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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
[15]. Recent surveys also indicate that kratom may be
used as a self-medication substitute for prescription and
illicit opioids in the United States [6]. Research suggests
that kratommay produce its effects without the respiratory
suppression induced by classical opioids [79]. Although
the therapeutic potential of kratom appears promising,
pending more carefully controlled clinical studies, the
risk/benet 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 [10]. Kratom
falls under narcotic law in Australia, Malaysia, Myanmar
and Thailand and under the Medicines Amendment
Regulations in New Zealand [2]. 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 [11]. 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 [10]. 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 identied as the causative agent [13].
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
Administrations (FDA) Commissioner recently referred to
kratom as a narcotic-like opioid with respect to potential
for abuse, addiction, and serious health consequences;
including death[14]. 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 condent in calling
compounds found in kratom, opioids[14].
It is our opinion that the evidence does not support
such conclusions regarding the risks of kratom. Although
using well-dened, validated in-silico models in hypothesis
development can provide valuable insights, an isolated
receptor interaction study does not reect 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 [8]. The
available scientic 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 [12]. Further, frequency of
kratom consumption and dosing are important to
tolerance or risk for withdrawal, which appear mild
relative to classical opioid withdrawal [15]. Further re-
search is necessary to make a denitive 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%) classied 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 scientic literature and long-
standing traditional use suggests an acceptable risk prole,
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 scientic evidence
regarding the effects and safety of kratom, and use exibil-
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 denition,
licensing, dispensing, manufacturing and trade, based on
well-established standards of evidence for safety, quality
and efcacy of herbal products [1921].
Declaration of interests
J.H. and M.S. have consulted for the American Kratom
Association (AKA), a not-for-prot 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 scientic research guidance on
dietary supplement manufacture and regulatory compli-
ance to companies, associations and government.
Keywords Dietary supplement, kratom, mitragyna
speciosa, mitragynine, opioids, regulation.
OLIVER GRUNDMANN
1
, PAULA N. BROWN
2
,
JACK HENNINGFIELD
3,4
, MARC SWOGGER
5
&ZACHWALSH
6
Department of Medicinal Chemistry, College of Pharmacy, University
of Florida, Gainesville, FL, USA,
1
Natural Health and Food Products
Research Group, BC Institute of Technology, Burnaby, BC, Canada,
2
Pinney Associates, Bethesda, MD, USA,
3
Department of Psychiatry
and Behavioral Sciences, The Johns Hopkins University School of
Medicine, Baltimore, MD, USA,
4
Department of Psychiatry, University
of Rochester Medical Center, Rochester, NY, USA
5
and Department of
Psychology, University of British Columbia, Kelowna, BC, Canada
6
E-mail: grundman@u.edu
References
1. Suwanlert S. A study of kratom eaters in Thailand. Bull Narc
1975; 27:217.
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; 21:2838.
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; 11:116575.
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; 231:1325.
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
2017; 202:30225.
6. Grundmann O. Patterns of kratom use and health impact in
the USresults from an online survey. Drug Alcohol Depend
2017; 176:6370.
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; 59:838197.
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: 675464.
9. White C. M. Pharmacologic and clinical assessment of
kratom. Am J Health Syst Pharm 2018; 75:2617.
10. European Monitoring Centre for Drugs and Drug Addiction
(EMCDDA). Kratom (Mitragyna speciosa) drug prole. Lisbon,
Portugal: EMCDDA; 2015.
11. FengL.Y.,BattulgaA.,HanE.,ChungH.,LiJ.H.New
psychoactive substances of natural origin: a brief review.
J Food Drug Anal 2017; 25:46171.
12. HenningeldJ.E.,FantR.V.,WangD.W.Theabusepotential
of kratom according the 8 factors of the controlled substances
act: implications for regulation and research. Psychopharma-
cology (Berl) 2018; 235:57389.
13. Anwar M., Law R., Schier J. Notes from the eld:
kratom (Mitragyna speciosa) exposures reported to poison
centersUnited St ates, 201 02015. Morb Mortal Wkly
Rep 2016; 65:7489.
14. US Food and Drug Administration (FDA). Statement from FDA
Commissioner Scott Gottlie b, M.D., on the agencysscientic
evidence of the presence of opioid compounds in kratom,
underscoring its potential for abuse. Silver Spring, MD, 2018:
US FDA.
15. Swogger M. T., Walsh Z. Kratom use and mental h ealth: a
systematic review. Drug Alcohol Depend 2018; 183:13440.
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; 47:3607.
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; 180:3408.
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
2012; 6:15460.
21. Sharma S. Current status of herbal product: regulatory over-
view. J Pharm Bioallied Sci 2015; 7:2936.
