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Intrahepatic Cholestasis Following Abuse of Powdered Kratom (Mitragyna speciosa)
Abstract
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.
... Kratom is an herbal product that is derived from Southeast Asian Mitragyna speciosa tree leaves [1][2][3][4][5][6][7][8][9][10]. Such leaves contain psychoactive opioid compounds that can be utilized for many purposes such as stimulation, euphoria, or analgesia [1][2][3][4][5][6][7][8][9][10]. ...
... Kratom is an herbal product that is derived from Southeast Asian Mitragyna speciosa tree leaves [1][2][3][4][5][6][7][8][9][10]. Such leaves contain psychoactive opioid compounds that can be utilized for many purposes such as stimulation, euphoria, or analgesia [1][2][3][4][5][6][7][8][9][10]. As a popular drug, Kratom is used widely for conditions such as chronic pain, diarrhea, or fatigue management. ...
... Liver toxicity and histopathology from Kratom has not been documented extensively despite the United States Drug Enforcement Administration listing this drug on its "Drugs and Chemicals of Concern" list [8]. Research about Kratom's potential toxicities is scarce except for scattered case reports [1,2,[4][5][6]. Given the scarce literature of Kratom, this report describes a novel case of Kratom induced hepatotoxicity disguised as choledocholithiasis in a young female with chronic back pain. ...
... 11 Recreational use of kratom has been associated with rare instances of acute liver injury. [12][13][14][15][16] We report a case of kratom-induced liver inflammation complicated by opioid withdrawal symptoms precipitated by initiation of IM naltrexone. ...
... [21][22][23] Kratom is also associated with instances of acute liver injury in previous case reports. [12][13][14][15] In this case, other potential causes of transaminitis were ruled out based on lab work. Naltrexone is also associated with transaminitis, but hepatic enzyme abnormalities were present in this patient prior to the administration of IM naltrexone. ...
... In addition, kratom is found to be detectable in urine for up to 2 weeks after last use. 12 These variables in pharmacokinetics and urine testing present barriers to initiation of opioid antagonist treatment and place patients with AUD and OUD at risk of withdrawal when starting treatment. ...
Kratom is an herbal supplement that has gained popularity for recreational use within the United States. Kratom exerts opioid-like effects and, although not US FDA approved, is commonly used for self-treatment of pain, withdrawal management from opioids, and euphoria. Drug-related hepatic injury has been associated with kratom use. All of this raises concern for patient safety and monitoring. The potential for additive liver toxicity must be considered when kratom is used concurrently with hepatotoxic, over-the-counter, herbal, and prescription medications. This case report describes a case of kratom-induced liver inflammation complicated by opioid withdrawal that was precipitated by initiation of IM naltrexone. To our knowledge, there are no published case reports related to opioid withdrawal following naltrexone administration in patients using kratom (without other opioids). The purpose of this case report is to demonstrate potential complications that may arise with kratom use and considerations that should be taken prior to initiation of naltrexone in kratom users.
... Articles state that only a few kratom liver injury cases have been described; however, searching revealed a total of 26 formally described cases: 11 case reports [27][28][29][30][31][32][33][34][35][36][37], 13 conference abstracts representing 12 unique cases [38][39][40][41][42][43][44][45][46][47][48][49][50], 1 case not formally published [51], and 2 cases in the NIH LiverTox database (Table 1) [52,53]. In instances of data omission, we contacted authors to determine whether missing data were available. ...
... Most case reports met the laboratory criteria for DILI based on consensus case definitions [54]. Three cases did not meet the DILI criteria; two further cases had insufficient documentation and were excluded [41,44], and one was included due to an otherwise suggestive case [27,44]. The included case that did not meet the DILI criteria had mild elevation in transaminases and ALP, and a direct hyperbilirubinemia of 28.6 mg/dL. ...
... Twelve human liver biopsies have been described in case reports, not inclusive of internet forums. Kapp et al. found pure cholestatic injury without hepatocellular damage, with bile precipitations and canalicular cholestasis [27]. Kesar et al. found cholestasis, lobular inflammation, and increased eosinophils in sinusoids [39]. ...
Kratom (Mitragyna speciosa) leaves contain the mu opioid Kupferschmidt,partial agonists mitragynine and 7-hydroxymitragynine. The US Drug Enforcement Agency considers it a ‘drug of concern’, and the US FDA is reviewing kratom, but there is a paucity of information regarding health effects. Liver injury is often cited as a potential health consequence, however the same few case reports are repeatedly referenced, without a broader context. Furthermore, reports have largely lacked standardized causality assessment methods. The objective is to evaluate causality in kratom liver injury, through a comprehensive scoping review of human cases, and by reviewing epidemiologic, animal, and mechanistic reports that relate to kratom liver injury. Hepatotoxicity causality was systematically examined using the Roussel Uclaf Causality Assessment Method (RUCAM) for case reports. Biopsy findings, potential pathophysiologic mechanisms, and management options are discussed. This review identified 26 case reports and abstracts, in addition to 7 cases reported from the Drug-Induced Liver Injury Network, 25 in FDA databases, and 27 in internet user forums. Latency periods to symptom onset had a median of 20.6 days and mean of 21 days (range 2–49). Common presenting signs and symptoms were abdominal discomfort, jaundice, pruritis, and dark urine. Histologic findings were predominantly cholestatic, although, biochemically, the condition was heterogenous or mixed; the median R ratio was 3.4 and the mean was 4.6 (range 0.24–10.4). Kratom likely causes liver injury based on the totality of low-quality human evidence, and, in the context of epidemiologic, animal, and mechanistic studies. It remains unclear which subgroups of users are at heightened risk.
... Overall, there were 41 cases on kratom-associated adverse events or toxicities (Table 1). Kratom-associated adverse events were as follows: kratom-associated withdrawal symptoms (KAWS) in adults [41][42][43][44][45][46][47][48][49][50][51][52], kratom-associated neonatal abstinence syndrome (KANAS) [48,[52][53][54][55][56], hypothyroidism [43], hypogonadism [57], kratom-induced hepatoxicity (KIH) [58][59][60][61][62][63][64][65], CNS effects causing seizure and coma or posterior reversible encephalopathy syndrome (PRES) [39,66,67], acute respiratory distress syndrome (ARDS) [68,69], overdose toxidrome [70,71], and fatalities [72][73][74][75][76][77][78][79][80]. There were six case series of aggregated patient's data [48,49,51,73,77,80]. ...
... Kratom-Induced Hepatoxicity [58][59][60][61][62][63][64][65] Kratom-induced hepatotoxicity (KIH) has been reported after 2 to 4 weeks of use and rechallenge has led to recurrence [59,65]. The reported dose resulting in KIH was 14 to 21 g per day. ...
... The reported dose resulting in KIH was 14 to 21 g per day. In one case report, there was rapid dose-escalation (3 to 6 times the starting dose in 2 weeks) [58]. In all cases, patients presented to the emergency department for symptoms associated with hepatotoxicity including at least one of the following symptoms: dark-colored urine, light-colored stools, profound weakness, weight loss, nausea, vomiting, fever, or night sweats. ...
Purpose of Review
This review describes case reports for patients with kratom-associated adverse events in order to assist clinicians with patient management. A stepwise approach is proposed for assessing active kratom users as well as considerations for the management of toxicities or withdrawal.
Recent Findings
Multiple in vitro and in vivo studies illustrate the pharmacologic and toxicologic effects of kratom extract. No randomized controlled trials in humans exist that assess the safety and efficacy of the substance. Cross-sectional surveys from active users and reports from poison control centers have shown acute and chronic physiological and psychological adverse events.
Summary
Reports of adverse effects associated with kratom use have demonstrated hypothyroidism, hypogonadism, hepatitis, acute respiratory distress syndrome, posterior reversible encephalopathy syndrome, seizure, and coma. Overdose toxidrome leads to respiratory failure, cardiac arrest, and fatalities. Adult and neonatal withdrawal symptoms have also occurred. Clinicians should be aware of the risks and benefits of kratom use.
... While several studies attempted to understand the addictive potential of kratom [5][6][7], reports describing kratom toxicity manifesting in specific organs are relatively few [8][9][10][11]. Also, although kratom-induced cholestatic and/or hepatocellular pattern liver injuries have been reported [12][13][14], reports with detailed histopathologic examination of the liver biopsy are rare [15][16][17]. ...
... A few studies documented liver injury caused by kratom [8,12,13,[15][16][17]30], three with histologic examination of the liver biopsies [15][16][17]. Seven of the reported cases are summarized in Table 2 [8,12,13,[15][16][17]30]. ...
... A few studies documented liver injury caused by kratom [8,12,13,[15][16][17]30], three with histologic examination of the liver biopsies [15][16][17]. Seven of the reported cases are summarized in Table 2 [8,12,13,[15][16][17]30]. In addition, hepatomegaly that is possibly associated with kratom use [31] has been reported. ...
Kratom is an herbal supplement used to relieve chronic pain or opioid withdrawal symptoms. Recent news articles covering adverse effects associated with kratom use have brought attention to its organ toxicities. Reports of kratom-induced hepatic toxicity are limited and only three case reports of kratom-induced liver injury with histopathologic examination of the liver biopsies are available. A 40-year-old female presented with symptoms of mixed cholestatic and hepatocellular liver injury without clear etiology. The laboratory and imaging workup suggested possibilities of autoimmune hepatitis, autoimmune hepatitis-primary biliary cholangitis (PBC) overlap syndrome, or drug-induced liver injury. Autoantibodies including anti-mitochondrial antibody (AMA) were negative. Liver biopsy showed granulomatous hepatitis with prominent duct injury, suggestive of AMA-negative PBC. She subsequently was referred to a hepatologist and a history of recent kratom use was finally revealed. Kratom was discontinued and the symptoms improved. Kratom-induced hepatic toxicity may manifest with variable biochemical and clinical abnormalities. Histologically, it may mimic AMA-negative PBC. Our case highlights the importance of thorough history taking, interdisciplinary approach and communication for optimal patient care.
... Long term kratom consumption has been linked to kratom toxicity [79,80] such as cardiovascular risk [81], inflammatory cytokines [82]. toxicity characterized by seizure activity [28], liver damage [79,80], and other major adverse consequences [80]. ...
... Long term kratom consumption has been linked to kratom toxicity [79,80] such as cardiovascular risk [81], inflammatory cytokines [82]. toxicity characterized by seizure activity [28], liver damage [79,80], and other major adverse consequences [80]. Cellular opioid dependence resulting from continuous stimulation of opioid-regulated signaling networks may ultimately lead to alterations in protein activities [83,84]. ...
... Kratom is associated with several severe toxic effects including hypertension, nephrotoxicity, psychosis, seizures, and hepatotoxicity. The risks of long-term use of kratom are currently unknown. There are no pharmacological or pharmacokinetic studies on humans published or studies on drug interactions involving kratom (Kapp et. al, 2011). ...
... Chronic recreational use of kratom was also associated with intrahepatic cholestasis, autoimmune hepatitis, acute hepatic failure, acute respiratory distress syndrome and intractable vomiting (Kapp, et al., 2011;Pantano, et al., 2016;Jaliawala et al, 2018;Aldyab, et al. 2019;. ...
... Although the rise of kratom use in the West has been an opportunity for increased scientific study, the resultant publication of a great deal of research of limited rigor has created confusion for health practitioners attempting to understand the benefits and risks of the plant and the heterogeneity of kratom products. Case studies, poison control center briefings, and tallied coroner and medical examiners' reports have disproportionately emphasized, as these forms of inquiry often do, extreme and rare events, including seizure, liver damage, and death (e.g., Nelsen et al., 2010;Sheleg and Collins, 2011;Kapp et al., 2011;Neerman et al., 2013;Anwar et al., 2016;Wang and Walker, 2018;Post et al., 2019;Afzal et al., 2020), even as some have elucidated that adverse health outcomes from kratom exposure have been mild to moderate and resolved quickly (Anwar et al., 2016). Still, there remains considerable ambiguity on the potential harms from kratom use. ...
