Discovery of procyanidin condensed tannins of (-)-epicatechin from Kratom, Mitragyna speciosa, as virucidal agents against SARS-CoV-2.

Kratom, Mitragyna speciosa, is one of the most popular herbs in the West and Southeast Asia. A number of previous works have focused on bioactive alkaloids in this plant; however, non-alkaloids have never been investigated for their biological activities. Antiviral and virucidal assays of a methanol leaf extract of Kratom, M. speciosa, revealed that a crude extract displayed virucidal activity against the SARS-CoV-2. Activity-guided isolation of a methanol leaf extract of Kratom led to the identification of B-type procyanidin condensed tannins of (-)-epicatechin as virucidal compounds against SARS-CoV-2. The fraction containing condensed tannins exhibited virucidal activity with an EC50 value of 8.38 µg/mL and a selectivity index (SI) value >23.86. LC-MS/MS analysis and MALDI-TOF MS identified the structure of the virucidal compounds in Kratom as B-type procyanidin condensed tannins, while gel permeation chromatograph (GPC) revealed weight average molecular weight of 238,946 Da for high molecular-weight condensed tannins. In addition to alkaloids, (-)-epicatechin was found as a major component in the leaves of M. speciosa, but it did not have virucidal activity. Macromolecules of (-)-epicatechin, i.e., procyanidin condensed tannins, showed potent virucidal activity against SARS-CoV-2, suggesting that the high molecular weights of these polyphenols are important for virucidal activity.

An In Vitro Examination of Whether Kratom Extracts Enhance the Cytotoxicity of Low-Dose Doxorubicin against A549 Human Lung Cancer Cells.

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 Retail Availability in Fort Worth, Texas.

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.

Discovering Dynamic Plant Enzyme Complexes in Yeast for Kratom Alkaloid Pathway Identification.

Discovering natural product biosynthetic pathways of medicinal plants is challenging and laborious. Capturing the coregulation patterns of pathway enzymes, particularly transcriptomic regulation, has proven an effective method to accelerate pathway identification. In this study, we developed a yeast-based screening method to capture the protein-protein interactions (PPI) between plant enzymes, which is another useful pattern to complement the prevalent approach. Combining this method with plant multiomics analysis, we discovered four enzyme complexes and their organized pathways from kratom, an alkaloid-producing plant. The four pathway branches involved six enzymes, including a strictosidine synthase, a strictosidine ß-D-glucosidase (MsSGD), and four medium-chain dehydrogenase/reductases (MsMDRs). PPI screening selected six MsMDRs interacting with MsSGD from 20 candidates predicted by multiomics analysis. Four of the six MsMDRs were then characterized as functional, indicating the high selectivity of the PPI screening method. This study highlights the opportunity of leveraging post-translational regulation features to discover novel plant natural product biosynthetic pathways.

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

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.

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

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.

Case Report: Possible Serotonin Syndrome in a Patient Taking Kratom and Multiple Serotonergic Agents.

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.

Buprenorphine-Naloxone in the Setting of Kratom Withdrawal, Opioid Use Disorder, and Stage IV Lung Adenocarcinoma.

Management of cancer-associated pain warrants consideration of many factors, including characterization and etiology of the pain, socioeconomic factors, medication tolerance, and substance use history. Kratom (Mitragyna speciosa) is an herbal substance with stimulant and analgesic properties that is becoming a popular drug in the United States. In this report, we present a patient with a history of opioid use disorder (OUD) who had been using high doses of kratom to alleviate progressive chest pain and dyspnea secondary to newly diagnosed stage IV lung adenocarcinoma. He underwent kratom withdrawal shortly after his index admission and was reluctant to continue full opioid agonists given his history of OUD and complex living situation. His kratom withdrawal and cancer-associated symptoms were successfully managed with buprenorphine-naloxone. Providers should obtain a careful history of novel substance use such as kratom. Furthermore, buprenorphine-naloxone is a safe and effective option to simultaneously manage kratom withdrawal and cancer-associated pain.

