Neuropharmacology

Volume 134, Part A, 15 May 2018, Pages 108-120
Neuropharmacology

Invited review
The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse

https://doi.org/10.1016/j.neuropharm.2017.08.026Get rights and content

Highlights

  • •
    Kratom leaves contain indole alkaloids with affinity for opioid receptors.
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    7-hydroxy- and mitragynine do not recruit β-arrestin to the mu-opioid receptor.
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    Low doses of kratom exert stimulant, while high doses induce analgesic effects.
  • •
    Kratom is used for analgesia, opioid withdrawal symptoms, and as mood enhancer.
  • •
    Kratom and its alkaloids do not present with significant respiratory depression.

Abstract

The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast Asia, have been used traditionally for their stimulant, mood-elevating, and analgesic effects and have recently attracted significant attention due to increased use in Western cultures as an alternative medicine. The plant's active alkaloid constituents, mitragynine and 7-hydroxymitragynine, have been shown to modulate opioid receptors, acting as partial agonists at mu-opioid receptors and competitive antagonists at kappa- and delta-opioid receptors. Furthermore, both alkaloids are G protein-biased agonists of the mu-opioid receptor and therefore, may induce less respiratory depression than classical opioid agonists. The Mitragyna alkaloids also appear to exert diverse activities at other brain receptors (including adrenergic, serotonergic, and dopaminergic receptors), which may explain the complex pharmacological profile of raw kratom extracts, although characterization of effects at these other targets remains extremely limited. Through allometric scaling, doses of pure mitragynine and 7-hydroxymitragynine used in animal studies can be related to single doses of raw kratom plant commonly consumed by humans, permitting preliminary interpretation of expected behavioral and physiological effects in man based on this preclinical data and comparison to both anecdotal human experience and multiple epidemiological surveys. Kratom exposure alone has not been causally associated with human fatalities to date. However, further research is needed to clarify the complex mechanism of action of the Mitragyna alkaloids and unlock their full therapeutic potential.
This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’

Introduction

The leaves of the psychoactive plant Mitragyna speciosa (Fig. 1A), known commonly as “kratom” in Thailand, or “biak biak” in Malaysia, have been used by humans in Southeast Asia for centuries to treat a variety of ailments. The plant material is typically consumed directly or as a tea. At low doses, kratom is primarily used for its stimulating effects. At higher doses, opioid-like effects are present, and the plant is used as a general analgesic, and as a substitute for opium or to treat opium withdrawal symptoms. Kratom's mood-elevating effects have also raised concerns about the plant's potential for misuse as an addictive recreational drug, and legal controls have been instituted in some regions. However, to date there have been no fatalities that can be solely attributed to kratom overdose. Other medicinal applications are also known, including use as a treatment for fever, cough, diarrhea, depression, and anxiety (Adkins et al., 2011; Matsumoto, 2006; Raffa et al., 2013, Takayama, 2004, Takayama et al., 2002). In the past decade, use of kratom has expanded significantly in the United States. This growing interest, combined with the explosion of social media, has considerably increased the anecdotal knowledge base related to kratom's efficacy in treating a large variety of medical conditions. Importantly, favorable reports in treatment of intractable pain syndromes and substance use disorders suggest the potential of kratom to address multiple areas of unmet medical need. Accordingly, the study of kratom is of high relevance to public health and has resulted in a number of scientific reviews in recent years (Hassan et al., 2013, Prozialeck et al., 2012, Suhaimi et al., 2016, Warner et al., 2016)
The present review aims to place both recent and historical observations concerning the behavioral and physiological effects of kratom in man into the context of the most up-to-date knowledge of the molecular pharmacology of kratom alkaloids. Similarly, an attempt is made to rationally link animal studies with human experience through dose correlation and critical analysis. Lastly, we aim to highlight key aspects of the field that remain underexplored, with the goal of guiding future research.

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Section snippets

Major alkaloids

In light of its well-documented medicinal properties, the molecular constituents of kratom have been extensively studied, with more than 40 unique indole alkaloids having been identified in the plant (Adkins et al., 2011, León et al., 2009, Shellard, 1974, Takayama, 2004). Among these, the indole alkaloid mitragynine (Fig. 1B) has been universally cited as the primary alkaloid constituent of kratom, accounting for up to 66% by mass of crude alkaloid extracts (Shellard, 1974, Takayama, 2004).

Mu-opioid receptor

The major kratom alkaloids have recently been profiled for binding and functional activity at the human and rodent opioid receptors (Kruegel et al., 2016). Using radioligand displacement assays in transfected cells, binding affinities at the human MOR (hMOR) were determined for mitragynine (Ki = 233 nM) and 7-OH (Ki = 47 nM). In bioluminescence resonance energy transfer (BRET) functional assays at hMOR, mitragynine exhibited low efficacy partial agonist activity (Emax = 34%, relative to [D-Ala2

In vivo pharmacology and toxicology in animals

The behavioral and physiological effects of both kratom extracts and pure alkaloids have been studied in a number of animal species. As a whole, these studies have placed a particular emphasis on kratom's analgesic effects and confirmation of the purported opioid mechanism in vivo. Some work has also been directed towards quantification of kratom's addictive potential.

In vitro ADME

One study has evaluated mitragynine and 7-OH in several in vitro assays of absorption, distribution, metabolism, and excretion (ADME) (Manda et al., 2014). Both mitragynine and 7-OH were partially degraded in simulated gastric fluid (∼25% after 2 h) but stable in simulated intestinal fluid. Both mitragynine and 7-OH exhibited moderate to high apparent permeability coefficients (Papp) and efflux ratios of ∼1 (not effluxed by P-gp) in both Caco-2 and MDR1-MDCK cell models, suggesting that both

Correlating animal studies with human experiencenotes on dosing and route of administration

Mitragynine and 7-OH do not appear to be available in a pure form to the typical consumer and thus, the potential toxicity and/or abuse liability of such pure compounds is not directly relevant to the risks associated with consumption of the unadulterated plant material or extracts. Likewise, the potential for administration by intravenous or intranasal routes is not currently relevant, given that injection or insufflation of ground plant matter is not reasonably possible. Instead, it is most

Conclusions

Kratom leaf or extracts exert a dose-dependent and complex range of pharmacological effects, some of which can be explained by the opioid activity of the alkaloids mitragynine and 7-OH. Other known but poorly characterized alkaloids or as-yet-unidentified compounds in the plant may also contribute to the observed behavioral effects, particularly the enigmatic stimulant activity. Available in vitro, in vivo, and observational human data are consistent with opioid agonist activity and a proposed

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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