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Risk of death associated with kratom use compared to opioids
Abstract
Kratom use appears to be increasing across the United States, increasing attention to deaths in which kratom use was detected. Most such deaths have been ascribed to fentanyl, heroin, benzodiazepines, prescription opioids, cocaine and other causes (e.g., homicide, suicide and various preexisting diseases). Because kratom has certain opioid-like effects (e.g., pain relief), and is used by some people as a substitute for opioids for pain or addiction, kratom has been compared to "narcotic-like opioids" (e.g., morphine) with respect to risk of death despite evidence that its primary alkaloid, mitragynine, carries little of the signature respiratory depressing effects of morphine-like opioids. This commentary summarizes animal toxicology data, surveys and mortality data associated with opioids and kratom to provide a basis for estimating relative mortality risk. Population-level mortality estimates attributed to opioids as compared to kratom, and the per user mortality risks of opioids as compared to kratom are provided. By any of our assessments, it appears that the risk of overdose death is >1000 times greater for opioids than for kratom. The limitations of the mortality risk estimate warrants caution in individuals with unknown factors such as use of other substances and medications, or other preexisting conditions. More research on kratom safety and risks is needed, as is regulation of commercial kratom products to ensure that consumers are informed by FDA labeling and that kratom products are not contaminated or adulterated with other substances.
... Deaths attributed directly to kratom use in the US and globally are rare and were not documented in Southeast Asia (Prozialeck et al. 2019;Ramanathan and McCurdy 2020). Analyses of kratom-associated deaths found that most of such deaths are more likely attributed to the use of other substances and causes not related to kratom (Gershman et al. 2019;Henningfield et al. 2019; National Institute on Drug Abuse 2020; Olsen et al. 2019). ...
... Mitragynine in isolation and kratom produce diverse opioid and nonopioid mediated effects that warrant further study (Ahmad et al. 2022;Harun et al. 2022;Behnood-Rod et al. 2020;Hemby et al. 2019;Henningfield et al. 2018Henningfield et al. , 2022Reeve et al. 2020;Sharma and McCurdy 2021;Wilson et al. 2020;Yue et al. 2018). However, as compared to opioids and other substances that contributed to the 2021 annualized rate of 108,000 drug overdose deaths, the relative risk of kratom appears to be far lower than that of opioids, methamphetamine and cocaine, alcohol, and many other substances of abuse (CDC 2021;Giroir 2018;Henningfield et al. 2019; United Nations Commission on Narcotic Drugs 2021). ...
Rationale
Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like decoctions, and commercial extracts are taken orally, primarily for health and well-being by millions of people globally. Others take kratom to eliminate opioid use for analgesia and manage opioid withdrawal and use disorder. There is debate over the possible respiratory depressant overdose risk of the primary active alkaloid, mitragynine, a partial μ-opioid receptor agonist, that does not signal through ß-arrestin, the primary opioid respiratory depressant pathway.
Objectives
Compare the respiratory effects of oral mitragynine to oral oxycodone in rats with the study design previously published by US Food and Drug Administration (FDA) scientists for evaluating the respiratory effects of opioids (Xu et al., Toxicol Rep 7:188–197, 2020).
Methods
Blood gases, observable signs, and mitragynine pharmacokinetics were assessed for 12 h after 20, 40, 80, 240, and 400 mg/kg oral mitragynine isolate and 6.75, 60, and 150 mg/kg oral oxycodone hydrochloride.
Findings
Oxycodone administration produced significant dose-related respiratory depressant effects and pronounced sedation with one death each at 60 and 150 mg/kg. Mitragynine did not yield significant dose-related respiratory depressant or life-threatening effects. Sedative-like effects, milder than produced by oxycodone, were evident at the highest mitragynine dose. Maximum oxycodone and mitragynine plasma concentrations were dose related.
Conclusions
Consistent with mitragynine’s pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating β-arrestin pathway, mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans.
... Indonesia, however, allows its export as a cash crop which generates the primary market for kratom in the US and globally. 17 Aside from its use as a harm reduction strategy for other substance use disorders, kratom can lead to tolerance and dependence development itself as evidenced by surveys among long-term users in Malaysia. 18 Tolerance and dependence develop in a dose-dependent manner in those who take kratom in higher frequency on a daily basis with withdrawal symptoms primarily mirroring those of mild opioid craving symptoms such as diarrhea, muscle spasms, fever, pain, reduced appetite, mood swings, sleep disturbances, tension, nervousness, and restlessness. ...
... 54 , 76 , 96-100 The majority of deaths attributed to kratom have involved additional substances, such as opioids, benzodiazepines, or stimulants, making it difficult to determine causality. 17 Others have had insufficient testing to evaluate for co-ingestants. 98 However, cases exist where extensive testing and examination did not determine an alternative cause of death 81 , 85 or have detected only therapeutic concentrations of other substances. ...
Kratom (Mitragyna speciosa Korth.) is a tree native to Southeast Asia with dose-dependent stimulant and opioid-like effects. Dried, powdered leaf material is among the kratom products most commonly consumed in the US and Europe, but other formulations also exist including enriched extracts, resins, tinctures, and edibles. Its prevalence in the US remains debated and the use pattern includes self-treatment of mood disorders, pain, and substance use disorders. Most of the adverse effects of kratom and its alkaloid mitragynine have been reported in the literature as case reports or part of surveys necessitating confirmation by clinical trials. Toxicities associated with kratom consumption have focused on hepatic, cardiac, and CNS effects with the potential to cause fatalities primarily as part of polydrug exposures. Kratom may also present with drug-drug interactions primarily through CYP 3A4 and 2D6 inhibition, although the clinical significance remains unknown to date. The variability in composition of commercially available kratom products complicates generalization of findings and requires further investigation by employing clinical trials. Healthcare professionals should remain cautious in counseling patients on the use of kratom in a therapeutic setting.
... Regular use of kratom might lead to dependence, withdrawal symptom development, and craving [4]. Most deaths among people who ingested kratom have also involved the use of other substances [5,6]. Kratom is not scheduled under the U.S. Controlled Substances Act; however, the Drug Enforcement Administration considers kratom a drug of concern and as of September 2019 was under active review by the U.S. Food and Drug Administration [7e9]. ...
... The increased "popularity" of kratom, based on the results from adults and other surveys, might be explained by its multiple easy-to-use presentations, ease of purchase via the Internet by individuals of all ages, perception that this substance provides a "legal high," and its easy availability, as it is increasingly being used by middle-aged people in their home environments [10], potentially facilitating access for adolescents at home. Additionally, perceptions of safety of kratom use might be changing as new studies reveal low rates of negative side effects among individuals using kratom to reduce withdrawal symptoms for opioid use disorders [6] and lower kratom-related death rates compared to opioid-related death rates in the U.S. [5]. ...
Background
Kratom (Mitragyna speciosa) is an opioid-like psychoactive substance not approved by the U.S. Food and Drug Administration that could be used due to its euphoric, stimulant, and analgesic effects. Kratom is gaining popularity in the U.S. and becoming a reason of concern among pediatricians.
Methods
Data from the 2019 National Survey on Drug Use and Health were analyzed to estimate the prevalence and identify correlates of lifetime and past 12-month kratom use among 13,397 U.S. adolescents. Multivariable logistic regression models were conducted to assess the associations of interest.
Results
Lifetime and past 12-month prevalence of kratom use was .44% (95% confidence interval [CI] .32–.60) and .27% (95% CI .18–.40), respectively. Past 12-month cigarette use was associated with lifetime kratom use (adjusted odds ratio 2.60, 95% CI 1.07–6.35). Past 12-month cannabis use was associated with past 12-month kratom use (adjusted odds ratio 2.48, 95% CI 1.15–5.35).
Conclusions
This first report on the epidemiology of adolescent kratom use provides a baseline to assess kratom use trends in future years and identify potential correlates of use among adolescents.
