Article

Patterns of Kratom use and health impact in the US − Results from an online survey

May 2017
Drug and Alcohol Dependence 176

DOI:10.1016/j.drugalcdep.2017.03.007

Authors:

University of Florida

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.

Targeting Opioid Receptors in Addiction and Drug Withdrawal: Where Are We Going?

Article

Full-text available

Jun 2023
INT J MOL SCI

This review article offers an outlook on the use of opioids as therapeutics for treating several diseases, including cancer and non-cancer pain, and focuses the analysis on the opportunity to target opioid receptors for treating opioid use disorder (OUD), drug withdrawal, and addiction. Unfortunately, as has been well established, the use of opioids presents a plethora of side effects, such as tolerance and physical and physiological dependence. Accordingly, considering the great pharmacological potential in targeting opioid receptors, the identification of opioid receptor ligands devoid of most of the adverse effects exhibited by current therapeutic agents is highly necessary. To this end, herein, we analyze some interesting molecules that could potentially be useful for treating OUD, with an in-depth analysis regarding in vivo studies and clinical trials.

Investigating the Impact of Kratom (Mitragyna speciosa) Use Upon Male Sexual Health

Article

Full-text available

Feb 2023

Purpose: Kratom (Mitragyna speciosa) exhibits μ-receptor agonism and is used as an opioid substitute. While opioids are known to inhibit sexual behavior, less is known regarding kratom. We conducted a pilot study to assess the subjective impact of kratom upon male sexual health including erectile and ejaculatory function. Patients and methods: Twitter and Reddit (r/Kratom) were accessed to disseminate our survey featuring validated instruments (the International Index of Erectile Function, IIEF, and the premature ejaculation diagnostic tool, PEDT). Sexual health prior to and after 4 weeks of kratom use was assessed. Results: Most males surveyed (n = 165) were 18-40 years old (84.9%), with 95.8% of respondents using it at least weekly and 82.4% using kratom for ≥1 year. Reasons for use included treating pain (39.4%), and mental health conditions (63.6%). Kratom was associated with a positive (37.7%) and negative (20.5%) impact on sexual health. Kratom subjectively increased time to ejaculation in 104 (66.6%) patients, perceived as positive by 62 (59.6%). Seventy-eight patients answered questions about premature ejaculation. The median (with interquartile range, IQR, following;) pre-kratom and kratom use scores were 13.0; 8.0 and 6.5; 5.0, respectively (p < 0.001). Ejaculation before 5 minutes improved after kratom (51.3% vs 12.8%) (p < 0.0001). Following kratom use, patients reported lack of frustration with ejaculation prior to desire (21.8% vs 61.5%) (p < 0.001). The erectile function domain of the IIEF was statistically significantly different however - clinically similar pre-kratom use (29.0; 5.75) versus 27.0; 6.75 during kratom use (p = 0.037). Conclusion: Clinicians treating male sexual health should be aware of kratom and its potential effect on ejaculatory and erectile function.

For Better or Worse: Self-reported Changes in Kratom and Other Substance Use as a Result of the COVID-19 Pandemic

Article

Full-text available

Sep 2022

Background Kratom is taken to self-treat pain and symptoms of psychiatric disorders, including substance-use disorders (SUDs) and opioid withdrawal. Before COVID-19, kratom use was increasing in the US, however, there are few published data on whether that trend continued during the COVID-19 pandemic, which could have affected kratom use in multiple ways. Aim To examine COVID-19-related changes in kratom use and how these changes were experienced, relative to changes in other commonly used substances. Methods Using Amazon Mechanical Turk, 2615 evaluable surveys were completed between September 2020 and March 2021. Responses from past-month and past-year kratom-using adults (N = 174) indicating changes for the better or worse were examined using generalized linear mixed effects models, and relevant open-text responses (n = 85) were thematically coded. Results For kratom 33% (n = 58) reported a Covid-related increase and 24% (n = 42) reported a Covid-related decrease. Controlling for changes in amount used, alcohol (OR = 5.02), tobacco (OR = 4.72), and nonmedical opioid use (OR = 3.42) were all more likely to have changed for the worse, compared with kratom use. Relative to decreases in kratom use, decreases in alcohol (OR = 3.21) and tobacco (OR = 6.18) use were more likely to be changes for the better. Cannabis use was the only substance to display a probability lower than 50% of being a decrease for the better, and of the increases, cannabis use displayed the highest probability of being for the better. Conclusions Increases in kratom and cannabis use were less likely than alcohol and tobacco to be reported as changes for the worse, and decreases in kratom and cannabis use were more likely than alcohol and tobacco to be reported as changes for the better. These findings indicate that people differently conceptualize their relationships with kratom and cannabis, compared to their relationships with alcohol and tobacco.

Kratom: Substance of Abuse or Therapeutic Plant?

Article

Jul 2022
PSYCHIAT CLIN N AM

David Gorelick

Kratom is the common term for Mitragyna speciosa and its products. Its major active compounds are mitragynine and 7-hydroxymitragynine. An estimated 2.1 million US residents used kratom in 2020, as a "legal high" and self-medication for pain, opioid withdrawal, and other conditions. Up to 20% of US kratom users report symptoms consistent with kratom use disorder. Kratom use is associated with medical toxicity and death. Causality is difficult to prove as almost all cases involve other psychoactive substances. Daily, high-dose use may result in kratom use disorder and opioid-like withdrawal on cessation of use. These are best treated with buprenorphine.

Examining the Psychoactive Differences between Kratom Strains

Article

Full-text available

Jul 2023
Int J Environ Res Publ Health

Kratom (Mitragyna speciosa) is a Southeast Asian plant containing various alkaloids that induce pharmacological effects in humans. In Western countries, online vendors sell a variety of different kratom strains which are marketed to have distinct effect profiles. However, as of yet such marketing claims are unsubstantiated, and therefore the current study investigated whether differently colored kratom products can induce distinct effects, as self-reported by users. Six hundred forty-four current kratom users were anonymously surveyed to compare the self-reported effects of and motivations for using kratom products sold as red, green, and white strains. Most of the survey respondents were customers of the same kratom vendor, the products of which had been analyzed for their alkaloid content by an independent laboratory. The survey respondents reported distinct subjective experiences for different kratom strains, in a manner congruent with common marketing descriptions. However, the product analyses revealed no significant cross-strain differences in alkaloid content, suggesting that the reported effect differences might be disproportionally influenced by marketing narratives and anecdotal reports. Future studies should engage a more diverse population and include kratom strains from various vendors. Controlled, blinded experiments could assess whether the reported effect differences stem from a placebo effect or from alternative factors, e.g., minor alkaloids and terpenes.

Cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid mitragynine against neuropathic, but not inflammatory pain

Article

Jun 2023

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.

Examining The Psychoactive Differences Between Kratom Strains

Preprint

Full-text available

Jun 2023

Kratom (Mitragyna speciosa) is a Southeast Asian plant containing various alkaloids which induce pharmacological effects in humans. In Western countries, online vendors sell a variety of different kratom strains which are marketed to have distinct effect profiles. However, as of yet such marketing claims are unsubstantiated, and therefore the current study investigated whether differently colored kratom products can induce unique effects, as self-reported by users. 644 current kratom users were anonymously surveyed to compare the self-reported effects and motivations for using kratom products sold as red, green, and white strains. Most of the survey respondents were customers of the same kratom vendor, the products of which had been assessed for their alkaloid content by an independent laboratory. The survey respondents reported distinct subjective experiences for different kratom strains, in a manner congruent with common marketing descriptions. However, the product analyses revealed no significant cross-strain differences in alkaloid content, suggesting that the reported effect differences might be disproportionally influenced by marketing narratives and anecdotal reports. Future studies should engage a more diverse population and include kratom strains from various vendors. Controlled, blinded experiments could assess whether the reported effect differences stem from a placebo effect or from alternative factors, e.g. minor alkaloids and terpenes.

