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Kratom (Mitragyna speciosa) is a plant indigenous to Southeast Asia. Its leaves and the teas brewed from them have long been used by people in that region to stave off fatigue and to manage pain and opioid withdrawal. In a comprehensive review published in 2012, Prozialeck et al presented evidence that kratom had been increasingly used for the self-management of opioid withdrawal and pain in the United States. At the time, kratom was classified as a legal herbal product by the US Drug Enforcement Administration. Recent studies have confirmed that kratom and its chemical constituents do have useful pharmacologic actions. However, there have also been increasing numbers of reports of adverse effects resulting from use of kratom products. In August 2016, the US Drug Enforcement Administration announced plans to classify kratom and its mitragynine constituents as Schedule 1 controlled substances, a move that triggered a massive response from kratom advocates. The purpose of this report is to highlight the current scientific and legal controversies regarding kratom.
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... Kratom and its alkaloids have been classified as atypical opioids because they are structurally and biologically distinct from classical opioids (e.g., morphine) that are derived from the poppy (Papaveraceae) family (Raffa et al., 2018). Kratom has emerged as a natural product available for purchase over the internet Prozialeck, 2016), and has been identified as a Drug of Concern by the US Drug Enforcement pathway like classical opioids (Kruegel et al., 2016;Váradi et al., 2016). It is thus hypothesized to confer analgesic effects with lower risk of respiratory depression than classical opioids (Kruegel et al., 2016;Siuda et al., 2017;Váradi et al., 2016). ...
... It was also impossible to distinguish medically prescribed from illicit use of opioid medications in the current dataset, representing another significant limitation of the present study. Kratom is currently unscheduled in the US, although the US Drug Enforcement Administration and Food and Drug Administration have raised the possibility of Schedule I classification of kratom and its alkaloids, which would strongly deter research and pose a significant public health risk for individuals currently using kratom in place of other opioids (DEA, 2017;Henningfield et al., 2018;Prozialeck, 2016). The rationale for Schedule I classification includes 44 possible kratomrelated deaths worldwide over the past decade, most of which are known to involve other substances and/or preexisting medical conditions (Henningfield et al., 2018). ...
Article
Background: Kratom, a Southeast Asian plant with opioid-receptor mediated effects, has emerged as a potential substance of abuse, with limited data on its use and effects. This study characterized kratom user demographics, use patterns, and perceived drug effects. Methods: A cross-sectional, anonymous online survey was conducted between January and December 2017. Results: 2,798 kratom users - mean age 40 (SD = 12); predominantly White (90 %), female (61 %), and located in the US (97 %) - completed the survey. Kratom was primarily taken orally in doses of 1-3 g (49 %), with daily use (59 %) being most common. Kratom was used for pain (91 %), anxiety (67 %), and depression (65 %), with high ratings of effectiveness. 1,144 (41 %) used kratom to stop or reduce prescription or illicit opioid use, citing decreased opioid withdrawal and craving related to kratom use, with 411 reporting >1-year continuous abstinence from opioids attributed to kratom use. Roughly one-third of respondents reported adverse effects of kratom, largely rated as mild in severity and lasting ≤24 h. Seventeen participants (0.6 %) sought treatment for adverse effects. Fifty-six individuals (2 %) met DSM-5 criteria for a past-year moderate or severe kratom-related substance use disorder (SUD). When asked how troubled they felt regarding their kratom use, the mean (SD) rating was 3.2 (9.8) on a scale from 0 to 100. Conclusion: Kratom is used among White, middle-aged Americans for symptoms of pain, anxiety, depression, and opioid withdrawal. Although regular use was typical, kratom-related SUD and serious adverse effects were uncommon. Additional research on kratom epidemiology and pharmacology is imperative in light of the present opioid epidemic.
... In the US, kratom is regarded as a new dietary ingredient under the United States Food and Drug Administration (FDA) and Drug Enforcement Administration policies, and is not regulated as a dietary supplement according to the Dietary Supplement Health and Education Act (for reviews see: [12,19,20]). Although it remains legal in most of the US, at the time of writing several states, such as Alabama, Florida, Indiana, Arkansas, Wisconsin and Tennessee, have passed legislation banning the local sale and possession of kratom (for reviews see [19]). ...
