Evaluating kratom using a human drug development methodology

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Project Summary This R01 study will evaluate the safety, tolerability, and human abuse potential (HAP) of a well-characterized whole leaf formulation of Mitragyna speciosa (“kratom”) in healthy adults. Kratom is a botanical indigenous to Asia and predominantly legal in the US. This proposed study is essential as commercial kratom use grows and as there are increasing indicators of the therapeutic potential for some kratom alkaloids. To date, there are no published clinical data on the safety and HAP of kratom which could be used to inform our understanding of relative risk or drug development pathways. Kratom leaves have over 40 bioactive alkaloids with opioidergic, adrenergic, and serotonergic activity, which results in analgesic and stimulatory effects. Our prior research with experienced kratom users found euphoria, analgesia, and increased energy/alertness following kratom use along with additional HAP indictors of drug “liking” and “wanting.” Self-report suggests that whole leaf kratom doses between 0.5-10g produce acute effects that are well tolerated among chronic consumers; this has not been demonstrated in controlled clinical studies using healthy adults and a standardized formulation. Likewise, the HAP of a standardized kratom product has not been determined, nor has there been a comprehensive characterization of kratom’s pharmacokinetics (PK) and pharmacodynamics (PD). This R01 will fill critical public health and scientific gaps through two projects: Project 1 will be a triple-blind, randomized, between- subject single ascending dose evaluation of kratom to determine the safety/tolerability of a well-characterized whole leaf kratom product. Eighty-eight (44 men/44 women) healthy adults across 11 cohorts will be randomized to receive an active kratom dose between 0.5g to 10g. A-priori go/no-go criteria will determine dose escalation; a low and high well tolerated dose will be selected, with contingency plans for dose selection in place. Project 2 will be a triple-blind, placebo-controlled, within-subject evaluation of the low and high dose of kratom (determined by Project 1) relative to a prototypic opioid and stimulant. Outcomes will be a HAP and PK/PD characterization. Forty healthy adults (20 men/20 women) will complete 5 randomized outpatient sessions, where they will orally ingest capsules of either: placebo, active kratom low dose, active kratom high dose, oxycodone (10mg; opioid comparator), or methylphenidate (20mg; stimulant comparator). Outcomes will include HAP, PD (physiological and subjective drug effect ratings, cognitive assessments), and PK. This R01 will be conducted by an interdisciplinary team with extensive substantive knowledge on kratom, and the methodological skills needed for achieving all aims. This would be the first NIH-funded study to examine the safety, tolerability, and HAP of kratom in humans and the first large-scale study to sensitively characterize kratom PK/PD. Findings have immediate public health value as they articulate an empirically derived safe dose and provide a relative risk profile of kratom’s HAP that we currently lack. They will also serve as a foundation for future studies investigating therapeutic potential of isolated kratom alkaloids, beginning with mitragynine.