Conditions: Interaction Drug Food
Keywords: Pharmacokinetics Kratom Mitragynine Midazolam Dextromethorphan Natural product
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 15
Healthy volunteers: yes

Brief summary:
Kratom is a botanical natural product that has opioid-like effects. Kratom is commonly used to self-treat withdrawal symptoms associated with opioid addiction, as well as pain. Kratom products include pills, extracts, and powders, most of which contain two primary psychoactive constituents: mitragynine and 7-hydroxymitragynine. Preliminary data from the investigator's laboratory has shown that these two constituents and extracts made from commercially available kratom products are strong inhibitors of the drug metabolizing enzymes cytochrome P450 (CYP) 2D6 and CYP3A4. These enzymes are responsible for metabolizing more than 50% of marketed drugs, including several opioids, benzodiazepines, and antidepressants. Thus, co-consumption of kratom products with drugs metabolized by CYP2D6 and CYP3A4 could increase the risk of serious adverse effects. The effects of a well-characterized kratom product on CYP2D6 and CYP3A4 activity will be assessed in healthy volunteers using a 'cocktail' approach consisting of the validated probe drugs dextromethorphan and midazolam. Results will (1) provide useful information regarding risks associated with co-consuming kratom with opioids and other CYP2D6 and CYP3A4 drug substrates and (2) inform the design of future kratom-drug interactions studies.

Detailed description:
Many patient groups often supplement their drug regimens with herbal and other natural products (NPs), raising concern for adverse NP-drug interactions. Due to a lack of rigorous guidelines for assessing the risk of NP-drug interactions, the NIH-funded Center of Excellence for Natural Product-Drug Interaction Research (NaPDI Center) was established to facilitate the identification, evaluation, and dissemination of potentially clinically relevant pharmacokinetic NP-drug interactions.Kratom is one of four high priority NPs selected by the NaPDI Center for rigorous study of drug interaction potential.

Kratom (Mitragyna speciosa) is a tree native to Southeast Asia that produces constituents with opioid-like effects. Oral supplements made from the leaves are readily available in the United States and are used for several purported medicinal benefits, such as pain relief, treatment of post-traumatic stress disorder, and management of opioid addiction. Two psychoactive constituents of the kratom leaf, mitragynine and 7- hydroxymitragynine, are believed to contribute to these effects.

Calls to poison control centers in the United States involving kratom exposures increased from 2011 to 2017 by 52-fold. More than one-third of the calls reported combined use of kratom with other substances, including opioids and benzodiazepines. In October 2017, the opioid crisis was declared a public health emergency. Many opioids are metabolized by the major drug metabolizing enzymes CYP2D6 and CYP3A4, which have been shown to be inhibited by an extract prepared from a well-characterized kratom product and purified major kratom constituents, including mitragynine and 7-hydroxymitragynine. As such, co-consuming kratom with these opioids could increase the risk of serious adverse effects via inhibition of opioid metabolism, notably respiratory depression, the primary cause of death from opioid overdose.

The purpose of this study is to assess the effects of a well-characterized kratom product on CYP2D6 and CYP3A4 activity in healthy volunteers using a cocktail approach consisting of the validated probe drugs dextromethorphan and midazolam. The primary objective is to evaluate the potential for a pharmacokinetic kratom-drug interaction with midazolam, a 'probe' drug for CYP3A4, when administered to participants previously exposed to kratom. Secondary objectives are to evaluate the pharmacokinetics of kratom constituents and the effect of kratom on the pharmacokinetics of dextromethorphan, a probe drug for CYP2D6.

Results will be used to develop physiologically-based pharmacokinetic (PBPK) models to predict the likelihood and magnitude of kratom-drug interactions, including those involving opioids. These PBPK models could be adapted to other CYP2D6 and CYP3A4 drug substrates with high abuse potential (e.g., benzodiazepines and 'Z-drugs') and used to inform the design of future kratom-drug interactions studies.

Arms:
arm 1: Six non-naive\* subjects (3 males, 3 females) will be administered a single low dose of a well-characterized kratom product (2 g) by mouth as a tea. These subjects may or may not choose to participate in Arms 2a and 2b. For subjects who will participate in Arms 2a and 2b, a washout period of 7 days will separate Arm 1 and Arm 2. Plasma will be collected from 0-120 hours and during the washout period. Urine will be collected from 0-120 hours.