... Most recent estimates of kratom use, based on the tonnage of imported kratom and survey reports of dosing ranges, suggest 10-16 million users in the US alone 83 . Numerous anecdotal reports, including those collected by the United States Drug Enforcement Administration (>23,000 publicly available reports) 8 , point to remarkable medicinal effects of kratom in self-medication for chronic pain, depression, anxiety, substance use disorders, and other ailments. ...
... Interestingly, the correlation between the cAMP signaling efficacy obtained in vitro in cultured cells and the in vivo analgesic efficacy determined in living animals, for the 11-X-7OH series, suggests that the in vitro amplified system may mimic the receptor reserve and/or receptor-effector situation in the neurons of relevant pain circuitry, and thus provides a useful model system. Considering the recent surveys that document much improved safety of kratom compared to the prescription or illicit opioids 83,93,94 , a further decrease of MOR's G protein signaling efficacy of the key mediator of kratom's opioid-like effects, 7OH 17 , may lead to even safer compounds, and illustrates the potential importance of the present work. Further, a recent report showed that 7OH attenuated alcohol intake in drinking mice and that this effect was mediated by DOR activation, while 7OH exhibited rewarding effects on its own 80 . ...
Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We have developed a synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. Through this work we discover that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. 7-Hydroxymitragynine (7OH), the parent compound with low efficacy on par with buprenorphine, is transformed to an even lower efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.
... In fact, the link between mitragynine and the reported death rates has been poorly elucidated, since 71% of the fatalities were reported as accidental (including misadventure), while 9% were classified as intentional (suicide) (7). A recent study estimated that the risk of overdose death is >1000 times greater for opioids than for kratom (15). In fact, the majority who have encountered adverse health problems were those who had current histories of drug use problem, chiefly opioid abuse (7,15). ...
... A recent study estimated that the risk of overdose death is >1000 times greater for opioids than for kratom (15). In fact, the majority who have encountered adverse health problems were those who had current histories of drug use problem, chiefly opioid abuse (7,15). Meanwhile, in Southeast Asia, traditional kratom use has, thus far, not been associated with any major health concerns, although it has been placed under the Poisons Act 1952 in Malaysia (1). ...
Introduction: Kratom or (Mitragyna speciosa) leaves are consumed as a folk remedy and opioid substitute in the Southeast Asian region. There is still a lack of information about the long-term or toxic-causing effects of kratom use. Methods: A total of thirteen regular kratom users, with long-term (>20 twenty years) kratom use history were recruited for this cross-sectional pilot study. Respondents were required to undergo a blood-test and laboratory anaysis was conducted to determine the mitragynine content in an acquired street sample of kratom. Results: The regular, long-term consumption of brewed kratom decoction did not cause any significant alterations in haematological, kidney, liver, thyroid, inflammatory and gastrointestinal analytes in a cohort of kratom users who had no history of substance misuse. However, those who had a higher intake (>3 glasses per day) of kratom exhibited higher lipid values (except for HDL-cholesterol), and a moderate elevation of homocysteine level. Conclusion: Long-term (>20 years with a daily intake of ≥87.54mg of mitragynine) kratom consumption was not associated with altered biochemical levels, although prolonged and heavy use (>3 glasses daily) may result in cardiovascular risks. The latter finding, however, requires further investigation.
... The authors suggest that this high therapeutic index supports the contention that the drug is "safe" because it is unlikely to result in a fatal overdose from overconsumption of the drug alone. A recent study estimated that the risk of an overdose is greater than 1,000 times greater for opioids than for kratom (Henningfield et al., 2019). Numerous fatalities have been reported, most frequently in combination with other drugs (Domingo et al., 2017;Gershman et al., 2019;Holler et al., 2011;Hughes, 2019;Karinen, Fosen, Rogde, & Vindenes, 2014;Kronstrand et al., 2011;Mata & Andera, 2020;Matson & Schenk, 2019;McIntyre, Trochta, Stolberg, & Campman, 2015;Neerman, Frost, & Deking, 2013;O'Malley Olsen et al., 2019;Wang & Walker, 2008). ...
... Numerous fatalities have been reported, most frequently in combination with other drugs (Domingo et al., 2017;Gershman et al., 2019;Holler et al., 2011;Hughes, 2019;Karinen, Fosen, Rogde, & Vindenes, 2014;Kronstrand et al., 2011;Mata & Andera, 2020;Matson & Schenk, 2019;McIntyre, Trochta, Stolberg, & Campman, 2015;Neerman, Frost, & Deking, 2013;O'Malley Olsen et al., 2019;Wang & Walker, 2008). Due to the frequency of polydrug use among kratom users, additional research is needed, with particular emphasis on the potential for drug-drug interactions (Dinesh Sangarran, Thenmoly, Hadzliana, Vikneswaran, & Surash, 2019;Han et al., 2019;Henningfield et al., 2019;White, 2019;Ya, Tangamornsuksan, Scholfield, Methaneethorn, & Lohitnavy, 2019). ...
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.
... Kratom is consumed orally by chewing fresh or dried leaves, drinking crushed or boiled leaves in a tea, or by consuming encapsulated leaf powder [1][2][3][4]. In the United States, there are an estimated 10-16 million kratom users [3,[5][6][7][8][9]. Kratom is comprised of over 40 unique alkaloid constituents, with mitragynine (MG) being the most prominent, accounting for roughly 66 % of the crude base alkaloid content and 6 % of the plant's dried weight [10]. ...
Aims:
Mitragynine (MG) is an alkaloid found in Mitragyna speciosa (kratom), a plant used to self-treat symptoms of opioid withdrawal and pain. Kratom products are commonly used in combination with cannabis, with the self-treatment of pain being a primary motivator of use. Both cannabinoids and kratom alkaloids have been characterized to alleviate symptoms in preclinical models of neuropathic pain such as chemotherapy-induced peripheral neuropathy (CIPN). However, the potential involvement of cannabinoid mechanisms in MG's efficacy in a rodent model of CIPN have yet to be explored.
Main methods:
Prevention of oxaliplatin-induced mechanical hypersensitivity and formalin-induced nociception were assessed following intraperitoneal administration of MG and CB1, CB2, or TRPV1 antagonists in wildtype and cannabinoid receptor knockout mice. The effects of oxaliplatin and MG exposure on the spinal cord endocannabinoid lipidome was assessed by HPLC-MS/MS.
Key findings:
The efficacy of MG on oxaliplatin-induced mechanical hypersensitivity was partially attenuated upon genetic deletion of cannabinoid receptors, and completely blocked upon pharmacological inhibition of CB1, CB2, and TRPV1 channels. This cannabinoid involvement was found to be selective to a model of neuropathic pain, with minimal effects on MG-induced antinociception in a model of formalin-induced pain. Oxaliplatin was found to selectively disrupt the endocannabinoid lipidome in the spinal cord, which was prevented by repeated MG exposure.
Significance:
Our findings suggest that cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid MG in a model of CIPN, which may result in increased therapeutic efficacy when co-administered with cannabinoids.
... Kratom has become readily available in the United States, where the American Kratom Association estimates 10-16 million people use kratom regularly as an opioid alternative and for recreational purposes. [8][9][10] It is frequently publicized as a psychoactive alternative to other stimulant-type and sedative drugs, the latter including opioids. However, there are no US Food and Drug Administration (FDA)-approved medical uses for kratom, 11 and only two clinical trials involving kratom have been registered in clini caltr ials.gov to date. 3 The US Drug Enforcement Administration (DEA) listed kratom among its "Drugs of Concern" because of its sedative effects and addiction potential, leading to efforts to ban the sale of kratom in some US cities and states (11). ...
