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


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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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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.
Submitted March 1, 2012; revision received August 24, 2012; accepted August
29, 2012.
JAOA Vol 112 • No 12 • December 2012 793Prozialeck et al • Special Communication
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.
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
794 • JAOA • Vol 112 • No 12 • December 2012 Prozialeck et al • Special Communication
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
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
JAOA Vol 112 • No 12 • December 2012 795Prozialeck et al • Special Communication
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
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
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
Blocks stimulation of 5-hydroxytryptamine2A
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
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
Paynantheine40,44 Inhibits twitch contraction in naloxone-
insensitive manner
Inhibits muscarine receptors on ileal smooth
Speciogynine40,44 Inhibits twitch contraction in naloxone-
insensitive manner
Inhibits muscarine receptors in ileal smooth
796 • JAOA • Vol 112 • No 12 • December 2012 Prozialeck et al • Special Communication
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
JAOA Vol 112 • No 12 • December 2012 797Prozialeck et al • Special Communication
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
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
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.
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.
798 • JAOA • Vol 112 • No 12 • December 2012 Prozialeck et al • Special Communication
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... Kratom (Mitragyna speciosa) is a plant native to Southeast Asia that has been used for centuries as a traditional medicine and herbal remedy. Kratom is consumed orally by chewing fresh or dried leaves, drinking crushed or boiled leaves in a tea, or by consuming encapsulated leaf powder [1][2][3][4]. In the United States, there are an estimated 10-16 million kratom users [3,[5][6][7][8][9]. ...
Aims: Mitragynine (MG) is an alkaloid found in Mitragyna speciosa (kratom), a plant used to self-treat symptoms of opioid withdrawal and pain. Kratom products are commonly used in combination with cannabis, with the self-treatment of pain being a primary motivator of use. Both cannabinoids and kratom alkaloids have been characterized to alleviate symptoms in preclinical models of neuropathic pain such as chemotherapy-induced peripheral neuropathy (CIPN). However, the potential involvement of cannabinoid mechanisms in MG's efficacy in a rodent model of CIPN have yet to be explored. Main methods: Prevention of oxaliplatin-induced mechanical hypersensitivity and formalin-induced nociception were assessed following intraperitoneal administration of MG and CB1, CB2, or TRPV1 antagonists in wildtype and cannabinoid receptor knockout mice. The effects of oxaliplatin and MG exposure on the spinal cord endocannabinoid lipidome was assessed by HPLC-MS/MS. Key findings: The efficacy of MG on oxaliplatin-induced mechanical hypersensitivity was partially attenuated upon genetic deletion of cannabinoid receptors, and completely blocked upon pharmacological inhibition of CB1, CB2, and TRPV1 channels. This cannabinoid involvement was found to be selective to a model of neuropathic pain, with minimal effects on MG-induced antinociception in a model of formalin-induced pain. Oxaliplatin was found to selectively disrupt the endocannabinoid lipidome in the spinal cord, which was prevented by repeated MG exposure. Significance: Our findings suggest that cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid MG in a model of CIPN, which may result in increased therapeutic efficacy when co-administered with cannabinoids.
... Terms such as 'legal highs' or 'herbal highs' give the perception that kratom is a safe alternative to opioids (Anand and Hosanagar, 2022). Sales of these products at affordable prices via internet vendors or at gas stations and smoke/head shops are widespread (Prozialeck et al., 2012;Williams and Nikitin, 2020). ...
