Mitragynine, a primary constituent of kratom reinstates morphine-seeking behaviour in rats

Abstract

Mitragynine (MG) is a pharmacologically active alkaloid derived from the leaves of Mitragyna speciosa Korth (Kratom). This plant has sparked significant interest as a potential alternative treatment for managing opioid dependence and withdrawal due to its opioid-like pharmacological effects. However, whether MG exposure would trigger opioid-seeking behaviour following abstinence has not been investigated. The present study examined the effects of MG priming on morphineseeking behaviour in rats. Male Sprague-Dawley rats were initially trained to intravenously self-administer morphine (0.5 mg/kg/infusion) under a fixed ratio-3 schedule of reinforcement. Removal of both morphine infusions and drug-associated cues led to the subsequent extinction of the drug-seeking behaviour. Tests of reinstatement were made following exposure to a randomised order of intraperitoneal injections of MG (3, 10 and 30 mg/ kg), morphine (5 mg/kg) and vehicle. Significant levels of drug-seeking behaviour were observed following extended access to morphine self-administration, which was extinguished following removal of morphine and cues indicative of morphine-seeking behaviour, supporting the relapse model. The present finding demonstrated that MG priming in a dose of 10 mg/kg resulted in the reinstatement of morphine-seeking behaviour, whereas the higher MG dose (30 mg/kg) tested suppressed the seeking response. This study indicated that exposure to a low MG dose may increase the likelihood of relapsing to opioids, suggesting that the potential of MG as a treatment for opioid management merits further scientific assessment of its ability to trigger relapse to opioid abuse.

Kratom safety and toxicology in the public health context: research needs to better inform regulation

“…With the caveat that none of the above should be interpreted as supporting the conclusion that kratom should be considered a therapeutic drug by FDA's drug approval process standard, the findings do support the conclusion that many kratom consumers in the United States and globally report improved health, wellbeing, and quality-of-life from taking kratom (Grundmann et al, 2019;Sharma and McCurdy, 2021). Such human use patterns, and the preponderance of consumer self-report of efficacy, are consistent with nonhuman animal studies investigating kratom alkaloids to attenuate pain, opioid withdrawal, and other conditions (Harun et al, 2021b;Henningfield et al, 2022d;Grundmann et al, 2023). Such convergence of evidence is unsurprising given the known pharmacology of kratom alkaloids (Smith et al, 2023d).…”

“…In animals which were made physically dependent on opioids by daily opioid administration, pretreatment MG can prevent opioid withdrawal when chronic opioid administration was discontinued. Conversely, opioids that are approved by FDA for treating opioid withdrawal can treat MG withdrawal when chronic administration of MG is abruptly discontinued (Harun et al, 2020;Hassan et al, 2020;Wilson et al, 2020;Harun et al, 2021a;Hassan et al, 2021;Johari et al, 2021; See summary of earlier studies and additional discussion in Henningfield et al, 2022d;Henningfield et al, 2023).…”

Translating Kratom-Drug Interactions: From Bedside to Bench and Back

“…The ready availability of kratom products and low cost make kratom the preferred treatment of pain and opioid withdrawal symptoms among kratom users ( Coe et al, 2019 ). People often use kratom in an attempt to wean themselves from other dangerous drugs on the market, but they may relapse ( White, 2018 ; Japarin et al, 2023 ). Hence, the likelihood of concomitant use of kratom with other psychoactive substances like opioids, benzodiazepines, or antidepressants is high.…”

“…People often use kratom in an attempt to wean themselves from other dangerous drugs on the market, but they may relapse (Michael White, 2018;Japarin et al, 2022). Hence, the likelihood of concomitant use of kratom with other psychoactive substances like opioids, benzodiazepines, or antidepressants is high.…”