Kratom and Mitragynine

"The primary psychoactive alkaloid in kratom is mitragynine. This compound and its metabolite 7α-hydroxy-7 H-mitragynine are partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors. In contrasts to classical opioids, mitragynine and 7-hydroxymitragynine also bind to adrenergic (α1 and α2) and serotonergic (5-HT1A and 5-HT2B) receptors (Henningfield et al. 2024; Hiranita et al. 2022; Kruegel et al. 2016; Kruegel and Grundmann 2018; Obeng et al. 2020, 2022; Raffa et al. 2018). In regular kratom users, the estimated, daily dose of mitragynine can typically range between 75 and 435 mg divided over 3 to 4 glasses of kratom juice (Leong Abdullah et al. 2021; Singh et al. 2018). In Western countries, kratom users typically consume between three and eight grams of raw plant material (Smith et al. 2022). However, kratom products might have variable mitragynine concentrations, making it hard to estimate a typical mitragynine dose. Mitragynine’s pharmacokinetic profile has been studied in preclinical research (Ramachandram et al. 2019; Ya et al. 2019) and in humans (Huestis et al. 2024). In the latter study, 12 participants received dried kratom leaf powder capsules (500–4000 mg) containing between 6.65 and 53.2 mg of mitragynine. The median mitragynine Tmax was 1.0–1.3 h after single and 1.0–1.7 h after multiple doses; for 7-hydroxymitragynine Tmax, it was 1.2–1.8 h and 1.3–2.0 h. Steady-state mitragynine concentrations were reached in 8–9 days and 7-hydroxymitragynine within 7 days. Clinical data consistently indicate that mitragynine fits a two-compartment model when orally administered (Tanna et al. 2022; Trakulsrichai et al. 2015). Following 10–20 min, individuals may experience initial euphoric effects, which are reported to reach their peak intensity within 0.5–1 h, and can last 5 to 7 h (Prozialeck et al. 2012; Rosenbaum et al. 2012; Scott et al. 2014; Warner et al. 2016). Knowledge of adverse effects of kratom is scarce and mainly comes from user reports on drug fora and case reports that have suggested risks of dependence, withdrawal, cardiorespiratory problems, and kidney and liver injury (Alsarraf et al. 2019; Corkery et al. 2019; Peran et al. 2023; Schimmel and Dart 2020). However case reports often lack thoroughness because they may not provide a full assessment of the patient’s kratom use (Feldman et al. 2023). Systematic reviews of case reports (Smith et al. 2023b) and in-depth interviews (Smith et al. 2023a) with chronic kratom users confirmed risk of dependence, while the latter also identified feelings of jitter at high doses.

"To our knowledge, little comprehensive research has been conducted to evaluate the acute effects of mitragynine on measures of safety and neurocognition in healthy volunteers. A recent observational study in 10 chronic kratom users revealed only minor changes in vital signs and mild increments of euphoria after self-administration of 5.16 g (on average) of kratom leave powder (Smith et al. 2024b). Self-reported (n = 357) and simulated driving reports (n = 10) have suggested that kratom effects at self-selected doses among regular kratom consumers do not produce significant changes in subjective and objective measures of driving impairment (Zamarripa et al. 2024). However, systematic, controlled studies with mitragynine are presently missing."