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This chapter focuses on the resurgence of Kratom (Mitragyna speciosa, mitragynine, 7-hydroxymitragynine) use in Thailand and its emergence on the global market. Currently neither Kratom, mitragynine, nor other alkaloids from the M. speciosa plant are listed under the Schedules of the United Nations Drug Conventions; therefore, its legal status is i...
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... cases of intoxication associated with the use of Krypton, a mixture of mitragynine and O-desmethyltramadol, have been described in the scientific literature (Forrester, 2013). However, these fatalities have been attributed to the addition of O-desmethyltramadol to the dried Kratom leaves (Kronstrand et al., 2011) (Table 1). ...
Citations
... Despite extensive research on the pharmacological effects of MTG in recent years, its application in the clinic is yet to be approved, mainly due to safety concerns, including risks of misuse and toxicity, particularly when combined with other substances. Furthermore, growing global interest in kratom has led regulatory authorities in various countries to reassess its legal classification, resulting in notable policy changes (Bergen-Cico & MacClurg, 2016;Charoenratana et al., 2021). However, the lack of uniform regulations has created a patchwork of legal frameworks, with some regions imposing strict controls due to safety concerns, while others permit its regulated use for potential therapeutic benefits (Ahmad et al., 2022). ...
Mitragynine (MTG), the primary psychoactive alkaloid in Mitragyna speciosa (kratom), has garnered much attention for its therapeutic properties, which is attributed mainly to its selective action on opi- oid receptors. Despite its clinical potential, the molecular framework of its binding to plasma proteins remains incomplete. Specifically, no studies have thoroughly examined its interaction with a1-acid glycoprotein (AAG), a carrier protein in the circulatory system that influences drug disposition and bio- availability. Hence, this study aims to explore the binding dynamics between MTG and AAG using a combination of spectroscopic, calorimetric, microscopic, and computational methods. Based on iso- thermal titration calorimetric and fluorescence studies, an intermediate affinity for the MTG–AAG bind- ing was determined (Ka � 105 M−1). Despite evidence of microenvironmental changes around Trp residues, MTG binding did not disrupt the overall structural integrity of AAG. Thermodynamic analysis indicated that the MTG–AAG interaction was energetically favorable, and enthalpy driven mainly by hydrogen bonding and van der Waals forces, with negative entropy change suggesting a more ordered complex formation. Docking analysis showed MTG embedded more deeply within the central cavity of variant F1�S, enhancing complex stability, as opposed to binding near the cavity entrance in variant A. Molecular dynamics simulations supported the stable complexation of MTG with both AAG variants, with variant F1�S maintaining more structural compactness while variant A exhibited slight unfolding upon binding. These findings have clear significance on the potential therapeutic applica- tions of kratom-derived drugs, especially those structurally related to MTG.
... There is widespread concern over the level of usage that encompasses the boundary of the beneficial use of Kratom compared to its detrimental effect. Bergen-Cico and MacClurg (2016) highlighted that Kratom produces stimulant-like effects at low doses, similar to those achieved by chewing coca leaves. However, Kratom also has depressant effects similar to opiates at higher doses. ...
Kratom has caught the attention of governments, policymakers, and academicians due to its unique characteristics. This paper explores the scholarly works related to the different aspects of Kratom to elucidate its research progress and identify future research agendas. We reviewed existing publications on Kratom using a bibliometric methodology. By analyzing 431 scientific publications, we identified publication sources, document analysis, countries analysis, and research keywords, which helped us understand the research locus on Kratom. After reviewing the publications, we discovered significant disagreements in categorizing and defining Kratom amongst authors based on their nationalities. We also showed the knowledge structure of existing publications via thematic analysis, illustrating that the studies focused on the opioid nature of Kratom. Also, drug abuse-related issues evolved as the motor theme of research, while other aspects are prevalent as niche or emerging research themes. This paper contributes to the literature by providing a broad idea of existing literature and offering a comprehensive outlook on Kratom, which could be helpful for policy formulation in the future.
... Undoubtedly, MTG appears as a cheaper alternative to opioids for drug addiction with potentially fewer withdrawal symptoms [16]. Therefore, MTG has been identified as a potential candidate in the treatment of opiate withdrawal symptoms as a replacement therapy [17,18]. MTG is categorised as Biopharmaceutical Classification System Class II drugs with a high permeability but poor solubility in water [19]. ...
