Kratom (Mitragyna speciosa): Recent advances in understanding the chemistry, pharmacology, and human uses

Mitragyna speciosa Korth (Rubiaceae) is a tree that was first identified in Southeast Asia where the borders of Thailand and Malaysia meet. The leaves are the origin of the ethnopharmacological preparation “kratom”. Traditional use involves decoction of the leaves and has paradoxical effects that include a coca-like stimulant as well opium-like depressant actions. Traditionally, the plant extract has been used as an opium substitute, and it has been clinically used in Thailand to wean addicts off opiates. Much attention has been drawn to this recently due to the exponential increases of users in the Western world where some harm has been reported. For centuries kratom has been used to increase mood, stamina, energy, and decrease anxiety and pain. The historical use of kratom to prevent withdrawal and ween users from opioids is of great relevance to the current global opioid crisis. As kratom use has steadily increased in the United States (US), reports of adverse events have risen. It is estimated that >15 million US individuals consume kratom products. Poison control center calls mentioning kratom totaled 682 in 2017. This number of kratom incidents is small when put in context with other analgesics, sedatives, and antidepressants which resulted in 334,729 calls in 2019. Nonetheless, there has been increased scrutiny around the opioid nature of kratom.

From our conducted studies, supported by two (2) large grants from the National Institute on Drug Abuse (totaling $11,535,437), we conclude that kratom has low abuse liability when it is utilized in its pure leaf/plant material form. We believe issues arise from concentrated extracts and other formulations that utilize dried or cured leaf materials. The abuse liability in these products is most likely due to the varying concentrations of one alkaloid, 7-hydroxymitragynine (7OHMG). We have not detected this alkaloid in freshly harvested leaf material or freshly prepared traditional teas in SE Asia. As part of our research, we monitor products in the US marketplace and over the past decade, the presence of 7OHMG has been decreasing to low or non-detectable levels in many products. This is a result of the published science around 7OHMG from our team as well as other kratom researchers. 7OHMG is a potent mu opioid receptor agonist with abuse potential. It is a metabolite or decomposition product of the major alkaloid, mitragynine (MG). We, and others, have shown that MG has no abuse potential and has a unique pharmacology involving several neurotransmitter systems. In fact, alkaloids in kratom interact with the adrenergic and serotonergic systems to a greater extent than opioid systems. This polypharmacology renders kratom unique from other opioids and to label kratom an opioid is scientifically and factually incorrect. MG and lyophilized kratom tea can reduce opioid withdrawal symptoms in opioid dependent subjects.

Two reports in the literature demonstrate the ability of MG to block self-administration of opioids in animals. We have reconfirmed through a more extensive study that is not yet published. In 2016, the US determined further research was needed before a ban. That research has exponentially increased to the point of FDA sanctioned human clinical trials where results are pending. In October 2021, the 44th Expert Committee (ECDD) on Drug Dependency of the World Health Organization convened to determine if kratom should undergo ‘critical review’ for an International ban. The ECDD determined that there was inadequate evidence to recommend a critical review and kratom will be kept under surveillance.