Kratom is a widely used Asian botanical that has gained popularity in the United States due to a perception that it can treat pain, anxiety, and opioid withdrawal symptoms. The American Kratom Association estimates 10-16 million people use kratom. Kratom-associated adverse drug reactions (ADRs) continue to be reported and raise concerns about the safety profile of kratom. However, studies are lacking that describe the overall pattern of kratom-associated adverse events and quantify the association between kratom and adverse events. ADRs reported to the US Food and Drug Administration Adverse Event Reporting System from January 2004 through September 2021 were used to address these knowledge gaps. Descriptive analysis was conducted to analyze kratom-related adverse reactions. Conservative pharmacovigilance signals based on observed-to-expected ratios with shrinkage were estimated by comparing kratom to all other natural products and drugs. Based on 489 de-duplicated kratom-related ADR reports, users were young (mean age 35.5), and more often male (67.5%) than female (23.5%). Cases were predominantly reported since 2018 (94.2%). Fifty-two disproportionate reporting signals in 17 system-organ-class (SOC) categories were generated. The observed/reported number of kratom-related accidental death reports was 63-fold greater than that expected. There were eight strong signals related to addiction or drug withdrawal. An excess proportion of ADR reports were about kratom-related drug complaints, toxicity to various agents, and seizures. Although further research is needed to assess the safety of kratom, clinicians and consumers should be aware that real-world evidence points to potential safety threats.
... Kratom's safety received support through a comprehensive assessment of the evidence via the 8 factors of the Controlled Substance Act [80]. Here, Henningfield et al. do not disagree that kratom carries a certain mortality risk; however, they report that the anticipated risk is a thousand times lower than the mortality risk associated with opioids [81]. ...
Purpose of Review
The rising public interest in kratom is paralleled by concerns of adverse outcomes, particularly overdose. Such claims span a multitude of reporting modalities, including case reports, analyses of data from poison control and coroners’ reports, and warnings from government agencies. Here we evaluate the literature in efforts to assess kratom’s potential overdose risk. A keyword search of online literature databases identified 12 preclinical studies, 23 case reports, and 15 observational studies/reports meeting our pre-selected criteria.
Recent Findings
Case reports describe outcomes where kratom products are coingested with illicit substances and pharmaceuticals. Opioids are common coingestants, and presentations describe pulmonary edema and findings resembling opioid overdoses. However, seizures and hyperadrenergic features are also common. Where reported, post-mortem mitragynine (MG) concentrations are inconclusive of attributed toxicities. Animal studies found oral LD50s in the range of 200–960 mg/kg for MG, and 200–591 mg/kg for Malaysian total alkaloid extract. Deaths were preceded by restlessness, tremors, and convulsions. Analyses of a variety of reported toxicities yield signs and symptoms that resemble hyperadrenergic components, with autopsies finding coingestants in addition to alkaloids.
Summary
As with any compound ingested in large quantities, it is possible to develop lethal toxicities with kratom in a dose-dependent fashion. Use via the traditional mode of consumption, such as chewing or brewing the leaves as a tea, would require a tremendous amount of kratom to be ingested. The currently available kratom products, and pure alkaloid isolates, greatly increase this risk, in addition to combining kratom with illicit substances, and pharmacokinetic/pharmacodynamic interactions.
... 5 Animal studies have also been unclear with regard to lethal dose levels. 6 Thus, it is unclear what dose of kratom is potentially dangerous, and lethality may depend on many factors including comorbid conditions and genetic risk factors. 5 Given the increasing use, unknown risk factors, and consequences of use it is essential to discover demographic and behavioral corelates of kratom use to better define strategies to reduce risk for misuse. ...
Objective: Kratom use represents a growing risk for public health. The present study examined demographic and behavioral factors linked with kratom use. Participants: Participants were college students in the United States who participated in the 2019-2020 Healthy Minds Study. Methods: Participants completed survey-based assessment of kratom use and related demographic, behavioral, and mental health variables. Results: Kratom use was linked with being White, male or transgender/gender nonconforming, identifying as a sexual minority, use of alcohol or marijuana, and depressive symptoms. Kratom use was not uniquely linked to exercise or anxiety. Conclusions: The results of the present study can be used to inform initial targeting of efforts to reduce kratom use among college students.
... Lacking surveys of kratom use in BC, estimates of 10 million to 16 million current regular users in the US might suggest that 100 000 or more BC residents use kratom. 38 Accordingly, we suspect that only a small fraction of exposures in BC result in poison centre calls and that a much smaller fraction is associated with serious acute effects on health. ...
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.
... Although adverse health effects are not experienced by most kratom users, physicians should bear in their mind, the side effects, toxicity, addictive potential, and withdrawal symptoms of kratom which are increasingly met in emergency department due to widespread use (Galbis-Reig, 2016). Henningfield et al. (2019) one of defenders of kratom as safe products, noted that the risk of overdose death is >1000 times greater for opioids than for kratom. Also, Yue and Katz (2018) experimental study demonstrated a limited abuse liability of mitragynine, and its use in reducing opioid abuse. ...
... Use of herbal supplements has increased in the United States with many patients opting to use these as alternatives or in addition to prescription medications for treatment of a multitude of conditions. 1 Kratom is an herbal supplement that has emerged as a mood enhancer for treatment of anxiety and depression, in addition to use as a stimulant, pain reliever, and for opioid withdrawal. 2 Based on survey data, it is estimated that up to 16 million people in the United States (US) use kratom, with 66% of users consuming it for treatment of emotional or mental conditions. 3,4 Kratom comes from leaves of the Mitragyna speciosa plant in Southeast Asia. It contains mitragynine and 7-hydroxymitragynine (7-HMG), both indole alkaloids that have been shown in animal studies to exhibit pharmacologic activity on both the serotonin and dopamine pathways, which are important in treatment of anxiety and depression. ...
Introduction
Kratom, an unregulated herbal supplement, has emerged as self-treatment for anxiety/depression. Kratom exhibits inhibition at multiple cytochrome P450 isozymes involved in metabolism of prescription medications, including serotonergic agents. We report a case of possible serotonin syndrome induced by kratom use in combination with prescription psychotropic medications.
Case
A 63-year-old male presented with diaphoresis, flushing, aphasia, confusion, dysarthria, right facial droop, and oral temperature of 39.6 o C (103.2 o F), lactate 2.7 mmol/L, and creatine phosphokinase of 1507 IU/L. Initial differential diagnoses included acute ischemic stroke and bacterial meningitis. Despite partial treatment with alteplase and broad-spectrum antibiotics, symptoms persisted, and subsequent physical exam noted hyperreflexia, clonus, tremors, and temperature of 41.1 o C (106 o F). Home medications included a chronic regimen for anxiety/depression with bupropion, buspirone, desvenlafaxine, trazodone, and ziprasidone, in addition to kratom. Clinical suspicion for serotonin syndrome led to initiation of cyproheptadine, lorazepam, and cooling blankets. Aphasia, facial droop, and confusion improved after administration of cyproheptadine. Bupropion was restarted during hospitalization; remaining medications restarted at the discretion of the primary care provider.
Discussion
Risk of serotonin syndrome with multiple serotonergic agents is well-known. Kratom is metabolized by cytochrome P40 isozymes 3A4, 2C9, and 2D6, and exhibits inhibition at those enzymes, in addition to 1A2. Pharmacokinetic interactions of kratom with prescription serotonergic agents metabolized through these isozymes has the potential to increase systemic exposure of serotonin, potentially leading to serotonin syndrome.
Conclusion
Because substances contained in kratom can inhibit metabolism of prescription serotonergic medications, clinicians must be aware of potential development of serotonin syndrome.
... Because most kratom users usually do not consume only kratom, some of the adverse health effects associated with its use may be caused by other substances or may be exacerbated by pre-existing health conditions [29]. Adulteration is a concern because serious adverse effects or even death may result [1,13]. ...
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
... Blood concentrations where mitragynine was ruled as a contributing COD ranged from 10 to 870 ng/mL in central blood and 24.6 to 1,210 ng/mL in peripheral blood. Kratom is not without risk, but estimates suggest that morphine-like opioids impart a risk of serious toxicity (e.g., overdose), which is thousand times greater than kratom (29). It is acknowledged that users of kratom organically carry other factors that greatly increase the risk of kratomassociated mortality. ...
