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Pharmacology of Kratom: An emerging botanical agent with stimulant, analgesic and opioid-like effects

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Abstract

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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... The subjects were divided into three age groups: children (<12 years), adolescents (12-18 years), and adults (>18 years). Because different kratom doses can affect clinical manifestations, the subjects were stratified into 3 groups according to the self-reported dose of kratom exposure within the past 24 hours: the low dose group (1-5 g); the moderate dose group (>5-15 g); and the high dose group (>15 g) [1,3]. In acute exposure patients, the dose was calculated from the patient's report of the total dose the patient took during acute exposure. ...
... The alkaloids mitragynine and 7-HMG are the main active substances in this plant [13], and research has demonstrated dose dependent CNS stimulant and sedative effects [1]. ...
... Because most kratom users usually do not consume only kratom, some of the adverse health effects associated with its use may be caused by other substances or may be exacerbated by pre-existing health conditions [29]. Adulteration is a concern because serious adverse effects or even death may result [1,13]. The current literature suggests that kratom may sometimes contain carisoprodol, modafinil, diphenhydramine, Datura stramonium, fentanyl, caffeine, morphine, or tramadol. ...
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Kratom is a plant that is indigenous to Southeast Asia and has recently attracted attention in the United States; its primary active alkaloid mitragynine has stimulant effects at low doses and sedative effects at high doses. The purpose of this study was to provide updated information on the characteristics, clinical effects, treatment and patient outcomes of kratom exposure. Methods: This was a retrospective analysis of kratom exposures reported to two statewide poison control centers between January 2016 and June 2020. Subjects who reported coexposure to other substances of abuse or intentional xenobiotic overdoses were excluded. The data were stratified by the consumption of kratom alone and with nonoverdose exposure to other medications. Results: In total, 153 kratom exposures were included. Patients were classified into 3 groups according to kratom use within the past 24 hours: low dose (1–5 g; 45.1%), moderate dose (>5–15 g; 17.0%) and high dose (>15 g; 12.4%) groups. The two common clinical effects were central nervous system excitation (kratom, 32.3%; coexposure, 53.3%) and tachycardia (kratom, 46.6%; coexposure, 44.6%). Dose dependent sedative effects of kratom were not observed. Coexposure accounted for 39.2% of cases and was associated with higher rates of ICU admission (28.3% vs. 8.6%; p<0.01) and serious medical outcomes (28.3% vs. 7.5%; p<0.01). Conclusion: Kratom exposure is associated with a wide range of symptoms. Despite the perception that kratom is safe, the probability of more severe symptoms and serious effects should be o
... Kratom (Mitragyna speciosa) is a tree indigenous to Southeast Asia of which extracts from the leaves have known opioid-like properties and are marketed for treating chronic pain and for its ability to benefit those struggling with opioid addiction and withdrawal. [1][2][3] Most studies of kratom focus on the psychoactive properties, whereas its toxicity is only recently gaining attention. Specifically, kratom hepatoxicity with histological examination is rarely reported but clinically significant. ...
... 3 opioid-like properties have made it a popular herb of abuse. 2,3 The US Drug Enforcement Agency has had kratom on its "Drugs of Concern" list since 2014 and stated that more research and safety profiling must be performed before any Federal Drug Administration approved uses of kratom. 2,5 The main active components of kratom are alkaloid compounds, including mitragynine, 7-hydroxymitragynine, and corynantheidine. ...
... Its analgesic and stimulant effects are due to their interaction with CNS m-opioid and d-opioid receptors and postsynaptic alpha-2 adrenergic receptors, respectively. [1][2][3] In vitro cytochrome P450 inhibition studies of these alkaloid compounds demonstrated potent CYP2D6 inhibition by mitragynine and corynantheidine. CYP2D6 is known to metabolize nearly 25% of clinically used medications, which increases the concern for kratom use in those who are taking other medications or substances. ...
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Kratom is a plant with opioid-like properties known to produce stimulant and analgesic effects. Although there are numerous studies on the psychoactive components of kratom, less is known about the toxicity. Specifically, few reports describe kratom-induced hepatotoxicity and demonstrate histological features. We provide a case report detailing the clinicopathologic findings of drug-induced liver injury caused by kratom. The laboratory workup included significant elevation of total bilirubin and alkaline phosphatase. Liver biopsy demonstrated a prominent canalicular cholestatic pattern, mixed portal inflammation, and newly described perivenular necrosis. This report provides additional information on kratom toxicity because its use continues to rise.
