Chronic mitragynine (kratom) enhances punishment resistance in natural reward seeking and impairs place learning in mice

Abstract

Kratom (Mitragyna speciosa) is a widely abused herbal drug preparation in Southeast Asia. It is often consumed as a substitute for heroin, but imposing itself unknown harms and addictive burdens. Mitragynine is the major psychostimulant constituent of kratom that has recently been reported to induce morphine-like behavioural and cognitive effects in rodents. The effects of chronic consumption on non-drug related behaviours are still unclear. In the present study, we investigated the effects of chronic mitragynine treatment on spontaneous activity, reward-related behaviour and cognition in mice in an IntelliCage® system, and compared them with those of morphine and Δ-9-tetrahydrocannabinol (THC). We found that chronic mitragynine treatment significantly potentiated horizontal exploratory activity. It enhanced spontaneous sucrose preference and also its persistence when the preference had aversive consequences. Furthermore, mitragynine impaired place learning and its reversal. Thereby, mitragynine effects closely resembled that of morphine and THC sensitisation. These findings suggest that chronic mitragynine exposure enhances spontaneous locomotor activity and the preference for natural rewards, but impairs learning and memory. These findings confirm pleiotropic effects of mitragynine (kratom) on human lifestyle, but may also support the recognition of the drug's harm potential.

Changing trends in the use of kratom (Mitragyna speciosa) in Southeast Asia

“…There have been different studies linking M.speciosa preparation and mitragynine administration with elevated blood pressure, hepatotoxicity, and nephrotoxicity effects in rats (Harizal, Mansor, Hasnan, Tharakan, & Abdullah, 2010). Impaired cognitive behavioural function (Apryani, Hidayat, Moklas, Fakurazi, & Idayu, 2010;Ismail, Jayabalan, Mansor, Müller, & Muzaimi, 2017;Yusoff et al, 2014), unpleasant withdrawal symptoms (Yusoff et al, 2014), and toxicity and mortality incidences have been reported in humans (Singh et al, 2016).…”

“…Acute administration of mitragynine produces anxiolytic-like effects attributed to the interactions among opioidergic receptor systems (Hazim, Ramanathan, Parthasarathy, & Muzaimi, 2014). Findings from animal studies have indicated that M.speciosa is toxic and may cause lethal effects at higher doses (Hassan et al, 2013;Ismail et al, 2017). Recent findings from a Poison Centre in Thailand recorded 52 kratom exposure cases that were reported to the Centre's surveillance system from 2005 to 2009.…”

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

“…; Ismail et al . ). Moreover, MG and 7‐HMG fully generalize to the discriminative stimulus effects of morphine, suggesting the potential for abuse (Harun et al, ).…”

Healthcare Provider’s Guide to Kratom: Succinct Introduction to the Basics and the Questions

“…Concern of potential abuse is expressed because low doses act as a stimulant and therefore might pose the risk of a milder version of the stimulation produced by amphetamines or cocaine, and higher doses produce more sedative effects, possibly posing the risk of a milder version of opioids [56][57][58]. In some preclinical studies, mitragynine has been reported to be mildly rewarding, or to impair learning and memory [51,59,60]. But recent studies have shown that mitragynine is not self-administered by rats [61,62].…”