Letter to the Editor
THE THERAPEUTIC POTENTIAL OF KRATOM
The leaves of Mitragyna speciosa (Korth.) Havil.
(Rubiaceae), ‘kratom’, have been used traditionally as a
relaxant, stimulant, anxiolytic and to treat minor pain
[1–5]. Recent surveys also indicate that kratom may be
used as a self-medication substitute for prescription and
illicit opioids in the United States . Research suggests
that kratommay produce its effects without the respiratory
suppression induced by classical opioids [7–9]. Although
the therapeutic potential of kratom appears promising,
pending more carefully controlled clinical studies, the
risk/beneﬁt determinations for human use depend upon
accurate characterizations of available data.
The genus Mitragyna encompasses 10 species with
documented ethnomedicinal use; however, stimulant and
analgesic effects are characteristic only for Mitragyna
speciosa [5,10]. Currently kratom is not scheduled by the
United Nations Drug Conventions and has no approved
medical uses, although some European Union (EU)
Member states currently control Mitragyna speciosa,
mitragynine and/or 7-hydroxymitragynine . Kratom
falls under narcotic law in Australia, Malaysia, Myanmar
and Thailand and under the Medicines Amendment
Regulations in New Zealand . Kratom attracted
mainstream attention in North America and Europe in
the 2000s when products containing no mitragynine,
but labeled as ‘Kratom or mitragynine acetate’,were
marketed in Europe . Concerns escalated, with nine
fatalities in Sweden attributed to the kratom product
‘krypton’, although it was later found adulterated and the
tramadol metabolite O-desmethyltramadol causative for
the deaths . As kratom has been marketed in
the United States as a dietary supplement, increased
consumption and demand have accelerated discussion
about its legal status [5,12].
In the United States, proposed regulatory responses to
kratom appear overmatched to evidence of harms. In
2016 the US Drug Enforcement Administration
(DEA) announced its intention to place kratom
alkaloids mitragynine and 7-hydroxymitragynine into the
Controlled Substance Act Schedule 1, based on 660 poison
control center calls and 30 deaths where kratom use was
reported but not identiﬁed as the causative agent .
Following extensive public comments and bipartisan
objections from the US Congress, the DEA withdrew its
proposal and provided a public comment period of several
months. In 2018, efforts in the United States to restrict
kratom appear to be resurgent; the US Food and Drug
Administration’s (FDA) Commissioner recently referred to
kratom as a narcotic-like opioid with respect to ‘potential
for abuse, addiction, and serious health consequences;
including death’. This statement by the FDA is based
primarily on isolated adverse event reports and an in-silico
receptor binding model: the Public Health Assessment via
Structural Elucidation (PHASE). Based on this model, the
FDA statement concludes that ‘we feel conﬁdent in calling
compounds found in kratom, opioids’.
It is our opinion that the evidence does not support
such conclusions regarding the risks of kratom. Although
using well-deﬁned, validated in-silico models in hypothesis
development can provide valuable insights, an isolated
receptor interaction study does not reﬂect the complexity
of a living organism and has never been considered an
acceptable replacement for experimental in-vivo data for
FDA drug evaluations and approval. The physiological
consequences of opioid receptor bindings vary widely, from
the deadly effects of fentanyl to the relatively innocuous
effects of the non-scheduled dextromethorphan. In the
case of mitragynine, whole cell assay research shows
binding to mu-opioid receptors without recruitment of
beta-arrestin 2, which is linked to many adverse effects
associated with classical opioids, such as respiratory
depression, euphoria and tolerance development . The
available scientiﬁc evidence indicates that the kratom in-
dole alkaloids mitragynine and 7-hydroxymitragynine are
not functionally identical to opioids; their molecular and
pharmacodynamic mechanisms of action are distinctly dif-
ferent. This has been shown at the molecular and cellular
level, as well as with whole organisms in animal models
and observational studies . Further, frequency of
kratom consumption and dosing are important to
tolerance or risk for withdrawal, which appear mild
relative to classical opioid withdrawal . Further re-
search is necessary to make a deﬁnitive and evidence-based
statement that encompasses all aspects of kratom pharma-
cokinetics and pharmacodynamics in vivo.