Mitragynine is a promising candidate for pain relief and opiate replacement but the investigations for drug delivery are lacking. This study aims to investigate the potential of mitragynine to be delivered through the skin with an emphasis on developing and validating a gradient HPLC-UV analytical method to determine mitragynine in the samples collected during in vitro skin permeation studies. The optimised method involves a gradient elution using a C18 column with a mobile phase comprising acetonitrile and 0.1%v/v of formic acid (0 – 1 min: 30:70 to 70:30 (v/v) and hold up to 4 min; 4 – 6 min: return to 30:70 (v/v) and hold up to 10 min) at a flow rate of 1.2 mL/min. This method was validated based on the standards set by the International Council on Harmonisation guidelines. The method showed mitragynine elution at ∼4 min with adequate linearity (R² ≥ 0.999 for concentration ranges of 0.5 – 10 and 10 – 175 μg/mL) and acceptable limits of detection and quantification at 0.47 and 1.43 μg/mL, respectively. The analytical performance is robust with excellent precision and accuracy. This method was used to evaluate the in vitro skin permeation of mitragynine (5%w/v) from simple solvent systems over 48 hr. The results showed a cumulative amount of mitragynine permeated at ∼11 μg/cm² for dimethyl sulfoxide and ∼4 μg/cm² for propylene glycol. The study not only addressed the issues of the currently available HPLC-UV methods that limit the direct application but also affirmed the potential of mitragynine to be delivered through the skin.
... M. speciosa preparations are available in pill, resin, herb, leaf extract, and leaf powder forms [5,50]. In 2008, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) surveyed 27 European online sites selling "legal highs" and found that M. speciosa was one of the most widely offered and available drugs on 44% of the online sales sites investigated [152,153]. ...
... The wide availability of M. speciosa on the internet shows a wide public demand [153]. Since 2013, some dosage forms of the M. speciosa leaf, such as bottles of liquid preparations, were available for purchase in US head shops; however, this unique formula was no longer available in 2014. ...
... Small packs of 60 g (1.5 oz) beverages (known as "Kratom Premix") are available for purchase. Powder and liquid forms became available in Dutch "smart shops" in 2014 [153]. ...
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. Citation: Ahmad, I.; Prabowo, W.C.; Arifuddin, M.; Fadraersada, J.; Indriyanti, N.; Herman, H.; Purwoko, R.Y.; Nainu, F.; Rahmadi, A.; Paramita, S.; et al.
... M. speciosa preparations are available in pill, resin, herb, leaf extract, and leaf powder forms [5,50]. In 2008, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) surveyed 27 European online sites selling "legal highs" and found that M. speciosa was one of the most widely offered and available drugs on 44% of the online sales sites investigated [152,153]. ...
... The wide availability of M. speciosa on the internet shows a wide public demand [153]. Since 2013, some dosage forms of the M. speciosa leaf, such as bottles of liquid preparations, were available for purchase in US head shops; however, this unique formula was no longer available in 2014. ...
... Small packs of 60 g (1.5 oz) beverages (known as "Kratom Premix") are available for purchase. Powder and liquid forms became available in Dutch "smart shops" in 2014 [153]. ...
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.
... Since 2004, due to the growing concerns over the plant's narcotic properties and abuse liabilities, the Malaysian government has criminalized kratom's major alkaloid, mitragynine, under the Third Schedule of Poisons (Psychotropic Substances) Regulations, Poison Act 1952. Kratom is also currently regulated under the respective Narcotics Act in Thailand, Australia, and Myanmar (Bergen-Cico and MacClurg, 2016;Singh et al., 2017). Despite legal restrictions in such countries, the recreational use and abuse of kratom remains prevalent throughout Malaysia and Thailand (Ahmad and Aziz, 2012;Singh et al., 2017;Singh et al., 2019). ...