... 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). ...
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.
... Frequent users report tremors, anorexia, weight loss, seizures, and psychosis [53,118]. In addition, seizures and addiction are mainly experienced by individuals following long-term M. speciosa consumption, and liver toxicity can occur after M. speciosa overdose [118,133]. Individuals with long-term addiction to M. speciosa have been reported to have hyperpigmentation of the cheeks, tremors, anorexia, weight loss, and psychosis [33]. ...
... Drug-induced intrahepatic cholestasis was identified after liver biopsy. Mitragynine was confirmed after both urine and serum samples were examined [133]. ...
Mitragyna is a genus belonging to the Rubiaceae family and is a plant endemic to Asia and Africa. Traditionally, the plants of this genus were used by local people to treat some diseases from generation to generation. Mitragyna speciosa (Korth.) Havil. is a controversial plant from this genus, known under the trading name “kratom”, and contains more than 40 different types of alkaloids. Mitragynine and 7-hydroxymitragynine have agonist morphine-like effects on opioid receptors. Globally, Mitragyna plants have high economic value. However, regulations regarding the circulation and use of these commodities vary in several countries around the world. This review article aims to comprehensively examine Mitragyna plants (mainly M. speciosa) as potential pharmacological agents by looking at various aspects of the plants. A literature search was performed and information collected using electronic databases including Scopus, ScienceDirect, PubMed, directory open access journal (DOAJ), and Google Scholar in early 2020 to mid-2021. This narrative review highlights some aspects of this genus, including historical background and botanical origins, habitat, cultivation, its use in traditional medicine, phytochemistry, pharmacology and toxicity, abuse and addiction, legal issues, and the potential of Mitragyna species as pharmaceutical products.
... Frequent users report tremors, anorexia, weight loss, seizures, and psychosis [53,118]. In addition, seizures and addiction are mainly experienced by individuals following long-term M. speciosa consumption, and liver toxicity can occur after M. speciosa overdose [118,133]. Individuals with long-term addiction to M. speciosa have been reported to have hyperpigmentation of the cheeks, tremors, anorexia, weight loss, and psychosis [33]. ...
... Drug-induced intrahepatic cholestasis was identified after liver biopsy. Mitragynine was confirmed after both urine and serum samples were examined [133]. ...
Mitragyna is a genus belonging to the Rubiaceae family and is a plant endemic to Asia and Africa. Traditionally, the plants of this genus were used by local people to treat some diseases from generation to generation. Mitragyna speciosa (Korth.) Havil. is a controversial plant from this genus, known under the trading name "kratom", and contains more than 40 different types of alkaloids. Mitragynine and 7-hydroxymitragynine have agonist morphine-like effects on opioid receptors. Globally, Mitragyna plants have high economic value. However, regulations regarding the circulation and use of these commodities vary in several countries around the world. This review article aims to comprehensively examine Mitragyna plants (mainly M. speciosa) as potential pharmacological agents by looking at various aspects of the plants. A literature search was performed and information collected using electronic databases including Scopus, ScienceDirect, PubMed, directory open access journal (DOAJ), and Google Scholar in early 2020 to mid-2021. This narrative review highlights some aspects of this genus, including historical background and botanical origins, habitat , cultivation, its use in traditional medicine, phytochemistry, pharmacology and toxicity, abuse and addiction, legal issues, and the potential of Mitragyna species as pharmaceutical products. Citation: Ahmad, I.; Prabowo, W.C.; Arifuddin, M.; Fadraersada, J.; Indriyanti, N.; Herman, H.; Purwoko, R.Y.; Nainu, F.; Rahmadi, A.; Paramita, S.; et al.
... Adverse effects were more likely to be seen in rats exposed to 200 and 500 mg/kg. Hepatotoxicity is supported by a case study where intrahepatic cholestasis was observed in a 25-year-old male following 2 weeks of kratom use (Kapp, Maurer, Auwärter, Winkelmann, & Hermanns-Clausen, 2011). Cholestatic hepatitis was solely linked to kratom usage in at least one study (Dorman, Wong, & Khan, 2015). ...
... The patient was unresponsive at the time of admission to the emergency department, but the presence of other drugs was not known or reported. In other clinical reports, mitragynine was identified in the serum and urine of a 25-year-old male with intrahepatic cholestasis several days after drug cessation (Kapp et al., 2011), and in the urine of a 33-year-old woman with opioid use disorder that had used Krypton, an herbal blend containing kratom leaves and Odesmethyltramadol (Arndt et al., 2011). In a clinical setting, identification of Mitragyna alkaloids is rare due to the reliance on self-reported kratom use. ...
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.
... If accurate, this would correspond to approximately 0.9-1.5% of the US population reportedly using kratom. This trend is also reflected in the expanding scientific literature, where the number of case reports describing kratom intoxication continue to accumulate [20][21][22][23]. ...
... Case studies reveal that a wide range of organ systems are susceptible to kratom-mediated injury (Table 1). For example, instances of kidney injury [67], cardiotoxicity and arrhythmia [98,99], thyroid injury and hypothyroidism [100] lung injury/acute respiratory distress syndrome (ARDS) [101,102], neonatal abstinence syndrome, [103][104][105][106][107] and hepatic injury [23,[108][109][110][111][112][113][114][115][116] have all been linked to kratom. ...
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.
... Among the subjects in these case reports, 2 cases (13%) occurred in individuals under the age of 18 years old, 11 patients (73%) were between the ages of 18 to 60 years old, 1 patient case (7%) was older than 60 years of age, and 1 case report excluded the subjects age. Outcomes of the case reports included death (26%) [12][13][14][15], hepatotoxicity (20%) [16][17][18], withdrawal (20%) [19][20][21], seizure (20%) [5,9,22], hypogonadism (7%) [23], and posterior reversible leukoencephalopathy syndrome (7%) [24] (Table 1). ...
... Dorman et al. [18] 58-year-old male ingesting kratom daily with long-term concomitant use of quetiapine and sertraline was admitted with jaundice and liver function test abnormalities. With treatment patient was discharged 2 days later with normalizing labs Hepatotoxicity Kapp et al. [17] 25-year-old male presented with jaundice and pruritis after using kratom for a period of 2 weeks. Riverso et al. [16] 38-year-old patient developed acute cholestatic liver injury characterized by mild portal mixed inflammation and lymphocyte-mediated bile duct injury. ...
Purpose of Review
Kratom (Mitragyna speciosa) is an herb with no current indication for medical use with potentially addictive properties, yet it is being used in the management of pain, depression, and anxiety. The agent’s pharmacology lends itself for concern regarding recreational misuse (Drugs of Abuse, 2017).
Recent Findings
Kratom’s increasing popularity for use in the USA is reflected by National Poison Data System data that in 2011 there were 13 cases reported to poison control centers while in 2017 there were 682 calls in response to kratom exposure (Kratom exposure in the US linked to serious medical outcomes, 2019; Post et al. in Clin Toxicol. 57:847–54, 2019). Subjects most commonly use kratom for the self-treatment of pain, mood swings, and opioid-related withdrawal symptoms (Grundmann in Drug Alcohol Depend. 176:63–70, 2017). Known serious adverse events include hallucinations, delusions, reduced respiratory drive, and death (Kratom: unsafe and ineffective, 2019). Additional anecdotally reported side effects include hypothyroidism, seizure, hepatotoxicity, coma, and injury to the posterior white matter of the brain (Anwar et al. in MMWR Morb Mortal Wkly Rep. 65:748–9, 2016; Nelsen et al. in J Med Toxicol. 6:424–6, 2010; Sheleg and Collins in J Addict Med. 5:300–1, 2011; Castillo et al. in Proc (Baylor Univ Med Cent). 30:355–7, 2017).
Summary
At this time, kratom remains without regulations on a federal level. The substance’s opioid-like pharmacology, ease of use, and lack of demonstrated safety or efficacy justify the need for continued extensive research (Brooks, 2019).
... One study describes the administration of Kratom tea, containing 104, 166 and 192 mg/L of mitragynine, to 10 chronic Kratom users over 7 days; mitragynine plasma concentrations ranged from 18-105 ng/mL within ∼1 h (18). No adverse effects were reported, aside from recorded elevated blood pressure and heart rate that were likely attributed to the stimulant effects of the low doses (∼30 mg of mitragynine while chronic Kratom users in Malaysia reported using up to 276.5 mg) (19). Although Kratom has a historic, traditional use in Southeast Asia, it has been consumed recreationally as a "4×100" cocktail of Kratom tea, cough syrup, Coca-Cola and other illicit drugs prompting a ban in several countries (20). ...
... Other adverse events include a 64-year-old male who suffered a seizure at home following Kratom consumption (26). Reported adverse effects include seizures, psychosis and liver toxicity including cholistastis and hyperthyroidism (19,(27)(28)(29). Naloxone was successfully used to reverse the respiratory depression in a 38year-old female who presented to the ER with clinical symptoms of an opioid overdose (30). ...
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.
... 3,4,6 There have been reports of kratom use being linked to hepatotoxicity, seizures, coma, and in some cases, death. [8][9][10][11][12] Regular kratom use for 2 weeks and longer has been associated with acute cholestasis. 8,9 Kratom co-ingestion with other drugs, such as benzodiazepines, o-desmethlytramadol, propylhexedrine, and antidepressants has been associated with significant morbidity and mortality. ...
... [8][9][10][11][12] Regular kratom use for 2 weeks and longer has been associated with acute cholestasis. 8,9 Kratom co-ingestion with other drugs, such as benzodiazepines, o-desmethlytramadol, propylhexedrine, and antidepressants has been associated with significant morbidity and mortality. 6,11,13 There is still limited information regarding the pharmacology of kratom and its co-interaction with other substances to understand the potential outcomes and adverse effects. ...
An 18-year-old male with history of polysubstance abuse presented to the emergency department with intractable vomiting, diarrhea, and abdominal pain for one day after the consumption of kratom. Examination revealed arterial hypotension, tachycardia, and prolonged capillary refill. Laboratory studies showed white blood cell count (WBC) of 23.6 × 109/L, serum creatinine 4.0 mg/dL, lactate 6 mmol/L, and procalcitonin >200 ng/mL. Urine and blood drug screen were unremarkable. Radiology and echocardiogram were noncontributory. He received fluid resuscitation and broad spectrum antibiotics. Vasopressors were subsequently added to manage persistent shock. He remained afebrile, and his blood cultures were negative. His shock and associated organ dysfunctions improved over the next 72 hours. On discharge, his procalcitonin level decreased to 9.55 ng/mL, leukocytosis resolved, and the creatinine returned to baseline. This case describes an extremely rare presentation related to kratom, an herb marketed as an opioid alternative, with significant potential for addiction and withdrawal syndrome. How to cite this article: Zuberi M, Guru PK, Bansal V, Diaz-Gomez J, Grieninger B, Alejos D. Undifferentiated Shock and Extreme Elevation of Procalcitonin Related to Kratom Use. Indian J Crit Care Med 2019;23(5):239-241.
... Kratom use was described as being associated with or related to the morbidities observed in the titles of 9 studies (e.g., "Kratom-Associated Ventricular Fibrillation" [27]; or "Multiorgan Dysfunction Related to Kratom Ingestion" [28]). In the remaining 15 studies, the title described the morbidity as occurring after kratom use or in a person who used kratom (e.g., "Seizure and Coma Following Kratom" [29]; "Posterior Reversible Leukoencephalopathy Syndrome after Kratom Ingestion" [30]; or "Intrahepatic Cholestasis Following Abuse of Powdered Kratom (Mitragyna speciosa)" [31]). ...