Mitragyna speciosa, a species of plant that is native to Thailand, Malaysia and Southeast Asia, contains two major psychoactive alkaloids: mitragynine and 7-hydroxymitragynine. Pharmacologically, the alkaloids exhibit biphasic effects - at low dose, stimulant effects are realized, while high doses exhibit sedative effects. For years, the plant has been used recreationally and medicinally for these effects, but its use has been implicated in and associated with intoxications and deaths. In this case report we describe two cases whereby decedents presented with single substance fatal intoxications by mitragynine in the absence of other postmortem toxicological findings. The cases entail young male decedents in outdoor settings (e.g. driving a vehicle and bicycle). Postmortem blood concentrations were 2,325 ng/mL and 3,809 ng/mL. The medical examiner (ME) certified cause of death (COD) as acute mitragynine intoxication in both cases. The toxicology results presented become useful when considering mitragynine to be the offending agent in lethal single drug intoxications; further, the information included is pertinent to medical examiners, forensic pathologists, forensic toxicologists, and emergency department personnel in evaluating possible poisoning and lethality by mitragynine.
... 9,18 This may explain the less severe respiratory depression and other adverse effects reported by kratom usingadults, as activation of the β-arrestin pathway is associated with many of the adverse effects typical of classical opioids, such as morphine, oxycodone, or fentanyl. 9,[19][20][21][22][23] Despite its perceived beneficial effects, long-term kratom use has been associated with the development of tolerance and dependence, and case studies report kratom withdrawal symptoms similar to opioids that required treatment with buprenorphine and/or naloxone. [24][25][26][27][28] Kratom remains differentially scheduled in various countries. ...
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.
... Another recent study employed an open-field test and an elevated-plus maze test to evaluate naloxone-precipitated withdrawal from MG as compared to morphine, and provided additional evidence confirming that MG can induce physical dependence and measurable signs of withdrawal in rats (Harun et al., 2021a). Overall, the research is consistent with human reports that (Giroir, 2018), (Food and Drug Admini, 2018;Gershman et al., 2019;Henningfield et al., 2019;Olsen et al., 2019) Risk of kratom associated death appears to be at least a thousand times lower than for morphine-like opioids Approximately 80% of kratom positive or "involved" deaths also detected other drugs of abuse or the decedent had a history of substance use disorders in one study contribution by other drugs not possible to rule out Mortality Risks Projected as a Result of Banning Licit Kratom (Henningfield et al., 2018a), (Ingraham, 2016b), (Giroir, 2018), Coe et al., 2019;Garcia-Romeu et al., 2020), (Grundmann, 2017), (Henningfield et al., 2018b;Henningfield et al., 2018c;Henningfield et al., 2018d;Prozialeck et al., 2020) Surveys suggest that it is likely that some kratom users would return to opioid use if kratom use and possession is banned ...
Drugs are regulated in the United States (US) by the Controlled Substances Act (CSA) if assessment of their abuse potential, including public health risks, show such control is warranted. An evaluation via the 8 factors of the CSA provides the comprehensive assessment required for permanent listing of new chemical entities and previously uncontrolled substances. Such an assessment was published for two kratom alkaloids in 2018 that the Food and Drug Administration (FDA) have identified as candidates for CSA listing: mitragynine (MG) and 7-hydroxymitragynine (7-OH-MG) (Henningfield et al., 2018a). That assessment concluded the abuse potential of MG was within the range of many other uncontrolled substances, that there was not evidence of an imminent risk to public health, and that a Schedule I listing (the only option for substances that are not FDA approved for therapeutic use such as kratom) carried public health risks including drug overdoses by people using kratom to abstain from opioids. The purpose of this review is to provide an updated abuse potential assessment reviewing greater than 100 studies published since January 1, 2018. These include studies of abuse potential and physical dependence/withdrawal in animals; in-vitro receptor binding; assessments of potential efficacy treating pain and substance use disorders; pharmacokinetic/pharmacodynamic studies with safety-related findings; clinical studies of long-term users with various physiological endpoints; and surveys of patterns and reasons for use and associated effects including dependence and withdrawal. Findings from these studies suggest that public health is better served by assuring continued access to kratom products by consumers and researchers. Currently, Kratom alkaloids and derivatives are in development as safer and/or more effective medicines for treating pain, substances use disorders, and mood disorders. Placing kratom in the CSA via scheduling would criminalize consumers and possession, seriously impede research, and can be predicted to have serious adverse public health consequences, including potentially thousands of drug overdose deaths. Therefore, CSA listing is not recommended. Regulation to minimize risks of contaminated, adulterated, and inappropriately marketed products is recommended.
... However, as Palamar noted (2021), such surveys can often under-estimate usage within the general population. Other estimates of kratom usage based on import data from Indonesia and average kratom consumption may actually be much higher, perhaps as many as 10-20 million (AKA, 2019;Henningfield et al., 2019). Unfortunately, data on levels of kratom imports over the years are not reliable and are skewed by import alerts by the FDA and seizures of kratom shipments in recent years (FDA, 2021). ...
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.
... A limitation of the current review is that the supposed benefits-to-risk ratio of kratom use cannot be currently addressed adequately. There is insufficient epidemiological documentation as to the extent of kratom use worldwide and in specific countries (119), so to estimate how many people use it and how many develop unwanted effects. Besides this, risks may increase, as many kratom users have concurrent other substance use (120), and this is difficult to disentangle. ...
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.
... Based on import and sales of kratom, there are an estimated 10-15 million kratom users in the US, meaning that disruptions for even a small proportion of regular users could result in an outsized effect (25). In the coming months, it will be important to monitor kratom supplies and purchasing avenues (e.g., Internet and local shops). ...
Kratom ( Mitragyna speciosa Korth., Rubiaceae) is native to and has traditional use in Southeast Asia. The number of kratom users outside of Southeast Asia has increased significantly in recent decades with use spreading to the Unites States (US) and Europe. Because of its reputed opioid-like psychoactive effects at higher doses, kratom has been regulated in several countries and is subject to an import ban by the US Food and Drug Administration. Nonetheless, in the US it is estimated that 10–15 million people consume kratom primarily for the self-treatment of pain, psychiatric disorders, to mitigate withdrawal from or dependence on opioids, and to self-treat opioid use disorder or other substance use disorders (SUDs). Due to the global COVID-19 pandemic, a shortage in the supply of kratom products may place unexpected burdens on kratom users, potentially influencing some who use kratom for SUD self-treatment to regress to harmful drug use, hence increasing the likelihood of adverse outcomes, including overdose. Inadequate treatment, treatment barriers, and increases in the sales of adulterated kratom products on the internet or in convenience stores could exacerbate circumstances further. Although there are currently no verified indications of kratom scarcity, researchers and clinicians should be aware of and remain vigilant to this unanticipated possibility.
... Fatalities involving kratom are rare and, autopsy findings indicate that in such instances kratom is concurrently used with illicit substances or anti-depressants, and not kratom per se, or the user had an underlying health condition (28,29). So far, there have been no reports specifically on fatal kratom overdose incidences (30). ...
Among the symptoms of COVID-19 fever, general malaise, pain and aches, myalgia, fatigue, and headache can affect the quality of life of patients, even after the end of the acute phase of the infection and can be long lasting. The current treatment of these symptoms, also because COVID-19 patients have been asked not to use non-steroidal anti-inflammatory drugs (NSAIDs), in particular ibuprofen are often unsatisfactory. Among the above mentioned symptoms malaise and fatigue seem the most difficult to treat. In this case report we describe the use of kratom (Mitragyna speciosa) by a patient with confirmed COVID-19 infection. What we observed was a fast and sustained relieve of the above mentioned symptoms.
... Thus, it can be postulated that users with regular kratom consumption in the form of a brewed solution (tea/juice) in amounts observed in this study did not present with more ECG abnormalities than non-users as has been suggested as a potential contribution to some cases of kratom-associated mortality [8]. Most of the adverse health problems which have been linked with kratom use were caused by the couse of kratom with other substances or were aggravated by underlying medical problems and not kratom use per se [2,29]. It has been shown that significant adverse drug interactions may occur when mitragynine is co-administered with drugs that are metabolised by cytochrome P450 enzymes, as mitragynine is a CYP2D6 inhibitor [30]. ...
