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Kratom (Mitragyna speciosa) is a plant indigenous to Southeast Asia. Its leaves and the teas brewed from them have long been used by people in that region to stave off fatigue and to manage pain and opioid withdrawal. In a comprehensive review published in 2012, Prozialeck et al presented evidence that kratom had been increasingly used for the self-management of opioid withdrawal and pain in the United States. At the time, kratom was classified as a legal herbal product by the US Drug Enforcement Administration. Recent studies have confirmed that kratom and its chemical constituents do have useful pharmacologic actions. However, there have also been increasing numbers of reports of adverse effects resulting from use of kratom products. In August 2016, the US Drug Enforcement Administration announced plans to classify kratom and its mitragynine constituents as Schedule 1 controlled substances, a move that triggered a massive response from kratom advocates. The purpose of this report is to highlight the current scientific and legal controversies regarding kratom.
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... Kratom 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. ...
... Patients have used this drug for chronic pain management when interchanging with opiates. Kratom can also be used recreationally in teas consisting of Kratom leaves, cough syrup, Coca-Cola, and ice; this can induce euphoria and hallucinations when consumed [3,8,9]. ...
... Women experience withdrawal when discontinuing kratom and their newborns can develop NAS requiring pharmacologic treatment, prolonging hospital stay and potentially resulting in separation of mom and baby. Symptoms seen in newborns are typical of NAS due to opioids (diarrhea, tachypnea, excessive cry, excoriations, poor feeding) and seem to present 1-2 days after birth [22,23,[33][34][35][36][37]. The American Kratom Society (https://www.americankatom.org/science) ...
... Transmission through breastmilk is unstudied, but one case reports improvement in withdrawal symptoms with breastfeeding [35]. Most of the published cases of kratom use by pregnant women do not report amounts consumed, however duration and frequency are cited as chronic and daily [22,23,[33][34][35][36][37]. ...
... Detection in urine is by liquid chromatography or mass spectrometry. Time to results is highly variable but can take 1-2 weeks, well after signs of withdrawal present [33]. ...
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Kratom is an herbal alkaloid dietary supplement that acts agonistically at opioid receptors. It is increasingly used by those with opioid dependency to treat symptoms of opioid withdrawal. Classification and regulation of kratom is controversial. Currently it is unregulated, widely available and heavily advertised. Advocates tout its potential to help those with opioid dependency however risks to kratom use are well documented. It has been associated with dependency, withdrawal, toxicity and more recently neonatal abstinence syndrome (NAS) or withdrawal in newborns. For these reasons, pediatricians need to be aware of its existence and potential to impact their patients.
... Various investigators have noted that the increased interest in kratom seemed to coincide with several aspects of the evolving opioid crisis in the United States (Boyer et al., 2008;Prozialeck et al., 2012;Prozialeck, 2016;Bestha, 2018;Coe et al., 2019;Prozialeck et al., 2019) and that recent restrictions on access to prescription opioids for pain management may have further increased demand for kratom (Prozialeck, 2016;Prozialeck et al., 2019). With the emergence of COVID-19 in 2019, and the evolution of the COVID-19 pandemic in 2020, many patients may have faced even further reductions in access to prescription opioids, which could have contributed to an increase in the use of illicit "street" opioids such as heroin, fentanyl and new fentanyl analogs (Manchikanti et al., 2021;Nguyen and Buxton, 2021). ...
... Various investigators have noted that the increased interest in kratom seemed to coincide with several aspects of the evolving opioid crisis in the United States (Boyer et al., 2008;Prozialeck et al., 2012;Prozialeck, 2016;Bestha, 2018;Coe et al., 2019;Prozialeck et al., 2019) and that recent restrictions on access to prescription opioids for pain management may have further increased demand for kratom (Prozialeck, 2016;Prozialeck et al., 2019). With the emergence of COVID-19 in 2019, and the evolution of the COVID-19 pandemic in 2020, many patients may have faced even further reductions in access to prescription opioids, which could have contributed to an increase in the use of illicit "street" opioids such as heroin, fentanyl and new fentanyl analogs (Manchikanti et al., 2021;Nguyen and Buxton, 2021). ...