Purpose of review
In this systematic review, we examined case reports of patients who use kratom and evaluated their rigor based on reporting of clinically relevant information.
Recent findings
Millions of people use kratom in the USA each year. Despite its prevalence, there is little peer-reviewed clinical literature available on kratom, and clinicians must predominantly rely on case reports for guidance in the assessment, diagnosis, and treatment of patients who use kratom.
Summary
We found considerable variation in reported information and in the thoroughness of the case reports. Reports tended to be inadequate in full assessment of the patient’s kratom use. As kratom use continues to increase in the USA, consistent and detailed reporting, usage of biospecimen testing and kratom product assays, consultation of experts to aid with patient workup, usage of causality assessment tools, and acknowledgement of limitations will improve the quality of case reports.
... A study on kratom consumption in the northern areas of peninsular Malaysia also reported that they used kratom to reduce their intake of more expensive opiates like heroin [8]. Although kratom has perceived therapeutic effects, several studies suggested abuse and addiction potential, synergistic toxic effects and fatal interactions with other psychoactive drugs [37,38]. In Malaysia, kratom is under the jurisdiction of the Poisons Act 1952 [39], where the law stated that any activity involving the possession, sale, use, transportation, processing, importation, and exportation of kratom is prohibited and may result in legal action. ...
Introduction:
Polysubstance use is the use of more than one non-prescribed licit or illicit substance at one time. This is a common phenomenon, but little is known about the severity and the various substances used by adults in Malaysia.
Objective:
To determine the pattern of polysubstance use and its associated factors among general adults in Malaysia.
Methodology:
This was a secondary data analysis from the National Health and Morbidity Survey (NHMS) 2019), a cross-sectional population survey with a two-stage stratified random sampling design. A total of 10,472 Malaysians aged 18 years and above participated in this survey. Polysubstance use was defined as concurrent use of more than one substance, either alcohol, tobacco, or drugs (opioids, marijuana, amphetamine/ methamphetamine or kratom). A latent class analysis (LCA) was used to identify the membership of polysubstance groups. The association of class membership with demographic profiles was examined using Multinomial Logistic Regression analysis.
Results:
Fit indices (AIC = 16458.9, BIC = 16443.6) from LCA supported 3 classes solution: Class 1; "moderate-drug" group primarily combination used of tobacco and alcohol (2.4%), Class 2; "high-drug" group using multiple substance including kratom (0.3%) and Class 3; "low-drug" group reporting minimal alcohol and tobacco use or non-user (97.3%). The multinomial model showed young adults (18-40 years) had a higher likelihood of being polysubstance users both for moderate-drug class (OR = 4.1) and high-drug class (OR = 3.9) compared to older age (≥60 years). Chinese (OR = 18.9), Indian (OR = 23.3), Indigenous Sabah & Sarawak (OR = 34.6) and others ethnicity (OR = 8.9) showed higher odds of being moderate-drug users than Malays. The greater odds of moderate-drug use for males (OR = 35.5), working groups (OR = 1.5) and low education level group (OR = 3.2).
Conclusion:
Our study highlights patterns and demographics related to the use of polysubstances among adults in Malaysia. These results would help formulate specific prevention programmes for these high-risk groups.
... A variety of organ systems can be affected due to kratom usage, which include kidney injury [97], cardiotoxicity and arrhythmia [98,99], thyroid injury and hypothyroidism [100], lung injury/acute respiratory distress syndrome [101,102], neonatal abstinence syndrome [103][104][105][106][107], and hepatic injury [108][109][110][111]. Amongst these, hepatic injury such as cholestatic hepatitis pattern similar to other drug-related injuries is frequently reported [112]. ...
... One of the interesting features of kratom-induced liver injury is the continuously rising level of bilirubin even for some time after discontin-uation of the product (Fernandes et al., 2019). This may be explained by the prolonged half-life/slow rates of metabolism of kratom, as in one study it was reported that kratom metabolites could be detected in urine for at least two weeks after discontinuation of its ingestion (Kapp et al., 2011). ...
Dietary supplements (DS) constitute a widely used group of products comprising vitamin, mineral, and botanical extract formulations. DS of botanical or herbal origins (HDS) comprise nearly 30% of all DS and are presented on the market either as single plant extracts or multi-extract-containing products. Despite generally safe toxicological profiles of most products currently present on the market, rising cases of liver injury caused by HDS – mostly by multi-ingredient and adulterated products – are of particular concern. Here we discuss the most prominent historical cases of HDS-induced hepatotoxicty – from Ephedra to Hydroxycut and OxyELITE Pro-NF, as well as products with suspected hepatotoxicity that are either currently on or are entering the market. We further provide discussion on overcoming the existing challenges with HDS-linked hepatotoxicity by introduction of advanced in silico, in vitro, in vivo, and microphysiological system approaches to address the matter of safety of those products before they reach the market.
... 4,13 Cases where the patient presented primarily with abdominal pain, jaundice, pruritus or discoloured urine, and with evidence of hepatotoxicity such as elevated liver enzymes, bilirubin or evidence of biliary tree changes on imaging were labelled as "hepatotoxic effect." 2,5 The DPIC also records opioid-related exposure calls. We accessed these calls using a cluster of 53 AAPCC codes encompassing (typically) prescription opioids, (typically) street opioids, analgesic-opioid combinations, antihistamines/ decongestants with opioids, and anti-addiction agents. ...
Background:
Kratom, a plant indigenous to Southeast Asia, which has been used both recreationally and in the treatment of pain and opioid dependence, has received little scrutiny in the United States and almost none in Canada. We analyzed calls to the British Columbia poison centre to describe caller-declared exposures to kratom and the acute health effects of these exposures.
Methods:
For this descriptive analysis, we accessed electronic records, including transcriptions and extracted variables, of calls specifying kratom exposure managed by the BC Drug and Poison Information Centre (DPIC) from 2012 to 2019. We describe changes in case numbers, reasons for exposure, concurrent drug exposures and clinical outcomes over the study period.
Results:
We identified 32 cases during the study period. In 23 cases (72%), the DPIC was consulted by a health care worker. Case numbers increased from 0 in 2012 to 9 in 2019. Numbers were highest for males in their 20s (n = 17, 53%). A total of 27 cases (84%) involved ingestion, with online distributors and local stores named as sources of procurement. A concurrent drug exposure was identified in 13 (41%) cases. There were no deaths; in 1 case, the exposed individual was intubated to manage agitation following kratom withdrawal.
Interpretation:
We observed a steady increase in kratom-related poison centre calls from 2012 to 2019, especially in young adult males. Rising call numbers may reflect increasing availability of kratom and may be a consequence of BC's opioid crisis, with kratom used by some to lessen symptoms of opioid withdrawal.
... Previously described clinical symptomatology and histology are mostly consistent with a cholestatic pattern in which canalicular cholestasis seems to be the most common histological finding. 11,12 Three of the 4 cases also described mixed portal inflammation; however, they identified mild bile duct injury, which was not seen in our case. [13][14][15] One case described an additional component of granulomatous inflammation of the bile ducts and lobular areas. ...
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.
... Its use is well established in Southeast Asia for its narcotic and stimulant-like effects (Jansen and Prast, 1988;Suwanlert, 1975;Hassan et al., 2013;Singh et al., 2019). The traditional use and potential abuse of M. speciosa preparations as well as its purified active compound, mitragynine, have been well-reported in Southeast Asia, Europe and the US (Boyer et al., 2008;Boyer et al., 2007;Kapp et al., 2011;McWhirter and Morris, 2010;Müller et al., 2020Müller et al., , 2021. A particular use was reported for various types of pain management (Grundmann, 2017;Garcia-Romeu et al., 2020;Vicknasingam et al., 2020). ...
Kratom, derived from the plant Mitragyna speciosa (M. speciosa) Korth is a traditional psychoactive preparation widely used in Southeast Asia and increasingly in the rest of the world. Use and abuse of Kratom preparations can be attributed to mitragynine (MIT), the main psychoactive compound isolated from its leaves. While MIT may have beneficial effects as a recreational drug, for pain management, and for opiate withdrawal, it may have an addiction potential at higher doses. However, its action in the reward system of the brain is currently unknown. This study investigated how mitragynine (10 mg/kg, i.p.) affects extracellular activity of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) of the brain, compared to morphine (MOR; 10 mg/kg, i.p.) and methamphetamine (METH; 10 mg/kg, i.p.). Using in-vivo microdialysis in freely moving rats, we found a significant increase of extracellular DA after MOR and METH, but not after MIT in all three brain regions. MIT led to a significant increase of DOPAC and/or HVA in these brain regions while MOR and METH had only moderate effects. These findings suggest a strong and prolonged effect of MIT on DA synthesis/metabolism, but not on extracellular DA activity, which may limit the addiction risk of MIT, in contrast to MOR and METH.
... Kratom and mitragynine are marketed for Western users either as a pure preparation (Cornara et al., 2013;Forrester, 2013;Coe et al., 2019) or as one herbal ingredient of "legal" or "herbal high" preparations, which are distributed in the form of powders, pills, and capsules under various names such as Krypton, K2, or Spice (Dresen et al., 2010;Arndt et al., 2011;Singh et al., 2014;Tavakoli et al., 2017). The emergence of reports on the serious adverse effects associated with kratom/mitragynine abuse has prompted a ban on kratom in several states in the United States (McWhirter and Morris, 2010;Nelsen et al., 2010;Holler et al., 2011;Kapp et al., 2011;Kronstrand et al., 2011;Forrester, 2013;Neerman et al., 2013;Trakulsrichai et al., 2013;Eggleston et al., 2019). Currently, the United States Drug and Enforcement Administration and Food and Drug Administration remain vigilant in considering to place kratom into Schedule I of the Controlled Substances Act (Henningfield et al., 2018). ...
Kratom is a widely abused plant-based drug preparation with a global interest in recent years, well beyond its native grounds in Southeast Asia. Mitragynine, its major psychoactive constituent is known to exhibit opioid-like behavioral effects with resultant neuroplasticity in the brain reward system. Its chronic administration is associated with cognitive impairments in animal studies. However, the underlying molecular mechanism for such a deficit remains elusive. In this study, the involvement of cannabinoid type-1 (CB 1 ) receptors in cognitive deficits after chronic mitragynine exposures was investigated for 28 days (with incremental dose sensitization from 1 to 25 mg/kg) in adult male Swiss albino mice using the IntelliCage ® system. Chronic high-dose mitragynine exposure (5–25 mg/kg, intraperitoneal [i.p.]), but not low-dose exposure (1–4 mg/kg, i.p.), induced hyperlocomotion, potentiated the preference for sucrose reward, increased resistance to punishment, and impaired place learning and its reversal. Comparable deficits were also observed after chronic treatments with Δ-9-tetrahydrocannabinol (THC, 2 mg/kg, i.p.) or morphine (5 mg/kg, subcutaneous). Mitragynine-, morphine-, and THC-induced learning and memory deficits were reversed by co-treatment with the CB 1 receptor antagonist, NIDA-41020 (10 mg/kg, i.p.). A significant upregulation of CB 1 receptor expression was found in the hippocampal CA1 region and ventral tegmental area after chronic high-dose mitragynine and morphine, whereas a downregulation was observed after chronic THC. In conclusion, the present study suggests a plausible role of the CB 1 receptor in mediating the dose-dependent cognitive deficits after chronic high-dose mitragynine exposure. This also highlights the potential of CB 1 receptor antagonism in ameliorating the cognitive deficits associated with long-term kratom/mitragynine consumption in humans.
... In this review, the mean age of kratom-induced HILI was 36 years, with a higher prevalence in men (62%). The onset of kratom induced HILI usually takes place within 1 wk to 8 wk after regular use of powder or tablets, ingested doses varied from 3 g to 15 g daily [81,82]. The cause of kratom induced HILI is unknown. ...
