Assessing the Pharmacokinetics and Drug Interaction Liability of Kratom, an Opioid-like Natural Product

NCT ID: NCT04392011

Last Updated: 2023-12-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-09
• Study Completion Date: 2021-08-31

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.

Conditions

Interaction Drug Food

Keywords

Pharmacokinetics; Kratom; Mitragynine; Midazolam; Dextromethorphan; Natural product

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Kratom

Intervention Type: DIETARY_SUPPLEMENT

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.

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.

Group Type: EXPERIMENTAL

Midazolam HCl

Intervention Type: DRUG

Oral syrup, 2 mg/mL

Dextromethorphan HBr

Intervention Type: DRUG

Oral liquid capsules, 15 mg

Kratom

Intervention Type: DIETARY_SUPPLEMENT

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.

Interventions

Midazolam HCl

Oral syrup, 2 mg/mL

Intervention Type: DRUG

Dextromethorphan HBr

Oral liquid capsules, 15 mg

Intervention Type: DRUG

Kratom

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.

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

Inclusion Criteria

• 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, including kratom, 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 but willing to abstain for several weeks)
• 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

Exclusion Criteria

• Men and women under the age of 18 or over the age of 55
• Unwilling to abstain from kratom for several weeks
• 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
• 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 dextromethorphan, midazolam, or related drugs
• Have a history of intolerance or allergy to kratom or opioids
• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Center for Complementary and Integrative Health (NCCIH)

NIH

Sponsor Role: collaborator

Washington State University

OTHER

Sponsor Role: lead

Responsible Party

Mary Paine

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Washington State University College of Pharmacy and Pharmaceutical Sciences

Spokane, Washington, United States

Countries

United States

References

Post S, Spiller HA, Chounthirath T, Smith GA. Kratom exposures reported to United States poison control centers: 2011-2017. Clin Toxicol (Phila). 2019 Oct;57(10):847-854. doi: 10.1080/15563650.2019.1569236. Epub 2019 Feb 20.

Reference Type: BACKGROUND

PMID: 30786220 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

U54AT008909

Identifier Type: NIH

Identifier Source: secondary_id

View Link

17823

Identifier Type: -

Identifier Source: org_study_id