Pharmacology of Kratom: An Emerging Botanical Agent With Stimulant, Analgesic and Opioid-Like Effects

Abstract

Kratom (Mitragyna speciosa) is a plant indigenous to Thailand and Southeast Asia. Kratom leaves produce complex stimulant and opioid-like analgesic effects. In Asia, kratom has been used to stave off fatigue and to manage pain, diarrhea, cough, and opioid withdrawal. Recently, kratom has become widely available in the United States and Europe by means of smoke shops and the Internet. Analyses of the medical literature and select Internet sites indicate that individuals in the United States are increasingly using kratom for the self-management of pain and opioid withdrawal. Kratom contains pharmacologically active constituents, most notably mitragynine and 7-hydroxymitragynine. Kratom is illegal in many countries. Although it is still legal in the United States, the US Drug Enforcement Administration has placed kratom on its "Drugs and Chemicals of Concern" list. Physicians should be aware of the availability, user habits, and health effects of kratom. Further research on the therapeutic uses, toxic effects, and abuse potential of kratom and its constituent compounds are needed.

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SPECIAL COMMUNICATION
792 • JAOA • Vol 112 • No 12 • December 2012 Prozialeck et al • Special Communication
Pharmacology of Kratom: An Emerging Botanical Agent
With Stimulant, Analgesic and Opioid-Like Effects
Walter C. Prozialeck, PhD
Jateen K. Jivan, BS
Shridhar V. Andurkar, PhD
Kratom (Mitragyna speciosa) is a plant indigenous to
Thailand and Southeast Asia. Kratom leaves produce
complex stimulant and opioid-like analgesic effects. In
Asia, kratom has been used to stave off fatigue and to
manage pain, diarrhea, cough, and opioid withdrawal.
Recently, kratom has become widely available in the
United States and Europe by means of smoke shops and
the Internet. Analyses of the medical literature and select
Internet sites indicate that individuals in the United
States are increasingly using kratom for the self-man-
agement of pain and opioid withdrawal. Kratom contains
pharmacologically active constituents, most notably
mitragynine and 7-hydroxymitragynine. Kratom is illegal
in many countries. Although it is still legal in the United
States, the US Drug Enforcement Administration has
placed kratom on its “Drugs and Chemicals of Concern”
list. Physicians should be aware of the availability, user
habits, and health effects of kratom. Further research on
the therapeutic uses, toxic effects, and abuse potential
of kratom and its constituent compounds are needed.
J Am Osteopath Assoc. 2012;112(12):792-799
Throughout history, humans have used plant-derived
materials (often referred to as “herbal” or “botanical”
remedies) to treat diseases, cope with the stresses of life,
and achieve altered states of awareness. Even with the
development of modern pharmaceuticals and medical
practices, many people still use herbal remedies either as
alternatives to or in conjunction with mainstream medical
care. Several years ago, Barnes et al1found that more than
30% of US patients had or were using some form of herbal-
based remedy. They also noted that the agents were being
used primarily for “musculoskeletal or other conditions
involving chronic pain.”1
Even though the efficacies of most of these herbal
remedies have yet to be proven in controlled clinical trials,
it is clear that such products are being used extensively.
Whether they are consumed alone or in combination with
prescribed medications, herbal remedies have the potential
to cause toxic effects, interact with prescription drugs, and
complicate the diagnosis and treatment of disease.2At the
same time, however, herbal remedies may have substantial
therapeutic effects. Some evidence2suggests that certain
herbal products may, in fact, have therapeutic actions that
are equivalent to those of modern pharmaceuticals. More-
over, research on the effects of herbal supplements and
their active constituents may provide insight that could
lead to the development of new and more effective thera-
peutic agents.
Given the extensive use of herbal remedies, it is impor-
tant that physicians and other health care professionals
have some knowledge of their attendant issues. This topic
is especially relevant to osteopathic physicians because
the tenets of osteopathic medicine focus on a unified
approach to patient care, musculoskeletal health, and self-
healing.3Osteopathic physicians should be familiar with
common herbal remedies that their patients may be using.
