Neuropharmacology: Invited Review

Neuropharmacology xxx (2017) 1e13
Contents lists available at ScienceDirect
Neuropharmacology
journal homepage: www.elsevier.com/locate/neuropharm
Invited review
The medicinal chemistry and neuropharmacology of kratom: A

preliminary discussion of a promising medicinal plant and analysis of
its potential for abuse
Andrew C. Kruegel a, Oliver Grundmann b, *
a
Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, United States
b
Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, FL 32611, United States
a r t i c l e i n f o a b s t r a c t
Article history: The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast
Received 1 May 2017 Asia, have been used traditionally for their stimulant, mood-elevating, and analgesic effects and have
Received in revised form recently attracted signicant attention due to increased use in Western cultures as an alternative
12 July 2017
medicine. The plant's active alkaloid constituents, mitragynine and 7-hydroxymitragynine, have been
Accepted 17 August 2017
Available online xxx
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 ag-
onists of the mu-opioid receptor and therefore, may induce less respiratory depression than classical
Keywords:
Kratom
opioid agonists. The Mitragyna alkaloids also appear to exert diverse activities at other brain receptors
Mitragynine (including adrenergic, serotonergic, and dopaminergic receptors), which may explain the complex
7-hydroxymitragynine pharmacological prole of raw kratom extracts, although characterization of effects at these other targets
Analgesia remains extremely limited. Through allometric scaling, doses of pure mitragynine and 7-
Opioid receptor 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 associ-
ated with human fatalities to date. However, further research is needed to clarify the complex mecha-
nism of action of the Mitragyna alkaloids and unlock their full therapeutic potential.
2017 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.1. Background and significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Molecular constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Major alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Alkaloid content of raw plant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. In vitro pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Opioid pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.1. Mu-opioid receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.2. Kappa- and delta-opioid receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.3. Biased signaling at MOR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Non-opioid pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3. Synthesis and structure-activity relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. In vivo pharmacology and toxicology in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
* Corresponding author. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1345 Center Drive, Room P6-20, Gainesville, FL 32611, United
States.
E-mail addresses: [email protected] (A.C. Kruegel), [email protected] (O. Grundmann).
http://dx.doi.org/10.1016/j.neuropharm.2017.08.026
0028-3908/ 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kruegel, A.C., Grundmann, O., The medicinal chemistry and neuropharmacology of kratom: A preliminary
discussion of a promising medicinal plant and analysis of its potential for abuse, Neuropharmacology (2017), http://dx.doi.org/10.1016/
j.neuropharm.2017.08.026
2 A.C. Kruegel, O. Grundmann / Neuropharmacology xxx (2017) 1e13
4.1. Analgesic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4.1.1. Analgesic studies with kratom extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.2. Analgesic studies with mitragynine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.3. 7-OH analgesia and side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.1. Toxicology of kratom extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.2. Mitragynine side effects and acute toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.3. Mitragynine chronic toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3. Other therapeutic effects of kratom alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4. Animal studies of abuse potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. ADME and pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. In vitro ADME . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.2. Pharmacokinetics of mitragynine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.3. Pharmacokinetics of 7-OH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Observations from human use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1. Correlating animal studies with human experiencenotes on dosing and route of administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1.1. At typical doses of raw kratom plant, exposure to 7-OH is expected to be sub-pharmacological . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2. Qualitative behavioral and physiological effects in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.3. Current legal status in the United States, use pattern, and toxic events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction 2. Molecular constituents
1.1. Background and signicance 2.1. Major alkaloids
The leaves of the psychoactive plant Mitragyna speciosa (Fig. 1A), In light of its well-documented medicinal properties, the mo-
known commonly as kratom in Thailand, or biak biak in lecular constituents of kratom have been extensively studied, with
Malaysia, have been used by humans in Southeast Asia for centuries more than 40 unique indole alkaloids having been identied in the
to treat a variety of ailments. The plant material is typically plant (Adkins et al., 2011; Leo n et al., 2009; Shellard, 1974;
consumed directly or as a tea. At low doses, kratom is primarily Takayama, 2004). Among these, the indole alkaloid mitragynine
used for its stimulating effects. At higher doses, opioid-like effects (Fig. 1B) has been universally cited as the primary alkaloid con-
are present, and the plant is used as a general analgesic, and as a stituent of kratom, accounting for up to 66% by mass of crude
substitute for opium or to treat opium withdrawal symptoms. alkaloid extracts (Shellard, 1974; Takayama, 2004). This alkaloid
Kratom's mood-elevating effects have also raised concerns about was rst isolated in 1921 and the structure assigned in the 1960s by
the plant's potential for misuse as an addictive recreational drug, chemical and crystallographic means (Field, 1921; Zacharias et al.,
and legal controls have been instituted in some regions. However, 1965). The other major alkaloids of kratom are paynantheine,
to date there have been no fatalities that can be solely attributed to speciogynine, and speciociliatine (Fig. 1C) (Shellard, 1974). The
kratom overdose. Other medicinal applications are also known, quantities of these four major alkaloids are subject to signicant
including use as a treatment for fever, cough, diarrhea, depression, variation among different regional varieties of the plant, and are
and anxiety (Adkins et al., 2011; Matsumoto, 2006; Raffa et al., also dependent on plant age, ndings that considerably complicate
2013; Takayama, 2004; Takayama et al., 2002). In the past decade, the interpretation of reported psychoactive and medicinal effects
use of kratom has expanded signicantly in the United States. This from the raw plant material (Adkins et al., 2011; Leo n et al., 2009;
growing interest, combined with the explosion of social media, has Shellard, 1974.; Takayama, 2004). Among the various minor alka-
considerably increased the anecdotal knowledge base related to loids, the oxidized derivative 7-hydroxymitragynine (7-OH)
kratom's efcacy in treating a large variety of medical conditions. (Fig. 1C) is of particular interest, as it has been reported to exhibit
Importantly, favorable reports in treatment of intractable pain analgesic effects mediated through agonist activity at the mu-
syndromes and substance use disorders suggest the potential of opioid receptor (MOR) exceeding in potency those of the proto-