Article
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Kratom (Mitragyna speciosa, Korth) is a tree-like plant that is indigenous to Southeast Asia. Kratom leaf products have been used in traditional folk medicine for their unique combination of stimulant and opioid-like effects. Kratom is being increasingly used in the West for its reputed benefits in the treatment of pain, depression and opioid use disorder. Recently, the United States Food and Drug Administration and Centers for Disease Control have raised concerns regarding the contamination of some kratom products with toxic metals (Pb and Ni) and microbes such as Salmonella. To further explore this issue, eight different kratom products were legally purchased from various “head”/”smoke” shops in the Western Suburbs of Chicago and then tested for microbial burden, a panel of metals (Ni, Pb, Cr, As, Hg, Cd), and levels of the main psychoactive alkaloid mitragynine. All of the samples contained significant, but variable, levels of mitragynine (3.9–62.1 mg/g), indicating that the products were, in fact, derived from kratom. All but two of the samples tested positive for the presence of various microbes including bacteria and fungi. However, none of the samples tested positive for Salmonella. Seven products showed significant levels of Ni (0.73–7.4 µg/g), Pb (0.16–1.6 µg/g) and Cr (0.21–5.7 µg/g) while the other product was negative for metals. These data indicate that many kratom products contain variable levels of mitragynine and can contain significant levels of toxic metals and microbes. These findings highlight the need for more stringent standards for the production and sale of kratom products.
... An increase in consumption of kratom based products has been also reported in recent years in the US and other countries due to claims of successful self-management of pain and opioid withdrawal symptoms [6][7][8]. ...
Article
Background: Kratom has a long history of traditional medicine use in Southeast Asia. Consumption of kratom products has also been reported in the US and other regions of the world. Pain relief is among many self-reported kratom effects but have not been evaluated in controlled human subject research. Methods: Kratom effects on pain tolerance were assessed in a randomized, placebo-controlled, double-blind study. During a 1-day inpatient stay, participants received a randomized sequence of kratom and placebo decoctions matched for taste and appearance. Pain tolerance was measured objectively in a cold pressor task (CPT) as time (seconds) between the pain onset and the hand withdrawal from the ice bath. Health status, vital signs, objective, and subjective indicators of withdrawal symptoms, self-reported data on lifetime kratom use patterns, and assessments of blinding procedures were also evaluated. Results: Twenty-six males with the mean (SD) age 24.3 (3.4) years were enrolled. They reported the mean (SD) 6.1 (3.2) years of daily kratom consumption. Pain tolerance increased significantly 1 hour after kratom ingestion from the mean (SD) 11.2 (6.7) seconds immediately before to 24.9 (39.4) seconds 1 hour after kratom consumption (F(2,53.7)=4.33, p=0.02). Pain tolerance was unchanged after consuming placebo drinks: 15.0 (19.0) seconds immediately before and 12.0 (8.1) seconds 1 hour after consumption of placebo (F(2,52.8)=0.93, p=0.40). No discomfort or signs of withdrawal were reported or observed during 10-20 hours of kratom discontinuation. Conclusions: Kratom decoction demonstrated a substantial and statistically significant increase in pain tolerance. Further rigorous research on kratom pain-relieving properties and a safety profile is needed.
... the Food and Drug Administration (FDA) [7,11]. However, placing kratom into Schedule I will severely limit the researchers' access to the plant in order to decipher all potential benefits and liabilities of kratom. ...
