![]() ![]() 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. 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. 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. 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. 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. 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. In October 2017, the opioid crisis was declared a public health emergency. More than one-third of the calls reported combined use of kratom with other substances, including opioids and benzodiazepines. Two psychoactive constituents of the kratom leaf, mitragynine and 7- hydroxymitragynine, are believed to contribute to these effects.Ĭalls to poison control centers in the United States involving kratom exposures increased from 2011 to 2017 by 52-fold. 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. Kratom (Mitragyna speciosa) is a tree native to Southeast Asia that produces constituents with opioid-like effects. 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. Many patient groups often supplement their drug regimens with herbal and other natural products (NPs), raising concern for adverse NP-drug interactions. ![]() Condition or diseaseĭrug: Midazolam HCl Drug: Dextromethorphan HBr Dietary Supplement: Kratom 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. 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. Thus, co-consumption of kratom products with drugs metabolized by CYP2D6 and CYP3A4 could increase the risk of serious adverse effects. These enzymes are responsible for metabolizing more than 50% of marketed drugs, including several opioids, benzodiazepines, and antidepressants. 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. Kratom products include pills, extracts, and powders, most of which contain two primary psychoactive constituents: mitragynine and 7-hydroxymitragynine. Kratom is commonly used to self-treat withdrawal symptoms associated with opioid addiction, as well as pain. Kratom is a botanical natural product that has opioid-like effects. Why Should I Register and Submit Results?.
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