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The rising prevalence of kratom use in the United States has led to increased encounters with individuals who consume kratom and those who develop Kratom Use Disorder (KUD) among healthcare professionals. This case series highlights the need for diverse treatment approaches tailored to the individual motivations for kratom consumption. Three cases are presented: one involving the progression from kratom use for energy to opioid-driven use with subsequent challenges in detoxification and transition to naltrexone necessitating buprenorphine low-dose induction for maintenance; another detailing successful inpatient detoxification using methadone and symptom-driven clonidine, followed by successful maintenance treatment with naltrexone; and a final case involving kratom consumption for pain and anxiety self-management by an individual without a history of addictive disorders, without meeting KUD criteria. These cases underscore the complexity of managing individuals who consume kratom as well as those who develop dependence, emphasizing the need for individualized treatment approaches considering various factors such as motivation for use, psychiatric comorbidities, and response to interventions. [ABSTRACT FROM AUTHOR]

Background: Herbal treatment has been proposed and researched as an alternative to cancer treatment. One of the reasons contains compounds that have cytotoxic effects. Mitragyna speciosa are known to contain alkaloids and have a cytotoxic effect. Objective: This review aimed to provide information about preclinical studies and investigates the cytotoxicity or anticancer activity of M. speciosa. Methods: Search articles through PubMed, Springer, and Science Direct databases focusing on preclinical trials according to PRISMA guidelines. A database search yielded a total of 206 identifiable studies. Then duplicate removal and feasibility screening were carried out, resulting in 11 studies that were eligible for final analysis. Results: The anticancer potentials reviewed in this study include Neuroblastoma, Leukemia, Colon Cancer, Breast Cancer, Kidney & Liver Cytotoxicity, Glutathione Transferases Metabolizing Enzymes, Alkaloid Combination of M. speciosa & Cisplatin, Alkaloid Combination of M. speciosa & Doxorubicin and Mutagenic-Antimutagenic Activity of M. speciosa. Extracts and dominant alkaloids of M. speciosa have the potential for anticancer neuroblastoma, leukemia, colon, lung and breast cancer. Based on the safety aspect of the mitragynine compound, there is no mutagenic effect on cells. Conclusion: M. speciosa contains the dominant active alkaloid compound, mitragynine. Extracts and alkaloids dominant in M. speciosa have the potential as an anticancer. [ABSTRACT FROM AUTHOR]

Monoterpene indole alkaloids (MIAs) from Mitragyna speciosa ("kratom"), such as mitragynine and speciogynine, are promising novel scaffolds for opioid receptor ligands for treatment of pain, addiction, and depression. While kratom leaves have been used for centuries in South-East Asia as stimulant and pain management substance, the biosynthetic pathway of these psychoactives have only recently been partially elucidated. Here, we demonstrate the de novo production of mitragynine and speciogynine in Saccharomyces cerevisiae through the reconstruction of a five-step synthetic pathway from common MIA precursor strictosidine comprising fungal tryptamine 4-monooxygenase to bypass an unknown kratom hydroxylase. Upon optimizing cultivation conditions, a titer of ∼290 μg/L kratom MIAs from glucose was achieved. Untargeted metabolomics analysis of lead production strains led to the identification of numerous shunt products derived from the activity of strictosidine synthase (STR) and dihydrocorynantheine synthase (DCS), highlighting them as candidates for enzyme engineering to further improve kratom MIAs production in yeast. Finally, by feeding fluorinated tryptamine and expressing a human tailoring enzyme, we further demonstrate production of fluorinated and hydroxylated mitragynine derivatives with potential applications in drug discovery campaigns. Altogether, this study introduces a yeast cell factory platform for the biomanufacturing of complex natural and new-to-nature kratom MIAs derivatives with therapeutic potential. • De novo production of mitragynine and speciogynine in Saccharomyces cerevisiae achieved. • Five-step synthetic pathway reconstructed from strictosidine in yeast. • Optimized cultivation conditions yielded ∼290 μg/L of kratom MIAs from trehalose and glycerol. • Metabolomics analysis identified shunt products, highlighting enzyme engineering targets for further cell factory optimization. • Production of fluorinated and hydroxylated mitragynine derivatives demonstrated. [ABSTRACT FROM AUTHOR]

Mitragyna speciosa is a perennial plant native to Asia, well known for its psychoactive properties. Its major alkaloid mitragynine is known to have sedative and euphoric effects. Hence, the plant has been a subject of abuse, leading to addiction, necessitating efficient analytical methods to detect its psychoactive constituents. However, current chromatography‐based methods for detecting the alkaloids are time consuming and costly. Quantitative nuclear magnetic resonance (qNMR) spectroscopy emerges as a promising alternative due to its nondestructive nature, structural insights, and short analysis time. Hence, a rapid and precise qNMR method was developed to quantify selected major psychoactive alkaloids in various parts of M. speciosa. Mitragynine, specioliatine, and speciogynine were quantified in relation to the integral value of the ‐OCH3 groups of the alkaloids and the internal standard 1,4‐dinitrobenzene. The precision and reproducibility of the method gave a relative standard deviation (RSD) of 2%, demonstrating the reliability of the method. In addition, the method showed excellent specificity, sensitivity, high linearity range (R2 = 0.999), and limits of detection (LOD) and quantification (LOQ) values. The analysis revealed that the red‐veined M. speciosa leaves contained higher levels of mitragynine (32.34 mg/g), specioliatine (16.84 mg/g) and speciogynine (7.69 mg/g) compared to the green‐veined leaves, stem bark, or fruits. [ABSTRACT FROM AUTHOR]

