ......................................................................................................................... 12 
1.4. Risk/Benefit Assessment ............................................................................................................................... 13 
1.4.1. Known Potential Risks ........................................................................................................................... 13 
1.4.2. Known Potential Benefits....................................................................................................................... 13 
2. 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................................... 14 
3. 
STUDY DESIGN ................................................................................................................................................ 15 
3.1. Overall Study Design .................................................................................................................................... 15 
3.2. Adaptive Features and Risk Management of Study Design .......................................................................... 16 
3.3. Maximum Tolerated Dose ............................................................................................................................. 17 
4. 
SUBJECT POPULATION ................................................................................................................................ 17 
4.1. Inclusion Criteria ........................................................................................................................................... 17 
4.2. Exclusion Criteria .......................................................................................................................................... 19 
4.3. Withdrawal Criteria ....................................................................................................................................... 21 
4.3.1. Before First Treatment Administration .................................................................................................. 21 
4.3.2. After First Treatment Administration ..................................................................................................... 21 
4.4. Lifestyle and/or Dietary Requirements.......................................................................................................... 23 
4.5. Concomitant Treatment ................................................................................................................................. 24 
5. 
STUDY TREATMENTS .................................................................................................................................... 24 
5.1. Investigational Products ................................................................................................................................ 24 
5.1.1. Kratom 500 mg Capsules ....................................................................................................................... 24 
5.1.2. Placebo ................................................................................................................................................... 24 
5.2. Investigational Product Management ............................................................................................................ 24 
5.2.1. Packaging, Labeling and Dispensing ..................................................................................................... 24 
5.2.2. Storage and Handling ............................................................................................................................. 25 
5.2.3. Method of Assigning Subjects to Treatment Groups ............................................................................. 25 
5.2.4. Blinding .................................................................................................................................................. 25 
5.2.5. Study Drug Accountability ..................................................................................................................... 25 
5.3. Administration of Study Drug ....................................................................................................................... 26 

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5.3.1. Treatment Compliance ........................................................................................................................... 26 
5.4. Meals ............................................................................................................................................................. 26 
5.5. Fluids ............................................................................................................................................................. 26 
5.6. Other Protocol Restrictions ........................................................................................................................... 26 
6. 
STUDY PROCEDURES .................................................................................................................................... 26 
6.1. Safety Assessments ....................................................................................................................................... 31 
6.1.1. Medical History ...................................................................................................................................... 31 
6.1.2. Medication, Recreational Drug, Alcohol, and Nicotine Use History ..................................................... 31 
6.1.3. Physical Examination ............................................................................................................................. 31 
6.1.4. Vital Signs .............................................................................................................................................. 32 
6.1.5. 12-Lead Electrocardiogram .................................................................................................................... 33 
6.1.6. Laboratory Evaluations .......................................................................................................................... 33 
6.1.7. Columbia Suicide Severity Rating Scale (C-SSRS) ............................................................................... 34 
6.1.8. Rescue Therapy ...................................................................................................................................... 34 
6.2. Pharmacokinetic Assessments ....................................................................................................................... 34 
6.2.1. Pharmacokinetic Sample Processing, Storage and Shipping .................................................................. 36 
6.3. Pharmacodynamic Assessments .................................................................................................................... 36 
6.3.1. Pupillometry ........................................................................................................................................... 36 
6.3.2. Subjective Effects ................................................................................................................................... 37 
7. 
ADVERSE EVENTS DOCUMENTATION .................................................................................................... 44 
7.1. Definitions ..................................................................................................................................................... 44 
7.2. Severity Assessment ...................................................................................................................................... 45 
7.3. Causality Assessment .................................................................................................................................... 45 
7.4. Adverse Event Monitoring ............................................................................................................................ 45 
7.5. Reporting of Pregnancy ................................................................................................................................. 46 
7.6. Serious Adverse Event Reporting ................................................................................................................. 47 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................................................... 48 
8.1. Analysis Populations ..................................................................................................................................... 48 
8.1.1. Randomized Population ......................................................................................................................... 48 
8.1.2. Safety Population ................................................................................................................................... 48 
8.1.3. Pharmacokinetic Population ................................................................................................................... 48 
8.1.4. Completer Population ............................................................................................................................. 48 
8.2. Demographic Data and Other Baseline Characteristics ................................................................................. 48 
8.3. Safety............................................................................................................................................................. 48 
8.4. Pharmacokinetics .......................................................................................................................................... 48 
8.5. Pharmacodynamics ........................................................................................................................................ 49 

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8.6. Planned Interim Analyses .............................................................................................................................. 49 
8.7. Determination of Sample Size ....................................................................................................................... 49 
9. 
REFERENCES ................................................................................................................................................... 50 
10. APPENDIX 1: ETHICS ..................................................................................................................................... 51 
10.1. Institutional Review Board ............................................................................................................................ 51 
10.2. Ethical Conduct of the Study ......................................................................................................................... 51 
10.3. Subject Information and Consent .................................................................................................................. 51 
10.4. Subject Confidentiality .................................................................................................................................. 51 
11. APPENDIX 2: DATA COLLECTION, RETENTION, AND MONITORING ............................................ 52 
11.1. Case Report Forms ........................................................................................................................................ 52 
11.2. Data Management and Processing ................................................................................................................. 52 
11.3. Quality Control and Quality Assurance ........................................................................................................ 52 
11.4. Record Retention ........................................................................................................................................... 52 
11.5. Monitoring of the Study ................................................................................................................................ 52 
12. APPENDIX 3: ADMINISTRATIVE PROCEDURES .................................................................................... 53 
12.1. Liabilities ....................................................................................................................................................... 53 
12.2. Adherence to Protocol ................................................................................................................................... 53 
12.3. COVID-19 Response Plan ............................................................................................................................. 53 
12.4. Statement of Investigator ............................................................................................................................... 53 
12.5. Delegation of Investigator Duties .................................................................................................................. 53 
12.6. Premature Termination or Suspension of a Study ......................................................................................... 54 
13. APPENDIX 4: PROTOCOL REVIEW AND APPROVALS ......................................................................... 55 
14. APPENDIX 5: LIST OF ABBREVIATIONS .................................................................................................. 58 
15. APPENDIX 6: CLINICAL LABORATORY EVALUATIONS ..................................................................... 60 
16. APPENDIX 7: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
BASELINE/SCREENING VERSION ..................................................................................................................... 61 
17. APPENDIX 8: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – SINCE LAST VISIT 
VERSION ................................................................................................................................................................... 62 
 

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LIST OF IN-TEXT TABLES 
Table 2-1. Study Objectives and Endpoints .................................................................................. 14 
Table 3-1. Sample Dose Levels .................................................................................................... 16 
Table 3-2. Adaptive Features and Boundaries .............................................................................. 17 
Table 6-1. Schedule of Activities .................................................................................................. 28 
Table 6-2. Acceptable Windows for Vital Sign (Blood Pressure, Pulse, Body Temperature, 
Spot Oxygen Saturation, and Respiratory Rate) Assessments ....................................... 32 
Table 6-3. Vital Sign (Blood Pressure, Pulse, Body Temperature, and Respiratory Rate) 
Recording Schedule ........................................................................................................ 32 
Table 6-4. Spot Oxygen Saturation Schedule ............................................................................... 33 
Table 6-5. Electrocardiogram Recording Schedule ...................................................................... 33 
Table 6-6. Acceptable Windows for Electrocardiogram Assessments ......................................... 33 
Table 6-7. Pharmacokinetic Blood Sampling Schedule ............................................................... 35 
Table 6-8. Acceptable Windows for Timed PK Blood Specimen Collection Procedures ............ 36 
Table 6-9. Pupillometry Schedule ................................................................................................. 37 
Table 6-10. Acceptable Windows for Timed Pupillometry Measurements ................................. 37 
Table 6-11. Subjective Measures Schedule .................................................................................. 38 
Table 6-12. Acceptable Windows for Timed Subjective Measurements ..................................... 38 
Table 6-13. Visual Analog Scale (VAS) Descriptions ................................................................. 39 
Table 6-14. Description of Drug Similarity Visual Analog Scales .............................................. 41 
Table 6-15. Addiction Research Center Inventory (ARCI) Scales Descriptions .......................... 42 
Table 7-1. Adverse Event Relationship to Study Drug................................................................. 45 

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STUDY SYNOPSIS 
Name of 
Sponsor/Company: 
Food and Drug Administration (FDA), USA 
Name of Product: 
Kratom 500 mg capsules 
Title of Study: 
Adaptive Study to Evaluate the Safety, Pharmacokinetics, and 
Pharmacodynamics of Single Ascending Doses of Kratom in Healthy, 
Nondependent, Adult Recreational Polydrug Users with Opioid Experience 
Study 
Development 
Phase: 
1 
Objectives: 
Primary objective: 
The primary objective of the study is to evaluate the safety and tolerability of 
single ascending oral doses of kratom relative to placebo when administered in 
healthy nondependent recreational polydrug users with opioid experience. 
Secondary objectives: 
The secondary objectives of the study are: 
• 
To evaluate the pharmacokinetics (PK) of mitragynine, 
7-hydroxy-mitragynine, paynantheine, speciogynine, and peciociliatine 
following single ascending oral doses of kratom in healthy 
nondependent recreational polydrug users with opioid experience. 
• 
To evaluate the pharmacodynamics (PD) of single ascending oral doses 
of kratom in healthy nondependent recreational polydrug users with 
opioid experience. 
Endpoints: 
Primary endpoint: 
Safety: 
Safety will be evaluated through the assessment of adverse events (AEs), 
laboratory tests, vital signs (blood pressure, pulse, respiratory rate, oxygen 
saturation, and body temperature), electrocardiogram (ECG), physical 
examination findings, and Columbia Suicide Severity Rating Scale (C-SSRS). 
Secondary Endpoints: 
Pharmacokinetic: 
The PK endpoints of this study are the following PK parameters of 
mitragynine, 7-hydroxy-mitragynine, paynantheine, speciogynine, and 
peciociliatine: maximum observed concentration (Cmax), time of maximum 
observed concentration (Tmax), area under the curve from time 0 to the last 
measurable observed concentration (AUC0-T), and area under the curve from 
time 0 to infinity (AUC0-∞). 
Additionally, dose-normalized PK parameters Cmax/D, AUC0-T/D, and 
AUC0-∞/D will be estimated. 
 

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Pharmacodynamic: 
The PD endpoint of this study is the maximum (peak) effect (Emax) over 
24 hours for Drug Liking (“at this moment”), assessed on a bipolar (0 to 
100 points) visual analog scale (VAS). 
Key secondary PD endpoints are: 
• 
Overall Drug Liking VAS (Emax) 
• 
Take Drug Again VAS (Emax) 
• 
High VAS (Emax) 
Non-key secondary PD endpoints are: 
• 
Balance of Effects 
o Drug Liking VAS (minimum effect [Emin], time of maximum effect 
[TEmax], time of minimum effect [TEmin], and time-averaged area 
under the effect-time curve [TA_AUE]) 
• 
Positive Effects 
o Good Effects VAS (Emax, TEmax, and TA_AUE) 
o High VAS (Emax, TEmax, and TA_AUE) 
• 
Negative Effects 
o Bad Effects VAS (Emax, TEmax, and TA_AUE) 
• 
Other Subjective Effects 
o Any Effects VAS (Emax, TEmax, and TA_AUE) 
o Feeling Drunk VAS (Emax, TEmax, and TA_AUE) 
o Drowsiness/Alertness VAS (Emax, TEmax, Emin, TEmin, and area over 
and under the effect-time curve [TA_AOE, TA_AUE]) 
o Relaxation/Agitation (Emax, TEmax, Emin, TEmin, and TA_AOE, 
TA_AUE) 
o Addiction Research Center Inventory (ARCI): 
o Morphine-Benzedrine Group (MBG) Scale (Emax, TEmax, and 
TA_AUE) 
o Amphetamine (A) Scale (Emax, TEmax, and TA_AUE) 
o Benzedrine Group (BG) Scale (Emax, TEmax, and TA_AUE)  
o Pentobarbital–Chlorpromazine–Alcohol Group (PCAG) 
Scale (Emax, TEmax, and TA_AUE) 
o Lysergic acid diethylamide (LSD) Scale (Emax, TEmax, and 
TA_AUE) 
o Bowdle VAS Internal and External Perceptions composite scores 
(Emax) 
o Drug Similarity VAS 12-hour postdose scores 
• 
Pupillometry  
o Maximum pupil constriction as assessed by the difference between 
initial pupil diameter and minimum pupil diameter (MPC) 

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o Time to maximum pupil constriction  
o Pupillometry area over the curve (time-averaged pupillometry area 
over the effect curve relative to baseline [TA_PAOC]) 
Investigational 
Product, Dose, and 
Mode of 
Administration: 
Kratom 500 mg capsules 
Manufacturer: Sun Distribution, Super Organics 
Mode of administration: Oral 
Placebo and Mode 
of Administration: 
Placebo-to-match kratom 500 mg capsules 
Mode of administration: Oral 
Study Population: 
Healthy, male and female nondependent, recreational polydrug users with 
opioid experience 
Planned Number 
of Subjects: 
A total of 40 subjects (8 subjects in each of the 5 cohorts) will be included. 
Study Design: 
This single center, single-dose, randomized, adaptive, double-blind, placebo-
controlled study will consist of 5 single ascending dose (SAD) cohorts. The 
sample dose levels by cohort are as follows: 
Cohort 
Number of Subjects 
(active:placebo) 
Dosea 
Regimen 
1 
8 
(6:2) 
1 g (2 capsules) 
Single oral 
administration of 
kratom or placebo 
on Day 1 
2 
8 
(6:2) 
E.g., 2 g (4 capsules) 
3 
8 
(6:2) 
E.g., 4 g (8 capsules) 
4 
8 
(6:2) 
E.g., 6 g (12 capsules) 
5 
8 
(6:2) 
E.g., 8 g (16 capsules) 
a. 
Or until the maximum tolerated dose is defined 
Dose levels presented are approximations and may be increased or decreased 
based on interim safety reviews. Doses may be increased, above those shown in 
the table above, if there are no safety concerns and if it is deemed that there are 
minimal effects on PD measures. The upper dose may exceed 8 g if deemed 
appropriate and safe by interim data reviews. 
Blood samples for PK assessments will be collected before and over 48 hours 
after study drug administration. Assessments for the evaluation of PD will be 
performed before and over 24 hours after study drug administration. Safety and 
tolerability will be assessed throughout the study. 
Dosing of each cohort will be adequately scheduled apart to ensure sufficient 
time for review of the safety and PD data prior to dosing of the next cohort. 
Duration of 
Treatment and 
Subject 
Confinement: 
Duration of clinical trial (per subject): 
Screening: Day -28 to Day -1 (up to 28 days) 