Letter to the Editor 3
© 2018 Society for the Study of Addiction Addiction
... A variety of reports confirm kratom use to self-manage opioid withdrawal and that abstinence from high chronic kratom use is typically associated with milder symptomatology than abstinence from classical opioids Smith et al., 2019;Garcia-Romeu et al., 2020). The conclusion of Prozialeck et al. (2019) and Grundmann et al. (2018) Prozialeck et al., 2019) were further strengthened by two published US surveys which found that the overwhelming majority of kratom consumers reported that their use was for various health benefits and not for recreational purposes (Coe et al., 2019;Garcia-Romeu et al., 2020;Harun et al., 2021b). ...
... Although neither kratom nor any of its alkaloids are approved for therapeutic use for any disorder, surveys discussed in Factors 4, 5, and 6-History and Current Patterns of Abuse; the Scope, Significance and Duration of Abuse; what, if Any, Risk is There to the Public Health and elsewhere (Henningfield et al., 2018a;Grundmann et al., 2018;Swogger and Walsh, 2018;Coe et al., 2019;Prozialeck et al., 2019;Garcia-Romeu et al., 2020) show individuals in the US and around the world describe using kratom for its health benefits. Research characterizing kratom's effects, mechanisms of action, and therapeutic kratom alkaloid use rapidly advanced since 2018. ...
... Surveys and more than 20,000 comments to the DEA suggest that many kratom users fear resumption of opioid use and the need to resort to illicit kratom markets (Drug Enforcement Adm, 2016;Grundmann, 2017;Coe et al., 2019;Garcia-Romeu et al., 2020). It is not possible to project how many people would relapse to opioids and potentially overdose (Henningfield et al., 2018a;Henningfield et al., 2018b;Henningfield et al., 2018c;Henningfield et al., 2018d;Grundmann et al., 2018;Prozialeck et al., 2020). This was a concern of the DEA in withdrawing its 2016 kratom scheduling proposal (Ingraham, 2016b) and in the US DHHS kratom scheduling recission letter (Giroir, 2018). ...
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Drugs are regulated in the United States (US) by the Controlled Substances Act (CSA) if assessment of their abuse potential, including public health risks, show such control is warranted. An evaluation via the 8 factors of the CSA provides the comprehensive assessment required for permanent listing of new chemical entities and previously uncontrolled substances. Such an assessment was published for two kratom alkaloids in 2018 that the Food and Drug Administration (FDA) have identified as candidates for CSA listing: mitragynine (MG) and 7-hydroxymitragynine (7-OH-MG) (Henningfield et al., 2018a). That assessment concluded the abuse potential of MG was within the range of many other uncontrolled substances, that there was not evidence of an imminent risk to public health, and that a Schedule I listing (the only option for substances that are not FDA approved for therapeutic use such as kratom) carried public health risks including drug overdoses by people using kratom to abstain from opioids. The purpose of this review is to provide an updated abuse potential assessment reviewing greater than 100 studies published since January 1, 2018. These include studies of abuse potential and physical dependence/withdrawal in animals; in-vitro receptor binding; assessments of potential efficacy treating pain and substance use disorders; pharmacokinetic/pharmacodynamic studies with safety-related findings; clinical studies of long-term users with various physiological endpoints; and surveys of patterns and reasons for use and associated effects including dependence and withdrawal. Findings from these studies suggest that public health is better served by assuring continued access to kratom products by consumers and researchers. Currently, Kratom alkaloids and derivatives are in development as safer and/or more effective medicines for treating pain, substances use disorders, and mood disorders. Placing kratom in the CSA via scheduling would criminalize consumers and possession, seriously impede research, and can be predicted to have serious adverse public health consequences, including potentially thousands of drug overdose deaths. Therefore, CSA listing is not recommended. Regulation to minimize risks of contaminated, adulterated, and inappropriately marketed products is recommended.
... There are numerous active compounds within kratom that appear to have multiple physiologic and psychologic effects beyond analgesia. Online and in-person studies have indicated there may be potential for kratom to produce antidepressant, anxiolytic and antipsychotic effects (Swogger et al., 2015;Grundmann et al., 2018;Coe et al., 2019;Ramanathan and McCurdy, 2020;Grundmann et al., 2021;Sharma and McCurdy, 2021;Smith et al., 2021). In light of these findings, there is clearly a need for further research on safety and efficacy of kratom and its active compounds. ...