\*Non-naive subjects are defined as intermittent users who consume 2-8 g kratom at least once per month but no more than three times daily within the last six months prior to screening and are willing to abstain for several weeks. arm 2: Arm 2 is divided into Arms 2a and 2b. Twelve non-naive subjects (6 males, 6 females) will participate in Arm 2a. Subjects who participate in this study arm will be administered an oral probe drug cocktail of dextromethorphan HBr (2 x 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma will be collected from 0-24 hours. Urine will be collected from 0-24 hours. A washout period of 7 days will separate Arms 2a and 2b.

For Arm 2b, the same 12 subjects will be administered a combination of a well-characterized kratom product (2 g) by mouth as a tea with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma will be collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine will be collected from 0-24 hours.

Interventions: intervention 1: Midazolam HCl intervention 2: Dextromethorphan HBr intervention 3: Kratom
Intervention descriptions: intervention 1: Oral syrup, 2 mg/mL intervention 2: Oral liquid capsules, 15 mg intervention 3: Kratom (Moon Kratom Yellow Indonesian, lot 51) is supplied as a dry leaf powder in clear plastic bags, each weighing 5 kg. Two g of kratom dry leaf powder will be stirred into 240 mL of hot water to make a tea. The tea will be cooled to 50 degrees Celsius before administration. Subjects will drink the tea within 10 minutes of administration.

Protocol document:
Prot_SAP_000.pdf: 
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).  

ICF_001.pdf: 
Page 1 of 14 
Washington State University 
ASSESSING THE PHARMACOKINETICS AND DRUG 
INTERACTION LIABILITY OF KRATOM, AN OPIOID-LIKE 
NATURAL PRODUCT 
NCT04392011 
Document date: 20 August 2020 
Mary F. Paine, RPh, PhD 
Professor, Pharmaceutical Sciences 
College of Pharmacy and Pharmaceutical Sciences 
Washington State University 
205 E Spokane Falls Blvd 
Spokane, WA, 99202 
Office: 509-358-7759 
mary.paine@wsu.edu 


IRB Ver. 2/2019 
Template Date: 02/12/2020 
Version No.: 3 
Page 1 of 12 
WASHINGTON STATE UNIVERSITY 
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences 
Research Study Consent Form 
Study Title: 
Assessing the pharmacokinetics and drug interaction liability of kratom, an 
opioid-like natural product 
Researchers: 
Mary F. Paine, RPh, PhD; Principal Investigator; Associate Professor, 
Department of Pharmaceutical Sciences, College of Pharmacy; 509-358-
7759 (office); 24-hour emergency telephone: 919-259-5020 
Matthew E. Layton, MD, PhD; Co-investigator and Study Physician; 
Clinical Professor, College of Medical Sciences; 509-358-7502 
John R. White, PharmD, PA-C; Co-investigator; Professor and Chair, 
Department of Pharmacotherapy, College of Pharmacy; 509-358-7731 
Deena Hadi, BS; Program Manager 
James Nguyen, PharmD candidate; Co-Study Coordinator 
Sabrina Judson, PharmD candidate; Co-Study Coordinator 
Rakshit Tanna, PhD student; Co-Study Coordinator  
Karen Vo, PharmD candidate; Study Assistant 
Dallas Carbaugh, PharmD candidate; Study Assistant 
Emily Gallagher, PharmD candidate; Study Assistant 
Boris Yang, PharmD; Study Assistant 
Victoria Oyanna, PhD student; Study Assistant 
Sponsor: 
National Institutes of Health 