kratom to address multiple areas of unmet medical need. Accord- typical opioid agonist morphine (Matsumoto et al., 2004; Ponglux
ingly, the study of kratom is of high relevance to public health and et al., 1994)
has resulted in a number of scientic reviews in recent years
(Hassan et al., 2013; Prozialeck et al., 2012; Suhaimi et al., 2016; 2.2. Alkaloid content of raw plant
Warner et al., 2016)
The present review aims to place both recent and historical Kratom is readily available for purchase from a large number of
observations concerning the behavioral and physiological effects of internet vendors, most commonly as dried and powdered leaves.
kratom in man into the context of the most up-to-date knowledge Two reports have quantied mitragynine and 7-OH in such com-
of the molecular pharmacology of kratom alkaloids. Similarly, an mercial kratom preparations by liquid chromatography-mass
attempt is made to rationally link animal studies with human spectrometry (LC-MS) methods (Kikura-Hanajiri et al., 2009;
experience through dose correlation and critical analysis. Lastly, we Lydecker et al., 2016). A compilation and analysis of these results
aim to highlight key aspects of the eld that remain underexplored, is presented in Table 1. The term leaf refers to products described
with the goal of guiding future research. as dried leaves, while powder refers to products obtained in a
A.C. Kruegel, O. Grundmann / Neuropharmacology xxx (2017) 1e13 3
Fig. 1. (A) Leaves of Mitragyna speciosa (kratom); (B) Structure of mitragynine; (C) Structure of other major kratom alkaloids.
pre-ground form, either loose or encapsulated (presumably rep- quite consistent across products and reports, with mean concen-
resenting simple dried and ground Mitragyna speciosa leaf, trations of mitragynine in the range of ~1.5e2 mass% and 7-OH in
although this cannot be veried). Products described as extracts, the range of ~0.02e0.03 mass% (based on dry leaf weight).
resins, or mixtures with other botanicals in these studies are Accordingly, the mitragynine concentration in most kratom prod-
excluded from the present analysis, as their methods of preparation ucts is 50- to 100-fold higher than the 7-OH concentration. Con-
and origins are likely to be too varied to draw meaningful conclu- centrations of 7-OH in powdered products are also found to be
sions regarding the typical potency of such products on the broader marginally higher than in leaf products, but the signicance of this
market. It should be noted however, that none of these more ill- observation is questionable given the large product-to-product
dened products contained 7-OH at concentrations higher than variability and limited data points available.
simple leaf material. Overall, the mean observed concentrations are Approximate concentrations of mitragynine and 7-OH in raw
Table 1
Average mass% of mitragynine and 7-OH in raw kratom leaf or powder.
Mass% STD
Reference
mitragynine (leaf) mitragynine (powder) 7-OH (leaf) 7-OH (powder)
Kikura-Hanajiri et al., 2009 1.80 0.51 2.02 0.13 0.0196 0.010 0.0286 0.0099
Lydecker et al., 2016 e 1.67 0.28 e 0.0328 0.0093
Combined Ave 1.80 0.36 Combined Ave 0.0273 0.014
leaf have also been determined by extraction and purication of the correlate potency in vitro to expected receptor occupancy at various
pure alkaloids (Ponglux et al., 1994). In this case, the 7-OH content dose levels.
(0.026 mass%) was within the typical range as determined by the
LC-MS studies, while the mitragynine content (0.86 mass%) was 3.1.2. Kappa- and delta-opioid receptor
signicantly lower, but this may be due to poor extraction/puri- The activity of the major Mitragyna alkaloids have also been
cation efciency. Unfortunately, to our knowledge no study has proled at the human kappa-opioid receptor (hKOR) and human
rigorously quantied the content of the other major alkaloids delta-opioid receptor (hDOR) (Kruegel et al., 2016). Both mitragy-
(paynantheine, speciogynine, and speciociliatine) across different nine and 7-OH bind to hKOR (Ki mitragynine 772 nM; Ki 7-
kratom products, complicating interpretations of their inuence on OH 188 nM) and in functional assays, act as competitive antag-
kratom pharmacology. However, one study has reported that onists with IC50 values in the micromolar range. In the case of
extraction of powdered kratom leaf yielded a combined ~0.5e0.7 hDOR, binding was observed for 7-OH (Ki 219 nM), but was
mass% for these three alkaloids, suggesting that their potential negligible for mitragynine (Ki > 10 mM), while both alkaloids
involvement in kratom's effects should not be ignored (Kruegel exhibited only weak antagonist activity in functional assays at this
et al., 2016). Thus, it is necessary to recognize that the effects of receptor (IC50 > 10 mM). Interspecies and interassay differences
kratom leaf, powder, or extracts are expected to diverge widely have again been observed at these receptors. For example, reported
from both the pure Mitragyna alkaloids themselves and classical afnities of mitragynine for mouse DOR in transfected cells
MOR agonists, based on variable concentrations of mitragynine, 7- (Ki 1.0 mM) and DOR in guinea pig brain (Ki 60 nM) are much
OH, and minor alkaloids depending on area and time of harvest, stronger than observed with the human receptor (Kruegel et al.,
and the potential contribution of other Mitragyna alkaloids and as- 2016; Takayama et al., 2002; V aradi et al., 2016). Similarly, for 7-
yet-unknown substances in the plant. OH, submicromolar mDOR antagonism has been demonstrated in
the [35S]GTPgS displacement assay (Va radi et al., 2016). Therefore,
3. In vitro pharmacology the contribution of KOR and DOR antagonism to kratom's in vivo
effects remains unclear at this time.
3.1. Opioid pharmacology
3.1.3. Biased signaling at MOR
3.1.1. Mu-opioid receptor The activation of hMOR induced by both mitragynine and 7-OH
The major kratom alkaloids have recently been proled for has been shown to be biased toward G protein signaling and
binding and functional activity at the human and rodent opioid neither alkaloid recruits b-arrestin to a measurable degree (Kruegel
receptors (Kruegel et al., 2016). Using radioligand displacement et al., 2016). This observation may be of relevance in explaining the
assays in transfected cells, binding afnities at the human MOR apparently superior side effect prole of kratom (as well as
(hMOR) were determined for mitragynine (Ki 233 nM) and 7-OH mitragynine and 7-OH, see below) compared to classical opioid
(Ki 47 nM). In bioluminescence resonance energy transfer (BRET) agonists, particularly in regard to respiratory depression and con-
functional assays at hMOR, mitragynine exhibited low efcacy stipation. Animal studies and early human data have suggested that
partial agonist activity (Emax 34%, relative to [D-Ala2, NMe-Phe4, G protein-biased MOR agonists may induce less respiratory
Gly-ol5]-enkephalin, DAMGO) with an EC50 of 339 nM. Similarly, 7- depression and inhibition of gastrointestinal transit compared to
OH was a partial agonist at hMOR (Emax 47%), but with higher classical opioids, which activate both the G protein and b-arrestin
potency (EC50 35 nM). The other major alkaloids, specically signaling pathways (Siuda et al., 2017). Further studies should
paynantheine, speciogynine, and speciociliatine, were found to address the potential for mitragynine and 7-OH derivatives to
exhibit competitive antagonist activity at hMOR with IC50 values in provide analgesia without signicant respiratory depression or
the micromolar range. Accordingly, it may be expected that the constipation due to G protein-biased signaling.
overall hMOR activity of raw kratom plant or extracts is a complex
interplay of competing agonist and antagonist effects, dependent 3.2. Non-opioid pharmacology
on the mixture of alkaloids present. As a point of reference, the
prototypical MOR agonist morphine is a potent full agonist in these A number of studies have implicated non-opioid receptors in the
same functional assays (EC50 3 nM) and thus, in vitro, 7-OH and actions of mitragynine. This compound has been shown to bind to