Kratom is a botanical natural product belonging to the coffee family, with stimulant effects at low doses and opioid-like effects at higher doses. During the last two decades, kratom has been purported as a safer alternative to pharmaceutical and illicit drugs to self-manage pain and opioid withdrawal symptoms. Kratom alkaloids, typically mitragynine, have been detected in biological samples from overdose deaths. These deaths are often observed in combination with other drugs and are suspected to result from polyintoxications. This review focuses on the potential for kratom to precipitate pharmacokinetic interactions with object drugs involved in these reported polyintoxications. The legal status, chemistry, pharmacology, and toxicology are also summarized. The aggregate in vitro and clinical data identified kratom and select kratom alkaloids as modulators of cytochrome P450 (CYP) enzyme activity, notably as inhibitors of CYP2D6 and CYP3A, as well as P-glycoprotein-mediated efflux activity. These inhibitory effects could increase the systemic exposure to co-consumed object drugs, which may lead to adverse effects. Collectively, the evidence to date warrants further evaluation of potential kratom-drug interactions using an iterative approach involving additional mechanistic in vitro studies, well-designed clinical studies, and physiologically based pharmacokinetic modeling and simulation. This critical information is needed to fill knowledge gaps regarding the safe and effective use of kratom, thereby addressing ongoing public health concerns. Significance Statement The botanical kratom is increasingly used to self-manage pain and opioid withdrawal symptoms due to having opioid-like effects. The legal status, chemistry, pharmacology, toxicology, and drug interaction potential of kratom are reviewed. Kratom-associated polyintoxications and in vitro-in vivo extrapolations suggest that kratom can precipitate pharmacokinetic drug interactions by inhibiting CYP2D6, CYP3A, and P-gp. An iterative approach that includes clinical studies and PBPK modeling and simulation is recommended for further evaluation of the drug interaction potential of this increasingly popular botanical.
In recent years, mitragynine has been consistently detected in driving under the influence of drug (DUID) cases. In this paper, we evaluate three years (2017–2019) worth of DUID data from arrested drivers in Orange County, CA, USA. From the 25,398 DUID cases received in those three years, there were 60 (0.24%) cases with detectable concentrations, >10 ng/mL, of mitragynine. The majority of the drivers were male (90%), and were stopped during the week (81%), considered Monday 0000 to Friday 1159. The concentration range for all mitragynine cases was 10.5-960 ng/mL, with a mean of 109 ng/mL and a median of 58 ng/mL. Forty-four of the 60 cases were also screened for 7-hydroxymitragynine and 27 (63%) were positive. The police reports and drug recognition expert evaluations were collected and evaluated. No case contained solely mitragynine and the most common drugs detected in combination were central nervous system depressants (ethanol, followed by benzodiazepines), stimulants (methamphetamine and cocaine), and opioids (fentanyl and indication of heroin). Two cases containing only one other psychoactive substance are discussed more thoroughly to attempt to identify the contributions of mitragynine to driving impairment. Collected demographic, toxicological, and field observations are presented for all cases.
Substance abuse is on the rise, and while many people may use illicit drugs mainly due to their rewarding effects, their societal impact can range from severe, as is the case for opioids, to promising, as is the case for psychedelics. Common with all these drugs' mechanisms of action are G protein-coupled receptors (GPCRs), which lie at the center of how these drugs mediate inebriation, lethality, and therapeutic effects. Opioids like fentanyl, cannabinoids like THC, and psychedelics like LSD all directly bind to GPCRs to initiate signaling which elicits their physiological actions. We herein review recent structural studies and provide insights into the molecular mechanisms of opioids, cannabinoids, and psychedelics at their respective GPCR subtypes. We further discuss how such mechanistic insights facilitate drug discovery, either towards the development of novel therapies to combat drug abuse, or towards harnessing therapeutic potential.
In this review, an attempt was made to compile and include published data of cardiotoxic plants from all over the world. The plants have been listed with their scientificand common names, a family from which they belong, their parts that specifically contain toxic active principles causing cardiotoxicity. Moreover, the review also has specific symptoms, which can provide great help in understanding the patient’s condition and help in providing medicinal aid and treatment. This review is the first of its kind involving the details of the cardiotoxic plants worldwide. A short description of how the toxins affect the heart and possible treatments for dealing with the symptoms have also been presented here.
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Work translated title (English): THESIS: "OPIOID RECEPTORS: in vitro VALUATION OF THE ACTIVITY OF NOVEL BIOACTIVE MOLECULES". DISCLAIMER: The file that is included is not the exact same as the one submitted to the University. Some minor changes have been made.