One herbal remedy that has been receiving increased public
attention in recent years is kratom.4In the present article,
we discuss current patterns of usage, basic pharmacology,
legal standing, and medicinal potential of kratom.
From the Department of Pharmacology at the Midwestern University/Chicago
College of Osteopathic Medicine (Dr Prozialeck and Mr Jivan) and the Depart-
ment of Pharmaceutical Sciences at the Midwestern University, Chicago Col-
lege of Pharmacy (Dr Andurkar), both in Downers Grove, Illinois.
Financial Disclosures: None reported.
Address correspondence to Walter C. Prozialeck, PhD, Department of
Pharmacology, Midwestern University/Chicago College of Osteopathic Med-
icine, 555 31st St, Downers Grove, IL 60515-1235.
E-mail: wprozi@midwestern.edu
Submitted March 1, 2012; revision received August 24, 2012; accepted August
29, 2012.

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Background
The term kratom refers to a group of tree-like plants belong-
ing to the Mitragyna genus of the Rubiaceae family.4-9
Other members of the Rubiaceae family include the coffee
and gardenia plants. From a medical perspective, the most
important species of kratom is Mitragyna speciosa, which
is indigenous to Thailand and surrounding countries in
Southeast Asia.7Images of a kratom plant and a kratom
leaf are shown in Figure 1.
Kratom has been widely used in Southeast Asia for
hundreds of years.5,6 In Thailand, kratom use typically
involves ingestion of the plant’s raw leaves or consumption
of teas that are brewed or steeped from the leaves.4,6,9
Kratom leaves are used for their complex, dose-dependent
pharmacologic effects.4,6,9-12 Low to moderate doses (1-5g)
of the leaves reportedly produce mild stimulant effects that
enable workers to stave off fatigue.6,9-11,13 Moderate to high
doses (5-15 g) are reported to have opioid-like effects.6,9-11,13
At these doses, kratom has been used for the management
of pain, diarrhea, and opioid withdrawal symptoms, as
well as for its properties as a euphoriant.5,6,9-11,14 Very high
doses (>15 g) of kratom tend to be quite sedating and can
induce stupor, mimicking opioid effects.4,5,9
Growth of Kratom Use in the West
Recent Research
Despite its long history and widespread use in Southeast
Asia, kratom has only recently begun to receive attention
and be used as an herbal remedy in the West. The emer-
gence of kratom as a product or drug of interest in the
United States is evident from the results of our literature
search. Our search of the US National Library of Medicine’s
PubMed database in February 2012, using the keyword
“kratom,” yielded a total of 35 published articles and
reviews. Of those, 30 (86%) were published in or after 2004,
4 (11%) were published between 1988 and 1997, and 1
(3%) was published in 1975. Another PubMed search,
using the keywords “Mitragyna speciosa,” yielded a total
of 65 published articles. Of those, 49 (75%) were published
within the past 10 years.
In addition to these general trends in the number of
publications on kratom, we found that an increasing num-
ber of reports of adverse effects resulting from the use of
kratom have been published.15-19 Recent news reports
have highlighted the increasing level of kratom use, par-
ticularly among college-aged populations.20,21 Moreover,
published studies indicate that vast numbers of online
vendors and general information Web sites for kratom
have appeared in the past few years, suggesting that there
is a substantial demand for kratom products.22,23
Increased Internet Presence
In February 2012, we also conducted an Internet search
using the Google search engine. A search for the keyword
“kratom” found more than 2 million results. Of the first
100 Web sites listed in the search results, 78 were primarily
focused on the sale of kratom, while 22 Web sites primarily
focused on disseminating information about kratom
through the use of discussion boards. We want to strongly
emphasize that the scientific validity of the claims and
anecdotes reported on these Web sites has not been sub-
stantiated. Moreover, for the purpose of the present review,
we did not believe it was appropriate to cite all sources of
anecdotal information. However, we did find 3 Web sites
to be particularly informative: Erowid.org24; Sagewisdom
.org25; and WebMD.com26. These Web sites contain a variety
of information including the drug’s uses and effects, dis-
cussions of individuals’ personal experiences, and adverse
reactions when using kratom. Some of the Web sites24,25
even describe the biology of Mitragyna speciosa, including
optimal methods and conditions for growing. In addition,
an analysis by León et al7suggests cultivation exists here
in the United States. It is also important to note that much
of the content of these Web sites clearly indicates that kratom
is being used for medicinal purposes. Although some
sites24-26 portray users of kratom as recreational drug users,
many posts on kratom blogs are from patients dealing with
pain management issues.24-26 In some cases,24-26 individuals
report finding relief of various types of pain with kratom
use. In addition, recent publications have highlighted the
use of kratom products for the self-management of opioid
withdrawal symptoms.20,27 Although the anecdotal claims
reported on the aforementioned Web sites and publications
have not been substantiated, their existence indicates that
kratom is being used in these contexts.