mitragynine are 10- and 100-fold less potent than morphine at some degree to several non-opioid central nervous system (CNS)
hMOR, respectively (Andrew Kruegel, unpublished data). targets, including alpha-2 adrenergic receptors (a2R), adenosine
This same study also reported comparable binding afnities at A2a receptors, dopamine D2 receptors, and the serotonin receptors
mouse MOR (mMOR) for mitragynine (Ki 230 nM) and 7-OH 5-HT2C and 5-HT7, but the strength of these afnities has not been
(Ki 37 nM). However, in functional assays with mMOR, inter- reported (Boyer et al., 2008). Mitragynine analgesia has also been
species variation was observed, with mitragynine acting as a shown to be inhibited by the a2R antagonist idazoxan, and by the
competitive antagonist, while 7-OH retained its partial agonist non-specic serotonin antagonist cyproheptadine (Matsumoto
activity, although with lower efcacy (EC50 38 nM; Emax 23%) et al., 1996a). However, another study showed that in a cell line
(Kruegel et al., 2016). However, another recent report using a expressing a2R, mitragynine did not act directly as an agonist of
different assay method ([35S]GTPgS displacement) did demonstrate this receptor (Tohda et al., 1997). Accordingly, there remains un-
partial agonist activity with mitragynine at mMOR (Emax 65%; certainty regarding the importance of other CNS receptors in
EC50 203 nM), while results with 7-OH were similar (Emax 77%; mediating mitragynine's effects. Furthermore, there are no reports
EC50 53 nM) (Va radi et al., 2016). Likewise, an earlier report that concerning the pharmacology of the other major kratom alkaloids
studied binding in guinea pig brain homogenates reported a similar (paynantheine, speciogynine, and speciociliatine). Considering that
afnity for 7-OH (Ki 13 nM), but a much higher binding afnity together, these three alkaloids often constitute 0.5e0.7 mass% of
for mitragynine (Ki 7.2 nM) (Takayama et al., 2002). These raw kratom (in total, almost as much as mitragynine itself), a better
interspecies and interassay differences necessarily complicate the understanding of their molecular targets is essential to under-
application of this in vitro data for interpreting in vivo ndings in standing this plant.
animals or man. Further, since actual brain concentrations of Conicting antagonism studies with nalorphine have also been
mitragynine and 7-OH have not been studied, it is not possible to conducted in vivo. Oddly, certain behavioral effects of mitragynine
(e.g. mydriasis in cats) were reversed by this treatment, while 4.1. Analgesic effects
others (e.g. analgesia in rats) were not (Macko et al., 1972). How-
ever, given more recent studies demonstrating antagonism of 4.1.1. Analgesic studies with kratom extracts
mitragynine analgesia by naloxone (Matsumoto et al., 1996b), and A number of reports have demonstrated the analgesic activity of
the fact that nalorphine is actually a partial opioid agonist (Paul kratom extracts (both crude alcohol extract and mixed alkaloid
et al., 1991), these ndings should be taken with reservation. It fractions) in rodents (Carpenter et al., 2016; Reanmongkol et al.,
seems more likely that the analgesic effects of oral (p.o.) mitragy- 2007; Sabetghadam et al., 2010, 2013a; Shaik Mossadeq et al.,
nine are indeed opioid mediated (see below). Since little is known 2009). A selection of key results from these studies are collected
about the molecular targets of other Mitragyna alkaloids or com- in Table 2. Overall, both the alcohol extract and crude alkaloid
pounds present in kratom, further studies are required to elucidate fraction of kratom are low potency analgesics in several rodent
the molecular mechanisms of potentially non-opioid antidepres- models. By the oral route, typical active doses are >50 mg/kg for the
sant and stimulating effects reported for kratom at lower doses. alcohol extract and >20 mg/kg for the alkaloid fraction. In all cases
where it was examined, naloxone inhibited or reversed the
3.3. Synthesis and structure-activity relationships observed analgesic effects, indicating that said effects of kratom
alkaloids are at least partially mediated by opioid receptors. How-
The mitragynine molecular scaffold has been explored through ever, available studies should be considered incomplete for several
both total and partial synthesis of the natural products and a reasons. First, the alkaloid content and composition of the extracts
number of analogs (Jun Ma et al., 2007; Kerschgens et al., 2012; used are not typically analyzed or standardized and thus, it is
Kruegel et al., 2016; Ma et al., 2009; Takayama et al., 2002, 1995). difcult to correlate these studies using complex mixtures, to the
This work has afforded a preliminary understanding of the struc- complementary data available with pure alkaloids (see below).
tural determinants of MOR activity in this scaffold (Fig. 2). As a Second, most of these studies do not study a complete dosage range
whole, the known structure-activity relationships (SAR) for and thus, the analgesic potency of kratom extracts in animals re-
mitragynine and 7-OH dene a pharmacophore that is fairly mains poorly dened.
intolerant to structural modication, with small changes, particu-
larly to the acrylate and ethyl groups on ring D, being sufcient to 4.1.2. Analgesic studies with mitragynine
abolish opioid activity. Further, demethylation of the aryl methoxy A number of reports have demonstrated the analgesic activity of
group to give phenolic analogs reduces the potency of both pure mitragynine in multiple animal species and tests (Carpenter
mitragynine and 7-OH at MOR, in contrast to morphinan-based et al., 2016; Macko et al., 1972; Matsumoto et al., 1996b;
opioids, where such a change greatly enhances potency. In com- Matsumoto, 2006; Sabetghadam et al., 2013a). Key results from
bination with molecular docking, this SAR suggests that mitragy- these studies are presented in Table 2. The most extensive in-
nine and its analogs adopt a distinct binding pose in the pocket of vestigations were conducted by Macko and colleagues, who studied
the MOR (Kruegel et al., 2016). Additional studies are needed to the analgesic activity of mitragynine in mice, rats, and dogs (Macko
explore the SAR of mitragynine and 7-OH in more detail and also et al., 1972). In all species, mitragynine was an active analgesic
the other alkaloids, if and when their molecular targets are iden- when given p. o. or intraperitoneally (i.p.), with potency compa-
tied. Likewise, the eld would benet from further development rable to codeine. Oddly, mitragynine was largely inactive in both
of robust synthetic methods to access the mitragynine scaffold, mice and rats when administered subcutaneously (s.c.). A similar
particularly if such approaches are amenable to rapid structural dependence on route of administration may also be inferred by
diversication or large-scale synthesis. examination of later reports (Carpenter et al., 2016; Matsumoto
et al., 1996b; Matsumoto, 2006). This unusual observation sug-
4. In vivo pharmacology and toxicology in animals gests that an active metabolite, formed most efciently during rst-
pass metabolism following p. o. or i. p. administration, may be
The behavioral and physiological effects of both kratom extracts involved in mediating the analgesic activity of mitragynine. How-
and pure alkaloids have been studied in a number of animal spe- ever, this hypothesis is conicted by the nding that mitragynine is
cies. As a whole, these studies have placed a particular emphasis on also active by intracerebroventricular (i.c.v) administration
kratom's analgesic effects and conrmation of the purported opioid (Matsumoto et al., 1996b), where hepatic metabolism would not be
mechanism in vivo. Some work has also been directed towards expected to play a major role. Therefore, the potential involvement
quantication of kratom's addictive potential. of metabolites or pharmacokinetics (PK) in the analgesic actions of
mitragynine remains unclear and warrants further study.
4.1.3. 7-OH analgesia and side effects