... In 2016, the DEA proposed that kratom's alkaloid constituents mitragynine and 7hydroxymitragynine be classified as Schedule I controlled substances, which would have effectively banned the use of kratom in the US (DEA, 2016a;2016b). The announcement of these plans sparked vigorous opposition from many patients and patient advocacy groups who claim that kratom had helped them manage opioid withdrawal or chronic pain (Anson, 2016;Prozialeck, 2016;Wing, 2016;Prozialeck et al., 2019). The advocates' responses included a march and demonstration at the White House on September 13, 2016, and a petition was sent to President Obama. ...
Article
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Kratom (Mitragyna speciosa, Korth.) is an evergreen tree that is indigenous to Southeast Asia. When ingested, kratom leaves or decoctions from the leaves have been reported to produce complex stimulant and opioid-like effects. For generations, native populations in Southeast Asia have used kratom products to stave off fatigue, improve mood, alleviate pain and manage symptoms of opioid withdrawal. Despite the long history of kratom use in Asia, it is only within the past 10–20 years that kratom has emerged as an important herbal agent in the United States, where it is being used for the self-treatment of pain, opioid withdrawal symptoms, and mood disorders. The increase in the use of kratom in the United States has coincided with the serious epidemic of opioid abuse and dependence. Since 2015, efforts to restrict access to prescription opioids have resulted in a marked increase in the use of “street” opioids such as heroin and illicit fentanyl. At the same time, many patients with chronic pain conditions or opioid use disorder have been denied access to appropriate medical help. The lack of access to care for patients with chronic pain and opioid use disorder has been magnified by the emergence of the COVID-19 pandemic. In this report, we highlight how these converging factors have led to a surge in interest in kratom as a potential harm reduction agent in the treatment of pain and opioid use disorder.
... Asia, kratom has been used for the treatment of a wide range of ailments ranging from fever to malaria to cough to hypertension to diarrhea to depression to analgesia [11, 24,25]. The pharmacological effects of kratom and its possible toxicity remain unclear. ...
... The pharmacological effects of kratom and its possible toxicity remain unclear. Kratom can have significant side effects [26], but it appears to be most harmful when used in conjunction with other drugs [25][26][27][28][29][30]. ...
... As kratom use has increased in the United States, there have been growing concerns about the safety of kratom products. Much of the concern has focused on the increase in the number of reports to poison control centers in which kratom was mentioned as a contributing factor in the poisoning scenarios including several deaths [16,[20][21][22][23]. Such reports of adverse effects were cited by the United States Drug Enforcement Administration (DEA, Springfield, VA, USA) in a proposal to place kratom and its mitragynine constituents into Schedule I of the Controlled Substance Act [24], an action that would have effectively banned the possession and sale of kratom products in the USA. ...
... In some cases, the kratom products may have even been adulterated with exogenous substances including synthetic opioids [16,28,29]. The DEA's proposal to ban kratom prompted a massive response by kratom advocates that led the DEA to place the scheduling of kratom and its mitragynine constituents on indefinite hold [23]. In October 2021, the World Health Organization's (WHO, Geneva, Switzerland) Expert Committee on Drug Dependence (ECDD) met to consider a proposal to move kratom and its mitragynine to Schedule I status at the level of the WHO. ...
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Kratom (Mitragyna speciosa) is a tropical tree that is indigenous to Southeast Asia. Kratom leaf products have been used in traditional folk medicine for their unique combination of stimulant and opioid-like effects. Kratom is being increasingly used in the West for its reputed benefits in the treatment of pain, depression, and opioid use disorder (OUD). Recent studies from the United States Food and Drug Administration (FDA, Silver Spring, MD, USA) and our laboratory have shown that many kratom products being sold in the United States are contaminated with potentially hazardous levels of lead (Pb). In this commentary, we discuss the public health implications of the presence of Pb in kratom products, particularly as they relate to the predicted levels of Pb exposure among kratom users. We also considered the specific toxic effects of Pb and how they might relate to the known physiologic and toxicologic effects of kratom. Finally, we consider the possible sources of Pb in kratom products and suggest several areas for research on this issue.