AB
Figure 1. Images of a kratom plant (A) and a kratom leaf (B).
Images were obtained from the US Drug Enforcement Admin-
istration Web site.4,29

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Legal Status and Availability
Although the findings of our literature and Internet searches
strongly suggest a marked increase in kratom use in the
United States and Europe, kratom still appears to be some-
what of an “underground phenomenon.” During our
searches of the literature and the internet, we found no
evidence that kratom is currently marketed by any of the
large nutritional supplement chain stores in the United
States. However, a wide variety of kratom products—
including raw leaves, capsules, tablets, and concentrated
extracts—are readily available from Internet-based sup-
pliers.20,21 In addition, these products are often sold in spe-
cialty stores commonly known as “head shops” or “smoke
shops.” In February 2012, our own informal in-person and
telephone survey of 5 smoke shops in the metropolitan
Chicago area revealed that purported kratom products
were available in all of them. Figure 2 and Figure 3 show
images of several kratom products (ie, chopped leaves,
capsules, and pressed tablets) that were legally purchased
at a smoke shop in suburban Chicago.
From a legal standpoint, kratom is regulated as an
herbal product under US law and US Food and Drug
Administration and US Drug Enforcement Administration
(DEA) policies. As of this writing, Mitragyna speciosa
(kratom) is not prohibited by the Controlled Substances
Act28 and is considered a legal substance in the United
States. However, the DEA’s December 2010 version of the
Drugs and Chemicals of Concern list states that “there is
no legitimate medical use for kratom in the U.S.”29 There-
fore, it cannot legally be advertised as a remedy for any
medical condition.
Pharmacology of Kratom
Chemistry and Pharmacognosy
As the use of kratom in the West has grown during the
past 15 years,4,20,23,30 there have been increased efforts to
identify and characterize the active pharmacologic agents
that mediate the effects of kratom in the body. Thus far,
more than 20 active compounds have been isolated from
kratom, and considerable evidence shows that these com-
pounds do, in fact, have major pharmacologic effects.30,31
Various aspects of the medicinal chemistry and pharma-
cognosy of kratom have recently been reviewed by Adkins
et al.30 Accordingly, only a few key points regarding these
topics will be considered in the present article. The Table
shows the chemical structures and summarizes the major
pharmacologic actions of some of the kratom-derived com-
pounds that have been studied most extensively. The most
extensively-characterized of kratom’s active pharmacologic
ABC
Figure 2. Images of kratom products purchased at a “smoke shop” in suburban Chicago. The images show chopped
leaves (A), which are typically brewed into “kratom tea”, capsules containing finely chopped leaves (B), and compressed
tablets containing leaves or resin (C).
Figure 3. Warning label on the back of a package of kratom
capsules.

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agents have been the mitragynine analogs.30 These agents
contain an indole ring and are, in some respects, structurally
similar to yohimbine.30 These agents have been shown to
produce a wide variety of pharmacologic effects, both in
vivo and in vitro.30 In the following sections, we will con-
sider the importance of these compounds as they relate
to the primary pharmacologic effects of kratom, particularly
analgesia and the ability to suppress symptoms of opioid
withdrawal.