Several reports have described potent analgesia elicited by 7-OH
in mice (Matsumoto et al., 2008, 2004) (summarized in Table 3). In
mice, this compound is approximately 4- to 5-fold more potent
than morphine via s.c. administration and 10- to 20-fold more
potent by the oral route (due to morphine's poor oral bioavail-
ability) (Matsumoto et al., 2008). The analgesic effects of 7-OH have
also been demonstrated to be opioid mediated through antagonism
studies with naloxone and exhibit tolerance development similar to
morphine (Matsumoto et al., 2005). However, 7-OH induces less
inhibition of GI transit than morphine in mice (Matsumoto et al.,
2008). Therefore, 7-OH represents a potential starting point for
the development of new opioid analgesics with reduced side ef-
fects. Unfortunately, no toxicological data is available for 7-OH and
Fig. 2. Key structure-activity relationships of the mitragynine and 7-OH molecular its potential to induce other well-known opioid side effects, most
scaffolds. importantly respiratory depression, has also not been quantied.
Table 2
Summary of analgesic activity of kratom extracts and pure mitragynine.
Substance Reference Species Dose/Routea Test ED50 (mg/kg)b Naloxone Reversalc
Alcohol Extract Carpenter et al., 2016 Rat 300 mg/kg, i.p. hot plate inactive e
300 mg/kg, p.o. hot plate inactive e
Shaik Mossadeq et al., 2009 Mouse i.p. writhing >100 e
i.p. hot plate >50 yes
Rat i.p. formalin >100 e
Sabetghadam et al., 2010 Rat p.o. hot plate >200 yes
p.o. tail ick >100 yes
Reanmongkol et al., 2007 Mouse p.o. hot plate >50 yes
Rat p.o. tail ick inactive at 200 e
Crude Alkaloid Extract Carpenter et al., 2016 Rat 75 mg/kg, i.p. hot plate inactive e
Sabetghadam et al., 2010 Rat p.o. hot plate >10 yes
p.o. tail ick >20 yes
Reanmongkol et al., 2007 Mouse p.o hot plate >20 yes
Rat p.o. tail ick inactive at 20 e
Sabetghadam et al., 2013a Mouse p.o. hot plate 194 e
Mitragynine Carpenter et al., 2016 Rat 30 mg/kg, i.p. hot plate active e
100 mg/kg, p.o. hot plate active e
Matsumoto et al., 1996b Mouse i.p. tail pinch >10 yes
i.p. hot plate >30 yes
i.c.v. tail pinch >1 mg/mouse yes
i.c.v. hot plate >3 mg/mouse yes
Matsumoto, 2006 Mouse s.c. tail ick >60 e
Sabetghadam et al., 2013a Mouse p.o. hot plate 22 e
Macko et al., 1972,e Mouse 92 mg/kg, s.c. hot plate inactive e
92 mg/kg, p.o. hot plate 100% analgesia e
Rat s.c. tail ick >31 e
i.p. tail ick 14.4 e
p.o. tail ick 17.8 nod
p.o. paw inam. 16.8 e
Dog p.o. thermal ~4-8 e
a
When no dose given, multiple doses were examined in the study.
b
When no ED50 was given, value of >X indicates the minimum dose, X, eliciting detectable analgesia.
c
- indicates not tested.
d
Using nalorphine.
e
ED50s have been corrected for counterion mass to reect freebase values.
Table 3 morphine induces similar toxicological signs at sufciently high

