Assessing the Pharmacokinetics and Drug Interaction Liability of Kratom, an Opioid-like Natural Product
Phase: EARLY_PHASE1
Conditions: Interaction Drug Food
Sponsor: Washington State University

NCT #04392011 
Assessing the pharmacokinetics and drug 
interaction liability of kratom, an opioid-like 
natural product 
PI: Mary F. Paine, RPh, PhD 
8/12/2019

STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
FIGURE 1. Overview of procedures. 
SUBJECTS 
Healthy adult volunteers who are intermittent users of kratom (‘non-naïve’) will be recruited from the local 
community to participate in this safety study (FIGURE 1). Intermittent users are defined as those who use from 2-
8 grams of kratom at least once per month but no more than three times per day within the past six months prior 
to screening and are not trying to quit. 
PRE-SCREENING 
Inclusion criteria: 
• Men and women, aged from 18-55 years and healthy
• Not taking any medications (prescription and non-prescription) or dietary/herbal supplements known
to alter the pharmacokinetics of either study drug or kratom constituents
• Willing to abstain from consuming dietary/herbal supplements and citrus juices for several weeks
• Willing to abstain from consuming caffeinated beverages or other caffeine-containing products the
evening before and morning of the first day of a study arm
• Willing to abstain from consuming any alcoholic beverages for one day prior to any study day, during
the 14-hour inpatient days, and for the 5 and/or 1 outpatient visit(s) following 14-hour visit
• Willing to use an acceptable method of contraception that does not include oral contraceptive pills or
patches (such as abstinence, copper IUD, condom)
• Have the time to participate
• Are non-naïve kratom users (intermittent users who are not trying to quit), i.e. an intermittent user who
uses between 2 to 8 grams of kratom at least once per month but no more than three times per day
within the past six months prior to screening.
YES 
YES
NO 
 NO 
Meets 
inclusion/ 
exclusion 
criteria? 
Screening 
visit (2 h) 
Schedule 
study days 
Eligible to 
participate
? 
ID potential 
subjects 
Do not 
screen 
Do not enroll 
Arm 1: one 14-hour visit, 
followed by 6 outpatient 
visits. 
Arm 2a: one 14-hour visit 
followed by 1 outpatient 
visit. 
Arm 2b: one 14-hour visit 
followed by 2 outpatient 
visits. 
Blood will be drawn 15 min, 30 min, 1, 
1.5, 2, 3, 4, 6, 8, and 12 h after 
administration of kratom. 
Blood will be drawn 15 min, 30 min, 1, 
1.5, 2, 3, 4, 6, 8, and 12 h after 
administration of study drugs. 
Blood will be drawn 15 min, 30 min, 1, 
1.5, 2, 3, 4, 6, 8, and 12 h after 
administration of kratom and study drugs. 

• Carry a CYP2D6 genotype designated as having an intermediate, extensive, or ultra-extensive 
metabolizer phenotype 
• Written informed consent (and assent when applicable) obtained from subject or subject’s legal 
representative and ability for the subject to comply with the requirements of the study 
• History of self-reported kratom use (self-reported intake ≥1 time per month) 
 
Exclusion criteria: 
• Men and women under the age of 18 or over the age of 55 
• Any current major illness or chronic illness such as (but not limited to) kidney disease, hepatic disease, 
diabetes mellitus, hypertension, coronary artery disease, chronic obstructive pulmonary disease, 
cancer, or HIV/AIDS 
• No previous exposure to kratom 
• History of anemia or any other significant hematologic disorder 
• History of drug or alcohol addiction or major psychiatric illness 
• A need for chronic opioid analgesics 
• Use of opioid analgesics 3 weeks prior to initiation of the study 
• An imminent likely need for opioid analgesics (e.g., planned dental or surgical procedure) 
• Female and pregnant or nursing 
• Have a history of allergy to kratom or other opioid-containing natural products, other opioids, 
midazolam or other benzodiazepines, or dextromethorphan. 
• Taking concomitant medications, both prescription and non-prescription (including dietary 
supplements/herbal products), known to alter the pharmacokinetics of either study drug or kratom 
constituents 
• Carry a CYP2D6 genotype designated as having a poor metabolizer phenotype 
• Presence of a condition or abnormality that, in the opinion of the Investigator, would compromise the 
safety of the patient or the quality of the data 
• History of sleep apnea 
• Use of monoamine oxidase inhibitors (MAOIs) 14 days prior to the initiation of the study 
• A need for chronic opioid analgesics 
• Recreational drug use other than kratom, such as amphetamines, benzodiazepines, cocaine, 
marijuana, MDMA, opioids, and PCP 
• Current recreational use of marijuana 
• History of intolerance to kratom 
• Out-of-range clinical laboratory value that the study physician considers participation in the study a 
health risk 
• Subjects with seizure disorders 
 