... Ketum is believed to be the potential substitution for classical opioid analgesics such as morphine because it does not only fulfil the need for pain relief but also is less addictive and has a lower risk of overdose [41]. Although ketum is generally used as a supplement in the US, several states have initiated the control of ketum by banning the use or having enacted laws to prohibit the sales of adulterated products that are not properly labelled [62,63]. The possession and use of ketum are controlled in several European countries including Denmark, Lithuania, Poland, Latvia, Romania and Sweden [64]. ...
Article
Mitragynine is a promising candidate for pain relief and opiate replacement but the investigations for drug delivery are lacking. This study aims to investigate the potential of mitragynine to be delivered through the skin with an emphasis on developing and validating a gradient HPLC-UV analytical method to determine mitragynine in the samples collected during in vitro skin permeation studies. The optimised method involves a gradient elution using a C18 column with a mobile phase comprising acetonitrile and 0.1%v/v of formic acid (0 – 1 min: 30:70 to 70:30 (v/v) and hold up to 4 min; 4 – 6 min: return to 30:70 (v/v) and hold up to 10 min) at a flow rate of 1.2 mL/min. This method was validated based on the standards set by the International Council on Harmonisation guidelines. The method showed mitragynine elution at ∼4 min with adequate linearity (R² ≥ 0.999 for concentration ranges of 0.5 – 10 and 10 – 175 μg/mL) and acceptable limits of detection and quantification at 0.47 and 1.43 μg/mL, respectively. The analytical performance is robust with excellent precision and accuracy. This method was used to evaluate the in vitro skin permeation of mitragynine (5%w/v) from simple solvent systems over 48 hr. The results showed a cumulative amount of mitragynine permeated at ∼11 μg/cm² for dimethyl sulfoxide and ∼4 μg/cm² for propylene glycol. The study not only addressed the issues of the currently available HPLC-UV methods that limit the direct application but also affirmed the potential of mitragynine to be delivered through the skin.
Article
Opioid overprescribing, with resultant overdose and death, has led to a national focus on alternative treatments for pain. With the decline in legal access to opioids, kratom has gained popularity as a legal, "natural," and easily accessible nonprescription analgesic for consumers wishing to self-medicate for pain, opioid use disorder, and other mental health conditions. While implications of kratom use in patients with chronic pain and/or opioid use disorder have been published, information on perianesthetic implications is lacking. Anesthesiologists should be informed about kratom, including the potential for unexpected physiologic derangements and adverse drug interactions resulting from complex pharmacologic activity, cytochrome P450 interactions, and common adulterations of the drug that may result in unpredictable clinical effects. This article explores the relevance of kratom to perioperative anesthetic care, including suggestions for anesthesiologists extrapolated from published information in nonoperative settings that may improve patient safety in individuals using kratom.