Analgesic activity of 7-OH in mice. doses, so the relevance of these ndings with extracts to the
Test Analgesic ED50 (mg/ toxicity of raw kratom or the pure alkaloids at therapeutic doses
Reference kg) remains uncertain.
s.c. p.o.
Matsumoto et al., 2004,a tail ick 3 5

4.2.2. Mitragynine side effects and acute toxicity
hot plate 2.5 13
Matsumoto et al., 2008 tail ick 0.80 4.4 Macko and colleagues also report on a number of gross behav-
hot plate 0.93 2.2 ioral effects and negative side effects elicited by mitragynine, with
a
ED50s are estimated from provided dose-response curves.
several measures demonstrating a clear distinction between
mitragynine and the classical opioid codeine (a prodrug of
morphine). Respiratory depression was either nonexistent or
signicantly attenuated relative to codeine and morphine in cats
4.2. Toxicology
(i.p.) and relative to codeine in anesthetized (intravenous, i. v.) and
unanesthetized (p.o.) dogs. Likewise, by the oral route, codeine
4.2.1. Toxicology of kratom extracts
elicited emesis in dogs, while mitragynine did not. Mitragynine
The toxic effects of kratom extracts have been studied. For total
induced only slight inhibition of GI transit (<20%) in rats by both p.
alkaloid extracts in mice, p. o. LD50s of 173 mg/kg (Reanmongkol
o. and i. p. routes, while codeine produced more signicant inhi-
et al., 2007) and 592 mg/kg (Sabetghadam et al., 2013b) were
bition by both routes (Macko et al., 1972). However, mitragynine
found. For methanolic extracts in mice, a p. o. LD50 of 4900 mg/kg
cessation after chronic administration in rats did induce a with-
has been reported (Reanmongkol et al., 2007). After 14-day p. o.
drawal syndrome in a more recent study (Yusoff et al., 2016).
treatment with methanol extract at 100, 500, and 1000 mg/kg, rats
Qualitative observations by Macko also revealed that mitragy-
showed mild nephrotoxicity and more moderate hepatotoxicity,
nine given p. o. or i. p. produced only mild disturbances in gross
which were severe at the highest dose, although no signicant
behavior in rats (807 mg/kg, p. o.) and cats (46 mg/kg, i. p.), and no
changes in hematology, organ weights, body weights, food and
notable effects in dogs (80 mg/kg, p. o.). Likewise, in Rhesus mon-
water consumption, or gross behavior were noted (Harizal et al.,
keys, mitragynine did not elicit notable behavioral effects by the
2010). Similarly, 28-day p. o. exposure to methanol extract at 100,
oral route (46 mg/kg). In contrast, i. v. administration of mitragy-
200, and 500 mg/kg also produced biochemical and histopatho-
nine evoked pronounced negative side effects in cats, dogs, and
logical signs of liver and kidney toxicity but no hematological
monkeys, including respiratory depression, convulsions, and in one
changes (Ilmie et al., 2015). It should be mentioned however, that
cat, death (Macko et al., 1972). The reasons for this contrast in side
effects depending on route of administration remain unclear, but motor stimulation are observed in mice at a dose of 2 mg/kg s.c.
recapitulate the similar dependence of analgesic potency on de- (Matsumoto et al., 2008), and the compound substitutes for
livery route (see above) and may be related to rst-pass meta- morphine at 3 mg/kg i.p. in rats (Harun et al., 2015). These results
bolism. Sabetghadam also observed low acute toxicity for are certainly concerning, especially for mitragynine, where the
mitragynine administered orally in mice, reporting an LD50 of dosing corresponds to levels of exposure expected to be achievable
477 mg/kg (Sabetghadam et al., 2013a). In contrast, death of a single with reasonable doses of kratom (for 7-OH, these doses are well
rat at the lower dose of 200 mg/kg p. o. has been described, but no above expected human exposures, see below). However, the oral
further details were provided (Janchawee et al., 2007). bioavailability of mitragynine is low and the PK prole following i.p.
Overall, mitragynine appears to act as an atypical opioid re- administration is not known (see below), but is expected to present
ceptor agonist in vivo when administered p. o., with an improved greater concentrations of mitragynine to the systemic circulation
side effect prole compared to classical morphinan-based opioids (compared to p.o.). Considering this, in combination with the stark
and limited toxicity following acute administration at reasonable differences in effects observed by Macko depending on adminis-
doses. tration route, care should be taken in correlating these results to
man. Further, the Sufka study also reported that crude alcohol and
4.2.3. Mitragynine chronic toxicology alkaloid extracts of kratom did not induce CPP in rats at doses of
Macko and colleagues also proled the toxicity of mitragynine 300 and 75 mg/kg i.p., respectively (Sufka et al., 2014). Notably,
following chronic administration in rats and dogs. In rats receiving similar doses of such extracts have also been shown to induce
mitragynine at 4 or 40 mg/kg/day p.o., 5 days per week for 6 weeks, analgesic effects in rats, and thus, kratom extracts appear to achieve
minor changes in body weight and liver and kidney weights were analgesic activity with limited reinforcement. This observation
observed, but no other behavioral or physiological side effects were highlights the difculty in correlating animal studies using pure
noted. In dogs, no adverse effects were observed after 3 weeks of alkaloids, often delivered by parenteral routes, to experience in
dosing at 5 or 20 mg/kg/day p.o. however, an additional 3-week man, where oral use of raw kratom or its extracts is the most
dosing period at 40 mg/kg/day p.o. in the high-dose dogs resulted common method of use. The complex mixture of alkaloids present
in changes in blood chemistry (that reversed on drug withdrawal), in the kratom plant may present a polypharmacological activity
liver cell morphology, and lymphatic hyperplasia (Macko et al., prole that has less potential for abuse, the mitragynine content of
1972). Sabetghadem observed similar results in rats, with low the extracts may be too low, or pharmacokinetic differences be-
(1 mg/kg/day, p.o.) and intermediate (10 mg/kg/day, p.o.) doses tween oral and parenteral routes attenuate reinforcing effects.
showing little sign of toxicity, but a higher dose (100 mg/kg/day, These observations are also consistent with both the mixed agonist
p.o.) inducing hematological and liver and brain histopathological and antagonist activity of the major kratom alkaloids at the opioid
changes suggestive of toxicity (Sabetghadam et al., 2013b). receptors and potentially, the other non-opioid receptor activities
Accordingly, additional chronic toxicology studies are indicated to observed in vitro (see above). The US Food and Drug Administration
further explore the negative effects observed at higher doses and (FDA), Center for Drug Evaluation and Research (CDER), has pub-
further dene a safe dose ceiling for chronic administration in lished a guidance on the Assessment of Abuse Potential for Drugs
humans. It should also be noted that toxicological studies with pure which includes a battery of tests that should be performed before a
mitragynine are of limited relevance to current patterns of human drug can be deemed abuse liable (FDA, 2017). Although both CPP
use, where alkaloids are often consumed in the matrix of raw plant and drug discrimination studies have been conducted for kratom
matter and the actual systemic exposure to those alkaloids remains and its alkaloids, the route of administration and doses may not
poorly dened following this type of administration (for further adequately reect human use. In addition, other tests such as the
discussion, see below, ADME and Pharmacokinetics). Irwin and motor performance tests, physical dependence assess-
