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

NCT04392011 | Completed Early Phase 1 Results DMC FDA Drug

• 2 other identifiers: 17823U54AT008909
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Interaction Drug Food

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Midazolam Area Under the Concentration vs. Time Curve (AUC)

  Area under the plasma concentration time curve (AUC) of midazolam

  0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72 , 96, 120, and 144 hours

Secondary Outcomes (6)

• Dextromethorphan Area Under the Concentration vs. Time Curve (AUC)

  0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96, 120, and 144 hours

• Mitragynine Area Under the Concentration vs. Time Curve (AUC)

  0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96, and 120 hours

• Midazolam and Dextromethorphan Cmax

  0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96,120, and 144 hours

• Mitragynine Cmax

  0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96, and 120 hours

• Midazolam and Dextromethorphan Half-life

  0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96,120, and 144 hours

Study Arms (2)

Arm 1

EXPERIMENTAL

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.

Dietary Supplement: Kratom

Arm 2

EXPERIMENTAL

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.

Drug: Midazolam HCl; Drug: Dextromethorphan HBr; Dietary Supplement: Kratom

Interventions

Midazolam HCl DRUG

Oral syrup, 2 mg/mL

Arm 2

Dextromethorphan HBr DRUG

Oral liquid capsules, 15 mg

Arm 2

Kratom 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 1; Arm 2

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington State University: lead
• National Center for Complementary and Integrative Health (NCCIH): collaborator

Study Sites (1)

Washington State University College of Pharmacy and Pharmaceutical Sciences

Spokane, Washington, 99202, United States

Location

Related Publications (1)

• 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.

  PMID: 30786220 BACKGROUND

MeSH Terms

Interventions

Midazolam; Dextromethorphan; mitragynine

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Mary Paine
• Organization: Washington State University

mary.paine@wsu.edu

509-358-7759

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: May 13, 2020
• First Posted: May 18, 2020
• Study Start: October 9, 2019
• Primary Completion: August 31, 2021
• Study Completion: August 31, 2021
• Last Updated: December 20, 2023
• Results First Posted: June 8, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)