The majority of kratom-related calls to poison control
centers were categorized as minor or moderate in severity,
with 49 (7%) classiﬁed as major exposure. This is
consistent with recent user surveys, including a 2016
study showing that fewer than 1% of respondents sought
medical or mental health treatment related to consumption
[6,12]. The most common dose-dependent adverse effects
reported are constipation, nausea/vomiting, stomach irri-
tability and drowsiness, and it has been proposed that these
unpleasant opioid-like effects that may lead users to self-ti-
trate kratom intake to avoid excessive dosing [6,16]. The
more precise characterization of adverse effects of kratom
will require targeted studies that examine individual
© 2018 Society for the Study of Addiction Addiction
differences in users and co-ingested substances, with par-
ticular attention to factors that might contribute to more
severe negative reactions.
In sum, although the scientiﬁc literature and long-
standing traditional use suggests an acceptable risk proﬁle,
kratom is not benign and requires regulatory oversight
with regard to marketing and quality to ensure public
health. Although caution regarding compounds such as
kratom alkaloids that bind to opioid receptors is warranted,
equating kratom with more dangerous known opioids runs
the risk of casting premature judgment on a herbal product
used by millions as an opioid substitute. For some
consumers, decreased access to kratom has the potential
to increase risk of resumption of opioid use, with potential
for disordered use, overdose and death [17,18].
In light of this, we urge the FDA and regulatory
bodies world-wide to reconsider recent scientiﬁc evidence
regarding the effects and safety of kratom, and use ﬂexibil-
ity in developingan approach within legal frameworksthat
ensures continued lawful and safe access to kratom for
those using it therapeutically and as a self-treatment for
opioid and prescription drug dependence [17,18].
Precedents for such regulatory approaches may be found
internationally among legislative controls for herbal
medicines that vary widely with respect to deﬁnition,
licensing, dispensing, manufacturing and trade, based on
well-established standards of evidence for safety, quality
and efﬁcacy of herbal products [19–21].
Declaration of interests
J.H. and M.S. have consulted for the American Kratom
Association (AKA), a not-for-proﬁt organization that is
advocating for keeping kratom legal in the United
States. J.H. also consults on the development of new
opioid analgesics and new treatments for opioid use
disorders. P.N.B. provides scientiﬁc research guidance on
dietary supplement manufacture and regulatory compli-
ance to companies, associations and government.
Keywords Dietary supplement, kratom, mitragyna
speciosa, mitragynine, opioids, regulation.
, PAULA N. BROWN
, MARC SWOGGER
Department of Medicinal Chemistry, College of Pharmacy, University
of Florida, Gainesville, FL, USA,
Natural Health and Food Products
Research Group, BC Institute of Technology, Burnaby, BC, Canada,
Pinney Associates, Bethesda, MD, USA,
Department of Psychiatry
and Behavioral Sciences, The Johns Hopkins University School of
Medicine, Baltimore, MD, USA,
Department of Psychiatry, University
of Rochester Medical Center, Rochester, NY, USA
and Department of
Psychology, University of British Columbia, Kelowna, BC, Canada
1. Suwanlert S. A study of kratom eaters in Thailand. Bull Narc
2. Vicknasingam B., Narayanan S., Beng G. T., Mansor S. M. The
informal use of ketum (Mitragyna speciosa) for opioid
withdrawal in the northern states of peninsular Malaysia
and implications for drug substitution therapy. Int J Drug
Pol i c y 2010; 21:283–8.
3. Adkins J. E., Boyer E. W., McCurdy C. R. Mitragyna speciosa,a
psychoactive tree from Southeast Asia with opioid activity.