Evaluating health information provided to kratom consumers by good manufacturing practice-qualified vendors

Article

Full-text available

Apr 2023
SUBST ABUSE TREAT PR

Background “Kratom” commonly refers to the botanical Mitragyna speciosa, native to Southeast Asia, which is increasingly used globally for its unique pharmacological effects. Motives for using the whole plant material or kratom-derived products include self-management of pain, mental health disorders, symptoms related to substance use disorders, and/or to increase energy. In the United States, kratom products have varying alkaloid content, potencies, and marketing profiles. There is little regulatory oversight over kratom, as it is currently not approved as a dietary supplement by the Food and Drug Administration. This results in substantial variability in labeling of kratom products and the product information provided to consumers. Methods In January 2023, we evaluated the American Kratom Association’s Good Manufacturing Practices (GMP) qualified vendors’ websites (n = 42) using the well-established and validated DISCERN instrument to examine the quality of health information provided to consumers. DISCERN contains 15 five-point Likert-scale questions on specific criteria, with the highest possible score being 75, indicating that all the DISCERN criteria have been fulfilled by the website (i.e., the highest quality information is provided to consumers). Results The mean DISCERN score for all evaluated online kratom vendors was 32.72 (SD = 6.69; score range 18.00–43.76). Overall, vendors scored higher on DISCERN questions assessing the website’s reliability, as vendors typically provided clear information for consumers about product availability, purchasing, shipping, etc. On average, vendors scored poorly on the DISCERN section pertaining to the quality of the health information provided. Information on kratom’s potential risks and benefits was particularly insufficient. Conclusions Consumers require high quality information in order to make informed decisions concerning use, which entails disclosure of known risks and potential benefits. The online kratom vendors evaluated in this study should consider enhancing the quality of health information provided, especially information regarding kratom’s risks and benefits. Further, consumers should be made aware of current knowledge gaps related to kratom’s effects. Clinicians must also be aware of the lack of evidence-based information available to their patients who use kratom or are interested in using kratom products, in order to facilitate educational discussions with them.

Diagnostic Ambiguities and Underuse of Clinical Assessment Tools: A Systematic Review of Case Reports on Kratom Addiction and Physical Dependence

Article

Full-text available

Apr 2023

Purpose of Review This systematic review examines case reports of kratom physical dependence or addiction, focusing on assessment, diagnosis, and treatment methods and the completeness of the clinical data presented. Recent Findings Most peer-reviewed clinical literature on kratom physical dependence and addiction comes in the form of case reports. However, these reports often provide incomplete descriptions of complex circumstances, and there remain no standardized assessment, diagnostic, or treatment methods for patients presenting with these morbidities. Summary Many reports were difficult to interpret due to missing information. Despite the lack of standardized assessment and diagnostic tools for kratom addiction, withdrawal, or dependence, medications for opioid use disorder were frequently prescribed, which is problematic for opioid naïve patients. Findings suggest that case reports involving kratom should include established standardized assessments of history and symptomatology, incorporating laboratory testing where possible. Development of best practices for treatment of kratom-associated dependence or addiction is warranted.

Kratom Withdrawal: Discussions and Conclusions of a Scientific Expert Forum

Article

Full-text available

Mar 2023

Correlations of kratom (Mitragyna speciosa Korth.) use behavior and psychiatric conditions from a cross-sectional survey

Article

Jan 2023
EXP CLIN PSYCHOPHARM

Kratom (Mitragyna speciosa Korth.) use has increased substantially over the past decade outside of its indigenous regions, especially for the self-treatment of psychiatric conditions. An anonymous, cross-sectional, online survey was completed by 4,945 people who use kratom (PWUK) between July 2019 and July 2020. A total of 2,296 respondents completed an extended survey that included clinical scales for measuring attention deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), depressive and anxiety disorders. PWUK and met criteria for ADHD, PTSD, depressive or anxiety disorders were primarily middle-aged (31-50 years), employed, college-level educated, and reported greater concurrent or prior use of kratom with cannabis, cannabidiol, and benzodiazepines. For all psychiatric conditions, PWUK reported decreased depressive and anxious moods than before kratom use. Based on this self-report study, observational and other clinical studies are warranted for kratom. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Respiratory effects of oral mitragynine and oxycodone in a rodent model

Article

Full-text available

Oct 2022
PSYCHOPHARMACOLOGY

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.

Correlations of Kratom (Mitragyna speciosa Korth.) Use Behavior and Psychiatric Conditions from a cross-sectional survey

Preprint

Full-text available

Aug 2022

Kratom (Mitragyna speciosa Korth.) use has increased substantially over the past decade outside of its indigenous regions, especially for the self-treatment of psychiatric conditions. An anonymous, cross-sectional, online survey was completed by 4,945 people who use kratom (PWUK) between July 2019 and July 2020. A total of 2,296 respondents completed an extended survey utilizing clinical scales for attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), depressive and anxiety disorders. PWUK and met criteria for ADHD, PTSD, depressive or anxiety disorders were primarily middle-aged (31-50 years), employed, more likely to have college-level education (81.3% vs. 80.0%), and reported increased concurrent or prior use of kratom with cannabis products, cannabidiol, and benzodiazepines. In all psychiatric conditions, PWUK reported less depressive and anxious moods. Self-reported quality of life was worse in psychiatric conditions whereas current pain was more severe. Based on this observational study, further clinical studies are warranted for kratom.

Public Health Implications and Possible Sources of Lead (Pb) as a Contaminant of Poorly Regulated Kratom Products in the United States

Article

Full-text available

Jul 2022

Kratom (Mitragyna speciosa) is a tropical tree that is indigenous to Southeast Asia. Kratom leaf products have been used in traditional folk medicine for their unique combination of stimulant and opioid-like effects. Kratom is being increasingly used in the West for its reputed benefits in the treatment of pain, depression, and opioid use disorder (OUD). Recent studies from the United States Food and Drug Administration (FDA, Silver Spring, MD, USA) and our laboratory have shown that many kratom products being sold in the United States are contaminated with potentially hazardous levels of lead (Pb). In this commentary, we discuss the public health implications of the presence of Pb in kratom products, particularly as they relate to the predicted levels of Pb exposure among kratom users. We also considered the specific toxic effects of Pb and how they might relate to the known physiologic and toxicologic effects of kratom. Finally, we consider the possible sources of Pb in kratom products and suggest several areas for research on this issue.

Examining the paradoxical effects of kratom: a narrative inquiry

Article

Full-text available

May 2023

Introduction: Surveys and case reports have documented kratom use in the United States (US) for over a decade. However, those reports have generally not examined in depth the role kratom plays in the lives of those who use it regularly for sustained periods. Until there are controlled studies of the pharmacology and subjective effects of kratom alkaloids in humans, one of the best sources of insight on kratom-product use remains qualitative data with nuanced descriptions of kratom effects from those who use it regularly. Method: We conducted semistructured qualitative interviews with adults who regularly use kratom products, as part of a laboratory study of kratom-product self-administration. This qualitative component of the study was conducted as a narrative case-report series (n = 10). Results: Despite some differences among participants, all experienced acute combination effects that were largely, even simultaneously, analgesic and stimulatory. Most participants had decreased their dosages over time, and one planned to quit. Five of the 10 participants met DSM-5-based criteria for kratom-use disorder (3 mild, 1 moderate, 1 severe, by symptoms counts). When kratom was inadvertently taken in larger than intended doses, participants described a constellation of symptoms that they called “the wobbles” (a jittery feeling accompanied by what seemed to be nystagmus); this was rare, but could be of scientific and clinical interest as a possible manifestation of serotonin syndrome. Most participants described tolerance but considered kratom generally safe at low-moderate doses, providing perceived benefits with less potential risk for adverse effects compared to pharmaceuticals or illicit drugs. Discussion: In-depth interview data like these help confirm and clarify findings from larger survey studies and clinician-driven case reports. They are needed to inform the policy practice regarding kratom and may also help inform future experimental designs.

Forensic Implications of Kratom: Kratom Toxicity, Correlation with Mitragynine Concentrations, and Polypharmacy

Article

Full-text available

May 2023

Purpose of Review Kratom, a preparation of the leaves collected from the Southeast Asian plant Mitragyna speciosa, has increased in use within the United States (US) predominantly due to its stimulant and opioid-like effects. It contains many active alkaloids, most notably mitragynine. Clinical pharmacological research and toxicological information are limited, hindering forensic interpretation and an understanding of the role kratom use may play in death. Despite arguments from some vocal proponents and vendors that kratom poses no risk to users, there is a growing body of evidence that kratom use can result in significant adverse events, including death. Recent Findings Toxicological data for blood specimens analyzed between January 2018 and September 2022 in postmortem and driving under the influence of drugs cases were reviewed for the presence of mitragynine, the primary alkaloid of Mitragyna speciosa. Reported blood mitragynine concentrations, compound positivity, and concomitant findings were evaluated. Summary The forensic interpretation of mitragynine continues to be challenging. Kratom has been implicated in an increasing number of overdoses and deaths, and its significance is difficult to ascertain due to a substantial number of confounding variables, including a limited scope of toxicological testing and frequent co-positivity with drugs of abuse. Mitragynine has been listed as the primary toxicological finding in several overdose deaths albeit at a lower frequency compared to overall positivity, particularly when present at elevated concentrations (> 1000 ng/mL); these cases provide forensic confirmation of harms due to kratom use.