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Kratom (Mitragyna speciosa, Korth.) is an evergreen tree that is indigenous to Southeast Asia. When ingested, kratom leaves or decoctions from the leaves have been reported to produce complex stimulant and opioid-like effects. For generations, native populations in Southeast Asia have used kratom products to stave off fatigue, improve mood, alleviate pain and manage symptoms of opioid withdrawal. Despite the long history of kratom use in Asia, it is only within the past 10–20 years that kratom has emerged as an important herbal agent in the United States, where it is being used for the self-treatment of pain, opioid withdrawal symptoms, and mood disorders. The increase in the use of kratom in the United States has coincided with the serious epidemic of opioid abuse and dependence. Since 2015, efforts to restrict access to prescription opioids have resulted in a marked increase in the use of “street” opioids such as heroin and illicit fentanyl. At the same time, many patients with chronic pain conditions or opioid use disorder have been denied access to appropriate medical help. The lack of access to care for patients with chronic pain and opioid use disorder has been magnified by the emergence of the COVID-19 pandemic. In this report, we highlight how these converging factors have led to a surge in interest in kratom as a potential harm reduction agent in the treatment of pain and opioid use disorder.
... Administration has proclaimed that mitragynine and 7hydroxymitragynine, the psychoactive alkaloids found in kratom, as opioids. 6 Kratom use has now become a worldwide issue, in which it is no longer confined to Southeast Asia. For example, it is estimated that 3-5 million Americans use kratom. ...
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Background: Kratom (Mitragyna speciosa Korth.) is a traditional folk remedy used in Southeast Asia and is known to have a significant opioid-like effect. However, it is unknown whether kratom consumption can impair quality of life (QoL). This study aimed to examine the QoL of people who use kratom by comparing it with that of healthy non-kratom using controls and to determine the association between patterns of kratom use and QoL among people who use kratom. Methods: 200 respondents (100 subjects who use kratom and 100 healthy controls) were recruited for this cross-sectional study. The World Health Organization Quality of Life-BREF was administered to all the respondents to assess QoL, while the Kratom Dependence Scale (KDS) was used to assess the severity of kratom dependence among the subjects who use kratom. Results: The physical health, psychological, and environment QoL scores of the subjects who use kratom were significantly lower than those of the healthy controls. Multiple linear regression analysis revealed greater KDS score and longer duration of kratom use were significant predictors of physical health QoL, while only greater KDS score significantly predicted psychological and environment QoL scores. Conclusion: Prolonged kratom use and kratom dependence may negatively impact the QoL of people who use kratom, hence kratom addiction has to be treated adequately.
... It has a long history of traditional uses for ailments such as fever, diarrhea, diabetes, stress, fatigue, and pain [1,2]. In recent years, kratom has entered the Western herbal and recreational drug market and is touted by many as a safe and legal psychoactive substance that improves mood, relieves pain, and may possess medicinal qualities to combat opioid addiction [3,4]. In the United States, kratom can be purchased as leaves, powders, gums, resins, capsules, pills, and extracts for consumption, traditional smoking, and smoking in electronic cigarettes. ...
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... Despite these perceived benefits, increasing rates of kratom use have led to concomitant increases in reports of adverse effects following consumption, although to date, no fatal overdoses have been attributed to kratom use alone (Cinosi et al., 2015;Kruegel & Grundmann, 2017). While the Drug Enforcement Administration recently decided to withhold its decision on classifying kratom as a Schedule I drug (Griffin & Webb, 2018;Grundmann, Brown, Henningfield, Swogger, & Walsh, 2018), reservations about the safety of kratom remain, leading to increased scrutiny of its current legal status in the United States (Henningfield, Fant, & Wang, 2018;Prozialeck, 2016). ...
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Plant-based drugs of abuse are as old as recorded human history. Although traditional addictive substances, such as opium, cannabis and coca, have been controlled by the United Nations anti-drug conventions, many, if not most, natural plants with addictive or abuse liability remain elusive. Therefore, the United Nations Office on Drugs and Crime (UNODC) has warned the emerging threat from new psychoactive substances (NPS), which are mostly derived or modified from the constituents of natural origin. For example, synthetic cannabinoids and synthetic cathinones are derived from the cannabis and khat plant, respectively. In this review, we briefly discussed the chemistry, pharmacology and toxicology of five common NPS of natural origin, i.e., khat, kratom, salvia, magic mushroom and mandrake. Through the review, we hope that professionals and general public alike can pay more attention to the potential problems caused by natural NPS, and suitable control measures will be taken.
