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Abstract

Introduction Kratom (Mitragyna speciosa), a plant native to Southeast Asia, has been used for centuries for its stimulant and opium-like effects. Mitragynine and 7-hydroxymitragynine, exclusive to M. speciosa, are the alkaloids primary responsible for Kratom's biologic and psychoactive profile, and likely contribute to its problematic use. We purchased several commercially available Kratom analogs for analysis and through our results, present evidence of probable adulteration with the highly potent and addictive plant alkaloid, 7-hydroxymitragynine. Methods A simple and sensitive LC-MS/MS method was developed for simultaneous quantification of mitragynine and 7-hydroxymitragynine in methanol extract of marketed Kratom supplements. Results We found multiple commercial Kratom products to have concentrations of 7-hydroxymitragynine that are substantially higher than those found in raw M. speciosa leaves. Conclusions We have found multiple packaged commercial Kratom products likely to contain artificially elevated concentrations of 7-hydroxymitragynine, the alkaloid responsible for M. speciosa's concerning mechanistic and side effect profile. This study describes a unique form of product adulteration, which stresses the importance of increased dietary supplement oversight of Kratom-containing supplements.

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... It also stimulates α2-adrenergic receptors, inhibiting norepinephrine release (white, 2018). the content of mitragynine in leaves can vary considerably depending on variant, age, and plant origin, as well as environmental factors and harvest time, and can constitute up to 66% of the total alkaloid content (warner, kaufman, Grundmann, 2016; Suhaimi et al., 2016;Lydecker et al., 2016). in addition to this compound, more than 40 other alkaloids have been isolated from M. speciosa, including paynantheine and speciogynine (Fig. 1). the total alkaloid content of dried leaves ranges from 0.5-1.5% (Lydecker et al., 2016). ...
... It also stimulates α2-adrenergic receptors, inhibiting norepinephrine release (white, 2018). the content of mitragynine in leaves can vary considerably depending on variant, age, and plant origin, as well as environmental factors and harvest time, and can constitute up to 66% of the total alkaloid content (warner, kaufman, Grundmann, 2016; Suhaimi et al., 2016;Lydecker et al., 2016). in addition to this compound, more than 40 other alkaloids have been isolated from M. speciosa, including paynantheine and speciogynine (Fig. 1). the total alkaloid content of dried leaves ranges from 0.5-1.5% (Lydecker et al., 2016). ...
... The first effects are observed after about 5 minutes and last for two to five hours (Rech, Donahey cappiello dziedzic, oh, Greenhalgh, 2015). in low doses (1-5 g dry leaves), kratom is characterised by stimulant action similar to cocaine -it improves mood, induces euphoria and increased alertness, enhances empathy and facilitates social interaction. Higher doses (5-15 g dry leaves) mimic the analgesic and sedative effects of opioids (Lydecker et al., 2016). After taking kratom, nausea, dizziness, constipation, itch (pruritus) and sexual dysfunction may occur. ...
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Kratom is a colloquial term for the Mitragyna speciosa plant, as well as for products derived from this plant, whose main psychoactive compounds are mitragynine and 7-hydroxymitragynine. Kratom is used as a traditional medicine to relieve muscle pain and intestinal infections, increase energy and appetite, and also as a psychoactive and mood enhancer. In recent years, the popularity of this substance has increased both in Europe and in the United States, where it can be easily purchased online in the form of leaves, capsules, tablets, powders and concentrated extracts. Products obtained from kratom were analyzed within casework at the Institute of Forensic Research in 2009, 2014 and 2019. Gas chromatography-mass spectrometry (GC-MS) and ultra-performance liquid chromatography with diode detection (UPLC-PDA) were used for the analyses. The presence of mitragynine was confirmed in all the analysed materials. The concentration of mitragynine in powdered substances analysed in 2019 was 1.1–1.4%. The number of cases investigated at the Institute in recent years in which mitragynine was detected does not indicate that kratom was (is) a significant problem on the Polish illegal drug market, but the growing interest in this substance may change this situation. An increasing number of cases related to the identification of kratom ingredients in biological materials collected from users, including fatally intoxicated people, are reported worldwide. Although administration of kratom alone may seem relatively safe, its mixtures with other psychoactive compounds pose a significant threat to the health and life of users.
... Importantly, Kratom purchased online is more potent than the natural plant because it contains higher concentrations of its psychoactive alkaloids 11 . is not prohibited by the Controlled Substances Act and federally is considered a legal substance 14 . It is regulated as a "herbal product" by the US Food and Drug Administration 15 . ...
... Kratom has distinctive dose-dependent effects. At low doses (1-5 grams) it has stimulant-like effect, at moderate to high doses (5-15 grams) it has opioid-like effects and at very high doses (>15 grams) it is sedating effects and can induce stupor 11,14 . At his most maximum use, our patient was consuming up to thirty grams three times a day, which explains why he endorsed sedation as an adverse effect. ...
... Common short-term adverse effects include nausea, constipation, sleep problems, temporary erectile dysfunction, itching, sweating and hypertension 2,11 . Long-term adverse effects include anorexia, dry mouth, hyperpigmentation, diuresis, and hair loss 11,14 Fatalities have been reported when Kratom is used alongside other drugs specifically modafinil, carisoprodol, fentanyl, tramadol, diphenhydramine, caffeine, morphine, loperamide, zopiclone, citalopram, lamotrigine, venlafaxine, mirtazapine and propylhexidine 3,26-28 . These drugs interact metabolically with Kratom. ...
... This is particularly concerning as there are no published clinical studies that describe the results of kratom administration for any of these therapeutic purposes. While animal models have indicated that the main component of kratom, mitragynine, has a low abuse potential [7,8], mitragynine may be metabolized into 7-hydroxymitragynine [9], a component of kratom with demonstrated abuse potential and drug dependency [10,11], exhibited analgesic effects that exceed the potency of morphine [12], and is a suspected adulterant of commercial kratom products [13]. ...
... 3. The oxindole congeners (13)(14)(15)(16)(17)(18)(19)(20)(21) formed by a rearrangement product of the mitragynine congeners. ...
... The Quickprep function performs an energy minimization and sets the protonation state of any titratable residues. The structural similarity of the alkaloids with respect The four general alkaloid classes include the mitragynine congeners (1-10), pyran-fused mitragynine congeners (11)(12), oxindole congeners (13)(14)(15)(16)(17)(18)(19)(20)(21), and the pyran-fused oxindole congeners (22)(23)(24)(25). The chiral centers that are addressed in this manuscript are indicated by wavy bonds and asterisks ( � ), and the locations of varying side chains are marked as R 1 , R 2 and R 3 . ...
Article
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Kratom is a botanical substance that is marketed and promoted in the US for pharmaceutical opioid indications despite having no US Food and Drug Administration approved uses. Kratom contains over forty alkaloids including two partial agonists at the mu opioid receptor, mitragynine and 7-hydroxymitragynine, that have been subjected to the FDA’s scientific and medical evaluation. However, pharmacological and toxicological data for the remaining alkaloids are limited. Therefore, we applied the Public Health Assessment via Structural Evaluation (PHASE) protocol to generate in silico binding profiles for 25 kratom alkaloids to facilitate the risk evaluation of kratom. PHASE demonstrates that kratom alkaloids share structural features with controlled opioids, indicates that several alkaloids bind to the opioid, adrenergic, and serotonin receptors, and suggests that mitragynine and 7-hydroxymitragynine are the strongest binders at the mu opioid receptor. Subsequently, the in silico binding profiles of a subset of the alkaloids were experimentally verified at the opioid, adrenergic, and serotonin receptors using radioligand binding assays. The verified binding profiles demonstrate the ability of PHASE to identify potential safety signals and provide a tool for prioritizing experimental evaluation of high-risk compounds.
... Lydecker observed concentrations of 7-hydroxymitragynine in commercial kratom products that were substantially higher than those reported in raw M. speciosa leaves. Almost five-fold increases in concentration were observed for some products, suggestive of adulteration of the plant material (Lydecker et al., 2016). These findings are of toxicological significance given the increased potency of this substance relative to both mitragynine and morphine. ...
... In a more recent series of 20 fatalities, median concentrations of 7-hydroxymitragynine in central (104 ng/ml) and peripheral blood (78 ng/ml) exceeded those of mitragynine (54 and 21 ng/ml, respectively). Despite the analytical challenges associated with its measurement, inclusion of 7-hydroxymitragynine within the scope of testing may be highly desirable given its increased potency and reports of kratom products being fortified with this substance (Lydecker et al., 2016). Postmortem redistribution (PMR) of Mitragyna alkaloids is not particularly well-studied, although preliminary reports do not suggest the drug is particularly susceptible to this phenomenon. ...
Article
Kratom is a botanical substance derived from the leaves of Mitragyna speciosa. Although kratom has been used traditionally in Southeast Asia for over a century, recreational use and non‐medically supervised use of the drug in the West has escalated considerably over the past decade. Viewed as a legal, “safe” or “natural” alternative to opioids, kratom has gained widespread use for the non‐medically supervised treatment of chronic pain, anxiety, and opioid withdrawal. Kratom consists of a complex mixture of more than 50 alkaloids, of which mitragynine and 7‐hydroxymitragynine are the principal compounds of interest due to their abundance and heightened affinity for the mu opioid receptor, respectively. Mitragynine, which is structurally and pharmacologically distinct from traditional opioids, exhibits a multimodal mechanism of action which accounts for its complex adrenergic, serotonergic, and opioid‐like effects. Adverse effects including fatalities have been associated with kratom's use, often in combination with other drugs. While users report numerous benefits associated with its use, lack of regulatory control and escalating use among individuals with opioid use disorder has attracted widespread concern. In this review the origins, pharmacology, uses, effects, and analysis of the drug are reviewed from a toxicological standpoint. This article is categorized under: • Toxicology > New Psychoactive Substances • Toxicology > Opioids • Toxicology > Plants and Poisons Abstract Kratom: A systematic review of toxicological issues.
... Levels of mitragynine and 7-hydroxymitragynine in kratom products are in the range of 1.5-2 mass % and about 0.02-0.33 mass % respectively Lydecker et al., 2016). So, the concentration of mitragynine is 50-100 times that of its hydroxy metabolite (Kruegel and Grundmann, 2018). ...
... However, Griffin et al. (2016) found that products marketed as liquid pain relief and containing mitragynine contained kratom. It is also worth noting that the concentrations of 7-hydroxymitragynine found in products may be artificially made considerably higher than those found in kratom leaves (Lydecker et al., 2016). ...
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.
... It is noteworthy that MTG and 7-OH-MTG are found in dramatically different concentrations in kratom leaves, with roughly two-thirds of alkaloid content present as MTG and the latter only occurring in trace amounts < 1%. 1,8 It is relevant that 7-OH-MTG, which demonstrates exponentially higher binding affinity at multiple receptors, 6 has been implicated in the majority of deleterious effects associated with kratom use, including misuse and dependence. ...
... 9 In a sharply contrasting study from the Journal of Medical Toxicology in the same year, artificially increased levels of 7-OH-MTG were appreciated in 7 out of 8 samples, and with variability between some samples over 500%. 8 Other adulterants to enhance opioid effects had also been appreciated, resulting in deaths in Europe. Cases exist in the literature of kratom supplements being adulterated with other stimulants, such as a case of phenylethylamine linked to an intracerebral hemorrhage. ...
Article
Kratom (Mitragyna speciosa) is an easily accessible dietary supplement gaining notoriety in medicine for its use as a surrogate form of self-driven opioid use disorder treatment, albeit one with a lack of evidence and significant risks. Both misuse and withdrawal from kratom have been appreciated in the literature and addressed in a fashion analogous to that of opioids. Because of this, it has largely been studied through the looking glass of its properties of agonizing μ-opioid and likely α 2-adrenergic receptors. While an important area of study, the correlation with kratom and stimulant use, reflected in the National survey on Drug Use and Health, is one that often gets neglected clinically. In our manuscript we present three unique cases, demonstrative of the overlap kratom misuse may have with stimulant use disorders in distinct settings. We provide a discussion and review of this correlation in light of kratom use increasing in the United states.