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Treatment period: Subjects will be confined to the clinical site from the day 
prior to drug administration until 48 hours following drug administration. 
Subjects will return to the clinical site for a follow-up visit on Day 7 ± 2. 
Total study duration: up to 37 days (including screening) 
Safety Meetings 
for Dose Escalation 
and Adjustments: 
Following completion of each cohort, a Safety Review Committee will review 
all safety and PD data to evaluate progression to the next dose cohort. 
The Safety Review Committee will be comprised of the Principal Investigator 
at the Investigational site, the Study Manager and personnel from the Sponsor’s 
scientific team at a minimum. 
Dose levels presented are approximations and may be increased or decreased 
based on interim safety reviews. The upper dose may exceed 8 g if deemed 
appropriate and safe by interim data reviews. 
Bioanalysis: 
Mitragynine, 7-hydroxy-mitragynine, paynantheine, speciogynine, and 
peciociliatine plasma concentrations will be measured by validated 
bioanalytical methods. 
Safety Analysis:  
Clinical laboratory tests, AEs, vital signs (blood pressure, pulse, respiratory 
rate, oxygen saturation, and body temperature), ECG findings, physical 
examination findings, and C-SSRS will be used to perform safety analyses. 
Safety analyses will be fully detailed in the statistical analysis plan (SAP). 
Pharmacokinetic 
Analysis: 
The PK parameters Cmax, Cmax/D, Tmax, AUC0-T, AUC0-T/D, AUC0-∞, AUC0-∞/D, 
AUCT/∞, λZ, and Thalf will be estimated for mitragynine, 7-hydroxy-mitragynine, 
paynantheine, speciogynine, and peciociliatine. Additional parameters may be 
calculated. 
The PK analyses will be performed by non-compartmental analysis. 
The PK analysis will be detailed in the SAP. 
Pharmacodynamic 
Analysis: 
The PD measures at each time point will be summarized by treatment using 
descriptive statistics and presented graphically. Derived endpoints will be 
summarized by treatment and paired difference using descriptive statistics. 
A mixed-effects model will be used to compare PD endpoints between Kratom 
dose levels and placebo for all primary and secondary PD endpoints other than 
the 12-hour postdose results from Drug Similarity VAS. The model will include 
dose level as a fixed effect and the baseline score as a covariate [where 
applicable]. P-values for key components of variance, least-square means 
(LSmeans), and 95% CI for contrasts will be output. 
The Hodges-Lehmann estimate of the location shift, the asymptotic confidence 
limits, and the asymptotic standard error estimate will be used to estimate the 
95% CIs of TEmax/TEmin between the Kratom dose levels and placebo. The 
asymptotic standard error estimate is based on the length of the CIs. Rank sums 
and p-values from the Wilcoxon Rank Sum test will also be output. 
The PD analysis will be fully detailed in a SAP. 
Statistical 
Analysis: 
The statistical analysis will be fully detailed in a SAP. 

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STUDY ADMINISTRATIVE STRUCTURE 
SPONSOR’S CONTACT: 
 
Chad Reissig, PhD, Supervisory Pharmacologist 
10903 New Hampshire Ave. 
Silver Spring MD 20903 
Phone: 301-796-3434 
E-mail: Chad.Reissig@fda.hhs.gov 
CLINICAL RESEARCH UNIT: 
Altasciences 
10103 Metcalf Avenue 
Overland Park, Kansas, 66212 
10203 Metcalf Avenue 
Overland Park, Kansas, 66212 
10183 Metcalf Avenue 
Overland Park, Kansas, 66212 
MEDICAL LABORATORY: 
 
Quest Diagnostics 
10101 Renner Blvd 
Lenexa, KS 66219 
BIOANALYTICAL FACILITIES: 
Altasciences (analysis of mitragynine and 7-OH-mitragynine) 
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
University of Florida (analysis of paynantheine, speciogynine, and 
speciociliatine) 
1345 Center Drive, MSB, P1-04 
Gainesville, FL 32610 
PHARMACOKINETIC AND STATISTICAL FACILITY: 
Altasciences 
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
DATA MANAGEMENT FACILITY: 
Altasciences 
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
PROJECT MANAGEMENT: 
 
Altasciences 
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
 
COGNITIVE TESTS: 
Cambridge Cognition 
2750 Rasmussen Road 
Park City 
Utah 84098, USA 
 

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1. INTRODUCTION 
1.1. Study Rationale 
The Food and Drug Administration (FDA) has previously warned consumers about the use of 
kratom (Mitragyna speciosa). Kratom has both affinity and activity at mu opioid receptors, 
receptor sites known to be associated with abuse. Although kratom use is prevalent, to date, 
clinical evaluations of abuse potential have not been performed. The Controlled Substance Staff 
(CSS) at FDA is proposing to initiate a pilot, single ascending dose (SAD) study of botanical 
kratom. Currently there are limited safety data and chemical, manufacturing, and control data to 
support clinical research with botanical kratom and isolated kratom alkaloids. The present study 
will provide data in these areas that will inform future clinical research with kratom. 
The dose escalation will include 5 cohorts (8 subjects per cohort) of subjects randomized to 
receive either active drug (kratom) or placebo (6:2 active:placebo). Following each dosing, 
safety and pharmacodynamic (PD) data will be reviewed by a safety review board to determine if 
further dose escalation can safely commence. 
A placebo control is used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active treatment as well as to minimize subject and 
investigator bias. Blinded treatment, including the use of double-blind procedures, will be used 
to reduce potential bias during data collection and evaluation of clinical endpoints. 
The FDA guidance “Bioavailability Studies Submitted in NDAs or INDs — General 
Considerations” recommends conducting studies under fed conditions if tolerability issues or 
serious adverse events (SAEs) are anticipated under fasted conditions. The current study will 
therefore administer the study drug following intake of a high-fat breakfast to avoid potential 
tolerability issues (i.e., vomiting). 
Subjects will be healthy individuals, with previous non-therapeutic (recreational) polydrug use 
and opioid experience. Furthermore, subjects will be required to have experience with drugs that 
have psychoactive properties, particularly since supratherapeutic (high) doses of kratom will be 
evaluated in this study. 
In addition to the requirement that subjects be “history qualified” (i.e., have a history of 
recreational opioid use), medical history and clinical assessments will also be used to confirm 
that subjects meet the required study eligibility criteria and to confirm that they are not 
dependent on drugs or alcohol. Urine drug screens and alcohol checks, as well as other 
assessments (e.g., pregnancy tests) will be used to confirm compliance and eligibility.  
1.2. Background 
Kratom is a botanical product that contains a mixture of indole-based alkaloid compounds. 
Though at least 25 alkaloid compounds have been isolated from kratom, most represent only a 
small portion of the total alkaloid content (≤1%) and thus, depending on their potency, may not 
significantly contribute to the overall effects of kratom individually.2 Mitragynine represents 
66% of the total extractable alkaloid content of kratom, with paynantheine (9%), speciogynine 
(7%), and 7-hydroxymitragynine (2%) being the next most abundant. Of note, 
7-hydroxymitragynine is thought to be the most potent of these compounds with regard to 
psychoactive effects.2 Paynantheine and speciogynine have been reported to exhibit high affinity 

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for the 5-HT1A and 5-HT2B serotonin receptors and produce antinociception in rats, via an 
opioid-receptor independent mechanism that was blocked by a 5-HT1A receptor antagonist.3 
Thus, while mitragynine and 7-hydroxymitragynine are thought to mediate most of kratom’s 
pharmacologic effects, the presence of other minor alkaloid compounds may contribute to the 
overall effect of kratom use and may do so through multiple pharmacologic pathways.1 
The kratom plant, M. speciosa, is a member of the coffee family and is native to many countries 
in Southeast Asia, including but not limited to Thailand, Malaysia, New Guinea, and the 
Philippines. For many centuries, the leaves of this plant have been used in Southeast Asia for 
cultural, recreational, health, and medicinal purposes. The leaves are most often chewed or dried 
and made into tea. Kratom uses vary widely; users seek desired benefits that range from calming 
effects to stimulative effects.1,4,5 
While there are extensive reports in the literature regarding the use of kratom in the US, 
Malaysia, and Thailand, overall, the available clinical literature is not strong. Most of the 
published studies on kratom use are not controlled or prospective. There are very few studies 
directly correlating specific doses of kratom with adverse effects. Rather, there are a large 
number of case reports available. However, many of the patients described in these cases had a 
history of chronic kratom use, consumed large amounts of kratom, and/or used multiple 
substances simultaneously. The case reports cover the years 2010 to 2021. There are a fair 
number of studies reported in the literature, but they are mostly retrospective analyses of poison 
center databases, case study series, autopsies, and social media posts, as well as survey (self-
reported information) and interview (conducted by trained professional) studies. There are a few 
small prospective pharmacokinetics studies and in vitro pharmacokinetics studies. The reported 
studies cover the years 1998-2021.1 
The available literature describing human PK and metabolism studies with kratom are 
summarized in the Investigator’s Brochure of kratom.1 
1.3. Rationale for Dose Selection 
Human abuse potential studies investigate a range of doses from the highest proposed therapeutic 
dose to supratherapeutic doses (2-3× highest therapeutic dose, if it can be done safely). In order 
to determine an appropriate kratom dose range for a future human abuse potential study, kratom 
will first be evaluated in this dose escalation study to examine the safety, tolerability, PK, and 
PD effects in the intended study population (healthy nondependent recreational polydrug users 
with opioid experience). Based on published epidemiological papers, doses of kratom used for 
medical or non-medical purposes range widely from 1 to 12 g. Doses below 6 g are typically 
considered low doses, whereas doses over 6 g are considered high doses. Doses in excess of 7 to 
8 g are considered to produce strong sedation and analgesia effects, whereas lower doses < 5 g 
are reported as producing stimulant-like effects .6  To evaluate the full range of PD effects, up to 
5 dose levels will be evaluated starting with a low dose (1 g) and escalating to approximately 8 g 
to evaluate the pharmacological properties of kratom. Doses may exceed 8 g if it is deemed safe 
based on interim safety reviews. Doses will be adjusted as needed between cohorts based on 
review of safety and PD data. 

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1.4. Risk/Benefit Assessment 
1.4.1. Known Potential Risks 
The true incidence of adverse reactions associated with the use of kratom is difficult to 
determine, due to the lack of randomized, controlled clinical studies. However, the adverse 
events (AEs) most commonly reported related to kratom use, in 10% or more of populations 
identified in published, peer-reviewed articles, are as follows: acute kidney injury, agitation, 
altered consciousness, anxiety, apathy, appetite loss, blood pressure increase (delayed onset), 
confusion, constipation, diaphoresis/feeling hot, depression, dizziness, 
drowsiness/lethargy/fatigue, dyspnea, hallucinations, headaches, heart rate increase (delayed 
onset), hypotension, hypertension, insomnia, feeling intoxicated, irritability, elevated low-density 
lipoprotein and high-density lipoprotein, libido/sexual performance decrease, miosis, decreased 
motivation, mydriasis, nausea, palpitation, physical pain, respiratory failure, stomach 
ache/abdominal pain, tachycardia, tongue numbness, tremor, weight loss, and vomiting.1 
The doses of kratom administered in this study are not anticipated to induce unmanageable risks 
to the subjects. The safety monitoring practices employed in this protocol (i.e., AE questioning, 
clinical laboratory assessments, vital signs [blood pressure, pulse, respiratory rate, oxygen 
saturation and body temperature], electrocardiogram [ECG], physical examination findings, and 
Columbia Suicide Severity Rating Scale [C-SSRS]) are appropriate to protect the subjects’ safety 
and should detect treatment--emergent AEs (TEAEs). 
1.4.2. Known Potential Benefits 
As the study treatments are not being given to subjects to treat a medical disorder, there will be 
no direct medical benefit from participation in this trial. 

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2. STUDY OBJECTIVES AND ENDPOINTS 
The objectives and endpoints of the study are presented in Table 2-1. 
Table 2-1. Study Objectives and Endpoints 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To evaluate the safety and tolerability of single 
ascending oral doses of kratom relative to 
placebo when administered in healthy 
nondependent recreational polydrug users with 
opioid experience. 
Safety will be evaluated through the assessment of 
AEs, laboratory tests, vital signs (blood pressure, 
pulse, respiratory rate, oxygen saturation, and body 
temperature), ECGs, physical examination findings, 
and C-SSRS. 
Secondary 
 
To evaluate the PK of mitragynine, 
7-hydroxy-mitragynine, paynantheine, 
speciogynine, and peciociliatine following 
single ascending oral doses of kratom in healthy 
nondependent recreational polydrug users with 
opioid experience. 
The PK endpoints of this study are the following 
PK parameters of mitragynine, 7-hydroxy-
mitragynine, paynantheine, speciogynine, and 
peciociliatine: Cmax, Tmax, AUC0-T, and AUC0-∞. 
Additionally, dose-normalized PK parameters 
Cmax/D, AUC0-T/D, and AUC0-∞/D will be estimated. 
To evaluate the PD of single ascending oral 
doses of kratom in healthy nondependent 
recreational polydrug users with opioid 
experience. 
The PD endpoint of this study is the maximum 
(peak) effect (Emax) over 24 hours for Drug Liking 
(“at this moment”), assessed on a bipolar (0 to 
100 points) VAS. 
Key secondary PD endpoints are: 
• 
Overall Drug Liking VAS (Emax) 
• 
Take Drug Again VAS (Emax) 
• 
High VAS (Emax) 
Non-key secondary PD endpoints are: 
• 
Balance of Effects 
o Drug Liking VAS (minimum effect 
[Emin], time of maximum effect [TEmax], 
time of minimum effect [TEmin], and 
time-averaged area under the effect-time 
curve [TA_AUE]) 
• 
Positive Effects 
o Good Effects VAS (Emax, TEmax, and 
TA_AUE) 
o High VAS (Emax, TEmax, and TA_AUE) 
• 
Negative Effects 
o Bad Effects VAS (Emax, TEmax, and 
TA_AUE) 
• 
Other Subjective Effects 

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OBJECTIVES 
ENDPOINTS 
o Any Effects VAS (Emax, TEmax, and 
TA_AUE) 
o Feeling Drunk VAS (Emax, TEmax, and 
TA_AUE) 
o Drowsiness/Alertness VAS (Emax, TEmax, 
Emin, TEmin, and area over and under the 
effect-time curve [TA_AOE, TA_AUE]) 
o Relaxation/Agitation (Emax, TEmax, Emin, 
TEmin, TA_AOE, and TA_AUE) 
o ARCI MBG Scale (Emax, TEmax, and 
TA_AUE) 
o ARCI A Scale (Emax, TEmax, and 
TA_AUE) 
o ARCI BG Scale (Emax, TEmax, and 
TA_AUE) 
o ARCI PCAG Scale (Emax, TEmax, and 
TA_AUE) 
o ARCI LSD Scale (Emax, TEmax, and 
TA_AUE) 
o Bowdle VAS Internal and External 
Perceptions composite scores (Emax) 
o Drug Similarity VAS12-hour postdose 
scores 
• 
Pupillometry  
o Maximum pupil constriction as assessed 
by the difference between initial pupil 
diameter and MPC 
o Time to maximum pupil constriction 
o Pupillometry area over the curve 
(time--averaged pupillometry area over 
the effect curve relative to baseline 
[TA_PAOC]) 
Abbreviations: AE = adverse event; ARCI = Addiction Research Center Inventory; C-SSRS = Columbia Suicide 
Severity Rating Scale; ECG = electrocardiogram; LSD = Lysergic acid diethylamide; MBG = Morphine-Benzedrine 
Group; MPC = minimum pupil diameter; PCAG = Pentobarbital–Chlorpromazine–Alcohol Group; PD = 
pharmacodynamic; PK = pharmacokinetic; VAS = visual analog scale. 
3. STUDY DESIGN 
3.1. 
Overall Study Design 
This single center, single-dose, randomized, adaptive, double-blind, placebo-controlled study 
will consist of 5 SAD cohorts. A total of 40 healthy, male and female nondependent, recreational 
polydrug users with opioid experience (8 subjects in each of the 5 cohorts) will be included. 