BACKGROUND
The use of herbal supplements and alternative medicines has been increasing in the last decades. Despite popular belief that the consumption of natural products is harmless, herbs might cause injury to various organs, particularly to the liver, which is responsible for their metabolism in the form of herb-induced liver injury (HILI).
AIM
To identify herbal products associated with HILI and describe the type of lesion associated with each product.
METHODS
Studies were retrieved using Medical Subject Headings Descriptors combined with Boolean operators. Searches were run on the electronic databases Scopus, Web of Science, MEDLINE, BIREME, LILACS, Cochrane Library for Systematic Reviews, SciELO, Embase, and Opengray.eu. Languages were restricted to English, Spanish, and Portuguese. There was no date of publication restrictions. The reference lists of the studies retrieved were searched manually. To access causality, the Maria and Victorino System of Causality Assessment in Drug Induced Liver Injury was used. Simple descriptive analysis were used to summarize the results.
RESULTS
The search strategy retrieved 5918 references. In the final analysis, 446 references were included, with a total of 936 cases reported. We found 79 types of herbs or herbal compounds related to HILI. He-Shou-Wu, Green tea extract, Herbalife, kava kava, Greater celandine, multiple herbs, germander, hydroxycut, skullcap, kratom, Gynura segetum, garcinia cambogia, ma huang, chaparral, senna, and aloe vera were the most common supplements with HILI reported. Most of these patients had complete clinical recovery (82.8%). However, liver transplantation was necessary for 6.6% of these cases. Also, chronic liver disease and death were observed in 1.5% and 10.4% of the cases, respectively.
CONCLUSION
HILI is normally associated with a good prognosis, once the implied product is withdrawn. Nevertheless, it is paramount to raise awareness in the medical and non-medical community of the risks of the indiscriminate use of herbal products.
Key Words: Herb-induced liver injury, Drug induced liver injury, Dietary supplements, Herbal hepatotoxicity, Liver transplantation
Core Tip: The use of herbal supplements has been increasing in the last decades. Despite popular belief that natural products are harmless, they might cause herb-induced liver injury (HILI). This study aimed to identify herbal products associated with HILI. The search strategy retrieved 5918 references. In the final analysis, 446 references were included, with a total of 936 cases reported. We found 79 types of herbs related to HILI. Most of these patients had complete clinical recovery (82.8%). However, liver transplantation was necessary for 6.6% of these cases. Also, chronic liver disease and death were observed in 1.5% and 10.4%, respectively.
Ballotin VR, Bigarella LG, Brandão ABM, Balbinot RA, Balbinot SS, Soldera J. Herb-induced liver injury: Systematic review and meta-analysis. World J Clin Cases 2021; 9(20): 5490-5513 [PMID: 34307603 PMCID: PMC8281430 DOI: 10.12998/wjcc.v9.i20.5490]
... Kratom use has been often linked to liver toxicity. Kratom has been associated with biliary cholangitis and cholestasis in several cases (67,(103)(104)(105)(106)(107)(108)(109)(110) and with one case of hepatomegaly (111), but also with acute hepatitis (112). Mitragynine inhibits hepatic and intestinal cytochrome P450 3A activities (113) and hepatic microsomal CYP2D6 (114), thus increasing blood levels of other concomitantly administered drugs that are metabolized by these isoenzymes, that is, most psychiatric drugs. ...
Kratom or Mitragyna speciosa (Korth.) is an evergreen tree of the coffee family native to South-East Asia and Australasia. It is used by locals recreationally to induce stimulant and sedative effects and medically to soothe pain and opiate withdrawal. Its leaves are smoked, chewed, or infused, or ground to yield powders or extracts for use as liquids. It contains more than 40 alkaloids; among these, mitragynine and 7-hydroxymitragynine are endowed with variable mu, delta, and kappa opioid stimulating properties (with 7-hydroxymitragynine having a more balanced affinity), rhynchophylline, which is a non-competitive NMDA glutamate receptor antagonist, but is present in negligible quantities, and raubasine, which inhibits α1-adrenceptors preferentially over α2-adrenceptors, while the latter are bound by 7-hydroxymitragynine, while mitragynine counters 5-HT2A receptors. This complexity of neurochemical mechanisms may account for kratom's sedative-analgesic and stimulant effects. It is commonly held that kratom at low doses is stimulant and at higher doses sedative, but no cut-off has been possible to define. Long-term use of kratom may produce physical and psychological effects that are very similar to its withdrawal syndrome, that is, anxiety, irritability, mood, eating, and sleep disorders, other than physical symptoms resembling opiate withdrawal. Kratom's regulatory status varies across countries; in Italy, both mitragynine and the entire tree and its parts are included among regulated substances. We describe the case of a patient who developed anxiety and dysphoric mood and insomnia while using kratom, with these symptoms persisting after withdrawal. He did not respond to a variety of antidepressant combinations and tramadol for various months, and responded after 1 month of clomipramine. Well-being persisted after discontinuing tramadol.
... It is unlikely that the lower serum total cholesterol and LDL levels were due to liver damage, which impairs biosynthesis of cholesterol, because the liver function test results of kratom users in our study were shown to be in the normal range. Although hepatotoxicity of kratom has been reported in a series of case reports in Western countries [33][34][35][36][37], it has not been reported in Southeast Asian nations such as Malaysia and Thailand [15,38]. This discrepancy may be a result of the co-ingestion of kratom with other substances, such as benzodiazepine, amphetamine, and ethanol, or kratom intake in those with underlying medical problems in the West. ...
Background and aim
Kratom, or Mitragyna speciosa Korth., is a tropical plant that has been reported to exhibit opioid-like effects. Although opioids have been demonstrated to alter the lipid profile of regular users, data on the lipid-altering effects of kratom are scarce. This study aimed to compare the fasting lipid profile of regular kratom users to that of healthy subjects who do not use kratom. It also determined the association between various characteristics of kratom users and the serum triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels of regular kratom users.
Methods
A total of 200 participants (n = 100 kratom users and n = 100 healthy subjects who do not use kratom) were recruited for this analytical cross-sectional study. Data on sociodemographic status, kratom use characteristics, cigarette smoking, physical activity, body mass index (BMI), fasting serum lipid profile, and liver function were collected from all participants.
Results
The liver parameters of the study participants were within normal range. The serum total cholesterol and LDL of kratom users were significantly lower than those of healthy subjects who do not use kratom. There were no significant differences in the serum triglyceride and HDL levels. However, higher average daily frequency of kratom use and increasing age were associated with increased serum total cholesterol among kratom users. Other kratom use characteristics such as age of first kratom intake, duration of kratom use, and quantity of daily kratom intake were not associated with increased serum triglyceride, total cholesterol, LDL, and HDL levels.
Conclusions
Our findings suggest regular kratom consumption was not linked to elevated serum lipids, except when there is a higher frequency of daily kratom intake. However, the study was limited by the small sample size, and hence a more comprehensive study with larger sample size is warranted to confirm the findings.
... Unfortunately, the actual cause of death remained unknown and non-conclusive. Kratom has been reported to cause serious adverse effects, such as elevated blood pressure, nephrotoxic effects, impaired cognition and behavior and hepatic failure 2,7,[14][15][16] . ...
Mitragyna speciosa Korth (M. speciosa) has been widely used as a recreational product, however, there are growing concerns on the abuse potentials and toxicity of the plant. Several poisoning and fatal cases involving kratom and mitragynine have been reported but the underlying causes remain unclear. The human ether-a-go-go-related gene 1 (hERG1) encodes the pore-forming subunit underlying cardiac rapidly delayed rectifier potassium current (IKr). Pharmacological blockade of the IKr can cause acquired long QT syndrome, leading to lethal cardiac arrhythmias. This study aims to elucidate the mechanisms of mitragynine-induced inhibition on hERG1a/1b current. Electrophysiology experiments were carried out using Port-a-Patch system. Quantitative RT-PCR, Western blot analysis, immunofluorescence and co-immunoprecipitation methods were used to determine the effects of mitragynine on hERG1a/1b expression and hERG1-cytosolic chaperones interaction. Mitragynine was found to inhibit the IKr current with an IC50 value of 332.70 nM. It causes a significant reduction of the fully-glycosylated (fg) hERG1a protein expression but upregulates both core-glycosylated (cg) expression and hERG1a-Hsp90 complexes, suggesting possible impaired hERG1a trafficking. In conclusion, mitragynine inhibits hERG1a/1b current through direct channel blockade at lower concentration, but at higher concentration, it upregulates the complexation of hERG1a-Hsp90 which may be inhibitory towards channel trafficking.
... Singh reported that approximately 23% of regular users reported high craving for mitragynine, while the other 77% admitted low craving [11]. Mitragynine has been noted to cause intrahepatic cholestasis, seizures, heart arrhythmia, calcium channel blockage, impaired motor function, coma, and death [1,[3][4][5]9,[13][14][15]. Kapp reported a case of mitragynine overdose where the individual took 2-6 teaspoons of ground mitragynine leaves for two weeks. ...
Mitragynine is the major psychoactive component in kratom (Mitragyna speciosa), a medicinal plant originating in southwest Asia, whose leaves have been used as an herbal drug for many years. This paper presents 20 death investigation cases from 2017 and 2018 in Orange County, California where mitragynine was detected, including the circumstances surrounding the deaths. Quantitative results by liquid chromatography dual mass spectrometry (LCMSMS) for central blood, peripheral blood, liver, gastric contents, brain, and vitreous humor are given, when analyzed. Postmortem central blood concentrations ranged from 10 to 4310 ng/mL, with a mean of 626 ng/mL and median of 123 ng/mL. Postmortem redistribution ratios were determined for the 13 cases in which both central blood and peripheral blood were evaluated (range 0.37–1.26 with one outlier removed). Although kratom is marketed as a safe alternative to more common illicit drugs, such as heroin or methamphetamine, these cases demonstrate that it can contribute to overdose deaths. For three of the 20 cases, the pathologist listed mitragynine as the sole drug in the cause of death. However, in no cases was mitragynine the only drug detected, suggesting that routine screening for mitragynine would be beneficial for evaluating overdoses due to drug combinations.
... Reported adverse effects, following high doses and/or the use of concentrated extracts, include tachycardia (Lu et al., 2014), intrahepatic cholestasis (Griffiths et al., 2018;Kapp et al., 2011;Riverso et al., 2018), hepatitis (including cholestatic) and liver toxicity (Dorman et al., 2015;Drago et al., 2017;Forrester, 2013;Kupferschmidt, 2011), seizure and coma (Nelsen et al., 2010;Pantano et al., 2016;Roche et al., 2008), Adult Respiratory Distress Syndrome (Jaliawala et al., 2018;Pathak et al., 2014), and hypothyroidism (Sheleg and Collins, 2011). Repeated kratom use can lead to generalised tonic-clonic seizures and possible structural brain lesions and symptomatic focal epilepsy (Tatum et al., 2018). ...
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.
... Kratom use has also been reported to be associated with adverse health effects including intrahepatic cholestasis, gastrointestinal related discomfort (e.g. nausea, constipation, drowsiness), and poisoning or deaths (Kapp et al., 2011;Kronstrand et al., 2011;Anwar et al., 2016;Grundmann, 2017). Virtually all reports published to date concerning immediate or long-term effects of human kratom consumption are based on self-reported subjective experiences. ...
