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Letter to the Editor
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.
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
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Santacroce R., Roman-Urrestarazu A. Changing trends in
2Letter to the Editor
© 2018 Society for the Study of Addiction Addiction
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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. ...
Full-text available
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. ...
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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Objective: Kratom (Mitragyna speciose) is a tropical tree used in traditional herbal medicine. It has gained popularity as an herbal remedy and recreational drug. Bioactive alkaloids isolated from kratom shows stimulant and opiate-like effects and raise concern for potential abuse, dependence, and toxicity. The intent is to characterize the association of kratom use with toxicity-related deaths, determine the profile of mixed-drug usage, characterize the demographics of those using kratom, and to identify opportunities for public health interventions. Methods: This is a retrospective study of postmortem toxicology from suspected drug-related deaths from January 2018 to March 2019. The data was aggregated from the Wayne County and Washtenaw County Medical Examiners' Offices, which serve Livingston, Monroe, Wayne, and Washtenaw counties in the State of Michigan. Thirty-three (33) decedents with postmortem toxicology positive for the kratom compound mitragynine were identified in suspected drug-related deaths; none were excluded. Results: We examined the demographics and co-occurring drug profiles in mitragynine-related drug deaths. Of 33 identified cases, 31 (94%) were certified as drug toxicity-related deaths. Decedents were predominantly male (88%) and Caucasian (94%) with a median age of 36 years and with known substance abuse history (80%).We examined the demographics and co-occurring drug profiles in mitragynine-related drug deaths. Of 33 identified cases, 31 (94%) were certified as drug toxicity-related deaths. Decedents were predominantly male (88%) and Caucasian (94%) with a median age of 36 years and with known substance abuse history (80%). Co-occurrence of opioids was observed in 84% of cases with fentanyl being most common. Stimulants such as cocaine and amphetamines were found in 52%. In cases where mitragynine was determined to be contributory to death, the median concentration was 180 ng/mL. A single-agent mitragynine death was confirmed in one decedent (2400 ng/ mL). Conclusion: In the medical examiner setting, kratom found in postmortem toxicology is rising and associated deaths are no longer esoteric. Kratom positivity has a strong association with substance abuse history and mixed-drug toxicity suggestive of recreational use. Despite backlash from consumers and advocacy groups, the known potential for abuse and increasing evidence of toxicity likely warrants some measure of regulation.
... 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). ...
Full-text available
Background and purpose: Mitragyna speciosa, more commonly known as kratom, is a plant that contains opioidergic alkaloids, but is unregulated in most countries. Kratom is used in the self-medication of chronic pain and to reduce illicit and prescription opioid dependence. Kratom may be less dangerous than typical opioids because of the stronger preference of kratom alkaloids to induce receptor interaction with G proteins over beta-arrestin proteins. We hypothesized that kratom (alkaloids) can also reduce alcohol intake. Experimental approach: We pharmacologically characterized kratom extracts, kratom alkaloids (mitragynine, 7-hydroxymitragynine, paynantheine, and speciogynine), and synthetic carfentanil-amide opioids for their ability to interact with G proteins and beta-arrestin at mu, delta and kappa opioid receptors in vitro. We used C57BL/6 mice to assess to which degree these opioids could reduce alcohol intake and whether they had rewarding properties. Key results: Kratom alkaloids were strongly G protein-biased at all three opioid receptors and reduced alcohol intake, but kratom and 7-hydroxymitragynine were rewarding. Several results indicated a key role for delta opioid receptors, including that the synthetic carfentanil-amide opioid MP102 - a G protein-biased agonist with modest selectivity for delta opioid receptors - reduced alcohol intake, whereas the G protein-biased mu opioid agonist TRV130 did not. Conclusion and implications: Our results suggest that kratom extracts can decrease alcohol intake, but still carry significant risk upon prolonged use. Development of more delta opioid-selective synthetic opioids may provide a safer option than kratom to treat alcohol use disorder with fewer side effects.
Full-text available
Kratom (Mitragyna speciosa Korth., Rubiaceae) is a plant native to Southeast Asia, where it has been used for centuries as a mild stimulant and as medicine for various ailments. More recently, as kratom has gained popularity in the West, United States federal agencies have raised concerns over its safety leading to criminalization in some states and cities. Some of these safety concerns have echoed across media and broad-based health websites and, in the absence of clinical trials to test kratom's efficacy and safety, considerable confusion has arisen among healthcare providers. There is, however, a growing literature of peer-reviewed science that can inform healthcare providers so that they are better equipped to discuss kratom use with consumers and people considering kratom use within the context of their overall health and safety, while recognizing that neither kratom nor any of its constituent substances or metabolites have been approved as safe and effective for any disease. An especially important gap in safety-related science is the use of kratom in combination with physiologically active substances and medicines. With these caveats in mind we provide a comprehensive overview of the available science on kratom that has the potential to i clarity for healthcare providers and patients. We conclude by making recommendations for best practices in working with people who use kratom.