Polysubstance use profiles among US adults using Kratom (Mitragyna speciosa): A latent class analysis using The National Survey on Drug Use and Health (NSDUH).

BACKGROUND AND OBJECTIVES: Kratom (Mitragyna speciosa) use is associated with polysubstance use (PSU) and use disorders. However, additional research on PSU heterogeneity in populations using this novel psychoactive substance is necessary. The authors investigated patterns of past 12-month PSU among US adults reporting past 12-month use of kratom and at least one additional substance. METHODS: Latent class models were fit using 2019 National Survey on Drug Use and Health (NSDUH) data which was collected from 412 US adults reporting past 12-month use of kratom and at least one of 11 additional substances. RESULTS: Three distinct profiles were identified: "marijuana/alcohol/tobacco" (63.3%), "marijuana/alcohol/tobacco + psychedelics" (19.3%), and "marijuana/alcohol/tobacco + psychedelics/heroin/prescriptions" (17.4%). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This is the first epidemiological study in which a latent class analysis was used to identify unique PSU profiles among US adults using kratom and other substances. Understanding the profiles of people using kratom in relation to the use of other drugs might help guide screening interventions, treatment needs, and policy.

The association between E-cigarette use and Kratom use among US adults.

Kratom, an herbal substance with stimulant and opioid-like effects commonly used in capsules or powder to be ingested or brewed as a tea, has been gaining popularity in the United States (US). US e-cigarette use (i.e., vaping) has exponentially increased in recent years. Given the potential risks of kratom (e.g., poisonings) and the increasing prevalence of e-cigarette use, understanding the association between them is important to inform prevention strategies and regulatory policies. We harnessed data from the 2020 National Survey on Drug Use and Health (NSDUH; n = 27,170) to examine past-year kratom use by past-year e-cigarette use among adults. We ran a logistic regression model on kratom use by e-cigarette use adjusting for associated factors with substance use. Among all respondents, the estimated prevalence of past-year kratom use was 0.9% and an estimated 9.7% reported past-year e-cigarette use. Our multivariable model found those with e-cigarette use (vs. not) had 4.80 higher odds of using kratom in the past year (aOR = 4.80; 95% CI = 2.62, 8.80). These findings might help inform the need for continuing education for physicians and healthcare providers related to practice in managing patients with kratom use, future studies for regulatory policies on e-cigarettes (e.g., e-liquids), or other FDA policies related to kratom.

Methyl ester and aromatic ether modification of mitragynine for generation of mitragynine-specific polyclonal antibodies.

Mitragynine is an alkaloid from Mitragyna speciosa Korth. (kratom), a native tropical plant in Southeast Asia. It could render psychotropic effects and is often misused in substitution for commercial drugs. In recent years, the consumption of kratom has grown rapidly and has led some countries to ban its use. The misuse of kratom can be detected and monitored through the determination of mitragynine from biological samples of the users. Therefore, the development of a rapid and effective detection method is needed. In this study, polyclonal antibodies were produced using mitragynine coupled to a carrier protein (cationic bovine serum albumin, cBSA) as an immunogen, which was prepared with coupling agents (i.e., N, N- dicyclohexylcarbodiimide, DCC and N-hydroxysuccinimide, NHS). It was conjugated to different mitragynine structure, 16-COOCH3 (methyl ester) and 9-OCH3 (aromatic ether). 2,4,6-Trinitrobenzenesulfonic acid (TNBS) method showed that 45 and 46 amino groups were bound to C22-MG-cBSA and C9-MG-cBSA, respectively. Fourier-transform infrared spectroscopy (FTIR) spectral changes at C22- and C9-hydroxymitragynine indicated reduction and demethylation process. In UV-Vis spectra, conjugated mitragynine to cBSA and OVA were displayed at a spectral region at 240-300 nm. For the antibody titre, the C22-MG-cBSA anti-serum showed a significantly higher titre than the C9-MG-cBSA at 1/128000 and 1/32000 dilutions, respectively. The detection range of the developed competitive indirect ELISA (CI-ELISA) was 0.01 to 10.00 µg/mL (R2 = 0.9964). The assay exhibited a limit of detection (LOD) and limit of quantification (LOQ) at 0.041 and 0.124 µg/mL, respectively. The antibody produced is a high-value biorecognition molecule that can be further used in developing immuno-based detection methods such as immunosensors and immunochromatographic lateral flow assays. This will benefit the task force or forensic agencies for toxicological screening with high speed and efficiency.

