Abuse liability of mitragynine assessed with a self-administration procedure in rats
Substantial use of the plant kratom for psychoactive effects has driven interest in its abuse liability. Several place conditioning studies suggest abuse liability of the active ingredient mitragynine, though studies of its self-administration have not been published.
Binding of mitragynine to rat brain mu, kappa, and delta opioid receptors was compared to that for heroin and morphine. Self-administration of mitragynine, heroin, methamphetamine, or saline was assessed during single-session substitutions in rats trained to self-administer methamphetamine (0.022 mg/kg/injection, i.v.) during 1-h daily sessions.
Mitragynine had > 2- or ~ 16-fold greater affinity for the mu opioid receptor than, respectively, for kappa or delta opioid receptors. Its affinity for the mu receptor was ~ 200-fold less than that for morphine. In rats trained to self-administer methamphetamine, saline substitutions significantly decreased the number of responses, whereas different doses of methamphetamine (0.002–0.068 mg/kg/injection) or heroin (0.001–0.03 mg/kg/injection) maintained self-administration with maximal responding at 0.022 or 0.01 mg/kg/injection, respectively. In contrast, no dose of mitragynine maintained response rates greater than those obtained with saline. Presession mitragynine treatment (0.1 to 3.0 mg/kg) decreased response rates maintained by heroin but had little effect on responding maintained by methamphetamine across the same range of doses.
These results suggest a limited abuse liability of mitragynine and potential for mitragynine treatment to specifically reduce opioid abuse. With the current prevalence of opioid abuse and misuse, it appears currently that mitragynine is deserving of more extensive exploration for its development or that of an analog as a medical treatment for opioid abuse.
KeywordsMitragynine Kratom Abuse liability Self-administration Methamphetamine Heroin Medical treatments Opioid abuse Rats
We thank Drs. Christopher R. McCurdy for the initial advice on mitragynine and James H. Woods for the advice on the writing of this report.
This project was funded by the National Natural Science Foundation of China (81302762) and the National Institute on Drug Abuse, Intramural Research Program. These studies were initiated at NIDA when Kai Yue was funded by a scholarship from the China Scholarship Council (CSC), a non-profit institution affiliated with the Ministry of Education of the P.R. China, Level 13, Building A3, No. 9 Chegongzhuang Avenue, Beijing 100044, P. R. China.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Cheaha D, Reakkamnuan C, Nukitram J, Chittrakarn S, Phukpattaranont P, Keawpradub N, Kumarnsit E (2017) Effects of alkaloid-rich extract from Mitragyna speciosa (Korth) Havil on naloxone-precipitated morphine withdrawal symptoms and local field potential in the nucleus accumbens of mice. J Ethnopharmacol 208:129–137CrossRefGoogle Scholar
- Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant (KI) and the concentration which causes 50% inhibition of an enzymatic reaction. Biochem Pharmacol 22:403–411Google Scholar
- Harrigan SE, Downs DA (1978) Continuous intravenous naltrexone effects on morphine selfadministration in rhesus monkeys. J Pharmacol Exp Ther 204: 481–486Google Scholar
- Hemby SE, Mcintosh S, Cutler SJ, McCurdy CR (2018) Abuse liability of mitragynine and 7-hydroxymitragynine putative primary alkaloids of Mitragyna speciosa (kratom). Soc Neurosci Abstr 794:21Google Scholar
- Himmelsbach CK (1941) The effects of certain chemical changes on the addiction characteristics of drugs of the morphine, codeine series. J Pharmacol Exp Ther 71:41–48Google Scholar
- Kai Y, Ma B, Chen L, Tian X, Ru Q, Gan Y, Wang D, Jin G, Li C (2014) l-Stepholidine, a naturally occurring dopamine D1 receptor agonist and D2 receptor antagonist, attenuates heroin self-administration and cue-induced reinstatement in rats. Neuroreport 25:7–11Google Scholar
- US Drug Enforcement Administration (2016) Schedules of controlled substances: placement of mitragynine and 7-Hydroxymitragynine into schedule I. Federal Register. https://www.federalregister.gov/documents/2016/08/31/2016-20803/schedules-of-controlledsubstances-temporary-placement-of-mitragynine-and-7-hydroxymitragynine-into. Accessed 10 April 2017
- Váradi A, Marrone GF, Palmer TC, Narayan A, Szabó MR, Le Rouzic V, Grinnell SG, Subrath JJ, Warner E, Kalra S, Hunkele A (2016) Mitragynine/Corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism, which do not recruit β-Arrestin-2. J Med Chem 59:8381–8397CrossRefGoogle Scholar
- Way EL, Young JM, Kemp JW (1965) Metabolism of heroin and its pharmacologic implications. Bull Narc 17:25–33Google Scholar