Objectives:
Little is known about the cardiotoxic effects of kratom (Mitragyna speciosa Korth.), a medicinal plant. This analytical cross-sectional study investigated the prevalence of electrocardiogram (ECG) abnormalities and QTc intervals in regular kratom users compared with non-kratom-using control subjects.
Methods:
We enrolled regular kratom users and non-kratom-using control subjects from three communities. Demographic data, clinical data, kratom use characteristics, and ECG findings were recorded. The mitragynine content of kratom juice was quantified using a validated gas chromatography-mass spectrometry (GC-MS) method.
Results:
A total of 200 participants (100 kratom users and 100 control subjects) participated in this study. The prevalence of ECG abnormalities in kratom users (28%) did not differ from that of control subjects (32%). Kratom use was not associated with ECG abnormalities, except for significantly higher odds of sinus tachycardia (OR = 8.61, 95% CI = 1.06-70.17, p = 0.035) among kratom users compared with control subjects. The odds of observing borderline QTc intervals were significantly higher for kratom users compared with control subjects, regardless of the age of first use, the duration of use, the daily quantity consumed, and the length of time that had elapsed between last kratom use and ECG assessment. Nevertheless, there were no differences in the odds of having prolonged QTc intervals between kratom users and controls. The estimated average daily intake of mitragynine consumed by kratom users was 434.28 mg.
Conclusion:
We found no link between regular kratom use and electrocardiographic abnormalities with an estimated average daily intake of 434.28 mg of mitragynine.
... Published data from more than 20,000 kratom users [3,5,7] suggests that the proportion of kratom users in the general population is far higher, and the consequences of its use far less severe. Opioid overdose mortality data in the United States indicate that the risk of death is more than 1000 times greater for illicit opioids than for kratom [11]. Some user reports suggest that regular kratom consumption carries risks of dependency and addiction, although with generally self-manageable withdrawal [12]. ...
... Sufficient scientific understanding of the analgesic effects and addiction potential of opioids is available to avoid repeating the swings of the pendulum on prescribing practices that contributed to the current epidemic. Henningfield et al. (2019b) pivot from that insightful overview to a more targeted essay arguing that recent actions to curtail use of kratom, a naturally growing plant in several Asian countries, out of concerns of overdose are incongruent with extant evidence on its pharmacology and risk for fatal overdose. Closing out the contributions on the opioid epidemic, Peck and colleagues (Peck et al., 2019, in this issue) contribute evidence from a U.S. nationally representative survey that when young adults are queried about reasons for past year non-medical use of opioids, they endorse treatment of physical pain at more than twice the rate of using to feel good/get high or experimentation. ...
This Special Issue of Preventive Medicine (PM) is the 6th in a series on behavior change, health, and health disparities. This is a topic of critical importance to improving U.S. population health. There is broad consensus that personal behavior patterns or lifestyle such as substance abuse, physical inactivity/obesity, and non-adherence with medical regimens are among the most important modifiable causes of chronic disease, premature death and population health. Hence, effectively promoting health-related behavior change needs to be a key component of health care research and policy. In this issue we devote the majority of space (14 of 20 reports) to the U.S. opioid epidemic, especially the ongoing but still woefully inadequate efforts to build the necessary clinical infrastructure in rural communities to effectively address the epidemic. The remaining six reports focus on addressing the substantive challenges that tobacco use and non-adherence with medical regimens represent in these same communities. While giving the opioid epidemic the attention that it well deserves, we cannot afford to do so at the expense of these other longstanding and also devastating public health problems. Across each of these topics we include contributions from well-regarded investigators, clinicians, and policymakers to acquaint readers with recent accomplishments while also noting knowledge gaps and unmet challenges.
Kratom (Mitragyna speciosa) is a tree in the coffee family, indigenous to Southeast Asia (SEA), whose leaves have historically been used as a natural remedy and for its purported stimulating and analgesic properties. Kratom has gained popularity in recent years in the United States, where internet-based sales have driven growing numbers of people to experiment with kratom products. Kratom contains over 40 unique alkaloids displaying complex pharmacological properties including opioid- and non opioid-receptor mediated effects. Data from animal research indicates therapeutic potential of kratom; for instance, as an analgesic agent or in mitigating opioid and alcohol withdrawal symptoms. Some adverse effects and risks are also attributable to kratom and its alkaloids, including possible liver damage and potential for dependence, particularly in the context of high dosage and/or chronic administration. However, in comparison to commonly used opioid medications, these risks are generally lower for kratom, consistent with human observational data from SEA and the US. Prevalence of kratom use remains difficult to conclusively assess, with estimates ranging between 1.8 to 15.6 million kratom-using adults in the US alone. The limited human data, comprised of survey and case report, suggest kratom may be effective for pain relief, to address mood and anxiety symptoms, and as a potential future aid in the treatment of substance use disorders and drug withdrawal. Overall, limited data indicate kratom and its alkaloids warrant a significant investment of rigorous basic and clinical research to better characterize its pharmacology, potential risks, and therapeutic benefits.
Background
The legal status of kratom in the United States is complex and varies by state. The U.S. Food and Drug Administration (FDA) and the U.S. Drug Enforcement Administration have repeatedly subjected kratom to regulatory review. However, there hasn't been a systematic review of the public's perception of kratom. The present study analyzed open-ended responses from the public to an FDA solicitation for information regarding kratom with the goal of providing a comprehensive assessment of motives for kratom use.
Methods
To guide decisions regarding kratom regulation, the FDA solicited comments regarding kratom abuse potential, medical usefulness, and impact of scheduling changes from July through August 2021 and posted them to the Federal Register website. We analyzed comments posted during the first 6 weeks of comment solicitation (6,353) using an inductive approach via qualitative content analysis.
Results
Respondents reported 106 independent health-related reasons for kratom use, with most categorized as mental health, pain management, substance use disorder, or miscellaneous purposes that included increasing focus, treating insomnia, and decreasing fatigue. Neurological diseases and digestive disorders were also reported. Relatively few (< 2%) responses reported recreational use, abuse potential, or adverse effects of kratom.
Conclusions
Although kratom is not approved as a safe and effective therapy for any indication, individuals use kratom for a broad spectrum of health-related purposes. Limitations of this study include potential bias for respondents with perceived positive experiences using kratom, lack of demographics data, and lack of independent verification of claims made by respondents. Regardless, this study reflects perceptions regarding the therapeutic uses of kratom and provides insight into potential individual-level consequences of regulating kratom in the U.S. It is important to study the public's perception of kratom use, which can aid regulatory purposes and provide clinically important information on individuals’ use and valuation of kratom.
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.
