Following “the Roots” of Kratom ( Mitragyna speciosa ): The Evolution of an Enhancer from a Traditional Use to Increase Work and Productivity in Southeast Asia to a Recreational Psychoactive Drug in Western Countries

Abstract

The use of substances to enhance human abilities is a constant and cross-cultural feature in the evolution of humanity. Although much has changed over time, the availability on the Internet, often supported by misleading marketing strategies, has made their use even more likely and risky. This paper will explore the case of
Mitragyna speciosa
Korth. (kratom), a tropical tree used traditionally to combat fatigue and improve work productivity among farm populations in Southeast Asia, which has recently become popular as novel psychoactive substance in Western countries. Specifically, it (i) reviews the state of the art on kratom pharmacology and identification; (ii) provides a comprehensive overview of kratom use cross-culturally; (iii) explores the subjective experiences of users; (iv) identifies potential risks and side-effects related to its consumption. Finally, it concludes that the use of kratom is not negligible, especially for self-medication, and more clinical, pharmacological, and socioanthropological studies as well as a better international collaboration are needed to tackle this marginally explored phenomenon.

Full text

Research Article
Following (the Roots)of Kratom (Mitragyna speciosa):
The Evolution of an Enhancer from a Traditional Use to Increase
Work and Productivity in Southeast Asia to a Recreational
Psychoactive Drug in Western Countries
Eduardo Cinosi,1,2 Giovanni Martinotti,1,2 Pierluigi Simonato,1
Darshan Singh,3Zsolt Demetrovics,4Andres Roman-Urrestarazu,5,6
Francesco Saverio Bersani,1,7 Balasingam Vicknasingam,3Giulia Piazzon,1
Jih-Heng Li,8Wen-Jing Yu,8Máté Kapitány-Fövény,4,9,10 Judit Farkas,4,10
Massimo Di Giannantonio,2and Ornella Corazza1,7
1CentreforClinical&HealthResearchServices,SchoolofLifeandMedicalSciences,UniversityofHertfordshire,CollegeLaneCampus,
Hateld, Her ts AL10 9AB, UK
2Department of Neuroscience, Imaging and Clinical Sciences, Gabriele D’Annunzio University, Chieti, Italy
3Centre for Drug Research, Universiti Sains, Penang, Malaysia
4Institute of Psycholog y, E¨
otv¨
os Lor´
andUniversity,Budapest,Hungary
5London School of Economics and Political Science, LSE Health and Social Care, London, UK
6Department of Psychiatry, University of Cambridge, Cambridge, UK
7Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
8School of Pharmacy and Ph.D. Program in Toxicology, Kaohsiung Medical University, Kaohsiung, Taiwan
9Faculty of Health Sciences, Semmelweis University, Budapest, Hungary
10Ny´
ır˝
o Gyula Hospital, National Institute of Psychiatry and Addictions, Budapest, Hungary
Correspondence should be addressed to Ornella Corazza; o.corazza@herts.ac.uk
Received  August ; Revised  October ; Accepted  October 
Academic Editor: Yu-Ping Tang
Copyright ©  Eduardo Cinosi et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
e use of substances to enhance human abilities is a constant and cross-cultural feature in the evolution of humanity. Although
much has changed over time, the availability on the Internet, oen supported by misleading marketing strategies, has made their use
even more likely and risky. is paper will explore the case of Mitragyna speciosa Korth. (kratom), a tropical tree used traditionally
to combat fatigue and improve work productivity among farm populations in Southeast Asia, which has recently become popular
as novel psychoactive substance in Western countries. Specically, it (i) reviews the state of the art on kratom pharmacology and
identication; (ii) provides a comprehensive overview of kratom use cross-culturally; (iii) explores the subjective experiences of
users; (iv) identies potential risks and side-eects related to its consumption. Finally, it concludes that the use of kratom is not
negligible, especially for self-medication, and more clinical, pharmacological, and socioanthropological studies as well as a better
international collaboration are needed to tackle this marginally explored phenomenon.
1. Introduction
Kratom (Mitragyna speciosa Korth., of the Rubiaceae family)
is a –-metre high tropical tree, indigenous to Southeast
Asia, the Philippines, and New Guinea. Traditionally, in
certain regions of Southeast Asia, the chopped fresh or dried
leaves of the tree are chewed or made into tea by local manual
labourers to combat fatigue and improve work productivity
[]. In addition, kratom preparations have also been used
for centuries during socioreligious ceremonies and to treat
Hindawi Publishing Corporation
BioMed Research International
Volume 2015, Article ID 968786, 11 pages
http://dx.doi.org/10.1155/2015/968786

BioMed Research International
66%
7%
9%
1% 2%
15%
Other
Mitragynine (C23H30 N2O4)
Paynantheine (C23H28N2O4)
Hydroxymitragynine (C23H30N2O5)
Speciogynine (C23H30 N2O4)
Speciociliatine (C23H30N2O4)
F : An estimate of ai kratom extract composition. e
phytochemicals isolated from various parts of the tree include
overall  structurally related alkaloids as well as several avonoids,
terpenoid saponins, polyphenols, and various glycosides.
various medical conditions, such as morphine dependence
in ailand [], and as opium substitute in Malaya []. It
has been suggested that the genus was given the “Mitragyna”
name by the Dutch botanist Korthals because the leaves and
the stigmas of the owers of the plant resemble the shape
of a bishop’s mitre []. However, considering its variety of
uses, it could be speculated that the term derives from the
“Mithraic cults,” seen as a source of spiritual transcendence
for thousands of years [].