[An Outpatient Withdrawal Treatment of Kratom in Social Phobia: Psychotherapeutic Surgery Meets Addiction Psychiatric Outpatient Clinic]. / Eine ambulante Entzugsbehandlung von Kratom bei sozialer Phobie: psychotherapeutische Praxis trifft suchtpsychiatrische Institutsambulanz.

BACKGROUND: An increase in the use of kratom is reported worldwide. The substance is not classified as illegal in Germany. The psychoactive effects and withdrawal symptoms are opioid-like. METHOD: A patient visited a psychotherapy practice for treatment of his social phobia. Problematic use of kratom was disclosed, and treatment planning was adjusted accordingly. RESULTS: The physical withdrawal treatment was carried out in cooperation of the psychiatric outpatient clinic and the psychotherapeutic practice. Securing abstinence and treatment of social phobia are now upcoming goals in the psychotherapeutic practice. DISCUSSION: The use of kratom is more widespread than apparently assumed. Detoxification can be performed on an outpatient basis. CONCLUSION: The case underlines the importance of a detailed addiction anamnesis, but especially of the individual case-related cooperation therapists.

LC/ESI/TOF-MS Characterization, Anxiolytic and Antidepressant-like Effects of Mitragyna speciosa Korth Extract in Diabetic Rats.

In this study, the attenuative effects of the hydro-alcoholic extract from Mitragyna speciosa (MSE) against diabetes-induced anxiety and depression-like behaviors were examined. In addition, UPLC/ESI/TOF-MS analysis was performed to identify the phytochemical nature of MSE. DM was induced using a combination of high fructose/streptozotocin, and the diabetic rats were treated with MSE (50 and 200 mg/kg) for 5 weeks. After treatment, the animals were subjected to a forced swim test, open field test and elevated plus-maze tests. Additionally, proinflammatory cytokines and oxidative stress parameters were evaluated in the brain tissues of the rats. UPLC/ESI/TOF-MS analysis revealed that MSE is abundantly rich in polyphenolic constituents, notably flavonoid and phenolic glycosides. Behavioral tests and biochemical analyses indicated that diabetic rats showed significantly increased anxiety and depressive-like behavioral deficits, brain oxidative stress and pro-inflammatory cytokines levels (IL-1ß, IL-6 and TNF-α). Treatment with MSE (50 and 200 mg/kg) significantly attenuated increased blood glucose level, depressive and anxiety-like behaviors in diabetic rats. Additionally, the antioxidant enzymes activities were markedly increased in MSE-treated animals, while TNF-α, IL-1ß and IL-6 cytokines were notably suppressed. Taken together, these results suggested that MSE has potentials as antidepressant and anxiolytic-like effects and improves the brain oxido-inflammatory status in diabetic rats.

Pressure Necrosis Requiring Fasciotomy After Kratom Overdose.

INTRODUCTION: Kratom (Mitragyna speciosa) is a popular plant-based extract that has dose-dependent stimulatory and sedative effects. It has been used for self-treatment of opioid withdrawal and can result in seizures, hepatotoxicity, and infectious complications from bacterial contamination. Reports of morbidity and mortality associated with Kratom may be confounded by coingestants. We report a case of severe rhabdomyolysis and pressure necrosis leading to fasciotomy in a patient who was using Kratom. CASE REPORT: A 31-year-old male with substance use presented to the emergency department after loss of consciousness for 6 hours after smoking Kratom. He was found to have rhabdomyolysis, acute renal and hepatic injury, and electrolyte disturbances. No ethanol was detected, and urine drug screen was negative. Over the next 3 hours, the patient developed signs of compartment syndrome and he was transferred to the operating room for fasciotomy. He required continuous renal replacement therapy for 48 hours and his labs and clinical status improved. He was discharged 18 days later. A serum and urine sample from the first day of presentation were analyzed for mitragynine and 7-hydroxymitragynine using an Ultra Performance Liquid Chromatography-Tandem Mass Spectrometer (UPLC-MSMS) method. The serum mitragynine was 5 ng/mL and the urine mitragynine 6 ng/mL. CONCLUSIONS: Although there are numerous reports of opioids resulting in prolonged periods of immobilization and rhabdomyolysis, this is not commonly reported in Kratom overdoses.This case report highlights the profound sedative effect of Kratom and the potential of pressure necrosis injury resulting in rhabdomyolysis and compartment syndrome requiring fasciotomy.