... In a traditional setting, freshly harvested leaf material of kratom is consumed by natives to treat cough, diarrhoea, fatigue and to improve their physical endurance either by chewing, brewing as tea or by smoking the dried leaves (Cinosi et al., 2015;Lee et al., 2018). In the United States, kratom is widely available and it is currently being used by more than 1 million individuals, either self-prescribed for pain management, to treat opiate withdrawal symptoms, or for recreational purposes (Prozialeck et al., 2019(Prozialeck et al., , 2012Swogger et al., 2015; reported are mainly due to the consumption of kratom products adulterated either by other substances or by the higher content of 7HMG content compared to its natural abundance (Kronstrand et al., 2011;Lydecker et al., 2016;Prozialeck et al., 2019). In February 2018, the United States Food and Drug Administration (US FDA) had reported 44 deaths associated with kratom use, however, the actual causes of deaths were reported to be unknown (Gershman et al., 2019;Prozialeck et al., 2019). ...
... Surprisingly, in the United States, MTG serum concentration levels reported in deceased kratom users varied widely from 16 to 4800 ng/mL (0.041-12.05 μM) (Gershman et al., 2019). This extent of variation in the systemic concentration of MTG is likely caused by the type of products consumed by the United States population (which include dried leaf powder, tablets, capsules, extracts, etc.) compared to the native users of kratom (fresh leaf material consumed either by chewing or brewing into tea) (Lydecker et al., 2016;Sharma et al., 2019). Importantly, these MTG serum concentrations represent concentrations obtained during autopsies, whereas the actual C max concentration is expected to be higher than the reported concentration post-mortem. ...
Article
In vitro cytochrome P450 inhibition of major kratom alkaloids: mitragynine (MTG), speciogynine (SPG), speciocilliatine (SPC), corynantheidine (COR), 7-hydroxymitragynine (7HMG) and paynantheine (PAY) was evaluated using human liver microsomes (HLMs) to understand their drug-drug interaction potential. CYP450 isoform-specific substrates of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4/5 were incubated in HLMs with or without alkaloids. Preliminary CYP450 inhibition (IC50) data were generated for each of these isoforms. In addition, the type of inhibition and estimation of the inhibition constants (Ki) of MTG and COR were determined. Among the tested alkaloids, MTG and COR were potent inhibitors of CYP2D6 (IC50, 2.2 and 4.2 µM, respectively). Both MTG and COR exhibited competitive inhibition of CYP2D6 activity and the Ki were found to be 1.1 and 2.8 µM, respectively. SPG and PAY showed moderate inhibition of CYP2D6 activity. Additionally, moderate inhibitory effects by SPC, MTG, and SPG were observed on CYP2C19 activity. Interestingly, inhibition of only midazolam hydroxylase CYP3A4/5 activity by COR, PAY, and MTG was observed while no inhibitory effect was observed when testosterone was used as a probe substrate. In conclusion, MTG and COR may lead to clinically significant adverse drug interactions upon coadministration of drugs that are substantially metabolized by CYP2D6.
... Due to the higher polar surface area of the molecule, 7-hydroxymitragynine has a more limited ability to cross the blood-brain barrier when compared to mitragynine, and it is further converted to even more potent and efficacious metabolite, mitragynine pseudoindoxyl specifically in human plasma [8,9]. Levels of 7-hydroxymitragynine in Malaysian street samples and other freshly prepared extracts are below the lower limit of quantification (0.01%w/w) of analytical methods, but in commercial kratom products in the United States are present up to 2%w/w [1,10]. According to our experience with freshly prepared kratom samples, 7-hydroxymitragynine is not produced by the plant but rather, oxidation of mitragynine occurs post-harvest during the drying, transportation, and/or manufacturing processes. ...
... According to our experience with freshly prepared kratom samples, 7-hydroxymitragynine is not produced by the plant but rather, oxidation of mitragynine occurs post-harvest during the drying, transportation, and/or manufacturing processes. Levels of 7-hydroxymitragynine in commercial kratom products in the United States are considerably (109-520%) higher than that of kratom preparations in native settings [10]. Substantially high levels of 7-hydroxymitragynine, an alkaloid with abuse potential, in commercial kratom products may be the cause of the harm that has been associated with kratom use in the United States. ...
... Differences in preparation and use have likely contributed to reports of toxicity and mortality among new users in the United States and Europe. Deaths attributed to kratom use, however, are often associated with product adulteration or consumption with other, often toxic, compounds (McWhirter and Morris, 2010;Nelsen et al., 2010;Lydecker et al., 2016;Swogger and Walsh, 2018). Interestingly, no reports of mortality among kratom users have occurred in Southeast Asia where it has a long history of use. ...
... Sabetghadam et al. (2013) administered mitragynine at varying concentrations in rats and reported that mitragynine was relatively safe at lower sub-chronic doses (1-10 mg·kg −1 ) but toxic at higher doses (100 mg·kg −1 ). 7-Hydroxymitragynine, a minor constituent present at concentrations of up to 2% in leaves, is believed to be the major contributor to the addictive potential of kratom given its activity as a potent µ-opioid receptor agonist (Ponglux et al., 1994;Kruegel et al., 2016;Lydecker et al., 2016;Yue et al., 2018;Hemby et al., 2019). Although structurally different from morphine and produced by hydroxylation of mitragynine, 7hydroxymitragynine resulted in tolerance of the antinociceptive effect and produced withdrawal symptoms similar to morphine when administered chronically to mice (Matsumoto et al., 2005). ...
Article
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Leaves harvested from the Southeast Asian tree Mitragyna speciosa (kratom) have a history of use as a traditional ethnobotanical source of medicine to combat fatigue, improve work productivity, and to reduce opioid-related withdrawal symptoms. Kratom leaves contain an array of alkaloids thought to be responsible for the bioactivity reported by users. Interest in the consumptive effects of kratom has led to its recent popularity and use in North America, Western Europe, and Australia. Although the chemistry and pharmacology of select kratom alkaloids are understood, studies have not examined the influence of production environment on growth and alkaloidal content. To directly address this need, 68 kratom trees were vegetatively propagated from a single mother stock to reduce genetic variability and subjected to four varying fertilizer application rates. Leaves were analyzed for chlorophyll concentration, biomass, and alkaloidal content to understand the physiological response of the plant. While increasing rates of fertilizer promoted greater plant growth, relationships with alkaloidal content within leaves were highly variable. Fertility rate had little influence on the concentration of mitragynine, paynantheine, speciociliatine, mitraphylline, and corynoxine per leaf dry mass. 7-Hydroxymitragynine was below the lower limit of quantification in all the analyzed leaf samples. Low to medium rates of fertilizer, however, maximized concentrations of speciogynine, corynantheidine, and isocorynantheidine per leaf dry mass, suggesting a promotion of nitrogen allocation for secondary metabolism occurred for these select alkaloids. Strong correlations (r2 = 0.86) between extracted leaf chlorophyll and rapid, non-destructive chlorophyll evaluation (SPAD) response allowed for development of a reliable linear model that can be used to diagnose nutrient deficiencies and allow for timely adjustment of fertilization programs to more accurately manage kratom cultivation efforts. Results from this study provide a greater understanding of the concentration and synthesis of nine bioactive alkaloids in fresh kratom leaves and provide foundational information for kratom cultivation and production.
... Although kratom is indigenous to these aforementioned East Asian nations, today kratom products are produced and distributed in many other countries across the world. Kratom is available to consumers in various forms including pills, capsules, powder, and leaves [11]. Kratom contains multiple psychoactive alkaloids, all of which are naturally occurring [12]. ...
Article
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Background Amid a Canadian opioid crisis, many have turned to natural health products, such as kratom ( Mitragyna speciosa ), to manage their opioid withdrawal. Kratom has also been reported to relieve anxiety, improve stamina, and heighten physical performance. Given that kratom is not authorized for sale by Health Canada, many have turned to online retailers to purchase kratom due to its easy accessibility online. This study investigated the quality of consumer health information provided on the websites of online vendors selling kratom to consumers in Canada. Methods Following searches on Google.ca using search terms designed to simulate the information-seeking behaviour of a typical patient-user online, eligible websites were assessed using the 16-question DISCERN instrument, a tool designed to assess the quality of consumer health information. Searches were conducted on March 27, 2020 and only websites presenting information in English were included. Results A total of 200 webpages were identified; after screening based on eligibility criteria and combining different webpages that belonged to the same website, 51 websites were found to be eligible. The mean summed DISCERN score across all 51 websites was 36.95 (SD = 2.44) out of 75, which reflects poor quality consumer health information across the subset of websites. The overall quality of websites was poor, as 78% ( n = 40) of vendors received a score of 2 or less out of 5. Conclusions Individuals who seek information about kratom online are frequently exposed to poor quality consumer health information. Those looking to purchase kratom online are not provided with the critical information necessary to make an informed decision regarding its use, such as the complete details about the risks and side effects or a description of how kratom affects the body. Given the growing interest in kratom, knowledge of the quality of information available can lead to improved dialogue between healthcare providers and patients.
... Because of its relatively high abundance, mitragynine plays an important role in the psychopharmacologic activity of kratom [8]. In contrast, the amount of 7-hydroxymitragynine (7-HMG) is much lower and represents < 0.01% w/w of fresh Malaysian kratom samples, although some reports have demonstrated ~2% w/w in the kratom products available in the US [9]. Although 7-HMG is present in much smaller amounts than mitragynine in kratom products, it has a much greater affinity for the MOR than mitragynine (K i = 7.2 ± 0.9 nM vs. 161 ± 10 nM, respectively) and is considerably more potent at activating µ-opioid receptor (MOR) G-protein signaling [10][11][12][13]. ...
Article
Background and Objectives7-Hydroxymitragynine (7-HMG) is an oxidative metabolite of mitragynine, the most abundant alkaloid in the leaves of Mitragyna speciosa (otherwise known as kratom). While mitragynine is a weak partial µ-opioid receptor (MOR) agonist, 7-HMG is a potent and full MOR agonist. It is produced from mitragynine by cytochrome P450 (CYP) 3A, a drug-metabolizing CYP isoform predominate in the liver that is also highly expressed in the intestine. Given the opioidergic potency of 7-HMG, a single oral dose pharmacokinetic and safety study of 7-HMG was performed in beagle dogs.Methods Following a single oral dose (1 mg/kg) of 7-HMG, plasma samples were obtained from healthy female beagle dogs. Concentrations of 7-HMG were determined using ultra-performance liquid chromatography coupled with a tandem mass spectrometer (UPLC-MS/MS). Pharmacokinetic parameters were calculated using a model-independent non-compartmental analysis of plasma concentration-time data.ResultsAbsorption of 7-HMG was rapid, with a peak plasma concentration (Cmax, 56.4 ± 1.6 ng/ml) observed within 15 min post-dose. In contrast, 7-HMG elimination was slow, exhibiting a mono-exponential distribution and mean elimination half-life of 3.6 ± 0.5 h. Oral dosing of 1 mg/kg 7-HMG was well tolerated with no observed adverse events or significant changes to clinical laboratory tests.Conclusions These results provide the first pharmacokinetic and safety data for 7-HMG in the dog and therefore contribute to the understanding of the putative pharmacologic role of 7-HMG resulting from an oral delivery of mitragynine from kratom.
... A series of nine unintentional overdose deaths were linked to a product called Krypton; O-desmethyltramadol, a potent μ-opioid receptor agonist, was detected with mitragynine, which ranged from 0.02 to 0.18 mcg/g (51). Another report suggests that there may be products on the market fortified with 7-OH mitragynine, which has higher potency than mitragynine (52). ...