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Subjects will only participate in 1 cohort. The planned dose levels by cohort are presented in 
Table 3-1. 
Table 3-1. Sample Dose Levels 
Cohort 
Number of Subjects 
(active:placebo) 
Dosea 
Regimen 
1 
8 
(6:2) 
1 g (2 capsules) 
Single oral 
administration of 
kratom or placebo on 
Day 1 
2 
8 
(6:2) 
E.g., 2 g (4 capsules) 
3 
8 
(6:2) 
E.g., 4 g (8 capsules) 
4 
8 
(6:2) 
E.g., 6 g 
(12 capsules) 
5 
8 
(6:2) 
E.g., 8 g 
(16 capsules) 
a. 
Or until the maximum tolerated dose is defined 
Dose levels presented are approximations and may be increased or decreased based on interim 
safety reviews. Doses may be increased, above those shown above in Table 3-1, if there are no 
safety concerns and if it is deemed that there are minimal effects on PD measures. The upper 
dose may exceed 8 g if deemed appropriate and safe by interim data reviews.  
Subjects will be confined to the clinical site from the day prior to drug administration until 
48 hours following drug administration. Subjects will return to the clinical site for a Follow-Up 
Visit on Day 7 ± 2. The total duration of the study including Screening will be up to 37 days. 
Blood samples for PK assessments will be collected before and over 48 hours after study drug 
administration. Assessments for the evaluation of PD will be performed before and over 
24 hours after study drug administration. Safety and tolerability will be assessed throughout the 
study. 
Following completion of each cohort, a Safety Review Committee (SRC) will review all safety 
and/or PD data to evaluate progression to the next dose cohort. The SRC will be comprised of 
the Principal Investigator at the Investigational site, the Study Manager and personnel from the 
Sponsor’s scientific team at a minimum. Dosing of each cohort will be adequately scheduled 
apart to ensure sufficient time for review of the safety and PD data prior to dosing of the next 
cohort.  
Subjects who terminate the study early will perform End of Study procedures (procedures from 
the Follow-Up Visit) as soon as possible after the time of Early Termination. 
The schedule of activities of the study is described in Table 6-1. 
3.2. 
Adaptive Features and Risk Management of Study Design 
The rational of having the following adaptive features is based on the hypothesis-forming 
approach of this clinical trial. The features from Table 3-2 may be adapted during the study. 

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Table 3-2. Adaptive Features and Boundaries 
Adaptive study design 
category 
Adaptive Features 
Boundaries 
Dose level for cohorts 
Dose levels may be adjusted 
Doses are intended to escalate, 
however, they may be adjusted 
to higher or lower doses on the 
basis of safety, tolerability, and 
PD data reported in the previous 
cohort(s). 
Abbreviations: PD = pharmacodynamic; PK = pharmacokinetic. 
Decision-making process for the above adaptive study categories will be as follows: 
• Interim review of safety and tolerability of kratom and emerging data (PD) from 
completed or ongoing cohorts in a blinded fashion by the SRC. 
• Outcome on the adaptive study category will be documented by the SRC. 
Based on the above, implementation can be performed without delay and Research Ethic 
Committee approval. If any adaptive features are outside the above pre-specified boundaries, 
Research Ethic Committee approval is mandatory before implementation.  
3.3. 
Maximum Tolerated Dose 
The Maximum Tolerated Dose (MTD) definition: Transient, mild or moderate AEs occurring at 
a given dose level will be evaluated by the SRC prior to dose escalation. If such AEs occurred in 
≥ 3 subjects at a given dose level, dose escalation may be ceased and this dose level or the next 
lower one will be considered the MTD, or an intermediate dose level can be investigated. If such 
AEs occurred in ≤ 2 subjects depending on the particular adverse effects observed, the current 
dose level may be considered the MTD, or dose escalation may proceed. 
4. SUBJECT POPULATION 
Subjects meeting all the inclusion criteria and none of the exclusion criteria at Screening may be 
eligible for participation in this study. Continued eligibility will be assessed upon admission to 
the clinical site, prior to study drug administration. 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. 
4.1. Inclusion Criteria 
1. Provision of signed and dated informed consent form (ICF) 
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study 
3. Healthy adult male or female 

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4. Current nondependent, polydrug recreational user who has used opioid drugs for 
recreational (nontherapeutic) purposes (i.e., for psychoactive effects) at least 10 times in 
the subject’s lifetime and at least once in the last 12 weeks from Screening; and has a 
history of recreational use of at least 2 or more of any of the perception-altering (e.g., 
lysergic acid diethylamide [LSD], kratom, cannabis, dronabinol, ketamine, phencyclidine 
[PCP], dextromethorphan, 3,4 methylenedioxymethamphetamine [MDMA], mescaline, 
psilocybin, tryptamine derivatives or ring-substituted amphetamines with perception 
altering effects) or stimulant (e.g., cocaine, amphetamine, methamphetamine, 
methylphenidate, methcathinone, and other synthetic cathinones) drugs on at least 
5 occasions in the subject’s lifetime 
5. If male, meets one of the following criteria: 
a) Is able to procreate and agrees to use one of the accepted contraceptive regimens and 
not to donate sperm from study drug administration to at least 90 days after study 
drug administration. An acceptable method of contraception includes one of the 
following: 
• Abstinence from heterosexual intercourse 
• Double-barrier method (e.g., male condom with spermicide or male condom with 
a vaginal spermicide [gel, foam, or suppository]) 
Or 
b) Is unable to procreate; defined as surgically sterile (i.e., has undergone a vasectomy at 
least 180 days prior to study drug administration) 
6. If female, meets one of the following criteria: 
a) Is of childbearing potential and agrees to use an acceptable contraceptive method. 
Acceptable contraceptive methods include: 
• Abstinence from heterosexual intercourse from the Screening visit through to at 
least 30 days after study drug administration 
or 
• One of the following contraceptive methods, used from at least 28 days prior to 
the Screening visit through to at least 30 days after study drug administration: 
▪ Systemic contraceptives (combined birth control pills, 
injectable/implant/insertable hormonal birth control products, or 
transdermal patch) 
▪ Intrauterine device (with or without hormones) 
▪ Male partner vasectomized at least 6 months prior to the Screening visit 
or 
• One of the following double-barrier contraceptive methods, used from the 
Screening visit through to at least 30 days study drug administration: 

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▪ Male condom plus spermicide 
▪ Diaphragm plus spermicide 
▪ Cervical cap plus spermicide 
Or 
b) Is of non-childbearing potential, defined as surgically sterile (i.e., has undergone 
complete hysterectomy, bilateral oophorectomy, or tubal ligation), or is in a 
postmenopausal state (i.e., at least 1 year without menses without an alternative 
medical condition prior to the Screening visit and follicle stimulating hormone levels 
≥ 40 mIU/mL at Screening) 
7. Aged at least 18 years but not older than 59 years (inclusive) at Screening 
8. Body mass index (BMI) within 18.0 kg/m2 to 34.0 kg/m2, inclusively at Screening 
9. Minimum weight of 50.0 kg at Screening 
10. Have no clinically significant diseases captured in the medical history or evidence of 
clinically significant findings on the physical examination (including vital signs, oxygen 
saturation [SpO2], and respiratory rate) and/or ECG, as determined by an Investigator 
4.2. Exclusion Criteria 
1. Difficulty swallowing capsules 
2. Female who is lactating 
3. Female who is pregnant according to the pregnancy test at Screening or prior to study 
drug administration 
4. Male with female partner who is pregnant, lactating, or planning to become pregnant 
during this study or within 90 days after study drug administration 
5. History of significant hypersensitivity to kratom or any related products (including 
excipients of the formulations) as well as severe hypersensitivity reactions (like 
angioedema) to any drugs 
6. Presence or history of significant gastrointestinal, liver or kidney disease, or surgery that 
may affect drug bioavailability with the exception of cholecystectomy that is permitted at 
the discretion of an Investigator 
7. History of significant hepatic, renal, cardiovascular, pulmonary, hematologic, 
neurological, psychiatric, gastrointestinal, endocrine, immunologic, ophthalmologic, or 
dermatologic disease 

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8. Presence of any significant respiratory illness or presence or history of chronic 
respiratory disease (e.g., upper respiratory illness, sleep apnea, emphysema, asthma) at 
Screening (subjects with acute respiratory illness may be rescheduled upon resolution at 
the discretion of an Investigator) 
9. History of substance or alcohol moderate to severe use disorder (excluding nicotine and 
caffeine) within the past 2 years, as defined by the Diagnostic and Statistical Manual of 
Mental Disorders, 5th Edition (DSM-5) 
10. Is a heavy smoker (> 20 cigarettes per day) and/or is unable to abstain from smoking or 
unable to abstain from the use of prohibited nicotine-containing products for at least 
1 hour before and 8 hours after study drug administration (including e-cigarettes, pipes, 
cigars, chewing tobacco, nicotine topical patches, nicotine gum, or nicotine lozenges) 
11. Regularly consumes excessive amounts of caffeine or xanthines, defined as greater than 
6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, 
cola, or other caffeinated beverages per day 
12. History of suicidal behavior within 2 years of Screening, showing suicidal tendency as 
per the C-SSRS administered at Screening (APPENDIX 7), or is currently at risk of 
suicide in the opinion of an Investigator 
13. Presence of clinically significant ECG abnormalities at the Screening visit, as defined by 
medical judgment. Note: QT corrected according to Fridericia's formula (QTcF) interval 
of > 450 msec in male subjects or > 470 msec in female subjects will be exclusionary. 
The ECG may be repeated once for confirmatory purposes if the initial value obtained 
exceeds the limits specified. 
14. Estimated glomerular filtration rate (eGFR) ≤ 60 mL/min as calculated by the CKD-EPI 
equation 
15. Any clinically significant illness in the 28 days prior to study drug administration 
16. Use of any prescription drugs (with the exception of hormonal contraceptives or hormone 
replacement therapy) in the 28 days prior to study drug administration, that in the opinion 
of an Investigator would put into question the status of the participant as healthy 
17. Use of St. John’s wort in the 28 days prior to study drug administration 
18. Positive test result for alcohol and/or drugs of abuse at admission (prior to study drug 
administration). Subjects with positive results at admission may be rescheduled at the 
discretion of an Investigator. If tetrahydrocannabinol (THC) is positive at admission a 
cannabis intoxication evaluation will be done by an Investigator and subjects may be 
permitted to continue in the study at the discretion of an Investigator. Other positive test 

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results should be reviewed to determine if the subject may be rescheduled, in the opinion 
of the investigator. 
19. Positive screening results to HIV Ag/Ab combo, hepatitis B surface antigen or hepatitis C 
virus tests 
20. Any other clinically significant abnormalities in laboratory test results at Screening that 
would, in the opinion of an Investigator, increase the subject's risk of participation, 
jeopardize complete participation in the study, or compromise interpretation of study data 
21. Inclusion in a previous group for this clinical study 
22. Intake of kratom in the 14 days prior to study drug administration 
23. Intake of an Investigational Product (IP) in the 28 days prior to study drug administration 
24. Donation of plasma in the 7 days prior to study drug administration 
25. Donation of 1 unit of blood to American Red Cross or equivalent organization or 
donation of over 500 mL of blood in the 56 days prior to study drug administration 
26. Subject cannot eat dairy and/or is lactose intolerant 
27. Is, in the opinion of an Investigator or designee, considered unsuitable or unlikely to 
comply with the study protocol for any reason 
4.3. Withdrawal Criteria 
4.3.1. Before First Treatment Administration 
Before the first treatment administration, inclusion/exclusion criteria will govern the subjects to 
be dosed. Subjects withdrawn before first treatment administration will not be followed up and 
will not undergo End-of-Study/Early Termination assessments. Other safety assessments may be 
performed if required. 
Subjects are free to withdraw their consent to participate in the study at any time, without 
prejudice. The reason for their withdrawal or for deciding to end their participation will be 
documented. 
4.3.2. After First Treatment Administration 
Subjects may, at any time, voluntarily withdraw from the study or be removed from the study at 
the discretion of an Investigator or Sponsor. An Investigator may withdraw a subject at any time 
if it is determined that continuing the study would result in a significant safety risk to the subject 
or if their behavior is deleterious to the study environment. If such withdrawal occurs, or if the 
subject fails to return for visits, an Investigator should determine the primary reason for a 