Date: 02/12/2020 
IRB Ver. 2/2019 
Version No.: 3 
Page 2 of 12 
KEY INFORMATION ABOUT THIS STUDY 
• Your consent is being sought for research. Participation is voluntary.
• Study Purpose – The purpose of this study is to determine whether or not kratom, a
natural product currently available in the U.S., has an effect on enzymes that are
responsible for breaking down drugs in the body.
• Major Activities of Subject Participation – If you are asked to participate in this study,
you will be asked to avoid consuming dietary/herbal supplements and citrus juices for
several weeks. You will also be asked to avoid consuming caffeinated beverages or
other caffeine-containing products the evening before and the morning of a study day.
You will be asked to avoid consuming alcoholic beverages for at least 1 day prior to
the study day and during the study day. If you are female, you will be asked to use an
acceptable method of contraception that does not include oral contraceptive pills (such
as abstinence, copper IUD, or condoms).
During the study, you will first present for a screening visit at the Nursing
Building or Sleep and Performance Research Center on the WSU Spokane campus.
During this visit, you will read, understand, and sign this consent form. You will have
a medical history and physical exam completed. You will have blood drawn during this
visit. If you are female, you will be asked to provide urine for a pregnancy test. If your
results indicate that you are fit for the study, you will be asked to participate.
The study is broken into two study arms: Arm 1 and Arm 2. Arm 2 is further
broken down into Arm 2a and 2b. For the first day of each study arm, you will be asked
to present for one 14-hour inpatient visit, where blood will be drawn through an
intravenous (IV) line before and after you are given the study drugs (midazolam and
dextromethorphan) with or without kratom. After an initial blood draw, you will be given
kratom alone (Arm 1), a combination of study drugs alone (Arm 2a), or a combination
of kratom with study drugs (Arm 2b). Overall, blood will be drawn at 11 different time
points during the visit, and a total of approximately 60 milliliters (about one-fourth of a
cup) of blood will be collected. You will not be allowed to eat until after the 4-hour blood
draw. You will also be asked to collect urine throughout this visit by voiding into a jug.
Depending on which study arm(s) you choose to participate in, you will be
asked to return to the clinical research unit once every day for 6 days after the inpatient
visit (Arm 1), or once after the inpatient visit (Arm 2a and 2b). Blood will be drawn
through an IV line or needlestick during these visits. About 5 milliliters (one
teaspoonfuls) of blood will be taken on each day. If you choose to participate in Arm 2
(2a and/or 2b), you will be asked to wait at least one week before starting either arm.
• Duration of Participation – This study is divided into two arms: Arm 1 and Arm 2. The
duration of participation will depend on which arm(s) you choose to participate in.
Those who complete Arm 1 only will participate for a minimum of 7 days. Participation
time for those who complete Arm 2 only (Arm 2a and 2b) will be at least 12 days.
Participants who choose to complete both study arms will be a part of the study for at
least 5 weeks, with flexibility of completion time of up to 6 months.
• Significant Risks – Risks pertaining to this study can include bruising, pain, or bleeding
at the site of blood draw; inflammation of the vein; fainting, allergic reactions to the
study drugs (midazolam, dextromethorphan) or kratom; stimulant-like effects;
drowsiness; dizziness; low blood pressure; confusion; excitement; irritability;
nervousness; dizziness; somnolence (sleepiness); or serotonin syndrome, defined as


Date: 02/12/2020 
IRB Ver. 2/2019 
Version No.: 3 
 
 
Page 3 of 12 
 
an excessive amount of serotonin that is characterized by symptoms including but not 
limited to diarrhea, shivering, and fever. If you are female and are pregnant or become 
pregnant, there may be unforeseeable risks to the embryo/fetus. 
• Potential Benefits – There are no direct benefits to you. However, the information 
learned from the study may help people, such as those in your community, in the 
future. 
• This is a clinical trial and should not be considered medical treatment. 
 
What you should know:  
You are being asked to take part in a research study carried out by Dr. Mary Paine. This 
form explains the research study and your part in it if you decide to participate in the study. 
Please read the form carefully, taking as much time as you need. Ask the researcher to 
explain anything you don’t understand. Your participation in the study is strictly voluntary. 
You can decide not to join the study. If you join the study, you can change your mind later 
or quit at any time. You may refuse any question, test, or procedure. There will be no penalty 
or loss of services or benefits if you decide not to take part in the study or quit later. This 
study has been approved for human subject participation by the Washington State 
University (WSU) Institutional Review Board (IRB). 
 
What is the purpose of this study? 
The effects of dietary/herbal supplements and other natural products, including foods, on 
drug concentrations in the body represent an understudied area of research. It is typical for 
doctors and pharmacists to check for potential drug-drug interactions when prescribing or 
dispensing medicines to patients, but they may not always check for potential natural 
product-drug interactions. The researchers believe this is because there is still little 
information on how natural products interact with drugs. St. John's wort is one example of a 
natural product that is known to change the way some drugs are broken down in the body, 
and patients are warned not to take St. John's wort when these drugs are prescribed to 
them. Grapefruit juice is another natural product that is known to change the way some 
drugs are broken down in the body, and patients are advised to avoid consuming grapefruit 
juice when taking many different drugs. 
 
This research study is being done to determine whether another natural product, kratom, 
has an effect on the enzymes of the body that break down (metabolize) drugs. This is a 
clinical study and should not be considered medical treatment. 
 