Article
Mitragynine is the primary active alkaloid in the leaves of the tropical tree Mitragyna speciosa, and goes by the popular names "Kratom", biak-biak and maeng da. Mitragynine is increasingly seen in forensic toxicology casework including driving under the influence of drugs and medicolegal death investigation cases. The toxicity of mitragynine continues to be debated in the scientific community as advocates highlight its long history of use in Southeast Asia and testimonials to its benefits by present-day users, while opponents point to an increasing number of adverse events tied to mitragynine use in Western societies. Quantitative reports of mitragynine in biological specimens from forensic investigations in the literature are sparse and may be influenced by poor analyte stability and inadequate resolution of mitragynine from its diastereomers, which could lead to falsely elevated concentrations and subsequently render those reported concentrations inappropriate for comparison to a reference range. Over the course of 27 months, 1,001 blood specimens submitted to our laboratory tested positive for mitragynine using a sensitive and specific quantitative LC-MS/MS method; concentrations ranged from 5.6-29,000 ng/mL, with mean and median concentrations of 410 ± 1,124 and 130 ng/mL, respectively. Mitragynine presents an analytical challenge that requires a method that appropriately separates and identifies mitragynine itself from its isomers and other related natural products. We describe a validated analytical method and present a short series of case reports that provide examples of apparent adverse events, and the associated range of mitragynine concentrations. This type of analytical specificity is required to appropriately interpret mitragynine concentrations detected in biological specimens from forensic casework and assess its potential toxicity.
... The alkaloid 7-hydroxymitragynine has been reported to have a higher potency than morphine [5]. A major challenge in understanding the actions and effects of kratom is the varying dosage of the alkaloids, additives, or alterations of kratom, the variability of dosage, and simultaneous polysubstance use by consumers [6,7]. ...
Article
Kratom is a legal, widely available substance that contains opioid agonist alkaloids. Due to the marketing of kratom as an opioid alternative for treatment of pain, anxiety, depression, or to reduce opioid withdrawal symptoms, the use of kratom has increased among persons in the USA including pregnant women. This systematic review of the peer-reviewed literature regarding kratom in relation to maternal and infant outcomes resulted in analysis of six case reports of prenatal kratom exposure. Maternal and infant withdrawal from kratom exposure was described in each case, resulting in pharmacologic treatment for both mothers and infants.
... Mice treated with LKT show no significant signs of inactivity in CLAMS-measured ambulations or in the rotarod assays, potentially discounting the involvement of physical inactivity. However, the individual alkaloid mitragynine has been reported to possess relevant non-opioid activity, activating dopamine-2 (D2) and serotonin receptors (Lydecker et al., 2016), both of which modulate respiration and which warrant future examination. ...
Article
Background Made as a tea, the Thai traditional drug “kratom” reportedly possesses pharmacological actions that include both a coca-like stimulant effect and opium-like depressant effect. Kratom has been used as a substitute for opium in physically-dependent subjects. The objective of this study was to evaluate the antinociception, somatic and physical dependence produced by kratom tea, and then assess if the tea ameliorated withdrawal in opioid physically-dependent subjects. Methods Lyophilized kratom tea (LKT) was evaluated in C57BL/6 J and opioid receptor knockout mice after oral administration. Antinociceptive activity was measured in the 55 °C warm-water tail-withdrawal assay. Potential locomotor impairment, respiratory depression and locomotor hyperlocomotion, and place preference induced by oral LKT were assessed in the rotarod, Comprehensive Lab Animal Monitoring System, and conditioned place preference assays, respectively. Naloxone-precipitated withdrawal was used to determine potential physical dependence in mice repeatedly treated with saline or escalating doses of morphine or LKT, and LKT amelioration of morphine withdrawal. Data were analyzed using one- and two-way ANOVA. Results Oral administration of LKT resulted in dose-dependent antinociception (≥1 g/kg, p.o.) absent in mice lacking the mu-opioid receptor (MOR) and reduced in mice lacking the kappa-opioid receptor. These doses of LKT did not alter coordinated locomotion or induce conditioned place preference, and only briefly reduced respiration. Repeated administration of LKT did not produce physical dependence, but significantly decreased naloxone-precipitated withdrawal in morphine dependent mice. Conclusions The present study confirms the MOR agonist activity and therapeutic effect of LKT for the treatment of pain and opioid physical dependence.
... 7-hydroxymitragynine) being artificially increased in commercially available kratom. 5 There is a paucity of literature on psychiatric symptoms associated with kratom withdrawal. A 2018 study of chronic users in Malaysia sought to assess depression and anxiety in withdrawal, both of which were noted to be mildly increased. ...
Article
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Commercially available Kratom (Mitragyna speciosa) is a dietary supplement that has gained popularity in the United States for its psychoactive effects and potential medicative properties as an opioid receptor agonist. Likewise, sudden discontinuation may be accompanied by an opioid-like withdrawal. We present the first case in the literature of the withdrawal manifesting in disturbing obsessive thoughts after the substance was used as an opioid replacement treatment by our patient, as well as the first case where lorazepam is utilized for mitigation of these thoughts.
... In conjunction with the mitragynine studies, we also tried to measure levels of 7-hydroxymitragynine, which is an active constituent or metabolite of mitragynine. In addition, there is evidence that some unscrupulous purveyors of kratom may have fortified their products with exogenous 7-hydroxymitragynine [39]. The results of our studies indicated that all of the samples had very low or undetectable levels of 7-hydroxymitragynine (data not shown), which strongly suggests that the products were not fortified with exogenous 7-hydroxymitragynine. ...
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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.
... However, several spontaneous saliva multi target screenings by LC-MS/MS by a physician during this period found besides mitragynine (1.7 ng/ml, cutoff: 1.0 ng/ml) also hydromorphone in trace amounts (0.11-0.46 ng/ml, cutoff: 0.1 ng/ml). Thus, adulterations of commercially available Kratom cannot be excluded in this case, as it was also previously reported (Lydecker et al., 2016). The patient self-manufactured pills from the Kratom powder to have a storable reserve. ...
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Background Kratom is a Southeast Asian plant, which is widely used in this region, and making an increasing appearance in Europe and the US. Case report We present the case of a 26-year-old man in Substitol-assisted treatment of excessive Kratom and Tilidin use expressing the wish for a drug-free management of a chronic pain condition. After an accidental calcaneus impression fracture, the patient was suffering from severe chronic pain and anxiety of further accidents. This was managed initially with Tilidin. Resulting from the wish to self-manage the pain condition in a way that permitted continuation of a job, the patient searched for a ‘natural’ treatment alternative obtained from an Internet vendor. He successfully instrumentalized Kratom for 3 years with daily consumption intermixed with occasional Tilidin for pain management. However, the dose of Kratom was increased considerably up to a level of effect reversal, when no analgesic and behaviorally activating effects occurred any more, but only intense drowsiness. The patient was treatment seeking and subsequently detoxified from Kratom and Tilidin. Pain management was shifted to retarded morphine. Conclusion Kratom instrumentalization for pain management might appear to be more problematic for addiction development than when its use is established for other consumption motives.
... Consequently, it is difficult to know for certain what is actually present within commercially available kratom preparations, and the concentration of mitragynine contained can vary considerably [90]. For instance, it has been reported that kratom products may be altered by artificially increasing levels of 7-OH-mitragynine to enhance potency [91]. In addition, multiple instances of deliberate adulteration of kratom have been documented, for instance, by adding synthetic substances such as phenylethylamine (PEA) or O-desmethyltramadol, both of which have resulted in patient deaths [92,93]. ...
Article
Kratom, or Mitragyna, is a tropical plant indigenous to Southeast Asia, with unique pharmacological properties. It is commonly consumed by preparing the leaves into decoction or tea, or by grinding them into a powder. Recent evidence has revealed that kratom has physiological effects similar to opioids, including pain relief and euphoria, as well as stimulant properties, which together raise potential concern for dependence and addiction. Moreover, growing evidence suggests that the prevalence of kratom use is increasing in many parts of the world, raising important considerations for healthcare providers. This manuscript will discuss the most current epidemiology, pharmacology, toxicity, and management related to kratom, while seeking to provide a contemporary perspective on the issue and its role in the greater context of the opioid epidemic.
... In the West, advocacy groups, as well as kratom researchers have urged the relevant agencies to regulate kratom distribution, as this would minimize unscrupulous traders from distributing dubious kratom products which could cause deleterious health consequences (Henningfield, Fant, and Wang 2018). This is because most of the adverse kratom use health problems in the West may stem from the use of adulterated kratom products or drug interactions (Anwar, Law, and Schier 2016;Lydecker et al. 2016;Olsen et al. 2019). To prevent kratom use health threats, some states in the US have already introduced the "Kratom Consumer Protection Act" to safeguard consumers from avoidable health consequences (Henningfield, Fant, and Wang 2018). ...
Article
Kratom (Mitragyna speciosa), an indigenous medicinal plant of Southeast Asia, is believed to be harmful. We compared the perceptions toward kratom use among kratom users and non-users in Malaysia. 356 respondents (137 kratom users and 219 non-users) were recruited for this cross-sectional study. The majority of respondents were male (60%, n = 212/356), Malays (88%), and 51% were ≥37 years old. Non-users showed higher unadjusted odds of reporting a perception that kratom use can cause addiction (OR = 6.72, CI: 3.91–11.54, p < .0001), withdrawal symptoms (OR = 7.58, CI: 4.62–12.42, p < .0001), illicit drug use problems (OR = 10.12, CI: 6.14–16.68, p < .0001), impaired social-functioning (OR = 12.05, CI: 7.24–20.05, p < .0001), and health problems (OR = 10.44, CI: 6.32–17.24, p < .0001). Similarly, non-users viewed kratom policies differently from kratom users, displaying increased odds of reporting the belief that kratom use and sales must be regulated with stringent laws (OR = 5.75, CI: 3.61–9.18, p < .0001), and kratom should be regulated instead under the Dangerous Drugs Act 1952 to overcome kratom use problems (OR = 8.26, CI: 4.94–13.82, p < .0001). Because of the disconnect in kratom use perceptions and personal experiences between kratom users and non-users, hastily criminalizing kratom without investigating carefully its scientific merits can significantly impede future kratom research.
... It also ignores the potential for deliberate adulteration of Kratom through unregulated production and distribution, the harm from coingestion of Kratom with other sedatives, the effect that lack of regulation has on safety and the perception of safety, and the potential for interaction between Kratom and medications. 12,13 The debate over regulating Kratom use and its potential role as a treatment for pain and opioid use disorder is ongoing and, like other active compounds, should ultimately be guided by science and rigorous study. What is not debatable, and what the growing popularity of Kratom informs us of, is that physicians and other clinicians should know when to suspect Kratom use and ask directly about it, in a nonjudgmental and patient-centered way. ...
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As overdose mortality rises, overdose morbidity - complications seen as a result of overdose events - is rising too. Although comorbidity is often thought of as psychiatric or psychological, a case report of compartment syndrome, rhabdomyolysis, and acute renal insufficiency in a patient with loss of consciousness for 6 hours after smoking Kratom highlights medical comorbidity. The case is a reminder that a broad range of medical comorbidities can occur in patients with overdose and with unhealthy substance use. Patients with these comorbidities will often be cared for by clinicians who are not addiction specialists, who will need to have sufficient training to recognize and address them.
... The mitragynine content in kratom leaves can vary significantly depending on stage of maturity and ecosystem (Brown et al., 2017). There are significant variations in the phytochemical content of commercial kratom products (Kikura-Hanajiri et al., 2011;Lydecker et al., 2016). In most instances, users experienced a mixed pain relieving and energy increasing effects after kratom consumption, though higher (> 5 g of kratom powder) intake of kratom use was reported to be beneficial in aiding cessation from opioid medication (Grundmann, 2017). ...