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subject’s premature withdrawal from the study and record the reason in the subject’s study 
documents.  
An Investigator may remove a subject from the study on the recommendation of the PK facility 
and/or Sponsor due to an unanticipated event that could result in an inadequately characterized 
PK profile (e.g., a missed blood draw, an AE, meal deviation, concomitant medication intake, 
etc). 
In the case of a clinically significant illness detected during the trial (including Coronavirus 
Disease 2019 [COVID-19] diagnosis), the Principal Investigator (or delegate) will, in concert 
with the Sponsor, determine the most appropriate course of action on an individual basis. 
Evaluations will include but are not limited to: 
• The safety of the subject and other study participants 
• The possible effect the illness would have on the results gathered during the trial, and 
their ability to be appropriately analyzed or interpreted 
• The possibility of suspending participation then re-initiating it after recovery 
• The implication of any inclusion or exclusion criteria that would contradict possible 
actions 
• The implication of any adherence to regulatory guidelines that may be affected by actions 
decided; for example group effect analysis 
• The sample size calculation, current number of subjects, and possibility of replacement 
subjects 
Evaluations and decision-making for subject removal will be documented in the study file, 
reported to the Sponsor, and discussed where appropriate in the Clinical Study Report. 
Attempts should be made to have such subjects complete the End-of-Study/Early Termination 
assessments. End-of-Study/Early Termination assessments should be performed as soon as 
possible after the last study treatment administration. 
For subjects lost to follow-up (i.e., those subjects whose status is unclear because they fail to 
appear for study visits without stating an intention to withdraw), an Investigator should show 
"due diligence" by documenting in the source documents steps taken to contact the subject, 
e.g., dates of telephone calls, registered letters, etc. 
4.3.2.1. Stopping Rules 
4.3.2.1.1. Individual Subject Stopping Rules 
Participation in the clinical study may be discontinued by an Investigator (or delegate) in charge 
of the study or by the Sponsor for any of the following reasons, but not limited to: 
• AEs (including if a subject develops any significant illness or needs to undergo any major 
surgery during course of the study) or laboratory abnormalities that would put the subject 
at risk to continue in the opinion of the Investigator and/or the Sponsor 

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• Subject non-compliance (including any violation of protocol requirements which may 
affect the study outcome) 
4.3.2.1.2. Cohort Stopping Rules 
If any of the following safety concerns are observed, dosing of all subjects at the given dose level 
or higher will be suspended/halted and all available data will be evaluated by the SRC. Dose 
continuation (remaining subjects within a cohort or remaining dosing for a subject) or escalation 
should not proceed for any of, but not limited to, the following reasons: 
• If 1 kratom-related SAE occurs in a cohort 
• Moderate or severe AEs in 50% of the subjects in the cohort or more 
Dose escalation will be discussed during the SRC meeting and may be stopped depending on 
Principal Investigator’s or Sponsor’s decision. 
4.3.2.1.3. Trial Stopping Rules 
Clinical trial stopping rules: 
• If 2 kratom-related SAEs occur in a cohort 
• Occurrence of 1 death attributable to kratom 
4.4. Lifestyle and/or Dietary Requirements 
• Subjects will be prohibited from consuming food or beverages containing grapefruit 
and/or pomelo for 7 days prior to dosing and during the study. 
• Subjects will be prohibited from consuming alcohol for 48 hours prior to dosing and 
during the study. Throughout the study (including the Follow-Up Visit), in case of any 
doubt about alcohol consumption, a test for alcohol may be performed if requested by an 
Investigator. 
• Subjects will be prohibited from consuming food or beverages containing xanthines (i.e., 
tea, coffee, cola drinks, energy drinks or chocolate) for 48 hours prior to dosing and 
during the study. 
• Subjects will be prohibited from consuming all recreational drugs (including cannabis) 
from the time of screening and for the duration of the study. 
• Subjects will eat only the food provided by the study site during confinement at the 
clinical site. 
• During the study, subjects who are smokers should not smoke more than the equivalent 
of 20 cigarettes per day. Subjects will abstain from smoking for 1 hour prior to and until 
8 hours after study drug administration. 
• Subjects will be asked to refrain from driving, operating machinery, or engaging in 
hazardous activities until they and an Investigator are convinced the study drug is not 
impairing their judgment and/or ability to perform skilled tasks. 

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• Female subjects of childbearing potential will have to take appropriate measures to 
prevent pregnancy as described in Section 4.1. It is the participant’s responsibility to 
notify the clinical site if a pregnancy occurs from the end of their study participation until 
30 days after study drug administration. 
• Male subjects will be expected to use an acceptable contraceptive regimen and not to 
donate sperm as described in Section 4.1. 
4.5. Concomitant Treatment 
In addition to the drugs prohibited as per the exclusion criteria (Section 4.2), subjects will also be 
prohibited from taking any over-the-counter products for 7 days prior to dosing and during the 
study, unless deemed acceptable by an Investigator. 
Except for medication which may be required to treat AEs, no other treatment or medication 
other than the study drugs will be allowed from the first dosing until all study activities and 
evaluations have been completed. 
Systemic contraceptives and hormone replacement therapy are permitted for female subjects. 
Subjects will be instructed to notify the study site about any new medications taken after the start 
of the study treatment. All medications and significant non-drug therapies (including physical 
therapy and blood transfusions) administered after the subject has received the study treatment 
must be listed in the subject case report form (CRF). The drug name and dose taken will be 
noted. An Investigator or delegate and/or the Sponsor will decide whether the subject will be 
permitted to remain in the study, depending on the drug used, the time of drug intake, etc. 
5. STUDY TREATMENTS 
5.1. Investigational Products 
All IPs will be provided by the Sponsor. 
5.1.1. Kratom 500 mg Capsules 
Kratom capsules consist of 500 mg kratom leaf powder filled into light blue gelatin capsules. 
Kratom 500 mg capsules are manufactured by Sun Distribution, Super Organics for oral 
administration. 
5.1.2. Placebo 
Placebo capsules made with microcrystalline cellulose will be matched to Kratom 500 mg 
Capsules. The weight will be matched to the Kratom 500 mg Capsules and the composition will 
be the same, including excipients. 
5.2. Investigational Product Management 
5.2.1. Packaging, Labeling and Dispensing 
The Sponsor will be responsible for ensuring that the IPs are manufactured in accordance with 
applicable current Good Manufacturing Practice regulations and requirements. 

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The IPs will be labeled according to the requirements of local law and legislation. The IPs will 
be dispensed by the clinical site’s pharmacy, unless the Sponsor supplies the pharmacy with 
prelabeled individual dosing samples. 
5.2.2. Storage and Handling 
All study drugs will be shipped from the client or client resources to the clinical site’s pharmacy. 
Storage and handling conditions are described in the Investigator’s Brochure of kratom.1 
The clinical site’s pharmacy will maintain an inventory record of the IPs received, stored (in a 
secure restricted area), and dispensed. IPs will be provided to study subjects only. 
5.2.3. Method of Assigning Subjects to Treatment Groups 
In each cohort, subjects will be randomized 6:2 (active: placebo). The clinical site will generate 
the randomization code with a computer program according to the study design, the number of 
subjects and the number of treatments. Once generated, the randomization code will be final and 
will not be modified. 
5.2.4. Blinding 
The randomization code will not be available to the personnel of the bioanalytical facility until 
the bioanalytical phase of the study has been completed. The treatment assignment (active or 
placebo) will not be known by the study participants. Study participants will be informed of the 
dose range they could receive but will not be informed of the actual dose assigned to them. 
Furthermore, the randomization code will not be available to the Investigator and clinical staff 
involved in the collection, monitoring, revision, or evaluation of AEs, as well as clinical staff 
who could have an impact on the outcome of the study including the pharmacokineticist (or 
delegate) and biostatistician, until all the CRFs have been approved and signed and the 
bioanalytical phase of the study has been completed. 
The preparation and/or administration of the products will be done by designated personnel who 
are not directly involved in the clinical aspects of the trial. 
The randomization code must not be broken except in emergency situations where the 
identification of a subject’s study treatment is required by an Investigator for further treatment to 
the subject or to complete a SAE report. Randomization information will be held by designated 
individual(s). The date and reason for breaking the blind must be recorded. 
The results of the PD analyses will be made available only to the personnel responsible for 
evaluating the safety data before proceeding with the next dose level. 
5.2.5. Study Drug Accountability 
Complete and accurate inventory records of all study drugs will be maintained. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), subject 
dispensing records, and returned or destroyed study product. 
At the conclusion of the study, all unused IPs and all medication containers will be returned to 
the Sponsor unless the Sponsor has approved other arrangements. Drug accountability will be 
performed at the completion of the trial. 

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5.3. Administration of Study Drug 
Study drug will be administered in the morning. The date and time of each dose will be recorded. 
For each subject, all scheduled postdose activities and assessments will be performed relative to 
the time of study drug administration. 
Thirty (30) minutes after the start of a high-fat breakfast (refer to Section 5.4 for details), an oral 
dose of the assigned formulation will be administered to subjects with approximately 240 mL of 
water at ambient temperature. Considering the high number of capsules to be taken for certain 
cohorts, an additional 240 mL of water will be allowed if required. Time of dosing will be set 
equal to the time when the first capsule is administered to the subject. The complete dosing 
procedure must be completed within 5 minutes. Dosing procedures done up to 2 minutes outside 
the allowed time window will not be considered as protocol deviations but will be documented. 
The start and end times, as well as the volume of water ingested during drug administration will 
be recorded. The capsules must be swallowed whole and must not be chewed or broken. 
5.3.1. Treatment Compliance 
The study drugs will be dispensed only to eligible subjects and administered under the 
supervision of study personnel. Treatment compliance will be verified according to the site’s 
standard operating procedures (SOPs). 
5.4. Meals 
Food intake will be controlled during the confinement period and for all subjects. 
Following an overnight fast of at least 10 hours, subjects will receive a standardized high-fat 
meal 30 minutes before drug administration. The meal will consist of 2 eggs fried in butter, 2 
strips of bacon, 2 slices of toast with butter, 4 ounces of hash brown potatoes, and 8 ounces of 
whole milk. Substitutions in this test meal may be made provided that the meal delivers a similar 
amount of calories from protein, carbohydrate, and fat and has comparable meal volume and 
texture. Subjects must eat the total content of this meal in 30 minutes or less. A subject who eats 
less than 75% of the high-fat meal will be removed from the study. A standardized lunch will be 
served at least 4 hours after dosing. 
5.5. Fluids 
Fluid intake other than water will be controlled during the confinement period and for all 
subjects. 
Water will be permitted as needed except from 1 hour predose until 1 hour after dosing. 
5.6. Other Protocol Restrictions 
Subjects will not engage in strenuous activity at any time during the confinement periods. 
6. STUDY PROCEDURES 
An overview of the study activities for each participant is detailed in Table 6-1. 
Subjects may leave the clinical site 48 hours following drug administration. However, they may 
be advised to stay at the clinical site for safety reasons, if judged necessary by an Investigator or 
delegate in charge. Subjects will return to the clinical site for a Follow-Up Visit on Day 7 ± 2. 

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Unless otherwise stated in the protocol, the SOPs of the study facilities, which are available for 
all activities relevant to the quality of the study, will be followed during this study. When the 
nominal time for multiple events occurs simultaneously, the events will be staggered using their 
acceptable windows (acceptable windows for each assessment are specified in the following 
sections of this protocol). When timepoints coincide, procedures should be carried out in the 
following order: 
1. Vital signs (prior to nominal time) 
2. ECG (prior to nominal time) 
3. PK blood sampling (at nominal time) 
4. Pupillometry (following nominal time, immediately following PK blood sampling and 
prior to other PD assessments) 
5. Subjective measures (following nominal time, immediately following pupillometry) 
Any deviation from protocol procedures should be noted in the source documentation and 
compiled for reporting in the Clinical Study Report. 
 

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Table 6-1. Schedule of Activities 
 
Screening 
Treatment Period 
Follow-Up Visit 
Day 
-28 to -1 
-1 
1 
2 
3 
7 ± 2 (EOS/ET) 
Subject Review 
Informed Consent a 
X 
 
 
 
 
 
Eligibility Criteria Review 
X 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
Medication, Recreational Drug, Alcohol, and Nicotine Use History 
X 
X 
 
 
 
 
DSM-5 Diagnostic 
X 
 
 
 
 
 
Safety 
C-SSRS Questionnaireb 
X 
X 
 
 
X 
X 
Height, Weight, and BMIc 
X 
 
 
 
 
X 
Blood Pressure, Pulse, Body Temperature, and Respiratory Rate d 
X 
X 
X 
X 
X 
X 
Continuous SpO2 Monitoringe 
 
 
X 
 
 
 
Spot SpO2f 
X 
 
X 
 
 
 
Physical Examination g 
X 
X 
 
 
X 
X 
 
 
a The latest version of the consent form must be signed prior to subject's inclusion (prior to study drug administration). 
b Details presented in Section 6.1.7. 
c At the Follow-Up Visit, only weight and BMI will be measured. 
d Timepoints of each parameter (blood pressure, pulse, body temperature, and respiratory rate) are detailed in Section 6.1.4.1. 
e Continuous monitoring will be performed up to 1 hour prior to study drug administration and will continue for up to 6 hours following study drug 
administration, or longer if deemed medically necessary. Additional details are presented in Section 6.1.4.2. 
f Timepoints are detailed in Section 6.1.4.2 for spot SpO2. 
g A full physical examination will be performed at Screening and at EOS/ET. A symptom-oriented physical examination will be performed as needed at all other 
timepoints. 

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Screening 
Treatment Period 
Follow-Up Visit 
Day 
-28 to -1 
-1 
1 
2 
3 
7 ± 2 (EOS/ET) 
General Biochemistry, Hematology, and Urinalysis h 
X 
X 
 
 
X 
X 
Lipid Profileh 
X 
 
 
 
 
X 
Serologyh 
X 
 
 
 
 
 
12-lead ECG i 
X 
X 
X 
X 
X 
X 
Alcohol and Drugs of Abuse Screenh 
X 
X 
 
 
 
 
Pregnancy Testh 
X 
X 
 
 
X 
X 
FSHh 
X 
 
 
 
 
 
AE Monitoring 
X 
X 
X 
X 
X 
X 
Concomitant Medication Recording 
X 
X 
X 
X 
X 
X 
Pharmacokinetics 
Blood sampling for PK j 
 
 
X 
X 
X 
 
Pharmacodynamics 
Training Sessionk 
 
X 
 
 
 
 
Pupillometryl 
 
 
X 
X 
 
 
Subjective Measuresm 
 
 
X 
X 
 
 
Confinement and Study Administration 
Admission 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
h Details are provided in APPENDIX 6. 
i ECG scheduled timepoints are detailed in Section 6.1.5. 
j Blood sampling time points for PK determinations are detailed in Section 6.2. 
k Details are presented in Section 6.3. Additional training sessions may be conducted as needed. 
l Pupillometry time points for PD evaluations are detailed in Section 6.3.1. 
m Type of subjective measures and timepoints are detailed in Section 6.3.2. 

