Decoding kratom: molecular mechanisms and epigenetic factors in use and dependence

Kratom (Mitragyna speciosa) is a traditional Southeast Asian botanical long used for alleviating pain and boosting energy. Its chief bioactive compound, mitragynine (MG), exhibits both opioid-like and stimulant properties and has prompted interest in its potential role in pain management and opioid withdrawal support. However, its safety profile and underlying mechanisms remain incompletely understood. This systematic review critically synthesizes preclinical evidence on kratom's molecular, pharmacological, and epigenetic effects. Guided by PRISMA 2020 criteria, studies indexed in Scopus and Web of Science (2000-2024) were analyzed, focusing on receptor activity, intracellular signaling, and gene regulation in in vitro and in vivo models. Among 20 eligible studies, key findings indicate that kratom alkaloids engage μ-opioid, adrenergic, and serotonergic receptors; modulate dopaminergic and glutamatergic systems; and exert anti-inflammatory and analgesic effects. Under chronic exposure followed by withdrawal, MG was associated with reduced histone acetylation and increased HDAC2 expression, while Rab35 emerged as a potential withdrawal-associated biomarker. MG also inhibited cardiac ion channels and altered CYP450 enzyme expression, highlighting safety concerns related to cardiotoxicity and drug-drug interactions. Despite these mechanistic insights, limitations in pharmacokinetic data, standardized dosing, and long-term safety preclude clinical application. Future research should prioritize controlled human studies, omics-driven biomarker discovery, and evidence-based regulatory evaluation to clarify kratom's therapeutic potential and risk profile.