الملخص: أهداف البحث: نبات القرطوم، المعروف علميا باسم ميتراجينا سبيسيوزا، هو نبات طبي تقليدي من جنوب شرق آسيا، يحتوي على قلويد الميتراجينين كمركب رئيسي. ومثل النباتات الطبية الأخرى، له آثار جانبية وتأثيرات سمية موثقة في الدراسات العلمية وتقارير الحالات. يحظر بيع وحيازة القرطوم في ماليزيا لكنه قانوني في تايلاند. في الولايات المتحدة، لا يسوق القرطوم قانونيا كمنتج دوائي أو مكمل غذائي أو مضاف للأغذية التقليدية. رغم هذه القيود، يستمر الأفراد في تعاطي القرطوم ذاتيا لتخفيف مشاكل صحية متنوعة، غالبا دون فهم شامل للسميات المرتبطة به. طرق البحث: تم إجراء بحث مرجعي لجمع المعلومات الأساسية لهذه المراجعة. ركزت الدراسات المخبرية على إنزيمات الأيض، مشيرة بشكل غير مباشر إلى سمية القرطوم. في المقابل، أظهرت نتائج الدراسات على الحيوانات التأثيرات السمية المباشرة للقرطوم على الكبد والكلى والرئتين والدماغ. تضمنت دراسات الحالة، التي أجريت بشكل رئيسي في الدول الغربية، استخدام القرطوم منفردا أو مع مواد أخرى. النتائج: تشير الدراسات إلى وجود تأثيرات سمية متعددة للقرطوم على أعضاء الجسم المختلفة. وتؤكد دراسات الحالة هذه المخاطر من خلال توثيق حالات التسمم المختلفة. الاستنتاجات: تهدف هذه المراجعة إلى تعزيز الوعي بين المتخصصين في الرعاية الصحية وعامة الناس حول مخاطر القرطوم. كما يساعد تحديد الفجوات الحالية في توجيه الدراسات العلمية المستقبلية. وبما أن الوقاية خير من العلاج، تقدم هذه المراجعة معلومات شاملة عن السميات المرتبطة باستخدام أوراق القرطوم. Abstract: Mitragyna speciosa (Roxb.) Korth, locally known as kratom, is a traditional medicinal plant from Southeast Asia, with mitragynine as its principal alkaloid. Similar to other medicinal plants, kratom has side effects and toxicities, which have been documented in scientific studies and case reports. The mitragynine sale and possession of kratom are prohibited in Malaysia but legalized in Thailand. In the US, kratom is not lawfully marketed as a drug product, a dietary supplement, or a food additive in conventional food. Despite these restrictions, individuals continue to self-administer kratom to alleviate various health problems, often without a comprehensive understanding of the associated toxicities. Hence, the primary aim of this review is to provide a comprehensive overview of the toxicities associated with kratom, drawing from scientific studies, case reports, and other relevant sources. It also addresses the management of these toxicities, identifies gaps in existing studies, and discusses future perspectives. Therefore, a literature review search was conducted to gather essential information for this review. The in vitro studies focused on metabolizing enzymes, indirectly indicating kratom toxicity. By contrast, the in vivo results directly demonstrated kratom's toxic effects on the liver, kidneys, lungs, and brain. Case studies, primarily from Western countries, involved both single and combination use of kratom. Thus, by shedding light on these aspects, we aim to enhance awareness among healthcare professionals and the general public. Additionally, identifying existing gaps can guide future scientific studies. Since prevention is better than cure, this review holistically presents information about the toxicities associated with the use of kratom leaves, serving anyone seeking to understand and prevent kratom-related toxicities.

Mitragynine is a natural compound found in the leaves of the Mitragyna speciosa tree, commonly known as kratom, which is primarily sourced from Southeast Asia. This review article highlights the methodologies of extraction techniques for isolating mitragynine, purification, characterization, and biosynthesis, including the complete synthesis of mitragynine and its derivatives, and briefly summarizes their biological activities and toxicology of mitragynine. The study was conducted by searching several scientific databases. There were extraction methods for mitragynine, including organic solvent extraction (hexane, chloroform, and methanol), green solvent extraction (distilled water), ultrasound-assisted extraction, and accelerated solvent extraction. The purification process of mitragynine using column chromatography with various eluen, including n-hexane, ethyl acetate, and petroleum ether. The natural mitragynine is mainly generated from the shikimate pathway and monoterpenoid secoiridoid pathway. Furthermore, there were several methods for the complete synthesis of mitragynine and the alteration of its structure. Mitragynine and its derivatives possess various pharmacological properties, including anticancer, Analgesic effects, gastrointestinal effects, antidepressant effects, Impact on cognitive function, antioxidant, and antidiabetic. The higher doses of mitragynine (100 mg/kg) in rats led to changes in hematology and the histopathological examination of the liver and brain indicates signs of toxicity. [ABSTRACT FROM AUTHOR]

Background: Kratom, also known as Mitragyna speciosa, is a plant that originates in Southeast Asia and possesses unique pharmacological characteristics. It is commonly consumed in the form of tea made by boiling the leaves or using the leaves to create the powder. According to its pain-relieving effects, the prevalence of kratom use around the world has increased, which has various implications for healthcare providers. Mitragynine is a well-known active compound in kratom. Objective: This review aims to provide a comprehensive perspective on the cardiovascular effects of mitragynine and its potential cardiotoxicity through the literature. Method: Authors searched PubMed, Scopus, and Google Scholar databases using appropriate search strategies for each database. After the screening, all relevant studies were included. Results: Although kratom may have the potential for therapeutic benefits, it has been associated with multi-organ damage and cardiac toxicity in some cases. According to the available data, tachycardia and hypertension are the most common adverse effects. Other possible cardiovascular effects include atherosclerosis, ventricular arrhythmia, cardiomyopathy, dose-dependent prolonged QTc interval, myocarditis, cardiomegaly, and cardiopulmonary arrest. Conclusion: While prior research has indicated the possible negative effects of mitragynine overdose on the cardiovascular system, there are no definitive conclusions, and additional investigations are needed. [ABSTRACT FROM AUTHOR]

Objective: This review aims to synthesize and critically evaluate the existing literature on kratom use and its possible association with induction of psychotic and manic symptoms, in order to identify potential areas for future research that would improve our understanding of the risks of kratom consumption. Methods: An electronic search was performed using five major databases: including PubMed, Scopus, Google Scholar, Web of Science, and PsycINFO. keywords such as kratom, Mitragyna speciosa, mania, psychosis, bipolar disorder, schizophrenia, schizoaffective, case report, and case series. The retrieved articles on initial search were screened based on predefined inclusion and exclusion criteria for this study, and then data synthesis was performed to analyze relevant information from the included studies. Results: Six prior papers were found using (1 case series and 5 case reports). These included 10 cases, involving kratom use association with mania and psychosis. The ages of patients ranged from 28 to 55 years mean age was 38, and (SD 13.74), the majority were males (8 out of 11). Patients had durations of kratom use ranging from 2 wk to 15 years. Significant association was found between kratom use and the worsening of psychotic and manic symptoms in individuals with psychiatric conditions. Conclusions: Our research highlights the possibility of worsening preexisting psychiatric conditions in the context of kratom use. This study emphasizes the need for clinical evaluation of patients for kratom use. Additional research is required to gain a deeper understanding of the potential mental health implications of kratom use, especially among vulnerable populations. [ABSTRACT FROM AUTHOR]

