Assessing the Pharmacokinetics and Drug Interaction Liability of Kratom, an Opioid-like Natural Product
Condition: Interaction Drug Food
Study type: Interventional
Phase: Early Phase 1

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.
    

Intervention name(s): Midazolam HCl; Dextromethorphan HBr; Kratom
Intervention type(s): Drug; Drug; Dietary Supplement
Intervention description(s): Oral syrup, 2 mg/mL; Oral liquid capsules, 15 mg; 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 MeSH terms: Midazolam; Dextromethorphan
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Pharmacokinetics; Kratom; Mitragynine; Midazolam; Dextromethorphan; Natural product