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Moeung S, Chassagne F, Goyet S, Nhoeung S, Sun L, Yang D, Vilhem S, Dim B, Ly S, Sov L, Sreng V, Chorn S, Chhun S, Borand L, Kim S, Segeral O. Traditional medicine consumption in postpartum for HBV-infected women enrolled in the ANRS 12345 TA PROHM study in Cambodia. PLoS One 2023; 18:e0288389. [PMID: 37561767 PMCID: PMC10414559 DOI: 10.1371/journal.pone.0288389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 06/26/2023] [Indexed: 08/12/2023] Open
Abstract
In Cambodia, traditional medicine was commonly described as being used by pregnant women at two time points: one month before birth and during early postpartum. The present study aims to describe traditional medicine consumption during postpartum phase for women enrolled in the TA PROHM study and to investigate the possible association between traditional medicine consumption and acute liver toxicity. An ethnobotanical survey was conducted in 2 groups of HBV-infected pregnant women (with and without postpartum hepatocellular injury) enrolled in the study. Hepatocellular injury was defined by having Alanine Aminotransferase (ALT) > 2.5 times the Upper Limit of Normal (ULN = 40 U/L) at the 6th week postpartum visit. Interviews were done using a standardized questionnaire. Plant samples were collected and later identified by two traditional healers. Chi-square test was used to find the association between hepatocellular injury and traditional medicine consumption or a specific plant species. In total, 75 women were enrolled and 52 (69.3%) used at least one traditional remedy composed of 123 different plants and 12 alcoholic macerations of porcupine stomach. Orally consuming at least one remedy with alcohol was significantly associated with hepatocellular injury (33% vs 13%, p = 0.034). Among the 123 plants species identified, four were found to be associated with hepatocellular injury, namely Amphineurion marginatum (Roxb.) D.J.Middleton [Apocynaceae] (p = 0.022), Selaginella tamariscina (P.Beauv.) Spring [Selaginellaceae] (p = 0.048), Mitragyna speciosa Korth. [Rubiaceae] (p = 0.099) and Tetracera indica (Christm. & Panz.) Merr. [Dilleniaceae] (p = 0.079). Consumption of traditional medicine in postpartum is a common practice for women enrolled in the TA PROHM study. Alcohol-based remedies may exacerbate the risk of acute hepatocellular injury in HBV-infected women already exposed to immune restoration. The complex mixtures of herbs need to be further evaluated by in vitro and in vivo studies.
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Affiliation(s)
| | | | - Sophie Goyet
- “Independent Researcher”, 7 Passage du Clair Matin, Annecy le Vieux, France
| | - Sovann Nhoeung
- Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | - Lynecta Sun
- Faculty of Pharmacy, University of Health Sciences, Phnom Penh, Cambodia
| | - Dorina Yang
- Faculty of Pharmacy, University of Health Sciences, Phnom Penh, Cambodia
| | - Steve Vilhem
- Faculty of Medicine, University of Health Sciences, Phnom Penh, Cambodia
| | - Bunnet Dim
- Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | - Socheat Ly
- Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | - Linda Sov
- Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | - Vouchleang Sreng
- Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | - Sokda Chorn
- Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | | | - Laurence Borand
- Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | - Sothea Kim
- Faculty of Pharmacy, University of Health Sciences, Phnom Penh, Cambodia
| | - Olivier Segeral
- ANRS, University of Health Sciences, Phnom Penh, Cambodia
- HIV Unit, Infectious Diseases Department, Geneva University Hospital, Geneva, Switzerland
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Feldman JD, Schriefer D, Smith KE, Weiss ST, Butera G, Dunn KE, Grundmann O, McCurdy CR, Singh D, Epstein DH. Omissions, Ambiguities, and Underuse of Causal Assessment Tools: a Systematic Review of Case Reports on Patients Who Use Kratom. CURRENT ADDICTION REPORTS 2023. [DOI: 10.1007/s40429-023-00466-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
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Basheer M, Khudhair Jasim R, Harn GL. Controversial usages of kratom ( Mitragyna speciosa): For good or for evil. World J Pharmacol 2022; 11:16-26. [DOI: 10.5497/wjp.v11.i3.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 10/04/2022] [Accepted: 11/23/2022] [Indexed: 11/28/2022] Open
Abstract
Kratom (Mitragyna speciosa) is a plant that grows well in tropical climates such as in Southeast Asia. Traditionally, people discovered it possessed a stimulating effect that relieved tiredness. Furthermore, it contains analgesic and medicinal properties for the treatment of pain, diarrhea, muscle discomfort, and blood pressure and to enhance stamina. Nevertheless, long term or regular consumption of kratom leads to addiction. This is because the main alkaloid of kratom, mitragynine, binds to opioid receptors and exerts a euphoric effect similar to that of morphine, which may lead to death. Due to this reason, kratom has been listed as a regulated substance in many countries including the United States, Thailand, Malaysia, Bhutan, Finland, Lithuania, Denmark, Poland, Sweden, Australia, and Myanmar. Usages of kratom carry two pharmacological effects depending on dosage. Low-dose kratom exerts a stimulating effect that refreshes the user. High-dose kratom exerts sedative effects that can lead to addiction similar to that of morphine. Despite the euphoric effect of kratom, the beneficial values of kratom to human health is indisputable. Therefore, a complete banning of kratom may cause a loss to pharmaceutical industry. Rather, a controlled or selective usage of kratom will be a better choice.