You are being asked to take part in this study because you: 
• Are from 18-55 years old and healthy 
• Are not taking any medications (prescription and non-prescription) or dietary/herbal 
supplements that can interfere with your ability to eliminate the study drugs and kratom 
• Are willing to abstain from consuming dietary/herbal supplements and citrus juices for 
several weeks 
• Are willing to abstain from consuming caffeinated beverages or other caffeine-
containing products the evening before and the morning of the first day of each study 
arm 


Date: 02/12/2020 
IRB Ver. 2/2019 
Version No.: 3 
 
 
Page 4 of 12 
 
• Are willing to abstain from consuming any alcoholic beverages for at least 1 day prior 
to any study day and during the study day 
• Are 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  
• Consume kratom intermittently (not regularly) and are willing to abstain from taking it 
for at least two weeks prior to beginning the study 
• Do not carry genes that make you a poor metabolizer of one of the test drugs 
 
You cannot take part in this study if you: 
• Are under 18 or over 55 years old 
• Are taking medications or dietary/herbal supplements that can interfere with your 
ability to eliminate the study drugs and kratom 
• Have never taken kratom 
• Have a chronic illness such as (but not limited to) kidney disease, liver disease, 
diabetes mellitus, high blood pressure, coronary artery disease, chronic obstructive 
pulmonary disease, cancer, or HIV/AIDS 
• Have a hematologic (blood) disorder 
• Have a history of drug or alcohol addiction or major psychiatric illness 
• Have a need for chronic opioid pain medications 
• Have used opioid pain medications within the last 3 weeks 
• Have an upcoming need for opioid pain medications (e.g., planned dental or surgical 
procedure) 
• Have a history of allergy to midazolam, dextromethorphan, or related drugs 
• Have a history of intolerance or allergy to kratom or opioids 
• Are pregnant or nursing 
• Carry genes that make you a poor metabolizer of one of the test drugs 
 
What will I be asked to do if I am in this study? 
Taking part in the study will last from anywhere from 6 days to 6 months, depending on your 
schedule. The study will require no more than 47 hours of active participation, including 
minimal time commitment at home while collecting urine. 
 
If you take part in the study, you will be asked to: 
• Present for a screening visit at the Nursing Building or Sleep and Performance 
Research Center on the WSU Spokane campus. This visit will last approximately 2 
hours and will include the following: 
• Reading, understanding, and signing this consent form 
• Undergoing a medical history and physical exam 
• Having about 1 tablespoonful of blood drawn for routine laboratory testing 
• Having about one-half teaspoonful of blood drawn to determine if you are a poor 
metabolizer of one of the test drugs 
• Providing urine for routine laboratory testing and test for multiple common drugs of 
abuse, including several opioids 
• Providing urine for a pregnancy test if you are female 


Date: 02/12/2020 
IRB Ver. 2/2019 
Version No.: 3 
 
 
Page 5 of 12 
 
• If your lab tests come back normal, the drug test comes back negative, you do not 
have the genes that make you a poor metabolizer of one of the test drugs, and if you 
are female and your pregnancy test comes back negative, you will be asked to 
participate in the study.  
• The study will be divided into 3 separate arms. Arm 1 will enroll 6 subjects and last 7 
days. Arms 2a and 2b will enroll 12 subjects. Arm 2a will consist of one inpatient visit 
and one outpatient visit. Arm 2b will consist of one inpatient visit and two outpatient 
visits. 
• Arm 1 will last 7 study days (20 hours in total across 7 days) and will take place in the 
clinical research unit in the Nursing Building or Sleep Performance Research Center. 
You will be asked to remain in the clinical research unit for about 14 hours on study 
day 1 and then return daily over the next 6 days (for less than 1 hour each day). 
• Each Arm will be separated by at least one week.  
• The 6 subjects who participate in Arm 1 will have the option to participate in Arms 2a 
and 2b. Arm 2a will require approximately 15 hours of active participation. Arm 2b will 
require approximately 16 hours of active participation.  
• Kratom or the study drugs (midazolam, dextromethorphan) may alter your ability to 
drive. You must arrange a safe ride home on all inpatient study days (i.e. day one of 
Study Arm 1, 2a, and 2b). This includes requesting a family member or friend to drive 
you home, calling a taxi, or using ride-share applications. 
 