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Kratom is a plant that is indigenous to Southeast Asia and has recently attracted attention in the United States; its primary active alkaloid mitragynine has stimulant effects at low doses and sedative effects at high doses. The purpose of this study was to provide updated information on the characteristics, clinical effects, treatment and patient outcomes of kratom exposure. Methods: This was a retrospective analysis of kratom exposures reported to two statewide poison control centers between January 2016 and June 2020. Subjects who reported coexposure to other substances of abuse or intentional xenobiotic overdoses were excluded. The data were stratified by the consumption of kratom alone and with nonoverdose exposure to other medications. Results: In total, 153 kratom exposures were included. Patients were classified into 3 groups according to kratom use within the past 24 hours: low dose (1–5 g; 45.1%), moderate dose (>5–15 g; 17.0%) and high dose (>15 g; 12.4%) groups. The two common clinical effects were central nervous system excitation (kratom, 32.3%; coexposure, 53.3%) and tachycardia (kratom, 46.6%; coexposure, 44.6%). Dose dependent sedative effects of kratom were not observed. Coexposure accounted for 39.2% of cases and was associated with higher rates of ICU admission (28.3% vs. 8.6%; p<0.01) and serious medical outcomes (28.3% vs. 7.5%; p<0.01). Conclusion: Kratom exposure is associated with a wide range of symptoms. Despite the perception that kratom is safe, the probability of more severe symptoms and serious effects should be o
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Zusammenfassung Kratom ist ein immergrüner Baum, der in Südostasien heimisch ist und dessen Blätter traditionell als Stimulans, als Therapie bei verschiedenen gesundheitlichen Problemen und zu religiösen Zwecken verwendet werden. Insbesondere in den USA (geringer auch in Europa) wird seit einigen Jahren eine relevante Prävalenz des Kratomkonsums beobachtet. In westlichen Ländern wird Kratom überwiegend als Analgetikum und Stimulans, zur Behandlung von Schmerzen und Opioidgebrauchsstörungen und zur günstigen Beeinflussung der psychischen Gesundheit (z. B. bei Depression, Angststörungen) verwendet. Die chemischen Hauptbestandteile von Kratom sind Alkaloide, von denen Mitragynin und 7-Hydroxymitragynin am bedeutsamsten erscheinen. Die Pharmakodynamik und -kinetik von Kratom sind komplex und unzureichend untersucht. Bekannt ist, dass Mitragynin und 7-Hydroxymitragynin Partialagonisten an humanen μ-Opioidrezeptoren und Antagonisten an κ- und δ-Opioidrezeptoren bei zusätzlichen Effekten an weiteren zentralen Rezeptoren sind. Die Verträglichkeit von Kratom scheint im Vergleich mit klassischen Opioiden besser zu sein, was mit fehlenden Effekten von Kratom auf β-Arrestin in Verbindung gebracht und als Ausgangspunkt für die Entwicklung besser verträglicher Opioide diskutiert wurde. Einige Alkaloide in Kratom sind Inhibitoren von CYP2D6, geringer auch CYP2C19 und CYP3A4. Das Abhängigkeitspotential von Kratom scheint geringer ausgeprägt zu sein als das von klassischen Opioiden, wobei die Datenlage dazu begrenzt ist und Kratomgebrauchsstörungen primär in westlichen Längern auftreten. Es sind zahlreiche Fälle von schwerwiegenden gesundheitlichen Problemen und Todesfälle im Zusammenhang mit Kratomkonsum in den USA bekannt, wobei in diesen Fällen meist mehrere Substanzen involviert waren. Kratomkonsum ist vermutlich mit hepatotoxischen und kardiotoxischen Effekten assoziiert. Kratom-assoziierte Morbidität und Mortalität unterscheiden sich zwischen westlichen Ländern und Südostasien, wo Kratomkonsum kein öffentliches Gesundheitsproblem darstellt, quantitativ erheblich. Als Gründe hierfür wurden der in westlichen Ländern verbreitete Mischkonsum, höhere Dosierungen konsumierten Kratoms, Verfälschungen und Verunreinigungen kommerziell erhältlicher Kratomprodukte in westlichen Ländern, pharmakokinetische Interaktionen und höhere Konzentrationen von 7-Hydroxymitragynin in getrockneten Kratomblättern (die typischerweise in westlichen Ländern konsumiert werden) im Vergleich mit frischen Blättern (die typischerweise in Südostasien konsumiert werden) genannt.