Kratom preparations contain varying amounts of several
phytochemicals, making their pharmacological and toxi-
cological evaluation unique and dicult (Figure ). e
main psychoactive components in the leaves are alkaloids
mitragynine and -hydroxymitragynine both found only in
Mitragyna speciosa, but other analogues have been identied
(e.g., speciogynine, paynantheine, and speciociliatine) [,
] (Figure ). e eects of kratom in humans are dose-
dependent where small doses produce stimulatory eects
resemblingthestimulanteectofdrugssuchascocaineor
amphetamines, while larger dosages tend to be associated
with sedative-narcotic eects that resemble drugs such as
opiates [].
Imported to Western countries from Southeast Asia,
kratom has become in recent years a popular enhancer,
which could also be classied as novel psychoactive substance
(NPS) []. Beyond kratom, some of the most widely used
psychoactive plants, largely not under international control,
include Salvia divinorum,khat(Catha edulis), Hawaiian baby
woodrose seeds (Argyreia nervosa), y agaric (Amanita mus-
caria), “Magic Mushrooms” (Psilocybe and related species),
Peyote (Lophophora williamsii), Ayahuasca (Banisteriopsis
caapi and Psychotria viridis), and “Genie” (a smoking mixture
containing multiple plant materials and of dubious phar-
macognostical identity) []. Natural products oen used
as enhancers are exceptionally complex in terms of their
chemistry. is adds complexity of their pharmacological
eects, with a paucity of data relating to the toxicology of
these materials, and even less regarding their interactions
with conventional drugs of abuse []. is is further compli-
cated by the possibility of adulteration processes []. e level
of complexity, variability, and the unknown nature of these
samples,coupledwiththerisksassociatedwithtakingpsy-
choactive materials, could oer further risks of ill health by
misadventure, with potentially life-threatening consequences
[]. In this scenario, predictions of novel psychoactive drug
trends in Western countries specically suggest that kratom
usewillincreaseinthenextyears[].
e aim of the present study was to study this new
phenomenon by (i) reviewing the state of the art on kratom
pharmacology and identication; (ii) providing a compre-
hensive overview of kratom use cross-culturally, ranging
from its traditional use in native societies in Southeast Asia to
its more recent diusion as a NPS in Western countries; (iii)
exploring the subjective experience of users; (iv) identifying
risks and side-eects related to its consumption.
2. Materials and Methods
A collaborative and multidisciplinary eort to study the
rapid diusion of kratom was carried internationally by ten
research centres: the School of Life and Medical Sciences,
University of Hertfordshire (United Kingdom), Department
of Neuroscience, Imaging and Clinical Sciences, Gabriele
D’Annunzio University, Chieti (Italy), Centre for Drug
Research, Universiti Sains, Penang (Malaysia), Institute of
Psychology, E¨
otv¨
os Lor´
and University, Budapest (Hungary),
London School of Economics and Political Science, LSE
Health and Social Care, London (United Kingdom), Depart-
ment of Psychiatry, University of Cambridge, Cambridge
(United Kingdom), Department of Neurology and Psychi-
atry, Sapienza University of Rome, Rome (Italy), School
of Pharmacy and Ph.D. Program in Toxicology, Kaohsiung
Medical University, Kaohsiung (Taiwan), Faculty of Health
Sciences, Semmelweis University, Budapest (Hungary), and
Ny´
ır˝
o Gyula Hospital National Institute of Psychiatry and
Addictions, Budapest (Hungary). A review of the literature
(–)onkratomanditsmaincomponentswasper-
formed in three databases: PsycINFO, PubMed, and Med-
scape. Keywords used to carry out the database searches
included the following: “kratom”, “Mitragyna speciosa”,
“mitragynine”, and “-hydroxymitragynine”. Peer-review
data that emerged from the search were integrated with
an exploratory qualitative assessment of  websites, drug
fora, and other online resources (i.e., e-newsgroups, chat-
rooms, mailing lists, e-newsletters, and bulletin boards). is
was carried out on a regular weekly basis (between January
andApril)usingtheGooglesearchenginein
three languages (English, Italian, and Hungarian). Once the
substance availability of information was identied, further
specic searches were carried out for narratives focusing on
the following issues: (i) motivations behind its recreational
use and possible trends of misuse; (ii) the nature of its
eects on users, including adverse reactions and polydrug
misuse/idiosyncratic combinations; (iii) any other relevant

BioMed Research International 
information. For the purpose of reporting the results in this
paper, any data collected from online fora, such as usernames
and complete URLs for specic threads that were considered
personal identiable, were anonymized. Additional searches
were conducted using the Global Public Health Intelligence
Network (GPHIN), a secure Internet-based early warning
system developed by Health Canada and the World Health
Organization (WHO), which monitors media reports in six
languages, Arabic, Chinese, English, French, Russian, and
Spanish.
Permission for the study was granted by the School of
Pharmacy Ethics Committee, University of Hertfordshire,
Hateld, United Kingdom (November ; PHAEC/-).