The study arms will include the following: 
• Study Arm 1: 
• This Arm will include 1 inpatient visit lasting up to 14 hours, subsequent 1-hour 
visits on the following 5 days, and 1 additional 1-hour visit a few days later. 
• You will be asked to void your bladder before coming in for the study day. 
• Your vital signs (blood pressure, pulse, respirations) and oxygen saturation will be 
checked and recorded on case forms when you arrive. 
• An intravenous (IV) line will be placed in one of your arms. One blood sample (5 
mL or one teaspoonful) will be drawn through the IV line. 
• You may be asked to provide one additional blood sample (< 3 mL, or about one-
half a teaspoonful) that will be drawn through the IV line. 
• You will be asked to take kratom (2 g) by mouth as a tea. 
• You will begin collecting your urine by voiding into a jug as needed. 
• Blood (5 mL, or about 1 teaspoonful) will be drawn at the following times after you 
take kratom: 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours.  
• A total of approximately 60 mL (one-fourth of a cup) will be drawn during the 14-
hour visit. Every attempt will be made to use your IV line for the blood draws.  
• You will not be allowed to eat until after the 4-hour blood draw. You will then receive 
lunch. 
• You will be discharged as soon as possible after the 12-hour blood draw and given 
a urine jug to take home and void into until you come back to the clinical research 
unit the next morning. 
• You will be asked to return to the clinical research unit for a blood draw 24 (day 2), 
48 (day 3), 72 (day 4), 96 (day 5), and 120 (day 6) hours after you take kratom. 


Date: 02/12/2020 
IRB Ver. 2/2019 
Version No.: 3 
 
 
Page 6 of 12 
 
The blood will be drawn through a needlestick in your arm. You will drop off your 
urine jug the mornings of days 2-6. 
• You will be asked to return to the clinical research unit for a 5 mL (about 1 
teaspoonful) blood draw up to 7 days after the 120-hour blood draw. 
• If you choose to participate in Arm 2, you will wait at least 1 week before starting 
Arm 2a. You will be asked not to take any dietary/herbal supplements (with the 
exception of the study herbal product) or consume citrus juices for the duration of 
the study. 
• If you choose not to participate in Arm 2, you will receive a follow-up call 5 days 
later from a member of the study team. 
 
• Study Arm 2a: 
• This Arm will include 1 inpatient visit lasting up to 14 hours and 1 outpatient visit 
lasting up to 1 hour. 
• You will be asked to void your bladder before coming in for the study day. 
• Your vital signs (blood pressure, pulse, respirations) and oxygen saturation will be 
checked and recorded on case forms when you arrive. 
• An IV line will be placed in one of your arms. Two blood samples (3 mL, or less 
than one teaspoonful, plus 5 mL, or about 1 teaspoonful) will be drawn through the 
IV line. 
• You may be asked to provide one additional blood sample (< 3 mL, or about one-
half a teaspoonful) that will be drawn through the IV line. 
• You will be asked to take a drug “cocktail” (combination) consisting of midazolam 
syrup (2.5 mg) and 2 capsules (15 mg each; 30 mg total) of dextromethorphan by 
mouth with 240 mL of water. 
• You will begin collecting your urine by voiding into a jug as needed. 
• Blood (5 mL or about 1 teaspoonful) will be drawn at the following times after you 
take the drugs: 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 6, 8, and 12 hours.  
• A total of approximately 60 mL (about one-fourth of a cup) will be drawn during the 
14-hour visit. Every attempt will be made to use your IV line for the blood draws.  
• You will not be allowed to eat until after the 4-hour blood draw. You will then receive 
lunch. 
• You will be discharged as soon as possible after the 12-hour blood draw. 
• You will be asked to return to the clinical research unit for a blood draw 24 hours 
after you take kratom. The blood will be drawn through a needlestick in your arm.  
• You will be asked to collect your urine and drop off your urine jug upon returning 
to the clinical research unit for the 24-hour blood draw. 
• After completing Arm 2a, you will wait at least 1 week before starting Arm 2b. You 
will be asked not to take any dietary/herbal supplements (with the exception of the 
study herbal product) or consume citrus juices for the duration of the study. 
 
 
 
• Study Arm 2b: 


