Kratom—Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review

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Abstract

Kratom, or Mitragyna, is a tropical plant indigenous to Southeast Asia, with unique pharmacological properties. It is commonly consumed by preparing the leaves into decoction or tea, or by grinding them into a powder. Recent evidence has revealed that kratom has physiological effects similar to opioids, including pain relief and euphoria, as well as stimulant properties, which together raise potential concern for dependence and addiction. Moreover, growing evidence suggests that the prevalence of kratom use is increasing in many parts of the world, raising important considerations for healthcare providers. This manuscript will discuss the most current epidemiology, pharmacology, toxicity, and management related to kratom, while seeking to provide a contemporary perspective on the issue and its role in the greater context of the opioid epidemic.

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Most cited references 113

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Alpha-2 adrenergic receptor agonists: a review of current clinical applications.

Joseph A Giovannitti, Sean Thoms, James Crawford (2015)

The α-2 adrenergic receptor agonists have been used for decades to treat common medical conditions such as hypertension; attention-deficit/hyperactivity disorder; various pain and panic disorders; symptoms of opioid, benzodiazepine, and alcohol withdrawal; and cigarette craving. (1) However, in more recent years, these drugs have been used as adjuncts for sedation and to reduce anesthetic requirements. This review will provide an historical perspective of this drug class, an understanding of pharmacological mechanisms, and an insight into current applications in clinical anesthesiology.

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Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2.

András Váradi, Gina Marrone, Travis C. Palmer … (2016)

Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [(35)S]GTPγS assays at the mu opioid receptor but failed to recruit β-arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic tolerance more slowly than morphine, showed limited physical dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.

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Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

Andrew Kruegel, Madalee M Gassaway, Abhijeet Kapoor … (2016)

Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa , represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacological properties. Here we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analog 7-hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid receptor, which do not recruit β-arrestin following receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles. Also presented is an enantioselective total synthesis of both (-)-mitragynine and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed Mannich-Michael reaction sequence as the key transformation. Pharmacological evaluation of (+)-mitragynine revealed its much weaker opioid activity. Likewise, the intermediates and chemical transformations developed in the total synthesis allowed the elucidation of previously unexplored structure-activity relationships (SAR) within the Mitragyna scaffold. Molecular docking studies, in combination with the observed chemical SAR, suggest that Mitragyna alkaloids adopt a binding pose at the mu-opioid receptor that is distinct from that of classical opioids.

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Author and article information

Contributors

Elyse M. Cornett: ecorne@lsuhsc.edu

Journal

Journal ID (nlm-ta): Pain Ther

Journal ID (iso-abbrev): Pain Ther

Title: Pain and Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 2193-8237

ISSN (Electronic): 2193-651X

Publication date (Electronic): 28 January 2020

Publication date PMC-release: 28 January 2020

Publication date (Print): June 2020

Volume: 9

Issue: 1

Pages: 55-69

Affiliations

[1 ]GRID grid.279863.1, ISNI 0000 0000 8954 1233, LSU Health Sciences Center School of Medicine, ; 1901 Perdido Street, New Orleans, LA 70112 USA

[2 ]GRID grid.411417.6, ISNI 0000 0004 0443 6864, Department of Anesthesiology, , LSU Health Shreveport, ; 1501 Kings Highway, Shreveport, LA 71103 USA

[3 ]GRID grid.279863.1, ISNI 0000 0000 8954 1233, Department of Anesthesiology, , Louisiana State University School of Medicine, ; 1501 Kings Hwy, Shreveport, LA 71103 USA

[4 ]GRID grid.279863.1, ISNI 0000 0000 8954 1233, Department of Pharmacology, Toxicology, and Neurosciences, , Louisiana State University School of Medicine, ; 1501 Kings Hwy, Shreveport, LA 71103 USA

[5 ]GRID grid.265219.b, ISNI 0000 0001 2217 8588, Tulane School of Medicine, ; New Orleans, LA 70112 USA

Article

Publisher ID: 151

DOI: 10.1007/s40122-020-00151-x

PMC ID: 7203303

PubMed ID: 31994019

SO-VID: baf10ed8-f619-4ecc-96ac-2f0f6dbc47f5

History

Date received : 25 November 2019

Custom metadata

Keywords: drug abuse,drug addiction, kratom,mitragynine,opioid,stimulant

Data availability:

Keywords: drug abuse, drug addiction, kratom, mitragynine, opioid, stimulant

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