A Case of Kratom Use: Implications for Managing Addiction and Addressing Comorbidity in Overdose Survivors, and for the Education of Clinicians Who Are Not Addiction Specialists.

As overdose mortality rises, overdose morbidity - complications seen as a result of overdose events - is rising too. Although comorbidity is often thought of as psychiatric or psychological, a case report of compartment syndrome, rhabdomyolysis, and acute renal insufficiency in a patient with loss of consciousness for 6 hours after smoking Kratom highlights medical comorbidity. The case is a reminder that a broad range of medical comorbidities can occur in patients with overdose and with unhealthy substance use. Patients with these comorbidities will often be cared for by clinicians who are not addiction specialists, who will need to have sufficient training to recognize and address them.

Kratom Use Among U.S. Adolescents: Analyses of the 2019 National Survey on Drug Use and Health.

BACKGROUND: Kratom (Mitragyna speciosa) is an opioid-like psychoactive substance not approved by the U.S. Food and Drug Administration that could be used due to its euphoric, stimulant, and analgesic effects. Kratom is gaining popularity in the U.S. and becoming a reason of concern among pediatricians. METHODS: Data from the 2019 National Survey on Drug Use and Health were analyzed to estimate the prevalence and identify correlates of lifetime and past 12-month kratom use among 13,397 U.S. adolescents. Multivariable logistic regression models were conducted to assess the associations of interest. RESULTS: Lifetime and past 12-month prevalence of kratom use was .44% (95% confidence interval [CI] .32-.60) and .27% (95% CI .18-.40), respectively. Past 12-month cigarette use was associated with lifetime kratom use (adjusted odds ratio 2.60, 95% CI 1.07-6.35). Past 12-month cannabis use was associated with past 12-month kratom use (adjusted odds ratio 2.48, 95% CI 1.15-5.35). CONCLUSIONS: This first report on the epidemiology of adolescent kratom use provides a baseline to assess kratom use trends in future years and identify potential correlates of use among adolescents.

Combinations of indole based alkaloids from Mitragyna speciosa (Kratom) and cisplatin inhibit cell proliferation and migration of nasopharyngeal carcinoma cell lines.

ETHNOPHARMACOLOGICAL RELEVANCE: Mitragyna speciosa (Korth.) or kratom is a medicinal plant indigenous to Southeast Asia. The leaf of M. speciosa is used as a remedy in pain management including cancer related pain, in a similar way as opioids and cannabis. Despite its well-known analgesic effect, there is a scarce of information on the cancer-suppressing potential of M. speciosa and its active constituents. AIM OF THE STUDY: To assess the potential applicability of M. speciosa alkaloids (mitragynine, speciociliatine or paynantheine) as chemosensitizers for cisplatin in Nasopharyngeal carcinoma (NPC) cell lines. MATERIALS AND METHODS: The cytotoxic effects of the extracts, fractions and compounds were determined by conducting in vitro cytotoxicity assays. Based on the cytotoxic screening, the alkaloid extract of M. speciosa exhibited potent inhibitory effect on the NPC cell line NPC/HK1, and therefore, was chosen for further fractionation and purification. NPC cell lines NPC/HK1 and C666-1 were treated with combinations of cisplatin and M. speciosa alkaloids combinations in 2D monolayer culture. The effect of cisplatin and mitragynine as a combination on cell migration was tested using in vitro wound healing and spheroid invasion assays. RESULTS: In our bioassay guided isolation, both methanolic and alkaloid extracts showed mild to moderate cytotoxic effect against the NPC/HK1 cell line. Both NPC cell lines (NPC/HK1 and C666-1) were insensitive to single agent and combination treatments of the M. speciosa alkaloids. However, mitragynine and speciociliatine sensitized the NPC/HK1 and C666-1 cells to cisplatin at ~4- and >5-fold, respectively in 2D monolayer culture. The combination of mitragynine and cisplatin also significantly inhibited cell migration of the NPC cell lines. Similarly, the combination also of mitragynine and cisplatin inhibited growth and invasion of NPC/HK1 spheroids in a dose-dependent manner. In addition, the spheroids did not rapidly develop resistance to the drug combinations at higher concentrations over 10 days. CONCLUSION: Our data indicate that both mitragynine and speciociliatine could be potential chemosensitizers for cisplatin. Further elucidation focusing on the drug mechanistic studies and in vivo studies are necessary to support delineate the therapeutic applicability of M. speciosa alkaloids for NPC treatment.