Date: 02/12/2020 
IRB Ver. 2/2019 
Version No.: 3 
 
 
Page 7 of 12 
 
• This Arm will include 1 inpatient visit lasting up to 14 hours and 2 outpatient visits, 
each lasting up to 1 hour. The first outpatient visit will occur at the 24-hour mark 
and the second outpatient visit will occur within the week following the first 
outpatient visit. The timing of the second outpatient visit will be flexible depending 
on your schedule. 
• You will be asked to void your bladder before coming to the clinical research unit 
for the study day. 
• Your vital signs (blood pressure, pulse, respirations) and oxygen saturation will be 
checked and recorded on case forms when you arrive. 
• An IV line will be placed in one of your arms. One blood sample (5 mL, or about 1 
teaspoonful) will be drawn through the IV line. 
• You may be asked to provide one additional blood sample (< 3 mL, or about one-
half a teaspoonful) that will be drawn through the IV line. 
• You will be asked to take kratom (2 g) by mouth as a tea, as well as a drug “cocktail” 
consisting of midazolam syrup (2.5 mg) and 2 capsules (15 mg each; 30 mg) of 
dextromethorphan by mouth with 240 mL of water.  
• Blood (5 mL or about 1 teaspoonful) will be drawn at the following times after you 
take kratom and the drug “cocktail”: 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 6, 
8, and 12 hours. 
• A total of approximately 60 mL (one-fourth of a cup) will be drawn during the 14-
hour visit. Every attempt will be made to use your IV line for the blood draws.  
• You will not be allowed to eat until after the 4-hour blood draw. You will then receive 
lunch. 
• You will be discharged as soon as possible after the 12-hour blood draw. 
• You will be asked to return to the clinical research unit for a blood draw 24 hours 
after you take kratom. The blood will be drawn through a needlestick in your arm.  
• You will be asked to collect your urine and drop off your urine jug upon returning 
to the clinical research unit for the 24-hour blood draw. 
• After completing Arm 2b, you will receive a follow-up call 5 days later from a 
member of the study team. 
 
If you choose to participate in Arm 1 only, your total participation time in the study will be a 
minimum of 7 days. If you choose to participate in Arm 2 only, your total participation time 
in the study will be a minimum of 12 days. If you choose to participate in Arms 1 and 2, your 
participation time in the study will be a minimum of 5 weeks. However, the researchers 
recognize that you may not be able to meet these tight schedules and can be flexible, as 
long as you can complete the entire study within 6 months. 
 
If significant new findings develop during the course of the research which may relate to 
your willingness to continue participation, these will be provided to you and you can decide 
whether to continue participating. 
 
Are there any benefits to me if I am in this study? 
There is no direct benefit to you from being in this study. However, the information learned 
from the study may help other people, such as those in your community, in the future. The 
knowledge gained from the study will benefit society because the information will provide 


Date: 02/12/2020 
IRB Ver. 2/2019 
Version No.: 3 
 
 
Page 8 of 12 
 
important insight into how a commonly consumed natural product can alter drug disposition, 
and ultimately, drug response. 
 
Are there any risks to me if I am in this study? 
The potential risks from taking part in this study are: 
• You might experience bruising, pain, or bleeding at the site of the blood draw, 
inflammation of your vein, or fainting.  
• You might have an allergic reaction to midazolam, dextromethorphan, or kratom. 
• You might experience stimulant-like effects, including increased energy and alertness, 
decreased appetite, increased sociability, and heightened libido as a result of kratom. 
These effects should be minimal because you will be receiving a single low dose. 
• You might experience drowsiness, dizziness, or low blood pressure as a result of 
midazolam. These effects should be minimal because you will be receiving a single 
low dose. 
• You might experience confusion, excitement, irritability, nervousness, dizziness, 
somnolence (sleepiness), mild fatigue, and serotonin syndrome (defined as an 
overaccumulation of serotonin, characterized by symptoms including but not limited to 
diarrhea, shivering, and fever) as a result of dextromethorphan. These effects should 
be minimal because you will be receiving a single dose. 
• As with any experimental procedure, there may be adverse events or side effects that 
are currently unknown, and it is possible these unknown risks could be permanent, 
severe, or life-threatening. 
• A description of this clinical study will be available on http://www.ClinicalTrials.gov as 
required by U.S. Law. This website will not include information that can identify you. 
At most, it will include a summary of the results. You may search this website at any 
time.  
• If you are female and are pregnant or become pregnant, there may be unforeseeable 
risks to the embryo or fetus. 
• Hardcopies containing personal/medical information about you may be misplaced. 
• If you experience any adverse effects or injury, you should contact the principal 
investigator (Dr. Mary Paine), study physician (Dr. Matthew Layton), or any of the 
researchers listed at the top of this form. If you require additional assistance or would 
like to report any concerns, you should contact the Washington State University 
Institutional Review Board at (509) 335-3668, or e-mail irb@wsu.edu, or regular mail 
at: Neill Room 427, PO Box 643143, Pullman, WA 99164-3143. 
 