3. Results
 studies emerged from the literature review and were
critically analysed. Among these,  results were considered
not relevant (resulting duplicated, botanical studies, or stud-
ies focusing mainly on other selected chemical compounds)
and therefore excluded. e remaining  articles were
further qualitatively analysed and thematically divided in
three main areas of interest related to Mitragyna speciosa
and its main constituents: () in vitro and preclinical data
on pharmacology and behavioral eects (𝑁=51), ()
laboratoristic techniques for identication/characterization
(𝑁=26), and () epidemiological/toxicological reports on
humans (𝑁=18). Data on kratom that emerged from the
online searches were identied, monitored, and registered
into  categories: (1) epidemiology and motivation of use; (2)
legal status, methods of purchase, and typical price; (3) forms
of kratom use; (4) subjective pleasurable eects, adverse
eects, and fatal intoxications related to kratom; (5)pattern of
polyabuse. e results from the review of scientic literature
and online sources were comprehensively integrated and
summarized in the following three main subsections: (i)
preclinical data about pharmacology and identication of
kratom constituents; (ii) kratom use in humans in Southeast
Asia; (iii) kratom use in humans in Western countries.
3.1. Pharmacology and Identication of Kratom Constituents.
Kratom has both opioid- and psychostimulant-like subjective
eects []. e phytochemicals isolated from various parts
ofthekratomtreeincludeoverstructurallyrelated
alkaloids [] of which mitragynine (Figure ) is the most
important with up to % purity in the extract of leaves
from ailand, and only % in kratom leaves from Malaysia.
is alkaloid is the one responsible for analgesic activity
thathasbeenlinkedtokratomusemostlyduetoitspotent
opioid agonist property []. Although mitragynine can act
on the mu (𝜇), kappa (𝜅), and delta (𝛿) opioid receptors, it
is structurally dierent from morphine and other compo-
nents from the opioid family; the reason why it has been
suggested is that it might also present with a more broad
receptorbindingactivity[].Mitragynineanditsanalogues
in kratom (including speciogynine (%), paynantheine (%),
and speciociliatine (%) (Figure )) are indole alkaloids of the
Corynanthe-type, possessing a monoterpene (iridoid) moiety
[]. Dierently, -hydroxymitragynine (Figure ), a minor
constituent (%) of M. speciosa, when isolated demonstrates
a potent antinociceptive activity in mice []. It is now
considered to be a major contributory factor for the analgesic
properties of M. speciosa due to its selectivity for 𝜇-and
𝜅-opioid receptors []. e presence of a hydroxyl group
at C- increases the potency of -hydroxymitragynine to
be - and -fold higher than morphine and mitragynine,
respectively, both in vitro and in vivo [, , ]. is might
be one of the main pharmacological markers of kratom
products’ quality and potency. Recent studies further revealed
how complex is kratom’s pharmacology, involving a 𝜅-opioid
and dopamine D receptors interaction in its various eects
[]. Serotonergic and adrenergic pathways have also been
involved in the eects of mitragynine, mostly due to its broad
anity to dierent receptors []. Indeed, the pharmacologi-
cal mechanisms responsible for stimulant activity are yet to be
clearly established []. Another confounding factor might be
the action of some other isolated compounds(speciociliatine,
speciogynine, and paynantheine), for example, whose eects
were not inhibited by naloxone in animal studies [, ].
It is possible that mitragynine is relatively safe at lower
subchronic dose but exhibits toxicity at a highest dose
[]. However, the erratic pharmacology of kratom makes
it dicult to dene a specic dose threshold. According to
online reports and traditional experiences, subjective eects
of kratom depend on the dosage: at low to moderate dose
(–g) it has a mild pleasant stimulant eect; at moderate-
high dose (– g) the compound has opioid-like analgesia
and sedation [, ]. No studies have been conducted so
far to determine the blood concentration in patients, and
future approach should consider this point in order to prevent
overdose, considering the possible risk of no response to
naloxone [, ]. e standard half-life of mitragynine is
. ±∼ hr, depending upon the individuals natural levels
of enzymes and other factors [, ]. -Hydroxymitragynine
has quite a bit shorter duration, with an average half-life of
. ±. hours [, ]. Recent evidences suggest that the
hydrophobicity, poor water solubility, high variability of drug
release in simulated biological uids, and acid degradable
characteristics of mitragynine probably further inuence the
large variability of its pharmacological responses reported
intheliterature[].iswasconrmedbyliver,kidney,
and brain histopathological changes, as well as hematological
and biochemical changes in mice []. Mitragynine, -
hydroxymitragynine, and mitraphylline exhibit high plasma
protein binding (>%) determined by equilibrium dialysis
[].emetabolismofkratomismainlyhepatic.While
itseemsthatkratomisunlikelytohaveanysignicant
clinical eects on CYPA activity, on the other hand
mitragynine might inhibit other cytochrome P enzyme
activities, specically CYPD [, ]. ese data indicate
the possibility of a drug interaction if mitragynine and -
hydroxymitragynine are coadministered with drugs that are
P-glycoprotein substrates [].