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Background: Kratom, a tree native to Southeast Asia, is increasingly used in Western countries for self-treatment of pain, psychiatric disorders, and mitigation of withdrawal symptoms from drugs of abuse. Because kratom is solely supplied from its native locations, supply shortages during the COVID-19 pandemic may impact the availability of preparations and hence force consumers to change their patterns of use. The aim of this study was to understand if and how COVID-19 was influencing kratom purchasing and use. Methods: Additional questions specific to kratom availability and changes in use during COVID-19 were added to an international online survey with responses collected between January and July 2020. During the same period, kratom-related social media posts to Twitter, Reddit, and Bluelight were analyzed for themes similar to the survey questions. Results: The survey results indicated no changes in kratom use patterns although the sample size was relatively small (n = 70) with younger consumers reporting a potential issue in obtaining their desired products from their usual sources. The survey respondents identified primarily as non-Hispanic whites (87.1%). Social media themes revolved primarily around quitting kratom during COVID-19, misinformation about the effects of kratom on COVID-19, and other non-COVID-related discussions. While some consumers may increase their kratom dose because of additional stress, a majority of discussions centered around reducing or rationing kratom due to COVID-19 or a perceived dependence. Access to quality kratom products was also a major discussion topic on social media. Conclusions: Kratom use patterns did not change due to COVID-19 but consumers were concerned about potential product shortages and resulting quality issues. Clinicians and public health officials need to be informed and educated about kratom use as a potential mitigation strategy for substance use disorders and for self-treatment of pain.
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Mitragynine is a major bioactive compound of Kratom, which is derived from the leave extracts of Mitragyna speciosa Korth or Mitragyna speciosa (M. speciosa), a medicinal plant from South East Asia used legally in many countries as stimulant with opioid-like effects for the treatment of chronic pain and opioid-withdrawal symptoms. Fatal incidents with Mitragynine have been associated with cardiac arrest. In this study, we determined the cardiotoxicity of Mitragynine and other chemical constituents isolated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The rapid delayed rectifier potassium current (IKr), L-type Ca2+ current (ICa,L) and action potential duration (APD) were measured by whole cell patch-clamp. The expression of KCNH2 and cytotoxicity was determined by real-time PCR and Caspase activity measurements. After significant IKr suppression by Mitragynine (10 µM) was confirmed in hERG-HEK cells, we systematically examined the effects of Mitragynine and other chemical constituents in hiPSC-CMs. Mitragynine, Paynantheine, Speciogynine and Speciociliatine, dosage-dependently (0.1∼100 µM) suppressed IKr in hiPSC-CMs by 67% ∼84% with IC50 ranged from 0.91 to 2.47 µM. Moreover, Mitragynine (10 µM) significantly prolonged APD at 50 and 90% repolarization (APD50 and APD90) (439.0±11.6 vs. 585.2±45.5 ms and 536.0±22.6 vs. 705.9±46.1 ms, respectively) and induced arrhythmia, without altering the L-type Ca2+ current. Neither the expression,and intracellular distribution of KCNH2/Kv11.1, nor the Caspase 3 activity were significantly affected by Mitragynine. Our study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of IKr in human cardiomyocytes.
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Although some novel psychoactive substances (NPS) are newly discovered chemicals, others are traditional or indigenous substances that are introduced to new markets. One of these latter substances is a plant many people refer to as kratom. Indigenous to Southeast Asia and used for a variety of instrumental and recreational purposes, kratom has recently become available to Western drug users. Kratom is somewhat unique in that the plant contains two different psychoactive chemicals, which have both stimulant (mitragynine) and narcotic (7-hydroxymitragynine) properties. Thus, kratom may appeal to different types of drug users for reasons other than curiosity. In the current study, 15 samples of products that were either directly advertised as kratom or were listed in the results of a web search (but were not directly advertised as kratom) were purchased for testing. After laboratory testing, it was determined that all products advertised as kratom contained the active chemical mitragynine, but 7-hydroxymitragynine was not detected in any of the samples. Implications are discussed.
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Prescription opioid (PO) misuse is a major health concern across North America, and it is the primary cause of preventable death for the 18–35 year old demographic. Medication assisted therapy including methadone and buprenorphine, is the standard of care for patients with opioid-dependence. Moreover, both of these medications are recognized as essential medicines by World Health Organization. In Ontario Canada, the availability of medication assisted therapy has expanded substantially, with almost a tenfold increase number of patients accessing methadone in Ontario in the past decade. In their manuscript, Fischer et. al. (2016), present a view that expansion of opioid maintenance therapy (OMT) has outpaced true patient need and alternate strategies should be considered as first-line treatments. Here, we present a countering perspective-that medication assisted therapy, along with other harm reduction strategies, should be widely available to all opioid-dependent people as first-line treatments.
