Mitragynine reduces methamphetamine self-administration in rats without disrupting food-maintained responding

Kratom (Mitragyna speciosa), a plant native to Southeast Asia, has become popular in the United States for its reported ability to treat substance use disorders (SUD). Mitragynine (MG) is the most abundant alkaloid found in kratom.

The present studies evaluated whether MG decreases methamphetamine self-administration under both fixed-ratio (FR) and progressive-ratio (PR) schedules. In a separate cohort we examined whether MG would alter food-maintained responding.

Three separate experiments were conducted in male and female adult Sprague-Dawley rats. In Experiment 1, rats self-administered methamphetamine (0.032 mg/kg/infusion, intravenous) under a fixed-ratio (FR) schedule. In Experiment 2, a separate group received food pellets under a FR schedule. In Experiment 3, a different group received methamphetamine (0.032 mg/kg/infusion) under a progressive-ratio (PR) schedule. In all experiments rats received pretreatment with MG (10-56 mg/kg, intraperitoneal) or vehicle 30 min before testing. Behavioral measures included active and inactive lever presses, response rates, and in the case of PR, breakpoints.

MG dose-dependently reduced methamphetamine delivery under both the FR and PR schedules, with significant decreases in active lever presses, and breakpoints at 32 and 56 mg/kg. Effects were generally comparable in males and females, without significant sex × treatment interaction detected.

MG decreased methamphetamine-maintained responding at doses that did not affect food-maintained responding, indicating a selective effect on methamphetamine reinforcement relative to natural reward. These findings identify MG as a compound with robust effects on methamphetamine-maintained behavior and support its continued evaluation in preclinical models of methamphetamine use disorder.