Current preclinical information on kratom suggests that
this ethnodrug, containing several dierent active alkaloids,
has a harmful toxicological prole and must be studied in
detail in order to better dene its potential as therapeutic
drug []. Acute administration of mitragynine produces

BioMed Research International
anxiolytic-like eects attributed to the interactions among
opioidergic receptor systems []. Other authors attempted
to reveal a possible link with the stress-related corticotropin
pathway []. Other evidences show that mitragynine exerts
an antidepressant eect in animal behavioral model inter-
acting with neuroendocrine HPA axis systems []. Among
its potential benets, in addition to analgesic activity [,
], mitragynine seems to be also a key component for
the anti-inammatory properties of kratom by suppressing
prostaglandin E (PGE-) production in the cyclooxygenase
 (COX-) pathway []. Moreover, some authors claim
that kratom might be promising antioxidant and anticancer
or chemopreventive compounds []. Kratom extracts and
mitragynine have been shown to possess cytotoxicity to some
human cancer cell lines, namely, SH-SYY cells (neuronal
cells), [] and avoid the tolerance and dependence on
chronic morphine treatment in mice as well as in human
neuroblastoma SK-N-SH cell [, ]. Other interesting prop-
erties of the compound might be the capability to modulate
muscle neurogenic contraction [–] and gastric secretion
[].
Whilekratommetabolitescouldhavethepotentialtobe
developed as new therapeutic agents, there are also possible
serious adverse eects of these materials under investigation.
ere have been dierent studies showing serious conditions
aer repeated administration as elevated blood pressure,
nephrotoxic eects [], impaired cognition and behaviour
[, ], dependence potential [], and hepatic failure [,
]. e onset of liver injury is described to occur within
 to  weeks of starting regular use of kratom powder or
tablets, with symptoms of fatigue, nausea, pruritus, and dark
urinefollowedbyjaundice[,].epatternofliverinjury
seems to be typically cholestatic and can be severe with
serum bilirubin levels rising above  mg/dL []. Kratom
constituents were also identied to be potentially cardiotoxic,
ideally potentiating Torsade de Pointes through inhibition
of rapid delayed rectier potassium current (IKr) in human
cardiomyocytes [].
At present, kratom constituents are not detected by
conventional drug screening tests: advanced tests like liq-
uid chromatography-tandem or ion-mass spectrometry are
required [].
3.2. Kratom Use in Southeast Asia
3.2.1. Diusion and Modalities of Consumption. Mitragyna
speciosa (Rubiaceae) is an indigenous plant of Southeast Asia.
isherbalplantisalsoknownas“kratom,”as“ketum”
or “biak” (Malaysia), or as “krathom” (ailand, “thom”
in Southern ailand) and has been used for millennia (a)
as a stimulant; (b) as a remedy in traditional medicine;
and (c) in social context [, ]. Historically, manual
labourers (e.g., sherman, farmers, and rubber-tappers) in
northern Malaysia and southern ailand commonly used
ketum leaves to improve their work productivity under the
sweltering sun and to relieve fatigue []. Rural folk have
traditionally ingested ketum leaves to self-treat common
medical problems (e.g., diabetes, diarrhoea, fever, and pain)
anduseditasawoundpoultice[,].Ketumwasalsoused
as an opium substitute in Malaya during opium scarcity [].
It is still popularly consumed in Asian communities during
social gatherings in the village [].
Traditionally, the fresh or dried leaves of kratom are
chewed or brewed into tea or smoked []. Ketum is bitter
and sugar or sweet beverages are commonly added to mask
its taste []. To experience vigour and euphoria, traditional
“kratom eaters” chew one to three fresh leaves at a time
[, ]. Regular and addicted users chew – times a day [].
Amattayakul[]reportedthatanaveragegreenleafweighs
about . g and a dry leaf about . g and twenty kratom
leaves contain about mg of mitragynine; no information
is available on other active compounds of the plant. Ketum
is currently widely available in many Asian countries (e.g., in
Malaysia) where it can be easily bought from ketum traders
in the community []. Consumers can be classied into two
maingroups:therstincludesthosewhosolelyuseketumto
improve physical tolerance to laborious work and the second
polydrug users who attempt to manage drug withdrawal
symptoms or reduce the intake of other opiates like heroin
[]. A recent study showed that out-of-treatment opiate users
in Malaysia oen use ketum to reduce their dependence
on illicit opiate as well as to ameliorate opiate withdrawal
symptoms [].
At present, there is no systematic data on the prevalence
of ketum use in all the native countries, but it seems to
be considerable in Malaysia and ailand. A survey per-
formed in  investigating kratom use in ailand (,
respondents aged – years) indicated that the lifetime,
past year, and past  days prevalences for kratom were
.%, .%, and .%, respectively []. ese gures, with
the exception of lifetime use, were signicantly higher than
those for cannabis making kratom the most widely used illicit
drug in ailand. Again in ailand past -day prevalence
studies among –-year-old students (𝑛 = 8 708–12148)
in , , and  showed an increase in the lifetime
use of kratom (from .% to .%) []. Another study
in ailand in  showed a prevalence of psychoactive
drugs in , motor vehicle drivers: .% were positive to
mitragynine []. Overall, reported seizures linked to kratom
quintupled in ailand from  to , far higher than
those reported for any other drug []. Kratom reported
seizures in Malaysia and Myanmar also reached record levels
in , at roughly one ton each []. Conversely, in Taiwan,
heroin, methamphetamine, and some new drugs such as syn-
thetic cathinones (methylone, mephedrone, and MDPV) and
synthetic cannabinoids (K) have been identied since s
according to the Substance Abuse Monitoring and Reporting
Systems (SAMRS), which is a national data collection system
for substance abuse []. However, use of kratom and its
major alkaloid mitragynine has not been detected via the
collected information from the SAMRS []. erefore, it
could be suggested that kratom may not yet be a drug of
choice in Taiwan and might still be considered a rather
culture-bounded phenomenon in Asian countries.