... Nonetheless, widespread use for health and well-being include diverse uses reported by consumers as reasons for their use. For example, at low doses, kratom has long been consumed orally as a stimulant to enhance stamina and productivity, making it particularly popular among field laborers working long days in arduous conditions (Tanguay, 2011;Prozialeck et al., 2012;Hassan et al., 2013;Warner et al., 2016). Consumption remains widespread in kratom's native lands, where people commonly chew raw kratom leaves or boil leaves to make tea . ...
... An estimated 10-16 million people in the United States take kratom, though current prevalence ranges of 1.3%-6.1% from national representative surveys may underestimate regular kratom users Covvey et al., 2020). Whereas in Southeast Asia users typically buy kratom leaves directly from a grower, Westerners often purchase capsules, powders, or extracts via the internet, specialty smoke shops, and gas stations (Prozialeck et al., 2012;Singh et al., 2016). Kratom is currently not recognized as a dietary supplement in the United States, and the Food and Drug Administration (FDA) has not issued guidance or regulatory standards on kratom regarding allowable product contents, alkaloid concentrations, packaging, labeling, or marketing of kratom products that is usually provided for dietary ingredients (Coe et al., 2019). ...
... In vitro studies reveal that biochemical pathways responsible for the analgesic and sedating effects of kratom do not carry risk of overdose comparable to classical opioids. Specifically, mitragynine and 7-hydroxymitragynine have partial affinity for the mu opioid receptor (Kapp et al., 2011;Prozialeck et al., 2012), whereas morphine is a full agonist. Binding of kratom alkaloids to this receptor largely activate G-protein coupled pathways, as opposed to the beta-arrestin pathway responsible for classical opioids' common deadly side effect of respiratory depression (Kruegel et al., 2016;Váradi et al., 2016;White, 2018;Kruegel et al., 2019;Basiliere and Kerrigan, 2020;Behnood-Rod et al., 2020). ...
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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.
... Numerous studies have focused on two alkaloids: mitragynine and 7-hydroxymitragynine [5,6,7]. A number of studies on the health benefits and consequences of kratom use are growing [8] as kratom consumption has increased in recent years in Europe and the United States [9] in addition to consumption in Southeast Asia, where kratom has been consumed over a century [10]. Nonetheless, the evidence for kratom's health benefits remains inconclusive, and kratom use patterns vary significantly across Asia, Europe, and North America [11]. ...
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Background and aims There are evidence about effects of kratom (Mitragyna speciosa) use on parameters related to metabolic syndrome (MetS). The present study aimed to determine the association between kratom use and MetS. Methods This study is a cross-sectional study of 581 subjects (kratom users and non-users) aged 18 and over from the Nam Phu sub-district, Surat Thani province, Thailand. The association was determined using multivariate logistic regression. Results MetS prevalence in kratom users and non-users was 11.9% (95% CI, 8.4–16.3%) and 21.6 % (95% CI, 17.1–26.8%), respectively. The use of kratom was associated with the lower odds of MetS (adjusted OR, 0.56; 95% CI, 0.33–0.96). Kratom use were associated with smaller waist circumference, lower triglycerides, and higher high-density lipoprotein. Conclusions The current study demonstrated a potential protective effect of kratom use against MetS.
... Ketum leaf or kratom or Mitragyna speciosa (MS) is a native tropical plant that grows in Southeast Asia and has been used as a traditional medication by the locals [1][2][3]. It can be chewed, taken with drinks, or smoked. ...