Kratom leaves from Mitragyna speciosa (Korth.) trees are believed to have medicinal value, and have a long-history of folk medicine use for self-treatment of a broad range of indications. In Southeast Asia, traditional uses of kratom include as an aphrodisiac and a sexual performance enhancer. The study evaluated sexual functioning in a cohort of long-term male kratom users in the state of Penang, Malaysia. A field face-to-face survey, including the Malay version of the Brief Male Sexual Function Inventory (BMSFI) called Mal-BMSFI was conducted between January and December of 2017. The mean (SD) age of the cohort (N = 92) was 37.0 (11.2) years, and the mean (SD) duration of kratom use was 9.14 (5.5) years. All participants reported consuming kratom decoction, with an average amount of 1200 ml daily. Seventy-two participants (78%) reported using kratom to enhance sexual performance, and 71 of them (71/72, 99%) reported experiencing improved sexual performance. Of those who reported not using kratom to enhance sexual performance, 7/20 (35%) also experienced improved sexual performance after kratom use. The reported enhancements of sexual performance included: more energy during sex (75/92), delayed ejaculation (71/92), help to maintain erection (70/92), longer climax (51/92), increased sexual desire (44/92), and reduced sex organ sensitivity (43/92). The mean (SD) Mal-BMSFI score was 33.9 (7.1) and 78/92 (85%) reported overall high satisfaction with their sex life in the past 30 days. In conclusion long-term daily, male users of kratom decoction in Malaysia reported improved sexual functioning attributed to their kratom consumption.
... Kratom-drug interactions are further indicated in several case reports resulting in hepatotoxicity or death. [41][42][43][44][45] A 70-year-old man with a history of hypertension and osteoarthritis, treated with amlodipine and oxycodone, presented with jaundice. 42 The patient admitted to consuming Kratom twice daily for 4 days approximately 2-3 weeks before his initial presentation at a medical center for jaundice. ...
The leaves from the tree Mitragyna speciosa, commonly known as Kratom, in the coffee plant family (Rubiaceae) are commonly used in their native habitat of Southeast Asia as a stimulant to sustain energy during hard day labor and as an opioid-like analgesic and sedative. Traditional and modern uses overlap based on the effects of the leaf extract which has also gained popularity in the United States and Europe in the last two decades. Kratom has and is being used for the mitigation of opioid withdrawal symptoms and as a harm reduction agent with a minority of users subsequently developing a dependence on the extract. The respective demographic use patterns of Kratom differ between Southeast Asia and the Western world. While pure Kratom is primarily used by day laborers and misused in conjunction with cough medicine by youth in Southeast Asia, a majority of users in the United States is middle-aged, has at least middle income, private health insurance, and completed some college. Deaths attributed to the use of Kratom have been reported in Europe and the United States but not in Southeast Asia. Although Kratom was detected as the alkaloid mitragynine in the blood of the decedents, causality could not be established in almost all cases because of poly-drug exposures. It is notable that Kratom can cause herb-drug interactions, especially with other central nervous system -active substances. Given the mostly unregulated market for Kratom products in Western countries, consumers may be exposed to adulterated or contaminated products, especially if purchased through websites or the darknet. A number of countries have scheduled Kratom because of its stimulant- and opioid-like effects and the established interaction of the alkaloid mitragynine with opioid receptors.
... More troubling have been occasional reports of more serious toxicities, often associated with high dose usage or usage of concentrated extracts in the West. Some of the reported adverse effects include tachycardia, liver damage, and seizures (Dorman, Wong, & Khan, 2015;Kapp, Maurer, Auwarter, Winkelmann, & Hermanns-Clausen, 2011;Lu et al., 2014;Nelsen, Lapoint, Hodgman, & Aldous, 2010;Pantano et al., 2016). In addition, several deaths have been attributed to the use of "kratom" products (Anwar et al., 2016;DEA, 2016b;FDA, 2018c;Gershman et al., 2019;Karinen, Fosen, Rogde, & Vindenes, 2014;McIntyre, Trochta, Stolberg, & Campman, 2015;Neerman, Frost, & Deking, 2013;Warner et al., 2016;Wing, 2018), although in many such cases causality was not clearly linked given that little is known about lethal dose levels of kratom in humans (Gershman et al., 2019;Wing, 2018). ...
Kratom (Mitragyna speciosa) is a tree-like plant indigenous to Southeast Asia. Its leaves, and the teas brewed from them have long been used by people in that region to stave off fatigue and to manage pain and opioid withdrawal. Evidence suggests kratom is being increasingly used by people in the United States and Europe for the self-management of opioid withdrawal and treatment of pain. Recent studies have confirmed that kratom and its chemical constituents have potentially useful pharmacological actions. However, there have also been increasing numbers of reports of adverse effects resulting from use of kratom products. In August 2016, the US Drug Enforcement Administration announced plans to classify kratom and its mitragynine constituents as Schedule I Controlled Substances, a move that triggered a massive response from pro-kratom advocates. The debate regarding the risks, and benefits and safety of kratom continues to intensify. Kratom proponents tout kratom as a safer and less addictive alternative to opioids for the management of pain and opioid addiction. The anti-kratom faction argues that kratom, itself, is a dangerous and addictive drug that ought to be banned. Given the widespread use of kratom and the extensive media attention it is receiving, it is important for physicians, scientists and policy makers to be knowledgeable about the subject. The purpose of this commentary is to update readers about recent developments and controversies in this rapidly evolving area. All of the authors are engaged in various aspects of kratom research and it is our intention to provide a fair and balanced overview that can form the basis for informed decisions on kratom policy. Our conclusions from these analyses are: (a) User reports and results of preclinical studies in animals strongly suggest that kratom and its main constituent alkaloid, mi-tragynine may have useful activity in alleviating pain and managing symptoms of opioid withdrawal, even though well-controlled clinical trials have yet to be done. (b) Even though kratom lacks many of the toxicities of classic opioids, there are legitimate concerns about the safety and lack of quality control of purported "kratom" products that are being sold in the US. (c) The issues regarding the safety and efficacy of kratom and its mi-tragynine constituent can only be resolved by additional research. Classification of the Mitragyna alkaloids as Schedule I controlled substances would substantially impede this important research on kratom.
Introduction
Opioid use disorder (OUD) is characterized by compulsive opioid seeking and taking, intense drug craving, and intake of opioids despite negative consequences. The prevalence of OUDs has now reached an all-time high, in parallel with peak rates of fatal opioid-related overdoses, where 15 million individuals worldwide meet the criteria for OUD. Further, in 2020, 120,000 opioid-related deaths were reported worldwide with over 75,000 of those deaths occurring within the United States.
Areas covered
In this review, we highlight pharmacotherapies utilized in patients with OUDs, including opioid replacement therapies, and opioid antagonists utilized for opioid overdoses and deterrent of opioid use. We also highlight newer treatments, such as those targeting the neuroimmune system, which are potential new directions for research given the recently established role of opioids in activating neuroinflammatory pathways, as well as over the counter remedies, including kratom, that may mitigate withdrawal.
Expert opinion
To effectively treat OUDs, a deeper understanding of the current therapeutics being utilized, their additive effects, and the added involvement of the neuroimmune system are essential. Additionally, a complete understanding of opioid-induced neuronal alterations and therapeutics that target these abnormalities – including the neuroimmune system – is required to develop effective treatments for OUDs.
p>Kratom ( Mitragyna speciosa (Korth.) Havil.) is a plant that originated from the rainforest in Southeast Asia, mainly grows in Thailand, Malaysia, and Indonesia. Kratom has been used traditionally as an herbal remedy for the treatment of various illnesses. Kratom gained notoriety due to its potential as an analgesic, opiate withdrawal treatment, anxiolytic, antidepressant, and antidiabetic with an unclear risk of addiction and toxicity fueled by a false sense of security due to its identity as a member of the coffee family. This article is a narrative review on kratom to highlight its pharmacological and toxicological properties, and the analytical method of Kratom, especially its potential as an opioid withdrawal therapy and its risk of abuse.</p
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.
Incluye las nuevas drogas de abuso que invaded el mundo en el año 2008, más adictivas, mortales, que circulan con fachada legal pot nuevos canales de venta y distribution favorecido por su center for internet en tiendas físico, que satisfaction el gusto de los usuario cada vez mas jóvenes y que en general incluyen las drogas consumidas en la actualidad.
Kratom, a tropical plant and dietary supplement with dose-dependent effects, has physiologic effects similar to opioids as well as stimulant effects. Kratom, like all dietary supplements, is not regulated in the United States and its effects have raised potential and safety concerns. This article describes a patient who presented to the ED with jaundice and acute liver injury, which after a thorough exclusion of alternative causes was attributed to kratom use.
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.
This chapter describes the pharmacology, clinical effects and toxicology of naturally occurring tryptamines (including dimethyltryptamine and mitragynine), and synthetic tryptamines (unsubstituted, 4-substituted and 5-substituted). A description of the diverse pharmacokinetic properties of tryptamines is followed by a review of receptor interactions, particularly serotonin receptor agonism responsible for hallucinogenic psychoactive effects. User reports detailing desired effects of tryptamines are reviewed. The chapter describes prevalence data demonstrating increasing use of synthetic tryptamines in the developed world, and the use of naturally occurring tryptamines including mitragynine outside of traditional settings. Animal and human experimental data demonstrating tryptamine toxicity is reviewed, followed by a summary of user reports describing unwanted effects. The chapter concludes by reviewing deaths associated with tryptamine exposure including deaths associated with the increasing use of mitragynine.
In recent years, there has been an emergence of numerous novel drugs. Such toxicity may occur in both adolescents and adults. This article discusses the opioid epidemic and several emerging opioids, including buprenorphine, loperamide, fentanyl, fentanyl derivatives, and others. Kratom, a plant occasionally used for opiate detoxification, along with the sedatives etizolam and phenibut, will be discussed. Lastly, this article discusses the phenethylamines and marijuana.
Mitragyna speciosa, a tropical tree also known as kratom, is an emerging substance of abuse with dose-dependent stimulant and opioid-like effects. Kratom may be purchased legally in the United States and is marketed online as a safe alternative to opioids and a cheap alternative to opioid replacement therapy. However, adverse reactions to ingestion are largely unknown and may pose a significant public health risk. This article describes a man with an intracerebral hemorrhage possibly secondary to kratom ingestion.
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.
BACKGROUND: Kratom is a psychoactive substance that is isolated from the plant Mitragyna speciosa. The leaves can be chewed fresh or dried, smoked, or infused similar to herbal teas. The plant leaves have been used by natives of Southeast Asia for centuries. The substance has been used for its stimulant activity at low doses, and as an opium substitute at higher doses due to a morphine like effect.
CASE SUMMARY: A 37-year-old female with a history of depression and obesity (body mass index: 32) presented to emergency room with a week-long history of nausea, decreased appetite, fatigue, and two days of jaundice. On admission bilirubin was markedly elevated. Her condition was thought to be due to consumption of Kratom 2 wk before onset of symptoms. Liver biopsy showed changes mimicking primary biliary cholangitis. Patient’s symptoms and jaundice improved quickly.
CONCLUSION: The use of Kratom has been on the rise in recent years across the United States and Europe. Several case reports have associated adverse health impact of Kratom-containing products including death due to its ability to alter levels of consciousness. Only a few case reports have highlighted the hepatotoxic effects of Kratom. Even fewer reports exist describing the detailed histopathological changes.