Kratom (Mitragyna speciosa): Pharmacology and Use of a Naturally Occurring Atypical Opioid

Chapter

Apr 2023

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.

Kratom’s Emergence and Persistence Within the US Polydrug Epidemic

Article

Full-text available

Apr 2023

Purpose of Review Use of “kratom” products, derived from the bioactive botanical Mitragyna speciosa have increased amidst US polydrug use epidemics. Kratom alkaloids interact with opioid, serotonergic, adrenergic, and other receptors and regular users have described experiencing a wide range of effects. Some with polydrug use histories have reported using kratom as a substitute for other drugs or to nonmedically self-manage substance use disorder (SUD) symptoms. Data describing this remain scare and come from self-report. We review this literature describing kratom use as a drug substitute, or as a nonmedical “self-treatment” for attenuating dependence or SUD symptoms. Recent Findings Kratom products have been documented as being used as a licit and illicit opioid substitute. Use to reduce alcohol or stimulant consumption is less well documented. Although prior and current polydrug use appear common among a some kratom users, it is unclear if co-use is contemporaneous or concomitant. Temporal order of use initiation is typically undocumented. Use for energy and recreation are also increasingly reported. Summary Data on kratom consumption come primarily from self-report with significant limitations. Until controlled human laboratory studies have been conducted, we can presently only describe what is known about human kratom use based on self-report. Such data describe real-world kratom use, leaving unaddressed human abuse liability or therapeutic potential of kratom alkaloids. Clinicians should be mindful of use motivations among people with SUD histories, sensitively assessing use. The paucity of data highlights the urgent need to increase funding and research for understanding kratom’s effects in humans.

Kratom-Induced Acute Respiratory Distress Syndrome (ARDS)

Article

Full-text available

Mar 2023

Unlabelled: The alkaloid derivatives of Mitragyna speciosa, commonly known as kratom, pose a threat to society due to its potential for abuse, adverse reactions and tendency to be used as self-medication for opioid withdrawal, pain and mood disorders. A number of deaths have been reported along with complications such as respiratory depression, cardiopulmonary arrest, torsade de pointes and seizures. Its various effects and potential are yet to be fully studied. We describe the case of a healthy young male who presented with progressive respiratory failure requiring mechanical ventilation. Imaging revealed multifocal lung infiltrates while extensive infectious and cardiac work-up was negative. Based on the clinical course, a diagnosis of acute respiratory distress syndrome (ARDS) caused by kratom was made. The patient showed gradual clinical improvement and was weaned off supplemental oxygen. This case highlights yet another adverse reaction to kratom and the growing threat posed by its use. Learning points: Kratom is a herbal supplement with opioid-like effects at high doses and stimulant effects at low doses.It is most commonly used to self-treat opioid withdrawal, mood disorders and pain.Acute respiratory distress syndrome (ARDS) is one of the adverse effects of kratom, which also include kratom withdrawal syndrome, seizures, rhabdomyolysis, torsades de pointes and sudden death.Kratom has growing abuse potential; the FDA is acting to prevent its use and recommends healthcare professionals voluntarily report any adverse reactions.

Receptor Selectivity and Therapeutic Potential of Kratom in Substance Use Disorders

Article

Full-text available

Mar 2023

Purpose of Review Kratom (Mitragyna speciosa Korth) contains several alkaloids, some interacting with opioid receptors and attracting recreational use in the western world. Human self-report has consistently documented the use of kratom for treating pain, mood elevation, and substance use disorders (SUDs). These anecdotal uses are also supported by preclinical findings. According to preclinical research, kratom may induce these positive effects without any respiratory suppression, unlike traditional opioids. This review summarizes kratom as a potential substitution for opioids and compiles all the latest inventions to determine if this natural product or its active alkaloids could offer a better alternative compared to the current treatment of opioid use disorder (OUD) and other SUDs. Recent Findings According to recent reports, kratom has been found to be very efficient for managing dependence, including attenuating opioid withdrawal. There are encouraging findings in pre-clinical paradigms of kratom as a feasible, safe, and efficient treatment for OUD. Summary Presently, kratom administration at low-moderate doses appears, based on preclinical work and self-report to have therapeutic potential for treating OUD irrespective of the etiology. Kratom leaf extracts and especially the purified, major alkaloid mitragynine, appear to have legitimate potential for being developed as treatments for pain, substance use disorders, and opioid withdrawal. These therapeutic uses have been hypothesized to be a result of biased signaling at opioid receptors and the poly-pharmacology of the alkaloids at opioid and adrenergic receptors, with little to no addiction potential demonstrated in pre-clinical studies. Thus, the present review highlights the most recent findings on receptor binding and preclinical evidence to explore the use of kratom and its alkaloids as potentially effective pharmacotherapies for OUD and possible other SUDs.

Omissions, Ambiguities, and Underuse of Causal Assessment Tools: a Systematic Review of Case Reports on Patients Who Use Kratom

Article

Full-text available

Mar 2023

Purpose of review In this systematic review, we examined case reports of patients who use kratom and evaluated their rigor based on reporting of clinically relevant information. Recent findings Millions of people use kratom in the USA each year. Despite its prevalence, there is little peer-reviewed clinical literature available on kratom, and clinicians must predominantly rely on case reports for guidance in the assessment, diagnosis, and treatment of patients who use kratom. Summary We found considerable variation in reported information and in the thoroughness of the case reports. Reports tended to be inadequate in full assessment of the patient’s kratom use. As kratom use continues to increase in the USA, consistent and detailed reporting, usage of biospecimen testing and kratom product assays, consultation of experts to aid with patient workup, usage of causality assessment tools, and acknowledgement of limitations will improve the quality of case reports.

An evaluation of adverse drug reactions and outcomes attributed to kratom in the US Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 through September 2021

Article

Full-text available

Mar 2023
CTS-CLIN TRANSL SCI

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 Retail Availability in Fort Worth, Texas

Article

Feb 2023

Kratom use is associated with cannabis use, so retail availability may also be related. Kratom and Delta-8 THC (a psychoactive cannabis product) are federally unregulated, marketed as “natural,” and often used for pain relief and/or relaxation. Kratom may have greater retail availability in more socioeconomically deprived areas because harmful substances are frequently marketed to lower-income communities. This study examined kratom retail availability in Fort Worth, Texas. Locations with alcohol, tobacco, and/or CBD licenses were called in July 2022: 1,025/1,223 (84%) answered the phone. T-tests examined potential differences in socioeconomic deprivation scores surrounding outlets by whether they sold kratom. Cross-tabulations examined overlap in kratom and Delta-8 THC availability. Kratom was available in 6% of locations. Most kratom retailers had a tobacco license (92%). However, most stores with a tobacco license did not sell kratom (14%), whereas most stores with a CBD license did (55%). Kratom availability was not associated with area deprivation scores. Most kratom retailers (95%) sold Delta-8 THC and two-thirds (65%) of Delta-8 THC retailers sold kratom. This study was the first to examine retail availability of kratom. Findings indicate the presence of niche stores specializing in the retail of federally unregulated substances.

Directed Biosynthesis of Mitragynine Stereoisomers

Article

Full-text available

Feb 2023

Mitragyna speciosa ("kratom") is used as a natural remedy for pain and management of opioid dependence. The pharmacological properties of kratom have been linked to a complex mixture of monoterpene indole alkaloids, most notably mitragynine. Here, we report the central biosynthetic steps responsible for the scaffold formation of mitragynine and related corynanthe-type alkaloids. We illuminate the mechanistic basis by which the key stereogenic center of this scaffold is formed. These discoveries were leveraged for the enzymatic production of mitragynine, the C-20 epimer speciogynine, and fluorinated analogues.

What Is the Kratom Overdose Risk? A Systematic Literature Review

Article

Full-text available

Jan 2023

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.

Application of Proteomics in Diagnosis of Kratom Addiction

Article

Dec 2022

Kratom: A Bibliometric Analysis of Scientific Publications

Article

Full-text available

Dec 2022
J PSYCHOACTIVE DRUGS

Kratom has caught the attention of governments, policymakers, and academicians due to its unique characteristics. This paper explores the scholarly works related to the different aspects of Kratom to elucidate its research progress and identify future research agendas. We reviewed existing publications on Kratom using a bibliometric methodology. By analyzing 431 scientific publications, we identified publication sources, document analysis, countries analysis, and research keywords, which helped us understand the research locus on Kratom. After reviewing the publications, we discovered significant disagreements in categorizing and defining Kratom amongst authors based on their nationalities. We also showed the knowledge structure of existing publications via thematic analysis, illustrating that the studies focused on the opioid nature of Kratom. Also, drug abuse-related issues evolved as the motor theme of research, while other aspects are prevalent as niche or emerging research themes. This paper contributes to the literature by providing a broad idea of existing literature and offering a comprehensive outlook on Kratom, which could be helpful for policy formulation in the future.