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Screening 
Treatment Period 
Follow-Up Visit 
Day 
-28 to -1 
-1 
1 
2 
3 
7 ± 2 (EOS/ET) 
Study Drug Administration 
 
 
Xn 
 
 
 
Discharge o 
 
 
 
 
X 
 
Abbreviations: BMI = body mass index; C-SSRS = Columbia Suicide Severity Rating Scale; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, 
5th Edition; ECG = electrocardiogram; EOS = end of study; ET = early termination; FSH = follicle stimulating hormone; PD = pharmacodynamic; 
PK = pharmacokinetic; SpO2 = respiratory rate. 
 
 
 
n Study drug will be administered 30 minutes after the start of a meal as detailed in Section 5.4. 
o Discharge from the clinical site will occur after the 48-hour PK blood sample. 

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6.1. Safety Assessments 
Safety assessments will include AEs monitoring, laboratory tests, vital signs (blood pressure, 
pulse, respiratory rate, oxygen saturation, and body temperature), ECG assessments, physical 
examination findings, and C-SSRS. At the discretion of an Investigator, additional safety 
assessments may be performed as needed to ensure subject safety. 
An Investigator or delegate in charge will be present at the clinical site for at least the first 
4 hours following drug administration and will remain available at all times throughout the 
study. 
6.1.1. Medical History 
The medical history at Screening will include all queries by the medical and clinical staff related 
to the subject’s well-being and history of relevant past medical events/experiences. Medical 
history will include all demographic data (age, sex, race, body weight, height, and BMI) and 
baseline characteristics. Alcohol and smoking habits will also be recorded. 
6.1.2. Medication, Recreational Drug, Alcohol, and Nicotine Use History 
6.1.2.1. Medication Use 
Medication history will be collected as scheduled in Table 6-1. 
6.1.2.2. Recreational Drug Use 
A lifetime history of all recreational drug use will be collected as scheduled in Table 6-1. 
History, including drug preference (i.e., drug of choice), frequency of use, and date of last use 
will be collected using reported drug names and drug class (e.g., cannabinoids, depressants, 
dissociative anesthetics, hallucinogens, opioids, and morphine derivatives, and stimulants). 
The DSM-5 modules will be included as a part of the recreational drug use history and used to 
screen for substance disorder. 
6.1.2.3. Alcohol and Nicotine Use 
A lifetime history of alcohol and nicotine use will be collected as scheduled in Table 6-1. 
History, amount, and frequency of use will be collected. 
DSM-5 modules will be included as a part of the alcohol use history and used to screen for 
alcohol disorder. 
6.1.3. Physical Examination 
A physical examination will be performed by a medically qualified and licensed individual as 
outlined in Table 6-1. 
The full physical examination will include a general review of the following body systems (at 
minimum): head and neck, cardiovascular, respiratory, gastrointestinal, brief neurological and 
general appearance, unless a symptom-oriented physical exam is indicated. 

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6.1.4. Vital Signs 
Windows for blood pressure, pulse, body temperature, spot SpO2, and respiratory rate 
assessments are presented in Table 6-2. Vital signs will be performed after the subject is in 
supine position for at least 3 minutes. 
Table 6-2. Acceptable Windows for Vital Sign (Blood Pressure, Pulse, Body Temperature, 
Spot Oxygen Saturation, and Respiratory Rate) Assessments 
Elapsed Time 
Acceptable Window 
Predose 
Within 60 minutes prior to study drug administration 
> 0 hour and ≤ 24 hours 
± 30 minutes 
> 24 hours and ≤ 48 hours 
± 1 hour 
 
6.1.4.1. Blood Pressure, Pulse, Body Temperature, Respiratory Rate 
Blood pressure, pulse, body temperature, and respiratory rate measurements will be measured as 
outlined in Table 6-1 and are further detailed in Table 6-3. 
Table 6-3. Vital Sign (Blood Pressure, Pulse, Body Temperature, and Respiratory Rate) 
Recording Schedule 
Vital Sign Recording - Scheduled Time 
Points 
Detail of Measures 
Screening 
Blood pressure, pulse rate, body temperature, and 
respiratory rate 
Day -1 
Blood pressure, pulse rate, and body temperature 
Day 1: predose 
Blood pressure, pulse rate, body temperature, 
respiratory rate 
Day 1: 1, 2, 4, and 6 hours postdose 
Blood pressure, pulse rate, and respiratory rate 
Day 2: 24 hours postdose 
Blood pressure and pulse rate 
Day 3: 48 hours postdose 
Blood pressure and pulse rate 
Follow-up visit/End of Study 
Blood pressure and pulse rate 
 
6.1.4.2. Continuous and Spot Oxygen Saturation 
Continuous and spot SpO2 monitoring will be performed as outlined in Table 6-1. Spot SpO2 will 
be measured using a portable pulse oximeter placed on the subject’s fingertip. 
SpO2 will be monitored for alarms set at <90% continuously up to 1 hour prior to study drug 
administration and will continue for up to 6 hours following study drug administration, or longer 
if deemed medically necessary. In addition, SpO2 will be recorded at the timepoints scheduled in 
Table 6-4. 

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Table 6-4. Spot Oxygen Saturation Schedule 
Spot Oxygen Saturation - Scheduled Time Points 
Screening 
Day 1: predose and approximately 1, 2, 3, 4, 6, 7, 8, 10, and 12 hours postdose 
 
6.1.5. 12-Lead Electrocardiogram 
Twelve-lead ECGs will be performed as outlined in Table 6-1. Electrocardiogram measurements 
are further detailed in Table 6-5. Subjects will be in supine position for at least 3 minutes prior to 
ECG measurements. 
Table 6-5. Electrocardiogram Recording Schedule 
Electrocardiogram Recording - Scheduled Time Points 
Screening 
Day -1 
Day 1: 1 and 4 hours postdose 
Day 2: 24 hours postdose 
Day 3: 48 hours postdose 
Follow-up visit/End of Study 
 
Windows for ECG assessments are presented in Table 6-6. 
Table 6-6. Acceptable Windows for Electrocardiogram Assessments 
Elapsed Time 
Acceptable Window 
> 0 hour and ≤ 24 hours 
± 30 minutes 
> 24 hours and ≤ 48 hours 
± 1 hour 
 
6.1.6. Laboratory Evaluations 
Laboratory evaluations will be performed as outlined in Table 6-1. 
The laboratory evaluations to be conducted for this study are presented in APPENDIX 6. 
Additional clinical laboratory tests may be performed by the medical laboratory as part of larger 
standard test panels (not required for subject safety). 
The Investigator or delegate in charge will assess each abnormal value to determine if it is 
clinically significant. Postdose clinically significant laboratory values will be reported as AEs, if 
applicable, as judged by the Investigator or delegate in charge. 
Only test results required by the protocol and/or abnormal results will be entered in the clinical 
database and reported in the Clinical Study Report, based on report requirement. 

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6.1.7. Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire designed for the assessment of suicidal ideation and behavior in 
adolescents and adults. 
To monitor for a history of or for the emergence of suicidal ideation and behavior, subjects will 
undergo C-SSRS evaluations at the time points indicated in Table 6-1. 
The questionnaire must be administered by an Investigator or other individual that is suitably 
qualified by education or training. See APPENDIX 7 for a sample C-SSRS – Baseline/Screening 
version assessment and APPENDIX 8 for a sample post-dose C-SSRS (Since Last Visit Version) 
assessment. 
If there is a positive result for suicidality on the C-SSRS after Screening (defined by a subject 
answering “yes’ to questions 4 or 5 on the suicidal ideation portion of the C-SSRS), the subject 
will be evaluated by an Investigator or medically qualified Sub-Investigator for continuation in 
the study. 
If a subject becomes suicidal during the study, an Investigator or medically qualified 
Sub-Investigator should provide the appropriate treatment to the subject. 
6.1.8. Rescue Therapy 
The clinical study site is equipped with emergency equipment and supplies that correspond with 
the level of risk associated with this study. In case of a medical emergency or an SAE requiring 
medical intervention, emergency equipment and supplies will be available and will include, but 
may not be limited to, stocked crash carts, oxygen source, suction pump, and defibrillator. 
Emergency medication (e.g., naloxone) or rescue medication required for advanced cardiac life 
support may be administered if deemed necessary by an Investigator or designee. If required, 
subjects will be transported to a hospital. 
The Principal Investigator or designee will be on-site at the time of study drug administration 
until at least 4 hours postdose. When not available on-site, the Principal Investigator or designee 
will be on-call until the end of the study. While confined in the clinical site, subjects will be 
supervised by staff nurses and/or paramedics. Dedicated nurses and/or paramedics will be 
available to monitor AEs and perform safety measures. The date and time of rescue medication 
administration as well as the name and dosage regimen of the rescue medication will be 
recorded. 
6.2. Pharmacokinetic Assessments 
A total of 15 blood samples will be collected for PK assessments. The complete blood sampling 
schedule is presented in Table 6-7. 

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Table 6-7. Pharmacokinetic Blood Sampling Schedule 
Sample No 
Nominal Timea (hours) 
01 
0.00 
02 
0.25 
03 
0.50 
04 
1.00 
05 
1.50 
06 
2.00 
07 
2.50 
08 
3.00 
09 
4.00 
10 
6.00 
11 
8.00 
12 
10.00 
13 
12.00 
14 
24.00 
15 
48.00 
a. 
Nominal times listed are relative to the time of study treatment administration. 
Blood samples will be collected by direct venipuncture into a labeled tube containing the 
appropriate anticoagulant as specified by the bioanalytical facility. As an option to the subject or 
if judged necessary by the clinical staff, blood samples may be collected from a catheter, which 
will be placed in the vein of the subject. 
The time of PK blood sample collection will be calculated relative to the time of treatment 
administration. The actual time of all PK blood draws will be recorded and reported for all 
subjects. 
Windows for timed PK blood sample collections are presented in Table 6-8. PK samples 
collected outside of the pre-specified windows will be documented as protocol deviations. Since 
actual times are to be used for the PK analysis, deviations will be reflected in the analysis unless 
indicated otherwise upon review of the data. 

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Table 6-8. Acceptable Windows for Timed PK Blood Specimen Collection Procedures 
Elapsed Time  
Accepted Window 
Predose 
Within 60 minutes prior to study drug administration 
> 0 hour to ≤ 30 minutes 
± 1 minute 
> 30 minutes to ≤ 4 hours 
± 2 minutes 
> 4 hours to ≤ 12 hours 
± 5 minutes 
> 12 hours to ≤ 24 hours 
± 10 minutes 
> 24 hours to ≤ 48 hours 
± 2 hours 
 
Mitragynine, 7-hydroxy-mitragynine, paynantheine, speciogynine, and peciociliatine 
concentrations for PK assessments will be obtained through bioanalysis of the plasma derived 
from the blood samples drawn during this study, using validated bioanalytical methods. 
6.2.1. Pharmacokinetic Sample Processing, Storage and Shipping 
Blood samples for PK determination will be processed, stored, and shipped according to the 
sample processing instructions supplied by the bioanalytical facility. 
6.3. Pharmacodynamic Assessments 
Pharmacodynamic assessments will be performed throughout the study as outlined in Table 6-1. 
Prior to completing the computerized PD measures, all subjects will undergo a scripted training 
and practice regimen. Eligible subjects who appear to have difficulty differentiating between 
bipolar and unipolar visual analog scales (VAS) (e.g., making errors such as selecting a score of 
50 to indicate the absence of a drug-effect on a unipolar scale) or difficulty distinguishing 
between "at this moment" and "next-day" measures will undergo additional training on the 
difference between the scale types. Additional training sessions will be documented in source 
files. 
Testing conditions for PD assessments should remain as consistent as possible. Subjects will be 
monitored carefully to ensure that they are completing the PD assessments appropriately; all 
reasonable attempts should be made to rouse subjects who fall asleep during testing cycles. If 
subjects cannot complete the PD assessments in a timely manner prior to the next required 
procedure or timepoint due to an AE, testing will be aborted. 
6.3.1. Pupillometry 
Pupillometry will be used as an objective physiological PD measure as it is a sensitive measure 
of central opioid action and appears to be resistant to tolerance development with repeated 
administration. An electronic pupillometer will be used to measure pupil diameter. Pupil 
diameter will be measured as outlined in Table 6-1 and is further detailed in Table 6-9. Data 
from a series of frames will be used in the calculation, and the final display will show the 
weighted average and standard deviation (SD) of the pupil size. Measurements will be collected 
under mesopic lighting conditions. For each subject, every effort will be made to use the same 

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eye for all assessments throughout the study. The pupillometry assessments will be completed 
immediately prior to the administration of all other PD measures. 
Table 6-9. Pupillometry Schedule 
Pupillometry - Scheduled Time Points 
Day 1: predose and 0.5 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours postdose 
Day 2: 24 hours postdose 
 
Windows for timed pupillometry measurements are presented in Table 6-10. 
Table 6-10. Acceptable Windows for Timed Pupillometry Measurements 
Elapsed Time  
Accepted Window 
Predose (Day 1) 
Within 60 minutes prior to study drug administration 
Postdose 
Within 5 minutes following collection of PK blood 
sample 
 
6.3.2. Subjective Effects 
Subjective measures will be evaluated as outlined in Table 6-1 and are further detailed in 
Table 6-11. 