Kratom, or Mitragyna speciosa Korth., is a tropical plant prevalent in Southeast Asia, and it is utilized as a traditional remedy for symptomatic relief of various illnesses. It has been labeled as an atypical opioid with significant narcoticlike properties, capable of inducing kratom dependence among those who misuse or abuse it. The prevalence of kratom use has drastically increased worldwide, raising concerns among healthcare providers, particularly regarding the availability of efficacious treatment options for kratom dependence. This manuscript provides a comprehensive narrative review of literature focusing on the psychoactive alkaloids of kratom, the possible neurobiological and pathophysiological models underlying the occurrence of kratom dependence, and the clinical presentations and effective treatment options available for kratom dependence. The psychoactive alkaloids of kratom, such as mitragynine (MG) and 7-hydroxymitragynine (7-HMG), act as partial mu opioid agonists and induce kratom dependence. As a result, regular kratom use leads to withdrawal symptoms on abstinence, along with craving, tolerance, and cross-tolerance to morphine. The psychological withdrawal symptoms reported include depressed mood, anxiety, restlessness, irritability, and feeling tense, while the physical withdrawal symptoms are myalgia and body ache, joint pain, lacrimation, running nose, yawning, insomnia, diarrhea, feverish sensation, loss of appetite, tremors, itching over the body, loss of concentration, and chills. Neonatal withdrawal symptoms, such as oral intolerance, restlessness, irritability, and vomiting, are also reported in newborns of women who are on regular kratom use. Sublingual buprenorphine-naloxone (Suboxone) is reported as a promising treatment for detoxification and maintenance replacement therapy for kratom-dependent users. Alternative treatments for in-patient detoxification include intravenous clonidine and a combination of oral dihydrocodeine and lofexidine. We conclude by adding a note on the research gap concerning kratom dependence, which future studies should focus on.
A case of a patient with a history of depression, who was concomitantly using Kratom has been described. Kratom (Mitragyna speciosa) is a psychoactive plant indigenous to certain regions of southeast Asia where it has been traditionally used for its stimulatory and analgesic effects. The active compounds in Kratom are mitragynine and 7-hydroxymitragynine. Kratom’s use for self-management of chronic pain and as supportive therapy for managing opioid withdrawal is increasing. This case highlights the observation that Kratom use is also prevalent amongst patients with other mental health and/or substance abuse conditions. The discussion explores the current understanding on pharmacology and toxicology of mitragynine and 7-hydroxymitragynine, and analytical methods used for kratom analysis in a toxicology laboratory.
Mitragyna speciosa (Kratom) is a psychotropic tropical tree that is indigenous to Southeast Asia, Africa and New Guinea. Kratom has gained popularity in the United States in more recent years as an opioid agonist. Although Kratom is considered an opioid agonist with abuse potential, its use is not federally regulated. We report on a 47 year-old male presenting to our clinic for treatment of an opioid use disorder. This began with the use of prescription opioids from a doctor, and when this was no longer available this patient started using Kratom. He had used Kratom for one year to treat opioid withdrawal symptoms and chronic pain, resulting in worsening depression, anxiety and pain. He experienced tolerance and withdrawal symptoms related to Kratom. He was initiated on buprenorphine-naloxone at home with improved pain management. Four months after initiation, the patient’s depression and anxiety symptoms resolved, and he was able to discontinue his antidepressant and anxiolytic medications. Kratom dependence and withdrawal appear similar to that of opioids, and may also lead to worsening depression and anxiety. Buprenorphine-naloxone may be a viable option to consider for treating opioid use disorder complicated by Kratom use, chronic pain, and depression.
Biak-biak(Mitragyna speciosa) is a medicinal plant including the family Rubiaceae. Empirically the people of BangunUlu City, Kota Bangun District, Kutai Kartanegara Regency, East Kalimantan, use the leaves of Biak-biak as herbal medicines. Biak-biak can be used to treat wounds, fevers, diarrhea, muscle aches, coughs, to increase endurance, to reduce high pressure, to increase energy, to overcome depression, antidiabetic and sexual stimulants. Reproduction plants contain flavonoid chemical compounds as the biggest phenolic group. This study aimed to determine the total phenolic and flavonoid levels as well as the antioxidant activity of the ethanol extract of the Biak-biak leaves. Determination of total phenolic levels used the folin-ciocalteau method while the determination of total flavonoids used the AlCl3 method. Determination of total phenolic and flavonoid levels used UV-visible spectrophotometer. The antioxidant activity test used the ABTS method [2,2-azinobis-(3-ethylbenzothiazolin)-6-sulfonicacid] by finding the IC50 value. The results obtained in total phenolic levels of ethanol extract of the Biak-biak leaves at 10.3696±0.2432 mg GAE/g show that every gram of ethanol extract of the leaves of the Biak-biak is equivalent to 10,3696 mg gallic acid. Determination of flavonoid levels measured at 440 nm wavelength is 3.951±0.033%. The ethanol extract of the leaves is categorized as very strong antioxidant because it has an IC 50 value of less than 50 ppm.
Mitragyna speciosa (kratom) is a drug that is increasingly used recreationally and "therapeutically", in the absence of medical supervision. The drug has been associated with a growing number of fatalities, and although its medicinal properties as an atypical opioid require further study, there are legitimate concerns regarding its unregulated use. Mitragynine is the most widely reported alkaloid within the plant, although more than forty other alkaloids have been identified. 7-Hydroxymitragynine is reported to have greater abuse liability due to its increased potency relative to mitragynine. In this report, biomarkers for mitragynine were investigated using liquid chromatography-quadrupole/time of flight mass spectrometry (LC-Q/TOF-MS). Speciociliatine and speciogynine were identified as alternative biomarkers, often exceeding the concentration of mitragynine in unhydrolyzed urine. 9-O-Demethylmitragynine and 7-hydroxymitragynine were identified in unhydrolyzed urine in 75% and 63% of the cases. Deconjugation of phase II metabolites using chemical hydrolysis was not suitable due to degradation of the Mitragyna alkaloids. Enzymatic hydrolysis was evaluated using three traditional glucuronidases, four sulfatases and four recombinant enzymes. Although enzymatic hydrolysis increased the concentration of 16-carboxymitragynine, it had nominal benefit for other metabolites. Deconjugation of urine was not necessary due to the abundance of parent drug (mitragynine), its diastereoisomers (speciociliatine and speciogynine) or metabolites (9-O-demethylmitragynine and 7-hydroxymitragynine).
Mitragyna speciosa (MS), a plant commonly known as kratom, is a widely used “legal high” opiate alternative for pain relief. DNA extracted from MS and 26 additional plant species was amplified by PCR using primers targeting the strictosidine beta‐D‐glucosidase (SGD) and secologanin synthase 2 (SLS2) genes and detected by high‐resolution melt curves using three intercalating dyes. Amplicon sizes were confirmed using agarose gel electrophoresis. The observed melt temperatures for SGD and SLS2 were 77.08 ± 0.38°C and 77.61 ± 0.46°C, respectively, using SYBR® Green I; 80.18 ± 0.27°C and 80.59 ± 0.08°C, respectively, using Radiant™ Green; and 82.19 ± 0.04°C and 82.62 ± 0.13°C, respectively, using the LCGreen® PLUS dye. The SLS2 primers demonstrated higher specificity and identified MS DNA at 0.05 ng/μL. In a duplex reaction, SLS2 and tetrahydrocannabinoic acid synthase gene primers detected and differentiated MS and Cannabis sativa (CS) by melt peaks at 82.63 ± 0.35°C and 85.58 ± 0.23°C, respectively, using LCGreen® PLUS.
Kratom is a psychoactive herb that has stimulant properties at low doses and has opioid-like properties at higher doses. It has been used for centuries in southeast Asia as a stimulant but has gained increasing popularity as a substitute for opioids in western countries as it is easily available. As most cases of kratom use involve other drugs too, the Food and Drug Administration (FDA) has stopped short of restricting kratom due to difficulty in assessing the adverse effects of kratom alone. We present the case of a young healthy 35-year-old man who suffered a cardiac arrest due to kratom use with no other coingestants. He was subsequently intubated and found to have systolic dysfunction and small brain infarcts. Fortunately, he made a successful recovery and was discharged after a stay at thebehavioural health centre. Our case highlights the potential adverse effects of kratom and the need to regulate its use.
Reports of toxicity secondary to Kratom are rare and lack of diagnostic testing in human specimens has prevented confirmatory explanation of observed clinical effects. We present a novel case of serious human toxicity following Kratom use confirmed via quantitative analysis of urine by high performance liquid chromatography coupled to electrospray tandem mass spectrometry. A 64 year-old male was witnessed to have a seizure at home following kratom consumption. Upon arrival to the emergency department (ED), the patient was unresponsive. While in the ED, the patient sustained a second seizure. He was intubated to protect his airway. The remainder of his hospital course was uneventful. A urine specimen was collected shortly after admission and sent for analysis. The mitragynine concentration in the urine was 167 ± 15 ng/ml. We report a rare case of Kratom toxicity characterized by a seizure and coma confirmed by urinary analysis of mitragynine by high performance liquid chromatography coupled to electrospray tandem mass spectrometry. The proposed mechanism for this reaction is unclear but suggested mechanisms include adenosine binding or stimulation of adrenergic and/or serotonergic receptors similar to tramadol.
In the present study, we investigate the effects of three different Mitragyna speciosa extracts, namely methanolic, aqueous and total alkaloid extracts, on glutathione transferase-specific activity in male Sprague Dawley rat liver cytosol in vitro and in vivo. In the in vitro study, the effect of Mitragyna speciosa extracts (0.01 to 750 microg/mL) against the specific activity of glutathione transferases was examined in rat liver cytosolic fraction from untreated rats. Our data show concentration dependent inhibition of cytosolic GSTs when Mitragyna speciosa extract was added into the reaction mixture. At the highest concentration used, the methanolic extract showed the highest GSTs specific activity inhibition (61%), followed by aqueous (50%) and total alkaloid extract (43%), respectively. In in vivo study, three different dosages; 50, 100 and 200 mg/kg for methanolic and aqueous extracts and 5, 10 and 20 mg/kg for total alkaloid extract were given orally for 14 days. An increase in GST specific activity was generally observed. However, only Mitragyna speciosa aqueous extract with a dosage of 100 mg/kg showed significant results: 129% compared to control.
Mitragyna speciosa (Rubiaceae) has traditionally been used in the tropical regions of Asia, Africa and Indonesia as a substitute for opium. Indole alkaloids are the most common compounds that have been isolated. We investigated the constituents of the leaves of M. speciosa that was grown at the University of Mississippi. Several alkaloids were isolated, including ajmalicine, corynantheidine, isomitraphylline, mitraphylline, paynantheine, isocorynantheidine, 7-hydroxymitragynine and mitragynine, but their percentages were lower than those in a commercial Thai sample of "kratom". In addition, we isolated the flavonoid epicatechin, a saponin daucosterol, the triterpenoid saponins quinovic acid 3-O-beta-D-quinovopyranoside, quinovic acid 3-O-beta-D-glucopyranoside, as well as several glycoside derivatives including 1-O-feruloyl-beta-D-glucopyranoside, benzyl-beta-D-glucopyranoside, 3-oxo-alpha-ionyl-O-beta-D-glucopyranoside, roseoside, vogeloside, and epivogeloside. This is the first report of the last group of compounds having been isolated from a Mitragyna species. Biological studies are currently underway to test these compounds for opioid activity.
The leaves of Mitragyna speciosa Korth. (M. speciosa) were extracted with methanol to give methanol extract. The methanol extract was made in acid and then in alkaline and extracted with chloroform to give alkaloid extract. The effects of the methanol and alkaloid extracts on analgesic activities in hot plate test in mice and tail flick test in rats and behavioral activities in locomotor activity and pentobarbital-induced sleep in mice, were examined. In acute toxicity test, the LD50 values of oral administration of the methanol and alkaloid extracts of M. speciosa leaves in mice were 4.90 g/kg and 173.20 mg/kg, respectively. Oral administration (50, 100 and 200 mg/kg) of the methanol extract of M. speciosa leaves significantly prolonged the latency of nociceptive response on hot plate test in mice. The alkaloid extract of M. speciosa also increased the pain response latency at the dose of 20 mg/kg but less potent than those of the methanol extract (100 mg/kg) in mice (comparing 5-10 mg/kg alkaloid extract with corresponding to approximately 200 mg/kg of methanol extract). The antinociceptive action of either methanol extract (100 mg/kg, p.o.) or alkaloid extract (20 mg/kg, p.o.) of M. speciosa leaves was blocked by naloxone (2 mg/kg, i.p.) in mice. Neither the methanol extract nor the alkaloid extract significantly prolonged latency of nociceptive response on tail flick test in rats. Both of the extracts had no significant change on spontaneous motor activity or pentobarbital-induced sleep in mice, respectively. These results suggest that the methanol and alkaloid extracts of M. speciosa leaves possess the analgesic activity which partly acted at opioid receptors in the supraspinal opioid system.