In recent years, the online sale of kratom (Mitragyna speciosa), a Southeast Asian plant with both medicinal and psychoactive properties, has raised health concerns mainly due to the uncontrolled diffusion of adulterated kratom-related products. This exploratory study provides, for the first time, a snapshot of the availability of kratom products on the darknet which has been further validated by data searches on the surface web. A total of 231 listings of kratom across 23 darknet marketplaces were identified between March 2020 and October 2021. Among these, 40 were found actively sold across five markets by thirteen vendors. Listed items were mainly advertised as "safe" substitutes for medicinal products for the self-management of pain and other health conditions and offered in various forms (e.g., dry leaf powder, pills, capsules). Purchases were made using cryptocurrencies, with some vendors offering Pretty Good Privacy, and were shipped from Europe, Australia, the United States, and the United Kingdom. Goods sold by the same sellers also included illicit drugs and fraud-related products. Our study discovered a previously unknown diffusion of kratom products on the darknet mainly for self-treating a variety of medical conditions, suggesting the need for further research and immediate interventions to safeguard the well-being and health of kratom consumers. [ABSTRACT FROM AUTHOR]

Background: Kratom/ketum is a psychoactive herbal preparation that has been used for a long time as a remedy and performance-enhancing substance in Southeast Asia. The advancement of globalization is making kratom increasingly more available in the western world, where it is becoming increasingly more used. Objective: The current research on kratom and its ingredients is presented. Material and methods: An overview of the use and effects of kratom is exemplary given on the basis of reports. The instrumentalization of the drug and its consequences up to the development of addiction are discussed. Results: Consumption is accompanied by several instrumentalizeable effects so that kratom is used as a therapeutic substance in the self-management of pain, anxiety and depression as well as other substance addictions. Another benefit comes from the performance-enhancing effects on physical work and in a social context. Consumption is usually well controlled, rarely escalates and has few and mostly mild aversive side effects. The danger arises from consumption particularly when there is an escalation of the dose and from mixed consumption with other psychoactive substances. The main alkaloid mitragynine and the more potent 7‑hydroxy-mitragynine are considered mainly responsible for the effect. Both have a complex pharmacology that involves partial µ‑opioid receptor agonism. Discussion: Epidemiological, clinical and neurochemical studies have shown that kratom only has a limited addictive drug profile, which might suggest a medical use as a remedy or substitute in addiction treatment. [ABSTRACT FROM AUTHOR]

Background There is an increase in the sale of legal drugs in our country. One of these substances is kratom. Kratom (Mitragyna speciosa) is a partial agonist of the opioid kappa, mu, and delta receptors. It acts as a stimulant at low concentrations, making users feel more energetic and euphoric. It has sedative and antinociceptive effects at higher doses. Case summary An 18-year-old man collapsed during football training and required cardiopulmonary resuscitation; the initial rhythm was ventricular fibrillation managed by defibrillation. Laboratory parameters were unremarkable. Blood samples sent for toxicological evaluation were positive for kratom and caffeine. Echocardiographic examination, coronary computed tomography angiography, and cardiac magnetic resonance imaging did not prove the cause. Genetic testing did not find a pathogenic gene variant associated with familial ventricular fibrillation, but a variant of unknown significance was found in MYOM1. Given this situation, we implanted an implantable cardioverter-defibrillator (ICD) from the secondary prevention of sudden cardiac death (SCD) according to the guidelines of the European Society of Cardiology (ESC). No recurrence of ventricular arrhythmia has been reported by ambulatory ICD memory checks on our patient. Discussion In some country, kratom is freely available and sold as a plant, not a drug. Only incident cases of ventricular fibrillation after kratom use are described in the literature. There is insufficient scientific evidence linking kratom to ventricular fibrillation. This is an absolutely crucial case report of this type, which has not yet been published in similar circumstances in the world. Therefore, the development of ventricular fibrillation was assumed to be due to a combination of kratom, caffeine, and exercise. The safety profile and effects of kratom should be the subject of future research. We would like to stress the importance of reporting further case series for more scientific evidence and thus increasing the pressure for stricter availability and regulation of kratom in some countries, especially where it is over-the-counter. [ABSTRACT FROM AUTHOR]

Background and Purpose: Kratom is a preparation from Mitragyna speciosa, which is used as a natural drug preparation for many purposes around the world. However, an overdose of Kratom may cause addiction‐like problems including aversive withdrawal states resulting in cognitive impairments via unknown mechanisms. Its main psychoactive alkaloid is mitragynine, showing opioid‐like properties. Experimental Approach: Here, we analysed the neuropharmacological effects of mitragynine compared with morphine withdrawal in rats and searched for a pharmacological treatment option that may reverse the occurring cognitive deficits that usually aggravate withdrawal. Key Results: We found that withdrawal from 14‐day mitragynine (1–10 mg·kg−1·day−1) treatment caused dose‐dependent behavioural withdrawal signs resembling those of morphine (5 mg·kg−1·day−1) withdrawal. However, mitragynine (5 and 10 mg·kg−1·day−1) withdrawal also induced impairments in a passive avoidance task. Mitragynine withdrawal not only reduced hippocampal field excitatory postsynaptic potential (fEPSP) amplitudes in basal synaptic transmission and long‐term potentiation (LTP) but also reduced epigenetic markers, such as histone H3K9 and H4K12 expression. At the same time, it up‐regulates HDAC2 expression. Targeting the epigenetic adaptations with the HDAC inhibitor, SAHA, reversed the effects of mitragynine withdrawal on epigenetic dysregulation, hippocampal input/output curves, paired‐pulse facilitation, LTP and attenuated the cognitive deficit. However, SAHA amplified the effects of morphine withdrawal. Conclusion and Implications: The data from this work show that changes in histone expression and downstream hippocampal plasticity may explain mitragynine, but not morphine, withdrawal behaviours and cognitive impairments. Thus, it may provide a new treatment approach for aversive Kratom/mitragynine withdrawal and addiction. [ABSTRACT FROM AUTHOR]