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Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [³⁵S]GTPγS assays at the mu opioid receptor but failed to recruit β-arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic tolerance more slowly than morphine, showed limited physical dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.
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This final rule increases access to medication-assisted treatment (MAT) with buprenorphine and the combination buprenorphine/naloxone (hereinafter referred to as buprenorphine) in the office-based setting as authorized under the United States Code. Section 303(g)(2) of the Controlled Substances Act (CSA) allows individual practitioners to dispense or prescribe Schedule III, IV, or V controlled substances that have been approved by the Food and Drug Administration (FDA). Section 303(g)(2)(B)(iii) of the CSA allows qualified practitioners who file an initial notification of intent (NOI) to treat a maximum of 30 patients at a time. After 1 year, the practitioner may file a second NOI indicating his/her intent to treat up to 100 patients at a time. This final rule will expand access to MAT by allowing eligible practitioners to request approval to treat up to 275 patients under section 303(g)(2) of the CSA. The final rule also includes requirements to ensure that patients receive the full array of services that comprise evidence-based MAT and minimize the risk that the medications provided for treatment are misused or diverted.
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Kratom (Mitragyna speciosa) is a plant consumed throughout the world for its stimulant effects and as an opioid substitute (1). It is typically brewed into a tea, chewed, smoked, or ingested in capsules (2). It is also known as Thang, Kakuam, Thom, Ketum, and Biak (3). The Drug Enforcement Administration includes kratom on its Drugs of Concern list (substances that are not currently regulated by the Controlled Substances Act, but that pose risks to persons who abuse them), and the National Institute of Drug Abuse has identified kratom as an emerging drug of abuse (3,4). Published case reports have associated kratom exposure with psychosis, seizures, and deaths (5,6). Because deaths have been attributed to kratom in the United States (7), some jurisdictions have passed or are considering legislation to make kratom use a felony (8). CDC characterized kratom exposures that were reported to poison centers and uploaded to the National Poison Data System (NPDS) during January 2010-December 2015. The NPDS is a national database of information logged by the country's regional poison centers serving all 50 United States, the District of Columbia, and Puerto Rico and is maintained by the American Association of Poison Control Centers. NPDS case records are the result of call reports made by the public and health care providers.
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With Lembke article and opioid PG.
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![Figure][1] Cannabis sativa. PHOTO: DANIEL ZGOMBIC Although the majority of the general public ([ 1 ][2]) and the professional medical community ([ 2 ][3]) in the United States support the therapeutic use of Cannabis sativa as a pharmacological agent, the U.S. federal government's
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Introduction: The objective of the paper was to highlight the differences in the traditional and non-traditional users of kratom in the South East Asian and Western contexts. Method: A literature survey of published kratom studies among humans was conducted. Forty published studies relevant to the objective were reviewed. Results: Apart from the differences in the sources of supply, patterns of use and social acceptability of kratom within these two regions, the most interesting finding is its evolution to a recreational drug in both settings and the severity of the adverse effects of kratom use reported in the West. While several cases of toxicity and death have emerged in the West, such reports have been non-existent in South East Asia where kratom has had a longer history of use. We highlight the possible reasons for this as discussed in the literature. More importantly, it should be borne in mind that the individual clinical case-reports emerging from the West that link kratom use to adverse reactions or fatalities frequently pertained to kratom used together with other substances. Therefore, there is a danger of these reports being used to strengthen the case for legal sanction against kratom. This would be unfortunate since the experiences from South East Asia suggest considerable potential for therapeutic use among people who use drugs. Conclusion: Despite its addictive properties, reported side-effects and its tendency to be used a recreational drug, more scientific clinical human studies are necessary to determine its potential therapeutic value.