Effect of mitragynine, an indole alkaloid isolated from Thai medicinal plant kratom (Mitragyna speciosa), on electrically stimulated contraction was studied in the guinea-pig ileum. Mitragynine (1 nM-3 microM) inhibited the ileum contraction elicited by electrical stimulation, and its pD2 value was 6.91 +/- 0.04 (n = 5). Morphine (1 nM-1 microM) also inhibited the electrically stimulated contraction in a concentration-dependent manner (pD2 7.68 +/- 0.11; n = 5). Mitragynine was 10 fold less potent than morphine. Mitragynine (3-10 microM) did not show any effect on the smooth muscle contraction induced by acetylcholine or histamine. Naloxone (10-300 nM) reversed the inhibitory effect of mitragynine on electrically stimulated contraction. Furthermore, naloxone showed a shift of concentration-response curve of mitragynine to the right. There was no significant difference in the affinity of naloxone (i.e. pA2) in the presence of mitragynine or morphine. Mitragynine (3-10 microM) inhibited the naloxone-precipitated withdrawal contraction following a brief (5 min) exposure of the ileum to morphine. Tetrodotoxin (1 microM) and atropine (1 microM) inhibited the withdrawal contraction. The present results suggest that mitragynine inhibits the electrically stimulated contraction of guinea-pig ileum through the opioid receptor.
This study used for the first time LC–MS/MS for the analysis of mitragynine (MIT), a mu-opioid agonist with antinociceptive and antitussive properties, in rat plasma. Mitragynine and the internal standard (amitriptyline)were extracted from plasma with hexane:isoamylalcohol and resolved on a Lichrospher®
RPSelectB column (9.80 and 12.90 min, respectively). The quantification limit was 0.2 ng/mL within a
linear range of 0.2–1000 ng/mL. The method was applied to quantify mitragynine in plasma samples of
rats (n = 8 per sampling time) treated with a single oral dose of 20mg/kg. The following pharmacokinetic
parameters were obtained (mean): maximum plasma concentration: 424 ng/mL; time to reach maximum
plasma concentration: 1.26 h; elimination halflife: 3.85 h, apparent total clearance: 6.35 L/h/kg, and apparent volume of distribution: 37.90 L/kg.
We present a case of massive overdose with the atypical antipsychotic quetiapine in a 34-year-old woman (body weight 65 kg). At admission, approximately 2 to 4 hours after ingestion of approximately 24 g of quetiapine, the patient was comatose (Glasgow Coma Scale score 5), requiring orotracheal intubation and transfer to the intensive care unit. Because of myoclonic jerks and generalized seizures, benzodiazepines were administered. In addition to transient mild hypotension after intubation, the main cardiovascular manifestation was sinus tachycardia. The QT interval was normal, and the QTc interval (Bazett's correction) was maximally prolonged to 620 ms. However, no malignant arrhythmias were observed. The patient recovered within 2 days but remained agitated and aggressive, for which she was transferred to the psychiatric clinic. The pharmacokinetics of quetiapine in such a large overdose could not be described by simple first-order kinetics. The initially observed rapid decline of the plasma concentrations of quetiapine could be simulated by first-order kinetics (half life = 4.1 hr) and can most probably be explained by rapid distribution into tissues. The final elimination of the drug from the body occurred after approximately 34 hours at much slower rate, most probably reflecting redistribution from tissues into blood and consecutive hepatic clearance of the drug.
There is discussion concerning the cardiac safety of citalopram in an overdose. The aim of this study was to investigate the toxic effects and toxicokinetic parameters of citalopram in an overdose as a single drug and in combination with other drugs. Cases observed between 1997 and 2006 were evaluated. Patient demographics, ingested doses, serum concentrations of citalopram, coingested drugs, and clinical parameters were acquired. Outcomes were observed symptoms of the gastrointestinal tract, respiratory tract, central nervous system, and cardiovascular system. Poisoning Severity Score was used to evaluate severity of every intoxicated patient. Individual toxicokinetic parameter values were calculated. Twenty-nine cases of citalopram overdose were observed; three cases had incomplete data so that 26 cases were evaluable. The ingested amount ranged from 200 to 4960 mg. Blood concentrations ranged from 0.21 to 7.5 mg/L with 20 minutes to 8 hours between suggested time of ingestion and blood sampling. Most frequently reported symptoms were drowsiness (seven cases), tachycardia (15 cases), QTc prolongation (eight cases), decrease of consciousness (eight cases), and seizures (four cases). Median length of hospital stay was 3 days (range, 1-8 days). Of the 26 evaluated cases, two fatalities occurred, one because of a cardiac arrest and one as a result of a respiratory arrest. According to Poisoning Severity Score, severity of intoxication was minor in three patients (11%), moderate in nine patients (35%), and severe in 14 patients (54%). Severity was mainly caused by neurologic and respiratory effects. Elimination half-life was prolonged but did not correlate with the amount of ingestion. Citalopram intoxications seem to proceed more severely than is known for other selective serotonin reuptake inhibitor intoxications, causing drowsiness, coma, and seizures in overdose. Cardiac toxicity is generally mild. Therefore, we recommend seizure precautions and intensive care unit admission with cardiac monitoring for citalopram-intoxicated patients. Because elimination half-life is prolonged, normal pharmacokinetics do not apply.
The effects of pure alkaloid, mitragynine and a methanolic extract of kratom leaves were investigated on neuromuscular junction and compound nerve action potential.
Wistar rats were killed by cervical dislocation and decapitated. The phrenic nerve-hemidiaphragms, hemidiaphragms and sciatic nerve were isolated.
Kratom methanolic extract present at 0.1-1 mg/mL and mitragynine (0.0156 mg/mL) decreased the muscle twitch on the isolated phrenic nerve-hemidiaphragm and hemidiaphragm preparation. Muscle relaxation caused by kratom extract (1 mg/mL) was greater than the effect of mitragynine. Pancuronium and succinylcholine potentiated the effect of kratom extract. It also had a direct relaxation effect on the hemidiaphragm muscle. The muscle relaxation caused by kratom extract was not antagonized by neostigmine, tetraethylammonium and calcium chloride. High concentrations of kratom extract (10-40 mg/mL) and mitragynine (2 mg/mL) blocked the nerve conduction, amplitude and duration of compound nerve action potential.
The mechanism of action of kratom extract might not act as a competitive antagonist of acetylcholine yet its dominant effect was at the neuromuscular junction and not at the skeletal muscle or somatic nerve.
The Thai medicinal plant Mitragyna speciosa (Kratom in Thai) is misused as a herbal drug of abuse. During studies on the main Kratom alkaloid mitragynine (MG) in rats and humans, several dehydro analogs could be detected in urine of Kratom users, which were not found in rat urine after administration of pure MG. Questions arose as to whether these compounds are formed from MG only by humans or whether they are metabolites formed from the second abundant Kratom alkaloid paynantheine (PAY), the dehydro analog of MG. Therefore, the aim of the presented study was to identify the phase I and II metabolites of PAY in rat urine after administration of the pure alkaloid. This was first isolated from Kratom leaves. Liquid chromatography–linear ion trap mass spectrometry provided detailed structure information of the metabolites in the MSn mode particularly with high resolution. Besides PAY, the following phase I metabolites could be identified: 9-O-demethyl PAY, 16-carboxy PAY, 9-O-demethyl-16-carboxy PAY, 17-O-demethyl PAY, 17-O-demethyl-16,17-dihydro PAY, 9,17-O-bisdemethyl PAY, 9,17-O-bisdemethyl-16,17-dihydro PAY, 17-carboxy-16,17-dihydro PAY, and 9-O-demethyl-17-carboxy-16,17-dihydro PAY. These metabolites indicated that PAY was metabolized via the same pathways as MG. Several metabolites were excreted as glucuronides or sulfates. The metabolism studies in rats showed that PAY and its metabolites corresponded to the MG-related dehydro compounds detected in urine of the Kratom users. In conclusion, PAY and its metabolites may be further markers for a Kratom abuse in addition of MG and its metabolites.
Figure
Isolation of paynantheine from kratom leaves; high-resolution mass spectrum of the glucuronide of its 9-O-demethyl metabolite, and paynantheine structure with marked sides of biotransformation.
Mitragynine (MG) is an indole alkaloid of the Thai medicinal plant Mitragyna speciosa (Kratom in Thai) and reported to have opioid agonistic properties. Because of its stimulant and euphoric effects, Kratom is used as a herbal drug of abuse. The aim of the presented study is to identify the phase I and II metabolites of MG in rat and human urine after solid-phase extraction (SPE) using liquid chromatography-linear ion trap mass spectrometry providing detailed structure information in the MSn mode particularly with high resolution. The seven identified phase I metabolites indicated that MG was metabolized by hydrolysis of the methylester in position 16, O-demethylation of the 9-methoxy group and of the 17-methoxy group, followed, via the intermediate aldehydes, by oxidation to carboxylic acids or reduction to alcohols and combinations of some steps. In rats, four metabolites were additionally conjugated to glucuronides and one to sulfate, but in humans, three metabolites to glucuronides and three to sulfates.
Kratom is indigenous to Thailand. Market gardeners, peasants and labourers often become addicted to kratom leaf use. In certain respects, kratom addiction resembles addiction to a drug with narcotic properties, except that long term kratom addicts develop a dark skin, particularly on the cheeks. The age of onset is apparently later than in heroin addiction, and females are rare amongst those who use the substance. There were 5 cases of kratom addiction revealing psychotic symptoms; these had been seen by the author in the last yr (1974) in the outpatient department. Initially, 3 cases were suspected of having kratom psychosis of the basis of their history of addiction and their general appearance and on psychiatric examination. The measure chosen by lar to control kratom addiction by banning the cultivation of the tree has not been found to be effective, since it is a local law It is hoped that drug education for the rural youth in areas where kratom can be grown will be a more effective step towards its control.
Mitragynine is a major alkaloidal constituent of young leaves of Mitragyna speciosa Korth, that is known to exhibit narcotic-like activity. In this study, we investigated the roles of central monoaminergic systems in the antinociceptive action of mitragynine by means of the tail-pinch and hot-plate tests in mice. Mitragynine (1.0-10 micrograms) injected i.c.v. exerted a dose-dependent antinociceptive activity in both tests. The activity of mitragynine (10 micrograms, i.c.v.) in the tail-pinch test was antagonized by reserpine, 6-hydroxydopamine plus nomifensine, and p-chlorophenylalnine treatment, whereas the antinociceptive activity of morphine (3 micrograms) given i.c.v. in this test was attenuated by 6-hydroxydopamine plus nomifensine but not by p-chlorophenylalanine treatment. Moreover, the activity of i.c.v. mitragynine was also antagonized by the alpha 2-adrenoceptor antagonist, idazoxan (10 micrograms), and cyproheptadine (1 microgram) administered intrathecally (i.t.). On the other hand, the antinociceptive action of i.c.v. mitragynine (10 micrograms) in the hot-plate test was abolished by reserpine and 6-hydroxydopamine plus nomifensine, but not by p-chlorophenylalanine treatment. This action was also antagonized by i.t. injection of idazoxan (10 micrograms). These results suggest that both descending noradrenergic and serotonergic systems are involved in the antinociceptive activity of supraspinally administered mitragynine on the mechanical noxious stimulation, while the descending noradrenergic system predominantly contributes to the effect of supraspinal mitragynine on the thermal noxious stimulation. The mechanisms underlying the suppressive action of mitragynine on the nociceptive response may differ from those of morphine in mice.