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Purpose: This article reviews the pharmacology, clinical utility, adverse effects, and abuse potential of kratom. Summary: The leaves of M. speciosa contain the biologically active alkaloids of kratom. Kratom exerts opioid and α-2 receptor agonistic effects as well as antiinflammatory and parasympathetic-impeding effects. There are no published human pharmacologic, pharmacokinetic, or drug interaction studies on kratom or mitragynine, making it virtually impossible to fully understand kratom's therapeutic potential and risks and the populations most likely to benefit or experience harm from its use. Kratom has been used to ameliorate opioid withdrawal symptoms but also induces withdrawal. Human pharmacologic, pharmacokinetic and clinical data are of low quality precluding any firm conclusions regarding safety and efficacy. Respiratory depression has not been commonly reported but kratom does cause a host of adverse effects without clear guidance for how they should be treated. There are numerous assessments where people have been unable to stop using kratom therapy and withdrawal signs and symptoms are problematic. Kratom does not appear in normal drug screens and, when taken with other substances of abuse, may not be recognized. Thirty-six deaths have been attributed to kratom, and the Food and Drug Administration issued a public health warning about the substance in November 2017. Conclusion: Kratom exerts opioid and α-2 receptor agonistic effects as well as antiinflammatory and parasympathetic-impeding effects. Human pharmacologic, pharmacokinetic, and clinical data are of low quality precluding any firm conclusions regarding safety and efficacy.
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Background: Kratom (Mitragyna speciosa) is a psychoactive plant native to Southeastern Asia that is receiving increased international attention as a potential therapeutic agent. While much of the limited scientific research on kratom is focused on its analgesic potential, kratom use also has important risks and benefits in the domain of mental health. Methods: We conducted a comprehensive systematic review of all studies on kratom use and mental health published between January 1960 and July 2017. Results: Findings indicate kratom's potential as a harm reduction tool, most notably as a substitute for opioids among people who are addicted. Kratom also enhances mood and relieves anxiety among many users. For many, kratom's negative mental health effects - primarily withdrawal symptoms - appear to be mild relative to those of opioids. For some users, however, withdrawal is highly uncomfortable and maintaining abstinence becomes difficult. Conclusion: Results inform clinicians working in the mental health and substance use fields, policy-makers, and researchers about the mental health effects of this plant.
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Background: Kratom use in the West has increased recently, yet the prevalence and motives for use among individuals with a history of substance use disorder (SUD) have not been fully examined. Kratom has been documented as a means of treating chronic pain, mitigating drug dependence, and easing withdrawal symptoms, yet it is unclear if substance users are utilizing kratom as a self-medication. Abuse liability, side effects, and overall appeal of kratom remain uncertain. Methods: In April 2017, an anonymous survey regarding kratom use and motivations was completed by clients enrolled in a 12-Step-oriented residential program. 500 respondents with a self-reported history of SUD completed the survey. Results: 20.8% of respondents endorsed lifetime kratom use and 10.2% reported past-12-month use. Kratom-users were younger (=32.1 vs. 35.9, p<0.001) and were more versatile substance users. A majority (68.9%) of kratom-users reported having used the drug as a means of reducing or abstaining from non-prescription opioids (NPO) and/or heroin, and 64.1% reported using kratom as a substitute for NPO/heroin. 18.4% of kratom-users reported using the drug due to a disability or chronic pain. One-third of kratom-users stated that kratom was a helpful substance and that they would try it again. However, kratom was not preferred and was indicated as having less appeal than NPO, heroin, amphetamines, and Suboxone. Conclusions: Among substance users, kratom use may be initiated for a variety of reasons, including as a novel form of harm-reduction or drug substitution, particularly in the context of dependence and withdrawal from other substances.
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Background: Kratom preparations have raised concerns of public health and safety in the US. Investigation into the demographics, perceived beneficial and detrimental effects of Kratom as well as common doses and purposes of its use are important to properly evaluate its potential health impact. Methods: An anonymous cross-sectional online survey was conducted in October 2016 of 10,000 current Kratom users through available social media and online resources from the American Kratom Association. A total of 8049 respondents completed the survey. Results: Kratom is primarily used by a middle-aged (31-50 years), middle-income ($35,000 and above) population for purposes of self-treating pain (68%) and emotional or mental conditions (66%). Kratom preparations present with a dose-dependent effect with negative effects, which were primarily gastrointestinal related including nausea and constipation, mainly presenting at high (5g or more/dose) and more frequent (22 or more doses/week) dosing. Conclusions: Kratom shows a dose-dependent opioid-like effect providing self-reported perceived beneficial effects in alleviating pain and relieving mood disorders. Kratom was primarily used for self-treatment of pain, mood disorders, and withdrawal symptoms associated with prescription opioid use.
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Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [³⁵S]GTPγS assays at the mu opioid receptor but failed to recruit β-arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic tolerance more slowly than morphine, showed limited physical dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.