e possession of kratom leaves has been illegal in
ailand since  []. Kratom is also controlled in a few
other countries in the region (Malaysia and Myanmar) and
elsewhere (Australia, Bhutan) []. In parallel, kratom-related

BioMed Research International 
arrests more than doubled between  and  in both
Myanmar and ailand []. To control its widespread abuse,
ketum was banned in Malaysia and regulated under the
Poisons Act  []. ose caught for possessing or pro-
cessing ketum leaves can be ned for approximately RM
, (US ) or imprisoned if found guilty []. e
Malaysian government is in the midst of regulating ketum
under the Dangerous Drugs Act , which will consider the
substances as harmful as opiates and amphetamines [].
3.2.2. Stigma and Side-Eects. Among rural folk, the believe
that kratom is a better alternative to illicit drugs, such
as heroin and methamphetamine, is still diuse and it is
mainly used for its invigorating-like eects [, ]. Five
to ten minutes aer kratom consumption users describe
themselves as feeling happy, strong, and active, especially
among those working in the agricultural sector []. ey
claim that “their mind is calm” aer the consumption of
the drug []. Overall, there is no real social stigma towards
ketum users and being dependent on ketum is not seen as
a major problem or taboo in Malaysia, at least for men.
Apparently,societyacceptsmaleaddictswhoworktosupport
their family but do not accept female addicts []. Moreover, it
seems that ketum dependents are not neglecting their family
and the impairment of their social functioning is still under
debate []. A recent cross-sectional survey in three northern
states of Peninsular Malaysia investigated  regular kratom
consumers []. Findings showed that regular kratom users
do not seem to experience major impairments in their
social functioning, despite being dependent on kratom for
prolonged periods []. Furthermore, ketum use does not
imply risky behaviours such as needle sharing, common in
heroin dependents []. On the other hand, evidence shows
that kratom can generate addiction problems and lead to
other social issues []. Considering how kratom use is
consistent, gures for treatment admissions for its use appear
rather low, accounting for, for example,  percent of all
drug treatment admissions in ailand in  (Figure ).
However,theyaredeclaredtobeconsiderablyontherise[].
Kratom-related treatment admissions almost tripled between
 and  (Figure ) []. is could be also partially due
to a more strict antidrug policy, where individuals caught
with kratom are obliged to engage in treatment programs.
Surely, ndings show that regular kratom use is associated
with drug dependency, development of withdrawal symp-
toms, and craving []. Many regular users declare their
diculty to abstain from kratom use and experiencing
sharp unpleasant symptoms during abstinence periods [].
Physical withdrawal symptoms include anorexia, weight loss,
decreased sexual drive, insomnia, muscle spasms and pain,
aching in the muscles and bones, jerky movement of the
limbs, watery eyes/nose, hot ushes, fever, decreased appetite,
and diarrhoea [, ]. Psychological withdrawal symptoms
commonly reported are nervousness, restlessness, tension,
anger, hostility, aggression, and sadness [, ]. Long-term
addicts are described to become thin and have skin pigmen-
tation on their cheeks, due to the capacity of mitragynine
to increase the production of melanocytes-stimulating sub-
stance [, ]. Regular ketum use is also reported to cause
0
500
1000
1500
2000
2500
3000
2007 2008 2009 2010 2011
Kratom-related treatment admissions in ailand
F : Kratom-related treatment admissions in ailand almost
tripled between  and . Source: United Nations Oce on
Drugs and Crime, Patterns and Trends of Amphetamine-Type
Stimulants and Other Drugs: Asia and the Pacic— (Bangkok,
).
psychotic symptoms such as mental confusion, delusion, and
hallucination [].
Regarding polydrug abuse, in Asia, patterns of com-
plex cointaking involving kratom are also reported. Beyond
“classic” substances and many NPS as synthetic phenylethy-
lamines and cathinones, peculiarly there have been cases
where codeine is added into kratom drinks to obtain a
better “high” or euphoria. In southern ailand, in recent
years, homemade ice-cold cocktails, called “ ×,” have
become popular for their alleged alcohol-mimicking eect
among young Muslim people []. e cocktails are made
from kratom leaves, a caeine-containing so drink, and
codeine- or diphenhydramine-containing cough syrup as the
three basic ingredients to which ice cubes, an anxiolytic, an
antidepressant, or an analgesic drug is added [, ].
So far, there have not been any mortality or toxicity
incidents directly related to ketum use reported in Asian
countries. One possibility is that ketum users in Asia nor-
mallybuyfreshketumjuice,fromalocalknownsupplier
intheruralarea,unlikelytobeanadulteratedpreparation.
Traditionally, ketum in Asia has been used for its stimulant
eects and the dose consumed might be lower than the
one consumed for recreational purposes []. But it is also
possible that local health care providers in Asia, perceiving
ketum as a safe traditional herbal drink, might not attribute
some of the medical problems reported by users to ketum use;
this factor may indeed contribute to the underreporting of
adverse eects among ketum users in Southeast Asia.