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Affiliation(s)
- Murtadha Basheer
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia
| | - Rana Khudhair Jasim
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia
| | - Gam Lay Harn
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia
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Striley CW, Hoeflich CC, Viegas AT, Berkowitz LA, Matthews EG, Akin LP, Iheanyi-Okeahialam C, Mansoor U, McCurdy CR. Health Effects Associated With Kratom ( Mitragyna speciosa) and Polysubstance Use: A Narrative Review. Subst Abuse 2022; 16:11782218221095873. [PMID: 35645563 PMCID: PMC9130800 DOI: 10.1177/11782218221095873] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 04/01/2022] [Indexed: 11/15/2022]
Abstract
Background Kratom (Mitragyna speciosa) consumption and associated health effects have raised debates in the United States. Although most people using this herb do not experience adverse health effects associated with kratom use, medical providers should be knowledgeable of emerging substances and concurrent, sequential, or simultaneous use of other drugs which may impact healthcare recommendations and prescribing practices. Methods The objective of this narrative review was to elucidate selected health effects associated with using kratom-either alone or with other substances. Since scientifically controlled human subjects research on kratom use is still limited, relevant case reports were also described. Results Cardiovascular, gastrointestinal, neurological, and psychiatric effects associated with kratom use were especially notable, and in-utero exposure accompanied concern regarding a neonate's risk for developing neonatal abstinence syndrome. Our ability to identify and understand the role of this herb in kratom-associated fatalities is complicated since kratom is not routinely screened for in standard forensic toxicology. If a screening is performed, it is usually for the major alkaloid, mitragynine, as a surrogate for kratom use. In addition to lacking a standard practice of screening decedents for kratom alkaloids, the association between mortality and kratom use may be confounded by polysubstance use, adulteration of kratom products, and drug-herb interactions. Conclusions Increasing medical awareness of this herb is vital to ensuring prompt administration of best-practice medical advice or treatment for people seeking information related to kratom use or for patients experiencing an adverse health effect that may be associated with using or withdrawing from kratom. Knowledge gained from continued surveillance and study of kratom and its associated health effects may assist in guiding clinical decision-making and preventing development of adverse health effects among people using kratom.
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Affiliation(s)
- Catherine W Striley
- Department of Epidemiology, College of Public Health & Health Professions and College of Medicine, University of Florida, Gainesville, FL, USA
| | - Carolin C Hoeflich
- Department of Epidemiology, College of Public Health & Health Professions and College of Medicine, University of Florida, Gainesville, FL, USA
| | - Andrew T Viegas
- Department of Epidemiology, College of Public Health & Health Professions and College of Medicine, University of Florida, Gainesville, FL, USA.,College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Lindsey A Berkowitz
- Department of Epidemiology, College of Public Health & Health Professions and College of Medicine, University of Florida, Gainesville, FL, USA.,Department of Occupational Therapy, College of Public Health & Health Professions, University of Florida, Gainesville, FL, USA
| | - Emily G Matthews
- Department of Epidemiology, College of Public Health & Health Professions and College of Medicine, University of Florida, Gainesville, FL, USA
| | - Leyla P Akin
- Department of Epidemiology, College of Public Health & Health Professions and College of Medicine, University of Florida, Gainesville, FL, USA.,Department of Anthropology, London School of Economics and Political Science, London, England, UK
| | - Chidinma Iheanyi-Okeahialam
- Department of Epidemiology, College of Public Health & Health Professions and College of Medicine, University of Florida, Gainesville, FL, USA
| | - Urmeen Mansoor
- Department of Epidemiology, College of Public Health & Health Professions and College of Medicine, University of Florida, Gainesville, FL, USA.,College of Journalism and Communications, University of Florida, Gainesville, FL, USA
| | - Christopher R McCurdy
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA
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Abstract
Kratom is a plant with opioid-like properties known to produce stimulant and analgesic effects. Although there are numerous studies on the psychoactive components of kratom, less is known about the toxicity. Specifically, few reports describe kratom-induced hepatotoxicity and demonstrate histological features. We provide a case report detailing the clinicopathologic findings of drug-induced liver injury caused by kratom. The laboratory workup included significant elevation of total bilirubin and alkaline phosphatase. Liver biopsy demonstrated a prominent canalicular cholestatic pattern, mixed portal inflammation, and newly described perivenular necrosis. This report provides additional information on kratom toxicity because its use continues to rise.