ment, and self-administration studies have not been reported to
4.3. Other therapeutic effects of kratom alkaloids date following oral administration in doses comparable to those
used by humans. A recent 8-factor analysis of abuse potential
Mitragynine and morphine via p. o. administration were equi- conducted according to the requirements of the Controlled Sub-
potent cough suppressants in dogs (Macko et al., 1972). In rodents, stances Act estimated the doses of oral kratom required in a 70-kg
both mitragynine and kratom extracts have demonstrated human to achieve either reinforcing effects or substitution for
antidepressant-like activity in the forced swim test and anxiolytic- morphine as 200 g and 630 g, respectively, because of the low oral
like activity in the elevated plus maze (Hazim et al., 2014; Idayu bioavailability of mitragynine (Pinney Associates, 2016). From the
et al., 2011; Kumarnsit et al., 2007; Mohamad et al., 2013; Yusoff preceding discussion, it should be clear that the current body of
et al., 2016). knowledge in regard to potential kratom and Mitragyna alkaloid
abuse liability is at best in its infancy and requires gathering both
4.4. Animal studies of abuse potential more animal and human data for clarication.
Given their opioid actions, several studies have examined the 5. ADME and pharmacokinetics
abuse potential of kratom and its alkaloids in classical animal
models. In a conditioned place preference (CPP) paradigm in rats, 5.1. In vitro ADME
mitragynine exhibited reinforcing effects following repeated
dosing at 10 and 30 mg/kg i.p. (Yusoff et al., 2016). These same One study has evaluated mitragynine and 7-OH in several
investigators later showed that the acquisition of this mitragynine- in vitro assays of absorption, distribution, metabolism, and
induced CPP at 10 mg/kg i.p. was inhibited by naloxone (0.3 or excretion (ADME) (Manda et al., 2014). Both mitragynine and 7-
1 mg/kg s.c.), suggesting an opioid-dependent effect (Yusoff et al., OH were partially degraded in simulated gastric uid (~25% after
2017). Similarly, another study demonstrated CPP in rats at 5 and 2 h) but stable in simulated intestinal uid. Both mitragynine and
30 mg/kg i.p., but not at an intermediate dose of 10 mg/kg i.p. 7-OH exhibited moderate to high apparent permeability co-
(Sufka et al., 2014). Mitragynine (15 mg/kg, i.p.) has also been efcients (Papp) and efux ratios of ~1 (not efuxed by P-gp) in
shown to substitute for morphine in a discriminative stimulus both Caco-2 and MDR1-MDCK cell models, suggesting that both
paradigm in rats (Harun et al., 2015). In the case of 7-OH, CPP and compounds have the potential for signicant GI absorption and
blood-brain barrier (BBB) penetration via passive diffusion. the mitragynine dose was delivered in the form of kratom tea, not
Mitragynine was fairly stable in both human liver microsomes and as a pure compound. Nevertheless, this report tentatively suggests
S9 fractions (t1/2 > 2 h), while 7-OH was rapidly metabolized (t1/ a long half-life (23.2 h) for mitragynine in man following p.o.
2 24 min) in microsomes, but more stable in S9 fractions without administration. Vd/F was also very high, consistent with the rat
NADPH (t1/2 > 2 h, Phase II metabolism only). This study also studies, suggesting similar low oral bioavailability. For one subject
demonstrated high plasma protein binding (>90%) and weak in- receiving a dose of ~0.3 mg/kg p.o., max concentration (Cmax) and
hibition of P-gp (IC50 > 15 mM) for both compounds. Another area under the curve (AUC(0/inf)) were also provided and were of
report showed that mitragynine is also stable in plasma the same order of magnitude as would be expected in rats at an
(Parthasarathy et al., 2010). Overall, this in vitro data is consistent equivalent estimated dose (~1.8 mg/kg, p.o. in rats by allometric
with favorable drug-like properties for a brain-penetrant anal- scaling, see below). The observed Cmax in this subject corresponds
gesic and is an acceptable starting point to develop new drugs to a plasma concentration of 260 nM. Considering that higher doses
based on these lead scaffolds. Two studies have demonstrated that of kratom yield effective mitragynine doses of ~2 mg/kg (see
extracts of kratom (both methanolic and crude alkaloid fractions) below), it is expected that maximal plasma concentrations of
are fairly potent inhibitors of CYP3A4 and CYP2D6 in vitro (Hanapi mitragynine in the low micromolar range may be achievable
et al., 2010; Kong et al., 2011). Accordingly, there exists the po- following consumption of higher doses of kratom plant. Whether
tential for kratom to precipitate unfavorable interactions with this is sufcient to elicit occupancy of central MORs by mitragynine
other drugs metabolized through these enzymes. These observa- is dependent on brain penetration, which presently remains un-
tions should be conrmed in vivo and efforts made to identify the known. Regardless, more rigorous studies in nave human subjects
specic alkaloids responsible for the observed bioactivity. Like- using pure mitragynine are required to better dene the PK pa-
wise, there exists the possibility for the gross behavioral effects of rameters and conrm any potential correlation between rodent
kratom to differ from the pure alkaloids based not only on poly- and human PK. When contrasted with the favorable membrane
pharmacology (see above), but also on metabolic interactions permeation and metabolic stability of mitragynine found in the
between the mixed alkaloids. in vitro assays described above, the apparently low oral bioavail-
ability of this compound is somewhat paradoxical, as it does not
5.2. Pharmacokinetics of mitragynine seem easily explained by either poor GI absorption or high rst-
pass metabolism. Further studies are required to reproduce the
Several studies have examined the PK of mitragynine in rats (de limited available data and explore the reasons for this low oral
Moraes et al., 2009; Janchawee et al., 2007; Parthasarathy et al., bioavailability. Regardless, administration in most animal studies
2010; Vuppala et al., 2011) and a single study has been conducted via i. v. or i. p. routes does not reect the predominant human use as
in humans (Trakulsrichai et al., 2015). The results of these studies an oral preparation. Differences in bioavailability, metabolism, and
are summarized in Table 4. By the oral route in rats, all studies are interactions with other components in the plant matrix are not
consistent, demonstrating intermediate half-life (t1/2 > 3 h) and sufciently considered to date.
Tmax, a high apparent volume of distribution (Vd/F), and linear
dose-response. By the i.v. route, the two available studies provide 5.3. Pharmacokinetics of 7-OH
conicting results for several PK parameters. However, the data
clearly indicates that the oral bioavailability (F) of mitragynine in The PK of 7-OH has been examined in one rat study at a single i.
rats is modest or low (<25% and possibly as low as 3%). The single v. dose (Vuppala et al., 2013) (see Table 4). This work revealed that
human study is difcult to interpret because 1) the subjects were 7-OH is more rapidly eliminated (t1/2 22.9 min) and has a lower
chronic consumers of kratom, 2) PK was studied following stabili- Vd than mitragynine. This rapid elimination is consistent with the
zation on a repeated daily dose, 3) subjects were given different low stability in liver microsomes (see above). The plasma Cmax
dose levels with small groups sizes (n 1e3) at each dose, and 4) observed was 7.2 mM and thus, given even modest brain
Table 4
Pharmacokinetic parameters of mitragynine and 7-OH.
Reference Species/Strain Dose/Route Analytical PK parameters in plasmaa