Introduction: Chronic neuropathic pain is as a severe detriment to overall quality of life for millions of Americans. Current pharmacological treatment options for chronic neuropathic pain are generally limited in efficacy and may pose serious adverse effects such as risk of abuse, nausea, dizziness, and cardiovascular events. Therefore, many individuals have resorted to methods of pharmacological self-treatment. This narrative review summarizes the existing literature on the utilization of two novel approaches for the treatment of chronic pain, cannabinoid constituents of Cannabis sativa and alkaloid constituents of Mitragyna speciosa (kratom), and speculates on the potential therapeutic benefits of co-administration of these two classes of compounds. Methods: We conducted a narrative review summarizing the primary motivations for use of both kratom and cannabis products based on epidemiological data and summarize the pre-clinical evidence supporting the application of both kratom alkaloids and cannabinoids for the treatment of chronic pain. Data collection was performed using the PubMed electronic database. The following word combinations were used: kratom and cannabis, kratom and pain, cannabis and pain, kratom and chronic pain, and cannabis and chronic pain. Results: Epidemiological evidence reports that the self-treatment of pain is a primary motivator for use of both kratom and cannabinoid products among adult Americans. Further evidence shows that use of cannabinoid products may precede kratom use, and that a subset of individuals concurrently uses both kratom and cannabinoid products. Despite its growing popularity as a form of self-treatment of pain, there remains an immense gap in knowledge of the therapeutic efficacy of kratom alkaloids for chronic pain in comparison to that of cannabis-based products, with only three pre-clinical studies having been conducted to date. Conclusion: There is sufficient epidemiological evidence to suggest that both kratom and cannabis products are used to self-treat pain, and that some individuals actively use both drugs, which may produce potential additive or synergistic therapeutic benefits that have not yet been characterized. Given the lack of pre-clinical investigation into the potential therapeutic benefits of kratom alkaloids against forms of chronic pain, further research is warranted to better understand its application as a treatment alternative.
Alternative medicine supplements have become the second most common cause of drug-induced liver injury (DILI) in the US. Kratom is a herbal supplement that is popular for its psychotropic and opioid-like activity. It has become increasingly available in western countries, which often have no specific regulations on its use. However, reports of adverse events linked to kratom use have been increasing; it has been implicated in acute liver injury (mostly cholestatic), acute liver failure, organ dysfunction, toxicity, coma, seizures, and death. Herein, we aim to increase healthcare provider and public awareness of the risks posed by kratom and ultimately support increased regulation of its use.
Kratom (Mitragyna speciosa) is a tree in the coffee family, indigenous to Southeast Asia (SEA), whose leaves have historically been used as a natural remedy and for its purported stimulating and analgesic properties. Kratom has gained popularity in recent years in the United States, where internet-based sales have driven growing numbers of people to experiment with kratom products. Kratom contains over 40 unique alkaloids displaying complex pharmacological properties including opioid- and non opioid-receptor mediated effects. Data from animal research indicates therapeutic potential of kratom; for instance, as an analgesic agent or in mitigating opioid and alcohol withdrawal symptoms. Some adverse effects and risks are also attributable to kratom and its alkaloids, including possible liver damage and potential for dependence, particularly in the context of high dosage and/or chronic administration. However, in comparison to commonly used opioid medications, these risks are generally lower for kratom, consistent with human observational data from SEA and the US. Prevalence of kratom use remains difficult to conclusively assess, with estimates ranging between 1.8 to 15.6 million kratom-using adults in the US alone. The limited human data, comprised of survey and case report, suggest kratom may be effective for pain relief, to address mood and anxiety symptoms, and as a potential future aid in the treatment of substance use disorders and drug withdrawal. Overall, limited data indicate kratom and its alkaloids warrant a significant investment of rigorous basic and clinical research to better characterize its pharmacology, potential risks, and therapeutic benefits.