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Ketum use is significantly prevalent amongst individuals in the northern states of Peninsular Malaysia. This study aims to investigate the prevalence and psychosocial correlates of Ketum use in individuals who are in the Methadone Maintenance Therapy (MMT) Programme at the Hospital Taiping. This is a cross-sectional study conducted in the methadone clinic at the Hospital Taiping. The study instruments used were Subjective Opiate Withdrawal Scale (SOWS), Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) questionnaire, and Kratom Dependence Scale (KDS). A total of 215 subjects were recruited for this study. The prevalence of ketum users was 49.3% (n = 106). Chinese and Indian ethnicity had a lower tendency to use ketum compared to Malay ethnicity, with OR = 0.386 (95% CI 0.134, 1.113) and 0.119 (95% CI 0.035, 0.408), respectively. Individuals who used other illicit drugs had a higher tendency to use ketum with the adjusted OR = 9.914 (95% CI: 1.109, 88.602). Every one unit increase in SOWS increased the odds of being a ketum user by 1.340 (95% CI: 1.070, 1.677), whereas every one unit increase in duration in the MMT programme reduced the odds of being a ketum user by 0.990 (95% CI: 0.982, 0.998). Ketum use is prevalent amongst those in the MMT programme in this study. The high prevalence of ketum use is of concern and further interventions should be carried out to address this.
... There is a general effect of "cocaine-like" stimulation in modest doses, while large amounts cause "morphine-like" drowsiness and nausea [23]. They may enhance immunity, reduce blood pressure, and have antiviral, diabetes-suppressing, and appetite-suppressing properties [24]. Long-term usage at high dosages might result in anorexia, dry mouth, diuresis, and constipation [25]. ...
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The objectives of the present study were to examine the influence of supplementation with dried kratom leaf (DKTL) on the performance, hematology, and nitrogen balance in goats. Four 12-month-old male crossbred (Thai Native x Anglo Nubian) goats with an initial body weight (BW) of 24.63 ± 0.95 kg were allocated randomly to receive four different levels of DKTL using a 4 × 4 Latin square design. The DKTL was added to a total mixed ration (TMR) diet with doses of 0, 2.22, 4.44, and 6.66 g/day to investigate the treatment's efficacy. The DKTL was high in secondary metabolites, including mitragynine, total phenolics, total tannins, flavonoids, and saponins. There were quad-ratic effects on total DMI in terms of kg/day (p = 0.04), %BW (p = 0.05), and g/kg BW.75 (p = 0.02). DKTL increased apparent digestibility with quadratic effects (DM; p = 0.01, OM; p = 0.01, CP; p = 0.04, NDF; p = 0.01, and ADF; p = 0.01). The pH value was within the rumen's normal pH range, whereas NH3-N and BUN concentrations were lower with DKTL supplementation, and also reduced cholesterol (CHOL, p = 0.05) and low-density lipoprotein (LDL, p = 0.01). The protozoa population decreased linearly as DKTL levels increased (p < 0.01), whereas Fibrobacter succinogenes increased quadratically at 0 h (p = 0.02), and mean values increased linearly (p < 0.01). The average value of acetic acid (C2) and methane production (CH4) decreased linearly (p < 0.05) when DKLT was added to the diet, whereas the quantity of propionic acid (C3) increased linearly (p = 0.01). Our results indicate that DKTL could be a great alternative supplement for goat feed. We believe that DKTL could provide opportunities to assist the goat meat industry in fulfilling the demands of health-conscious consumers.
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.
Article
Background and purpose: Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the mu-opioid receptor (MOR). CYP3A-dependent oxidation of mitragynine, results in the metabolite 7-OH mitragynine, a more efficacious MOR agonist. While both mitragynine and 7-OH mitragynine can induce anti-nociception in mice, recent evidence suggests that 7-OH mitragynine formed as a metabolite is sufficient to explain the anti-nociceptive effects of mitragynine. However, the ability of 7-OH mitragynine to induce MOR-dependent respiratory depression has not yet been studied. Experimental approach: Respiration was measured in awake, freely moving mice (male CD-1) using whole body plethysmography. Anti-nociception was measured using the hot plate assay. Morphine, mitragynine, 7-OH mitragynine and the CYP3A inhibitor ketoconazole were administered orally. Key results: The respiratory depressant effects of mitragynine showed a ceiling effect, whereby doses higher than 10 mg/kg produced the same level of effect. In contrast, 7-OH mitragynine induced a dose-dependent effect on mouse respiration. At equi-depressant doses, both mitragynine and 7-OH mitragynine induced prolonged anti-nociception. Inhibition of CYP3A reduced mitragynine-induced respiratory depression and anti-nociception without impacting the effects of 7-OH mitragynine. Conclusions and implications: Our results show that, like its anti-nociceptive effects, the respiratory depressant effects of mitragynine are partly due to its metabolic conversion to 7-OH mitragynine. The limiting rate of conversion of mitragynine into its active metabolite results in a built-in ceiling effect of the mitragynine-induced respiratory depression. These data suggest that such "metabolic saturation" at high doses may underlie the improved safety profile of mitragynine as an opioid analgesic.