Compound Method
cmax (mg/mL) tmax t1/2 Vd b (L/ CLb (L/ AUC ((mgah)/ F
(h) (h) kg) (hakg)) mL)
Mitragynine Janchawee et al., 2007 Wistar Rats 40 mg/kg, p.o. LC-UV 0.63 1.83 9.43 89.5 ~6.3c 6.99 ~26%d
Valaderes de Moraes Wistar Rats 20 mg/kg, p.o. LC-MS/MS 0.424 1.26 3.85 37.9 6.35 3.15 ~23%d
et al., 2009
Parthasarathy et al., 2010 Sprague-Dawley 50 mg/kg, p.o. LC-UV 0.70 4.5 6.6 64 7.0 8.2 3.0%
Rats
Sprague-Dawley 1.5 mg/kg, i.v. LC-UV 2.3 1.2 2.9 0.79 0.29 9.2
Rats
Vuppala et al., 2011 Sprague-Dawley 5.0 mg/kg, i.v. LC-MS/MS 3.9 0.017 2.6 8.2 1.2 3.4 e
Rats
Trakulsrichai et al., 2015 Humans various, oral tea LC-MS various 0.83 23.2 38.0 98.1f various e
(~0.3 mg/kge) (~0.105e) (~0.67e)
7-OH Vuppala et al., 2013 Sprague-Dawley 4.0 mg/kg, i.v. LC-MS/MS 3.0 0.033 0.382 1.60 2.65 1.64 e
Rats
a
Data has been converted to uniform units for ease of comparison.
b
For oral studies, Vd/F and Cl/F.
c
Estimated post hoc by mean rat bodyweight.
d
Calculated post hoc using i. v. data from Vuppala et al. (2011).
e
Representative data for a single subject.
f
This value appears to be erroneous or lack correct units since it could not possibly yield the observed t1/2 given the reported Vd/F.
penetration, this dose (4 mg/kg i. v.) should be easily sufcient to 6.1.1. At typical doses of raw kratom plant, exposure to 7-OH is
engage central MORs in the rat. However, doses of 7-OH delivered expected to be sub-pharmacological
through kratom consumption are much lower and by the oral route, Opioid-dependent analgesic activity may be considered a
not i. v. (see below). Therefore, there is insufcient data at present reasonable surrogate for opioid receptor occupancy. In most cases,
to determine whether the 7-OH dose provided by typical human it may also be considered a more sensitive measure than those of
doses of kratom is centrally active solely based on PK (although euphoria or drug-liking (indicative of abuse liability) considering
analgesic tests suggest that it is not, see below). that most opioid analgesics are used recreationally at doses above
those providing effective analgesia (even in nave individuals). An
ED50 dose of 2.2 mg/kg p. o., the most potent result for oral anal-
gesic activity in mice, is ~5-fold above the expected 7-OH dose
6. Observations from human use delivered by 8 g of kratom (corrected according to Table 5). Simi-
larly, the minimum dose of 7-OH that elicits motor stimulation and
6.1. Correlating animal studies with human experiencenotes on conditioned place preference (CPP) in mice is 2.0 mg/kg s. c.
dosing and route of administration (Matsumoto et al., 2008). When again corrected for route (p.o. at
least 2-fold less potent than s. c.) and body size, this suggests a
Mitragynine and 7-OH do not appear to be available in a pure human equivalent dose at least 10-fold greater than the typical
form to the typical consumer and thus, the potential toxicity and/or exposure from 8 g of kratom (considered a high dose by most
abuse liability of such pure compounds is not directly relevant to users). Accordingly, based on the body of scientic data available at
the risks associated with consumption of the unadulterated plant present, it is not clear that 7-OH plays a signicant role in the gross
material or extracts. Likewise, the potential for administration by behavioral and physiological effects of unadulterated kratom in
intravenous or intranasal routes is not currently relevant, given that man at reasonable doses.
injection or insufation of ground plant matter is not reasonably
possible. Instead, it is most appropriate to approximate exposure 6.2. Qualitative behavioral and physiological effects in humans
levels to said pure compounds at typical oral dose levels of the raw
plant matter (the most common administration route). In a recent Unlike animal data, human observations to date are entirely
survey of 8049 kratom users in the United States, 95% of re- based on observational and case reports. Kratom's main traditional
spondents reported consuming <8 g of raw plant matter per dose use in Southeast Asia, for stimulant effects at low doses and anal-
(Grundmann, 2017). Thus, based on known mean concentrations of gesic effects at high doses, has received both praise and criticism
mitragynine and 7-OH in kratom (see above, Table 1), at the upper from the research community and general public. The stimulant
end of this dose range (8 g), an individual may be exposed to a dose behavioral effects at single doses of 1e5 g of raw plant material
of approximately 120e180 mg of mitragynine and 1.1e3.4 mg of 7- include increased alertness, heightened physical energy, talka-
OH (1.7e2.5 mg/kg and 0.015e0.048 mg/kg, respectively, at 70 kg tiveness, and sociable behavior. A loss of muscle control may occur
bodyweight). towards the higher end of this dose range with occasional itching,
Utilizing standard dose-scaling allometric ratios based on body nausea, loss of appetite, and increased urination being reported as
surface area (3:6:20:37 mouse:rat:dog:human), these typical unwanted adverse effects (Swogger et al., 2015; Warner et al.,
human dose ranges may be converted to corresponding animal 2016). The effects clearly shift with doses above 8 g, mainly pre-
dose ranges to allow better correlation of animal data with obser- senting with dizziness, light-headedness, and sedation indicating
vations and expectations in man. Thus, an 8-g p. o. dose of kratom the opioid-predominant effects, which are accompanied by physi-
plant roughly corresponds to the p. o. animal doses of mitragynine ological symptoms of constipation, hypotension, sweating, and dry
and 7-OH listed in Table 5. It should be noted that this crude mouth. Tachycardia is also frequently reported by kratom users
analysis is highly preliminary and does not account for differences consuming 8 g or more of plant material at a time. The intermediate
in PK, which may be signicant between species. Thus, further dose range of between 5 and 8 g is least dened and presents with a
study is needed to better dene the PK prole of mitragynine and wide range of effects mixed between those of both higher and
7-OH in multiple animal species and man (see above). Nonetheless, lower doses. It appears that the antidepressant and anxiolytic ef-
the extrapolated dose ranges listed here are useful for preliminary fects of kratom are less dose dependent than the stimulant or
interpretation of animal studies. For example, the p. o. ED50 values analgesic effects and tend to be felt at lower doses of 3e6 g (Table 6)
determined by Macko in rats and dogs are in good agreement
(when corrected by allometry) with the expected dose of mitra-
gynine delivered through consumption of an 8-g dose of raw kra- Table 6
tom plant. Accordingly, at higher doses reported by human users, Reported dose-dependent effects of kratom in humans.
kratom is expected to be an efcacious analgesic (as is anecdotally Single kratom dose