Curr Top Med Chem 2011; 11:1165–75.
4. Stolt A. C., Schroder H., Neurath H., Grecksch G., Hollt V.,
Meyer M. R. et al. Behavioral and neurochemical
characterization of kratom (Mitragyna speciosa) extract.
Psychopharmacology (Berl) 2014; 231:13–25.
5. Brown P. N., Lund J. A., Murch S. J. A botanical, phytochemi-
cal and ethnomedicinal review of the genus Mitragyna Korth:
implications for products sold as kratom. J Ethnopharmacol
6. Grundmann O. Patterns of kratom use and health impact in
the US—results from an online survey. Drug Alcohol Depend
7. Varadi A., Marrone G. F., Palmer T. C., Narayan A., Szabo M.
R., Le Rouzic V. et al. Mitragynine/Corynantheidine
pseudoindoxyls as opioid analgesics with mu agonism and
delta antagonism, which do not recruit beta-arrestin-2.
J Med Chem 2016; 59:8381–97.
8. Kruegel A. C., Gassaway M. M., Kapoor A., Varadi A.,
Majumdar S., Filiz ola M. et al. Synthetic and receptor
signaling explorations of the Mitragyna alkaloids: mitragynine
as an atypical molecular framework for opioid receptor
modulators. JAmChemSoc2016; 138: 6754–64.
9. White C. M. Pharmacologic and clinical assessment of
kratom. Am J Health Syst Pharm 2018; 75:261–7.
10. European Monitoring Centre for Drugs and Drug Addiction
(EMCDDA). Kratom (Mitragyna speciosa) drug proﬁle. Lisbon,
Portugal: EMCDDA; 2015.
psychoactive substances of natural origin: a brief review.
J Food Drug Anal 2017; 25:461–71.
of kratom according the 8 factors of the controlled substances
act: implications for regulation and research. Psychopharma-
cology (Berl) 2018; 235:573–89.
13. Anwar M., Law R., Schier J. Notes from the ﬁeld:
kratom (Mitragyna speciosa) exposures reported to poison
centers—United St ates, 201 0–2015. Morb Mortal Wkly
Rep 2016; 65:748–9.
14. US Food and Drug Administration (FDA). Statement from FDA
Commissioner Scott Gottlie b, M.D., on the agency’sscientiﬁc
evidence of the presence of opioid compounds in kratom,
underscoring its potential for abuse. Silver Spring, MD, 2018:
15. Swogger M. T., Walsh Z. Kratom use and mental h ealth: a
systematic review. Drug Alcohol Depend 2018; 183:134–40.
16. Swogger M. T., Hart E., Erowid F., Erowid E., Trabold N., Yee K.
et al. Experiences of kratom users: a qualitative analysis. J
Psychoact Drugs 2015; 47:360–7.
17. Smith K. E., Lawson T. Prevalence and motivations for kratom
use in a sample of substance users enrolled in a residential
treatment program. Drug Alcohol Depend 2017; 180:340–8.
18. Singh D., Narayanan S., Vicknasingam B., Corazza O.,
Santacroce R., Roman-Urrestarazu A. Changing trends in
2Letter to the Editor
© 2018 Society for the Study of Addiction Addiction
the use of kratom (Mitragyna speciosa) in Southeast Asia.
Hum Psychopharmacol 2017; 32. DOI: 10.1002/hup.2582.
19. Dwyer J. T., Coates P. M., Smith M. J. Dietary supplements:
regulatory challenges and research resources. Nutrients
2018; 10. https://doi.org/10.3390/nu10010041.
20. Ajazuddin S. S. Legal regulations of complementary and alter-
native medicines in different countries. Pharmacogn Rev
21. Sharma S. Current status of herbal product: regulatory over-
view. J Pharm Bioallied Sci 2015; 7:293–6.
Letter to the Editor 3
© 2018 Society for the Study of Addiction Addiction