Kratom and Treatment for Alcohol Use Disorder

"Over the past decade, kratom has been reported as a source for naturally occurring, G-protein–biased opioidergic alkaloids, and has been investigated for its effects on pain management (Matsumoto et al., 2004; Kruegel et al., 2019; Chakraborty et al., 2021b; Chakraborty and Majumdar, 2021), opioid withdrawal (Wilson et al., 2020, 2021), and alcohol abuse (Gutridge et al., 2020) as well as its decreased reward profile relative to traditional opioids (Hemby et al., 2019; Wilson et al., 2021). Here, we further probed the effects of kratom alkaloids and synthetic kratom alkaloid derivatives to obtain a better understanding of its in vivo pharmacology and in search of novel treatment options for alcohol use disorder. We report 7-hydroxyspeciogynine as an effective lead compound to reduce alcohol with an MTD of at least 10 mg∙kg−1.

"We previously demonstrated that 7-hydroxymitragynine as well as paynantheine could decrease alcohol consumption (Gutridge et al., 2020). However, we were unable to obtain a MTD for 7-hydroxymitragyinine as it caused both hyperlocomotion and CPP at a 3 mg∙kg−1 dose, which was the minimal effective dose to reduce alcohol intake (Gutridge et al., 2020). It has been well-established that µOR agonism can cause CPP, and that these rewarding effects can be blocked by μOR antagonists (Negus et al., 1993; Piepponen et al., 1997) as well as μOR KO (Matthes et al., 1996). Here, we show that 7-hydroxymitragynine–induced hyperlocomotion also appears to be μOR-mediated as it is completely blocked by a dose of naloxone considered to be μOR-selective (Takemori and Portoghese, 1984; Pastor et al., 2005). Since the alcohol-reducing effect of 7-hydroxymitragynine was dependent on δORs (Gutridge et al., 2020), μOR potency may be a liability when exploring kratom alkaloids as treatment option for AUD. Paynantheine has much lower μOR potency, while retaining δOR potency and decreases alcohol intake in mice at a 10 mg∙kg−1 dose without causing hyperlocomotion (Gutridge et al., 2020). In line with the lower μOR potency, we find that 10 mg∙kg−1 paynantheine does not produce place preference in an extended CPP paradigm. In a brief CPP paradigm, however, the same dose of paynantheine induces conditioned place aversion (CPA). Kratom use can lead to seizures (Coonan and Tatum, 2021) and we noticed that at 30 mg∙kg−1, paynantheine induced minor seizure activity. It is possible that mice administered a dose of 10 mg∙kg−1 paynantheine did not feel well despite not showing overt tonic-clonic seizure activity that could contribute to the observed CPA at this dose. δOR agonism can cause seizures (Hong et al., 1998; Broom et al., 2002; Jutkiewicz et al., 2006); however, it is reported mostly for δOR agonists that are strong recruiters of β-arrestin, such as SNC80 and BW373U86 (O’Neill et al., 1997; Hong et al., 1998; Jutkiewicz et al., 2005). As such, we were not surprised that the G-protein–biased paynantheine-induced seizures were still present in δOR KO mice, indicating the seizures may be caused by an off-target interaction. Paynantheine can decrease alcohol consumption in wild-type mice (Gutridge et al., 2020); however, it also decreases alcohol consumption in δOR KO mice (Supplementary Figure S5; RM two-way ANOVA, dose: F (4, 32) = 6.407, p = 0.0007, time: F (1, 8) = 16.46, p = 0.0036, dose × time: F (4, 32) = 1.851, p = 0.1435, with Sidak’s MC (T-R vs F), p < 0.0001). This analysis provides further evidence that many of paynantheine’s in vivo effects are not mediated by δOR."