Article
Ethnopharmacological relevance: Kratom (Mitragyna speciosa) is a native medicinal plant of Southeast Asia widely reported to be used to reduce opioid dependence and mitigate withdrawal symptoms. There is also evidence to suggest that opioid poly-drug users were using kratom to abstain from opioids. Aim of the study: To determine the patterns and reasons for kratom use among current and former opioid poly-drug users in Malaysia. Materials and methods: A total of 204 opioid poly-drug users (142 current users vs. 62 former users) with current kratom use history were enrolled into this cross-sectional study. A validated UPLC-MS/MS method was used to evaluate the alkaloid content of a kratom street sample. Results: Results from Chi-square analysis showed that there were no significant differences in demographic characteristics between current and former opioid poly-drug users except with respect to marital status. Current users had higher odds of being single (OR: 2.2: 95%CI: 1.21-4.11; p < 0.009). Similarly, there were no significant differences in the duration (OR: 1.1: 0.62-2.03; p < 0.708), daily quantity (OR: 1.5: 0.85-2.82; p < 0.154) or frequency of kratom use between current and former opioid poly-drug users (OR: 1.1: 0.62-2.06; p < 0.680). While both current and former opioid users reported using kratom to ameliorate opioid withdrawal, current users had significantly higher likelihood of using kratom for that purpose (OR: 5.4: 95%CI: 2.81-10.18; p < 0.0001). In contrast, former opioid users were more likely to be using kratom for its euphoric (mood elevating) effects (OR: 1.9: 95%CI: 1.04-3.50; p < 0.035). Results from the UPLC-MS/MS analysis indicated the major alkaloids present in the representative kratom street sample (of approximately 300 mL of brewed kratom) were mitragynine, followed by paynantheine, speciociliatine and speciogynine, as well as low levels of 7-hydroxymitragynine. Conclusions: Both current and former opioid poly-drug users regularly used kratom (three glasses or about 900 mL daily or the equivalent of 170.19 mg of mitragynine) to overcome opioid poly-drug use problems.
... There is a possibility that some kratom-based products may be adulterated, potentially resulting in unintended exposure to chemical compounds such as phenylethylamine, 28 contaminants, 12 or concentrations of a kratom alkaloid. 73 Indeed, health effects associated with using kratom and other substances-either intentionally or unintentionally-may also differ depending on if the substance(s) were used concurrently, simultaneously, or sequentially with kratom. Further, a lack of widespread industry standards regarding the quality of kratom and kratombased products also presents a problem for patients seeking medical advice on the harms and benefits of differing doses and routes of kratom administration. ...
Article
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Background Kratom ( Mitragyna speciosa) consumption and associated health effects have raised debates in the United States. Although most people using this herb do not experience adverse health effects associated with kratom use, medical providers should be knowledgeable of emerging substances and concurrent, sequential, or simultaneous use of other drugs which may impact healthcare recommendations and prescribing practices. Methods The objective of this narrative review was to elucidate selected health effects associated with using kratom—either alone or with other substances. Since scientifically controlled human subjects research on kratom use is still limited, relevant case reports were also described. Results Cardiovascular, gastrointestinal, neurological, and psychiatric effects associated with kratom use were especially notable, and in-utero exposure accompanied concern regarding a neonate’s risk for developing neonatal abstinence syndrome. Our ability to identify and understand the role of this herb in kratom-associated fatalities is complicated since kratom is not routinely screened for in standard forensic toxicology. If a screening is performed, it is usually for the major alkaloid, mitragynine, as a surrogate for kratom use. In addition to lacking a standard practice of screening decedents for kratom alkaloids, the association between mortality and kratom use may be confounded by polysubstance use, adulteration of kratom products, and drug-herb interactions. Conclusions Increasing medical awareness of this herb is vital to ensuring prompt administration of best-practice medical advice or treatment for people seeking information related to kratom use or for patients experiencing an adverse health effect that may be associated with using or withdrawing from kratom. Knowledge gained from continued surveillance and study of kratom and its associated health effects may assist in guiding clinical decision-making and preventing development of adverse health effects among people using kratom.
... Mitragynine can constitute up to 38.7% in traditional and commercial kratom products [5,11,12]. 7-Hydroxymitragynine is produced by oxidation of mitragynine and is a minor constituent (< 0.01% in fresh leaves) found at concentrations of up to 2% in leaf extracts and commercial kratom products [13,14]; however, it is believed to be the major contributor to the known addictive potential of kratom given its activity as a potent μ-opioid receptor agonist [15][16][17][18]. In the U.S., commercially available, imported kratom products (in the format of capsules, dried leaves, powders, resins, and concentrated extracts) have variable concentrations of mitragynine (1.2-38.74%) ...
Article
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Leaves harvested from kratom [Mitragyna speciosa (Korth.)] have a history of use as a traditional ethnobotanical medicine to combat fatigue and improve work productivity in Southeast Asia. In recent years, increased interest in the application and use of kratom has emerged globally, including North America, for its potential application as an alternative source of medicine for pain management and opioid withdrawal syndrome mitigation. Although the chemistry and pharmacology of major kratom alkaloids, mitragynine and 7-hydroxymitragynine, are well documented, foundational information on the impact of plant production environment on growth and kratom alkaloids synthesis is unavailable. To directly address this need, kratom plant growth, leaf chlorophyll content, and alkaloid concentration were evaluated under three lighting conditions: field full sun (FLD-Sun), greenhouse unshaded (GH-Unshaded), and greenhouse shaded (GH-Shaded). Nine kratom alkaloids were quantified using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Greenhouse cultivation generally promoted kratom height and width extension by 93–114% and 53–57%, respectively, compared to FLD-Sun. Similarly, total leaf area and leaf number were increased by 118–160% and 54–80% under such conditions. Average leaf size of plants grown under GH-Shaded was 41 and 69% greater than GH-Unshaded and FLD-Sun, respectively; however, no differences were observed between GH-Unshaded and FLD-Sun treatments. At the termination of the study, total leaf chlorophyll a+b content of FLD-Sun was 17–23% less than those grown in the greenhouse. Total leaf dry mass was maximized when cultivated in the greenhouse and was 89–91% greater than in the field. Leaf content of four alkaloids to include speciociliatine, mitraphylline, corynantheidine, and isocorynantheidine were not significantly impacted by lighting conditions, whereas 7-hydroxymitragynine was below the lower limit of quantification across all treatments. However, mitragynine, paynantheine, and corynoxine concentration per leaf dry mass were increased by 40%, 35%, and 111%, respectively, when cultivated under GH-Shaded compared to FLD-Sun. Additionally, total alkaloid yield per plant was maximized and nearly tripled for several alkaloids when plants were cultivated under such conditions. Furthermore, rapid, non-destructive chlorophyll evaluation correlated well (r2 = 0.68) with extracted chlorophyll concentrations. Given these findings, production efforts where low-light conditions can be implemented are likely to maximize plant biomass and total leaf alkaloid production.
... The variability in self-reported ratings for pain and health conditions can be attributed to the dose and frequency of Kratom use, the specific Kratom product (different Kratom extracts in various formulations, eg capsule, tablets, chewable, powder, etc), duration of use, method of consumption (brewed Kratom tea vs oral consumption of dried Kratom products), and if the health condition is being treated with any other medications. People who use Kratom in the West can also be exposed to adverse health incidents if they are not cautious when buying Kratom, as some products may be adulterated, inconsistent with advertised product description, or marketed with dubious claims (Lydecker et al., 2016). ...
Article
Objectives: To determine whether diagnosed pre-existing health conditions correlate with Kratom demographics and use patterns. Methods: A cross-sectional, anonymous US national online survey was conducted among 8049 Kratom users in October, 2016 to obtain demographic, health, and Kratom use pattern information. Results: People who use Kratom to mitigate illicit drug dependence self-reported less pain and better overall health than individuals who used Kratom for acute/chronic pain. Self-reported improvements in pre-existing mental health symptoms (attention deficit and hyperactivity disorder/attention deficit disorder, anxiety, bipolar disorder, post-traumatic stress disorder, and depression) attributed to Kratom use were greater than those related to somatic symptoms (back pain, rheumatoid arthritis, acute pain, chronic pain, fibromyalgia). Demographic variables, including female sex, older age, employment status, and insurance coverage correlated with increased likelihood of Kratom use. Conclusions: Kratom use may serve as a self-treatment strategy for a diverse population of patients with pre-existing health diagnoses. Healthcare providers need to be engaging with patients to address safety concerns and potential limitations of its use in clinical practice for specific health conditions.
... Dosages of at least 5 g and frequency of 22 or more times per week were more likely to be associated with side effects (occurring in approximately 20% of 3,024 respondents), which were primarily gastrointestinal in nature (nausea, constipation, etc.). Other reported side effects of kratom use include vomiting, drowsiness, irritability, agitation, headache, runny nose, watery eyes, weight loss, insomnia, dehydration, and excessive thirst (Vicknasingam et al., 2010;Adkins et al., 2011;Anwar et al., 2016;Lydecker et al., 2016;Singh et al., 2016;Grundmann, 2017). These predominantly self-managed side effects occurred in about 13% of 3,024 respondents in the Coe et al. (2019) survey. ...
Article
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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.
... MG and 7-HG have been found to produce a range of mostly dosedependent acute and chronic effects (both adverse and potentially therapeutic) that are consistent with μ-opioid receptor activity in nonhuman animals, including: discriminability as opioids (with partial generalization to psychostimulants); self-administration; conditioned place preference; attenuation of opioid selfadministration and opioid withdrawal; and analgesic, antinociceptive, and anxiolytic effects (Hazim et al., 2014;Harun et al., 2015;Yusoff et al., 2017;Yue et al., 2018;Hemby et al., 2019;Hiranita et al., 2019;Hassan et al., 2020;Kamble et al., 2021;Obeng et al., 2021;Suhaimi et al., 2021). The complexity of the kratom botanical and variability of its alkaloid composition is influenced by the environmental conditions in which it grows and by harvesting or post-harvest handling practices (Zhang et al., 2012;Griffin et al., 2016;Lydecker et al., 2016;Prozialeck et al., 2020). kratom was not taken at 12-, 24-, and 48-h increments, and, among those who did experience negative effects when not using kratom, those effects were rarely characterized as severe. ...
Article
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There is limited understanding regarding kratom use among US adults. Although motivations for use are increasingly understood, typical kratom doses, threshold of (low and high) doses for perceived effectiveness, and effects produced during cessation are not well documented. We aimed to extend prior survey work by recruiting adults with current and past kratom exposure. Our goal was to better understand kratom dosing, changes in routines, and perception of effects, including time to onset, duration, and variability of beneficial and adverse outcomes from use and cessation. Among respondents who reported experiencing acute kratom effects, we also sought to determine if effects were perceived as helpful or unhelpful in meeting daily obligations. Finally, we attempted to detect any signal of a relationship between the amount of kratom consumed weekly and weeks of regular use with ratings of beneficial effects from use and ratings of adverse effects from cessation. We conducted an online survey between April-May 2021 by re-recruiting participants from a separate study who reported lifetime kratom use. A total of 129 evaluable surveys were collected. Most (59.7%) had used kratom >100 times and reported currently or having previously used kratom >4 times per week (62 weeks on average). Under half (41.9%) reported that they considered themselves to be a current “regular kratom user.” A majority (79.8%) reported experiencing acute effects from their typical kratom dose and that onset of effects began in minutes but dissipated within hours. Over a quarter reported that they had increased their kratom dose since use initiation, whereas 18.6% had decreased. Greater severity of unwanted effects from ≥1 day of kratom cessation was predicted by more weeks of regular kratom use ( β = 6.74, p = 0.02). Acute kratom effects were largely reported as compatible with, and sometimes helpful in, meeting daily obligations. In the absence of human laboratory studies, survey methods must be refined to more precisely assess dose-effect relationships. These can help inform the development of controlled observational and experimental studies needed to advance the public health understanding of kratom product use.