Kratom (Mitragyna speciosa) consists of over 40 alkaloids with two of them, mitragynine (MG) and 7‐OH‐mitragynine (7‐OH‐MG) being the main psychoactive compounds. MG and 7‐OH‐MG each target opioid receptors and have been referred to as atypical opioids. They exert their pharmacologic effects on the μ, δ, and κ opioid receptors. In addition, they affect adrenergic, serotonergic, and dopaminergic pathways. Kratom has been touted as an inexpensive, legal alternative to standard opioid replacement therapy such as methadone and buprenorphine. Other uses for kratom include chronic pain, attaining a “legal high,” and numerous CNS disorders including anxiety depression and post‐traumatic stress disorder (PTSD). Kratom induces analgesia and mild euphoria with a lower risk of respiratory depression or adverse central nervous system effects compared to traditional opioid medications. Nonetheless, kratom has been associated with both physical and psychological dependence with some individuals experiencing classic opioid withdrawal symptoms upon abrupt cessation. Kratom use has been linked to serious adverse effects including liver toxicity, seizures, and death. These risks are often compounded by poly‐substance abuse. Further, kratom may potentiate the toxicity of coadministered medications through modulation of cytochrome P450, P‐glycoprotein, and uridine diphosphate glucuronosyltransferase enzymes (UGDT). In 2016 the U.S. Drug Enforcement Administration (DEA) took steps to classify kratom as a federal schedule 1 medication; however, due to public resistance, this plan was set aside. Until studies are conducted that define kratom's role in treating opioid withdrawal and/or other CNS conditions, kratom will likely remain available as a dietary supplement for the foreseeable future. This article is protected by copyright. All rights reserved
Mitragyna speciosa (Kratom) is a psychotropic tropical tree that is indigenous to Southeast Asia, Africa and New Guinea. Kratom has gained popularity in the United States in more recent years as an opioid agonist. Although Kratom is considered an opioid agonist with abuse potential, its use is not federally regulated. We report on a 47 year-old male presenting to our clinic for treatment of an opioid use disorder. This began with the use of prescription opioids from a doctor, and when this was no longer available this patient started using Kratom. He had used Kratom for one year to treat opioid withdrawal symptoms and chronic pain, resulting in worsening depression, anxiety and pain. He experienced tolerance and withdrawal symptoms related to Kratom. He was initiated on buprenorphine-naloxone at home with improved pain management. Four months after initiation, the patient’s depression and anxiety symptoms resolved, and he was able to discontinue his antidepressant and anxiolytic medications. Kratom dependence and withdrawal appear similar to that of opioids, and may also lead to worsening depression and anxiety. Buprenorphine-naloxone may be a viable option to consider for treating opioid use disorder complicated by Kratom use, chronic pain, and depression.
Kratom use appears to be increasing across the United States, increasing attention to deaths in which kratom use was detected. Most such deaths have been ascribed to fentanyl, heroin, benzodiazepines, prescription opioids, cocaine and other causes (e.g., homicide, suicide and various preexisting diseases). Because kratom has certain opioid-like effects (e.g., pain relief), and is used by some people as a substitute for opioids for pain or addiction, kratom has been compared to "narcotic-like opioids" (e.g., morphine) with respect to risk of death despite evidence that its primary alkaloid, mitragynine, carries little of the signature respiratory depressing effects of morphine-like opioids. This commentary summarizes animal toxicology data, surveys and mortality data associated with opioids and kratom to provide a basis for estimating relative mortality risk. Population-level mortality estimates attributed to opioids as compared to kratom, and the per user mortality risks of opioids as compared to kratom are provided. By any of our assessments, it appears that the risk of overdose death is >1000 times greater for opioids than for kratom. The limitations of the mortality risk estimate warrants caution in individuals with unknown factors such as use of other substances and medications, or other preexisting conditions. More research on kratom safety and risks is needed, as is regulation of commercial kratom products to ensure that consumers are informed by FDA labeling and that kratom products are not contaminated or adulterated with other substances.
Pain and addiction are complex disorders with many commonalities. Beneficial outcomes for both disorders can be achieved through similar principles such as individualized medication selection and dosing, comprehensive multi-modal therapies, and judicious modification of treatment as indicated by the patient's status. This is implicit in the term "medication assisted treatment" (MAT) for opioid use disorders (OUD), and is equally important in pain management; however, for many OUD and pain patients, medication is central to the treatment plan and should neither be denied nor withdrawn if critical to patient well-being. Most patients prescribed opioids for pain do not develop OUD, and most people with OUD do not develop it as a result of appropriately prescribed opioids. Nonetheless, concerns about undertreatment of pain in the late 20th century likely contributed to inappropriate prescribing of opioids. This, coupled with a shortfall in OUD treatment capacity and the unfettered flood of inexpensive heroin and fentanyl, behavioral economics and other factors facilitated the 21st century opioid epidemic. Presently, injudicious reductions in opioid prescriptions for pain are contributing to increased suffering and suicides by pain patients as well as worsening disparities in pain management for ethnic minority and low-income people. Many of these people are turning to illicit opioids, and no evidence shows that the reduction in opioid prescriptions is reducing OUD or overdose deaths. Comprehensive, science-based policies that increase access to addiction treatment for all in need and better serve people with pain are vital to addressing both pain and addiction.