Directed Biosynthesis of Mitragynine Stereoisomers

Preprint

Full-text available

Dec 2022

Mitragyna speciosa (Kratom) is used as a natural remedy for pain and management of opioid dependence. The pharmacological properties of Kratom have been linked to a complex mixture of monoterpene indole alkaloids, most notably mitragynine. Here, we report the central biosynthetic steps responsible for the scaffold formation of mitragynine and related corynanthe-type alkaloids. We illuminate the mechanistic basis by which the key stereogenic centre of this scaffold is formed. These discoveries were leveraged for the enzymatic production of mitragynine, the C-20 epimer speciogynine, and a series of fluorinated analogues.

Variations in mitragynine content in the naturally growing Kratom (Mitragyna speciosa) population of Thailand

Article

Full-text available

Oct 2022

We analyzed the content of mitragynine (MG) found in kratom leaves (Mitragyna speciosa) and the influence of different environmental conditions (air and soil variables) on the yield in various regions of Thailand. The content of MG in kratom leaves ranged from 7.5 – 26.6 mg g-1 of dry leaf weight. Canonical correspondence analysis showed that the most significant environmental variables affecting the MG content among the various regions were light intensity, relative humidity, soil volumetric water content (VW), soil pH, and calcium. This study is a first step towards providing information about environmental conditions suitable to maximize the quality and quantity of bioactive alkaloids in kratom. Future studies should focus on leaf collection and the post-harvest processes in order to assure the desired alkaloidal content in finished products, when produced under suitable environmental conditions identified in this study.

Kratom as an opioid alternative: harm, or harm reduction? A systematic review of literature

Article

Aug 2022

Background: Kratom (Mitragyna speciosa Korth.) products are increasingly endorsed for self-management of multiple ailments, including as opioid substitution. The FDA has expressed that there is no evidence to indicate that this botanical is safe or effective for any medical use. Objective: We systematically review the current state of the literature concerning the impact of kratom and its alkaloids in all paradigms that involve opioids. Methods: A keyword search of online literature databases identified 16 preclinical studies, 25 case reports, and 10 observational studies meeting our pre-selected criteria. Results: All rodent models support alkaloids’ action on opioid receptors, translating in their ability to mitigate opioid withdrawal. Some studies found mitragynine (MG) to have less reinforcing properties than morphine, and possessing tolerance-sparing properties when coadministered with morphine. Two studies that assessed 7-hydroxymitragynine (7OHMG) found it to substitute for morphine with potential for tolerance and dependence. Aside from addiction development, case reports outline a variety of confounding toxicities. Ten surveys of users, some conducted with assistance from pro-kratom lobbying organizations, find a high self-reported efficacy as an opioid substitute, with minimal reported adverse effects. Conclusion: With no reported controlled human clinical trials, in the light of rising concerns surrounding kratom’s liabilities, there is insufficient evidence to allow any conclusions to be drawn. Case reports and observational studies carry significant bias toward harm and efficacy, respectively. Existing animal studies are heterogeneous in methodology and ultimately findings, with concern for interspecies variability and human translatability. Further research should investigate the safety and efficacy of using kratom alkaloids as opioid substitutes.

Demographic and behavioral factors associated with kratom use among U.S. college students

Article

Full-text available

Aug 2022

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.

Kratom as a novel cause of photodistributed hyperpigmentation

Article

Full-text available

Aug 2022

A Preliminary Inventory of Kratom (Mitragyna Speciosa) Products and Vendors on the Darknet and Cryptomarkets

Article

Sep 2023

Kratom Alkaloids, Cannabinoids, and Chronic Pain: Basis of Potential Utility and Role in Therapy

Article

Jul 2023

Introduction: Chronic neuropathic pain is as a severe detriment to overall quality of life for millions of Americans. Current pharmacological treatment options for chronic neuropathic pain are generally limited in efficacy and may pose serious adverse effects such as risk of abuse, nausea, dizziness, and cardiovascular events. Therefore, many individuals have resorted to methods of pharmacological self-treatment. This narrative review summarizes the existing literature on the utilization of two novel approaches for the treatment of chronic pain, cannabinoid constituents of Cannabis sativa and alkaloid constituents of Mitragyna speciosa (kratom), and speculates on the potential therapeutic benefits of co-administration of these two classes of compounds. Methods: We conducted a narrative review summarizing the primary motivations for use of both kratom and cannabis products based on epidemiological data and summarize the pre-clinical evidence supporting the application of both kratom alkaloids and cannabinoids for the treatment of chronic pain. Data collection was performed using the PubMed electronic database. The following word combinations were used: kratom and cannabis, kratom and pain, cannabis and pain, kratom and chronic pain, and cannabis and chronic pain. Results: Epidemiological evidence reports that the self-treatment of pain is a primary motivator for use of both kratom and cannabinoid products among adult Americans. Further evidence shows that use of cannabinoid products may precede kratom use, and that a subset of individuals concurrently uses both kratom and cannabinoid products. Despite its growing popularity as a form of self-treatment of pain, there remains an immense gap in knowledge of the therapeutic efficacy of kratom alkaloids for chronic pain in comparison to that of cannabis-based products, with only three pre-clinical studies having been conducted to date. Conclusion: There is sufficient epidemiological evidence to suggest that both kratom and cannabis products are used to self-treat pain, and that some individuals actively use both drugs, which may produce potential additive or synergistic therapeutic benefits that have not yet been characterized. Given the lack of pre-clinical investigation into the potential therapeutic benefits of kratom alkaloids against forms of chronic pain, further research is warranted to better understand its application as a treatment alternative.

Correlations of kratom (Mitragyna speciosa Korth.) tea bag preparations and reported pharmacological effects

Article

Jun 2023
J ETHNOPHARMACOL

Ethnopharmacological relevance: The use of herbal tea infusions is widespread in ethnomedicine throughout the world. One such ethnobotanical is kratom (Mitragyna speciosa Korth., Rubiaceae) which has gained considerable interest as an herbal supplement in recent years in the West beyond its native Southeast Asia. Traditional, kratom leaves are either chewed fresh or made into a tea infusion to treat fatigue, pain, or diarrhea. However, dried kratom leaf powder and hydroalcoholic extracts are more commonly used in Western countries, raising the question of exposure to kratom alkaloids and related effects. Aim of the study: A specific kratom tea bag product was analyzed for mitragynine content using tea infusion preparation and methanolic extraction. Consumers of both the tea bag product and other kratom products completed an online anonymous survey to determine demographics, kratom use patterns, and self-reported beneficial and detrimental effects. Materials and methods: Kratom tea bag samples were extracted using pH-adjusted water or methanol and analyzed using an established LC-QTOF method. A modified kratom survey was distributed to consumers of the kratom tea bag products and other kratom products over a 14-month period. Results: Tea infusion extraction of tea bag samples resulted in lower mitragynine levels (0.062-0.131% (w/w)) compared to methanolic extraction (0.485-0.616% (w/w)). Kratom tea bag consumers did report similar, although often milder beneficial effects compared to consumers using other kratom products. Overall self-reported health was better among kratom tea bag consumers whereas improvement of a diagnosed medical condition was less in tea bag consumers compared to those using other kratom products. Conclusions: Traditional tea infusions of Mitragyna speciosa dried leaves provide benefits to consumers despite substantially lower mitragynine content. These effects may be less pronounced but indicate that tea infusions provide a potentially safer formulation compared to more concentrated products.

Associations Between Kratom-Related State Policy Environments and Kratom Use in a Nationally Representative Population in the United States

Article

Jun 2023
J PSYCHOACTIVE DRUGS

Limited research has resulted in conflicting views on the risks versus benefits associated with kratom use. Despite no federal policy in the United States, individual states have implemented diverging policies through kratom bans, and legalization and regulation through Kratom Consumer Protection Acts (KCPAs). The Survey of Non-Medical Use of Prescription Drugs (NMURx) Program employs nationally-representative, repeated cross-sectional surveys on drug use. In 2021, weighted prevalence of past-12 month kratom use was compared across three state legal frameworks: no overarching state policy, KCPAs, and state bans. There was lower estimated prevalence of kratom use in banned states (prevalence: 0.75% (0.44, 1.06) relative to states with a KCPA (1.20% (0.89, 1.51)), and relative to states with no policies (1.04% (0.94, 1.13), though odds of use were not significantly associated with policy type. Kratom use was significantly associated with medicated treatment for opioid use disorder. While there were observed differences in the prevalence of past-12 month kratom use by state policy type, low uptake mitigated meaningful distinctions by limiting statistical precision, and potentially confounding effects, such as accessibility online. Future kratom-related policy decisions should be informed through evidence-based research.