... The similarity of morphological characteristics of plants in the same genus causes complications in assays (Fig. 1). However, mitragynine is found only in M. speciosa and can be used as a chemical marker [19]. Abundant chromatographic methods have been developed for the analysis of mitragynine in M. speciosa samples, such as TLC, HPLC [18], HPLC-DAD [20], HPLC-ESI/MS/MS [21] and GC-MS [22]. ...
Article
Plants in the genus Mitragyna (Rubiaceae) are used in traditional medicine because of their broad therapeutic activity. Four Mitragyna species, M. speciosa (Roxb.) Korth. (MS), M. rotundifolia (Roxb.) Kuntze (MR), M. diversifolia (Wall. ex G. Don) Havil. (MD), and M. hirsuta Havil. (MH), occur in Thailand. M. speciosa, commonly known as ‘Kratom’ in Thai, is the only narcotic species for which buying, selling, importing or possessing has been prohibited by law in Thailand and some other countries. Mitragynine and 7-hydroxymitragynine, the major psychoactive compounds, are important in the treatment of opioid withdrawal. However, this species is used in traditional medicine to relieve pain and inflammation. Consequently, a rapid and easy technique for differentiating M. speciosa from closely related species is needed for routine forensic analysis. In this study, polymerase chain reaction coupled with lateral flow immunochromatographic assay (PCR-LFA) based on matK was developed for the detection of M. speciosa in forensic specimens. Duplex primers (MS-F-FAM, Ctrl-F-DIG and Ctrl-R-Biotin) were designed based on species-specific nucleotide indels observed exclusively in the matK sequences of M. speciosa. Positive results for M. speciosa are indicated by the clear presence of three black lines on the lateral flow cassette. Forensic samples were investigated, and the three black test lines indicating M. speciosa were observed for seven of eight specimens. PCR-LFA has been proven to be fast, easy and efficient for detecting the narcotic M. speciosa and could be developed as a rapid forensic diagnostic technique for other plants.
... The consumption of brewed kratom tea is shown to be associated with less adverse health effects (Singh et al. 2018a) than the used of dried kratom extracts (Anwar et al., 2016;Olsen et al. 2019;Post et al. 2019). Though the increase in kratom exposure cases in the West remains perplexing, the adverse health incidents were probably caused by the use of adulterated kratom products (Lydecker et al. 2016), as well as the co-use of kratom with illicit substances (Olsen et al. 2019). Although several case-studies have indicated kratom to be harmful, most of these studies lack scientific-basis, resulting in clinical outcomes that are elusive . ...
Article
This study sought to determine the relationship between kratom (Mitragyna speciosa) initiation and regular consumption of illicit drugs and HIV risk behaviors in a cohort of illicit drug users in Malaysia. 260 illicit drug users with current kratom use were recruited through convenience sampling for this cross-sectional study. All were male, with the majority being Malays (95%, n = 246/260). Results suggest that kratom initiation was associated with significant decrease in the regular use of heroin (odds ratio (OR) = 0.50, 95% confidence interval (CI): 0.40– 0.72; p = .0001), methamphetamine (OR = 0.23, CI: 0.16– 0.35; p < .0001), and amphetamine (OR = 0.17, CI: 0.09– 0.34; p < .0001). Kratom initiation was also associated with reduction in regular HIV risk behaviors such as having sex with sex workers (OR = 0.20, CI: 0.12–0.32; p < .0001), using drugs before sexual intercourse (OR = 0.20, CI: 0.13– 0.31; p < .0001), injecting behaviors (OR = 0.10, CI: 0.04– 0.25; p < .0001), sharing of injection equipment (OR = 0.13, CI: 0.04– 0.43; p < .0001), and injecting with other injection drug users (IDUs) (OR = 0.07, CI: 0.02– 0.24; p < .0001).
... Although MTG has been reported to account for up to 66% of the total alkaloid content, more recent analyses demonstrate that MTG accounts for 0.7%-38.7% of total alkaloidal content in commercial products and traditional preparations. A metabolite of MTG, 7-hydroxymitragynine (7HMG, Figure 1 right), is also found as <0.01% in fresh samples and ~2% in commercial products (Lydecker et al., 2016;Hemby et al., 2019;Singh et al., 2020;Chear et al., 2021). As a metabolite of MTG, 7HMG formation is primarily catalyzed by cytochrome P450 3A4 enzyme in humans . ...
Article
Kratom (Mitragyna speciosa), a Southeast Asian tree, has been used for centuries in pain relief and mitigation of opium withdrawal symptoms. Mitragynine (MTG), the major kratom alkaloid, is being investigated for its potential to provide analgesia without the deleterious effects associated with typical opioids. Concerns have been raised regarding the active metabolite of MTG, 7-hydroxymitragynine (7HMG), which has higher affinity and efficacy at µ-opioid receptors than MTG. Here we investigated the hotplate antinociception, pharmacokinetics, and tissue distribution of MTG and 7HMG at equianalgesic oral doses in male and female C57BL/6 mice to determine the extent to which 7HMG metabolized from MTG accounts for the antinociceptive effects of MTG and investigate any sex differences. The mechanism of action was examined by performing studies with the opioid receptor antagonist naltrexone. A population pharmacokinetic/pharmacodynamic model was developed to predict the behavioral effects after administration of various doses of MTG and 7HMG. When administered alone, 7HMG was 2.8-fold more potent than MTG to produce antinociception. At equivalent effective doses of MTG and 7HMG, there was a marked difference in the maximum brain concentration of 7HMG achieved, i.e., 11-fold lower as a metabolite of MTG. The brain concentration of 7HMG observed 4 hours post administration, producing an analgesic effect <10%, was still 1.5-fold higher than the maximum concentration of 7HMG as a metabolite of MTG. These results provide strong evidence that 7HMG has a negligible role in the antinociceptive effects of MTG in mice. SIGNIFICANCE STATEMENT: Mitragynine (MTG) is being investigated for its potential to aid in pain relief, opioid withdrawal syndrome, and opioid use disorder. The active metabolite of MTG, 7-hydroxymitragynine (7HMG), has been shown to have abuse potential and has been implicated in the opioid-like analgesic effect after MTG administration. The results of this study suggest a lack of involvement of 7HMG in the antinociceptive effects of MTG in mice.
... Fourth, the number of cases requiring medical intervention was not reported. Fifth, Kratom products were declared by the U.S. Food and Drug Administration to be dietary supplements for which new dietary ingredient notification is required prior to market entry demonstrating compliance with good manufacturing practice, yet the contribution of adulteration or contamination to cases was ignored by Eggleston et al. 2 Finally, the peer-reviewed literature demonstrates that deaths associated with kratom exposure are accompanied by striking levels of polysubstance use, scientific findings ignored in Eggleston et al.'s report. 3 The report also fails to provide appropriate context for the safety risk posed by kratom, since it does not compare such risks to those posed by other regulated supplements and overthe-counter drugs (e.g. ...
... Kratom adulteration is a more insidious prospect that can and has occurred due to a lack of federal oversight. Several toxicology researchers have published findings of kratom being adulterated with added amounts of 7-hydroxymitragynine as well as phenethylamine which is another "mood-boosting" compound available commercially without a prescription [55,56]. There have even been reports of kratom being adulterated with hydrocodone which is a federally regulated opioid requiring a prescription for legal consumption [57]. ...
Article
Purpose This article presents updated information on kratom (Mitragyna speciosa), a natural opioid with stimulant properties that is currently sold in the United States without a prescription. Summary Kratom exerts opioid and alpha-2 agonistic effects, as well as anti-inflammatory and mild stimulant effects. Respiratory depression has not been commonly reported, but kratom does cause a host of adverse effects. While kratom may have a role in patients who are in chronic pain or dependent on opioid painkillers or heroin, this needs to be established in clinical trials. Kratom may have drug interactions as both a cytochrome P-450 system substrate and inhibitor. Kratom does not appear in normal drug screens and, especially when ingested with other substances of abuse, may not be recognized as an agent of harm. There are numerous cases of death in kratom users, but many involved polypharmaceutical ingestions. There are assessments where people have been unable to stop using kratom therapy and withdrawal signs/symptoms occurred in patients or their newborn babies after kratom cessation. Both banning and failure to ban kratom places people at risk; a middle-ground alternative, placing it behind the pharmacy counter, might be useful. Conclusion Kratom has a unique pharmacologic profile that might offer advantages over other opioids, but its high abuse liability, potential for drug interactions and adverse events, and inadequate research into the balance of benefits to harm are concerning. There is mounting information on the adverse events associated with kratom use and potential treatments that can be useful to clinicians.
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
The psychoactive plant kratom is a native plant to Southeast Asia, and its major bioactive alkaloid is mitragynine. Mitragynine exerts its analgesic properties by acting on the opioid receptors. One of its active metabolites, 7-hydroxymytraginine, is found to be 40 times more potent than mitragynine and 10 times more potent than morphine. Interestingly, current research suggests that mitragynine behaves as an atypical opioid agonist – possessing analgesic activity with less severe side effects than typical opioids. Although Thailand and Malaysia have criminalized the use, possession, growing, or selling of kratom due to its abuse potential, kratom still remains unregulated in the United States. The U.S. Drug Enforcement Agency (DEA) listed kratom as a “drug of concern” in 2008 with the intent to temporarily place mitragynine and 7-hydroxymitragynine onto Schedule I of the Controlled Substances Act. However, responses from the general public, U.S. Congress, and Kratom Alliances had the DEA retract their intent. Kratom is currently marketed in the U.S. as a dietary or herbal supplement used to treat chronic pain, anxiety, and depression with over $207 million in annual sales in the U.S. alone. Here, we will review the traditional and medicinal uses of kratom along with the synthesis of its bioactive ingredients, their pharmacology, metabolism, and structure-activity relationships. The importance in society of this currently controversial substance will also be discussed.
Article
Background The legal status of kratom in the United States is complex and varies by state. The U.S. Food and Drug Administration (FDA) and the U.S. Drug Enforcement Administration have repeatedly subjected kratom to regulatory review. However, there hasn't been a systematic review of the public's perception of kratom. The present study analyzed open-ended responses from the public to an FDA solicitation for information regarding kratom with the goal of providing a comprehensive assessment of motives for kratom use. Methods To guide decisions regarding kratom regulation, the FDA solicited comments regarding kratom abuse potential, medical usefulness, and impact of scheduling changes from July through August 2021 and posted them to the Federal Register website. We analyzed comments posted during the first 6 weeks of comment solicitation (6,353) using an inductive approach via qualitative content analysis. Results Respondents reported 106 independent health-related reasons for kratom use, with most categorized as mental health, pain management, substance use disorder, or miscellaneous purposes that included increasing focus, treating insomnia, and decreasing fatigue. Neurological diseases and digestive disorders were also reported. Relatively few (< 2%) responses reported recreational use, abuse potential, or adverse effects of kratom. Conclusions Although kratom is not approved as a safe and effective therapy for any indication, individuals use kratom for a broad spectrum of health-related purposes. Limitations of this study include potential bias for respondents with perceived positive experiences using kratom, lack of demographics data, and lack of independent verification of claims made by respondents. Regardless, this study reflects perceptions regarding the therapeutic uses of kratom and provides insight into potential individual-level consequences of regulating kratom in the U.S. It is important to study the public's perception of kratom use, which can aid regulatory purposes and provide clinically important information on individuals’ use and valuation of kratom.