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Smith KE, Rogers JM, Dunn KE, Grundmann O, McCurdy CR, Schriefer D, Epstein DH. Searching for a Signal: Self-Reported Kratom Dose-Effect Relationships Among a Sample of US Adults With Regular Kratom Use Histories. Front Pharmacol 2022; 13:765917. [PMID: 35300296 PMCID: PMC8921773 DOI: 10.3389/fphar.2022.765917] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 01/31/2022] [Indexed: 12/15/2022] Open
Abstract
There is limited understanding regarding kratom use among US adults. Although motivations for use are increasingly understood, typical kratom doses, threshold of (low and high) doses for perceived effectiveness, and effects produced during cessation are not well documented. We aimed to extend prior survey work by recruiting adults with current and past kratom exposure. Our goal was to better understand kratom dosing, changes in routines, and perception of effects, including time to onset, duration, and variability of beneficial and adverse outcomes from use and cessation. Among respondents who reported experiencing acute kratom effects, we also sought to determine if effects were perceived as helpful or unhelpful in meeting daily obligations. Finally, we attempted to detect any signal of a relationship between the amount of kratom consumed weekly and weeks of regular use with ratings of beneficial effects from use and ratings of adverse effects from cessation. We conducted an online survey between April-May 2021 by re-recruiting participants from a separate study who reported lifetime kratom use. A total of 129 evaluable surveys were collected. Most (59.7%) had used kratom >100 times and reported currently or having previously used kratom >4 times per week (62 weeks on average). Under half (41.9%) reported that they considered themselves to be a current "regular kratom user." A majority (79.8%) reported experiencing acute effects from their typical kratom dose and that onset of effects began in minutes but dissipated within hours. Over a quarter reported that they had increased their kratom dose since use initiation, whereas 18.6% had decreased. Greater severity of unwanted effects from ≥1 day of kratom cessation was predicted by more weeks of regular kratom use (β = 6.74, p = 0.02). Acute kratom effects were largely reported as compatible with, and sometimes helpful in, meeting daily obligations. In the absence of human laboratory studies, survey methods must be refined to more precisely assess dose-effect relationships. These can help inform the development of controlled observational and experimental studies needed to advance the public health understanding of kratom product use.
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Affiliation(s)
- Kirsten E Smith
- Real-World Assessment, Prediction, and Treatment Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, United States
| | - Jeffrey M Rogers
- Real-World Assessment, Prediction, and Treatment Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, United States
| | - Kelly E Dunn
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Oliver Grundmann
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Christopher R McCurdy
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Destiny Schriefer
- Real-World Assessment, Prediction, and Treatment Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, United States
| | - David H Epstein
- Real-World Assessment, Prediction, and Treatment Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, United States
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Abstract
PURPOSE OF REVIEW Drug-induced bile duct injury can be caused by a long list of agents. In most cases, damage is because of T-cell-mediated idiosyncratic reactions. Recently, a number of new agents, including not only drugs but also herbal supplements, have been incriminated and new mechanisms of bile duct injury have emerged. This review will focus on these new data. RECENT FINDINGS New members of drug families already known to be responsible for bile duct injury have been incriminated. New players have been identified, such as herbal supplements, like kratom, and recreational drugs, such as ketamine used outside the medical setting. Anticytokine monoclonal antibodies are rarely involved. In contrast, antineoplastic treatments are of growing concern, especially immune checkpoint inhibitors, which induce immune-related adverse effects because of the excessive stimulation of the immune system and its lack of regulation. SUMMARY Two patterns of bile duct injury are recognized. Drug-induced small-duct cholangiopathies target the smaller bile ducts; acute injuries eventually progress to chronic disease in the form of the vanishing bile duct syndrome. Drug-induced sclerosing cholangitis target large bile ducts, with a protracted chronic course; the onset of symptoms may be delayed after drug discontinuation; potentially severe, life-threatening complications can occur.