The Health Impact of Long-Term Kratom ( Mitragyna Speciosa ) Use in Southern Thailand

Article

Jun 2023

Background: Mitragyna speciosa or Kratom has been used in Thailand traditionally for its medicinal value. Despite case reports of kratom consumption causing adverse effects, research on its long-term health impact is limited. This study examines the long-term health impact of kratom use among people in Southern Thailand. Methods: Three community-based surveys were conducted from 2011 to 2015. In the first and second surveys (2011 and 2012) a total of 1,118 male respondents comprising 355 regular kratom users, 171 occasional kratom users, 66 ex-users, and 592 non-users aged 25 or above, were recruited from 40 villages. All respondents were followed up in this study. However, not all respondents were successfully followed up throughout the entire set of studies. Results: Common health complaints were no more common among kratom users than ex- and non-users, but more regular than occasional users claimed kratom to be addictive. Those with high kratom dependence scores were more likely to experience intense withdrawal symptoms, which developed 1-12 h after the last kratom intake. Over half (57.9%) of regular users had experienced intoxication effects compared to only 29.3% of occasional users. Kratom users were less likely to have a history of chronic diseases such as diabetes, hypertension, dyslipidemia than ex- and non-users. Conclusion: Regular long-term chewing of fresh kratom leaves was not related to an increase in common health complaints, but may pose a drug dependence risk. Severe kratom dependents were more likely to suffer from intense withdrawal symptoms. Medical records revealed no death due to traditional kratom use, but the high prevalence of tobacco or/and hand rolled cigarette smoking among kratom users should be of concern.

Psychoactive plant derivatives (ayahuasca, ibogaine, kratom) and their application in opioid withdrawal and use disorder - a narrative review

Article

May 2023
J ADDICT DIS

The opioid epidemic and limited access to treatment for opioid withdrawal (OW) and opioid use disorder (OUD) has led individuals to seek alternative treatments. This narrative review aims to educate clinicians on the mechanisms of action, toxicity, and applications of psychoactive plant-based substances patients may be using to self-treat OUD and OW. We specifically discuss ayahuasca, ibogaine, and kratom as they have the most evidence for applications in OUD and OW from the last decade (2012-2022). Evidence suggests these substances may have efficacy in treating OW and OUD through several therapeutic mechanisms including their unique pharmacodynamic effects, rituals performed around ingestion, and increased neuroplasticity. The current evidence for their therapeutic application in OUD and OW is primarily based on small observational studies or animal studies. High-quality, longitudinal studies are needed to clarify safety and efficacy of these substances in treatment of OW and OUD.

Changes in the Point-of-Sale Among Vape Shops in 6 US Metropolitan Areas Over Time, 2018-2021

Article

Mar 2023
NICOTINE TOB RES

Introduction E-cigarette retail/marketing surveillance is needed during regulatory changes, like the US increasing minimum legal sales age to 21 (T21) and flavor restrictions (2019 and 2020) and certain state/localities increasing related restrictions. Methods We examined regulatory compliance (e.g., minimum-age signage), promotional strategies (e.g., health claims), and products at 2 timepoints among vape shops across 6 US metropolitan statistical areas (MSAs; Atlanta, Boston, Minneapolis, Oklahoma City, San Diego, Seattle). In summer 2018, pairs of trained auditors assessed randomly-selected shops (n=~30/MSA). In fall 2021, audits were conducted among 2018 shops (if open and allowed) and additional randomly-selected shops (n=~20/MSA). Data from 179 shops in 2018 and 119 in 2021 (43 from the 2018 sample) were compared. Results There were decreases (p<.01) in the proportion of shops with (1) minimum-age signs (90.5% vs. 73.9%); (2) their own e-liquid brand (68.2% vs. 44.5%), onsite vaping (73.2% vs. 46.2%), counter seating (65.2% vs. 34.5%), and e-liquid sampling (90.0% vs. 33.6%); and (3) signs with product/price promotions (89.9% vs. 65.5%), health/cessation claims (29.1% vs. 12.6%), and cartoon imagery (27.4% vs. 11.8%). The proportions selling wet/dry vaporizers (26.4% vs. 39.5%), CBD products (23.3% vs. 71.4%), and pipes/glassware/papers (18.4% vs. 52.9%) increased. In 2021, many sold THC (12.6% e-liquids, 62.2% other products) and kratom (40.3%). Conclusions With increasing restrictions (e.g., on flavors, sampling, T21), fewer shops sold their own e-liquid brands or accommodated onsite use/sampling, but fewer also posted minimum-age signage. Notably, more offered cannabis-related products. These changes underscore the need for comprehensive surveillance to assess regulatory impact. IMPLICATIONS The past 6 years marked increasing e-cigarette sales restrictions in the US, yet limited research has examined the implications for tobacco specialty shops selling e-cigarettes. This study found that, from 2018 to 2021, there were significant decreases in the proportion of vape shops with their own e-liquid, onsite vaping, e-liquid sampling, lounge/counter seating, and price promotions, as well as minimum age signs. There were increases in the proportion selling cannabis-derived products and related paraphernalia. Tobacco control research and regulatory agencies must consider how tobacco specialty stores have evolved alongside legislative changes that impact them and consumers.

Mitragynine, a primary constituent of kratom reinstates morphine-seeking behaviour in rats

Article

Dec 2022

Mitragynine (MG) is a pharmacologically active alkaloid derived from the leaves of Mitragyna speciosa Korth (Kratom). This plant has sparked significant interest as a potential alternative treatment for managing opioid dependence and withdrawal due to its opioid-like pharmacological effects. However, whether MG exposure would trigger opioid-seeking behaviour following abstinence has not been investigated. The present study examined the effects of MG priming on morphine-seeking behaviour in rats. Male Sprague-Dawley rats were initially trained to intravenously self-administer morphine (0.5 mg/kg/infusion) under a fixed ratio-3 schedule of reinforcement. Removal of both morphine infusions and drug-associated cues led to the subsequent extinction of the drug-seeking behaviour. Tests of reinstatement were made following exposure to a randomised order of intraperitoneal injections of MG (3, 10 and 30 mg/kg), morphine (5 mg/kg) and vehicle. Significant levels of drug-seeking behaviour were observed following extended access to morphine self-administration, which was extinguished following removal of morphine and cues indicative of morphine-seeking behaviour, supporting the relapse model. The present finding demonstrated that MG priming in a dose of 10 mg/kg resulted in the reinstatement of morphine-seeking behaviour, whereas the higher MG dose (30 mg/kg) tested suppressed the seeking response. This study indicated that exposure to a low MG dose may increase the likelihood of relapsing to opioids, suggesting that the potential of MG as a treatment for opioid management merits further scientific assessment of its ability to trigger relapse to opioid abuse.

Controversial usages of kratom ( Mitragyna speciosa ): For good or for evil

Article

Full-text available

Nov 2022

Natural Products for the Treatment of Drug Addiction: Narrative Review

Article

Oct 2022

Mona Raslan

Drug addiction is considered a chronic disorder affecting the individual’s life, his/her family and society. Up till now the treatment of drug addiction is considered a problematic issue. Synthetic drugs available for the treatment of drug addiction are few, of limited efficacy and associated with serious side effects. Therefore, there is a continuous search for better therapeutic agents for drug addiction. Natural products represent a promising source for drug addiction treatment. This review summaries drug addiction definition, its mechanism of action, its types, its diagnosis, factors affecting its development and different available approaches for its treatment especially the use of natural products. Six plants were discussed thoroughly in this review, including, Tabernanthe iboga Baill., Mitragyna speciosa Korth., Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep, Hypericum perforatum L., Panax ginseng C.A. Mey., and Withania somnifera (L.) Dunal.