Article
Corynantheidine, a minor alkaloid found in Mitragyna speciosa (Korth.) Havil, has been shown to bind to opioid receptors and act as a functional opioid antagonist, but its unique contribution to the overall properties of kratom remains relatively unexplored. The first validated bioanalytical method for the quantification of corynantheidine in rat plasma is described. The method was linear in the dynamic range from 1 to 500 ng/mL, requires a small plasma sample volume (25 µL), and a simple protein precipitation method for extraction of the analyte. The separation was achieved with Waters BEH C18 2.1 x 50 mm column and the 3-minute gradient of 10 mM ammonium acetate buffer (pH = 3.5) and acetonitrile mobile phase. The method was validated in terms of accuracy, precision, selectivity, sensitivity, recovery, stability, and dilution integrity. It was applied to the analysis of the male Sprague Dawley rat plasma samples obtained during pharmacokinetic studies of corynantheidine administered both intravenously (I.V.) and orally (P.O.) (2.5 mg/kg and 20 mg/kg, respectively). The non-compartmental analysis performed in Certara Phoenix® yielded the following parameters: clearance 884.1 ± 32.3 mL/h, apparent volume of distribution 8.0 ± 1.2 L, exposure up to the last measured time point 640.3 ± 24.0 h*ng/mL, and a mean residence time of 3.0 ± 0.2 h with I.V. dose. The maximum observed concentration after a P.O. dose of 213.4 ± 40.4 ng/mL was detected at 4.1 ± 1.3 h with a mean residence time of 8.8 ± 1.8 h. Absolute oral bioavailability was 49.9 ± 16.4%. Corynantheidine demonstrated adequate oral bioavailability, prolonged absorption and exposure, and an extensive extravascular distribution.. In addition, imaging mass spectrometry analysis of the brain tissue was performed to evaluate the distribution of the compound in the brain. Corynantheidine was detected in the corpus callosum and some regions of the hippocampus.
... Recently, researchers began to pay more attention to the clinical implications of kratom in which there are several literatures reported the potential of kratom to be used as substitution therapy for treatment of opioid addiction due to its opioid-like properties and its ability to reduce and suppress opioid withdrawal symptoms, and as treatment of chronic pain. However kratom has fewer life-threatening side effects (even at high dose, kratom does not cause respiratory depression) and resulting in milder withdrawal despite regular use (5)(6)(7). ...
Article
Introduction: Kratom which is a tropical plant use as traditional remedy in rural areas of Malaysia and Thailand has recently been a research focus worldwide due to its potential as substitution therapy for opioid addiction. However, data on its effect on the quality of life of kratom users is scarce. This study aimed to describe the socio-demographic and history of kratom use as well as assessing the quality of life and its associated factors in Malaysian kratom users. Methods: This cross-sectional survey recruited 150 kratom users and they were administered with socio-demographic and substance history questionnaires, the World Health Organization Quality of Life-BREF (WHOQOL-BREF) to assess quality of life and the Kratom Dependence Scale (KDS) to assess severity of kratom dependence. Results: Respondents were all males with mean age of 34.4 years old (SD= 11.2). Sixty-percent of respondents use kratom > 6 years (mean duration = 8.5 years, SD= 5.3) while 55% (n=83/150) used >3 glasses of kratom daily. Duration of kratom use, quantity of kratom use and severity of kratom dependence were not associated with all the domains of quality of life except severe kratom dependence users had significant lower physical quality of life score when compared to that of users with mild to moderately severe kratom dependence. Conclusion: Based on our study, kra-tom consumption does not cause impairment in quality of life of kratom users except for severe kratom dependence which may cause deterioration in physical well-being of users.
... 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). ...
Article
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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.
... Kratom use appears to be increasing in the USA (Warner et al., 2016), especially for self-management of opioid withdrawal and pain relief (Grundmann, 2017;Prozialeck, 2016). Pain relief appears to be the most common reason, closely followed by emotional/mental conditions such as anxiety, depression and post-traumatic stress disorder, followed by drug dependency (Grundmann, 2017). ...