Article
Mitragyna speciosa, a species of plant that is native to Thailand, Malaysia and Southeast Asia, contains two major psychoactive alkaloids: mitragynine and 7-hydroxymitragynine. Pharmacologically, the alkaloids exhibit biphasic effects - at low dose, stimulant effects are realized, while high doses exhibit sedative effects. For years, the plant has been used recreationally and medicinally for these effects, but its use has been implicated in and associated with intoxications and deaths. In this case report we describe two cases whereby decedents presented with single substance fatal intoxications by mitragynine in the absence of other postmortem toxicological findings. The cases entail young male decedents in outdoor settings (e.g. driving a vehicle and bicycle). Postmortem blood concentrations were 2,325 ng/mL and 3,809 ng/mL. The medical examiner (ME) certified cause of death (COD) as acute mitragynine intoxication in both cases. The toxicology results presented become useful when considering mitragynine to be the offending agent in lethal single drug intoxications; further, the information included is pertinent to medical examiners, forensic pathologists, forensic toxicologists, and emergency department personnel in evaluating possible poisoning and lethality by mitragynine.
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This study aimed to compare whole blood and serum concentrations of quetiapine in acute poisoning cases. Authentic whole blood and respective serum samples were routinely collected from patients diagnosed with blood poisoning at our University Hospital. Accordingly, whole blood and serum paired samples from nine patients (one male and eight female patients) were analyzed for quetiapine using liquid chromatography-mass spectrometry (LC–MS). Quetiapine concentrations in whole blood and serum samples ranged widely from 5.4 to 2780 ng/mL and 9.9 to 2500 ng/mL, respectively. The whole blood/serum concentration ratio was 0.5–1.1 and increased together with an increase in whole blood and serum quetiapine concentrations. The ratio was reversed at around 2500 ng/mL to > 1. Our findings suggest that whole blood concentrations are more useful than serum concentrations in diagnosing quetiapine poisonings.
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Mitragyna speciosa Korth is a medicinal plant indigenous to Thailand and Malaysia and has been known for its narcotic and coca-like effects. Many studies have been performed on the antinociceptive effect of the plant extracts of Thai origin; however, limited studies have been reported till date on M. speciosa extracts of Malaysian origin. Various concentrations of alkaloid (5-20 mg/kg), methanolic (50-200 mg/kg), and aqueous (100-400 mg/kg) extracts of Malaysian M. speciosa leaves were prepared and orally administered to nine groups of rats. Morphine (5 mg/kg, s.c.) and aspirin (300 mg/kg, p.o.) were used as control. Antagonism of the antinociceptive activity was evaluated by pretreatment with naloxone at a dose of 2 mg/kg (i.p.). Results showed that oral administration of the alkaloid (20 mg/kg), methanolic (200 mg/kg), and aqueous (400 mg/kg) extracts significantly prolonged the latency of nociceptive response compared with control groups in both hot plate and tail flick tests (P < 0.05). Antinociceptive action of the alkaloid (20 mg/kg), methanolic (200 mg/kg), and aqueous (400 mg/kg) extracts was significantly blocked by naloxone. In conclusion, these results suggest the presence of antinociceptive effect in various extracts of Malaysian M. speciosa leaves. In addition, the antinociceptive effective doses vary depending on the type of solvents used for extraction.