Article
Background: Interest in the Southeast Asian natural remedy kratom has increased in Western countries recently, along with increasing concern over its potential toxic effects. Objective: To describe and compare demographics, common co-exposure substances, clinical effects, treatments, and medical outcomes of kratom “abuse” exposures in the United States (US) and Thailand. Methods: This is a retrospective analysis of kratom “abuse” exposures, defined as use when attempting to gain a psychotropic effect, reported to the National Poison Data System (NPDS) in the US and the Ramathibodi Poison Center (RPC) in Thailand from 2010 to 2017. Multivariate analysis identified risk factors for severe medical outcomes, defined as both ICU admissions and death. Results: Nine-hundred-twenty-eight cases were included (760 from NPDS and 168 from RPC). A greater proportion of cases involved co-exposures in Thailand (64.8% versus 37.4%; odds ratio [OR] = 3.10, 95% confidence interval [CI] = 2.15–4.47, p < .01). Both countries had a similar prevalence of opioid and benzodiazepine co-ingestions, but the US had more co-ingestions with other sedatives (4.6% versus 0%, OR = 0, 95% CI = 0–0.47, p < .01). Common clinical effects included tachycardia (30.4%), agitation/irritability (26.2%), and drowsiness/lethargy (21.1%). Six deaths occurred, including one single-substance exposure in the US, three multiple-substance exposures in the US, and two multiple-substance exposures in Thailand. IV fluid administration was provided more frequently in the US (OR = 18.82, 95% CI = 5.85–60.56, p < .01). Conclusions: Despite lower frequencies of co-ingestants overall, US kratom abuse exposures yielded greater clinical severity. This disparity may be attributable to differences in the products labeled “kratom,” greater sedative co-exposures in the US, and/or differences in population genetics or use patterns.
Article
Background:Kratom (Mitragyna speciosa Korth.) is a medicinal plant, widely used in Southeast Asia chiefly for its unique medicinal properties in treating chronic pain, opioid dependence and withdrawal, and as a mood enhancer.Method:Relevant articles describing kratom's medicinal utility was identified and reviewed.Results:In traditional settings, laborers chew fresh leaves or ingest a kratom decoction (tea) as a stimulant that increases work performance, while those with opioid use disorder (OUD) use kratom as an affordable substitute for opioids. Though kratom is alleged to cause adverse health effects if used frequently over prolonged periods, its use has not been linked to any major health threat in traditional settings.Conclusion:Currently, kratom’s pharmacological and long-term safety profile remains poorly elucidated and warrants further research. This paper provides a brief account of possibly overlooked medicinal potential of kratom.
Article
We report a case series of young adults who were admitted to hospital with seizures after regular kratom beverage consumption. This study aimed to determine kratom consumption habits and seizure characteristics and to explore whether chronic kratom ingestion without concomitant drug abuse leads to recurrent seizure or epilepsy. All patients underwent blood investigations, a brain computed tomography (CT) scan, electroencephalography, and urine testing for mitragynine and drug toxicology. Eleven participants who had a positive urine mitragynine test were included in the study. The longest duration of kratom consumption was 84 months: – most drank more than eight times per month (>200 mL/drink). Seizure developed within 10 minutes or up to 72 hours post-ingestion. Seizure occurred one to three times per year in most cases. Four patients had a focal to bilateral tonic-clonic seizure whereas the remaining participants had a generalized tonic-clonic seizure. Four patients mixed kratom with diphenhydramine syrup, and one patient took methamphetamine. Two patients had positive urine results for recreational drugs (opioid and amphetamine). This study provided indirect evidence that chronic kratom use with or without concomitant drug abuse can cause recurrent seizures in susceptible individuals, which may progress to epilepsy or require antiepileptic medication.
Article
Kratom is a substance similar to opioids that is often used for its euphoric effects, however it can be obtained legally in most of the United States. The substance is often not assessed on routine urine drug screen, however it is estimated that millions of people engage in kratom use each year and level of use is rising. Given the increasing prevalence of kratom use, and its potentially lethal consequences, it is imperative that primary care physicians be familiar with this substance and have a framework to approach identification and treatment of individuals with kratom use disorder. This manuscript offers a review of the epidemiology and pharmacology of kratom, along with guidance for care of individuals with kratom use disorder in the primary care setting.
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The dose-dependent consumptive effect of kratom and its potential application as an alternative source of medicine to mitigate opioid withdrawal symptoms has brought considerable attention to this plant. Increased interest in the application and use of kratom has emerged globally, including North America. Although the chemistry and pharmacology of major kratom alkaloids, mitragynine and 7-hydroxymitragynine, are well documented, foundational information on the impact of plant production environment on growth and kratom alkaloids synthesis is unavailable. To directly address this need, kratom plant growth, leaf chlorophyll content, and alkaloid concentration were evaluated under three lighting conditions: outdoor full sun, greenhouse unshaded, and greenhouse shaded. Nine kratom alkaloids were quantified using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Contents of six alkaloids to include: mitragynine, speciogynine, speciociliatine, mitraphylline, coynantheidine, and isocorynantheidine were not significantly impacted by lighting conditions, whereas 7-hydroxymitragynine was below the lower limit of quantification across all treatments. However, paynantheine concentration per leaf dry mass was increased by 40% and corynoxine was increased by 111% when grown under shade conditions in a greenhouse compared to outdoor full sun. Additionally, total alkaloid yield per plant was maximized when plants were under such conditions. Greenhouse cultivation generally promoted height and width extension, leaf number, leaf area, average leaf size, and total leaf dry mass, compared to outdoor full sun condition. Rapid, non-destructive chlorophyll evaluation correlated well (r2 = 0.68) with extracted chlorophyll concentrations. Given these findings, production efforts where low-light conditions can be implemented are likely to maximize plant biomass and total leaf alkaloid production.
Article
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
Article
Introduction Kratom is a medicinal plant native to Southeast Asia. This present study was primarily undertaken to investigate changes in the vital signs, hematological, and biochemical parameters of regular kratom users. Method Five male regular kratom users were recruited for this longitudinal study. Subjects volunteered to undergo two sessions of blood tests and vital signs assessments after a 3-month interval (baseline: T1; after 3 months: T2). Result There were no significant alterations found in the hematological and biochemical of kratom users, except for a decrease in white cell count after a 3-month interval. In general, the kidney, liver function tests, thyroid, and glucose parameters were not significantly affected. Calcium, total protein, and globulin levels were significantly increased at T2 compared to T1, but all these parameters were within the normal reference range. There were alterations in the lipid profile, where total cholesterol and LDL cholesterol parameters were elevated at both T1 and T2, while significant increase in HDL cholesterol, and decrease in triglycerides levels were observed at T2 compared to T1. Conclusion Our results indicated that continuous consumption of kratom decoction at a daily mitragynine dose of 76.3–114.8 mg did not appear to alter the safety hematological and biochemical parameters of kratom users.
Article
Objective: The increasingly widespread use of kratom in the United States has raised concerns about its safety as well as spurring research into potential applications of its active ingredients in medical treatments. Methods: We reviewed the literature published over the past 20 years, including peer-reviewed publications and data released by United States government health agencies to provide an overview of this topic. Results: A variety of potentially beneficial and adverse effects of kratom use related to its opioid and stimulant properties have been documented, including addiction and withdrawal. Preliminary research in animals and case reports in humans have suggested medical utility for kratom in treating alcohol and opioid use disorders, pain, depression, and anxiety. However, the lack of controlled, standardized studies limits the clinical utility of this agent and is a barrier to safe consumption. Conclusions: Historically, kratom has been used for medical purposes and for the treatment of alcohol and substance use disorders. The currently available literature suggests a potential for similar clinical applications. However, without controlled research studies or regulation, kratom poses numerous health risks to consumers.
Article
Background: Kratom (Mitragyna speciosa Korth.) use outside of Southeast Asia has increased over the past decade. Objectives: This investigation clarifies kratom's role in perceived well-being, overall health, and temporal correlation with drug use to understand kratom's role in the self-treatment of substance use disorders (SUDs). Methods: Between July 2019 and July 2020 an anonymous, cross-sectional, online survey was taken by 7,381 people who use kratom (PWUK) recruited through social media and other online resources. This included an assessment of (a) the relationship between self-reported overall health, concomitant use of drugs of misuse, and demographics; (b) the perceived effectiveness of kratom in self-treating diagnosed health conditions or symptoms; (c) the profile of PWUK primarily for drug dependence, pain, and mood or mental health conditions based on demographics. Results: A total of 5,152 valid responses (45.9% females/53.7% males) were collected. Kratom was primarily used for self-treating pain (73.0%) and improving emotional or mental health conditions (42.2%) without clinical supervision. Those with a SUD (synthetic opioids, methadone, benzodiazepines, or heroin) used kratom after discontinuing illicit or other drugs (94.8%). The primary substances taken before or concomitantly with kratom were cannabis, cannabidiol, benzodiazepines, or kava. PWUKs report a dose-dependent benefit for alleviating pain and relieving negative moods. Adverse effects were primarily gastrointestinal, typically at high (>5 g/dose) and frequent (>22 doses/week) dosing. Conclusions: Kratom was primarily used as a harm-reduction agent for SUDs and self-treatment of chronic conditions. Healthcare professionals need better information about kratom, its potential adverse effects, and clinically significant drug interactions.
Article
Zusammenfassung Kratom ist ein immergrüner Baum, der in Südostasien heimisch ist und dessen Blätter traditionell als Stimulans, als Therapie bei verschiedenen gesundheitlichen Problemen und zu religiösen Zwecken verwendet werden. Insbesondere in den USA (geringer auch in Europa) wird seit einigen Jahren eine relevante Prävalenz des Kratomkonsums beobachtet. In westlichen Ländern wird Kratom überwiegend als Analgetikum und Stimulans, zur Behandlung von Schmerzen und Opioidgebrauchsstörungen und zur günstigen Beeinflussung der psychischen Gesundheit (z. B. bei Depression, Angststörungen) verwendet. Die chemischen Hauptbestandteile von Kratom sind Alkaloide, von denen Mitragynin und 7-Hydroxymitragynin am bedeutsamsten erscheinen. Die Pharmakodynamik und -kinetik von Kratom sind komplex und unzureichend untersucht. Bekannt ist, dass Mitragynin und 7-Hydroxymitragynin Partialagonisten an humanen μ-Opioidrezeptoren und Antagonisten an κ- und δ-Opioidrezeptoren bei zusätzlichen Effekten an weiteren zentralen Rezeptoren sind. Die Verträglichkeit von Kratom scheint im Vergleich mit klassischen Opioiden besser zu sein, was mit fehlenden Effekten von Kratom auf β-Arrestin in Verbindung gebracht und als Ausgangspunkt für die Entwicklung besser verträglicher Opioide diskutiert wurde. Einige Alkaloide in Kratom sind Inhibitoren von CYP2D6, geringer auch CYP2C19 und CYP3A4. Das Abhängigkeitspotential von Kratom scheint geringer ausgeprägt zu sein als das von klassischen Opioiden, wobei die Datenlage dazu begrenzt ist und Kratomgebrauchsstörungen primär in westlichen Längern auftreten. Es sind zahlreiche Fälle von schwerwiegenden gesundheitlichen Problemen und Todesfälle im Zusammenhang mit Kratomkonsum in den USA bekannt, wobei in diesen Fällen meist mehrere Substanzen involviert waren. Kratomkonsum ist vermutlich mit hepatotoxischen und kardiotoxischen Effekten assoziiert. Kratom-assoziierte Morbidität und Mortalität unterscheiden sich zwischen westlichen Ländern und Südostasien, wo Kratomkonsum kein öffentliches Gesundheitsproblem darstellt, quantitativ erheblich. Als Gründe hierfür wurden der in westlichen Ländern verbreitete Mischkonsum, höhere Dosierungen konsumierten Kratoms, Verfälschungen und Verunreinigungen kommerziell erhältlicher Kratomprodukte in westlichen Ländern, pharmakokinetische Interaktionen und höhere Konzentrationen von 7-Hydroxymitragynin in getrockneten Kratomblättern (die typischerweise in westlichen Ländern konsumiert werden) im Vergleich mit frischen Blättern (die typischerweise in Südostasien konsumiert werden) genannt.