Article
Background Kratom ( Mitragyna speciosa Korth) use has increased in Western countries, with a rising number of associated deaths. There is growing debate about the involvement of kratom in these events. Aims This study details the characteristics of such fatalities and provides a ‘state-of-the-art’ review. Methods UK cases were identified from mortality registers by searching with the terms ‘kratom’, ‘mitragynine’, etc. Databases and online media were searched using these terms and ‘death’, ‘fatal*’, ‘overdose’, ‘poisoning’, etc. to identify additional cases; details were obtained from relevant officials. Case characteristics were extracted into an Excel spreadsheet, and analysed employing descriptive statistics and thematic analysis. Results Typical case characteristics ( n = 156): male (80%), mean age 32.3 years, White (100%), drug abuse history (95%); reasons for use included self-medication, recreation, relaxation, bodybuilding, and avoiding positive drug tests. Mitragynine alone was identified/implicated in 23% of cases. Poly substance use was common (87%), typically controlled/recreational drugs, therapeutic drugs, and alcohol. Death cause(s) included toxic effects of kratom ± other substances; underlying health issues. Conclusions These findings add substantially to the knowledge base on kratom-associated deaths; these need systematic, accurate recording. Kratom’s safety profile remains only partially understood; toxic and fatal levels require quantification.
... Because the survey originated from Florida, it may explain the high net and populationadjusted response rate. Some of the lowest response rates came from states where kratom is banned, namely, Wisconsin, Indiana, Tennessee, Vermont, Arkansas, and Alabama (Prozialeck, 2016). ...
Article
Objective: Kratom preparations have raised concerns of public health and safety in the United States. This paper analyzed the patterns and predictors of kratom use by four U.S. regions according to the U.S. Census. Method: An anonymous cross-sectional online survey yielded 8,049 valid responses. The data were categorised by regions (Northeast, South, Midwest, and West) and analyzed for the following predictors: age, gender, marital status, ethnicity, employment status, insurance coverage, education, and household income. Results: After adjusting for state population, the survey response rates were highest from Oregon, Idaho, and Florida. Kratom use was significantly lower for both prescription drug dependency and acute or chronic pain in the Northeast region than the rest of the country. Multiple logistic regression models found that gender, employment, and education were significant on the regional level. Higher education was associated with lower kratom use for an illicit drug dependency (p = .002) independent of region whereas men were less likely to use kratom for acute or chronic pain in the Northeast (p < .001) but more likely in the Midwest (p = .041). Conclusions: The regional pattern of kratom use differed from opioid use data in both demographics and trend direction warranting further investigation.
... Mitragynine is the alkaloid derived from Kratom (Mitragyna speciose), a plant commonly found in Thailand and throughout the South East Asia region [1,2]. Like many other opioid plants, there are claims of medical uses [3,4] but these plants are also potentially illegal drugs of abuse [5,6]. In additional to natural sources, mitragynine and its derivative may be obtained by total syntheses reported by researchers in Japan [7] and United States [8]. ...
Article
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Objective: Mitragynine is the main active compound of Mitragyna speciose (Kratom in Thai). The understanding of mitragynine derivative metabolism in human body is required to develop effective detection techniques in case of drug abuse or establish an appropriate dosage in case of medicinal uses. This in silico study is based upon in vivo results in rat and human by Philipp et al. (J Mass Spectrom 44:1249-1261, 2009). Results: Gas-phase structures of mitragynine, 7-hydroxymitragynine and their metabolites were obtained by quantum chemical method at B3LYP/6-311++G(d,p) level. Results in terms of standard Gibbs energies of reaction for all metabolic pathways are reported with solvation energy from SMD model. We found that 7-hydroxy substitution leads to changes in reactivity in comparison to mitragynine: position 17 is more reactive towards demethylation and conjugation with glucuronic acid and position 9 is less reactive towards conjugation with glucuronic acid. Despite the changes, position 9 is the most reactive for demethylation and position 17 is the most reactive for conjugation with glucuronic acid for both mitragynine and 7-hydroxymitragynine. Our results suggest that 7-hydroxy substitution could lead to different metabolic pathways and raise an important question for further experimental studies of this more potent derivative.
Article
Kratom is a plant material exhibiting both analgesic and stimulant effects and is also forensically relevant since it is abused as a “legal high.” It is regulated in several countries but not scheduled in the United States at the federal level. This study used inductively coupled plasma–mass spectrometry (ICP–MS) to measure the concentrations of 13 elements in 19 kratom samples obtained from an online distributor selling kratom, from Borneo, Malaysia, Indonesia, Thailand, and Vietnam, for the purpose of using the elements to discriminate among purported country of origin, “suborigin,” and strain. Analysis of variance revealed statistical differences in concentrations of elements from each group, while discriminant function analysis (using leave‐one‐out classification) successfully classified kratom samples by their purported country of origin (100%), “suborigin,” (100%), and strain (86%). Our method illustrates the possibility of utilizing ICP–MS for determination of commercially available kratom samples by purported origin, “subororign,” or by product line.