A Chromosome-Scale Genome Assembly of Mitragyna speciosa (Kratom) and the Assessment of Its Genetic Diversity in Thailand

Article

Full-text available

Oct 2022

Mitragyna speciosa (Kratom) is a tropical narcotic plant native to Southeast Asia with unique pharmacological properties. Here, we report the first chromosome-scale assembly of the M. speciosa genome. We employed PacBio sequencing to obtain a preliminary assembly, which was subsequently scaffolded using the chromatin contact mapping technique (Hi-C) into 22 pseudomolecules. The final assembly was 692 Mb with a scaffold N50 of 26 Mb. We annotated a total of 39,708 protein-coding genes, and our gene predictions recovered 98.4% of the highly conserved orthologs based on the BUSCO analysis. The phylogenetic analysis revealed that M. speciosa diverged from the last common ancestors of Coffea arabica and Coffea canephora approximately 47.6 million years ago. Our analysis of the sequence divergence at fourfold-degenerate sites from orthologous gene pairs provided evidence supporting a genome-wide duplication in M. speciosa, agreeing with the report that members of the genus Mitragyna are tetraploid. The STRUCTURE and principal component analyses demonstrated that the 85 M. speciosa accessions included in this study were an admixture of two subpopulations. The availability of our high-quality chromosome-level genome assembly and the transcriptomic resources will be useful for future studies on the alkaloid biosynthesis pathway, as well as comparative phylogenetic studies in Mitragyna and related species.

Kratom's Rising Role in the Potential Exacerbation of Mental Health Disorders: A Case Report and Review of the Literature

Article

Oct 2022

Kratom, a non-federally regulated botanical herb, is widely growing in popularity as a naturopathic alternative for mood, anxiety, and attention deficit symptoms, along with legal recreational use as a psychoactive agent. It is predominantly sold without restriction and easily accessible over the counter at naturopathic, specialty “vape” or “smoke shops” and on the internet. Kratom's most abundant alkaloids, Mytraginine (MG) and 7-hydroxymitragynine (7-MG), have demonstrated multi-mechanistic properties via dopamine, serotonin, adrenergic, and mu-opioid-type receptors interaction in a dose-dependent manner. Given the reported association between Kratom consumption and its mood-altering and stimulant-like effects, we considered its role in the exacerbation of those predisposed to or with certain preexisting mental health disorders. In addition, Kratom's psychoactive compound derivatives are not detected in routine urine toxicology screens, which may pose a diagnostic obstacle when suspecting its use in critical settings such as acute mania or bipolar disorder with psychotic features. Considering its growing availability, potential for addiction, and withdrawal, the authors aim to highlight the need for further research on the potential effects of Kratom and its use as a crucial consideration during assessment, as well as the association between Kratom use and the exacerbation of those predisposed to or with certain preexisting mental health disorders. We concluded that, on balance, there was sufficient evidence to justify the plausibility of the association between Kratom ingestion in exceeding doses and the exacerbation of certain psychiatric manifestations such as psychosis.

A Case of Severe Kratom Addiction Contributing to a Suicide Attempt

Article

Full-text available

Sep 2022

Kratom is a plant product native to Southeast Asia that is surging in popularity in the United States as consumers look for natural remedies for ailments like chronic pain, anxiety, and even opioid addiction. Kratom's risks are largely unknown, and the market is poorly regulated. Americans typically get advice from online forums and purchase powder formulations from tobacco shops or obscure websites. These risks are highlighted in this case of a 38-year-old woman with a history of major depressive disorder and opioid use disorder who switched from Suboxone to kratom and became addicted, eventually consuming large quantities per day. Amplified by other stressors, she reached a breaking point and overdosed on her regular medications for depression. At the psychiatric hospital, she exhibited classic kratom withdrawal symptoms, including vague abdominal pain and restlessness. After eight days of treatment, her symptoms eventually abated, and she was discharged on Suboxone.

Narrative Review of Kratom, an Emerging Psychoactive Substance With Perianesthetic Implications

Article

Aug 2022
ANESTH ANALG

Opioid overprescribing, with resultant overdose and death, has led to a national focus on alternative treatments for pain. With the decline in legal access to opioids, kratom has gained popularity as a legal, "natural," and easily accessible nonprescription analgesic for consumers wishing to self-medicate for pain, opioid use disorder, and other mental health conditions. While implications of kratom use in patients with chronic pain and/or opioid use disorder have been published, information on perianesthetic implications is lacking. Anesthesiologists should be informed about kratom, including the potential for unexpected physiologic derangements and adverse drug interactions resulting from complex pharmacologic activity, cytochrome P450 interactions, and common adulterations of the drug that may result in unpredictable clinical effects. This article explores the relevance of kratom to perioperative anesthetic care, including suggestions for anesthesiologists extrapolated from published information in nonoperative settings that may improve patient safety in individuals using kratom.

Kratom use categories and their associations with co-occurring substance use and mental health disorder symptoms during the COVID-19 pandemic

Article

Aug 2022
DRUG ALCOHOL DEPEN

Background Kratom, a psychoactive substance, use is an evolving research area that needs more studies to augment the limited literature. Our study examines the association between kratom use categories and mental health and substance use disorders in the U.S. population. Methods We used the 2020 National Survey on Drug Use and Health data (N = 32,893), a cross-sectional survey data, on the U.S. population aged 12 years or older. We used STATA/SE version 16 to perform a multinomial logistic regression analysis to assess our study aims. Results Bisexuals, compared to heterosexuals, had higher risks of kratom use within the past 30 days (relative risk ratio [RRR]= 2.47, 95% CI= 1.07, 5.71). Major depressive episode was positively associated with kratom use more than 30 days ago (RRR= 2.04, 95% CI= 1.24, 3.34). This association was also observed for mild (RRR= 2.04, 95% CI= 1.38, 3.02), moderate (RRR= 2.25, 95% CI= 1.13, 4.51), or severe alcohol use disorder (RRR= 1.88, 95% CI= 1.05, 3.36); and mild (RRR= 1.98, 95% CI= 1.27, 3.11), moderate (RRR= 2.38, 95% CI= 1.27, 4.45), or severe marijuana use disorder (RRR= 2.13, 95% CI= 1.02, 4.47). Illicit drug other than marijuana use disorder was associated positively with kratom use more than 30 days ago (RRR= 2.81, 95% CI= 1.85, 4.26) and kratom use within the past 30 days (RRR= 5.48, 95% CI= 1.50, 20.02). Conclusions Our findings suggested that identifying as bisexual, experiencing depression, alcohol use disorder, or illicit drug use disorder increased the risks of kratom use. There is a need to consider mental health and substance use disorders and sexual identity in kratom use interventions and policies geared toward reducing or preventing kratom use.

Qualitative content analysis of public responses to an FDA inquiry on the impact of scheduling changes to kratom

Article

Oct 2022
INT J DRUG POLICY

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.

Development and validation of ELISA for screening of Kratom (Mitragyna speciosa) habitual users using urinary AZ122 biomarker

Article

Aug 2022

Background Kratom (Mitragyna speciosa korth), has been used traditionally in Southeast Asia for its therapeutic properties. The major alkaloid of kratom, mitragynine binds to opioid receptors to give opioid‐like effects that causes addiction. In our previous study, we have identified AZ122 as a unique biomarker in habitual or regular kratom users through analysis of their urinary protein profiles. We aimed to develop and validate a screening method by means of ELISA for detection of kratom habitual users. Methods An ELISA approach was applied for the development of a screening method using urinary AZ122 as biomarker. Method validation was carried out using 3 QC materials at different concentration of AZ122. The data was analyzed statistically using SPSS (Version 25). Results The ELISA was presented with Pearson correlation coefficient of 0.9993. The repeatability and reproducibility were presented at CV <7%, while the accuracy ranged from 78% to 96% at various AZ112 concentrations. Upon testing on 176 male respondents (n = 88 regular kratom users, and n = 88 healthy controls), the specificity and sensitivity of the assay were both 100%. Conclusions The ELISA has been validated and can be potentially used as a reliable screening test for detection of kratom habitual users.

A Multiple-Serotype Outbreak of Salmonella Infections Linked to Kratom, United States, 2017–2018

Article

Aug 2022

In early 2018, we investigated a large national multiple-serotype Salmonella outbreak linked to contaminated kratom, a raw minimally processed botanical substance. Kratom is a plant consumed for its stimulant effects and as an opioid substitute. A case was defined as a laboratory-confirmed Salmonella infection with one of the outbreak strains (serotypes I 4,[5],12:b:-, Heidelberg, Javiana, Okatie, Weltevreden, or Thompson) with illnesses onset during January 11, 2017-May 8, 2018. State and local officials collected detailed information on product consumption and sources. Suspected products were tested for Salmonella and traceback was conducted to determine product distribution chains and suppliers. We identified 199 cases from 41 states; 54 patients were hospitalized. Early interviews indicated kratom was an exposure of interest. Seventy-six (74%) of 103 people interviewed reported consuming kratom in pills, powders, or teas. Multiple serotypes of Salmonella were detected in samples of kratom collected from the homes of the patients and from retail locations. Several companies issued recalls of kratom products due to Salmonella contamination. To the authors' knowledge, this investigation is the first to establish kratom as a vehicle for Salmonella infection. Our findings underscore the serious safety concerns regarding minimally processed botanical substances intended for oral consumption and the challenges in investigating outbreaks linked to novel outbreak vehicles.