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Ahmad I, Prabowo WC, Arifuddin M, Fadraersada J, Indriyanti N, Herman H, Purwoko RY, Nainu F, Rahmadi A, Paramita S, Kuncoro H, Mita N, Narsa AC, Prasetya F, Ibrahim A, Rijai L, Alam G, Mun’im A, Dej-adisai S. Mitragyna Species as Pharmacological Agents: From Abuse to Promising Pharmaceutical Products. Life (Basel) 2022; 12:life12020193. [PMID: 35207481 PMCID: PMC8878704 DOI: 10.3390/life12020193] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/13/2022] [Indexed: 01/07/2023] Open
Abstract
Mitragyna is a genus belonging to the Rubiaceae family and is a plant endemic to Asia and Africa. Traditionally, the plants of this genus were used by local people to treat some diseases from generation to generation. Mitragyna speciosa (Korth.) Havil. is a controversial plant from this genus, known under the trading name “kratom”, and contains more than 40 different types of alkaloids. Mitragynine and 7-hydroxymitragynine have agonist morphine-like effects on opioid receptors. Globally, Mitragyna plants have high economic value. However, regulations regarding the circulation and use of these commodities vary in several countries around the world. This review article aims to comprehensively examine Mitragyna plants (mainly M. speciosa) as potential pharmacological agents by looking at various aspects of the plants. A literature search was performed and information collected using electronic databases including Scopus, ScienceDirect, PubMed, directory open access journal (DOAJ), and Google Scholar in early 2020 to mid-2021. This narrative review highlights some aspects of this genus, including historical background and botanical origins, habitat, cultivation, its use in traditional medicine, phytochemistry, pharmacology and toxicity, abuse and addiction, legal issues, and the potential of Mitragyna species as pharmaceutical products.
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Affiliation(s)
- Islamudin Ahmad
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (M.A.); (J.F.); (N.I.); (N.M.)
- Pharmaceutical Research and Development Laboratory of FARMAKA TROPIS, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (W.C.P.); (H.H.); (H.K.); (A.C.N.); (F.P.); (A.I.); (L.R.)
- Correspondence:
| | - Wisnu Cahyo Prabowo
- Pharmaceutical Research and Development Laboratory of FARMAKA TROPIS, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (W.C.P.); (H.H.); (H.K.); (A.C.N.); (F.P.); (A.I.); (L.R.)
| | - Muhammad Arifuddin
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (M.A.); (J.F.); (N.I.); (N.M.)
| | - Jaka Fadraersada
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (M.A.); (J.F.); (N.I.); (N.M.)
| | - Niken Indriyanti
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (M.A.); (J.F.); (N.I.); (N.M.)
| | - Herman Herman
- Pharmaceutical Research and Development Laboratory of FARMAKA TROPIS, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (W.C.P.); (H.H.); (H.K.); (A.C.N.); (F.P.); (A.I.); (L.R.)
| | | | - Firzan Nainu
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; (F.N.); (G.A.)
| | - Anton Rahmadi
- Department of Agricultural Product Technology, Faculty of Agriculture, Universitas Mulawarman, Samarinda 75119, Indonesia;
| | - Swandari Paramita
- Research Center of Natural Products from Tropical Rainforest (PUI-PT OKTAL), Department of Community Medicine, Faculty of Medicine, Universitas Mulawarman, Samarinda 75119, Indonesia;
| | - Hadi Kuncoro
- Pharmaceutical Research and Development Laboratory of FARMAKA TROPIS, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (W.C.P.); (H.H.); (H.K.); (A.C.N.); (F.P.); (A.I.); (L.R.)
| | - Nur Mita
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (M.A.); (J.F.); (N.I.); (N.M.)
| | - Angga Cipta Narsa
- Pharmaceutical Research and Development Laboratory of FARMAKA TROPIS, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (W.C.P.); (H.H.); (H.K.); (A.C.N.); (F.P.); (A.I.); (L.R.)
| | - Fajar Prasetya
- Pharmaceutical Research and Development Laboratory of FARMAKA TROPIS, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (W.C.P.); (H.H.); (H.K.); (A.C.N.); (F.P.); (A.I.); (L.R.)