Kratom (Mitragyna speciosa) consists of over 40 alkaloids with two of them, mitragynine (MG) and 7‐OH‐mitragynine (7‐OH‐MG) being the main psychoactive compounds. MG and 7‐OH‐MG each target opioid receptors and have been referred to as atypical opioids. They exert their pharmacologic effects on the μ, δ, and κ opioid receptors. In addition, they affect adrenergic, serotonergic, and dopaminergic pathways. Kratom has been touted as an inexpensive, legal alternative to standard opioid replacement therapy such as methadone and buprenorphine. Other uses for kratom include chronic pain, attaining a “legal high,” and numerous CNS disorders including anxiety depression and post‐traumatic stress disorder (PTSD). Kratom induces analgesia and mild euphoria with a lower risk of respiratory depression or adverse central nervous system effects compared to traditional opioid medications. Nonetheless, kratom has been associated with both physical and psychological dependence with some individuals experiencing classic opioid withdrawal symptoms upon abrupt cessation. Kratom use has been linked to serious adverse effects including liver toxicity, seizures, and death. These risks are often compounded by poly‐substance abuse. Further, kratom may potentiate the toxicity of coadministered medications through modulation of cytochrome P450, P‐glycoprotein, and uridine diphosphate glucuronosyltransferase enzymes (UGDT). In 2016 the U.S. Drug Enforcement Administration (DEA) took steps to classify kratom as a federal schedule 1 medication; however, due to public resistance, this plan was set aside. Until studies are conducted that define kratom's role in treating opioid withdrawal and/or other CNS conditions, kratom will likely remain available as a dietary supplement for the foreseeable future. This article is protected by copyright. All rights reserved
Kratom, a plant that produces opioid-like effects, has gained popularity in the U.S. for self-treating symptoms of chronic pain, mood disorders, and substance-use disorders (SUDs). Most data on kratom are from surveys into which current kratom-using adults could self-select; such surveys may underrepresent people who have used kratom and chosen to stop. Available data also do not adequately assess important psychosocial factors surrounding kratom use. In this study, U.S. adults who reported past 6-month alcohol, opioid, and/or stimulant use (N = 1,670) were recruited via Amazon Mechanical Turk between September and December 2020. Of the 1,510 evaluable respondents, 202 (13.4%) reported lifetime kratom use. Kratom-using adults, relative to others, were typically younger, male, unpartnered, without children, and had lower income. They had higher rates of chronic pain (31.7% vs. 21.9%, p = .003), childhood adversity, anxiety, and depression (p < .001), and lower perceived social rank (d = .19, .02-.22) and socioeconomic status (d = .37 .16-.26). They also reported higher use rates for most substances (except alcohol); this included medically supervised and unsupervised use of prescription opioids and diverted opioid agonist therapy (OAT) medications. Most (83.2%) met diagnostic criteria for any past-year SUD. Those reporting kratom use were less likely to reside in an urban/suburban area. The strongest predictors of kratom use were use of other drugs: cannabidiol (OR = 3.73), psychedelics (OR = 3.39), and nonmedical prescription opioids (OR = 1.72). Another strong predictor was lifetime OAT utilization (OR = 2.31). Despite seemingly poorer psychosocial functioning and health among respondents reporting lifetime kratom use, use of other substances may be the strongest indicators of kratom use. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Opioids were the most common drug class resulting in overdose deaths in the United States in 2019. Widespread clinical use of prescription opioids for moderate to severe pain contributed to the ongoing opioid epidemic with the subsequent emergence of fentanyl‐laced heroin. More potent analogues of fentanyl and structurally diverse opioid receptor agonists such as AH‐7921 and MT‐45 are fueling an increasingly diverse illicit opioid supply. Overdose from synthetic opioids with high binding affinities may not respond to a typical naloxone dose, thereby rendering autoinjectors less effective, requiring higher antagonist doses or resulting in a confusing clinical picture for health care providers. Nonscheduled opioid drugs such as loperamide and dextromethorphan are associated with dependence and risk of overdose as easier access makes them attractive to opioid users. Despite a common opioid‐mediated pathway, several opioids present with unique pharmacodynamic properties leading to acute toxicity and dependence development. Pharmacokinetic considerations involve half‐life of the parent opioid and its metabolites as well as resulting toxicity, as is established for tramadol, codeine, and oxycodone. Pharmacokinetic considerations, toxicities, and treatment approaches for notable opioids are reviewed.
Background:
Mitragyna speciosa, referred to as "kratom", is increasingly used in the United States for self-treating pain, psychiatric, and substance use disorder symptoms. It is used by some to attenuate opioid withdrawal and as a longer-term drug substitute. Most self-report data have come from online surveys, small in-person surveys, and case reports. These may not be representative of the broader kratom-using population.
Purpose:
Analyze user-generated social media posts to determine if independent, descriptive accounts are generally consistent with prior U.S. kratom survey findings and gain a more nuanced understanding of kratom use patterns.
Methods:
Reddit posts mentioning kratom from 42 subreddits between June 2019-July 2020 were coded by two independent raters.
Findings:
Relevant posts (number of comments, upvotes, and downvotes) from 1274 posts comprised the final sample (n = 280). Of the 1521 codes applied, 1273 (83.69%) were concordant. Desirable kratom effects were described among a majority, but so too were adverse effects. Reports of kratom as acute self-treatment for opioid withdrawal were more prominent compared to longer-term opioid substitution. Quantitative analysis found higher kratom doses associated (p < .001) with greater odds of reported kratom addiction (OR = 3.56) or withdrawal (OR = 5.88), with slightly lower odds of desirable effects (OR = 0.53, p = .014). Despite perceived therapeutic benefits, kratom was characterized by some in terms of addiction that, in some cases, appeared dose-dependent. Polydrug use was also prominently discussed.
Conclusions:
Results validated many prior survey findings while illustrating complexities of kratom use that are not being fully captured and require continued investigation.
Background
Kratom (Mitragyna speciosa Korth.) is a medicinal plant, widely used in Southeast Asia chiefly for its unique medicinal properties in treating chronic pain, opioid dependence and withdrawal, and as a mood enhancer.
Method
Relevant articles describing kratom's medicinal utility was identified and reviewed.
Results
In traditional settings, laborers chew fresh leaves or ingest a kratom decoction (tea) as a stimulant that increases work performance, while those with opioid use disorder (OUD) use kratom as an affordable substitute for opioids. Though kratom is alleged to cause adverse health effects if used frequently over prolonged periods, its use has not been linked to any major health threat in traditional settings.
Conclusion
Currently, kratom’s pharmacological and long-term safety profile remains poorly elucidated and warrants further research. This paper provides a brief account of possibly overlooked medicinal potential of kratom.
Pain management devoid of serious opioid adverse effects is still far from reach despite vigorous research and development efforts. Alternatives to classical opioids have been sought for years, and mounting reports of individuals finding pain relief with kratom have recently intensified research on this natural product. Although the composition of kratom is complex, the pharmacological characterization of its most abundant alkaloids has drawn attention to three molecules in particular, owing to their demonstrated antinociceptive activity and limited side effects in vivo. These three molecules are mitragynine (MG), its oxidized active metabolite, 7-hydroxymitragynine (7OH), and the indole-to-spiropseudoindoxy rearrangement product of MG known as mitragynine pseudoindoxyl (MP). Although these three alkaloids have been shown to preferentially activate the G protein signaling pathway by binding and allosterically modulating the μ-opioid receptor (MOP), a molecular level understanding of this process is lacking and yet important for the design of improved therapeutics. The molecular dynamics study and experimental validation reported here provide an atomic level description of how MG, 7OH, and MP bind and allosterically modulate the MOP, which can eventually guide structure-based drug design of improved therapeutics.
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.
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.
Mitragyna speciosa, more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability, have highlighted the need for more careful study of its pharmacological activity. The major active alkaloid found in kratom, mitragynine, has been reported to have opioid agonist and analgesic activity in vitro and in animal models, consistent with the purported effects of kratom leaf in humans. However, preliminary research has provided some evidence that mitragynine and related compounds may act as atypical opioid agonists, inducing therapeutic effects such as analgesia, while limiting the negative side effects typical of classical opioids. Here we report evidence that an active metabolite plays an important role in mediating the analgesic effects of mitragynine. We find that mitragynine is converted in vitro in both mouse and human liver preparations to the much more potent mu-opioid receptor agonist 7-hydroxymitragynine and that this conversion is mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine is formed from mitragynine in mice and that brain concentrations of this metabolite are sufficient to explain most or all of the opioid-receptor-mediated analgesic activity of mitragynine. At the same time, mitragynine is found in the brains of mice at very high concentrations relative to its opioid receptor binding affinity, suggesting that it does not directly activate opioid receptors. The results presented here provide a metabolism-dependent mechanism for the analgesic effects of mitragynine and clarify the importance of route of administration for determining the activity of this compound. Further, they raise important questions about the interpretation of existing data on mitragynine and highlight critical areas for further research in animals and humans.
RationaleConsideration by the US Drug Enforcement Administration and Food and Drug Administration of placing kratom into Schedule I of the Controlled Substances Act (CSA) requires its evaluation of abuse potential in the context of public health. Objective
The objective of the study is to provide a review of kratom abuse potential and its evaluation according to the 8 factors of the CSA. ResultsKratom leaves and extracts have been used for centuries in Southeast Asia and elsewhere to manage pain and other disorders and, by mid-twentieth century, to manage opioid withdrawal. Kratom has some opioid effects but low respiratory depression and abuse potential compared to opioids of abuse. This appears due to its non-opioid-derived and resembling molecular structure recently referred to as biased agonists. By the early 2000s, kratom was increasingly used in the US as a natural remedy to improve mood and quality of life and as substitutes for prescription and illicit opioids for managing pain and opioid withdrawal by people seeking abstinence from opioids. There has been no documented threat to public health that would appear to warrant emergency scheduling of the products and placement in Schedule I of the CSA carries risks of creating serious public health problems. Conclusions
Although kratom appears to have pharmacological properties that support some level of scheduling, if it was an approved drug, placing it into Schedule I, thus banning it, risks creating public health problems that do not presently exist. Furthermore, appropriate regulation by FDA is vital to ensure appropriate and safe use.