3.3. Kratom Use in Western Countries
3.3.1. Diusion, Modalities, and Reasons of Consumption. In
recent years kratom has become popular in the EU, US,

BioMed Research International
and other countries (e.g., Japan) as a recreational novel
compound[,,].AvarietyofMitragyna speciosa related
products are easily accessible from local smart shops and
increasingly available forsale on the Internet, in particular on
web based “legal highs” pharmacies, but their exact content is
not always veried [, ]. Many dierent formulations are
available, including raw leaves, capsules, tablets, powder, and
concentrated extracts []. Prices vary between countries,
depending on the type and amount of the purchased product,
forexample,rangingfromtoeurospergramfor“kratom
X” extracts,  to  euros per  gram for dried kratom [],
or sometimes even for lower prices (from less than  euro per
gram for “kratom power”) [, –].
Mitragyna speciosa and/or mitragynine and/or -hydrox-
ymitragynine are currently controlled only in a small number
of EU Member States, such as Denmark, Latvia, Lithuania,
Poland, Romania, and Sweden []. Kratom is also largely
uncontrolled in the US at a federal level while at the state
level there are some exceptions such as Indiana, Iowa,
Louisiana, and Massachusetts. is means all parts of the
plant and its extracts are legal to cultivate, buy, possess, and
distribute without a license or prescription, and, when sold
as a supplement, sales must conform to US supplement laws
[]. Recently, in February , the Food and Drug Admin-
istration (FDA) issued “Import Alert -” that seems to
provide customs and border agents broad authority to seize
kratom products from a number of suppliers outside the US
[].
As kratom is oen not monitored in national drug abuse
surveys, there is still little information on prevalence of its
use. An initial warning about this phenomenon has been
launched by the Drug Enforcement Administration (DEA)
as early as  []. Internet surveys conducted by the
EMCDDA in  indicated that kratom was one of the most
widely oered “legal highs” in % of the investigated 
online shops across the EU []. A more extensive EMCDDA
Internet survey in July  showed that kratom was the
most widely oered product with  out of  (or %) of
online retailers shipping it to the EU. A further online study
identied  online shops selling NPS that would dispatch
products to at least one EU Member State (United Kingdom
appeared to be the most common) []. Kratom and Salvia
divinorum were the most frequently oered NPS, available
in  and  online shops, respectively []. In  the term
“kratom” was found in more than two million results. Of the
rst  websites listed in the search results,  were primarily
focused on the sale of kratom, while  were focused on
disseminating information about kratom through the use of
discussion boards [].
3.3.2. Subjective Experience: Online Reports. Since , an
exponential growing number of kratom’s subjective experi-
ences have been posted online by users (Box ) [, –].
Kratomcanbesmoked,butaccordingtousersthishasno
advantage over chewing or making a tea: the amount of leaves
that constitutes a typical dose is too much to be smoked
easily [, ]. A paste-like extract can be prepared by lengthy
boiling of fresh or dried leaves and the syrup produced can
bemixedwithnelychoppedleavesofthepalm,madeinto
pills and smoked in pipes (“madatin”) []. Small pellets of
thisextractcanbeingested,oragainthecompoundcanbe
dissolved in hot water and consumed alone or mixed with
other ordinary herbal teas to make it more palatable (the so-
calledtossandwash)[,,].Otheruserspreferalcoholic
beverages or to ingest it with food, mixing it with yoghurt or
preparing cookies, in order to contrast the bitterness of the
compound [, ]. Regarding desired/recreational eects of
kratom, users report that at low doses it is rather stimulant,
mind is “more alert,” physical energy and sometimes sexual
arousal are increased, and ability to do physical work may
be improved and they also described “entactogenic” eects,
like empathy and euphoria (Box ) [, , ]. Some people
nd this level edgy rather than pleasant [, ]. At higher
doses, experiences describe it as more sedative and analgesic;
users prefer to be less sensitive to physical or emotional
pain, to feel and look calm, and to have a general feeling of
comfortable pleasure [, ]. Others report an increase of
empathy feelings (Box ) [].
3.3.3. Side-Eects. A variety of less explored side-eects
experienced by users also emerged from our work (Table ).
ese frequently include nausea, constipation, sleep prob-
lems, temporary erectile dysfunction, itching, and sweating
and also hyperpigmentation and tremor and anorexia and
weight loss in long term [, –]. Some users describe
hair loss, probably related to a regular (daily) use of kratom
[]. Withdrawal symptoms are also common, including
muscle aches, irritability, mood disturbances, runny nose,
diarrhoea, and muscle jerking (Table ) []. Users describe
tolerance (requiring the consumption of higher doses to
achieve the same eects) and also a “cross-tolerance” to
both kratom and opiates aer repeated intake [, –].
Moreover, kratom is increasingly purchased from Internet
sources for self-medication [, ], especially by individuals
with chronic pain to self-manage opioid withdrawal [, ]
or heroin, methadone, or suboxone withdrawal symptoms
[], or for its anxiolytic and antidepressant eects [].