The pharmacology and toxicology of kratom: From traditional herb to drug of abuse

Article

Full-text available

Jan 2016
INT J LEGAL MED

Mitragyna speciosa (Rubiaceae), commonly known as kratom, is a tropical tree with a long history of traditional use in parts of Africa and Southeast Asia. In recent years, kratom has gained popularity for use as a recreational drug across the globe. Relatively new to the illicit market and used in a manner different from its traditional applications, preparations of kratom are touted by many as a safe and legal psychoactive product that improves mood, relieves pain, and may provide benefits in opiate addiction. Available literature was reviewed for M. speciosa via PubMed, Google Scholar, CINAHL, and EBSCO to summarize its traditional uses, phytochemical composition, pharmacology and toxicology of proposed active constituents, and potential for misuse and abuse. Research has demonstrated that both stimulant and sedative dose-dependent effects do exist, but a growing concern for the drug's effects and safety of use has resulted in national and international attention primarily due to an increase in hospital visits and deaths in several countries that are said to have been caused by extracts of the plant. The main active alkaloid substances in kratom, mitragynine and 7-hydroxymitragynine, present with a range of CNS stimulant and depressant effects mediated primarily through monoaminergic and opioid receptors. Recently, Palm Beach County, located in the southeastern corridor of Florida, has considered regulating kratom due to public safety concerns following the death of a young adult. At the local, state, and even federal levels, governments are now being confronted with the task of determining the safety and the possible regulation of kratom extracts. There are currently no standard analytical screening techniques for mitragynine and its metabolites following ingestion limiting its detection to more sophisticated techniques like liquid chromatography-mass spectrometry to determine kratom use. The growing concern of the abuse potential of kratom requires careful evaluation of its benefits and potential toxicities.

The Behavioral Risk Factor Surveillance System

Article

Full-text available

Oct 2014

Nicole M. S. Belanger

Prevalence and characteristics of e-cigarette users in Great Britain: Findings from a general population survey of smokers

Article

Full-text available

Jun 2014

Background E-cigarettes may be effective smoking cessation aids and their use by smokers has been growing rapidly. It is important to observe and assess natural patterns in the use of e-cigarettes while experimental data accumulates. This paper reports the prevalence of e-cigarette awareness, beliefs and usage, including brand choice, and characterises the socio-demographic and smoking profile associated with current use, among the general population of smokers and recent ex-smokers. Methods Data were obtained from 3538 current and 579 recent ex-smokers in a cross-sectional online survey of a national sample of smokers in Great Britain in December 2012. Differences between current and recent ex-smokers in the prevalence of e-cigarette awareness, beliefs and usage were examined and the socio-demographic and smoking profile associated with current use of e-cigarettes was assessed in a series of simple and multiple logistic regressions. Results Ninety-three per cent of current and recent ex-smokers (n = 3841) were aware of e-cigarettes. Approximately a fifth (n = 884) were currently using e-cigarettes, while just over a third (n = 1507) had ever used them. Sixty-seven per cent of the sample (n = 2758) believed e-cigarettes to be less harmful than cigarettes; however, almost a quarter (n = 994) remained unsure. Among both current and recent ex-smokers, the most popular reasons for using were health, cutting down and quitting (each > 80%) and 38% used the brand ‘E-lites’. Among current smokers who were aware of but had never used e-cigarettes, approximately half (n = 1040) were interested in using them in the future. Among current smokers, use was associated with higher socio-economic status (OR = 0.68, 95%CI = 0.57-0.80), smoking more cigarettes (OR = 1.02, 95%CI = 1.01-1.03) and having a past-year quit attempt (OR = 2.82, 95%CI = 2.38-3.34). Conclusions There is a near universal awareness of e-cigarettes and use appears to be common among smokers in Great Britain although a quarter of all smokers are unsure as to whether e-cigarettes are less harmful than cigarettes. E-lites – a brand that delivers a low dose of nicotine – is the most popular. E-cigarette users appear to have higher socio-economic status, to smoke more cigarettes per day and to have attempted to quit in the past year.

From Kratom to mitragynine and its derivatives: Physiological and behavioural effects related to use, abuse, and addiction

Article

Full-text available

Feb 2013
NEUROSCI BIOBEHAV R

Kratom (or Ketum) is a psychoactive plant preparation used in Southeast Asia. It is derived from the plant Mitragyna speciosa Korth. Kratom as well as its main alkaloid, mitragynine, currently spreads around the world. Thus, addiction potential and adverse health consequences are becoming an important issue for health authorities. Here we reviewed the available evidence and identified future research needs. It was found that mitragynine and M. speciosa preparations are systematically consumed with rather well defined instrumentalization goals, e.g. to enhance tolerance for hard work or as a substitute in the self-treatment of opiate addiction. There is also evidence from experimental animal models supporting analgesic, muscle relaxant, anti-inflammatory as well as strong anorectic effects. In humans, regular consumption may escalate, lead to tolerance and may yield aversive withdrawal effects. Mitragynine and its derivatives actions in the central nervous system involve μ-opioid receptors, neuronal Ca2+ channels and descending monoaminergic projections. Altogether, available data currently suggest both, a therapeutic as well as an abuse potential.

Pharmacology of Kratom: An Emerging Botanical Agent With Stimulant, Analgesic and Opioid-Like Effects

Article

Full-text available

Dec 2012

Kratom (Mitragyna speciosa) is a plant indigenous to Thailand and Southeast Asia. Kratom leaves produce complex stimulant and opioid-like analgesic effects. In Asia, kratom has been used to stave off fatigue and to manage pain, diarrhea, cough, and opioid withdrawal. Recently, kratom has become widely available in the United States and Europe by means of smoke shops and the Internet. Analyses of the medical literature and select Internet sites indicate that individuals in the United States are increasingly using kratom for the self-management of pain and opioid withdrawal. Kratom contains pharmacologically active constituents, most notably mitragynine and 7-hydroxymitragynine. Kratom is illegal in many countries. Although it is still legal in the United States, the US Drug Enforcement Administration has placed kratom on its "Drugs and Chemicals of Concern" list. Physicians should be aware of the availability, user habits, and health effects of kratom. Further research on the therapeutic uses, toxic effects, and abuse potential of kratom and its constituent compounds are needed.

Notes from the Field: Kratom (Mitragyna speciosa) Exposures Reported to Poison Centers - United States, 2010-2015

Article

Jul 2016

Kratom (Mitragyna speciosa) is a plant consumed throughout the world for its stimulant effects and as an opioid substitute (1). It is typically brewed into a tea, chewed, smoked, or ingested in capsules (2). It is also known as Thang, Kakuam, Thom, Ketum, and Biak (3). The Drug Enforcement Administration includes kratom on its Drugs of Concern list (substances that are not currently regulated by the Controlled Substances Act, but that pose risks to persons who abuse them), and the National Institute of Drug Abuse has identified kratom as an emerging drug of abuse (3,4). Published case reports have associated kratom exposure with psychosis, seizures, and deaths (5,6). Because deaths have been attributed to kratom in the United States (7), some jurisdictions have passed or are considering legislation to make kratom use a felony (8). CDC characterized kratom exposures that were reported to poison centers and uploaded to the National Poison Data System (NPDS) during January 2010-December 2015. The NPDS is a national database of information logged by the country's regional poison centers serving all 50 United States, the District of Columbia, and Puerto Rico and is maintained by the American Association of Poison Control Centers. NPDS case records are the result of call reports made by the public and health care providers.

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

Article

Apr 2016

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.