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Kratom (Mitragyna speciosa Korth.) is a tree native to Southeast Asia with dose-dependent stimulant and opioid-like effects. Dried, powdered leaf material is among the kratom products most commonly consumed in the US and Europe, but other formulations also exist including enriched extracts, resins, tinctures, and edibles. Its prevalence in the US remains debated and the use pattern includes self-treatment of mood disorders, pain, and substance use disorders. Most of the adverse effects of kratom and its alkaloid mitragynine have been reported in the literature as case reports or part of surveys necessitating confirmation by clinical trials. Toxicities associated with kratom consumption have focused on hepatic, cardiac, and CNS effects with the potential to cause fatalities primarily as part of polydrug exposures. Kratom may also present with drug-drug interactions primarily through CYP 3A4 and 2D6 inhibition, although the clinical significance remains unknown to date. The variability in composition of commercially available kratom products complicates generalization of findings and requires further investigation by employing clinical trials. Healthcare professionals should remain cautious in counseling patients on the use of kratom in a therapeutic setting.
Article
Kratom, Mitragyna speciosa Korth., is being widely consumed in the United States for pain management and the reduction of opioid withdrawal symptoms. The central nervous system (CNS) active alkaloids of kratom, including mitragynine, 7-hydroxymitragynine, and numerous additional compounds, are believed to derive their effects through opioid receptor activity. There is no literature describing the systemic exposure of many of these alkaloids after the consumption of kratom. Therefore, we have developed and validated a bioanalytical method for the simultaneous quantitation of 11 kratom alkaloids (mitragynine, 7-hydroxymitragynine, corynantheidine, speciogynine, speciociliatine, paynantheine, corynoxine, corynoxine-B, mitraphylline, ajmalicine, and isospeciofoline) in rat plasma. The validated method was used to analyze oral pharmacokinetic study samples of lyophilized kratom tea (LKT) and a marketed product, OPMS liquid shot, in rats. Among the 11 alkaloids, only mitragynine, 7-hydroxymitragynine, speciociliatine, and corynantheidine showed systemic exposure 8 h postdose, and the dose-normalized systemic exposure of these four alkaloids was higher (1.6–2.4-fold) following the administration of the commercial OPMS liquid. Paynantheine and speciogynine levels were quantifiable up to 1 h postdose, whereas none of the other alkaloids were detected. In summary, the method was successfully applied to quantify the exposure of individual kratom alkaloids after an oral dose of traditional or commercial products. This information will contribute to understanding the role of each alkaloid in the overall pharmacology of kratom and elucidating the pharmacokinetic differences between traditional and commercial kratom products.
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Mitragynine is a major bioactive compound of Kratom, which is derived from the leave extracts of Mitragyna speciosa Korth or Mitragyna speciosa (M. speciosa), a medicinal plant from South East Asia used legally in many countries as stimulant with opioid-like effects for the treatment of chronic pain and opioid-withdrawal symptoms. Fatal incidents with Mitragynine have been associated with cardiac arrest. In this study, we determined the cardiotoxicity of Mitragynine and other chemical constituents isolated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The rapid delayed rectifier potassium current (IKr), L-type Ca2+ current (ICa,L) and action potential duration (APD) were measured by whole cell patch-clamp. The expression of KCNH2 and cytotoxicity was determined by real-time PCR and Caspase activity measurements. After significant IKr suppression by Mitragynine (10 µM) was confirmed in hERG-HEK cells, we systematically examined the effects of Mitragynine and other chemical constituents in hiPSC-CMs. Mitragynine, Paynantheine, Speciogynine and Speciociliatine, dosage-dependently (0.1∼100 µM) suppressed IKr in hiPSC-CMs by 67% ∼84% with IC50 ranged from 0.91 to 2.47 µM. Moreover, Mitragynine (10 µM) significantly prolonged APD at 50 and 90% repolarization (APD50 and APD90) (439.0±11.6 vs. 585.2±45.5 ms and 536.0±22.6 vs. 705.9±46.1 ms, respectively) and induced arrhythmia, without altering the L-type Ca2+ current. Neither the expression,and intracellular distribution of KCNH2/Kv11.1, nor the Caspase 3 activity were significantly affected by Mitragynine. Our study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of IKr in human cardiomyocytes.
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The use of substances to enhance human abilities is a constant and cross-cultural feature in the evolution of humanity. Although much has changed over time, the availability on the Internet, often supported by misleading marketing strategies, has made their use even more likely and risky. This paper will explore the case of Mitragyna speciosa Korth. (kratom), a tropical tree used traditionally to combat fatigue and improve work productivity among farm populations in Southeast Asia, which has recently become popular as novel psychoactive substance in Western countries. Specifically, it (i) reviews the state of the art on kratom pharmacology and identification; (ii) provides a comprehensive overview of kratom use cross-culturally; (iii) explores the subjective experiences of users; (iv) identifies potential risks and side-effects related to its consumption. Finally, it concludes that the use of kratom is not negligible, especially for self-medication, and more clinical, pharmacological, and socioanthropological studies as well as a better international collaboration are needed to tackle this marginally explored phenomenon.
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Background 2,4-Dinitrophenol (DNP) poses serious health-risks to humans. The aims of this three-stage multidisciplinary project were, for the first time, to assess the risks to the general public from fraudulent sale of or adulteration/contamination with DNP; and to investigate motives, reasons and risk-management among DNP-user bodybuilders and avid exercisers. Methods Using multiple search-engines and guidance for Internet research, online retailers and bodybuilding forums/blogs were systematically explored for availability of DNP, advice offered on DNP use and user profiles. Ninety-eight pre-workout and weight-loss supplements were purchased and analysed for DNP using liquid-chromatography-mass-spectrometry. Psychosocial variables were captured in an international sample of 35 DNP users (26.06 ± 6.10 years, 94.3 % male) with an anonymous, semi-qualitative self-reported survey. Results Although an industrial chemical, evidence from the Internet showed that DNP is sold ‘as is’, in capsules or tablets to suit human consumption, and is used ‘uncut’. Analytical results confirmed that DNP is not on the supplement market disguised under fictitious supplement names, but infrequently was present as contaminant in some supplements (14/98) at low concentration (<100mcg/kg). Users make conscious and ‘informed’ decisions about DNP; are well-prepared for the side-effects and show nonchalant attitude toward self-experimentation with DNP. Steps are often taken to ensure that DNP is genuine. Personal experience with performance- and appearance enhancing substances appears to be a gateway to DNP. Advice on DNP and experiences are shared online. The significant discrepancy between the normative perception and the actual visibility suggests that DNP use is-contrary to the Internet accounts-a highly concealed and lonesome activity in real life. Positive experiences with the expected weight-loss prevail over the negative experiences from side effects (all but two users considered using DNP again) and help with using DNP safely is considered preferable over scare-tactics. Conclusion Legislation banning DNP sale for human consumption protects the general public but DNP is sold ‘as is’ and used ‘uncut’ by determined users who are not dissuaded from experimenting with DNP based on health threats. Further research with stakeholders’ active participation is imperative for targeted, proactive public health policies and harm-reduction measures for DNP, and other illicit supplements.
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Mitragyna speciosa (Rubiaceae), commonly known as kratom, is a tropical tree with a long history of traditional use in parts of Africa and Southeast Asia. In recent years, kratom has gained popularity for use as a recreational drug across the globe. Relatively new to the illicit market and used in a manner different from its traditional applications, preparations of kratom are touted by many as a safe and legal psychoactive product that improves mood, relieves pain, and may provide benefits in opiate addiction. Available literature was reviewed for M. speciosa via PubMed, Google Scholar, CINAHL, and EBSCO to summarize its traditional uses, phytochemical composition, pharmacology and toxicology of proposed active constituents, and potential for misuse and abuse. Research has demonstrated that both stimulant and sedative dose-dependent effects do exist, but a growing concern for the drug's effects and safety of use has resulted in national and international attention primarily due to an increase in hospital visits and deaths in several countries that are said to have been caused by extracts of the plant. The main active alkaloid substances in kratom, mitragynine and 7-hydroxymitragynine, present with a range of CNS stimulant and depressant effects mediated primarily through monoaminergic and opioid receptors. Recently, Palm Beach County, located in the southeastern corridor of Florida, has considered regulating kratom due to public safety concerns following the death of a young adult. At the local, state, and even federal levels, governments are now being confronted with the task of determining the safety and the possible regulation of kratom extracts. There are currently no standard analytical screening techniques for mitragynine and its metabolites following ingestion limiting its detection to more sophisticated techniques like liquid chromatography-mass spectrometry to determine kratom use. The growing concern of the abuse potential of kratom requires careful evaluation of its benefits and potential toxicities.
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A 24-year-old man whose medical history was significant for alcohol abuse and depression was found unresponsive in bed. He had several prior suicide attempts with 'pills' and had also been hospitalized for an accidental overdose on a previous occasion. Autopsy findings were unremarkable apart from pulmonary edema and congestion, and urinary retention. Postmortem peripheral blood initially screened positive for mitragynine 'Kratom' (by routine alkaline drug screen by gas chromatography-mass spectrometry, GC-MS), which was subsequently confirmed by a specific GC-MS selective ion mode analysis following solid-phase extraction. Concentrations were determined in the peripheral blood (0.23 mg/L), central blood (0.19 mg/L), liver (0.43 mg/kg), vitreous (<0.05 mg/L), urine (0.37 mg/L) and was not detected in the gastric. Therapeutic concentrations of venlafaxine, diphenhydramine and mirtazapine were also detected together with a negligible ethanol of 0.02% (w/v). The results are discussed in relation to previous cases of toxicity, and the lack of potential for mitragynine postmortem redistribution. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Herbal food supplements, claiming to reduce weight, may contain active pharmacological ingredients (APIs) that can be used for the treatment of overweight and obesity. The aim of this study was to determine whether herbal food supplements for weight loss on the Dutch market contain APIs with weight loss properties. Herbal food supplements intended for weight loss (n = 50), were sampled from August 2004 up to and including May 2013. A HPLC-DAD-MS/MS method was used to screen for the presence of the APIs in herbal supplements. In 24 samples the APIs sibutramine, desmethylsibutramine (DMS), didesmethylsibutramine (DDMS), rimonabant, sildenafil, and/or the laxative phenolphthalein were identified 41 times. The presence of these APIs was however not stated on the label. The potential pharmacological effects of the detected APIs were estimated using data from reported effective doses of approved drugs. Use of 20 of the 24 herbal food supplements, may result in potential pharmacological effects. Furthermore, risk assessment of phenolphthalein, a suspected carcinogen and found to be present in ten supplements, based on the Margin of Exposure (MOE) approach resulted in MOE values of 96-30,000. MOE values lower than 10,000 (96-220) were calculated for the daily intake levels of four out of these ten supplements in which phenolphthalein was found. However, taking into account that weight loss preparations may be used for only a few weeks or months rather than during lifetime, MOE values may be two to three orders of magnitude higher. The current study shows that the use of food supplements with sibutramine, DMS, DDMS, and/or phenolphthalein could result in pharmacological effects.