Mitragynine, a major constituent of the young leaves of Mitragyna speciosa KORTH., has been reported to exert antinociceptive activity in mice. To determine the mechanism the influence of mitragynine on cAMP content was measured in NG108-15 cells which possess delta opioid receptors and alpha 2B-adrenoceptors. Mitragynine inhibited the forskolin-stimulated cAMP content in a concentration dependent manner as well as morphine and noradrenaline. Mitragynine- and morphine-induced inhibition of cAMP content were blocked by naloxone. Although idazoxane inhibited noradrenaline-induced inhibition of the cAMP content, idazoxane had no effect on mitragynine-induced inhibition. These results suggest that mitragynine acts directly on opioid receptors, but not on alpha 2-adrenoceptors, to show antinociceptive activity.
We investigated the effects of mitragynine, a major alkaloid isolated from the leaves of Mitragyna speciosa Korth (Rubiaceae), on the 5-HT2A receptor-mediated head-twitch response in mice. Intraperitoneal injection of mitragynine (5-30 mg/kg), as well as intraperitoneal injection of 5-HT2A receptor antagonist ritanserin, inhibited the 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT: 16 mg/kg, IP)-induced head-twitch response in a dose-dependent manner. In contrast, mitragynine affected neither head-weaving caused by 5-MeO-DMT, nor drug-free spontaneous motor activity. Pretreatment of mice with reserpine (5 mg/kg, IP), p-chlorophenylalanine (p-CPA, 300 mg/kg x 3 times, IP), or 6-hydroxydopamine (6-OHDA, 50 micrograms/mouse, ICV) plus nomifensine (5 mg/kg, IP) did not change the suppressant effect of mitragynine on the head-twitch response caused by 5-MeO-DMT. On the other hand, the alpha 2-adrenoceptor antagonists yohimbine (0.5 mg/kg, IP), and idazoxan (0.2 mg/kg, IP), significantly attenuated the suppressant effect of mitragynine. Lesion of central noradrenergic systems by 6-OHDA plus nomifensine did not alter the effect of idazoxan (0.2 mg/kg) on mitragynine-induced suppression of the head-twitch response. These results indicate that stimulation of postsynaptic alpha 2-adrenoceptor, blockade of 5-HT2A receptors, or both, are involved in suppression of 5-HT2A receptor-mediated head-twitch response by mitragynine.
The leaves of a tropical plant, Mitragyna speciosa KORTH (Rubiaceae), have been traditionally used as a substitute for opium. Phytochemical studies of the constituents of the plant growing in Thailand and Malaysia have led to the isolation of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids, including new natural products. The structures of the new compounds were elucidated by spectroscopic and/or synthetic methods. The potent opioid agonistic activities of mitragynine, the major constituent of this plant, and its analogues were found in in vitro and in vivo experiments and the mechanisms underlying the analgesic activity were clarified. The essential structural features of mitragynines, which differ from those of morphine and are responsible for the analgesic activity, were elucidated by pharmacological evaluation of the natural and synthetic derivatives. Among the mitragynine derivatives, 7-hydroxymitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice.
Mitragynine is an indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa. We previously reported the morphine-like action of mitragynine and its related compounds in the in vitro assays. In the present study, we investigated the opioid effects of 7-hydroxymitragynine, which is isolated as its novel constituent, on contraction of isolated ileum, binding of the specific ligands to opioid receptors and nociceptive stimuli in mice. In guinea-pig ileum, 7-hydroxymitragynine inhibited electrically induced contraction through the opioid receptors. Receptor-binding assays revealed that 7-hydroxymitragynine has a higher affinity for micro-opioid receptors relative to the other opioid receptors. Administration of 7-hydroxymitragynine (2.5-10 mg/kg, s.c.) induced dose-dependent antinociceptive effects in tail-flick and hot-plate tests in mice. Its effect was more potent than that of morphine in both tests. When orally administered, 7-hydroxymitragynine (5-10 mg/kg) showed potent antinociceptive activities in tail-flick and hot-plate tests. In contrast, only weak antinociception was observed in the case of oral administration of morphine at a dose of 20 mg/kg. It was found that 7-hydroxymitragynine is a novel opioid agonist that is structurally different from the other opioid agonists, and has potent analgesic activity when orally administered.
A simple HPLC technique for determining mitragynine levels in serum was developed. The separation system consisted of a C18 column heated to 35 degrees C, a methanol-water (80:20, v/v) mobile phase, a flow rate of 0.8 mL/min and detection in the ultraviolet at 225 nm. Mitragynine, with a retention time of 10.09 min, was well resolved from any interferences in human serum and the internal standard peak. The calibration curve was linear from 0.1 to 10 microg/mL (r = 0.9995). Extraction of mitragy-nine from alkalinized serum using diethyl ether gave a high recovery (>or=85%). The intra- and inter-day precisions of the method were 4.29-5.88%RSD and 7.06-8.45%RSD, respectively. The accuracy ranged from -9.54 to +0.67%DEV. The limit of detection was 0.03 microg/mL and the lower limit of quantification was 0.1 microg/mL. Mitragynine in the stock solution was stable during 30 days of storage at 4 degrees C. This method was successfully applied to determine the pharmacokinetic characteristics of mitragynine levels in the serum of rats after it was administered orally.
The aim of this study was to clarify whether grape seed proanthocyanidins extracts (GSPE) were therapeutic agents against diabetic cardiomyopathy. After diabetes was induced by STZ intravenously into the tail veins, GSPE (250 mg/kg body weight/d) were administrated for 24 weeks. Serum glucose, glycated hemoglobin (HbA1c), and advanced glycation end products (AGEs) were determined. Electronic microscopy was used to observe the changes of myocardial ultrastructure. Reverse transcription polymerase chain reaction (RT-PCR) was used to evaluate the receptor of advanced glycation end products (RAGE), nuclear factor-kappaB (NF-kappaB), and transforming growth factor-betal (TGF-betal) gene expression in myocardial tissue. GSPE significantly reduced the AGEs of diabetic rats (P < 0.05). After being treated by GSPE, the levels of RAGE, NF-kappaB, and TGF-beta1 mRNA transcription in the myocardial tissue of diabetic rats were reduced (P < 0.05), the number of degenerated mitochondria was decreased, and the preservation of the fine structure of the LV myocardium was improved. In conclusion, GSPE plays an important role against diabetic cardiomyopathy. With the decreasing of AGEs, it can ameliorate glycation-associated cardiac damage. This study may provide a new recognition of natural medicine for the treatment of diabetic cardiomyopathy.
Kratom (Mitragyna speciosa Korth.) is an indigenous plant of Thailand used traditionally in folk medicine although it is claimed to cause addiction. It is used to treat diarrhea, however, there is no scientific evidence to support the use. The aim of this study is to investigate the effect of methanolic extract of kratom leaves on the rat gastrointestinal tract. Kratom extract at 50, 100, 200 and 400 mg/kg (p.o.) caused a dose dependent protection against castor oil-induced diarrhea in rats and also inhibited intestinal transit. The antidiarrheal effect was not antagonized by naloxzone. The inhibition of intestinal transit by kratom extract was significantly different from the control when treated with a single dose for 1 day. For longer-term treatments of 15 and 30 days, kratom extract did not decrease the intestinal transit time indicating that adaptation had occurred. Kratom extract at a dose level of 200 and 400 mg/kg for 30 days and morphine at 3 mg/kg (i.p.) caused a decrease in the increment of body weight that was significantly different from the control and kratom extract at lower doses (50 and 100 mg/kg). However it had no effect on the level of plasma cholecystokinin. The results suggested that methanolic kratom extract exhibited its antidiarrheal effect on rat gastrointestinal tract. The effects may occur via pathways in addition to the action on opioid receptors. High does of kratom extract decreased the increment of body weight similar to the effect of morphine.
Salvia divinorum and Mitragyna speciosa ("Kratom"), two unscheduled dietary supplements whose active agents are opioid receptor agonists, have discrete psychoactive effects that have contributed to their increasing popularity. Salvia divinorum contains the highly selective kappa- opioid receptor agonist salvinorin A; this compound produces visual hallucinations and synesthesia. Mitragynine, the major alkaloid identified from Kratom, has been reported as a partial opioid agonist producing similar effects to morphine. An interesting minor alkaloid of Kratom, 7-hydroxymitragynine, has been reported to be more potent than morphine. Both Kratom alkaloids are reported to activate supraspinal mu- and delta- opioid receptors, explaining their use by chronic narcotics users to ameliorate opioid withdrawal symptoms. Despite their widespread Internet availability, use of Salvia divinorum and Kratom represents an emerging trend that escapes traditional methods of toxicologic monitoring. The purpose of this article is to familiarize toxicologists and poison control specialists with these emerging psychoactive dietary supplements.
Kratom (Mitragynia speciosa korth) is recognized increasingly as a remedy for opioid withdrawal by individuals who self-treat chronic pain.
A patient who had abruptly ceased injection hydromorphone abuse self-managed opioid withdrawal and chronic pain using kratom. After co-administering the herb with modafinil he experienced a tonic-clonic seizure, but he reported only modest abstinence once kratom administration stopped. We confirmed the identity of the plant matter he ingested as kratom and identified no contaminants or adulterants. We also conducted high-throughput molecular screening and the binding affinity at mu, delta and kappa receptors of mitragynine.
We report the self-treatment of chronic pain and opioid withdrawal with kratom. The predominant alkaloid of kratom, mitragynine, binds mu- and kappa-opioid receptors, but has additional receptor affinities that might augment its effectiveness at mitigating opioid withdrawal. The natural history of kratom use, including its clinical pharmacology and toxicology, are poorly understood.
Kratom: a case of a legal high; Abstracts of the 2008 North American Congress of Clinical Toxicology Annual Meeting Determination of mitragynine in rat plasma by LC-MS/ MS: application to pharmacokinetics
- Roche Km
- Hart K B Sangalli
- J Lefberg
- Bayer
Roche KM, Hart K, Sangalli B, Lefberg J, Bayer M (2009) Kratom: a case of a legal high; Abstracts of the 2008 North American Congress of Clinical Toxicology Annual Meeting, September 11–16, 2008, Toronto, Canada. Clin Tox 46(7), p. 598 25. de Moraes NV, Moretti RAC, Furr EB, McCurdy CR, Lanchote VL (2009) Determination of mitragynine in rat plasma by LC-MS/ MS: application to pharmacokinetics. J Chromatogr B Analyt Technol Biomed Life Sci 877(24):2593–2597
http://www.aseansec.org/Nar- cotics%20Act%20B
Narcotics Act B.E. 2552 (1979). http://www.aseansec.org/Nar-
cotics%20Act%20B.E.%202552%20(1979)%20-%20Thailand.
doc. Accessed 10 Jan 2011
Herbal drug update: kratom
NDIC (2005) Herbal drug update: kratom. Narcotics Digest
Weekly 4(16):4
Mitragyna speciosa) vault (2010) (http://www. erowid.org/plants/kratom/kratom.shtml) Accessed 12
- Erowid Kratom
Erowid kratom (Mitragyna speciosa) vault (2010) (http://www.
erowid.org/plants/kratom/kratom.shtml). Accessed 12 Dec
2010
http://www.who-umc.org/DynPage.aspx? id=22682) Accessed
UMC (2010) (http://www.who-umc.org/DynPage.aspx?
id=22682). Accessed 10 Mar 2011
Understanding the ‘Spice’ phenomenon. European Monitoring Centre for Drugs and Drug Addiction
- EMCDDA
EMCDDA (2009) Understanding the 'Spice' phenomenon.
European Monitoring Centre for Drugs and Drug Addiction,
Lisbon