The researchers will make every attempt to minimize these potential risks, including: 
• Having only trained personnel (nurse, physician, physician’s assistant, pharmacist, 
pharmacy student) draw blood. 
• Monitoring your respirations, blood pressure, pulse, and oxygen saturation each study 
day. 
• Study personnel will ask you how you are feeling throughout the study day and will 
address any concerns you may have. 
• Having the anti-allergy medication, diphenhydramine; the opioid antidote, naloxone; 
and an Epi-kit available if needed. If you experience a severe adverse reaction, you 


Date: 02/12/2020 
IRB Ver. 2/2019 
Version No.: 3 
 
 
Page 9 of 12 
 
will be given diphenhydramine, naloxone, and/or epinephrine, 911 will be called, and 
you will be transported to a local emergency room. 
• Allowing only members of the study team to collect and store, as hardcopies, your 
personal/medical information. These hardcopies will be kept in a locked office and 
cabinet. Your personal information will not be entered on a computer. 
• Having the study physician or authorized licensed designee available at all times 
during the study in case you experience serious adverse events. 
 
Will my information be kept private? 
The data for this study will be kept confidential to the extent allowed by federal and state 
law. No published results will identify you, and your name will not be associated with the 
findings. Under certain circumstances, information that identifies you may be released for 
internal and external reviews of this project. The federal Food and Drug Administration 
(FDA) may also review the study data. 
 
The researchers will make every attempt to keep your information private, including: 
• Private conversations will occur only in closed-door offices or rooms. 
• Your personal information will be kept in hardcopy format in a locked office and 
cabinet. Such information will not be entered on a computer. 
• Data collected from you (clinical labs, vital signs) will not be linked to you and will be 
stored on a password-protected computer and in hardcopy format in a locked office. 
• Only members of the research team will have access to the data. 
 
The results of this study may be published or presented at professional meetings, but the 
identities of all research participants will remain anonymous.  
 
Identifiers might be removed from the identifiable private information or identifiable 
specimens and then the information or specimens could be used for future research studies 
or distributed to other researchers for future research studies without your additional 
permission. If you do not agree to this, you may choose not to join the study. 
 
The data for this study will be kept for 7 years. One blood sample will be retained indefinitely 
for genetic analysis if future research indicates a genetic variation may affect the way the 
body responds to any of the study drugs or components in kratom. The genetic analysis 
would only be conducted for the specific genes associated with the way the body responds 
to any of the study drugs and their metabolites, or components in kratom. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website at any time. 
National Institutes of Health Certificate of Confidentiality  
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, 
documents, or biospecimens that may identify you in any federal, state, or local civil, 
criminal, administrative, legislative, or other action, suit, or proceeding, or be used as 


Date: 02/12/2020 
IRB Ver. 2/2019 
Version No.: 3 
 
 
Page 10 of 12 
 
evidence, for example, if there is a court subpoena, unless you have consented for this use. 
Information, documents, or biospecimens protected by this Certificate cannot be disclosed 
to anyone else who is not connected with the research except, if there is a federal, state, or 
local law that requires disclosure (such as to report child abuse or communicable diseases 
but not for federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings, see below); if you have consented to the disclosure, including for your medical 
treatment; or if it is used for other scientific research, as allowed by federal regulations 
protecting research subjects. 
 
The Certificate cannot be used to refuse a request for information from personnel of the 
United States federal or state government agency sponsoring the project that is needed for 
auditing or program evaluation by the National Center for Complementary and Integrative 
Health, which is funding this project or for information that must be disclosed in order to 
meet the requirements of the FDA. You should understand that a Certificate of 
Confidentiality does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research. If you want your research information released to an 
insurer, medical care provider, or any other person not connected with the research, you 
must provide consent to allow the researchers to release it. 
 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, 
state, or local law. For example, if child abuse and neglect or harm to self or others is 
suspected, the researchers are required to report this information to relevant authorities. 
 
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose you 
have consented to in this informed consent document, including research data in the medical 
record. 
 
Are there any costs or payments for being in this study? 
 
There will be no costs to you for taking part in this study. 
 
Please review the table on the next page for a breakdown of compensation for participating 
in this study. 
 