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Despite their widespread Internet availability and use, many of the new drugs of abuse remain unfamiliar to health care providers. The herbal marijuana alternatives, like K2 or Spice, are a group of herbal blends that contain a mixture of plant matter in addition to chemical grade synthetic cannabinoids. The synthetic cathinones, commonly called "bath salts," have resulted in nationwide emergency department visits for severe agitation, sympathomimetic toxicity, and death. Kratom, a plant product derived from Mitragyna speciosa Korth, has opioid-like effects, and has been used for the treatment of chronic pain and amelioration of opioid-withdrawal symptoms. Salvia divinorum is a hallucinogen with unique pharmacology that has therapeutic potential but has been banned in many states due to concerns regarding its psychiatric effects. Methoxetamine has recently become available via the Internet and is marked as "legal ketamine." Moreover, the piperazine derivatives, a class of amphetamine-like compounds that includes BZP and TMFPP, are making a resurgence as "legal Ecstasy." These psychoactives are available via the Internet, frequently legal, and often perceived as safe by the public. Unfortunately, these drugs often have adverse effects, which range from minimal to life-threatening. Health care providers must be familiar with these important new classes of drugs. This paper discusses the background, pharmacology, clinical effects, detection, and management of synthetic cannabinoid, synthetic cathinone, methoxetamine, and piperazine exposures.
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Striking increases in the abuse of opioids have expanded the need for pharmacotherapeutic interventions. The obstacles that confront effective treatment of opioid addiction - shortage of treatment professionals, stigma associated with treatment and the ability to maintain abstinence - have led to increased interest in alternative treatment strategies among both treatment providers and patients alike. Herbal products for opioid addiction and withdrawal, such as kratom and specific Chinese herbal medications such as WeiniCom, can complement existing treatments. Unfortunately, herbal treatments, while offering some advantages over existing evidence-based pharmacotherapies, have poorly described pharmacokinetics, a lack of supportive data derived from well controlled clinical trials, and severe toxicity, the cause for which remains poorly defined. Herbal products, therefore, require greater additional testing in rigorous clinical trials before they can expect widespread acceptance in the management of opioid addiction.
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Here we present a case of a coincidence of addiction to "Kratom" (botanically known as Mitragyna speciosa Korth) and developed severe primary hypothyroidism. We are discussing a possibility that high dose of indole alkaloid mitragynine (the major alkaloid identified from "Kratom") might reduce the normal response of the thyroid gland to thyroid-stimulating hormone resulting in primary hypothyroidism. Further experimental investigations of mitragynine as a possible suppressor of thyroid gland function would be a matter of interest.
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Kratom (Mitragyna speciosa) is a common medical plant in Thailand and is known to contain mitragynine as the main alkaloid. According to an increase in published reports and calls at German poison control centers, it has been used more frequently as a drug of abuse in the western hemisphere during the last couple of years. Despite this increase, reports of severe toxicity are rare within the literature. We describe a case of a young man who presented with jaundice and pruritus after intake of kratom for 2 weeks in the absence of any other causative agent. Alkaloids of M. speciosa were detected in the urine. While M. speciosa is gaining in popularity among illicit drug users, its adverse effects remain poorly understood. This is the first published case of intrahepatic cholestasis after kratom abuse.
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ETHOPHARMACOLOGICAL RELEVANCE: Mitragyna speciosa Korth (Rubiaceae) is one of the medicinal plants used traditionally to treat various types of diseases especially in Thailand and Malaysia. Its anti-inflammatory and analgesic properties in its crude form are well documented. In this study, the cellular mechanism involved in the anti-inflammatory effects of mitragynine, the major bioactive constituent, was investigated. The effects of mitragynine on the mRNA and protein expression of COX-1 and COX-2 and the production of prostaglandin E(2) (PGE(2)) were investigated in LPS-treated RAW264.7 macrophage cells. Quantitative RT-PCR was used to assess the mRNA expression of COX-1 and COX-2. Protein expression of COX-1 and COX-2 were assessed using Western blot analysis and the level of PGE(2) production was quantified using Parameter™ PGE(2) Assay (R&D Systems). Mitragynine produced a significant inhibition on the mRNA expression of COX-2 induced by LPS, in a dose dependent manner and this was followed by the reduction of PGE(2) production. On the other hand, the effects of mitragynine on COX-1 mRNA expression were found to be insignificant as compared to the control cells. However, the effect of mitragynine on COX-1 protein expression is dependent on concentration, with higher concentration of mitragynine producing a further reduction of COX-1 expression in LPS-treated cells. These findings suggest that mitragynine suppressed PGE(2) production by inhibiting COX-2 expression in LPS-stimulated RAW264.7 macrophage cells. Mitragynine may be useful for the treatment of inflammatory conditions.