Penelitian ini bertujuan untuk mengevaluasi potensi antinosiseptif pada sediaan krim ekstrak daun kratom dan menentukan dosis efektifnya. Metode ekstraksi daun kratom yaitu dengan cara remaserasi menggunakan pelarut etanol 70%. Hasil ekstrak kental yang diperoleh dari proses maserasi dimasukkan ke dalam sediaan vanishing cream dengan dosis 0,26 gram; 0,56 gram; dan 0,86 gram. Pengujian antinosiseptif menggunakan metode hotplate test pada mencit jantan galur Deutschland Denken Yoken (DDY). Hasil pengamatan dianalisis menggunakan statistik nonparametrik Kruskal Wallis dan uji persamaan regresi linier. Hasil analisis menunjukkan bahwa ketiga dosis krim ekstrak daun kratom memiliki perbedaan dan pengaruh terhadap jumlah loncatan kaki pada hewan coba jika dibandingkan dengan kelompok kontrol negatif yang berpotensi sebagai antinosiseptif namun kurang bermakna, karena tidak menggunakan kontrol positif. Kata Kunci: Antinosiseptif, Krim,Uji Sediaan, Daun Kratom, Mitragyna speciosa Korth.This study aims to evaluate the antinociceptive potential of kratom leaf ekstract cream and determine its effective dose. The kratom leaf extraction method used maceration using 70% ethanol solvent. The crude extract obtained from the maceration process is put in to the vanishing cream preparation at a dose of 0.26 grams, 0.56 grams, and 0.86 grams. Antinociceptive testing used the hot plate method on DDY strain male mice. The results of the observations were analyzed using nonparametric statistics “kruskal wallis” and linear regression equation test. The results of analysis showed that the three doses of kratom leaf extract cream had an effect on the number of jumps on the legs of experimental animals when compared to the negative control group which had the potential to be antinociceptive but less significant, because it did not use a positive control.
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Mitragyna speciosa Korth is a medicinal plant indigenous to Thailand and Malaysia and has been known for its narcotic and coca-like effects. Many studies have been performed on the antinociceptive effect of the plant extracts of Thai origin; however, limited studies have been reported till date on M. speciosa extracts of Malaysian origin. Various concentrations of alkaloid (5-20 mg/kg), methanolic (50-200 mg/kg), and aqueous (100-400 mg/kg) extracts of Malaysian M. speciosa leaves were prepared and orally administered to nine groups of rats. Morphine (5 mg/kg, s.c.) and aspirin (300 mg/kg, p.o.) were used as control. Antagonism of the antinociceptive activity was evaluated by pretreatment with naloxone at a dose of 2 mg/kg (i.p.). Results showed that oral administration of the alkaloid (20 mg/kg), methanolic (200 mg/kg), and aqueous (400 mg/kg) extracts significantly prolonged the latency of nociceptive response compared with control groups in both hot plate and tail flick tests (P < 0.05). Antinociceptive action of the alkaloid (20 mg/kg), methanolic (200 mg/kg), and aqueous (400 mg/kg) extracts was significantly blocked by naloxone. In conclusion, these results suggest the presence of antinociceptive effect in various extracts of Malaysian M. speciosa leaves. In addition, the antinociceptive effective doses vary depending on the type of solvents used for extraction.
Despite their widespread Internet availability and use, many of the new drugs of abuse remain unfamiliar to health care providers. The herbal marijuana alternatives, like K2 or Spice, are a group of herbal blends that contain a mixture of plant matter in addition to chemical grade synthetic cannabinoids. The synthetic cathinones, commonly called "bath salts," have resulted in nationwide emergency department visits for severe agitation, sympathomimetic toxicity, and death. Kratom, a plant product derived from Mitragyna speciosa Korth, has opioid-like effects, and has been used for the treatment of chronic pain and amelioration of opioid-withdrawal symptoms. Salvia divinorum is a hallucinogen with unique pharmacology that has therapeutic potential but has been banned in many states due to concerns regarding its psychiatric effects. Methoxetamine has recently become available via the Internet and is marked as "legal ketamine." Moreover, the piperazine derivatives, a class of amphetamine-like compounds that includes BZP and TMFPP, are making a resurgence as "legal Ecstasy." These psychoactives are available via the Internet, frequently legal, and often perceived as safe by the public. Unfortunately, these drugs often have adverse effects, which range from minimal to life-threatening. Health care providers must be familiar with these important new classes of drugs. This paper discusses the background, pharmacology, clinical effects, detection, and management of synthetic cannabinoid, synthetic cathinone, methoxetamine, and piperazine exposures.