Analgesic and Opioid-Like Effects
In Southeast Asia, kratom has long been used for the man-
agement of pain and opium withdrawal.6,9-11,14 In the West,
kratom is increasingly being used by individuals for the
self-management of pain or withdrawal from opioid drugs
such as heroin and prescription pain relievers.20,27 It is
these aspects of kratom pharmacology that have received
the most scientific attention. Although to our knowledge,
no well-controlled clinical studies on the effects of kratom
on humans have been published, there is evidence30-38 that
kratom, kratom extracts, and molecules isolated from
kratom can alleviate various forms of pain in animal mod-
els. Studies have used a variety of methods including hot
plate,35,37,39 tail flick,32,39 writhing,37,38 and pressure/inflam-
mation35,38 tests in mice32,35,38,39 and rats,35,37 as well as more
elaborate tests in dogs and cats.35 In addition, a variety of
chemical compounds have been isolated from kratom and
shown to exhibit opioid-like activity on smooth muscle
systems31,33,34 and in ligand-binding studies.39,40 Most
notably, many of the central nervous system and peripheral
effects of these kratom-derived substances are sensitive to
inhibition by opioid antagonists.31-34,39-41
Table.
Structures and Pharmacologic Activities of Compounds Isolated From Kratom
Compound Structure Pharmacology
Mitragynine30,33,34,39,40,44 Structurally similar to yohimbine
Activity on μ, ␦, and κreceptors
Main activity on μreceptors creating opiate
and analgesic effects and physical dependence
Inhibits radioligand binding at central nervous
system receptors
Activates descending noradrenergic and
serotonergic pathways in spinal cord
Stimulates postsynaptic α2-adrenergic
receptors
Blocks stimulation of 5-hydroxytryptamine2A
receptors
7-Hydroxymitragynine30,33,34,39,40,44 13- and 46-fold higher potency than morphine
and mitragynine, respectively
Potency and quick-acting characteristics may be
caused by introduction of –OH group on C7
position
Induces clinically significant antinociceptive
responses in a dose-dependent manner
Speciociliatine30,44 C3 stereoisomer of mitragynine
Inhibits twitch contraction in naloxone-
insensitive manner
May inhibit acetylcholine release from
presynaptic nerve through means other than
opioid receptor
stimulation
Paynantheine40,44 Inhibits twitch contraction in naloxone-
insensitive manner
Inhibits muscarine receptors on ileal smooth
muscle
Speciogynine40,44 Inhibits twitch contraction in naloxone-
insensitive manner
Inhibits muscarine receptors in ileal smooth
muscle

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Most of the opioid-like activity of kratom has been
attributed to the presence of the indole alkaloids, mitrag-
ynine and 7-hydroxymitragynine. Both compounds have
been shown to have analgesic and antinociceptive effects
in animals, although 7-hydroxymitragynime is more
potent.30,32,40 These agents also produce opioid-like effects
on organs such as the intestines and male internal geni-
talia.33,34 Moreover, when they are given to animals for 5
days or longer, both compounds produce a state of physical
dependence, with withdrawal symptoms that resemble
those of opioid withdrawal.31,32,41 In addition, ligand-bind-
ing studies and those using opioid antagonists indicate
that these effects are largely mediated by means of actions
on μ- and δ-type opioid receptors.30,31,33 Along with these
various central nervous system effects, kratom also appears
to have anti-inflammatory activity.38Utar et al42recently
found that mitragynine can inhibit lipopolysaccharide-
stimulated cyclooxygenase-2 expression and prostaglandin
E2 production. In addition to direct mediation by means
of opioid receptors, the antinociceptive effects of mitrag-
ynine appear to involve the activation of descending nora-
drenergic and serotonergic pathways in the spinal cord.43
Additionally, animal studies have shown that mitragynine
may stimulate postsynaptic α2-adrenergic receptors and
possibly even block 5-hydroxytryptamine2A receptors.33
Although kratom contains lower levels of 7-hydroxymi-
tragynine than mitragynine, it has been suggested that
7-hydroxymitragynine is more potent and has better oral
bioavailability and blood brain-barrier penetration than
mitragynine,30,40 making it the predominant mediator of
analgesic effects of kratom in the body.