reported) through the opioid actions of mitragynine. Effect
1-5 g 5-8 g 8 g
Stimulant Increased alertness

Talkativeness Tachycardia
Table 5 Physical energy
Interspecies dosing conversions.
Mood-elevating Anxiolytic
Oral dose range equivalent to 8 g kratom (mg/ Antidepressant
Species kg)a Sociable behavior
mitragynine 7-OH Sedative/relaxing Loss of muscle Constipation

coordination
Human 1.7e2.5 0.015e0.048
Dizziness/unsteadiness
Dog 3.1e4.6 0.027e0.088
Hypotension
Rat 10e15 0.090e0.29
Mouse 20e30 0.18e0.59 Adverse effects Itching
a Loss of appetite
Upper and lower end of dose ranges calculated using combined averages from
Increased urination
Table 1 1 standard deviation and assuming a human body mass of 70 kg.
(Grundmann, 2017). et al., 2016). The major observed signs and symptoms in these cases
The major concern in regard to the unregulated legal status of align with case reports and earlier observations of kratom users and
kratom products is their potential for dependence and abuse based include tachycardia, drowsiness, irritability, nausea, and hyper-
on the effects of the alkaloids mitragynine and 7-OH at opioid re- tension. One reported risk associated with the use of kratom
ceptors. Various publications have reported a high potential for products has been contamination with undeclared O-desmethyl-
dependence with continued kratom use (Singh et al., 2016, 2014), tramadol, an active and more potent metabolite of the opioid
although the reported withdrawal symptoms are milder compared agonist tramadol (Arndt et al., 2011; Scott et al., 2014). Since O-
to those of classical opioids and last 1e3 days (Singh et al., 2014). desmethyltramadol is not currently regulated as a controlled sub-
Likewise, there seems to be a separation between doses inducing stance, it has been legally sold in combination with kratom under
the purported therapeutic benets and higher doses at which the brand name Krypton (Kronstrand et al., 2011). In nine fatal
physical and/or psychological dependence is more likely to develop exposures involving Krypton in Sweden, the whole blood concen-
(Grundmann, 2017). Furthermore, rapid dose escalation does not trations of mitragynine were 0.02e0.18 mg/g, within the proposed
appear to be a hallmark of typical kratom use patterns. The usual range for an oral chronic kratom dose of 5e8 g. In addition,
possession, planting, export or import of kratom is regulated under concentrations of O-desmethyltramadol ranged from 0.4 to 4.3 mg/g
the Narcotics Act in Thailand since 1973 because of the growing without tramadol or N-desmethyltramadol being present, indi-
concern by regulatory agencies of its dependency and abuse po- cating that O-desmethyltramadol itself was ingested (Kronstrand
tential (Singh et al., 2016). The use of kratom leaves in Thailand, et al., 2011). In all nine cases, the deceased had a range of addi-
however, has shifted over time with the growth of opium use and tional drugs in their systems including benzodiazepines, alcohol,
misuse/abuse. Kratom was no longer primarily used for its stimu- antidepressants, or illicit drugs. Given these polyintoxications, it
lant and analgesic properties, but rather to treat opium abuse, remains unclear what if any role kratom and its alkaloids played in
thereby causing a signicant number of former opium users to these fatalities. Perhaps most notably, to our knowledge there has
consume kratom to treat withdrawal symptoms. A majority of been no reported fatal kratom exposure with the classical symp-
kratom users, even with increasing chronic use, remain in good toms of opioid-induced respiratory depression as the cause of
health and do not engage in risky drug-seeking or criminal death, which suggests that the opioid-like effects of kratom are
behavior (Singh et al., 2015). The use of kratom, despite its legal different from that of classical full opioid agonists.
status in Thailand, is not seen as a social stigma since most kratom The use pattern in the US has not been explored systematically
users are older, maintain regular employment, and are married and to date. Advocacy groups claim that 4e5 million Americans are
living with their family. In many cases, they are working hard and current users of kratom based on membership alone, but these
use kratom to maintain energy and reduce pain resulting from numbers are likely unreliable. In an anonymous online survey study
increasing age. of kratom users, the subjective qualitative experiences of 161 in-
dividuals were analyzed and categorized according to predomi-
6.3. Current legal status in the United States, use pattern, and toxic nantly positive or negative themes such as euphoria and sociability
events or nausea and dizziness (Swogger et al., 2015). Swogger and col-
leagues determined that the effects were primarily positive and
The availability of kratom products in the US is not currently kratom beneted users in replacing unwanted substances such as
regulated at the federal level. The US Food and Drug Administration opioids and illicit drugs, but that mild symptoms of tolerance and
(FDA) issued a warning in 2014 and has seized a number of kratom- withdrawal effects were also felt. However, the authors caution that
containing shipments and dietary supplements based on consumer the sample was likely biased towards a favorable view of kratom
safety concerns (Warner et al., 2016). Several US states have placed given the small sample size and the retrieval resource from Ero-
kratom and the alkaloids mitragynine and 7-OH on the list of wid.org, a recreational-drug-focused website. The results from a
controlled substances while the US Drug Enforcement Adminis- large (N 8049), anonymous US online survey of current kratom
tration (DEA) has listed it as a Drug of Concern as of 2012. In users examining demographics, use patterns, adverse and toxic
August 2016, the DEA attempted to use emergency authority to effects, and abuse potential of kratom indicates that the average
place the main alkaloids of kratom (and thereby, also the plant it- user is middle-aged (31e50 years), with middle-class income
self) into federal Schedule I (DEA, 2016a) without a prior public ($35,000 and above), stable employment and health insurance, and
comment period and faced signicant public backlash, resulting in primarily uses kratom to treat pain (68%) and emotional or mental
the withdrawal of such intent in October 2016 (DEA, 2016b). The conditions (66%) (Grundmann, 2017). A dose-effect relationship
subsequent public commenting period ended on December 1, 2016 was observed for increased energy and focus, less depressed and
with no further action taken as of June 30, 2017. The reasoning for anxious mood, elevated mood, and decreased use of prescription or
the intended emergency scheduling by the DEA was based on a illicit opioid drugs, but not for decreased pain. This may indicate
report by the Centers for Disease Control and Prevention stating a that kratom for the most part is effective in relatively low doses
tenfold increase in calls to poison control centers involving kratom without a signicant risk for the development of a substance use
between 2010 and 2015 (Anwar et al., 2016). This relative increase is disorder. In order to understand the impact of kratom use on health
certainly concerning, although in absolute numbers, the total and safety in the US population, more epidemiological and clinical
number of cases (263 in 2015) is less dramatic (Fig. 3). For com- research is clearly needed. This is especially important given the
parison, in 2014 alone, single acetaminophen exposures resulted in ongoing legal situation of kratom in the US, with lawmakers, fed-
67,187 calls and 65 reported fatalities (Mowry et al., 2015). Out of eral and state regulatory agencies, users, and researchers dis-
the total 660 exposures over the 5-year period, 49 exposures to agreeing on the legal control of kratom and its major alkaloids. The
kratom alone or in combination with other medications/substances scientic community has to a large extent voiced concerns that
were categorized as major and life-threatening with potential replacing kratom, mitragynine, and/or 7-OH in federal Schedule I will
sidual impairment or disability. One death was reported in a user impair and prevent needed scientic research that may provide
who also used paroxetine and lamotrigine and therefore, it is not important insights into the harm reduction and medicinal potential
clear that the death can be solely attributed to the use of kratom, of kratom (Pinney Associates, 2016).
and there is also no data on the exposure level in this case (Anwar
Fig. 3. Number of reported exposure calls to poison centers related to kratom use, by year, United States and Puerto Rico, January 2010eDecember 2015.
7. Conclusions addictive potential of kratom plant or extracts appears lower than

that of typical opioid agonists. Likewise, despite a recent increase in
Kratom leaf or extracts exert a dose-dependent and complex kratom-related health incidents, some of them having been re-
range of pharmacological effects, some of which can be explained ported to be severe or even fatal, no single case can be solely
by the opioid activity of the alkaloids mitragynine and 7-OH. Other attributed to respiratory failure due to kratom, a sharp contrast to
known but poorly characterized alkaloids or as-yet-unidentied other opioids where respiratory depression is the most common
compounds in the plant may also contribute to the observed cause of death. Animal studies evaluating tolerance, dependence,
behavioral effects, particularly the enigmatic stimulant activity. and abuse liability have been ambiguous and it would behoove
Available in vitro, in vivo, and observational human data are regulatory agencies to rst consider ADME processes and common
consistent with opioid agonist activity and a proposed allometric dosing levels and routes before equating unadulterated kratom
scaling model suggests that analgesic effects require higher doses with potent, full opioid receptor agonists like morphine or heroin.
of extracts or raw plant material. However, in vitro studies have The potential chilling effect of Schedule I control on scientic
shown that mitragynine and 7-OH have mixed agonist-antagonist research should also be considered.
activity at the opioid receptors and also do not recruit b-arrestin
to MOR, which distinguishes them from classical opioids. Likewise, Funding
in animals, mitragynine and 7-OH have been shown to induce
limited constipation and in the case of mitragynine, less respiratory This research did not receive any specic grant from funding
depression. Thus, these compounds may serve as new molecular agencies in the public, commercial, or not-for-prot sectors.
scaffolds for the development of centrally acting analgesic drugs
with greater therapeutic index. To date, no human fatality can be References
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Neuropharmacology xxx (2017) 1e13

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The medicinal chemistry and neuropharmacology of kratom: A

4.1. Analgesic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction 2. Molecular constituents

1.1. Background and signicance 2.1. Major alkaloids

4.1.3. 7-OH analgesia and side effects

Substance Reference Species Dose/Routea Test ED50 (mg/kg)b Naloxone Reversalc

Table 3 morphine induces similar toxicological signs at sufciently high

Matsumoto et al., 2004,a tail ick 3 5

Reference Species/Strain Dose/Route Analytical PK parameters in plasmaa

kratom is expected to be an efcacious analgesic (as is anecdotally Single kratom dose

Stimulant Increased alertness

mitragynine 7-OH Sedative/relaxing Loss of muscle Constipation

7. Conclusions addictive potential of kratom plant or extracts appears lower than

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