Article
Prescription opioid (PO) misuse is a major health concern across North America, and it is the primary cause of preventable death for the 18–35 year old demographic. Medication assisted therapy including methadone and buprenorphine, is the standard of care for patients with opioid-dependence. Moreover, both of these medications are recognized as essential medicines by World Health Organization. In Ontario Canada, the availability of medication assisted therapy has expanded substantially, with almost a tenfold increase number of patients accessing methadone in Ontario in the past decade. In their manuscript, Fischer et. al. (2016), present a view that expansion of opioid maintenance therapy (OMT) has outpaced true patient need and alternate strategies should be considered as first-line treatments. Here, we present a countering perspective-that medication assisted therapy, along with other harm reduction strategies, should be widely available to all opioid-dependent people as first-line treatments.
Article
Kratom (Mitragyna speciosa) is a plant consumed throughout the world for its stimulant effects and as an opioid substitute (1). It is typically brewed into a tea, chewed, smoked, or ingested in capsules (2). It is also known as Thang, Kakuam, Thom, Ketum, and Biak (3). The Drug Enforcement Administration includes kratom on its Drugs of Concern list (substances that are not currently regulated by the Controlled Substances Act, but that pose risks to persons who abuse them), and the National Institute of Drug Abuse has identified kratom as an emerging drug of abuse (3,4). Published case reports have associated kratom exposure with psychosis, seizures, and deaths (5,6). Because deaths have been attributed to kratom in the United States (7), some jurisdictions have passed or are considering legislation to make kratom use a felony (8). CDC characterized kratom exposures that were reported to poison centers and uploaded to the National Poison Data System (NPDS) during January 2010-December 2015. The NPDS is a national database of information logged by the country's regional poison centers serving all 50 United States, the District of Columbia, and Puerto Rico and is maintained by the American Association of Poison Control Centers. NPDS case records are the result of call reports made by the public and health care providers.
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With Lembke article and opioid PG.
Article
Introduction: The objective of the paper was to highlight the differences in the traditional and non-traditional users of kratom in the South East Asian and Western contexts. Method: A literature survey of published kratom studies among humans was conducted. Forty published studies relevant to the objective were reviewed. Results: Apart from the differences in the sources of supply, patterns of use and social acceptability of kratom within these two regions, the most interesting finding is its evolution to a recreational drug in both settings and the severity of the adverse effects of kratom use reported in the West. While several cases of toxicity and death have emerged in the West, such reports have been non-existent in South East Asia where kratom has had a longer history of use. We highlight the possible reasons for this as discussed in the literature. More importantly, it should be borne in mind that the individual clinical case-reports emerging from the West that link kratom use to adverse reactions or fatalities frequently pertained to kratom used together with other substances. Therefore, there is a danger of these reports being used to strengthen the case for legal sanction against kratom. This would be unfortunate since the experiences from South East Asia suggest considerable potential for therapeutic use among people who use drugs. Conclusion: Despite its addictive properties, reported side-effects and its tendency to be used a recreational drug, more scientific clinical human studies are necessary to determine its potential therapeutic value.
Article
The leaves of a tropical plant, Mitragyna speciosa KORTH (Rubiaceae), have been traditionally used as a substitute for opium. Phytochemical studies of the constituents of the plant growing in Thailand and Malaysia have led to the isolation of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids, including new natural products. The structures of the new compounds were elucidated by spectroscopic and/or synthetic methods. The potent opioid agonistic activities of mitragynine, the major constituent of this plant, and its analogues were found in in vitro and in vivo experiments and the mechanisms underlying the analgesic activity were clarified. The essential structural features of mitragynines, which differ from those of morphine and are responsible for the analgesic activity, were elucidated by pharmacological evaluation of the natural and synthetic derivatives. Among the mitragynine derivatives, 7-hydroxymitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice.