Clinical Characterization of Kratom: Is it a Craze or Here to Stay?

Kratom (Mitragyna speciosa) is a tree native to Southeast Asia, the leaves of which have traditionally been consumed for their reported therapeutic effects.[1] The pharmacology of kratom is complex, with >40 known alkaloids, including four which act as partial agonists at mu opioid receptors.[2] One such alkaloid, mitragynine, is increasingly studied by preclinical researchers, as it has been shown to bind to mu, delta, and kappa opioid receptors, serotonin receptors, dopamine receptors, and adrenergic receptors to produce dose-dependent stimulant, analgesic, and anxiolytic effects.[2,3] Preliminary work suggests that mitragynine and other alkaloids may have therapeutic potential with less risk, yet more work is needed to understand mechanisms of action for each alkaloid. Since 2005, kratom use has dramatically increased in the West, as have online advertisements and social media framing kratom as a safe, nonaddictive alternative to traditional opioids, including as a method to self-treat pain, psychiatric, and substance use disorder symptoms, as well as for recreation and relaxation.[3,4] Amidst the current opioid crisis, people with opioid dependence or use disorder (OUD) have started using kratom to mitigate withdrawal or as an opioid substitute.[4] However, clinicians may not be aware of their patients’ kratom use, or may be unfamiliar with the pharmacology, risks, and benefits of kratom. This is problematic because kratom use is not risk-free and has even been associated with physical dependence and disordered use.[3,5] Although several addiction clinicians have anecdotally reported using buprenorphine to treat kratom dependence and withdrawal,[5] there are no standard guidelines for assessing or treating patients’ problems that have developed from use. This focus session will provide a thorough synthesis of the current state of knowledge about kratom, providing clinicians with information critical to clinical assessment and decision-making on kratom. Our overview will enable clinicians to feel comfortable identifying, diagnosing, and treating patients who use kratom either alone or in combination with other substances. We will first provide a definition, history, and overview of kratom, followed by a discussion of the epidemiology of kratom use in Western countries. Next, we will discuss the pharmacology of the kratom alkaloid mitragynine, the most predominant and best-studied of the kratom alkaloids. A pharmacodynamic analysis of several lines of evidence supporting kratom’s opioid properties, including in silico, in vitro, and in vivo studies in animals, as well as human surveys and case reports, will be provided. Evidence in favor of kratom’s other pharmacological activities, including serotonergic and adrenergic activity, will also be reviewed. The known pharmacokinetics of kratom, particularly its interactions with cytochrome P450 enzymes and efflux transporter proteins such as P-glycoprotein, will also be discussed. The final portion of our session will detail the clinical presentation of kratom toxicity and kratom use disorder, drawing from limited available data on treatment of these issues. Throughout the session, case examples from the literature and from our collective practice experience will be provided to engage attendees, helping to illustrate, clarify, and emphasize key points critical to understanding kratom.