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Table 6-11. Subjective Measures Schedule 
Category 
Evaluations 
Timepoints 
Drug-
specific 
VAS 
Drug Liking, Good Drug 
Effects, Bad Drug Effects, and 
Any Drug Effects 
0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours 
postdose 
Overall Drug Liking and Take 
Drug Again 
12 and 24 hours postdose 
Other VAS 
High, Feeling Drunk, 
Relaxation/Agitation, 
Drowsiness/Alertness, and 
Bowdle VAS 
Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 
and 24 hours postdose 
Drug Similarity 
12 hour postdose 
ARCI Scales 
MBG, A, BG, PCAG, and 
LSD 
Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 
and 24 hours postdose 
Abbreviations: A = amphetamine; ARCI = Addiction Research Center Inventory; BG = Benzedrine Group; 
LSD = Lysergic Acid Diethylamide; MBG = Morphine-Benzedrine Group; PCAG = Pentobarbital–
Chlorpromazine–Alcohol Group; VAS = visual analog scale. 
Windows for timed subjective measurements are presented in Table 6-12. 
Table 6-12. Acceptable Windows for Timed Subjective Measurements 
Elapsed Time  
Accepted Window 
Predose (Day 1) 
Within 60 minutes prior to study drug administration 
Postdose 
Within 5 minutes following pupillometry assessment 
 
6.3.2.1. Visual Analogue Scales 
All VAS will be scored on a 100-point scale, as shown in Table 6-13, and will be administered at 
the timepoints specified in Table 6-11. The VAS may be administered as bipolar or unipolar 
scales, as appropriate, and the choice is determined by the nature of the subjective effect being 
measured. Bipolar scales ask about the neutrality, the direction and the intensity of a subjective 
opinion, whereas unipolar scales only ask about the extremity or intensity of a subjective 
opinion. When VAS are administered as bipolar scales, a neutral point equal to 50 is embedded 

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within the scale (e.g., Drug Liking, Overall Drug Liking, Take Drug Again, 
Drowsiness/Alertness VAS). The neutral point reflects a state whereby a subject is experiencing 
neither negative nor positive effects (e.g., neither dislike nor like the effects of the drug) and is 
labeled with an anchor, such as “neither like nor dislike.” When VAS are administered as 
unipolar scales, anchors will be presented using text such as “Not at all” (score = 0) to 
“Extremely” (score = 100; e.g., Good, Bad, High, and Any Effects VAS). Unipolar scales do not 
include a neutral point but rather, a rating of “0” reflects the complete absence of a subjective 
effect while a rating of “100” reflects the maximum presence of a subjective effect (e.g., No 
Good Effects = 0, Extremely Good Effects = 100). Scales that refer specifically to drug (e.g., 
Drug Liking, Good Effects VAS, Bad Effects VAS, and Any Effects VAS) are not administered 
at predose. 
Table 6-13. Visual Analog Scale (VAS) Descriptions 
Scale 
Interpretation 
Include 
Predose 
Type of 
Scale 
Description 
Question Text 
Response 
Anchors 
Balance 
No 
Bipolar 
Drug Liking 
At this moment, my 
liking for this drug 
is 
0: Strong 
disliking 
50: Neither 
like nor dislike 
100: Strong 
liking 
Balance 
No 
Bipolar 
Overall Drug Liking 
Overall, my liking 
for this drug is 
Balance 
No 
Bipolar 
Take Drug Again 
I would take this 
drug again 
0: Definitely 
would not 
50: Neither 
would nor 
would not 
100: 
Definitely 
would 
Positive 
Yes 
Unipolar 
High 
At this moment, I 
am feeling high 
0: Not at all 
100: 
Extremely 
Positive 
No 
Unipolar 
Good Effects 
At this moment, I 
feel good drug 
effects 
Negative 
No 
Unipolar 
Bad Effects 
At this moment, I 
feel bad drug effects 
Other 
No 
Unipolar 
Any Effects 
At this moment, I 
feel any drug effect 

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Scale 
Interpretation 
Include 
Predose 
Type of 
Scale 
Description 
Question Text 
Response 
Anchors 
Other 
Yes 
Unipolar 
Feeling Drunk 
At this moment, I 
am feeling drunk 
Other  
Yes 
Bipolar 
Drowsiness/Alertness 
At this moment, my 
mental state is 
0: Very 
drowsy 
50: Neither 
drowsy nor 
alert 
100: Very alert 
Other 
Yes 
Bipolar 
Relaxation/Agitation 
At this moment, my 
mental state is 
0: Very 
relaxed 
50: Neither 
relaxed nor 
agitated 
100: Very 
agitated 
 
6.3.2.2. Bowdle VAS 
The Bowdle VAS consists of 13 items for which the subject is asked to rate his or her current 
feelings. An adapted computerized version of Bowdle VAS will be administered. The first 
11 items are used to derive two composite scores reflecting internal and external perceptions. 
Each VAS will be administered using a unipolar format and scored from 0 to 100, with 0 
reflecting “Not at all” and 100 reflecting “Extremely.” Lower individual and overall scores 
indicate fewer psychedelic effects. 
The individual items of the questionnaire are listed below: 
1. My body or body parts seemed to change their shape or position (BODY) 
2. My surroundings seemed to change in size, depth, or shape (SURROUNDINGS) 
3. The passing of time was altered (TIME) 
4. I had feelings of unreality (REALITY) 
5. It was difficult to control my thoughts (THOUGHTS) 
6. The intensity of colors changed (COLORS) 
7. The intensity of sound changed (SOUND) 
8. I heard voices or sounds that were not real (VOICES) 
9. I had the idea that events, objects, or other people had particular meaning that was specific 
for me (MEANING) 

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10. I had suspicious ideas or the belief that others were against me (SUSPICIOUS) 
11. I felt anxious (ANXIOUS) 
12. I felt high (HIGH) 
13. I felt drowsy (DROWSY) 
Responses to items 1, 2, 3, 5, 6, and 7 are summed to produce a “Subjective External 
Perceptions” composite score. Response to items 4, 8, 9, 10, and 11 are summed to produce a 
“Subjective Internal Perceptions” composite score.  Items 12 and 13 will not be included as 
they are administered as part of the individual VAS items. 
If a response to 1 of the items is missing, the associated composite score will not be calculated. 
6.3.2.3. Drug Similarity VAS 
The Drug Similarity unipolar VAS items provide an estimate of how close the drug classes with 
which drug users have familiarity with are when compared to the test drug. On a scale ranging 
from “Not at all similar” to “Very similar,” subjects are asked to compare a drug they had 
actually received to a comparison drug they previously declared having familiarity/experience 
with taking.  
A Drug History form is completed during the Screening Phase and used to create a subject-
specific Drug Similarity measure for use during the Treatment Phase. Drugs that a subject has 
not personally experienced often enough to use as a standard of comparison (< 2 lifetime uses of 
a given drug), will not be included in their questionnaire.  
Table 6-14. Description of Drug Similarity Visual Analog Scales 
Description 
Question Text 
Response Anchors 
Drug similarity 
How similar is the drug you most 
recently received to [drug name]? 
0: Not at all similar 
100: Very similar 
where the question will be repeated for each [drug name] in the following list: 
▪ 
Phencyclidine (PCP) 
▪ 
Caffeine 
▪ 
Cocaine (including crack) 
▪ 
Codeine, morphine, 
oxycodone, hydrocodone, 
hydromorphone 
▪ 
Ecstasy (MDMA) 
▪ 
Heroin 
▪ 
LSD 
▪ 
Methadone 
▪ 
Nicotine 
▪ 
Placebo 
▪ 
D-amphetamine (“Speed”) or 
methamphetamine 
▪ 
Pseudoephedrine 
(Sudafed) 
▪ 
Halcion, Xanax, or 
Valium 
▪ 
Ketamine (“Special 
K”)  
▪ 
THC (marijuana, 
cannabis, hash) 
At the conclusion of the list of specific drugs, a general question will appear: 
Overall Familiarity 
How familiar was the effect of the 
drug you most recently received? 
0: Very unfamiliar 
100: Very familiar 
 

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6.3.2.4. Addiction Research Center Inventory (ARCI) 
The Addiction Research Center Inventory (ARCI) Morphine-Benzedrine Group (MBG), 
Amphetamine (A), Benzedrine Group (BG), Pentobarbital–Chlorpromazine–Alcohol Group 
(PCAG), and LSD scales will be administered as scheduled in Table 6-11. 
The 49-item ARCI is a shortened version (49 true-false items) compiled by Martin et al. 7 from 
the 550-item ARCI originally developed by Haertzen. 8,9 This version contains 5 scales, which 
measure the following effects: Euphoria - MBG scale; Stimulant effects - Amphetamine (A) 
scale and Benzedrine Group (BG) scale; Dysphoria - LSD scale; and Sedation - PCAG scale. 
Subjects indicate their responses by selecting “False” or “True.” One point is given for each 
response that agrees with the scoring direction on the scale (i.e., True items receive a score of 1 
if the answer is “True;” no points are given when the answer is opposite to the scoring direction). 
The following scales will be administered: 
• Euphoria: Morphine-Benzedrine Group (MBG) scale 
• Stimulant effects: Amphetamine (A) scale, Benzedrine Group (BG) scale 
• Dysphoria: Lysergic Acid Diethylamide (LSD) scale 
• Sedation: Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) scale 
The items pertaining to the ARCI scales are presented in Table 6-15. 
Table 6-15. Addiction Research Center Inventory (ARCI) Scales Descriptions 
Question  
Scale 
A PCAG MBG BG LSD 
My speech is slurred  
 
T 
 
 
 
I am not as active as usual  
 
T 
 
 
 
I have a feeling of just dragging along rather than coasting  
 
T 
 
 
 
I feel sluggish  
 
T 
 
 
 
My head feels heavy  
 
T 
 
 
 
I feel like avoiding people, although I usually do not feel this way  
 
T 
 
 
 
I feel dizzy  
 
T 
 
 
 
It seems harder than usual to move around 
 
T 
 
 
 
I am moody  
 
T 
 
 
 
People might say that I am a little dull today  
 
T 
 
F 
 
I feel drowsy  
 
T 
 
 
F 
I am full of energy  
 
F 
 
 
 
Today I say things in the easiest possible way  
 
 
T 
 
 
Things around me seem more pleasing than usual  
 
 
T 
 
 
I have a pleasant feeling in my stomach  
 
 
T 
 
 

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Question  
Scale 
A PCAG MBG BG LSD 
I feel I will lose the contentment that I have now  
 
 
T 
 
 
I feel in complete harmony with the world and those about me  
 
 
T 
 
 
I can completely appreciate what others are saying when I am in 
this mood 
 
 
T 
 
 
I would be happy all the time if I felt as I feel now  
 
 
T 
 
 
I feel so good that I know other people can tell it  
 
 
T 
 
 
I feel as if something pleasant had just happened to me  
 
 
T 
 
 
I would be happy all the time if I felt as I do now  
 
 
T 
 
F 
I feel more clear headed than dreamy  
 
F 
T 
T 
 
I feel as if I would be more popular with people today  
T 
 
T 
 
 
I feel a very pleasant emptiness  
T 
 
T 
 
 
My thoughts come more easily than usual  
T 
 
T 
T 
 
I feel less discouraged than usual  
T 
 
T 
 
 
I am in the mood to talk about the feelings I have  
 
 
T 
T 
 
I feel more excited than dreamy  
T 
F 
 
 
 
Answering these questions is very easy todaya  
T 
 
 
T 
 
My memory seems sharper to me than usual  
T 
 
 
T 
 
I feel as if I could do these tests for hoursa 
T 
 
 
T 
 
I feel very patient  
T 
 
 
 
F 
Some parts of my body are tingling  
T 
 
 
T 
T 
I have a weird feeling  
T 
 
 
 
T 
My movements seem faster than usual  
 
 
 
T 
 
I have better control over myself than usual  
 
 
 
T 
 
My movements seem slower than usual 
 
 
 
F 
 
I find it hard to keep my mind on a task or job 
 
 
 
F 
 
I don’t feel like reading anything right now  
 
 
 
F 
 
It seems I’m spending longer than I should on each of these 
questions  
 
 
 
 
T 
My hand feels clumsy  
 
 
 
 
T 
I notice my hand shakes when I do these testsa 
 
 
 
 
T 
I have a disturbance in my stomach  
 
 
 
 
T 
I feel an increasing awareness of bodily sensations 
 
 
 
 
T 
I feel anxious and upset 
 
 
 
 
T 
I have unusual weakness of my muscles 
 
 
 
 
T 

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Question  
Scale 
A PCAG MBG BG LSD 
A thrill has gone through me one or more times since I started this 
test 
 
F 
 
 
T 
My movements are free, relaxed, and pleasurable 
 
 
 
 
F 
Abbreviations: A = Amphetamine; ARCI = Addiction Research Center Inventory; BG = Benzedrine Group; 
LSD = Lysergic acid diethylamide; MBG = Morphine-Benzedrine Group; PCAG = Pentobarbital–Chlorpromazine–
Alcohol Group. 
T = True item 
F = False item 
a. Question modified slightly for computerized presentation. 
Responses to individual items will be included. If one of the individual items is missing, the 
associated scale(s) score will not be calculated. 
7. ADVERSE EVENTS DOCUMENTATION 
7.1. Definitions 
An AE is defined as any untoward medical occurrence in a subject administered an 
investigational product and which does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal clinical laboratory finding, for example), symptom, or disease temporally 
associated with the use of an investigational product, whether or not related to the investigational 
product. 
A suspected adverse reaction is any AE for which there is a reasonable possibility the drug 
caused the AE. ‘Reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any AE caused by a drug. 
An AE may be: 
• A new illness, 
• Worsening of a concomitant illness, 
• An effect of the study drug including comparator; it could be an abnormal clinical 
laboratory value as well as a significant shift from baseline within normal range which an 
Investigator considers to be clinically important. 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
required surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. Planned surgical measures permitted by the clinical study 
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was 
(were) known before the start of study treatment. In the latter case, the condition should be 
reported as medical history. 
A SAE or reaction is any untoward medical occurrence that at any dose: 

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• Results in death, 
• Is life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions), 
• Is a congenital anomaly or birth defect, 
• Is an important medical event (including development of drug dependence or drug abuse) 
that may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed above (according to medical judgment of an Investigator) 
7.2. Severity Assessment 
All AEs will be graded per the current National Cancer Institute’s Common Terminology 
Criteria for Adverse Events. 
Every effort will be made to obtain an adequate evaluation of the severity. 
7.3. Causality Assessment 
An Investigator will determine the relationship of any AE to the study drug using the guidelines 
presented in Table 7-1. 
Table 7-1. Adverse Event Relationship to Study Drug 
Relationship to Drug 
Comment 
Reasonable Possibility 
A temporal relationship exists between the AE onset and 
administration of the investigational product that cannot be readily 
explained by the subject’s clinical state or concomitant therapies. 
Furthermore, the AE appears with some degree of certainty to be 
related, based on the known therapeutic and pharmacologic actions or 
AE profile of the investigational product. 
In case of cessation or reduction of the dose the AE may abate or 
resolve and it may reappear upon rechallenge. 
No Reasonable Possibility 
Evidence exists that the AE has an etiology other than the 
investigational product. 
For SAEs, an alternative causality must be provided (e.g., preexisting 
condition, underlying disease, intercurrent illness, or concomitant 
medication). 
Abbreviations: AE = adverse event; IP = investigational product; SAE = serious adverse event. 
7.4. Adverse Event Monitoring 
For the purposes of this study, the monitoring period for AEs extends from the pre-trial 
evaluation until collection of the last blood sample of the study. From screening to dosing of the 
study, AEs will be recorded as screening events or as part of the medical history, as applicable. 