| | - Arsyik Ibrahim
- Pharmaceutical Research and Development Laboratory of FARMAKA TROPIS, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (W.C.P.); (H.H.); (H.K.); (A.C.N.); (F.P.); (A.I.); (L.R.)
| | - Laode Rijai
- Pharmaceutical Research and Development Laboratory of FARMAKA TROPIS, Faculty of Pharmacy, Universitas Mulawarman, Samarinda 75119, Indonesia; (W.C.P.); (H.H.); (H.K.); (A.C.N.); (F.P.); (A.I.); (L.R.)
| | - Gemini Alam
- Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; (F.N.); (G.A.)
| | - Abdul Mun’im
- Laboratory of Pharmacognosy-Phytochemistry, Faculty of Pharmacy, Universitas Indonesia, Depok 16424, Indonesia;
| | - Sukanya Dej-adisai
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90110, Thailand;
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Hartley C, Bulloch M, Penzak SR. Clinical Pharmacology of the Dietary Supplement, Kratom (Mitragyna speciosa). J Clin Pharmacol 2021; 62:577-593. [PMID: 34775626 DOI: 10.1002/jcph.2001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 11/05/2021] [Indexed: 11/10/2022]
Abstract
Kratom (Mitragyna speciosa) consists of over 40 alkaloids with two of them, mitragynine (MG) and 7-OH-mitragynine (7-OH-MG) being the main psychoactive compounds. MG and 7-OH-MG each target opioid receptors and have been referred to as atypical opioids. They exert their pharmacologic effects on the μ, δ, and κ opioid receptors. In addition, they affect adrenergic, serotonergic, and dopaminergic pathways. Kratom has been touted as an inexpensive, legal alternative to standard opioid replacement therapy such as methadone and buprenorphine. Other uses for kratom include chronic pain, attaining a "legal high," and numerous CNS disorders including anxiety depression and post-traumatic stress disorder (PTSD). Kratom induces analgesia and mild euphoria with a lower risk of respiratory depression or adverse central nervous system effects compared to traditional opioid medications. Nonetheless, kratom has been associated with both physical and psychological dependence with some individuals experiencing classic opioid withdrawal symptoms upon abrupt cessation. Kratom use has been linked to serious adverse effects including liver toxicity, seizures, and death. These risks are often compounded by poly-substance abuse. Further, kratom may potentiate the toxicity of coadministered medications through modulation of cytochrome P450, P-glycoprotein, and uridine diphosphate glucuronosyltransferase enzymes (UGDT). In 2016 the U.S. Drug Enforcement Administration (DEA) took steps to classify kratom as a federal schedule 1 medication; however, due to public resistance, this plan was set aside. Until studies are conducted that define kratom's role in treating opioid withdrawal and/or other CNS conditions, kratom will likely remain available as a dietary supplement for the foreseeable future. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Chad Hartley
- Department of Pharmacy Practice, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, 36849, United States
| | - Marilyn Bulloch
- Department of Pharmacy Practice, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, 36849, United States
| | - Scott R Penzak
- Department of Pharmacy Practice, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, 36849, United States
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Teschke R, Eickhoff A, Schulze J, Danan G. Herb-induced liver injury (HILI) with 12,068 worldwide cases published with causality assessments by Roussel Uclaf Causality Assessment Method (RUCAM): an overview. Transl Gastroenterol Hepatol 2021; 6:51. [PMID: 34423172 PMCID: PMC8343418 DOI: 10.21037/tgh-20-149] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 04/13/2020] [Indexed: 12/11/2022] Open
Abstract
Herbal products including herbal medicines are worldwide used in large amounts for treating minor ailments and for disease prevention. However, efficacy of most herbal products has rarely been well documented through randomized controlled trials in line with evidence-based medicine concepts, which could be used to estimate the benefit/risk ratio. Instead, much better documented are adverse reactions such as liver injury associated with the consumption of some herbal products, so called herb-induced liver injury (HILI), which represents a clinical challenge. In order to establish HILI as valid diagnosis, the use of a diagnostic algorithms such as Roussel Uclaf Causality Assessment Method (RUCAM) is widely recommended, although physicians in some countries are reluctant to use RUCAM for their HILI cases. This review on worldwide HILI and RUCAM, developed as part of the artificial intelligence ideas, reveals that China is the leading country with 24 publications on HILI cases that were all assessed for causality using RUCAM, followed by Korea with 15 reports, Germany with 9 reports, the US with 7 reports, and Spain with 6 reports, whereas the remaining countries provided less than 4 reports. The total number of assessed HILI cases is 12,068 worldwide derived from 80 publications but in each report HILI case numbers were variable in a range from 1 up to 6,971. This figure compares with 46,266 cases of drug-induced liver injury (DILI) published worldwide from 2014 to early 2019 also assessed for causality by RUCAM. The original version of RUCAM was validated and established in 1993 and updated in 2016 that should be used in future HILI cases. RUCAM is an objective, structured, and validated method, specifically designed for liver injury. It is a scoring system including case data elements to be assessed and scored individually to provide a final score in five causality gradings. Among the 11,404/12,068 HILI (94.5%) cases assessable for evaluation, causality gradings were highly probable in 4.2%, probable in 15.5%, possible in 70.3%, and unlikely or excluded in 10.0%. To improve the future reporting of RUCAM based HILI cases, recommendations include the strict adherence to instructions outlined in the updated RUCAM and, in particular, to follow prospective data collection on the cases to ensure completeness of case data. In conclusion, RUCAM can well be used to assess causality in suspected HILI cases, and additional efforts are now required to increase the quality of the reported cases.