SCREENING VISIT 
Potential eligible subjects, based on the inclusion/exclusion criteria, will present for a screening visit at the 
Nursing Building or Sleep and Performance Research Center on the Spokane campus. Informed consent will be 
obtained after full explanation of the study protocol. Consented subjects will undergo the following: 
• A medical history and physical exam 
• CBC with differential, electrolytes, liver function tests, serum creatinine 
• Routine urine analysis 
• Urine toxicology screen for multiple common drugs of abuse, including several opioids 
• Urine pregnancy test for female subjects of child-bearing potential (prior to enrollment in the study and 
prior to each phase of the study using in-home urinalysis pregnancy screens) 
• Genotyping for common CYP2D6 single nucleotide polymorphisms to determine CYP2D6 metabolizer 
status (i.e., poor or extensive metabolizers) 
 
 
 
 
 

STUDY DESIGN  
 
 
 
 
 
 
FIGURE 3. Detailed timelines of the sequential arms. 
3.1. Arm 1 
3.2. Arm 2a 
 
 
3.3. Arm 2b 
This study will consist of two study arms (FIGURES 2 and 3). Arm 1 will include one 14-hour inpatient visit, followed 
by 6 outpatient visits. Arms 2a and 2b will include one 14-hour inpatient visit each; Arm 2b will include one 
additional outpatient visit. If a subject elects to participate in Arm 2, he/she will undergo a washout period of at 
least 7 days after completing Arm 1. A washout period of at least 7 days will separate Arms 2a and 2b. Subjects 
will be administered the following: 
Arm 1: Kratom (2 g) by mouth as a tea. 
 
Arm 2a: Two liquid-filled capsules of dextromethorphan (15 mg each, 30 mg total) by mouth + midazolam 
syrup (2.5 mg) by mouth. 
 
Arm 2b: Kratom (2 g) by mouth (as a tea) + two liquid-filled capsules of dextromethorphan (30 mg) by 
mouth + midazolam (2.5 mg) syrup by mouth. 
 
Study days. Subjects will be asked to present to the Clinical Research Unit in the Nursing Building or the Sleep 
and Performance Research Center on the morning of each 14-hour inpatient visit. Vital signs will be checked 
and recorded on case forms. Subjects will be asked of any change to their health status; responses will be 
recorded on case forms. An intravenous line will be placed in one arm, and two blood samples (5 mL and 3 mL) 
will be drawn through the intravenous line, after which subjects will receive kratom tea alone (Arm 1) and/or drug 
cocktail alone (Arm 2a) and drug cocktail + kratom tea (Arm 2b). Blood will be drawn from the intravenous line 
0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-kratom tea and/or post-drug cocktail administration. Urine will 
be collected into multiple jugs from 0-120 hours (Arm 1) and/or from 0-24 hours (Arms 2a and 2b). After the 12-
hour blood draw, subjects will be allowed to leave the Clinical Research Unit once deemed safe by the study 
coordinator.  
FIGURE 2. Overview of study design. 
Screening 
≥1 week  
washout  
Arm 1 
≥1 week  
washout 
Arm 2a 
≥1 week 
washout 
Arm 2b 