For this reason, it is oen advertised online as a cheaper
alternative to traditional opioid replacement therapies with
no need of medical prescription []. is could pose a
serious problem for doctors prescribing pain medication or
opioid substitution therapy to someone who is a regular
kratom user. Adverse eects and intoxications cases across
various countries have also been reported, including liver
toxicity, seizure, and coma [, –], reports of patients
suering from intrahepatic cholestasis aer two weeks of
kratom use [], Adult Respiratory Distress Syndrome [],
and hypothyroidism [] (Table ). Evidence also suggests
that kratom might be a deadly substance when mixed with
other compounds (Table ). Fatalities resulting from the use
of a kratom-based product known as “Krypton” have also
been reported [] with  documented cases in Sweden
[]. Subsequent forensic studies revealed that Krypton
contained high amounts of the exogenous pharmaceutical
agent O-desmethyltramadol, an opioid analgesic and the
main active metabolite of tramadol, and it had been added
to the plant material. e presence of this contaminant
in some online products is well documented [, , ].

BioMed Research International 
“About twenty minutes aer ingesting the Kratom, I began to feel a nice, pleasant euphoria
identical to that of an opiate...I did notice the simultaneous stimulant/depressant eect like
I notice in hydrocodone or oxycodone”
https://www.erowid.org/experiences/exp.php?ID=
“I start to feel this intense warmth come over my entire body, it feels like a combination of
my rst MDMA high with a nice OxyContin like twist, along with the social aspect of
Cocaine”
https://www.erowid.org/experiences/exp.php?ID=
“I felt my insides become so and pliable like the onset of most trippy drugs”
https://www.erowid.org/experiences/exp.php?ID=
“I felt relaxed, sedated, and free of my normal back and thumb pain in my right hand which
I thought would never be possible. I also felt a nice fuzzy feeling all over which I get from
smoking pot sometimes”
https://www.erowid.org/experiences/exp.php?ID=
“I began oating in and out of waking dreams, the ‘nod’, whatever you want to call it, where
you’re not really asleep but you still see dreamlets and dream fragments oating before your eyes.
is goes on for quite some time”.
https://drugs-forum.com/forum/showthread.php?t=
“I lost track of time at this point, as I was completely lost in the music and my own thoughts. I
wasn’t really feeling euphoria or a ‘high,’ like when using marijuana. I did feel very ‘stoned’ though,
and I guess I would refer to my state as being high because of my total relaxation and
contentment”.
https://www.erowid.org/experiences/exp.php?ID=
“When I’m at the peak, I feel a very pleasant body buzz, kind of like being wrapped around a warm,
so blanket all day long. On the comedown, I feel relaxed but scatterbrained and my
concentration takes a hit, and I can easily enter ‘waking dreams’ where I’m not sleeping but
dreaming while being unaware of either state of consciousness, which oen causes me to jolt
awake and open my eyes”
https://www.erowid.org/experiences/exp.php?ID=
B : Qualitative analysis of kratom users’ experiences.
Even though mitragynine was also detected in the products,
it was not determined how the two substances may have
interacted to cause death. Other “deadly cases” are available:
an article described a fatal reaction that appeared to be asso-
ciated with mixing with propylhexedrine (an 𝛼-agonist and
amphetamine-like stimulant, used as decongestant inhalers);
another case indicated that a mix of kratom, over-the-counter
cold medications, and benzodiazepines was responsible for
the death of a -year-old boy; a postmortem detection of
kratom together with venlafaxine, diphenhydramine, and
mirtazapine was screened in a -year man found unrespon-
sive in bed; a middle aged man in therapy with zopiclone,
citalopram, and lamotrigine was found dead at home and
postmortem analysis of peripheral blood revealed high con-
centrations of mitragynine and -hydroxymitragynine and
therapeutic values of intake of the other compounds [, ,
].
It must also be noted that kratom is commonly taken
in combination with a variety of other recreational “classic
drugs” (e.g., alcohol, cannabis, benzodiazepines, methadone,
cocaine, amphetamine, and hallucinogenic mushrooms) and
NPS (e.g., kava, mephedrone, and other synthetic cathinones,
tryptamines, and phenylethylamines such as C-E, AL-LAD,
and -HO-MiPT) [].
4. Discussion and Conclusions
Indeed, the use of substances to enhance human abilities
is a constant and cross-cultural feature in the evolution of
humanity.Opium,cocaleaves,mescaline,andvariousother
naturalsubstanceshavebeenusedformillenniainvarious
cultures for therapeutic purposes, religious ceremonies, and
improvement or modication of the physical and mental
abilities. Although much has changed over time, the drive
for human enhancement has not diminished and drugs
availability on the Internet, oen supported by misleading
marketing strategies, has made their use even more likely and
risky []. In this context,the tropical tree Mitragyna speciosa
Korth. (kratom) has now planted its “roots” of use worldwide.
Although the phenomenon has only been marginally studied,
an exponential number of kratom’s subjective experiences
have been posted online on drug fora by users in the EU
and US and elsewhere. Kratom, still easily available in native
countries, is now just “a click” away and potentially available

BioMed Research International
T : Report of adverse/toxicological eects of kratom.
Short time use eects
Nausea, constipation, sleep problems,
temporary erectile dysfunction,
itching, or sweating
Long time use eects Anorexia, dry mouth, problems in
diuresis, darker skin, and hair loss
Withdrawal
symptoms
Hostility, aggression, aching of muscles
and bones, jerky movements of the
limbs, anorexia and weight loss, and
insomnia
Infrequent eects
Seizures (individuals using high doses
of kratom, either alone or combined
with other drugs), intrahepatic
cholestasis, psychotic symptoms, Adult
Respiratory Distress Syndrome, and
hypothyroidism
Fatalities
Kratom mixed with other substances:
O-desmethyltramadol;
propylhexedrine;
over-the-counter cold medications and
benzodiazepines;
venlafaxine, diphenhydramine, and
mirtazapine;
zopiclone, citalopram, and lamotrigine
to wide range of new users, including vulnerable individuals.