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AEs occurring after initiation of study drug will be indicated as TEAEs in the clinical study 
report. 
Subjects will be questioned on their health status at the beginning of each study period and 
before each departure from the clinical site. Open-ended questions will be asked. 
During the study, all AEs spontaneously reported by the subject, observed by the clinical staff or 
elicited by general questioning will be recorded for all subjects and reported in the CRF. 
If necessary, every effort will be made to obtain an adequate follow-up of the subjects. Should 
any subject choose to withdraw from the study, they will be advised of the safety precautions to 
be taken. 
Any AE which remains unresolved as of the last visit will require an evaluation and follow-up 
until the AE has been resolved or a reasonable explanation for its persistence found, or is deemed 
mild and safely resolving. 
In the case of AEs deemed related to the Investigational Product, every effort will be made to 
determine the final outcome. 
It is an Investigator’s responsibility to ensure subjects experiencing AEs receive appropriate 
follow-up, treatment where required, and that every action is well documented. 
Classification of AEs will be performed by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA), version 24.0 or higher. 
Concomitant medications will be coded using the World Health Organization drug dictionary 
(WHO-DDE March 2021 or later). 
7.5. Reporting of Pregnancy 
Pregnancy in a female study subject shall be reported to the Sponsor within 24 hours of the 
knowledge of its occurrence by an Investigator or delegate (for pregnancies occurring during the 
course of the study or immediately following the end of the study). Because of the possibility the 
fetus/embryo could have been exposed to the study drug through the parent and for the subject’s 
safety, the pregnancy will be followed up to determine its outcome, including spontaneous or 
voluntary termination, details of birth, presence or absence of any birth defects, congenital 
anomalies, or maternal and/or newborn complications. 
Pregnancy that occurs within 90 days after study drug administration in a female partner of a 
male study subject shall be reported to the Sponsor within 24 hours of the knowledge of its 
occurrence by the clinical site that such pregnancy occurred during the course of the study or 
right after. Because of the possibility that the fetus/embryo could have been exposed to the study 
drug through the parent and for the safety of the subject’s female partner, the pregnancy will be 
followed up to determine its outcome, including spontaneous or voluntary termination, details of 
birth, presence or absence of any birth defects, congenital anomalies, or maternal and/or newborn 
complications. 
The pregnancy will be recorded and reported by the clinical site to the Sponsor. Pregnancy 
follow-up will also be properly recorded to ensure quality and completeness of the data 

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belonging to the study drug and will include an assessment of the possible causal relation 
between the study drug and any pregnancy outcome. Any SAE experienced during pregnancy 
will be reported on an SAE Report Form. 
7.6. Serious Adverse Event Reporting 
The clinical site will notify any SAE to the Sponsor, without regard to causality, within 24 hours 
after becoming aware of its occurrence. 
If, during follow-up, any non-serious AE worsens and eventually meets the criteria for an SAE, 
that AE should be recorded as a new SAE. 
The initial SAE report must be as complete as possible, including details of the current illness 
and SAE, and an assessment of the causal relationship between the event and the investigational 
product(s). Information not available at the time of the initial report (e.g., an end date for the AE, 
laboratory values received after the report, or hospital discharge summary) must be documented. 
All follow-up information must be reported as soon as the relevant info is available. 
The notification should be directed to the following Sponsor representative: 
Chad J Reissig, PhD 
Supervisory Pharmacologist Center for Drug Evaluation and Research 
Office of the Center Director, Controlled Substance Staff 
U.S. Food and Drug Administration 
Tel: 301-796-3434 
chad.reissig@fda.hhs.gov 
An SAE will be considered “unexpected” if the AE is not listed in the Investigator Brochure or is 
not listed at the specificity or severity that has been observed; or, if an Investigator Brochure is 
not required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. "Unexpected," as used in this 
definition, also refers to AEs that are mentioned in the Investigator Brochure as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation. 
The clinical site will determine whether any serious unexpected related AE must be reported to 
the Institutional Review Board (IRB). If so, the event will be reported via fax or email within 15 
calendar days of an Investigator or staff becoming aware of the event. 
The Sponsor will determine whether the SAE must be reported in an expedited manner to the 
applicable regulatory agencies. If so, the Sponsor will report the event to those agencies and to 
all participating Investigators. 
If reports of any new and unexpected AEs become available to the Sponsor during the clinical 
portion of this study (related or not to the present study), the Sponsor has to advise the clinical 
site, through its Clinical Investigator, of those events. 

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8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
8.1. Analysis Populations 
8.1.1. Randomized Population 
The Randomized population will include all subjects who are randomized to receive either active 
drug (kratom) or placebo (6:2 active:placebo) in each cohort. 
8.1.2. Safety Population 
The Safety population will include all subjects who received 1 dose of the kratom or placebo. 
The number of subjects who were included, who discontinued, and who completed the study will 
be tabulated. The primary reasons for discontinuation will be provided. 
8.1.3. Pharmacokinetic Population 
In most cases, the decision about which subjects will be included in the PK analysis, is to be 
taken before the start of the sample analysis by the bioanalytical facility. 
The PK population will be described in a statistical analysis plan (SAP). Generally, the PK 
population includes all the subjects who received kratom and have at least 1 postdose evaluable 
concentration value. 
The PK population will be detailed in a SAP. 
8.1.4. Completer Population 
All subjects in the Safety population who complete the dose level or placebo in their cohort, and 
have sufficient data for evaluation of the primary endpoint (based on a blinded review of data 
prior to database lock) will be included in the Completer population. Subjects who do not have at 
least 1 observation within 2 hours of Tmax for Drug Liking VAS will be excluded from the 
Completer population. 
8.2. Demographic Data and Other Baseline Characteristics 
Listings and descriptive summary statistics of demographic and baseline data will be presented. 
8.3. Safety 
The clinical laboratory tests, vital signs (blood pressure, pulse, respiratory rate, oxygen 
saturation, and body temperature), ECGs, physical examination findings, and C-SSRS will be 
used to perform the safety statistical analysis. 
Descriptive statistics will be used to summarize AEs and safety results. The safety analysis will 
be fully detailed in the SAP. 
8.4. Pharmacokinetics 
The PK parameters Cmax, Tmax, AUC0-T, AUC0-∞, AUCT/∞, λZ, and Thalf , as well as the 
dose-normalized parameters Cmax/D, AUC0-T/D, and AUC0-∞/D will be estimated for 
mitragynine, 7-hydroxy-mitragynine, paynantheine, speciogynine, and peciociliatine. Additional 
parameters may be calculated. 
The PK analyses will be performed by non-compartmental analysis. 

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The PK analysis will be carried out according to Altasciences SOPs. Pharmacokinetic data 
handling and statistical analysis will be fully detailed in a SAP. 
8.5. Pharmacodynamics 
Unless otherwise specified, all available PD data and analysis results will be presented for the 
Completer population. 
The PD measures at each time point will be summarized by treatment using descriptive statistics 
and presented graphically. Derived endpoints will be summarized by treatment and paired 
difference using descriptive statistics. 
A mixed-effects model will be used to compare PD endpoints between Kratom dose levels and 
placebo for all primary and secondary PD endpoints other than the 12-hour postdose results from 
Drug Similarity VAS. The model will include dose level as a fixed effect and the baseline score 
as a covariate (where applicable). P-values for key components of variance, least-square means 
(LSmeans), and 95% CI for contrasts will be output. 
For each PD endpoint, the following comparison will be made: 
• Kratom 1 g vs. Placebo 
• Kratom 2 g vs. Placebo 
• Kratom 4 g vs. Placebo 
• Kratom 6 g vs. Placebo 
• Kratom 8 g vs. Placebo 
The Hodges-Lehmann estimate of the location shift, the asymptotic confidence limits, and the 
asymptotic standard error estimate will be used to estimate the 95% CIs of TEmax/TEmin between 
the the Kratom dose levels and placebo. The asymptotic standard error estimate is based on the 
length of the CIs. Rank sums and p-values from the Wilcoxon Rank Sum test will also be output. 
The PD analysis will be fully detailed in a SAP. 
8.6. Planned Interim Analyses 
No formal interim analyses will be performed; blinded safety and PD data will be reviewed by an 
Investigator and medical monitor following completion of each kratom dose level. 
8.7. Determination of Sample Size 
No formal sample size analysis was performed. It is estimated that 8 subjects per cohort with 
6 subjects assigned to the active drug and 2 subjects assigned to the placebo should be sufficient 
to meet the objectives of the study. 

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9. REFERENCES 
1. Investigator’s Brochure of Kratom. Version 1.0 released on 31 May 2023 
2. Hassan Z, Muzaimi M, Navaratnam V, Yusoff NHM, Suhaimi FW, Vadivelu R, et al. 
From kratom to mitragynine and its derivatives: physiological and behavioural effects 
related to use, abuse, and addiction. Neurosci Biobehav Rev. 2013 Feb;37(2):138-51. 
3. León F, Obeng S, Mottinelli M, Chen Y, King TI, Berthold EC, et al. Activity of 
Mitragyna speciosa ("kratom") alkaloids at serotonin receptors. J Med Chem. 2021 Sep 
23;64(18):13510-13523. 
4. Han C, Schmitt J, Gilliland KM.  DARK Classics in Chemical Neuroscience: Kratom. 
ACS Chem Neurosci. 2020 Jan 13. 
5. Swogger MT, Walsh Z. Kratom use and mental health: A systematic review.  Drug 
Alcohol Depend.  2018 Feb 1;183:134-140. 
6. Kratom Dosage Guide. (n.d.). Kratom.org. Available at https://kratom.org/guides/dosage/ 
7. Martin WR, Sloan JW, Sapira JD, Jasinski DR. Physiologic, subjective, and behavioral 
effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and 
methylphenidate in man. Clin Pharmacol Ther 1971;12(2):245–258. 
8. Haertzen CA, Hill HE, Belleville RE. Development of the Addiction Research Center 
Inventory (ARCI): selection of items that are sensitive to the effects of various drugs. 
Psychopharmacologia 1963;70:155–166. 
9. Haertzen CA. An Overview of the Addiction Research Center Inventory (ARCI): An 
Appendix and Manual of Scales. Rockville, MD: National Institute on Drug Abuse; 1974. 

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10. APPENDIX 1: ETHICS 
10.1. Institutional Review Board 
This protocol and the ICF will be submitted to an IRB (or Independent Ethics Committee[IEC]) 
prior to initiation of the study and the study will not start until the Board has approved the 
documents. Notification of the Board’s approval will be appended to the final report. 
10.2. Ethical Conduct of the Study 
This study will be conducted in compliance with the study protocol, the ethical principles that 
have their origins in the Declaration of Helsinki, the International Council for Harmonisation 
(ICH) Guideline E6 for Good Clinical Practice (GCP), the FDA GCP Code of Federal 
Regulations (CFR) Title 21 (part 56), the EU Clinical Trial Directive (EC) No. 2001/20/EC, the 
European regulation EU 536/2014 and the Tri-Council Policy Statement (Canada). 
10.3. Subject Information and Consent 
Before screening activities commence, each volunteer will be given a copy of the ICF to read, as 
well as a full explanation of the purpose of the study, the procedures to be carried out, and the 
potential AE(s). Once this essential information is provided to the volunteer and the Investigator 
or delegate in charge has the conviction the volunteer understands the implications of 
participating in the study, and if the volunteer chooses to continue the screening process, they 
will be requested to sign and date a properly executed ICF prior to enrollment. Subjects will be 
assured they may withdraw from the study at any time without jeopardizing their medical care or 
future study participation (for which they qualify). 
Subjects will be given a signed copy of the ICF. If an amended or revised ICF is introduced 
during the study, each subject’s further consent must be obtained. 
10.4. Subject Confidentiality 
Investigators will preserve the confidentiality of all subjects taking part in the study, in 
accordance with GCP and local regulations. Subjects personally identifiable information will be 
replaced with a   unique subject identifier on all study documents . The key allowing for re-
identification of the subjects will be maintained by the investigator and will not be released to the 
FDA. In compliance with Federal regulations/ICH GCP Guidelines, it is required an Investigator 
and Sponsor (FDA) permit authorized representatives of the company, of the regulatory 
agency(s), and IRB access to review the subject’s original medical records for audit related 
activities including verification of study-related procedures and data. An Investigator is obligated 
to inform the subject that his/her study-related records will be reviewed by the above named 
representatives without violating the subject’s confidentiality. 

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11. APPENDIX 2: DATA COLLECTION, RETENTION, AND MONITORING 
11.1. Case Report Forms 
The subject level data is entered by the site from the source document into a study specific 
21 CFR Part 11 compliant electronic clinical database to accurately collect data for each subject 
included in a clinical trial. Screen failure data may be entered into the database at the discretion 
of the Sponsor, when included in the contracted scope of work. 
11.2. Data Management and Processing 
Data management develops documentation to define activities performed during the data 
management conduct of the study trial. The electronic data capture system is the tool used to 
conduct all data management data cleaning activities for monitoring, data review, and queries. 
Data management will use a combination of automated programmed edits and manual data 
review listings to issue queries for non-conforming or discrepant data. Data management 
activities are performed in accordance with the SOPs and study-specific data management 
documents. 
Database locking is guided by the Data Management Locking Checklist based on the concept 
that all site activities are complete, data are considered clean and without errors, and CRF signoff 
by the Principal Investigator or delegate has been completed. User access is removed as part of 
the locking process. 
Data from the clinical database will be output as SAS® datasets. All data will be included with 
the final report provided to the Sponsor. 
11.3. Quality Control and Quality Assurance 
Designated personnel from the quality assurance unit(s) will be responsible for maintaining 
quality assurance of the clinical, PK, statistical and bioanalytical facilities to ensure that the trial 
is conducted and data are generated, documented and reported in compliance with the protocol, 
ICH Guideline E6 for GCP, applicable requirements as outlined in the FDA and Organization for 
Economic Co-operation and Development Principles of Good Laboratory Practice, and the 
Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples 
(EMA/INS/GCP/532137/2010). 
Designated personnel from each corresponding operation unit will be responsible to maintain and 
assure the quality control of all data generated and documented in compliance with the protocol. 
11.4. Record Retention 
All essential documents and records will be maintained by the clinical site in accordance with, 
and for the period specified in the applicable regulatory requirement(s) (FDA CFR 312.57 [C]). 
11.5. Monitoring of the Study 
The sponsor or its representative may monitor the study in order to maintain current and personal 
knowledge of the study through review of the records, comparison with source documents, 
observation and discussion of the conduct and progress of the study. The clinical site will permit 
trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s) by providing direct 
and/or virtual access, where possible, to source data/documents. 