Development of a Physiologically Based Pharmacokinetic Model of Mitragynine, Psychoactive Alkaloid in Kratom (Mitragyna Speciosa Korth.), In Rats and Humans.

Mitragynine is a major psychoactive alkaloid in leaves of kratom (Mitragyna speciosa Korth.). To understand its disposition in organs, this study aimed to develop a physiologically based pharmacokinetic (PBPK) model that predicts mitragynine concentrations in plasma and organ of interests in rats and humans. The PBPK model consisted of six organ compartments (i.e. lung, brain, liver, fat, slowly perfused tissues, and rapidly perfused tissue). From systematic searching, three pharmacokinetic studies of mitragynine (two studies in rats and 1 study in humans) were retrieved from the literature. Berkeley Madonna Software (version 8.3.18) was used for model development and model simulation. The developed PBPK model consisted of biologically relevant features following involvement of (i) breast cancer-resistant protein (BCRP) in brain, (ii) a hepatic cytochrome P450 3A4 (CYP3A4)-mediated metabolism in the liver, and (iii) a diffusion-limited transport in fat. The simulations adequately describe simulated and observed data in the two species with different dosing regimens. PBPK models of mitragynine in rats and humans were successfully developed. The models may be used to guide optimal mitragynine dosing regimens.

Lipid profile of regular kratom (Mitragyna speciosa Korth.) users in the community setting.

BACKGROUND AND AIM: Kratom, or Mitragyna speciosa Korth., is a tropical plant that has been reported to exhibit opioid-like effects. Although opioids have been demonstrated to alter the lipid profile of regular users, data on the lipid-altering effects of kratom are scarce. This study aimed to compare the fasting lipid profile of regular kratom users to that of healthy subjects who do not use kratom. It also determined the association between various characteristics of kratom users and the serum triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels of regular kratom users. METHODS: A total of 200 participants (n = 100 kratom users and n = 100 healthy subjects who do not use kratom) were recruited for this analytical cross-sectional study. Data on sociodemographic status, kratom use characteristics, cigarette smoking, physical activity, body mass index (BMI), fasting serum lipid profile, and liver function were collected from all participants. RESULTS: The liver parameters of the study participants were within normal range. The serum total cholesterol and LDL of kratom users were significantly lower than those of healthy subjects who do not use kratom. There were no significant differences in the serum triglyceride and HDL levels. However, higher average daily frequency of kratom use and increasing age were associated with increased serum total cholesterol among kratom users. Other kratom use characteristics such as age of first kratom intake, duration of kratom use, and quantity of daily kratom intake were not associated with increased serum triglyceride, total cholesterol, LDL, and HDL levels. CONCLUSIONS: Our findings suggest regular kratom consumption was not linked to elevated serum lipids, except when there is a higher frequency of daily kratom intake. However, the study was limited by the small sample size, and hence a more comprehensive study with larger sample size is warranted to confirm the findings.