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Affiliation(s)
- Rolf Teschke
- Division of Gastroenterology and Hepatology, Department of Internal Medicine II, Klinikum Hanau, Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/ Main, Frankfurt/Main, Germany
| | - Axel Eickhoff
- Division of Gastroenterology and Hepatology, Department of Internal Medicine II, Klinikum Hanau, Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/ Main, Frankfurt/Main, Germany
| | - Johannes Schulze
- Institute of Occupational, Social and Environmental Medicine, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany
| | - Gaby Danan
- Pharmacovigilance consultancy, Paris, France
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Ballotin VR, Bigarella LG, Brandão ABDM, Balbinot RA, Balbinot SS, Soldera J. Herb-induced liver injury: Systematic review and meta-analysis. World J Clin Cases 2021; 9:5490-5513. [PMID: 34307603 PMCID: PMC8281430 DOI: 10.12998/wjcc.v9.i20.5490] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/03/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The use of herbal supplements and alternative medicines has been increasing in the last decades. Despite popular belief that the consumption of natural products is harmless, herbs might cause injury to various organs, particularly to the liver, which is responsible for their metabolism in the form of herb-induced liver injury (HILI). AIM To identify herbal products associated with HILI and describe the type of lesion associated with each product. METHODS Studies were retrieved using Medical Subject Headings Descriptors combined with Boolean operators. Searches were run on the electronic databases Scopus, Web of Science, MEDLINE, BIREME, LILACS, Cochrane Library for Systematic Reviews, SciELO, Embase, and Opengray.eu. Languages were restricted to English, Spanish, and Portuguese. There was no date of publication restrictions. The reference lists of the studies retrieved were searched manually. To access causality, the Maria and Victorino System of Causality Assessment in Drug Induced Liver Injury was used. Simple descriptive analysis were used to summarize the results. RESULTS The search strategy retrieved 5918 references. In the final analysis, 446 references were included, with a total of 936 cases reported. We found 79 types of herbs or herbal compounds related to HILI. He-Shou-Wu, Green tea extract, Herbalife, kava kava, Greater celandine, multiple herbs, germander, hydroxycut, skullcap, kratom, Gynura segetum, garcinia cambogia, ma huang, chaparral, senna, and aloe vera were the most common supplements with HILI reported. Most of these patients had complete clinical recovery (82.8%). However, liver transplantation was necessary for 6.6% of these cases. Also, chronic liver disease and death were observed in 1.5% and 10.4% of the cases, respectively. CONCLUSION HILI is normally associated with a good prognosis, once the implied product is withdrawn. Nevertheless, it is paramount to raise awareness in the medical and non-medical community of the risks of the indiscriminate use of herbal products.