Anxiolytic-like effects of mitragynine in the open-field and elevated plus-maze tests in rats

Article

Jan 2014
J PHYSIOL SCI

The effects of mitragynine on anxiety-related behaviours in the open-field and elevated plus-maze tests were evaluated. Male Sprague-Dawley rats were orally treated with mitragynine (10, 20 and 40 mg/kg) or diazepam (10 mg/kg) 60 min before behavioural testing. Mitragynine doses used in this study were selected on the basis of approximately human equivalent doses with reference to our previous literature reports. Acute administration of mitragynine (10, 20 and 40 mg/kg) or diazepam (10 mg/kg) increased central zone and open arms exploration in the open-field and elevated plus-maze tests respectively. These anxiolytic-like effects of mitragynine were effectively antagonized by intraperitoneal administration of naloxone (2 mg/kg), flumazenil (10 mg/kg), sulpiride (0.5 mg/kg) or SCH 23390 (0.02 mg/kg) 15 min before mitragynine treatments. These findings reveal that the acute administration of mitragynine produces anxiolytic-like effects and this could be possibly attributed to the interactions among opioidergic, GABAergic and dopaminergic systems in brain regions involved in anxiety.

Systematic Literature Review and Meta-Analysis of the Efficacy and Safety of Prescription Opioids, Including Abuse-Deterrent Formulations, in Non-Cancer Pain Management

Article

Sep 2013
PAIN MED

This study was conducted to compare safety and efficacy outcomes between opioids formulated with technologies designed to deter or resist tampering (i.e., abuse-deterrent formulations [ADFs]) and non-ADFs for commonly prescribed opioids for treatment of non-cancer pain in adults. PubMed and Cochrane Library databases were searched for opioid publications between September 1, 2001 and August 31, 2011, and pivotal clinical trials from all years; abstracts from key pain conferences (2010-2011) were also reviewed. One hundred and ninety-one publications were initially identified, 68 of which met eligibility criteria and were systematically reviewed; a subset of 16 involved a placebo group (13 non-ADFs vs placebo, 3 ADFs vs placebo) and reported both efficacy and safety outcomes, and were included for a meta-analysis. Summary estimates of standardized difference in mean change of pain intensity (DMCPI), standardized difference in sum of pain intensity difference (DSPID), and odds ratios (ORs) of each adverse event (AE) were computed through random-effects estimates for ADFs (and non-ADFs) vs placebo. Indirect treatment comparisons were conducted to compare ADFs and non-ADFs. Summary estimates for standardized DMCPI and for standardized DSPID indicated that ADFs and non-ADFs showed significantly greater efficacy than placebo in reducing pain intensity. Indirect analyses assessing the efficacy outcomes between ADFs and non-ADFs indicated that they were not significantly different (standardized DMCPI [0.39 {95% confidence interval (CI) 0.00-0.76}]; standardized DSPID [-0.22 {95% CI -0.74 to 0.30}]). ADFs and non-ADFs both were associated with higher odds of AEs than placebo. Odds ratios from indirect analyses comparing AEs for ADFs vs non-ADFs were not significant (nausea, 0.87 [0.24-3.12]; vomiting, 1.54 [0.40-5.97]; dizziness/vertigo, 0.61 [0.21-1.76]; headache, 1.42 [0.57-3.53]; somnolence/drowsiness, 0.47 [0.09-2.58]; constipation, 0.64 [0.28-1.49]; pruritus 0.41 [0.05-3.51]). ADFs and non-ADFs had comparable efficacy and safety profiles, while both were more efficacious than placebo in reducing pain intensity.

Opioid receptors: Distinct roles in mood disorders

Article

Dec 2012

The roles of opioid receptors in pain and addiction have been extensively studied, but their function in mood disorders has received less attention. Accumulating evidence from animal research reveals that mu, delta and kappa opioid receptors (MORs, DORs and KORs, respectively) exert highly distinct controls over mood-related processes. DOR agonists and KOR antagonists have promising antidepressant potential, whereas the risk-benefit ratio of currently available MOR agonists as antidepressants remains difficult to evaluate, in addition to their inherent abuse liability. To date, both human and animal studies have mainly examined MORs in the etiology of depressive disorders, and future studies will address DOR and KOR function in established and emerging neurobiological aspects of depression, including neurogenesis, neurodevelopment, and social behaviors.

Antidepressant-like effect of mitragynine isolated from Mitragyna speciosa Korth in mice model of depression

Article

Mar 2011

Mitragyna speciosa Korth. leaves have been used for decades as a traditional medicine to treat diarrhea, diabetes and to improve blood circulation by natives of Malaysia, Thailand and other regions of Southeast Asia. Mitragynine is the major active alkaloid in the plant. To date, the role of mitragynine in psychological disorders such as depression is not scientifically evaluated. Hence, the present investigation evaluates the antidepressant effect of mitragynine in the mouse forced swim test (FST) and tail suspension test (TST), two models predictive of antidepressant activity and the effect of mitragynine towards neuroendocrine system of hypothalamic-pituitary-adrenal (HPA) axis by measuring the corticosterone concentration of mice exposed to FST and TST. An open-field test (OFT) was used to detect any association of immobility in the FST and TST with changes in motor activity of mice treated with mitragynine. In the present study, mitragynine at dose of 10 mg/kg and 30 mg/kg i.p. injected significantly reduced the immobility time of mice in both FST and TST without any significant effect on locomotor activity in OFT. Moreover, mitragynine significantly reduced the released of corticosterone in mice exposed to FST and TST at dose of 10 mg/kg and 30 mg/kg. Overall, the present study clearly demonstrated that mitragynine exerts an antidepressant effect in animal behavioral model of depression (FST and TST) and the effect appears to be mediated by an interaction with neuroendocrine HPA axis systems.

Ethnopharmacology of kratom and the Mitragyna alkaloids

Article

Mar 1989
J ETHNOPHARMACOL

E.J. Shellard

Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa

Article

Apr 2004
LIFE SCI

Mitragynine is an indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa. We previously reported the morphine-like action of mitragynine and its related compounds in the in vitro assays. In the present study, we investigated the opioid effects of 7-hydroxymitragynine, which is isolated as its novel constituent, on contraction of isolated ileum, binding of the specific ligands to opioid receptors and nociceptive stimuli in mice. In guinea-pig ileum, 7-hydroxymitragynine inhibited electrically induced contraction through the opioid receptors. Receptor-binding assays revealed that 7-hydroxymitragynine has a higher affinity for micro-opioid receptors relative to the other opioid receptors. Administration of 7-hydroxymitragynine (2.5-10 mg/kg, s.c.) induced dose-dependent antinociceptive effects in tail-flick and hot-plate tests in mice. Its effect was more potent than that of morphine in both tests. When orally administered, 7-hydroxymitragynine (5-10 mg/kg) showed potent antinociceptive activities in tail-flick and hot-plate tests. In contrast, only weak antinociception was observed in the case of oral administration of morphine at a dose of 20 mg/kg. It was found that 7-hydroxymitragynine is a novel opioid agonist that is structurally different from the other opioid agonists, and has potent analgesic activity when orally administered.

Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa Korth)

Article

Jul 2008

Kratom (Mitragynia speciosa korth) is recognized increasingly as a remedy for opioid withdrawal by individuals who self-treat chronic pain. A patient who had abruptly ceased injection hydromorphone abuse self-managed opioid withdrawal and chronic pain using kratom. After co-administering the herb with modafinil he experienced a tonic-clonic seizure, but he reported only modest abstinence once kratom administration stopped. We confirmed the identity of the plant matter he ingested as kratom and identified no contaminants or adulterants. We also conducted high-throughput molecular screening and the binding affinity at mu, delta and kappa receptors of mitragynine. We report the self-treatment of chronic pain and opioid withdrawal with kratom. The predominant alkaloid of kratom, mitragynine, binds mu- and kappa-opioid receptors, but has additional receptor affinities that might augment its effectiveness at mitigating opioid withdrawal. The natural history of kratom use, including its clinical pharmacology and toxicology, are poorly understood.

Assessment of Kratom Under the CSA Eight Factors and Scheduling Recommendations

Jan 2016

J E Henningfield
R Fant

Henningfield, J.E., Fant, R., 2016. Assessment of Kratom Under the CSA Eight Factors and Scheduling Recommendations. http://216.30.191.148/HL-AKA-Eight_Factor_and_ Recommendations_by_PinneyAssoc.pdf.

American Kratom Association. Personal Communication, Oliver Grundmann

Jan 2017

S Ash

Ash, S., 2017. American Kratom Association. Personal Communication, Oliver Grundmann. University of Florida, Gainesville, FL.

DEA announces intent to schedule kratom. Drug Enforcement Administration. United States Department of Justice

Jan 2016

DEA, 2016. DEA announces intent to schedule kratom. Drug Enforcement Administration. United States Department of Justice, Washington, DC.

Patterns of Kratom use and health impact in the US − Results from an online survey

Abstract

No full-text available

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