Although kratom use has been part of life for centuries in Southeast Asia, the availability and use of kratom in the United States (US) increased substantially since the early 2000s when there was little information on kratom pharmacology, use patterns, and effects, all critical to guiding regulation and policy. Here we provide a synthesis of research with several hundred English-language papers published in the past 5 years drawing from basic research, epidemiological and surveillance data, and recent clinical research. This review of available literature aims to provide an integrated update regarding our current understanding of kratom's benefits, risks, pharmacology, and epidemiology, which may inform United States-based kratom regulation. Recent surveillance indicates there are likely several million past-year kratom consumers, though estimates vary widely. Even without precise prevalence data, kratom use is no longer a niche, with millions of United States adults using it for myriad reasons. Despite its botanical origins in the coffee tree family and its polypharmacy, kratom is popularly characterized as an opioid with presumed opioid-system-based risks for addiction or overdose. Neuropharmacology, toxicology, and epidemiology studies show that kratom is more accurately characterized as a substance with diverse and complex pharmacology. Taken together the work reviewed here provides a foundation for future scientific studies, as well as a guide for ongoing efforts to regulate kratom. This work also informs much-needed federal oversight, including by the United States Food and Drug Administration. We conclude with recommendations for kratom regulation and research priorities needed to address current policy and knowledge gaps around this increasingly used botanical product. [ABSTRACT FROM AUTHOR]

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Doxorubicin is an effective chemotherapeutic agent in the treatment of solid hematological and non-hematological carcinoma. However, its long-term usage could result in side effects, such as cardiomyopathy, chronic heart failure, neurotoxicity and cancer cell resistance. In this study, we reported the sensitivity enhancement of A549 human lung cancer cells on doxorubicin at a low dose (0.1 ppm) in combination with 10–60 ppm of crude and alkaloid extracts derived from the leaves of Kratom (Mitragyna speciosa (Korth.) Havil. Rubiaceae). A549 cancer cell lines were insensitive to the crude extract containing low mitragynine (MG) (4–5%), while these cells were moderately inhibited by the alkaloid extract containing 40–45% MG (IC50 of 48–55 ppm). The alkaloid extract was found to inhibit A549 cancer cells via apoptosis as suggested by the higher relative fluorescence intensity with Annexin compared to that in propidium iodide (PI), i.e., a positive Annexin and a negative PI. The combination of crude extract and doxorubicin sensitized A549 cancer cells to doxorubicin by 1.3 to 2.4 times, while the combination with the alkaloid induced a 2.6- to 3.4-fold increase in sensitivity. The calculated combination index (CI) for doxorubicin with the crude and alkaloid extracts was 0.6 and 0.3, respectively, showing potential synergistic combinations to reduce the level of dosage of doxorubicin used in chemotherapy. In addition, the synergistic enhancement effect of crude extract on the cytotoxic activity of doxorubicin provides insights into the plausibility of non-alkaloids to influence the biological activities of Kratom. [ABSTRACT FROM AUTHOR]

Kratom and cannabidiol products are used to self-treat a variety of conditions, including anxiety and pain, and to elevate mood. Research into the individual pharmacokinetic properties of commercially available kratom and cannabidiol products has been performed, but there are no studies on coadministration of these products. Surveys of individuals with kratom use history indicate that cannabidiol use is one of the strongest predictors of both lifetime and past month kratom use. The purpose of this study was to determine if there are changes in pharmacokinetic properties when commercially available kratom and cannabidiol products are administered concomitantly. It was found that with concomitant administration of cannabidiol, there was a 2.8-fold increase in the exposure of the most abundant kratom alkaloid, mitragynine, and increases in the exposure of other minor alkaloids. The results of this work suggest that with cannabidiol coadministration, the effects of kratom may be both delayed and increased due to a delay in time to reach maximum plasma concentration and higher systemic exposure of the psychoactive alkaloids found in kratom. [ABSTRACT FROM AUTHOR]

Kratom leaves, consumed by millions worldwide as tea or ground leaf powder, contain multiple alkaloids, with mitragynine being the most abundant and responsible for most effects. Mitragynine is a partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors; however, unlike morphine, it does not activate the β-arrestin-2 respiratory depression pathway. Due to few human mitragynine data, the largest randomized, between-subject, double-blind, placebo-controlled, dose-escalation study of 500–4000 mg dried kratom leaf powder (6.65–53.2 mg mitragynine) was conducted. LC-MS/MS mitragynine and 7-hydroxymitragynine plasma concentrations were obtained after single and 15 daily doses. Mitragynine and 7-hydroxymitragynine Cmax increased dose proportionally, and AUC was slightly more than dose proportional. The median mitragynine Tmax was 1.0–1.3 h after single and 1.0–1.7 h after multiple doses; for 7-hydroxymitragynine Tmax, it was 1.2–1.8 h and 1.3–2.0 h. Steady-state mitragynine concentrations were reached in 8–9 days and 7-hydroxymitragynine within 7 days. The highest mean mitragynine T1/2 was 43.4 h after one and 67.9 h after multiple doses, and, for 7-hydroxymitragynine, it was 4.7 and 24.7 h. The mean 7-hydroxy-mitragynine/mitragynine concentration ratios were 0.20–0.31 after a single dose and decreased (0.15–0.21) after multiple doses. These mitragynine and 7-hydroxymitragynine data provide guidance for future clinical kratom dosing studies and an interpretation of clinical and forensic mitragynine and 7-hydroxymitragynine concentrations. [ABSTRACT FROM AUTHOR]