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Affiliation(s)
| | | | - Ajacio Bandeira de Mello Brandão
- Post-Graduate Program in Medicine, Division of Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre 90050-110, RS, Brazil
| | - Raul Angelo Balbinot
- Department of Clinical Gastroenterology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, RS, Brazil
| | - Silvana Sartori Balbinot
- Department of Clinical Gastroenterology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, RS, Brazil
| | - Jonathan Soldera
- Department of Clinical Gastroenterology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, RS, Brazil
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Nayak LJ, Sondhi AR, Westerhoff M. History! Gastroenterology 2021; 160:e5-e6. [PMID: 33039473 DOI: 10.1053/j.gastro.2020.09.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 09/29/2020] [Indexed: 12/02/2022]
Affiliation(s)
- Luke J Nayak
- Department of Internal Medicine, Ann Arbor, Michigan.
| | - Arjun R Sondhi
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Ann Arbor, Michigan
| | - Maria Westerhoff
- Department of Pathology, University of Michigan, Ann Arbor, Michigan
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13
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Vento AE, de Persis S, De Filippis S, Schifano F, Napoletano F, Corkery JM, Kotzalidis GD. Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant. Front Psychiatry 2021; 12:640218. [PMID: 33868054 PMCID: PMC8044355 DOI: 10.3389/fpsyt.2021.640218] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/05/2021] [Indexed: 12/13/2022] Open
Abstract
Kratom or Mitragyna speciosa (Korth.) is an evergreen tree of the coffee family native to South-East Asia and Australasia. It is used by locals recreationally to induce stimulant and sedative effects and medically to soothe pain and opiate withdrawal. Its leaves are smoked, chewed, or infused, or ground to yield powders or extracts for use as liquids. It contains more than 40 alkaloids; among these, mitragynine and 7-hydroxymitragynine are endowed with variable mu, delta, and kappa opioid stimulating properties (with 7-hydroxymitragynine having a more balanced affinity), rhynchophylline, which is a non-competitive NMDA glutamate receptor antagonist, but is present in negligible quantities, and raubasine, which inhibits α1-adrenceptors preferentially over α2-adrenceptors, while the latter are bound by 7-hydroxymitragynine, while mitragynine counters 5-HT2A receptors. This complexity of neurochemical mechanisms may account for kratom's sedative-analgesic and stimulant effects. It is commonly held that kratom at low doses is stimulant and at higher doses sedative, but no cut-off has been possible to define. Long-term use of kratom may produce physical and psychological effects that are very similar to its withdrawal syndrome, that is, anxiety, irritability, mood, eating, and sleep disorders, other than physical symptoms resembling opiate withdrawal. Kratom's regulatory status varies across countries; in Italy, both mitragynine and the entire tree and its parts are included among regulated substances. We describe the case of a patient who developed anxiety and dysphoric mood and insomnia while using kratom, with these symptoms persisting after withdrawal. He did not respond to a variety of antidepressant combinations and tramadol for various months, and responded after 1 month of clomipramine. Well-being persisted after discontinuing tramadol.
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Affiliation(s)
- Alessandro E Vento
- ASL (Azienda Sanitaria Locale) Roma 2, Rome, Italy.,Addictions' Observatory (ODDPSS), Rome, Italy
| | | | - Sergio De Filippis
- Villa von Siebenthal Neuropsychiatric Clinic and Hospital, Genzano di Roma, Italy
| | - Fabrizio Schifano
- Psychopharmacology, Drug Misuse & Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
| | - Flavia Napoletano
- Psychopharmacology, Drug Misuse & Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
| | - John M Corkery
- Psychopharmacology, Drug Misuse & Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
| | - Georgios D Kotzalidis
- Villa von Siebenthal Neuropsychiatric Clinic and Hospital, Genzano di Roma, Italy.,NESMOS Department (Neurosciences, Mental Health, and Sensory Organs), School of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University, Rome, Italy
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14
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Gandhi D, Ahuja K, Quade A, Batts KP, Patel L. Kratom induced severe cholestatic liver injury histologically mimicking primary biliary cholangitis: A case report. World J Hepatol 2020; 12:863-869. [PMID: 33200023 PMCID: PMC7643221 DOI: 10.4254/wjh.v12.i10.863] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/02/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Kratom is a psychoactive substance that is isolated from the plant Mitragyna speciosa. The leaves can be chewed fresh or dried, smoked, or infused similar to herbal teas. The plant leaves have been used by natives of Southeast Asia for centuries. The substance has been used for its stimulant activity at low doses, and as an opium substitute at higher doses due to a morphine like effect.
CASE SUMMARY A 37-year-old female with a history of depression and obesity (body mass index: 32) presented to emergency room with a week-long history of nausea, decreased appetite, fatigue, and two days of jaundice. On admission bilirubin was markedly elevated. Her condition was thought to be due to consumption of Kratom 2 wk before onset of symptoms. Liver biopsy showed changes mimicking primary biliary cholangitis. Patient’s symptoms and jaundice improved quickly.