As it emerged from our previous studies [, –], the web
serves also as a repository of information for selected groups,
who can share experiences and suggest new products or
novel modalities of intake via online fora, chat-rooms, blogs,
videos, and others.
Anthropologically, drug addiction history is the complex
history of human vicissitude and desire, as human being is a
desiring being, trying in every way to assuage suerings, to
enhance feelings of pleasure, and to satisfy inexhaustible and
incessant desires []. Even today, the line between socially
acceptable and unlawful use of a variety of psychoactive
products seems to be culture-bound. Kratom is a plant with
a well-established traditional use in South Asia to enhance
work abilities as well as support traditional medicine and
culture, even if ocially banned. At the same time, its rapid
diusion in Western societies, where it is oen considered a
“natural” and thus safer option than illicit drugs or an alter-
native to opioid treatment, is not devoid of risks. According
to preclinical data and case reports published in scientic
literature as well as anecdotal experiences posted online,
kratom is not a safe drug. Its consumption is associated
per se with drug dependency, development of withdrawal
symptoms, craving, serious adverse eects, and life-threating
eects, especially in a multidrug-intoxicating scenario [,
, , ]. Furthermore, the idea that legality can equate
with the safety of a product might still remain a common
insidious misbelief amongst drug users []. On the other
hand, Suwanlert has pointed out in  that “it is hoped
that drug education will be a more eective step towards
kratom use control” [], foreseeing the failure of the legislative
measures in South Asian countries.
Kratom pharmacology itself is complex and requires
future research: this compound in fact acts on opioid as well
as on dopaminergic, serotonergic, GABAergic, and adren-
ergic systems [, ]. erefore, subjective eects are very
peculiar ranging from psychostimulant to sedative-narcotic.
Pharmacological mechanisms responsible for several of its
alkaloids activity deserve yet to be clearly established in future
studies. Altogether, available data on kratom suggest caution:
this unregulated plant could exhibit a serious harmful poten-
tial, far beyond any “therapeutic” desired eect; in parallel, its
anxiolytic, antidepressant, and analgesic properties need to be
better explored by scientic research works, like, for example,
in large blind randomized controlled clinical trials [].
Potential users who tend to self-medicate and health
professionals working with them should be clearly aware of
the risks associated with kratom consumption []. As it
emerged from this and other previous studies [], kratom
is advertised and sold online as “cheaper alternative” to
traditional opioid replacement therapies, as a painkiller for
chronic pain, or as an anxiolytic remedy in psychiatric
population, with no need of medical prescription or supervi-
sion. is encourages a tendency to self-medicate and could
become a serious problem for unaware doctors prescribing
medication to a patient who is a regular kratom user or in
case of acute intoxication related to the substance. Another
issue of concern is the action of other isolated compounds
(e.g., speciociliatine, speciogynine, and paynantheine) whose
eects were not inhibited by naloxone in animal studies [,
], meaning a potentially very dicult management in case
of overdose. erefore, in this scenario, the risk of adverse
reactions or possible misdiagnosis might be very high. It
might also be worth adding that kratom use is not detected
by conventional drug screening tests as advanced tests, like
liquid chromatography-tandem or ion-mass spectrometry,
arerequired[].Wealsoreiterateheretheimportanceof
focusing and asking direct questions on the nature and
patterns of drug intake, including medical products diversion
and consumption of NPS, during clinical assessments [].
Given that nowadays polydrug use represents the norm rather
than the exception, especially in emergency settings [], the
simultaneous use of drugs should also be promptly iden-
tied, investigated, and well discriminated. Future studies
should explicitly examine the eects of the combination in
complex patterns of polydrug intake, including kratom, to
fully understand the synergistic eects and associated clinical
and toxicological implications. Attention should also be paid
to the motivations behind such behaviours, social norms,
stigma, availability, and other lifestyle factors.
Surely, a possible limitation of our analysis could be
given by the fact that publicly available websites, fora, and
similar sources were also considered and included together
with a systematic literature review. One could wonder about
the limitations of carrying out a risk assessment of a drug
while taking into account also the online comments. It may
be inappropriate to trust information obtained from the
Internet without independent verication and we did not
have any possibility here to ascertain if the substance the
online alleged drug users were taking was indeed kratom. On
the other hand, online reports about kratom seem genuine

BioMed Research International 
and many users illustrate their detailed experiences as proper
experiments on themselves. us, in the lack of relevant peer-
reviewed data, the online monitoring seems to be indeed a
very useful method to obtain preliminary information about
new and emergent phenomena []. Further, as demon-
strated by the outcomes of this study, a better international
collaboration is necessary to tackle this rapidly growing drug
trend.
Conflict of Interests
e authors declare that there is no conict of interests
regarding the publication of this paper.
Acknowledgments
is publication arises from collaborative activities and
sta exchanges among collaborating institutions funded by
the European Commission. e authors would also like
to acknowledge the contribution of the Canadian Centre
on Substance Abuse (CCSA), the Public Health Agency of
Canada, and the World Health Organization (WHO) for
granting access to the Global Public Health Intelligence
Network (GPHIN) database to support the web-monitoring
activities.
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