Ethnopharmacological relevance:
Kratom (Mitragyna speciosa Korth.) from the Rubiaceae family is an indigenous tropical medicinal tree of Southeast Asia. Kratom leaves have been used for decades in Malaysia and Thailand in traditional context for its perceived vast medicinal value, and as a mild stimulant among manual labourers. Kratom consumption has been reported to cause side-effects in kratom users.
Aim of the study:
To evaluate kratom's effects towards hematological and clinical-chemistry parameters among regular kratom users in Malaysia.
Methods:
A total of 77 subjects (n=58 regular kratom users, and n=19 healthy controls) participated in this cross-sectional study. All the surveys were conducted through face-to-face interview to elicit subject's socio-demographic characteristics and kratom use history. A full-blood test was also administered. Laboratory analysis was conducted using GC-MS to determine mitragynine content in the acquired kratom samples in order to relate mitragynine consumption with possible alterations in the blood parameters of kratom users.
Results:
Findings showed that there were no significant differences in the hematological and clinical-chemistry parameters of traditional kratom users and healthy controls, except for HDL and LDL cholesterol values; these were found to be above the normal reference range for the former. Similarly, long-term kratom consumption (>5 years), and quantity of daily kratom use (≥3 ½ glasses; mitragynine content 76.3-114.8mg) did not appear to alter the hematological and biochemical parameters of kratom users.
Conclusion:
These data suggest that even long-term and heavy kratom consumption did not significantly alter the hematological and clinical-chemistry parameters of kratom users in a traditional setting.
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.
Objectives-This report presents final 2017 data on U.S. deaths, death rates, life expectancy, infant mortality, and trends, by selected characteristics such as age, sex, Hispanic origin and race, state of residence, and cause of death. Methods-Information reported on death certificates is presented in descriptive tabulations. The original records are filed in state registration offices. Statistical information is compiled in a national database through the Vital Statistics Cooperative Program of the National Center for Health Statistics. Causes of death are processed in accordance with the International Classification of Diseases, 10th Revision. Results-In 2017, a total of 2,813,503 deaths were reported in the United States. The age-adjusted death rate was 731.9 deaths per 100,000 U.S. standard population, an increase of 0.4% from the 2016 rate. Life expectancy at birth was 78.6 years, a decrease of 0.1 year from the 2016 rate. Life expectancy decreased from 2016 to 2017 for non-Hispanic white males (0.1 year) and non-Hispanic black males (0.1), and increased for non- Hispanic black females (0.1). Age-specific death rates increased in 2017 from 2016 for age groups 25-34, 35-44, and 85 and over, and decreased for age groups under 1 and 45-54. The 15 leading causes of death in 2017 remained the same as in 2016 although, two causes exchanged ranks. Chronic liver disease and cirrhosis, the 12th leading cause of death in 2016, became the 11th leading cause of death in 2017, while Septicemia, the 11th leading cause of death in 2016, became the 12th leading cause of death in 2017. The infant mortality rate, 5.79 infant deaths per 1,000 live births in 2017, did not change significantly from the rate of 5.87 in 2016. Conclusions-The age-adjusted death rate for the total, male, and female populations increased from 2016 to 2017 and life expectancy at birth decreased in 2017 for the total and male populations.
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.
Background:
Kratom is a South Eastern Asian tree whose leaves are used to make tea-like brews or swallowed in powdered form for various health and well-being reasons including to relieve pain and opioid withdrawal. It is important to learn more about the potential public health impact of kratom in the context of the opioid epidemic.
Methods:
An anonymous online survey of kratom users (2867 current users and 157 former users) was conducted in September 2017 through the American Kratom Association and associated social media sites.
Results:
Kratom was used primarily to relieve pain (endorsed by 48% of respondents), for anxiety, PTSD, or depression (22%), to increase energy or focus (10%) and to help cut down on opioid use and/or relieve withdrawal (10%). Over 90% of respondents who used it in place of opioids indicated that it was helpful to relieve pain, reduce opioid use, and relieve withdrawal. The reported incidence of bad adverse reactions was 13%, and reactions were overwhelmingly mild and self-managed.
Conclusions:
Respondents reported using kratom for conditions which often require use of opioids, including pain and reduction of opioid use. The high self-reported efficacy and low incidence of adverse reactions associated with kratom use suggest that it may provide a potential alternative to opioids for some persons even though it has not been evaluated in multi-center clinical trials or approved for any therapeutic purpose. Further study of kratom, including systematic characterization of its safety and efficacy for various conditions is warranted.
Kratom is an herbal drug that at high doses has opioid-like effects, but the potential for fatal overdose is unclear. This study of 15 kratom-related deaths in Colorado from 1999 through 2017 included comprehensive toxicologic screening of serum samples in which toxic drugs other than kratom were identified.
1. Mitragynine is the major indole-based alkaloid of Mitragyna speciosa (kratom). Decoctions (teas) of the plant leaves have been used traditionally for cough, diarrhoea, pain, hypertension, and for the treatment of opioid addiction. In the West, kratom has become increasingly utilized for mood elevation, pain treatment, and as a means of self-treating opioid addiction.
2. Metabolic pathways of mitragynine were identified in human liver microsomes (HLM) and S9 fractions. A total of thirteen metabolites were identified, four oxidative metabolites and a metabolite formed by demethylation at the 9-methoxy group were the major metabolites of mitragynine.
3. The cytochrome P450 enzymes involved in the metabolism of mitragynine were identified using selective chemical inhibitors of HLM and recombinant cytochrome P450. The metabolism of mitragynine was predominantly carried out through the CYP3A4 with minor contributions by CYP2D6 and CYP2C9. The formation of five oxidative metabolites (Met2, Met4, Met6 Met8 and Met11) was catalyzed by the CYP3A4.
4. In summary, mitragynine was extensively metabolized in HLM primarily to O-demethylated and monooxidative metabolites. The CYP3A4 enzyme plays a predominant role in the metabolic clearance of mitragynine and also in the formation of 7-hydroxymitragynine (Met2), a known active minor alkaloid identified in the leaf material.
Kratom (Mitragyna speciosa) has been examined for its opioid activity, especially for the treatment of opioid withdrawal and pain. Mitragynine, the most abundant alkaloid in kratom, is thought to be the major psychoactive alkaloid. An HPLC method was developed for the quantification of mitragynine in kratom leaf extracts. In addition, a multiple reaction mode based UPLC-MS/MS method was developed and validated for the quantification of mitragynine in rat plasma. Pharmacokinetic studies were performed by comparing a single intravenous dose of mitragynine (5 mg/kg, mitragynine hydrochloride) to a single oral dose of mitragynine (20 mg/kg, mitragynine hydrochloride), lyophilized kratom tea, and the organic fraction of the lyophilized kratom tea at an equivalent mitragynine dose of 20 mg/kg in rats. After intravenous administration, mitragynine exhibited a biexponential decrease in the concentration-time profile, indicating the fast distribution of mitragynine from the systemic circulation or central compartment to the peripheral compartments. Mitragynine hydrochloride, lyophilized kratom tea, and the lyophilized kratom tea organic fraction were dosed orally and the absolute oral bioavailability of mitragynine in rats was found to be 1.5- and 1.8-fold higher than that of mitragynine dosed alone. The results provide evidence that an equivalent oral dose of the traditional preparation (lyophilized kratom tea) and formulated/manufactured products (organic fraction) of kratom leaves provide better systemic exposure of mitragynine than that of mitragynine dosed alone.