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Background: To investigate the antioxidant value and anticancer functions of mitragynine (MTG) and its silane-reduced analogues (SRM) in vitro. Materials and methods: MTG and SRM was analyzed for their reducing power ability, ABTS radical inhibition and 1,1-diphenyl-2-picryl hydrazylfree radicals scavenging activities. Furthermore, the antiproliferation efficacy was evaluated using MTT assay on K 562 and HCT116 cancer cell lines versus NIH/3T3 and CCD18-Co normal cell lines respectively. Results: SRM and MTG demonstrate moderate antioxidant value with ABTS assay (Trolox equivalent antioxidant capacity (TEAC): 2.25±0.02 mmol trolox / mmol and 1.96±0.04 mmol trolox / mmol respectively) and DPPH (IC50=3.75±0.04 mg/mL and IC50=2.28±0.02 mg/mL respectively). Both MTG and SRM demonstrate equal potency (IC50=25.20±1.53 and IC50= 22.19±1.06 respectively) towards K 562 cell lines, comparable to control, betulinic acid (BA) (IC5024.40±1.26). Both compounds showed concentration-dependent cytototoxicity effects and exert profound antiproliferative efficacy at concentration > 100 μM towards HCT 116 and K 562 cancer cell lines, comparable to those of BA and 5-FU (5-Fluorouracil). Furthermore, both MTG and SRM exhibit high selectivity towards HCT 116 cell lines with selective indexes of 3.14 and 2.93 respectively compared to 5-FU (SI=0.60). Conclusions: These findings revealed that the medicinal and nutitional values of mitragynine obtained from ketum leaves that growth in tropical forest of Southeast Asia and its analogues does not limited to analgesic properties but could be promising antioxidant and anticancer or chemopreventive compounds.
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A corpse of 21-years-old man (Muslim) was investigated for the cause of death. His family declined consent for full autopsy. Thus, only blood and urine were used for toxicological analysis by liquid chromatography-electrosray ionization-time of flight mass spectrometry. These following substances were found in the blood and urine samples: Mitragynine (an alkaloid found in Kratom; Mitragyna speciosa leaves), caffeine, diphenhydramine, alprazolam, nortriptyline, methadone, tramadol, methamphetamine and some of their metabolites. The findings of this case suggested the possibility of polydrugs abuse calls "4×100", a Kratom juice cocktail that has been popular in Southernmost provinces of Thailand. It is made from four major ingredients, boiled Kratom leaves, Cola soft drink, cough syrup and tranquilizers or mosquito coils. In this case, the cause of death might be due to multidrugs intoxication of the additive adverse effects especially CNS and respiratory depression.
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Kratom (or Ketum) is a psychoactive plant preparation used in Southeast Asia. It is derived from the plant Mitragyna speciosa Korth. Kratom as well as its main alkaloid, mitragynine, currently spreads around the world. Thus, addiction potential and adverse health consequences are becoming an important issue for health authorities. Here we reviewed the available evidence and identified future research needs. It was found that mitragynine and M. speciosa preparations are systematically consumed with rather well defined instrumentalization goals, e.g. to enhance tolerance for hard work or as a substitute in the self-treatment of opiate addiction. There is also evidence from experimental animal models supporting analgesic, muscle relaxant, anti-inflammatory as well as strong anorectic effects. In humans, regular consumption may escalate, lead to tolerance and may yield aversive withdrawal effects. Mitragynine and its derivatives actions in the central nervous system involve μ-opioid receptors, neuronal Ca2+ channels and descending monoaminergic projections. Altogether, available data currently suggest both, a therapeutic as well as an abuse potential.
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Kratom (Mitragyna speciosa) is a plant indigenous to Thailand and Southeast Asia. Kratom leaves produce complex stimulant and opioid-like analgesic effects. In Asia, kratom has been used to stave off fatigue and to manage pain, diarrhea, cough, and opioid withdrawal. Recently, kratom has become widely available in the United States and Europe by means of smoke shops and the Internet. Analyses of the medical literature and select Internet sites indicate that individuals in the United States are increasingly using kratom for the self-management of pain and opioid withdrawal. Kratom contains pharmacologically active constituents, most notably mitragynine and 7-hydroxymitragynine. Kratom is illegal in many countries. Although it is still legal in the United States, the US Drug Enforcement Administration has placed kratom on its "Drugs and Chemicals of Concern" list. Physicians should be aware of the availability, user habits, and health effects of kratom. Further research on the therapeutic uses, toxic effects, and abuse potential of kratom and its constituent compounds are needed.
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Pharmaceutical adulterants are commonly found in herbal weight loss products, and analytical techniques for detecting these adulterants have become increasingly important to the public health community. Previously we reported a novel analytical method for the determination of adulterants in herbal formulations by capillary electrophoresis with contactless conductivity detection. The current study refines this previously described technique by testing if anxiolytics, diuretics, and laxatives interfered with the detection of anorectics and antidepressants. A survey of herbal weight loss products sold by compounding pharmacies in Brazil were analysed to determine the presence of pharmaceutical adulterants. A total of 106 herbal products, collected from 73 pharmacies in nine Brazilian states, were analysed for amfepramone, sibutramine, fenproporex, fluoxetine, paroxetine, sertraline and bupropion using the new analytical method. The method permitted the rapid and selective screening for the seven adulterants. Of the 106 weight loss products sampled, four (3.8%) were found to be adulterated by fenproporex or sibutramine. The adulterated samples were compounded by four different pharmacies located in three different Brazilian states. The novel capillary electrophoresis method we developed may be a useful tool for public health organisations tasked with analysing herbal weight loss products.
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The leaves of Mitragyna speciosa, a tropical plant known as “kratom,” have been traditionally used as a substitute for opium in Thailand and Malaysia. Mitragynine, a major constituent of M. speciosa, has an opioid agonistic activity, and its derivative 7-hydroxymitragynine (7-OH-mitragynine) (a minor constituent) is much more potent than mitragynine or morphine. Recently, many products containing this plant have been distributed as “incense” on the drug market in Japan for their expected narcotic effects. Despite their potency and their wide distribution for abuse, there are no reports on the quantitative analysis of mitragynine and 7-OH-mitragynine in the raw materials or in the commercial products of kratom. In this study, a method for simultaneous analysis of mitragynine, 7-OH-mitragynine, and other indole alkaloids (speciogynine, speciociliatine, and paynantheine), present in the raw materials and commercial products of kratom, was developed using liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS). By this method, mitragynine, 7-OH-mitragynine, and the other alkaloids were detected in 11 of the 13 products. The content of mitragynine in the products ranged from 1% to 6%, and that of 7-OH-mitragynine from 0.01% to 0.04%. Because 7-OH-mitragynine is much more potent than morphine, M. speciosa abuse is a matter of major concern. The present analytical method is considered useful for the screening of M. speciosa products in the drug market.
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The presence on the market of illegal products for slimming purposes or the treatment of overweight is a public health issue. These products may contain illicit chemicals in order to improve their effectiveness. Some of these weight-loss compounds are responsible for adverse events, including fatal outcomes. A general strategy for the analysis of any suspect formulation begins with a large screening for the general search of a wide range of compounds. A methodology for the qualitative and quantitative determination of 34 compounds in slimming preparations (such as dietary supplements or medicinal products) was used for the control of slimming formulations from the market, including over the Internet. The fast liquid chromatography system (ultra-high-pressure liquid chromatography) used a gradient of solvent (phosphate buffer and acetonitrile), a C18 endcapped column and a diode array detector. This system allows dual identification based on retention time and UV spectra. The analytical method is simple, fast and selective since 34 weight-loss compounds can be detected in a 15-min run time. Thus, 32 commercial slimming formulations were analysed using this method, allowing the detection and quantification of hazardous active substances: caffeine, clenbuterol, nicotinamide, phenolphthalein, rimonabant, sibutramine, didesmethylsibutramine, synephrine and yohimbine.
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The leaves of Kratom, a medicinal plant in Southeast Asia, have been used as an herbal drug for a long time. At least one of the alkaloids present in Kratom, mitragynine, is a mu-receptor agonist. Both Kratom and an additional preparation called Krypton are available via the internet. It seems to consist of powdered Kratom leaves with another mu-receptor agonist, O-desmethyltramadol, added. O-Desmethyltramadol is an active metabolite of tramadol, a commonly prescribed analgesic. We present nine cases of intoxication, occurring in a period of less than one year, where both mitragynine and O-desmethyltramadol were detected in the postmortem blood samples. Neither tramadol nor N-desmethyltramadol was present in these samples, which implies that the ingested drug was O-desmethyltramadol. The blood concentrations of mitragynine, determined by ultra-performance liquid chromatography-tandem mass spectrometry, ranged from 0.02 to 0.18 μg/g, and O-desmethyltramadol concentrations, determined by gas chromatography with nitrogen-specific detection, ranged from 0.4 to 4.3 μg/g. We believe that the addition of the potent mu-receptor agonist O-desmethyltramadol to powdered leaves from Kratom contributed to the unintentional death of the nine cases presented and conclude that intake of Krypton is not as harmless as it often is described on internet websites.
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A death involving abuse of propylhexedrine and mitragynine is reported. Propylhexedrine is a potent α-adrenergic sympathomimetic amine found in nasal decongestant inhalers. The decedent was found dead in his living quarters with no signs of physical trauma. Analysis of his computer showed information on kratom, a plant that contains mitragynine, which produces opium-like effects at high doses and stimulant effects at low doses, and a procedure to concentrate propylhexedrine from over-the-counter inhalers. Toxicology results revealed the presence of 1.7 mg/L propylhexedrine and 0.39 mg/L mitragynine in his blood. Both drugs, as well as acetaminophen, morphine, and promethazine, were detected in the urine. Quantitative results were achieved by gas chromatography-mass spectrometry monitoring selected ions for the propylhexedrine heptafluorobutyryl derivative. Liquid chromatography-tandem mass spectrometry in multiple reactions monitoring mode was used to obtain quantitative results for mitragynine. The cause of death was ruled propylhexedrine toxicity, and the manner of death was ruled accidental. Mitragynine may have contributed as well, but as there are no published data for drug concentrations, the medical examiner did not include mitragynine toxicity in the cause of death. This is the first known publication of a case report involving propylhexedrine and mitragynine.
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The weight-loss drug lorcaserin, a FDA approved anorectic drug, was isolated from the dietary supplement "Lose quickly" claimed to be a pure natural fast slimming diet pill. After its purification by means of preparative liquid chromatography, its structure was characterized using LC-UV, NMR, MS, MS/MS, and IR spectroscopy. The amount of lorcaserin measured by qNMR was 6.6mg/capsule.
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There have been a number of reports of dietary supplements contaminated with illegal adulterants that threaten consumers' health because of their adverse pharmacological effects. In the present study, a convenient and economic method was developed to detect illegal pharmaceutics, such as PDE-5 inhibitor and appetite suppressants, using liquid chromatography (LC)/photodiode array (PDA) for screening and LC/mass spectrometry (MS) for successive confirmation. Target peaks were identified by comparison of their chromatographic retention times and PDA spectra with those of synthetic standards and finally confirmed by LC/MS. As a result, tadalafil, a PDE-5 inhibitor, and N-desmethylsibutramine, a derivative of sibutramine, were detected in various dietary supplements at concentrations of 13.5-21.9 mg and 3.0 mg per single dose, respectively. The present study will contribute to the development of an analytical method enabling rapid screening of a variety of health foods, and the result suggests that consumers should be aware of serious health risks related to these illegal compounds.
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Identification of pharmaceutical active ingredients sildenafil and tadalafil and the characterization of a dimethylated thio-derivative of sildenafil, called thioaildenafil or thiodimethylsildenafil, in illicit dietary supplements were described. A multi-residual ultra-performance liquid chromatography–time of flight mass spectrometry (UPLC–TOF/MS) method was developed to screen for the presence of the phosphodiesterase-5 (PDE-5) inhibitors sildenafil, tadalafil, and vardenafil and their analogues thioaildenafil and thiohomosildenafil in powders and pharmaceutical dosage forms. The study was developed in connection with an operation supervised by the Italian Medicines Agency (A.I.F.A.), aimed to monitor dietary supplements in th