Other compounds that have been isolated from kratom
and implicated in some of its effects include speciociliatine,
speciogynine, and paynatheine.30,40 These compounds
have been shown to modulate intestinal smooth muscle
function and behavioral response in animals.33,34,40,44 How-
ever, these effects were not inhibited by the opioid receptor
antagonist naloxone, suggesting that they involve opioid-
independent mechanisms.40,44 It remains to be determined
how these compounds may contribute to the overall actions
of kratom in vivo.
Subjective Effects
In spite of the fact that kratom has been widely touted
and used as a “legal opioid,”23,31 few scientific studies
have addressed the psychoactive properties of
kratom.6,9,11,12 Most of the available information is based
on anecdotal reports and patient experiences. The general
subjective effects of kratom have been summarized in
various reviews.6,9,12,30 In addition, many individuals
have posted descriptions of their personal kratom expe-
riences on Web sites such as Erowid, Sagewisdom, and
WebMD.24-26 As noted previously, kratom produces an
unusual combination of stimulant- and opioid-like effects.
These effects are highly dependent on the dose of kratom
and can vary markedly from one individual to another.
Low to moderate doses (1-5 g of raw leaves) usually pro-
duce a mild stimulant effect that most individuals perceive
as pleasant but not as intense as those of amphetamine-
like drugs.24,25 Some individuals, however, report that
these low-dose effects are mainly characterized by an
unpleasant sense of anxiety and internal agitation.24-26 It
is noteworthy that those who have used kratom products
for pain management tend to view the stimulant effects
of kratom as being more desirable than the sedative effects
of traditional opioids.24-26
Opioid-like effects, such as analgesia, constipation,
euphoria, and sedation are typically associated with the
use of moderate-high doses of kratom (5-15 g). As with
the lower-dose effects, the higher-dose effects may be either
euphoric or dysphoric, depending on the individual. Of
note, the euphoric effects of kratom generally tend to be
less intense than those of opium and opioid drugs.6,10,11,25
Nevertheless, kratom is still sought by drug users.
Toxic Effects and Untoward Reactions
During the past 3 years, there have been an increasing
number of case reports15,17,29 describing unusual adverse
reactions in patients who had been using kratom or
kratom-based products. The acute adverse effects of
kratom experienced by many users appear to be a direct
result of kratom’s stimulant and opioid activities.6,9,11,30,31
Stimulant effects may manifest themselves in some indi-
viduals as anxiety, irritability, and increased aggression.
Opioid-like effects include sedation, nausea, constipation,
and itching. Again, these effects appear to be dose depend-
ent and to vary markedly from one individual to another.
Chronic, high-dose usage has been associated with several
unusual effects. Hyperpigmentation of the cheeks, tremor,
anorexia, weight loss, and psychosis have been observed
in individuals with long-term addiction.9Reports of serious
toxic effects are rare and have usually involved the use
of relatively high doses of kratom (>15 g).9,17,45,46 Of par-
ticular concern, there have been several recent reports of
seizures occurring in individuals who have used high
doses of kratom, either alone or in combination with other
drugs, such as modafinil.17,22,45 Kapp et al15 recently
described a case of intrahepatic cholestasis in a chronic
user of kratom.
It is important to note that in each of these case reports,
the patients may have had confounding health conditions,
may have been using other drugs along with kratom, or
both. One of the major problems in evaluating the potential
uses and safety of an herbal agent such as kratom is the
lack of understanding of how substances in kratom may
interact with prescription medications, drugs of abuse, or

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even other herbal supplements. This issue is compounded
by the relative lack of regulations and standardization
related to the production and sale of kratom. These poten-
tial hazards were highlighted in several case reports of
deaths resulting from the use of a kratom-based product
known as “Krypton”.16,47 This agent, which was touted
as a very potent form of kratom, had been marketed in
Sweden. During the past 5 years, there have been reports
of 9 deaths related to the use of Krypton.16In a case series
by Kronstad et al,16subsequent forensic studies revealed
that Krypton contained high amounts of the exogenous
pharmaceutical agent O-desmethyltramadol, which has
opioid and neuromodulator activity. Evidently, the exoge-
nous O-desmethyltramadol had been added to the plant
material. Even though mitragynine was also detected in
the products, it was not determined how the 2 substances
may have interacted to cause death. Another recent report48
described a fatal reaction that appeared to be associated
with the use of a combination of propylhexedrine—an α
agonist and an amphetamine-like stimulant—and mitrag-
ynine. This latter case highlights the fact that extracts and
tinctures containing purified mitragynine, 7-hydroxymi-
tragynine, and 7-acetoxymitragynine have become available
for purchase by means of the Internet. These sources can
easily be found by conducting an Internet search using
the term “mitragynine purchase.” The possibility that these
highly concentrated mitragynine alkaloid extracts could
be used in conjunction with other psychoactive drugs (eg,
alcohol, sedatives, opioids, stimulants, cannabinoids) raises
the potential for serious drug interactions.