CONCLUSION The use of Kratom has been on the rise in recent years across the United States and Europe. Several case reports have associated adverse health impact of Kratom-containing products including death due to its ability to alter levels of consciousness. Only a few case reports have highlighted the hepatotoxic effects of Kratom. Even fewer reports exist describing the detailed histopathological changes.
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Affiliation(s)
- Darshan Gandhi
- Department of Radiology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Kriti Ahuja
- Department of Internal Medicine, Maulana Azad Medical College, New Delhi 110002, Delhi, India
| | - Alexis Quade
- Internal Medicine-Pediatrics, University of California-San Diego and Rady Children's Hospital San Diego, San Diego, CA 92103, United States
| | - Kenneth P Batts
- Department of Pathology, Abbott Northwestern Hospital, Allina Health, Minneapolis, MN 55407, United States
| | - Love Patel
- Division of Hospital Medicine, Abbott Northwestern Hospital, Allina Health, Minneapolis, MN 55407, United States
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15
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Abstract
Kratom (Mitragyna speciosa) leaves contain the mu opioid partial agonists mitragynine and 7-hydroxymitragynine. The US Drug Enforcement Agency considers it a 'drug of concern', and the US FDA is reviewing kratom, but there is a paucity of information regarding health effects. Liver injury is often cited as a potential health consequence, however the same few case reports are repeatedly referenced, without a broader context. Furthermore, reports have largely lacked standardized causality assessment methods. The objective is to evaluate causality in kratom liver injury, through a comprehensive scoping review of human cases, and by reviewing epidemiologic, animal, and mechanistic reports that relate to kratom liver injury. Hepatotoxicity causality was systematically examined using the Roussel Uclaf Causality Assessment Method (RUCAM) for case reports. Biopsy findings, potential pathophysiologic mechanisms, and management options are discussed. This review identified 26 case reports and abstracts, in addition to 7 cases reported from the Drug-Induced Liver Injury Network, 25 in FDA databases, and 27 in internet user forums. Latency periods to symptom onset had a median of 20.6 days and mean of 21 days (range 2-49). Common presenting signs and symptoms were abdominal discomfort, jaundice, pruritis, and dark urine. Histologic findings were predominantly cholestatic, although, biochemically, the condition was heterogenous or mixed; the median R ratio was 3.4 and the mean was 4.6 (range 0.24-10.4). Kratom likely causes liver injury based on the totality of low-quality human evidence, and, in the context of epidemiologic, animal, and mechanistic studies. It remains unclear which subgroups of users are at heightened risk.
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Affiliation(s)
- Jonathan Schimmel
- Department of Emergency Medicine, Division of Medical Toxicology, Mount Sinai Hospital Icahn School of Medicine, New York, NY, USA.
| | - Richard C Dart
- Rocky Mountain Poison and Drug Safety, Denver Health and Hospital Authority, Denver, CO, USA
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16
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Metastasio A, Prevete E, Singh D, Grundmann O, Prozialeck WC, Veltri C, Bersani G, Corazza O. Can Kratom ( Mitragyna speciosa) Alleviate COVID-19 Pain? A Case Study. Front Psychiatry 2020; 11:594816. [PMID: 33329145 PMCID: PMC7717955 DOI: 10.3389/fpsyt.2020.594816] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 10/27/2020] [Indexed: 01/14/2023] Open
Abstract
Among the symptoms of COVID-19 fever, general malaise, pain and aches, myalgia, fatigue, and headache can affect the quality of life of patients, even after the end of the acute phase of the infection and can be long lasting. The current treatment of these symptoms, also because COVID-19 patients have been asked not to use non-steroidal anti-inflammatory drugs (NSAIDs), in particular ibuprofen are often unsatisfactory. Among the above mentioned symptoms malaise and fatigue seem the most difficult to treat. In this case report we describe the use of kratom (Mitragyna speciosa) by a patient with confirmed COVID-19 infection. What we observed was a fast and sustained relieve of the above mentioned symptoms.
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Affiliation(s)
- Antonio Metastasio
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom.,NHS Camden and Islington Trust, London, United Kingdom
| | - Elisabeth Prevete
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Darshan Singh
- Centre for Drug Research, Universiti Sains Malaysia, Minden, Malaysia
| | - Oliver Grundmann
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Walter C Prozialeck
- Department of Pharmacology, Midwestern University, Downers Grove, IL, United States
| | - Charles Veltri
- Department of Pharmaceutical Sciences, Midwestern University, Glendale, AZ, United States
| | - Giuseppe Bersani
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Ornella Corazza
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom.,Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
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