 
TABLE 1. Payments for participation 
STUDY VISITS 
PAYMENT TOTAL 
Screening 
$25 
Arm 1 Inpatient  
$300 
Arm 1 Outpatient (6 visits) 
$150 
Arm 1 Urine Collection (five 24-hour collections) 
$200 
Arm 2a Inpatient  
$300 
Arm 2a Outpatient 
$25 
Arm 2b Inpatient 
$300 
Arm 2b Outpatient (2 visits) 
$50 
Total 
$1,350 
 


Date: 02/12/2020 
IRB Ver. 2/2019 
Version No.: 3 
 
 
Page 11 of 12 
 
If you complete only Arm 1, you will receive a total of $475; if you complete and return your 
24-hour urine collections every day on days 2-6 of Arm 1, you will receive a total of $675. If 
you miss any of the 24-hour urine collections in Arm 1, you will forfeit the additional $200. If 
you complete only Arm 2, you will receive a total of $700. If you complete all study arms, 
you will receive a total of $1,150. If you complete all study arms and return your 24-hour 
urine collections every day on days 2-6 of Study Arm 1, you will receive a total of $1,350.  
 
You also will receive food and drink during each study day. If you decide to quit the study at 
any time, you will receive payment based on the number of study days you have completed 
and as soon as possible after your last study day. There will be no penalty for discontinuing 
participation at any time. 
 
If you receive payment for taking part in this study, you will be asked to provide your home 
address and social security number because this payment may be taxed as income. If you 
are a nonresident alien, a 30% withholding tax will apply to your payment per Washington 
State 
University’s 
Business 
Policies 
and 
Procedures 
Manual 
(BPPM 
45.53; 
https://policies.wsu.edu/prf/index/manuals/45-00-contents/45-53-incentive-payments-
research-participants). 
 
 
Who can I talk to if I have questions? 
If you have questions about this study or the information in this form, please contact the 
primary 
researcher, 
Dr. 
Mary 
Paine, 
by 
phone 
(509-358-7759), 
e-mail 
(mary.paine@wsu.edu), or regular mail (WSU College of Pharmacy and Pharmaceutical 
Sciences; PBS 323, 412 E Spokane Falls Blvd; Spokane, WA 99202-2131). If you have 
questions about your rights as a research participant, or would like to report a concern or 
complaint about this study, please contact the Washington State University Institutional 
Review Board at (509) 335-7646, or e-mail irb@wsu.edu, or regular mail at: Neill 427, PO 
Box 643143, Pullman, WA 99164-3143.  
 
What if I have a study-related injury or want to withdraw? 
If you have a study related injury, illness, distress and want to report this to the researchers, 
contact  the primary researcher, Dr. Mary Paine, by phone (509-358-7759), e-mail 
(mary.paine@wsu.edu), or regular mail (WSU College of Pharmacy and Pharmaceutical 
Sciences; 412 E Spokane Falls Blvd, PBS 341; Spokane, WA 99202-2131). To withdraw 
your previously collected data from the study, you must contact the primary researcher by 
e-mail or regular mail within 10 days of the incident, requesting that your collected data be 
withdrawn from the study.  
  
What are my rights as a research study volunteer? 
Your participation in this research study is completely voluntary. You may choose not to be 
a part of this study. There will be no penalty to you if you choose not to take part. You may 
choose not to answer specific questions or to stop participating at any time. You will be given 
a copy of the consent form for your records. 
 
What does my signature on this consent form mean? 
Your signature on this form means that: 


Date: 02/12/2020 
IRB Ver. 2/2019 
Version No.: 3 
 
 
Page 12 of 12 
 
• You understand the information given to you in this form 
• You have been able to ask the researcher questions and state any concerns 
• The researcher has responded to your questions and concerns 
• You believe you understand the research study and the potential benefits and risks 
that are involved 
• You are giving your voluntary consent to take part in the study 
 
Statement of Consent 
Yes, 
I agree 
No, 
I disagree 
The researcher may retain any leftover blood or tissue samples 
taken during the study. These samples may be used for other 
research not related to this study. These samples will be 
retained in de-identified form, meaning that there will be no 
information associated with the blood or samples that will allow 
anyone to readily ascertain my identity. I will not be re-
contacted for permission to use the samples. 
 
 
 
 
 
 
 
 
 
Your signature documents your permission to take part in this research.  You will be provided 
a copy of this signed document. 
 
___________________________________________ 
_____________________ 
Signature of Participant 
Date 
 
___________________________________________ 
Printed Name of Participant 
 
____________________________________________          _____________________ 
Signature of Person Obtaining Consent               
Date 
 
____________________________________________ 
Printed Name of Person Obtaining Consent 
 
Statement Confirming Driver Availability  
I confirm that a driver will be available to take me home after I am discharged from all of 
the inpatient study days.  
___________________________________________ 
_____________________ 
Signature of Participant 
Date 
 
___________________________________________ 
Printed Name of Participant