Even though several studies have been conducted in attempts to find the potential medical applications of kratom (Mitragyna speciosa) extracts, the molecular understanding of its main active substance, mitragynine, remains to be further elucidated. In this study, we used bioinformatic approaches to identify putative protein targets of mitragynine and their binding associations. Human targets of mitragynine were identified using 2 methods: protein and drug similarity approaches. First, 155 homologous proteins of delta-opioid receptor were obtained through a BLASTP search. Second, 12 drugs similar to mitragynine were identified, many of which are used for treating hypertension and cognitive and psychotic disorders. From both approaches, the protein targets with available 3D structures were verified using docking simulations. Out of 48 candidates (39 from BLASTP search and 9 from drug similarity approach), 10 are known in the literature while the rest require further in vitro investigation. Examples of these targets are orexin/hypocretin receptor type 1, 5-hydroxytryptamine receptor 1B, and orexin receptor type 2, which had very strong predicted binding affinity of -9.3, -9.2, and -9.0 kcal/mol, respectively. Moreover, docking simulations suggest that mitragynine may replace commercial drugs in most of the receptor binding pockets, highlighting its potential application in drug repositioning. This in silico study provides insights into the molecular mechanism of mitragynine, which can help inform clinical researchers in developing safe and effective medical applications of kratom. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa) has generated substantial clinical and scientific interest as a complex natural product. Its predominant alkaloid mitragynine and several stereoisomers have been studied for activity in opioid, adrenergic, and serotonin receptors. While awaiting clinical trial results, the pre-clinical evidence suggests a range of potential therapeutic applications for kratom with careful consideration of potential adverse effects. The focus of this review is on the pharmacology, pharmacokinetics, and potential drug–drug interactions of kratom and its individual alkaloids. A discussion on the clinical pharmacology and toxicology of kratom is followed by a summary of user surveys and the evolving concepts of tolerance, dependence, and withdrawal associated with kratom use disorder. With the increasing use of kratom in clinical practice, clinicians should be aware of the potential benefits and adverse effects associated with kratom. While many patients may benefit from kratom use with few or no reported adverse effects, escalating dose and increased use frequency raise the risk for toxic events in the setting of polysubstance use or development of a use disorder. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa) is a botanical substance whose leaves produce stimulant- and opioid-like effects. Kratom use has increased precipitously in the United States (U.S.) over the last decade, yet, in our experience, many pharmacists are unfamiliar with this herb. The purpose of this study was to assess pharmacists' awareness and knowledge of kratom. This cross-sectional study used an online questionnaire to preferentially solicit community pharmacists' knowledge of kratom and collect demographic information. The survey was sent via email to approximately 10,000 pharmacists, targeting those in the state of Alabama, U.S. Data were analyzed using descriptive statistics, and the Chi Square test was used to compare nominal data. A total of 257 participants responded to the survey. Almost 50% of participants had heard of kratom, and 50% had not. Compared to females, males were more likely to have heard of kratom (64% vs. 42%; p = 0.0015), as were pharmacists who worked for an independent pharmacy vs. a chain (61% vs. 41%; p = 0.025). Of the participants who had heard of kratom, only 14% considered themselves knowledgeable or very knowledgeable about the herb, and only 44% knew it was illegal in Alabama. These data indicate a need to further kratom education among community pharmacists in Alabama. [ABSTRACT FROM AUTHOR]

Although kratom use has been part of life for centuries in Southeast Asia, the availability and use of kratom in the United States (US) increased substantially since the early 2000s when there was little information on kratom pharmacology, use patterns, and effects, all critical to guiding regulation and policy. Here we provide a synthesis of research with several hundred English-language papers published in the past 5 years drawing from basic research, epidemiological and surveillance data, and recent clinical research. This review of available literature aims to provide an integrated update regarding our current understanding of kratom’s benefits, risks, pharmacology, and epidemiology, which may inform United States-based kratom regulation. Recent surveillance indicates there are likely several million past-year kratom consumers, though estimates vary widely. Even without precise prevalence data, kratom use is no longer a niche, with millions of United States adults using it for myriad reasons. Despite its botanical origins in the coffee tree family and its polypharmacy, kratom is popularly characterized as an opioid with presumed opioid-system-based risks for addiction or overdose. Neuropharmacology, toxicology, and epidemiology studies show that kratom is more accurately characterized as a substance with diverse and complex pharmacology. Taken together the work reviewed here provides a foundation for future scientific studies, as well as a guide for ongoing efforts to regulate kratom. This work also informs much-needed federal oversight, including by the United States Food and Drug Administration. We conclude with recommendations for kratom regulation and research priorities needed to address current policy and knowledge gaps around this increasingly used botanical product.

Substance use disorders contribute to considerable U.S. morbidity and mortality. While effective pharmacotherapy options are available to treat opioid and alcohol use disorders, for a variety of reasons, many patients lack access to treatment or may be reluctant to seek care due to concerns such as perceived stigma or a current lack of desire to completely curtail their substance use. Furthermore, treatment options are limited for patients with stimulant or polysubstance use disorders. Thus, there is considerable need to expand the substance use disorder harm reduction armamentarium. Kratom (Mitragyna speciosa Korth.) is an herbal substance that can produce both opioid and stimulant-like effects, and its use in the US is growing. Though there are concerns regarding adverse effects, dependence risk, and limited regulation of its manufacturing and sale, the pharmacology of kratom and early preclinical studies suggest a potential role as a harm reduction agent for various substance use disorders, and it has historically been used in Southeast Asia for such purposes. The goal of this review is to describe kratom’s history of use, pharmacology, and early pre-clinical and observational research regarding its therapeutic potential in opioid use disorder, as well as alcohol, stimulant, and polysubstance use disorders, while also highlighting current concerns around its use, existing gaps in the literature, and directions for future research.

A recent article in Frontiers in Psychiatry examines the presence of kratom in opioid overdose deaths, based on a toxicological report from a coroner. Kratom, a botanical product, has gained attention in the US due to reports of adverse effects and fatalities. While kratom is unregulated at the federal level in the US, it is considered illegal in some European and Southeast Asian countries. The article highlights some issues with the report, such as the misinterpretation of a blood concentration as a lethal dose. It also discusses the complexities of kratom use, the lack of established lethal doses, and the need for accurate information and documentation. The authors stress the importance of federal oversight to establish safe dosing recommendations and regulations for kratom products, ensuring consumer access to safe and properly labeled products. The article provides information about the authors' contributions, funding sources, conflicts of interest, and a disclaimer that the views expressed are solely those of the authors. [Extracted from the article]

This work aimed to test the efficacy of an ultrasound (US) and pulsed electric field (PEF) apparatus to extract mitragynine from dried Mitragyna speciosa cv. Karn Dang leaves. Four modes of the device were tested: PEF, US, US + PEF, and PEF + US, and the modes were compared using a conventional technique (maceration, as the control). The liquid chromatography/mass spectrometry (LC-MS/MS) analysis revealed that the mitragynine contents from M. speciosa leaves using the four different modes were significantly different (p < 0.05). The highest extraction (106.63 ± 0.85 mg/L) of mitragynine was obtained by the mode using a combination of PEF + US, followed by US + PEF (97.27 ± 1.33 mg/L), with increased extraction efficiencies of 45.81 ± 0.59% and 33.00 ± 1.85%, respectively. Moreover, the total energy consumption under the combination technique was 25.0% lower than that with PEF assistance. Scanning electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR) were used to analyze the structural and functional features of the alterations in M. speciosa leaves. This study demonstrated that a combination of PEF and US devices may be regarded as a green alternative technique and can assist in streamlining the implementation of agricultural products.