Striking increases in the abuse of opioids have expanded the need for pharmacotherapeutic interventions. The obstacles that confront effective treatment of opioid addiction - shortage of treatment professionals, stigma associated with treatment and the ability to maintain abstinence - have led to increased interest in alternative treatment strategies among both treatment providers and patients alike. Herbal products for opioid addiction and withdrawal, such as kratom and specific Chinese herbal medications such as WeiniCom, can complement existing treatments. Unfortunately, herbal treatments, while offering some advantages over existing evidence-based pharmacotherapies, have poorly described pharmacokinetics, a lack of supportive data derived from well controlled clinical trials, and severe toxicity, the cause for which remains poorly defined. Herbal products, therefore, require greater additional testing in rigorous clinical trials before they can expect widespread acceptance in the management of opioid addiction.
Here we present a case of a coincidence of addiction to "Kratom" (botanically known as Mitragyna speciosa Korth) and developed severe primary hypothyroidism. We are discussing a possibility that high dose of indole alkaloid mitragynine (the major alkaloid identified from "Kratom") might reduce the normal response of the thyroid gland to thyroid-stimulating hormone resulting in primary hypothyroidism. Further experimental investigations of mitragynine as a possible suppressor of thyroid gland function would be a matter of interest.
Kratom (Mitragyna speciosa) is a common medical plant in Thailand and is known to contain mitragynine as the main alkaloid. According to an increase in published reports and calls at German poison control centers, it has been used more frequently as a drug of abuse in the western hemisphere during the last couple of years. Despite this increase, reports of severe toxicity are rare within the literature. We describe a case of a young man who presented with jaundice and pruritus after intake of kratom for 2 weeks in the absence of any other causative agent. Alkaloids of M. speciosa were detected in the urine. While M. speciosa is gaining in popularity among illicit drug users, its adverse effects remain poorly understood. This is the first published case of intrahepatic cholestasis after kratom abuse.
ETHOPHARMACOLOGICAL RELEVANCE: Mitragyna speciosa Korth (Rubiaceae) is one of the medicinal plants used traditionally to treat various types of diseases especially in Thailand and Malaysia. Its anti-inflammatory and analgesic properties in its crude form are well documented. In this study, the cellular mechanism involved in the anti-inflammatory effects of mitragynine, the major bioactive constituent, was investigated. The effects of mitragynine on the mRNA and protein expression of COX-1 and COX-2 and the production of prostaglandin E(2) (PGE(2)) were investigated in LPS-treated RAW264.7 macrophage cells. Quantitative RT-PCR was used to assess the mRNA expression of COX-1 and COX-2. Protein expression of COX-1 and COX-2 were assessed using Western blot analysis and the level of PGE(2) production was quantified using Parameter™ PGE(2) Assay (R&D Systems). Mitragynine produced a significant inhibition on the mRNA expression of COX-2 induced by LPS, in a dose dependent manner and this was followed by the reduction of PGE(2) production. On the other hand, the effects of mitragynine on COX-1 mRNA expression were found to be insignificant as compared to the control cells. However, the effect of mitragynine on COX-1 protein expression is dependent on concentration, with higher concentration of mitragynine producing a further reduction of COX-1 expression in LPS-treated cells. These findings suggest that mitragynine suppressed PGE(2) production by inhibiting COX-2 expression in LPS-stimulated RAW264.7 macrophage cells. Mitragynine may be useful for the treatment of inflammatory conditions.