Analyzing the drug abuse epidemic
There is a developing drug epidemic in the United States. Jalal et al. analyzed nearly 600,000 unintentional drug overdoses over a 38-year period. Although the overall mortality rate closely followed an exponential growth curve, the pattern itself is a composite of several underlying subepidemics of different drugs. Geographic hotspots have developed over time, as well as drug-specific demographic differences.
Science , this issue p. eaau1184
Background:
Kratom (Mitragyna speciosa) is a psychoactive plant native to Southeastern Asia that is receiving increased international attention as a potential therapeutic agent. While much of the limited scientific research on kratom is focused on its analgesic potential, kratom use also has important risks and benefits in the domain of mental health.
Methods:
We conducted a comprehensive systematic review of all studies on kratom use and mental health published between January 1960 and July 2017.
Results:
Findings indicate kratom's potential as a harm reduction tool, most notably as a substitute for opioids among people who are addicted. Kratom also enhances mood and relieves anxiety among many users. For many, kratom's negative mental health effects - primarily withdrawal symptoms - appear to be mild relative to those of opioids. For some users, however, withdrawal is highly uncomfortable and maintaining abstinence becomes difficult.
Conclusion:
Results inform clinicians working in the mental health and substance use fields, policy-makers, and researchers about the mental health effects of this plant.
Background:
Kratom use in the West has increased recently, yet the prevalence and motives for use among individuals with a history of substance use disorder (SUD) have not been fully examined. Kratom has been documented as a means of treating chronic pain, mitigating drug dependence, and easing withdrawal symptoms, yet it is unclear if substance users are utilizing kratom as a self-medication. Abuse liability, side effects, and overall appeal of kratom remain uncertain.
Methods:
In April 2017, an anonymous survey regarding kratom use and motivations was completed by clients enrolled in a 12-Step-oriented residential program. 500 respondents with a self-reported history of SUD completed the survey.
Results:
20.8% of respondents endorsed lifetime kratom use and 10.2% reported past-12-month use. Kratom-users were younger (=32.1 vs. 35.9, p<0.001) and were more versatile substance users. A majority (68.9%) of kratom-users reported having used the drug as a means of reducing or abstaining from non-prescription opioids (NPO) and/or heroin, and 64.1% reported using kratom as a substitute for NPO/heroin. 18.4% of kratom-users reported using the drug due to a disability or chronic pain. One-third of kratom-users stated that kratom was a helpful substance and that they would try it again. However, kratom was not preferred and was indicated as having less appeal than NPO, heroin, amphetamines, and Suboxone.
Conclusions:
Among substance users, kratom use may be initiated for a variety of reasons, including as a novel form of harm-reduction or drug substitution, particularly in the context of dependence and withdrawal from other substances.
The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast Asia, have been used traditionally for their stimulant, mood-elevating, and analgesic effects and have recently attracted significant attention due to increased use in Western cultures as an alternative medicine. The plant's active alkaloid constituents, mitragynine and 7-hydroxymitragynine, have been shown to modulate opioid receptors, acting as partial agonists at mu-opioid receptors and competitive antagonists at kappa- and delta-opioid receptors. Furthermore, both alkaloids are G protein-biased agonists of the mu-opioid receptor and therefore, may induce less respiratory depression than classical opioid agonists. The Mitragyna alkaloids also appear to exert diverse activities at other brain receptors (including adrenergic, serotonergic, and dopaminergic receptors), which may explain the complex pharmacological profile of raw kratom extracts, although characterization of effects at these other targets remains extremely limited. Through allometric scaling, doses of pure mitragynine and 7-hydroxymitragynine used in animal studies can be related to single doses of raw kratom plant commonly consumed by humans, permitting preliminary interpretation of expected behavioral and physiological effects in man based on this preclinical data and comparison to both anecdotal human experience and multiple epidemiological surveys. Kratom exposure alone has not been causally associated with human fatalities to date. However, further research is needed to clarify the complex mechanism of action of the Mitragyna alkaloids and unlock their full therapeutic potential.
Objective:
Kratom (Mitragyna speciosa. Korth) is an indigenous medicinal plant of Southeast Asia. This review paper aims to describe the trends of kratom use in Southeast Asia.
Design:
A literature review search was conducted through ScienceDirect, Scopus, ProMed and Google Scholar. Twenty-five articles illustrating kratom use in humans in Southeast Asia were reviewed.
Results:
Kratom has long been used by rural populations in Southeast Asia as a remedy for common ailments, to fight fatigue from hard manual work, as a drink during social interaction among men, and in village religious functions. Studies based on self-reports suggest that prolonged kratom use does not result in serious health risks or impair social functioning. Two recent trends have also emerged: (a) Kratom is reportedly being used to ease withdrawal from opioid dependence in rural settings; whereas (b) in urban areas, adulterated kratom cocktails are being consumed by younger people to induce euphoria.
Conclusions:
Legal sanctions appear to have preceded serious scientific investigations into the claimed benefits of ketum. More objective-controlled trials and experiments on humans need to be conducted to validate self-report claims by kratom users in the community.
Background:
Kratom preparations have raised concerns of public health and safety in the US. Investigation into the demographics, perceived beneficial and detrimental effects of Kratom as well as common doses and purposes of its use are important to properly evaluate its potential health impact.
Methods:
An anonymous cross-sectional online survey was conducted in October 2016 of 10,000 current Kratom users through available social media and online resources from the American Kratom Association. A total of 8049 respondents completed the survey.
Results:
Kratom is primarily used by a middle-aged (31-50 years), middle-income ($35,000 and above) population for purposes of self-treating pain (68%) and emotional or mental conditions (66%). Kratom preparations present with a dose-dependent effect with negative effects, which were primarily gastrointestinal related including nausea and constipation, mainly presenting at high (5g or more/dose) and more frequent (22 or more doses/week) dosing.
Conclusions:
Kratom shows a dose-dependent opioid-like effect providing self-reported perceived beneficial effects in alleviating pain and relieving mood disorders. Kratom was primarily used for self-treatment of pain, mood disorders, and withdrawal symptoms associated with prescription opioid use.
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.
Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacological properties. Here we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analogue 7-hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid receptor, which do not recruit β-arrestin following receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles. Also presented is an enantioselective total synthesis of both (-)-mitragynine and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed Mannich-Michael reaction sequence as the key transformation. Pharmacological evaluation of (+)-mitragynine revealed its much weaker opioid activity. Likewise, the intermediates and chemical transformations developed in the total synthesis allowed the elucidation of previously unexplored structure-activity relationships (SAR) within the Mitragyna scaffold. Molecular docking studies, in combination with the observed chemical SAR, suggest that Mitragyna alkaloids adopt a binding pose at the mu-opioid receptor that is distinct from that of classical opioids.
Harmful and nonmedical use of prescription opioids has increased precipitously in the United States and some other countries in recent years, but not everywhere around the world. Addressing this problem requires attention to scientific data and to objective and balanced consideration of factors driving the problems. Unfortunately, the situation has been blurred by some politicians, health professionals, and the media by their using inadequate concepts, misrepresenting and exaggerating facts, and demonizing pain patients. In this article, we analyze what has occurred and present what we believe to be a balanced view of the problems. We advocate comprehensive drug control policies implemented in a way to reduce harmful use and diversion problems balancing the public health benefits and risks of opioid medications. We make recommendations for responsible prescribing, including implementing the World Health Organization (WHO) policy guidelines and similar United Nations Office of Drug Control (UNODC), which we believe can contribute measurably to the prevention of diversion of prescription opioids while ensuring patient access to the most appropriate medicines. Measures to reduce the risks of nonmedical use of opioid medicines should be based to the greatest extent possible on accurate evaluation of the mechanisms leading to such use, including diversion activities.
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.
Herbal drug kratom linked to almost 100 overdose deaths, CDC says
- R Miller
2017 National Survey on Drug Use and Health: Detailed Tables
- Center for Behavioral Health Statistics and Quality
CDC Study Shows Kratom-Linked Overdose Deaths
- G Galvin