The determination of mitragynine and psychoactive substances in kratom drinks is essential for forensic investigation and medical treatment. In this study, gas chromatography coupled with flame ionization was used to identify mitragynine, caffeine, diphenhydramine, promethazine, and tramadol in various kratom drinks. The analysis was conducted using the HP‑5 column with a nitrogen gas flowing at a rate of 1.8 mL/min. The oven temperature was held at 220°C for 1 min and then increased to 270°C at a rate of 5°C/min. It was further ramped to 300°C at a rate of 30°C/min and held for 13 min. The injector and detector temperatures were set at 280°C. Samples were injected using the split mode (50 : 1) and the total run time was 25 min. Alkalinized samples were extracted with an 80 : 20 (v/v) mixture of ethyl acetate and n-hexane. Method validation revealed acceptable linearity for all analytes (r > 0.990), good precision (0.7–4.2% RSD), accuracy (–11.0–15.2% RE), lower limit of quantification (3–15 µg/mL), and extraction recoveries (81.8–105.8%, except caffeine). The developed method successfully detected and quantified the target analytes. [ABSTRACT FROM AUTHOR]

Kratom is a plant originating in Southeast Asia that has been used for its dose‐dependent stimulant and opioid effects. The main active compound in kratom is mitragynine, an alkaloid with affinity for the mu‐opioid receptor. Toxicity and fatalities related to kratom use have increased substantially in recent years. In this case report, we describe a 44‐year‐old man who was found deceased in bed. The only significant finding at autopsy was abdominal distension with >4 L of ascites. Toxicology testing was performed on femoral blood which showed 79 ng/mL of hydromorphone, 560 ng/mL of mitragynine, and 240 ng/mL of olanzapine. In addition, creatinine and urea in vitreous humor were significantly elevated, consistent with renal impairment. Death was attributed to hydromorphone toxicity with mitragynine being a contributing factor. [ABSTRACT FROM AUTHOR]

This work aimed to test the efficacy of an ultrasound (US) and pulsed electric field (PEF) apparatus to extract mitragynine from dried Mitragyna speciosa cv. Karn Dang leaves. Four modes of the device were tested: PEF, US, US + PEF, and PEF + US, and the modes were compared using a conventional technique (maceration, as the control). The liquid chromatography/mass spectrometry (LC-MS/MS) analysis revealed that the mitragynine contents from M. speciosa leaves using the four different modes were significantly different (p < 0.05). The highest extraction (106.63 ± 0.85 mg/L) of mitragynine was obtained by the mode using a combination of PEF + US, followed by US + PEF (97.27 ± 1.33 mg/L), with increased extraction efficiencies of 45.81 ± 0.59% and 33.00 ± 1.85%, respectively. Moreover, the total energy consumption under the combination technique was 25.0% lower than that with PEF assistance. Scanning electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR) were used to analyze the structural and functional features of the alterations in M. speciosa leaves. This study demonstrated that a combination of PEF and US devices may be regarded as a green alternative technique and can assist in streamlining the implementation of agricultural products. [ABSTRACT FROM AUTHOR]

The term kratom is commonly used for both Mitragyna speciosa and herbal products prepared mainly from leaves. Kratom is well known as a drug that can serve as a less toxic and less-addictive painrelieving substitute for opium, as well as a therapy for hypertension, cough, and diarrhea. Its major alkaloid, mitragynine, also deserves concern. However, most people use kratom as a psychological stimulant, which carries a risk of addiction associated with negative social and health impacts. This paper reviews basic facts about kratom and its potential use in pharmacology, pharmacokinetics, and pharmacokinetics of its major alkaloid mitragynine (Tab. 3, Fig. 1, Ref. 87). Text in PDF www.elis.sk [ABSTRACT FROM AUTHOR]

Introduction: This scoping review aimed to provide a comprehensive summary and evaluation of solvents and methods for the extraction of bioactive compounds with pharmacological properties from Mitragyna speciosa (M. speciosa) Korth. Methods: The relevant articles were screened on electronic databases such as Scopus, PubMed, and Science Direct and verified their qualities based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guideline. Results: We selected 41 articles according to two features; the extraction of bioactive compounds and pharmacological properties of M. speciosa extract that involved different solvents and methods. Evidence shows that methanol was the commonly used solvent along with the maceration process in the extraction of M. speciosa to obtain valuable bioactive compounds with clinical benefits. Alternatively, Soxhlet provides less exertion to the extraction process with similar value. Conclusion: Despite various potential modern techniques and solvents available, the synergy between traditional maceration and Soxhlet and methanol was found to potentially attain pharmacological values and bioactive substances in M. speciosa. [ABSTRACT FROM AUTHOR]

