Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers
Nur Aziah Hanapi†, Nelson Jeng-Yeou Chear†, Juzaili Azizi† and Siti R. Yusof*†
Centre for Drug Research, Universiti Sains Malaysia, Minden, Malaysia
Parallel to the growing use of kratom, there is a wealth of evidence from self-report, preclinical, and early clinical studies on therapeutic benefits of its alkaloids in particular for treating pain, managing substance use disorder, and coping with emotional or mental health conditions. On the other hand, there are also reports on potential health risks concerning kratom use. These two aspects are often discussed in reviews on kratom. Here, we aim to highlight specific areas that are of importance to give insights into the mechanistic of kratom alkaloids pharmacological actions. This includes their interactions with drug-metabolizing enzymes and predictions of clinical drug-drug interactions, receptor-binding properties, interactions with cellular barriers in regards to barrier permeability, involvement of membrane transporters, and alteration of barrier function when exposed to the alkaloids.
1 Introduction
Kratom (Mitragyna speciosa Korth.) use in the traditional settings in Southeast Asian countries particularly Malaysia and Thailand to treat minor ailments and to increase work endurance among manual laborers is not new. Reports on the use of kratom as a substitute for opium in Malaya have been published as early as in the 1930s (Burkill and Haniff, 1930; Burkill, 1935). Now, kratom use has spread to the West particularly in the United States of which kratom products are widely marketed online (Williams and Nikitin, 2020). Reasons for kratom use in the States include to self-treat acute and chronic pain, to reduce or abstain from using non-prescription opioids and/or heroin, and to a lesser extent as a substitute for the drugs, and to cope with emotional or mental health conditions such as anxiety, depression and post-traumatic stress disorder (Grundmann, 2017; Smith and Lawson 2017; Smith et al., 2021). The increasing use of kratom which is no longer limited to Southeast Asian countries has sparked many interests within the scientific community to investigate the therapeutic potential of the plant and possible health risks. A breadth of evidence is available on pharmacological actions of kratom preparations and alkaloids, primarily central actions of mitragynine and 7-hydroxymitragynine. Apart from the two most studied alkaloids, there is a growing number of other alkaloids being reported and to date, approximately 45 alkaloids were identified in kratom (Ramanathan et al., 2021). Chemical structures of kratom alkaloids which are discussed in the later sections of this review are shown in Figure 1. Findings from preclinical studies, for example, antinociceptive activity to some extent corroborated with data from self-report studies of which among the reasons for kratom use is to manage pain, further supported by the recent randomized controlled study in humans (Vicknasingam et al., 2020). This also seems to be the case for use of kratom to alleviate opioid withdrawal (Hassan et al., 2020) and to relieve anxiety (Hazim et al., 2014). Further investigations at the cellular and molecular level aid to gain an understanding of the mechanistic of kratom alkaloids actions.