Subjects will be asked to return to the Clinical Research Unit for outpatient blood draws (5 mL) via venipuncture 
at 24, 48, 72, 96, and 120 hours post-kratom administration during Arm 1 and 24-hours post kratom and/or study 
drug administration. Subjects will be asked to return to the Clinical Research Unit for one additional outpatient 
blood draw (5 mL) via venipuncture up to 7 days after the 120-hour blood draw during Arm 1 and after the 24-
hour blood draw during Arm 2b. 
Each of the two study arms will be separated by at least 7 days, as the half-life of mitragynine is ~24 hours. 
Subjects will be asked to refrain from consuming any dietary/herbal supplements or citrus juices for at least 1 
week prior to each 14-hour inpatient visit and for the duration of the study and to refrain from alcoholic and 
caffeinated beverages the evening before and the morning of each inpatient and outpatient visit. 
Kratom product acquisition. A well-characterized, standardized, unadulterated, contaminant-free kratom 
product will be obtained from longstanding natural products chemist collaborators at the University of North 
Carolina at Greensboro led by Dr. Nicholas Oberlies.1 The Oberlies group has selected and tested Moon Kratom 
Yellow Indonesian, lot 51, as the kratom product to be administered. The Oberlies group has provided the Paine 
group with natural product study materials suitable for human consumption for more than 10 years. 
Midazolam and dextromethorphan acquisition. Dr. John White, a longstanding collaborator/co-investigator 
and registered pharmacist in WA, will oversee the acquisition and storage of oral midazolam and 
dextromethorphan. 
Pharmacokinetic and statistical analysis. Blood and urine samples for analysis of midazolam, midazolam 
metabolites, dextromethorphan, dextromethorphan metabolites, and kratom constituent concentrations will be 
collected. The pharmacokinetics of midazolam, midazolam metabolites, dextromethorphan, dextromethorphan 
metabolites, and kratom constituents will be determined using traditional noncompartmental analysis methods 
and the pharmacokinetics analysis software, Phoenix WinNonlin (v7.0, Certara, Princeton, NJ). A two one-sided 
testing procedure will be used for the primary endpoint analysis as recommended by the FDA for drug-drug 
interactions studies.2 Specifically, if the treatment/baseline ratio of log-transformed midazolam AUC lay between 
the predefined no-effect range (0.75-1.33), a kratom-midazolam interaction will not be evident. Secondary 
endpoints (e.g., treatment/baseline ratio of Cmax, t1/2, tmax, and oral clearance for midazolam and 
treatment/baseline ratio of AUC, Cmax, t1/2, tmax, and oral clearance for midazolam metabolites, dextromethorphan, 
and dextromethorphan metabolites) will be evaluated using a paired Student’s t-test or Wilcoxon signed-rank 
test as appropriate; a p-value <0.05 will be considered statistically significant. For study Arm 1, 6 evaluable 
subjects, who may or may not elect to participate in Arm 2, are deemed sufficient for definitive characterization 
of the half-life of the kratom constituents. For study Arm 2, a sample size of 12 evaluable subjects will provide 
80% power to detect a 25% change in the primary endpoint (midazolam AUC) with a Type I error of 0.05, 
assuming 20% intra-individual variability in midazolam AUC. 
 
ROLES OF STUDY PERSONNEL 
Mary Paine, RPh, PhD 
Principal investigator 
Oversee all aspects of the study 
Matthew Layton, MD, PhD 
Study physician 
Obtain medical history and perform physical exam 
Be on-call for the entire study period in case of adverse events 
John White, PA-C, PharmD 
Authorized licensed designee of Dr. Layton 
Acquire study drugs 
Deena Hadi, BS  
Schedule study days with staff and subjects 
Oversee financial matters 
Order study supplies 
James Nguyen, PharmD Candidate 
Co-study coordinator  
Assist in all aspects of the study 
Sabrina Judson, PharmD Candidate 
 
Co-study coordinator 
Assist in all aspects of the study 

Rakshit Tanna, PhD student 
 
Co-study coordinator 
Assist in all aspects of the study 
Karen Vo, PharmD Candidate 
Assist in all aspects of the study 
Dallas Carbaugh, PharmD Candidate 
Assist in all aspects of the study 
Emily Gallagher, PharmD Candidate 
 
Assist in all aspects of the study 
 
REFERENCES 
1. Kellogg JJ, Paine MF, McCune JS, Oberlies NH, and Cech NB. Selection and characterization of botanical 
natural products for research studies: a NaPDI Center recommended approach. Nat Prod Rep. 2019 Jan 25. 
doi: 10.1039/c8np00065d. [Epub ahead of print] 
2. U.S. Food and Drug Administration. Drug Interactions: Relevant Regulatory Guidance and Policy 
Documents: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-interactions-relevant-regulatory-
guidance-and-policy-documents (accessed August 11, 2019).