Kratom Abuse, Dependence, and Addiction
Potential
A large number of Internet posts refer to the use of kratom
as a euphoriant or “legal opioid.”23-26 A major question
that remains unanswered is, “How addictive is kratom?”
Although many anecdotal reports suggest that it may be
less addictive than classical opioids, there are also numerous
reports that, in some individuals, it may be highly addictive.
For example, in Southeast Asia, it has long been recognized
that individuals will seek out and abuse kratom for its
euphoric and mind-altering effects and that chronic users
can become tolerant of, physically dependent on, and
addicted to kratom.9,10 Kratom addiction is considered
such a problem that many Southeast Asian countries have
outlawed the use of kratom.9,10
As kratom use has expanded to Europe and the United
States, there have been increasing reports of individuals
becoming physically dependent on or addicted to
kratom.22,30,31,45,46 Most published studies are case
reports22,31,45,46 of heavy, compulsive users of kratom. In
each case, the individual exhibited substantial tolerance
to the effects of kratom and showed overt symptoms of
withdrawal when kratom use was stopped. The symptoms
of withdrawal were similar to those from traditional opioids
and included irritability, dysphoria, nausea, hypertension,
insomnia, yawning, rhinorrhea, myalgia, diarrhea, and
arthralgias. In a recent report, McWhirter and Morris45
described the use of an opioid agonist (dihydrocodeine)
and an α-adrenergic antagonist (lofexidine) to successfully
manage symptoms of withdrawal in an individual who
was addicted to kratom.
Drug Screening and Analyses
Kratom and kratom-derived compounds such as mitrag-
ynine and 7-hydroxymitragynine are not detected in most
routine drug testing or screening procedures.49 Although
various tests for kratom-derived compounds have been
developed,49they are not yet widely available for general
use. Moreover, there are still some controversies regarding
the designation of drug-level cutoff points for defining
the tests.49 The analytical and forensic aspects of kratom
toxicology have been summarized in a review by Philipp
et al.49
Conclusion
Evidence suggests that kratom is being used extensively
for both medical and nonmedical purposes. Recent studies
have shown that kratom contains a variety of active com-
pounds that produce major pharmacologic effects at opioid
and other receptors. Kratom and kratom-derived drugs
may potentially be used for the management of pain,
opioid withdrawal symptoms, and other clinical problems.
At the same time, serious questions remain regarding the
potential toxic effects and the abuse and addiction potential
of kratom. This issue is further confounded by the lack of
quality control and standardization in the production and
sale of kratom products. The possibilities of kratom prod-
ucts being adulterated or interacting with other drugs are
also serious concerns. Until these issues are resolved, it
would not be appropriate for physicians to recommend
kratom for the treatment of patients. Nevertheless, physi-
cians need to be aware that patients may use kratom or
kratom-based products on their own. Further studies to
clarify the efficacy, safety, and addiction potential of kratom
are needed.
Acknowledgments
The authors thank Victoria Sears and Laura Phelps, MA, in the
Department of Pharmacology at Midwestern University for
their help in preparing the manuscript. The authors also thank
Susan Hershberg at Midwestern University for her assistance
in capturing the photographic images of the kratom products.
(continued)

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SPECIAL COMMUNICATION
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