Kratom Alkaloids: A Blueprint?

Abstract

Alkaloids from the botanical Mitragyna speciosa (commonly referred to as "kratom") interact with opioid, adrenergic, serotonergic, and other receptors to provide myriad reported effects, including analgesia, energy, improved mood, and relaxation, among others. These alkaloids are complex and unique and may serve as a blueprint for the development of novel molecules to treat various substance use disorders.

Metabolite and Molecular Characterization of Mitragyna speciosa Identifies Developmental and Genotypic Effects on Monoterpene Indole and Oxindole Alkaloid Composition

“…Speciogynine, which is a C-20 epimer of mitragynine (Scheme 1), is not an hMOR agonist like mitragynine, but demonstrated high binding affinity to serotonergic receptors, 5 while mitraciliatine, a diastereomer of mitragynine (Scheme 1), is a partial hMOR agonist similar to mitragynine. 5 These examples indicate the significance of stereochemistry in dictating the pharmaco- logical activities of kratom alkaloids and signifying the importance of polymorphisms in the ITS barcode region which correlate to varying alkaloid profiles. Ms cv 3−7 were also characterized by the presence of the oxindole alkaloid mitraphylline, which is a predominant alkaloid in cat's claw, Uncaria, species 16 in addition to several other mitragyna species, including M. parvifolia, M. hirsuta, and M. rotundifolia, but not M. speciosa.…”

“…Mitragynine and its metabolite, 7-hydroxymitragynine (7-HMG), have been shown to be responsible for kratom's analgesic and opioid withdrawal-alleviating effects. 4,5 The U.S. is amid a devastating opioid crisis that has led to more than 500,000 deaths between 1999 and 2020. 6 Recently, kratom products have gained popularity in the U.S. and Europe as alternatives for pain medications and self-treatment of opioid addiction.…”

“…13 For example, the mitragynine diastereomers speciociliatine and mitraciliatine are partial hMOR agonists. 5,14 In addition, the MIAs speciogynine and paynantheine have serotonergic activity and pharmaceutical potential as stimulants, 5,14 and the oxindole mitraphylline has demonstrated potential in regulating the plasticity of human monocytes and attenuating inflammatory responses. 15,16 However, little is known about the genetic basis underlying the accumulation of MIAs and oxindole alkaloids and their diversification in M. speciosa.…”

“…Kratom leaves have long been used ethnobotanically, either by chewing leaves or as a tea for pain relief, for combating fatigue, and to alleviate opioid withdrawal. , Kratom leaves produce over 50 monoterpene indole and oxindole alkaloids, with the major monoterpene indole alkaloid (MIA) being mitragynine (Scheme ). Mitragynine and its metabolite, 7-hydroxymitragynine (7-HMG), have been shown to be responsible for kratom’s analgesic and opioid withdrawal-alleviating effects. , The U.S. is amid a devastating opioid crisis that has led to more than 500,000 deaths between 1999 and 2020 . Recently, kratom products have gained popularity in the U.S. and Europe as alternatives for pain medications and self-treatment of opioid addiction. , Mitragynine, specifically, shows promise to be developed as a treatment for pain, opioid use disorder, and opioid withdrawal. − …”

“…Most studies focusing on the pharmacology and pharmacokinetics have been performed on these two alkaloids in animal models. ,, In addition to these, several other alkaloids produced in kratom have also been associated with varied pharmaceutical uses . For example, the mitragynine diastereomers speciociliatine and mitraciliatine are partial hMOR agonists. , In addition, the MIAs speciogynine and paynantheine have serotonergic activity and pharmaceutical potential as stimulants, , and the oxindole mitraphylline has demonstrated potential in regulating the plasticity of human monocytes and attenuating inflammatory responses. , However, little is known about the genetic basis underlying the accumulation of MIAs and oxindole alkaloids and their diversification in M. speciosa .…”