Introduction: Kratom, an unregulated herbal supplement, has emerged as self-treatment for anxiety/depression. Kratom exhibits inhibition at multiple cytochrome P450 isozymes involved in metabolism of prescription medications, including serotonergic agents. We report a case of possible serotonin syndrome induced by kratom use in combination with prescription psychotropic medications. Case: A 63-year-old male presented with diaphoresis, flushing, aphasia, confusion, dysarthria, right facial droop, and oral temperature of 39.6oC (103.2oF), lactate 2.7 mmol/L, and creatine phosphokinase of 1507 IU/L. Initial differential diagnoses included acute ischemic stroke and bacterial meningitis. Despite partial treatment with alteplase and broad-spectrum antibiotics, symptoms persisted, and subsequent physical exam noted hyperreflexia, clonus, tremors, and temperature of 41.1oC (106oF). Home medications included a chronic regimen for anxiety/depression with bupropion, buspirone, desvenlafaxine, trazodone, and ziprasidone, in addition to kratom. Clinical suspicion for serotonin syndrome led to initiation of cyproheptadine, lorazepam, and cooling blankets. Aphasia, facial droop, and confusion improved after administration of cyproheptadine. Bupropion was restarted during hospitalization; remaining medications restarted at the discretion of the primary care provider. Discussion: Risk of serotonin syndrome with multiple serotonergic agents is well-known. Kratom is metabolized by cytochrome P40 isozymes 3A4, 2C9, and 2D6, and exhibits inhibition at those enzymes, in addition to 1A2. Pharmacokinetic interactions of kratom with prescription serotonergic agents metabolized through these isozymes has the potential to increase systemic exposure of serotonin, potentially leading to serotonin syndrome. Conclusion: Because substances contained in kratom can inhibit metabolism of prescription serotonergic medications, clinicians must be aware of potential development of serotonin syndrome. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa Korth. Havil) has been considered a narcotic drug for years, barred by the law in many parts of the world, while extensive research over the past few decades proves its several beneficial effects, some of which are still in ambiguity. In many countries, including Thailand, the indiscriminate use and abuse of kratom have led to the loss of life. Nonetheless, researchers have isolated almost fifty pure compounds from kratom, most of which are alkaloids. The most prevalent compounds, mitragynine and 7-hydroxy mitragynine, are reported to display agonist morphine-like effects on human μ-opioid receptors and antagonists at κ- and δ-opioid receptors with multimodal effects at other central receptors. Mitragynine is also credited to be one of the modulatory molecules for the Keap1-Nrf2 pathway and SOD, CAT, GST, and associated genes' upregulatory cascades, leading it to play a pivotal role in neuroprotective actions while evidently causing neuronal disorders at high doses. Additionally, its anti-inflammatory, antioxidative, antibacterial, and gastroprotective effects are well-cited. In this context, this review focuses on the research gap to resolve ambiguities about the neuronal effects of kratom and demonstrate its prospects as a therapeutic target for neurological disorders associated with other pharmacological effects. [ABSTRACT FROM AUTHOR]

BackgroundKratom (Mitragyna speciosa) use in the United States is becoming increasingly popular and its legal status varies widely from state to state. Multiple reports of adverse events associated with kratom use have ranged from liver injury, seizures, psychiatric disturbance, and rarely death.MethodsThis study investigated coroner autopsy reports from Kern County in California for the year 2020 which included qualitative data on substances from blood toxicological reports. Of the 214 opioid-associated accidental overdoses reported, 4 subjects (1.9%) had mitragynine (kratom) exposure on the autopsy report and were included in the study. We reported available demographic information and comorbid substance findings from the associated autopsy reports.ResultsAll 4 individuals with mitragynine (kratom) toxicology had accidental opioid overdose deaths noted in autopsy reports. Each subject also had toxicology positive for at least one other substance. Fentanyl was found in 3 (75%) of the cases and suspected to be the primary contributor to opioid-related deaths in those cases. However, one fatality was without fentanyl, but instead had tested positive for benzodiazepines, cannabis, and other psychiatric medications.DiscussionThe findings of this brief report provide insight into the role that mitragynine (kratom) may have in modulating risk of opioid-related deaths. The combined use of kratom with opioids such as fentanyl appears most likely to increase the risk of a fatal overdose, but it may also occur with other medications such as benzodiazepines and psychiatric medications. It is a serious concern that in the midst of the opioid overdose epidemic there is a growing presence of kratom use in the U.S. population with a largely unregulated status.

Objective: The purpose of this study was to investigate adverse events related to kratom cessation and the utilization of prescribed medications during hospitalization. Material and Methods: This retrospective study was conducted in Thanyarak Songkhla Hospital, Thailand. The study included patients aged 15 years and above who had a history of kratom consumption prior to hospitalization. Adverse events after kratom discontinuation during the patient’s hospital admission were documented. The prescribed drug regimens during hospitalization were recorded. Results: During the 4-year study period, 81 patients were enrolled. Fifty-four patients (67%) developed adverse events. The majority of enrolled patients were males between the ages of 15 and 34 years. The popular 4x100 kratom cocktail was commonly consumed prior to admission. Musculoskeletal pain (28%) and psychological disorders such as insomnia, agitation, and anxiety were observed as major adverse events. Patients with adverse events received more medications than those without adverse events (p-value=0.02). Typical antipsychotics were commonly prescribed for patients with adverse events related to kratom discontinuation (p-value

Summary: Mitragynine, an analgesic alkaloid from the plant Mitragyna speciosa (kratom), offers a safer alternative to clinical opioids such as morphine, owing to its more favorable side effect profile. Although kratom has been traditionally used for stimulation and pain management in Southeast Asia, the mitragynine biosynthesis pathway has remained elusive.We embarked on a search for mitragynine biosynthetic genes from the transcriptomes of kratom and other members of the Rubiaceae family. We studied their functions in vitro and in vivo.Our investigations led to the identification of several reductases and an enol methyltransferase that forms a new clade within the SABATH methyltransferase family. Furthermore, we discovered a methyltransferase from Hamelia patens (firebush), which catalyzes the final step. With the tryptamine 4‐hydroxylase from the psychedelic mushroom Psilocybe cubensis, we accomplished the four‐step biosynthesis for mitragynine and its stereoisomer, speciogynine in both yeast and Escherichia coli when supplied with tryptamine and secologanin.Although we have yet to pinpoint the authentic hydroxylase and methyltransferase in kratom, our discovery completes the mitragynine biosynthesis. Through these breakthroughs, we achieved the microbial biosynthesis of kratom opioids for the first time. The remarkable enzyme promiscuity suggests the possibility of generating derivatives and analogs of kratom opioids in heterologous systems. [ABSTRACT FROM AUTHOR]

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Mitragynine (MG) is an alkaloid found in Mitragyna speciosa (kratom) that is used as an herbal remedy for pain relief and opioid withdrawal. MG acts at μ-opioid and α-adrenergic receptors in vitro, but the physiological relevance of this activity in the context of neuropathic pain remains unknown. The purpose of the present study was to characterize the effects of MG in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN), and to investigate the potential impact of sex on MG’s therapeutic efficacy. Inhibition of oxaliplatin-induced mechanical hypersensitivity was measured following intraperitoneal administration of MG. Both male and female C57BL/6J mice were used to characterize potential sex-differences in MG’s therapeutic efficacy. Pharmacological mechanisms of MG were characterized through pretreatment with the opioid and adrenergic antagonists naltrexone, prazosin, yohimbine, and propranolol (1, 2.5, 5 mg/kg). Oxaliplatin produced significant mechanical allodynia of equal magnitude in both male and females, which was dose-dependently attenuated by repeated MG exposure. MG was more potent in males vs females, and the highest dose of MG (10 mg/kg) exhibited greater anti-allodynic efficacy in males. Mechanistically, activity at µ-opioid, α1- and α2-adrenergic receptors, but not β-adrenergic receptors contributed to the effects of MG against oxaliplatin-induced mechanical hypersensitivity. Repeated MG exposure significantly attenuated oxaliplatin-induced mechanical hypersensitivity with greater potency and efficacy in males, which has crucial implications in the context of individualized pain management. The opioid and adrenergic components of MG indicate that it shares pharmacological properties with clinical neuropathic pain treatments.

Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America. Consequently, the over-the-counter opioids loperamide (Imodium A-D) and mitragynine, the herbal ingredient in kratom, are increasingly used to avert withdrawal or induce euphoria. Arrhythmia events related to these nonscheduled drugs have not been systematically studied. In this study, we sought to explore opioid-associated arrhythmia reporting in North America. The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), and Canada Vigilance Adverse Reaction (CVAR) databases were searched (2015-2021). Reports involving nonprescription drugs (loperamide, mitragynine) and diphenoxylate/atropine (Lomotil) were identified. Methadone, a prescription opioid (full agonist), served as a positive control owing to its established arrhythmia risk. Buprenorphine (partial agonist) and naltrexone (pure antagonist), served as negative controls. Reports were classified according to Medical Dictionary for Regulatory Activities terminology. Significant disproportionate reporting required a proportional reporting ratio (PRR) of ≥2, ≥3 cases, and chi-square ≥4. Primary analysis used FAERS data, whereas CAERS and CVAR data were confirmatory. Methadone was disproportionately associated with ventricular arrhythmia reports (PRR: 6.6; 95% CI: 6.2-7.0; n = 1,163; chi-square = 5,456), including 852 (73%) fatalities. Loperamide was also significantly associated with arrhythmia (PRR: 3.2; 95% CI: 3.0-3.4; n = 1,008; chi-square = 1,537), including 371 (37%) deaths. Mitragynine demonstrated the highest signal (PRR: 8.9; 95% CI: 6.7-11.7; n = 46; chi-square = 315), with 42 (91%) deaths. Buprenorphine, diphenoxylate, and naltrexone were not associated with arrhythmia. Signals were similar in CVAR and CAERS. The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America. [Display omitted] [ABSTRACT FROM AUTHOR]

Doxorubicin is an effective chemotherapeutic agent in the treatment of solid hematological and non-hematological carcinoma. However, its long-term usage could result in side effects, such as cardiomyopathy, chronic heart failure, neurotoxicity and cancer cell resistance. In this study, we reported the sensitivity enhancement of A549 human lung cancer cells on doxorubicin at a low dose (0.1 ppm) in combination with 10–60 ppm of crude and alkaloid extracts derived from the leaves of Kratom (Mitragyna speciosa (Korth.) Havil. Rubiaceae). A549 cancer cell lines were insensitive to the crude extract containing low mitragynine (MG) (4–5%), while these cells were moderately inhibited by the alkaloid extract containing 40–45% MG (IC50 of 48–55 ppm). The alkaloid extract was found to inhibit A549 cancer cells via apoptosis as suggested by the higher relative fluorescence intensity with Annexin compared to that in propidium iodide (PI), i.e., a positive Annexin and a negative PI. The combination of crude extract and doxorubicin sensitized A549 cancer cells to doxorubicin by 1.3 to 2.4 times, while the combination with the alkaloid induced a 2.6- to 3.4-fold increase in sensitivity. The calculated combination index (CI) for doxorubicin with the crude and alkaloid extracts was 0.6 and 0.3, respectively, showing potential synergistic combinations to reduce the level of dosage of doxorubicin used in chemotherapy. In addition, the synergistic enhancement effect of crude extract on the cytotoxic activity of doxorubicin provides insights into the plausibility of non-alkaloids to influence the biological activities of Kratom.

Kratom leaves, consumed by millions worldwide as tea or ground leaf powder, contain multiple alkaloids, with mitragynine being the most abundant and responsible for most effects. Mitragynine is a partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors; however, unlike morphine, it does not activate the β-arrestin-2 respiratory depression pathway. Due to few human mitragynine data, the largest randomized, between-subject, double-blind, placebo-controlled, dose-escalation study of 500–4000 mg dried kratom leaf powder (6.65–53.2 mg mitragynine) was conducted. LC-MS/MS mitragynine and 7-hydroxymitragynine plasma concentrations were obtained after single and 15 daily doses. Mitragynine and 7-hydroxymitragynine Cmax increased dose proportionally, and AUC was slightly more than dose proportional. The median mitragynine Tmax was 1.0–1.3 h after single and 1.0–1.7 h after multiple doses; for 7-hydroxymitragynine Tmax, it was 1.2–1.8 h and 1.3–2.0 h. Steady-state mitragynine concentrations were reached in 8–9 days and 7-hydroxymitragynine within 7 days. The highest mean mitragynine T1/2 was 43.4 h after one and 67.9 h after multiple doses, and, for 7-hydroxymitragynine, it was 4.7 and 24.7 h. The mean 7-hydroxy-mitragynine/mitragynine concentration ratios were 0.20–0.31 after a single dose and decreased (0.15–0.21) after multiple doses. These mitragynine and 7-hydroxymitragynine data provide guidance for future clinical kratom dosing studies and an interpretation of clinical and forensic mitragynine and 7-hydroxymitragynine concentrations.

Kratom and cannabidiol products are used to self-treat a variety of conditions, including anxiety and pain, and to elevate mood. Research into the individual pharmacokinetic properties of commercially available kratom and cannabidiol products has been performed, but there are no studies on coadministration of these products. Surveys of individuals with kratom use history indicate that cannabidiol use is one of the strongest predictors of both lifetime and past month kratom use. The purpose of this study was to determine if there are changes in pharmacokinetic properties when commercially available kratom and cannabidiol products are administered concomitantly. It was found that with concomitant administration of cannabidiol, there was a 2.8-fold increase in the exposure of the most abundant kratom alkaloid, mitragynine, and increases in the exposure of other minor alkaloids. The results of this work suggest that with cannabidiol coadministration, the effects of kratom may be both delayed and increased due to a delay in time to reach maximum plasma concentration and higher systemic exposure of the psychoactive alkaloids found in kratom.