Abuse liability and therapeutic potential of the Mitragyna speciosa (kratom) alkaloids mitragynine and 7‐hydroxymitragynine

Abstract

Kratom, derived from the plant Mitragyna speciosa, is receiving increased attention as an alternative to traditional opiates and as a replacement therapy for opiate dependence. Mitragynine (MG) and 7-hydroxymitragynine (7-HMG) are major psychoactive constituents of kratom. While MG and 7-HMG share behavioral and analgesic properties with morphine, their reinforcing effects have not been examined to date. 7-HMG, but not MG, substituted for morphine self-administration in a dose-dependent manner in the rat self-administration paradigm. Following the substitution procedure, re-assessment of morphine self-administration revealed a significant increase following 7-HMG and a significant decrease following MG substitution. In a separate cohort, 7-HMG, but not MG, engendered and maintained intravenous self-administration in a dose-dependent manner. The effects of pretreatment with nalxonaxine (NLXZ), a μ1 opiate receptor antagonist, and naltrindole (NTI), a δ opiate receptor antagonist, on 7-HMG and morphine self-administration were also examined. Both NLXZ and NTI reduced 7-HMG self-administration, whereas only NLXZ decreased morphine intake. The present results are the first to demonstrate that 7-HMG is readily self-administered, and the reinforcing effects of 7-HMG are mediated in part by μ and δ opiate receptors. In addition, prior exposure to 7-HMG increased subsequent morphine intake whereas prior exposure to MG decreased morphine intake. The present findings indicate that MG does not have abuse potential and reduces morphine intake, desired characteristics of candidate pharmacotherapies for opiate addiction and withdrawal, whereas 7-HMG should be considered a kratom constituent with high abuse potential that may also increase the intake of other opiates.

Evaluating kratom alkaloids using PHASE

“…This is particularly concerning as there are no published clinical studies that describe the results of kratom administration for any of these therapeutic purposes. While animal models have indicated that the main component of kratom, mitragynine, has a low abuse potential [7,8], mitragynine may be metabolized into 7-hydroxymitragynine [9], a component of kratom with demonstrated abuse potential and drug dependency [10,11], exhibited analgesic effects that exceed the potency of morphine [12], and is a suspected adulterant of commercial kratom products [13].…”

Simultaneous quantification of ten key Kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra‐performance liquid chromatography−tandem mass spectrometry

“…In addition, mitragynine exhibits polypharmacology in that it interacts with multiple central nervous system (CNS) drug targets . Thus, given these unique pharmacological mechanisms of action, mitragynine is considered an “atypical opioid.” Importantly, mitragynine has recently been reported to reduce morphine or heroin self‐administration without any abuse or addiction potential in rodent models . However, a minor, but potent μ‐opioid receptor agonist kratom alkaloid, 7‐hydroxymitragynine, exerts actions through β‐arrestin‐2 mediated pathways and produces tolerance and cross‐tolerance to morphine, in addition to physical dependence, which most likely contributes to the liabilities associated with kratom use .…”

“…Thus, given these unique pharmacological mechanisms of action, mitragynine is considered an “atypical opioid.” Importantly, mitragynine has recently been reported to reduce morphine or heroin self‐administration without any abuse or addiction potential in rodent models . However, a minor, but potent μ‐opioid receptor agonist kratom alkaloid, 7‐hydroxymitragynine, exerts actions through β‐arrestin‐2 mediated pathways and produces tolerance and cross‐tolerance to morphine, in addition to physical dependence, which most likely contributes to the liabilities associated with kratom use . Interestingly, another minor kratom alkaloid, corynantheidine, acts as a functional antagonist at μ‐opioid receptor and can reverse morphine‐induced inhibition of twitch contraction in pig ileum .…”

“…16,17 However, a minor, but potent μ-opioid receptor agonist kratom alkaloid, 7-hydroxymitragynine, exerts actions FIGURE 1 Chemical structures of kratom alkaloids through β-arrestin-2 mediated pathways and produces tolerance and cross-tolerance to morphine, in addition to physical dependence, which most likely contributes to the liabilities associated with kratom use. 15,16 Interestingly, another minor kratom alkaloid, corynantheidine, acts as a functional antagonist at μ-opioid receptor and can reverse morphineinduced inhibition of twitch contraction in pig ileum. [18][19][20] Variance in the composition of alkaloids in kratom products, where there would be multiple alkaloids present including functional antagonist (corynantheidine) with partial (mitragynine) or full agonist (7hydroxymitragynine), could potentially affect the μ-opioid receptor mediated therapeutic outcomes.…”

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

“…[86] Mitragynine (85, Scheme 8), an indole alkaloid found in Kratom (Mitragyna spe-ciose korth), is am u-opioid agonist that hasr eceived attention as as afea lternative to traditional opiates (e.g.,m orphine) and as ar eplacement therapy for opiate dependence. [91][92][93][94][95][96] In addition, iboga root extracts were found to alleviateo piate withdrawals ymptoms, [97,98] whichh as initiated work to use iboga as at reatment for addiction. [99] Ibogaine (99,S cheme 9) is the active pharmacological substance of the iboga root and shares tryptophan/isoprenoid biosynthetic origins with all other monoterpenoid indole alkaloids.…”