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12. APPENDIX 3: ADMINISTRATIVE PROCEDURES 
12.1. Liabilities 
It is the Sponsor’s responsibility to guarantee sufficient insurance coverage should any serious 
events or deaths result, either directly or indirectly, from the execution of the present protocol. 
12.2. Adherence to Protocol 
Excluding an emergency situation in which proper treatment is required for the protection, safety 
and well-being of the study subjects, the study will be conducted as described in the approved 
protocol and performed according to ICH/GCP and the applicable regulatory requirements. Any 
deviation from the protocol will be recorded and explained. 
If amendments to the protocol and/or amendments or revisions to the ICF are required, the 
modifications will be documented and submitted to an IRB for approval. 
12.3. COVID-19 Response Plan 
Regulatory authorities have recognized that the COVID-19 pandemic may impact the conduct of 
clinical trials of medical products. Challenges may arise, for example, from quarantines, site 
closures, travel limitations, interruptions to the supply chain for the IP(s), or other considerations 
if site personnel or study participants become infected with COVID-19. These challenges may 
lead to difficulties in meeting protocol-specified procedures, including administering or using the 
IP or adhering to protocol-mandated visits and laboratory/diagnostic testing. To accommodate 
these challenges and mitigate safety risks associated with COVID-19, protocol modifications 
may be required which include (and are not limited to): 
• Conducting the study in multiple (smaller) subject groups; 
• Altering the timing of study procedures and subject confinement; 
• Modification of standard inclusion or exclusion criteria; 
The exact mitigations will be documented in the study Risk Assessment and Mitigation Plan and 
will be discussed with the Sponsor before implementation. 
Additional health checks including COVID-19 testing, body temperature monitoring, etc. may be 
performed during the trial, even if not planned within the protocol. 
12.4. Statement of Investigator 
The FDA 1572 form, Statement of Investigator [Title 21, CFR Part 312], will be signed by the 
Investigator, and will be kept on file. 
12.5. Delegation of Investigator Duties 
An Investigator will ensure all personnel involved in the trial are adequately qualified and 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
trial-related duties and functions. 
An Investigator will maintain a list of Sub-Investigator(s) and other appropriately-qualified 
persons to whom he/she delegates significant trial-related duties. 

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Should an Investigator delegate the supervision of the IP administration to a designated person, 
this individual must have the appropriate professional-legal qualifications and certifications. An 
Investigator should also ensure key staff personnel have the appropriate medical qualifications to 
effectively conduct or supervise any potential resuscitation procedures. 
12.6. Premature Termination or Suspension of a Study 
The Sponsor or its representative may terminate the study at any time for scientific or corporate 
reasons. 
If the trial is prematurely terminated or suspended for any reason, the clinical site or an 
Investigator (or delegate) should promptly inform the trial subjects, should assure appropriate 
therapy and follow-up for the subjects and should inform the regulatory authority(ies) when 
required. 

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13. APPENDIX 4: PROTOCOL REVIEW AND APPROVALS 
 

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TITLE: Adaptive Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of 
Single Ascending Doses of Kratom in Healthy, Nondependent, Adult Recreational Polydrug 
Users with Opioid Experience 
On behalf of the Sponsor, I am aware of, and agree to comply with, all of the procedures 
contained within this protocol. 
_____________________________ 
____________________ 
Chad J. Reissig, PhD 
 
Date (yyyy/mm/dd) 
Food and Drug Administration (FDA), USA 

Protocol No: 75F40121C00199 
Altasciences Project Number: FDU-P4-117 
 
Version 1.0, 05-JUN-2023 
Page 58 of 62 
14. APPENDIX 5: LIST OF ABBREVIATIONS 
A 
amphetamine 
 
AE 
adverse event 
 
ALT 
alanine aminotransferase 
 
ARCI 
Addiction Research Center Inventory 
 
BG 
Benzedrine Group 
 
BMI 
body mass index 
 
CFR 
Code of Federal Regulations 
 
COVID-19 
Coronavirus Disease 2019 
 
CRF 
Case Report Form 
 
C-SSRS 
Columbia Suicide Severity Rating Scale 
 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
 
ECG 
electrocardiogram 
 
eGFR 
estimated glomerular filtration rate 
 
EMA 
European Medicines Agency 
 
FDA 
Food and Drug Administration 
 
GCP 
Good Clinical Practice 
 
HIV 
human immunodeficiency virus 
 
ICF 
informed consent form 
 
ICH 
International Council for Harmonisation 
 
IEC 
Independent Ethics Committee 
 
IP 
investigational product 
 
IRB 
Institutional Review Board 
 
LSD 
lysergic acid diethylamide 
 
MBG 
morphine-benzedrine group 
 
MDMA 
3,4 methylenedioxymethamphetamine 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
MPC 
minimum pupil diameter 
 
MTD 
Maximum Tolerated Dose 
 
OAA/S 
Observer’s Assessment of Alertness/Sedation Scale 
 
PCAG 
pentobarbital–chlorpromazine–alcohol group 
 
PCP 
phencyclidine 
 
PD 
pharmacodynamic 
 

Protocol No: 75F40121C00199 
Altasciences Project Number: FDU-P4-117 
 
Version 1.0, 05-JUN-2023 
Page 59 of 62 
pH 
The Logarithm, On The Base 10, of The Reciprocal of The Hydrogen Ion 
Concentration 
 
PK 
pharmacokinetic 
 
PT 
Preferred Term 
 
QTcF 
QT Interval Corrected for Heart Rate using Fridericia's Correction Formula 
 
SAD 
single ascending dose 
 
SAE 
serious adverse event 
 
SAP 
statistical analysis plan 
 
SOC 
System Organ Class 
 
SOP 
Standard Operating Procedure 
 
SRC 
Safety Review Committee  
 
TEAE 
treatment-emergent adverse event 
 
ULN 
upper limit of normal 
 
VAS 
visual analog scale 
 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced  
 

Protocol No: 75F40121C00199 
Altasciences Project Number: FDU-P4-117 
 
Version 1.0, 05-JUN-2023 
Page 60 of 62 
15. APPENDIX 6: CLINICAL LABORATORY EVALUATIONS 
Clinical Laboratory Test 
Panel 
Description 
General biochemistry: 
Alanine aminotransferase, albumin, alkaline phosphatase, anion gap, 
aspartate aminotransferase, bilirubin total, blood urea nitrogen (BUN), 
BUN/creatinine ratio, calcium, carbon dioxide, chloride, creatinine, 
(including eGFR calculated using the CKD-EPI equation), glucose, 
phosphorus, potassium, protein total, sodium, and uric acid 
Lipid profile: 
Total cholesterol, cholesterol high-density lipoprotein, cholesterol low-
density lipoprotein and triglycerides 
Endocrinology: 
FSHa 
Hematology: 
White cell count with differential (absolute values of neutrophil, 
lymphocyte, monocyte, eosinophil, and basophil), red cell count, 
hemoglobin, hematocrit, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, and 
platelet count, red cell distribution width 
Serology: 
HIV Ag/Ab Combo, Hepatitis B surface antigen and Hepatitis C virus 
Urinalysis: 
Color, clarity, specific gravity, pH, leukocyte, protein, glucose, 
ketones, bilirubin, blood, nitrite, urobilinogen. Microscopic 
examination will only be performed if the dipstick test is outside of the 
reference range for leukocyte, blood, nitrite or protein 
Urine drug screen: 
Amphetamines, barbiturates, benzodiazepines, cocaine, fentanyl, 
MDMA, opiates, oxycodone, phencyclidine. and tetrahydrocannabinol, 
Pregnancy test: 
Serum pregnancy test at Screening only and urine pregnancy test at all 
other scheduled days 
Alcohol screen: 
Urine alcohol test 
Abbreviations: eGFR = estimated glomerular filtration rate; FSH = follicle-stimulating hormone; HIV = human 
immunodeficiency virus. 
a. 
Performed for females in a postmenopausal state only. 
 

Protocol No: 75F40121C00199 
Altasciences Project Number: FDU-P4-117 
 
Version 1.0, 05-JUN-2023 
Page 61 of 62 
16. APPENDIX 7: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
BASELINE/SCREENING VERSION 
 

C-SSRS Baseline Screening - United States/English - Mapi. 
C-SSRS-BaselineScreening_AU5.1_eng-USori.doc 
COLUMBIA-SUICIDE SEVERITY  
RATING SCALE  
(C-SSRS) 
Baseline/Screening Version 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J. 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 

 
© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Baseline/Screening (Version 1/14/09) 
Page 1 of 2 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
Lifetime: Time 
He/She Felt  
Most Suicidal 
Past __ 
Months 
1.  Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of 
ways to kill oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific 
plan with time, place or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes person who would 
say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do it… and I would 
never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts 
but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being 
the least severe and 5 being the most severe). Ask about time he/she was feeling the most suicidal. 
Most Severe 
Most 
Severe 
Lifetime - 
Most Severe Ideation:    __________ 
 __________________________________________  
 
Type # (1-5) 
Description of Ideation 
Past X Months - 
Most Severe Ideation:    __________ 
 __________________________________________  
 
Type # (1-5) 
Description of Ideation 
 
Frequency 
How many times have you had these thoughts? 
____ 
____ 
 
(1) Less than once a week 
(2) Once a week 
(3) 2-5 times in week 
(4) Daily or almost daily 
(5) Many times each day 
Duration 
When you have the thoughts how long do they last? 
 
 
(1) Fleeting - few seconds or minutes 
(2) Less than 1 hour/some of the time 
(3) 1-4 hours/a lot of time 
(4) 4-8 hours/most of day 
(5) More than 8 hours/persistent or continuous 
____ 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
 
 
(1) Easily able to control thoughts 
(2) Can control thoughts with little difficulty 
(3) Can control thoughts with some difficulty 
(4) Can control thoughts with a lot of difficulty 
(5) Unable to control thoughts 
(0) Does not attempt to control thoughts 
____ 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or 
acting on thoughts of committing suicide? 
 
 
(1) Deterrents definitely stopped you from attempting suicide 
(2) Deterrents probably stopped you 
(3) Uncertain that deterrents stopped you 
(4) Deterrents most likely did not stop you 
(5) Deterrents definitely did not stop you 
(0) Does not apply 
____ 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the pain or 
stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or 
was it to get attention, revenge or a reaction from others? Or both? 
 
 
(1) Completely to get attention, revenge or a reaction from others 
(2) Mostly to get attention, revenge or a reaction from others 
(3) Equally to get attention, revenge or a reaction from others and to 
end/stop the pain 
(4) Mostly to end or stop the pain (you couldn’t go on 
living with the pain or how you were feeling) 
(5) Completely to end or stop the pain (you couldn’t go on 
living with the pain or how you were feeling) 
(0) Does not apply 
____ 
____ 

 
© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Baseline/Screening (Version 1/14/09) 
Page 2 of 2 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Past __ 
Years 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, 
a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of 
a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you_____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, 
get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 Yes 
No 
 
 
 
 Yes 
No 
 
 
 
Total # of 
Attempts 
______ 
Total # of 
Attempts 
______ 
 Yes 
No 
 
 
 
 Yes 
No 
 
 
 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt 
would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. 
Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from 
ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything? 
If yes, describe: 
 
 Yes 
No 
 
 
 
 Yes 
No 
 
 
 
Total # of 
interrupted 
______ 
Total # of 
interrupted 
______ 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
 Yes 
No 
 
 
 
 Yes 
No 
 
 
 
Total # of 
aborted 
______ 
Total # of 
aborted 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
 Yes 
No 
 
 
 
 Yes 
No 
 
 
 
Answer for Actual Attempts Only 
Most Recent 
Attempt  
Date: 
Most Lethal 
Attempt  
Date: 
Initial/First 
Attempt  
Date: 
Actual Lethality/Medical Damage: 
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with 
reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-
degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
Enter Code 
______ 
Enter Code 
______ 
Enter Code 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
______ 
Enter Code 
______ 
Enter Code 
______ 
 

Protocol No: 75F40121C00199 
Altasciences Project Number: FDU-P4-117 
 
Version 1.0, 05-JUN-2023 
Page 62 of 62 
17. APPENDIX 8: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
SINCE LAST VISIT VERSION 
 

C-SSRS Since Last Visit - United States/English - Mapi. 
C-SSRS-SinceLastVisit_AU5.1_eng-USori.doc 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 

© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Since Last Visit (Version 1/14/09) 
Page 1 of 2 
 
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
Since Last 
Visit 
1.  Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…..and I would never go through with it”. 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I definitely 
will not do anything about them”. 
Have you had these thoughts and had some intention of acting on them? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being the least severe 
and 5 being the most severe). 
Most 
Severe 
Most Severe Ideation: 
 ________ 
 __________________________________________________  
 
Type # (1-5) 
Description of Ideation 
Frequency 
How many times have you had these thoughts? 
____ 
 
(1) Less than once a week 
(2) Once a week 
(3) 2-5 times in week 
(4) Daily or almost daily 
(5) Many times each day 
Duration 
When you have the thoughts how long do they last? 
 
(1) Fleeting - few seconds or minutes 
(2) Less than 1 hour/some of the time 
(3) 1-4 hours/a lot of time 
(4) 4-8 hours/most of day 
(5) More than 8 hours/persistent or continuous 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
 
(1) Easily able to control thoughts 
(2) Can control thoughts with little difficulty 
(3) Can control thoughts with some difficulty 
(4) Can control thoughts with a lot of difficulty 
(5) Unable to control thoughts 
(0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
 
(1) Deterrents definitely stopped you from attempting suicide 
(2) Deterrents probably stopped you 
(3) Uncertain that deterrents stopped you 
(4) Deterrents most likely did not stop you 
(5) Deterrents definitely did not stop you 
(0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
 
(1) Completely to get attention, revenge or a reaction from others 
(2) Mostly to get attention, revenge or a reaction from others 
(3) Equally to get attention, revenge or a reaction from others and to 
end/stop the pain 
(4) Mostly to end or stop the pain (you couldn’t go on living with the pain or 
how you were feeling) 
(5) Completely to end or stop the pain (you couldn’t go on living with the 
pain or how you were feeling) 
(0) Does not apply 
____ 
 

© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Since Last Visit (Version 1/14/09) 
Page 2 of 2 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since 
Last Visit 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury 
results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you_____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
 Yes 
No 
 
 
 
Total # of 
Attempts 
______ 
 Yes 
No 
 
 
 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
Total # of 
interrupted 
______ 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you actually did 
anything? 
If yes, describe: 
 
 Yes 
No 
 
 
 
Total # of 
aborted 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
 Yes 
No 
 
 
 
Suicide: 
 Yes 
No 
 
 
 
Answer for Actual Attempts Only 
Most Lethal 
Attempt  
Date: 
Actual Lethality/Medical Damage: 
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns 
less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
Enter Code 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
______