Clinical Pharmacology of the Dietary Supplement Kratom (Mitragyna speciosa)

Abstract

Kratom (Mitragyna speciosa) consists of over 40 alkaloids, with 2 of them, mitragynine and 7-OH-mitragynine (7-OH-MG) being the main psychoactive compounds. Mitragynine and 7-OH-mitragynine each target opioid receptors and have been referred to as atypical opioids. They exert their pharmacologic effects on the mu, delta, and kappa opioid receptors. In addition, they affect adrenergic, serotonergic, and dopaminergic pathways. Kratom has been touted as an inexpensive, legal alternative to standard opioid replacement therapy such as methadone and buprenorphine. Other uses for kratom include chronic pain, attaining a "legal high," and numerous central nervous system disorders, including anxiety, depression, and posttraumatic stress disorder. Kratom induces analgesia and mild euphoria, with a lower risk of respiratory depression or adverse central nervous system effects compared to traditional opioid medications. Nonetheless, kratom has been associated with both physical and psychological dependence, with some individuals experiencing classic opioid withdrawal symptoms upon abrupt cessation. Kratom use has been linked to serious adverse effects, including liver toxicity, seizures, and death. These risks are often compounded by polysubstance abuse. Further, kratom may potentiate the toxicity of coadministered medications through modulation of cytochrome P450, P-glycoprotein, and uridine diphosphate glucuronosyltransferase enzymes. In 2016, the US Drug Enforcement Administration took steps to classify kratom as a federal schedule 1 medication; however, due to public resistance, this plan was set aside. Until studies are conducted that define kratom's role in treating opioid withdrawal and/or other central nervous system conditions, kratom will likely remain available as a dietary supplement for the foreseeable future.

Kratom (Mitragyna speciosa): eine psychoaktive Pflanze mit Chancen und Risiken

“…Die Plasmaeiweißbin dung liegt bei > 90 %, bei schwacher Hemmung von PGlykoprote in [67]. Eine Modulation der UridinDiphopshatGlucoronyltrans ferase durch Kratom wurde auch beschrieben [68]. Ergebnisse von in vitro Studien (auch an humanen Zellen) fanden, dass Extrakte von Kratom starke Inhibitoren von Cytochrom P450 (CYP) 2D6 (vor allem durch Mitragynin und Corynantheidin, geringer auch Spe ciociliatein und Paynanthein [69]) und geringer auch CYP2C19 (vor allem Speciociiatin, Mitragynin und Speciogynin [69]) 3A4 sind [69][70][71], wobei in vivo Untersuchungen dazu fehlen.…”

Retrospective identification of new psychoactive substances in patient samples submitted for clinical drug analysis

“…Pharmacological classes found were stimulants (68 findings, 16 substances, in 22 patients) vastly dominated by synthetic cathinones and also represented by 3F‐phenmetrazine and ethylphenidate (the latter in the absence of methylphenidate indicating that it was not a metabolite of methylphenidate and ethanol); sedatives/hypnotics that were all benzodiazepines (44 findings, 5 substances, in 25 patients); synthetic cannabinoids (16 findings, 4 substances, in 6 patients); and potent opioids in the form of isotonitazene and four different fentanyl derivatives (13 findings, 5 substances, in 5 patients). In addition, the following substances were found: 3‐methoxy‐PCP, a dissociative hallucinogenic phencyclidine derivative 35 ; cyproheptadine, a sedating antihistamine with low abuse potential 36 but possibly self‐administered as a remedy against serotonergic, including sexual side effects of other substances 37 ; mitragynine, a stimulant at low doses but opioid‐like at high doses 38 ; and tianeptine, an atypical antidepressant with known abuse potential and opioid effects at high doses 39,40 . Of the 85 patients, 17 (20%) were positive for more than one NPS; 5 (6%) and 2 (2%) of these individuals were positive for NPS from two and three pharmacological NPS classes, respectively.…”

“…3-methoxy-PCP, a dissociative hallucinogenic phencyclidine derivative 35 ; cyproheptadine, a sedating antihistamine with low abuse potential 36 but possibly selfadministered as a remedy against serotonergic, including sexual side effects of other substances 37 ; mitragynine, a stimulant at low doses but opioid-like at high doses 38 ; and tianeptine, an atypical antidepressant with known abuse potential and opioid effects at high doses. 39,40 Of the 85 patients, 17 (20%) were positive for more than one NPS; 5 (6%) and 2 (2%) of these individuals were positive for NPS from two and three pharmacological NPS classes, respectively.…”

Natural Products for the Treatment of Drug Addiction: Narrative Review

“…Mitragynine and 7‐hydroxy mitragynine being the main phytoconstituents of kratom are atypical opioids. Each act on opioid receptors and impacts adrenergic, serotonergic, and dopaminergic pathways [85] . Several informal reports have recorded the administration of kratom preparations to attenuate opioid intake by decreasing withdrawal symptoms [86,87] .…”

“…β‐arrestin recruitment causes unfavourable central nervous system effects such as the risk of respiratory depression, sedation and constipation. These adverse effects are usually associated with traditional opioid replacement medications [85,88,89] . Mitragynine activates α‐2 adrenergic postsynaptic receptors, that regulate the decreasing pain pathways [88,90] .…”