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Many of the scientific and regulatory challenges that exist in research on the safety, quality and efficacy of dietary supplements are common to all countries as the marketplace for them becomes increasingly global. This article summarizes some of the challenges in supplement science and provides a case study of research at the Office of Dietary Supplements at the National Institutes of Health, USA, along with some resources it has developed that are available to all scientists. It includes examples of some of the regulatory challenges faced and some resources for those who wish to learn more about them.
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RationaleConsideration by the US Drug Enforcement Administration and Food and Drug Administration of placing kratom into Schedule I of the Controlled Substances Act (CSA) requires its evaluation of abuse potential in the context of public health. Objective The objective of the study is to provide a review of kratom abuse potential and its evaluation according to the 8 factors of the CSA. ResultsKratom leaves and extracts have been used for centuries in Southeast Asia and elsewhere to manage pain and other disorders and, by mid-twentieth century, to manage opioid withdrawal. Kratom has some opioid effects but low respiratory depression and abuse potential compared to opioids of abuse. This appears due to its non-opioid-derived and resembling molecular structure recently referred to as biased agonists. By the early 2000s, kratom was increasingly used in the US as a natural remedy to improve mood and quality of life and as substitutes for prescription and illicit opioids for managing pain and opioid withdrawal by people seeking abstinence from opioids. There has been no documented threat to public health that would appear to warrant emergency scheduling of the products and placement in Schedule I of the CSA carries risks of creating serious public health problems. Conclusions Although kratom appears to have pharmacological properties that support some level of scheduling, if it was an approved drug, placing it into Schedule I, thus banning it, risks creating public health problems that do not presently exist. Furthermore, appropriate regulation by FDA is vital to ensure appropriate and safe use.
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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.
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.
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.
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.
Objective: Kratom (Mitragyna speciosa. Korth) is an indigenous medicinal plant of Southeast Asia. This review paper aims to describe the trends of kratom use in Southeast Asia. Design: A literature review search was conducted through ScienceDirect, Scopus, ProMed and Google Scholar. Twenty-five articles illustrating kratom use in humans in Southeast Asia were reviewed. Results: Kratom has long been used by rural populations in Southeast Asia as a remedy for common ailments, to fight fatigue from hard manual work, as a drink during social interaction among men, and in village religious functions. Studies based on self-reports suggest that prolonged kratom use does not result in serious health risks or impair social functioning. Two recent trends have also emerged: (a) Kratom is reportedly being used to ease withdrawal from opioid dependence in rural settings; whereas (b) in urban areas, adulterated kratom cocktails are being consumed by younger people to induce euphoria. Conclusions: Legal sanctions appear to have preceded serious scientific investigations into the claimed benefits of ketum. More objective-controlled trials and experiments on humans need to be conducted to validate self-report claims by kratom users in the community.
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.
Ethnopharmacological relevance: The genus Mitragyna (Rubiacaeae) has been traditionally used in parts of Africa, Asia and Oceania. In recent years, there has been increased interest in species of Mitragyna with the introduction of products to western markets and regulatory uncertainty. Aim of the study: This paper reviewed the traditional ethnomedicinal uses of leaves for species belonging to the genus Mitragyna with reference to the botany and known chemistry in order to highlight areas of interest for products currently being sold as kratom. Materials and methods: A literature search was conducted using Web of Science, Google Scholar, the Royal Museum for Central Africa, Internet Archive, Hathi Trust, and Biodiversity Heritage Library search engines in the spring of 2015, fall of 2016 and winter of 2017 to document uses of bark, leaf and root material. Results: Leaves of M. speciosa (kratom) had the most common documented ethnomedicinal uses as an opium substitute or remedy for addiction. Other species of Mitragyna were reportedly used for treating pain, however the mode of preparation was most often cited as topical application. Other uses of Mitragyna included treatment of fever, skin infections, and as a mild anxiolytic. Conclusions: Mitragyna species have been used medicinally in various parts of the world and that there is significant traditional evidence of use. Modern products that include formulations as topical application of liniments, balms or tinctures may provide effective alternatives for treatment of certain types of pains. Future research is required to establish safety and toxicology limits, medicinal chemistry parameters and the potential for different physiological responses among varying genetic populations to support regulatory requirements for Mitragyna spp.
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.