Kratom is a widely abused plant-based drug preparation with a global interest in recent years, well beyond its native grounds in Southeast Asia. Mitragynine, its major psychoactive constituent is known to exhibit opioid-like behavioral effects with resultant neuroplasticity in the brain reward system. Its chronic administration is associated with cognitive impairments in animal studies. However, the underlying molecular mechanism for such a deficit remains elusive. In this study, the involvement of cannabinoid type-1 (CB1) receptors in cognitive deficits after chronic mitragynine exposures was investigated for 28 days (with incremental dose sensitization from 1 to 25 mg/kg) in adult male Swiss albino mice using the IntelliCage® system. Chronic high-dose mitragynine exposure (5–25 mg/kg, intraperitoneal [i.p.]), but not low-dose exposure (1–4 mg/kg, i.p.), induced hyperlocomotion, potentiated the preference for sucrose reward, increased resistance to punishment, and impaired place learning and its reversal. Comparable deficits were also observed after chronic treatments with Δ-9-tetrahydrocannabinol (THC, 2 mg/kg, i.p.) or morphine (5 mg/kg, subcutaneous). Mitragynine-, morphine-, and THC-induced learning and memory deficits were reversed by co-treatment with the CB1 receptor antagonist, NIDA-41020 (10 mg/kg, i.p.). A significant upregulation of CB1 receptor expression was found in the hippocampal CA1 region and ventral tegmental area after chronic high-dose mitragynine and morphine, whereas a downregulation was observed after chronic THC. In conclusion, the present study suggests a plausible role of the CB1 receptor in mediating the dose-dependent cognitive deficits after chronic high-dose mitragynine exposure. This also highlights the potential of CB1 receptor antagonism in ameliorating the cognitive deficits associated with long-term kratom/mitragynine consumption in humans.
... However, prolonged consumption of kratom leads to addiction and need of increasing dosage to achieve its effect [2]. Consequently, it was categorised as a controlled substance in countries including Myanmar, Thailand, Malaysia, Australia, New Zealand and the [4,5]. However, due to the wide availability and affordability, the consumption of kratom among youth has increased and is becoming a serious concern. ...
The indole alkaloid, mitragynine, is the prominent substance in Mitragyna speciosa Korth. (kratom), the use of which has led to addiction potential and adverse health effects. In this study, an electrochemical immunosensor was developed for the first time for the sensitive and rapid detection of mitragynine. Multiwalled carbon nanotubes (MWCNTs)/ chitosan (CS) nanocomposite was utilised as modifier for the sensor fabrication. The detection of mitragynine was based on an indirect competitive assay where, the electrochemical signal was produced from the enzymatic reaction of HRP-modified secondary antibody using 3,3’,5,5’-tetramethylbenzidine (TMB) as substrate. The electrochemical immunosensor exhibited higher sensitivity (10-fold) over conventional ELISA with a limit of detection (LOD) of 0.018 μg/mL and limit of quantification (LOQ) of 0.06 μg/mL. Detection of mitragynine in spiked urine samples resulted in good recoveries between 70–110 %. Hence, the developed immunosensor is a useful tool to detect mitragynine in urine to control the misuse of kratom.
... Although several studies strongly confirm Kratom's essential usages, the addictive and abuse capability of Kratom mainly associated to its narcotic component, mitragynine, has gained attention among international drug law enforcement agencies [7]. In fact, the UNODC categorized Kratom Mitragyna speciosa as plant-based NPS because of major global reports of abuse among recreational users taking advantage of Kratom's non-inclusion to any schedules of United Nations Drug Conventions, including its mitragynine drug [8]. ...
Kratom is a tropical tree indigenous to South East Asian countries and has been traditionally used by natives to increase work efficiency and treat selected illnesses. However, the United Nations Office on Drugs and Crime (UNODC) classified kratom, Mitragyna speciose, as a plant-based New Psychoactive Substance (NPS) that must be monitored worldwide, due to increasing reports of abuse. Many countries, including the Philippines, do not put restrictions on the said plant species including its major psychoactive drug, mitragynine. Under this prevailing provision, a research exploration was carried out to determine the distribution of kratom trees, locally known as “mambog”, in the Philippines and authenticate species identity of collected specimens through chemical determination of mitragynine and DNA analysis. Various samples, specifically leaves, twigs, barks and roots, from claimed kratom species in selected regions of Luzon and the Mindanao Islands of the Philippines were sampled and preserved accordingly before subjecting them to instrumental analysis using Gas-Chromatograph Mass Spectrometer (GC-MS) and DNA barcoding. During the field exploration, it was well documented that claimed kratom trees are mostly present in wetland areas at low altitudes, and sometimes co-exist with local bangkal (genus Nauclea) trees. Interestingly, while locals identified some of the collected species as kratom through botanical assessment, mitragynine was not detected in some selected sampling sites. Remarkably, among tree parts collected, only leaves and twigs showed evidence of mitragynine suggesting further disparity among kratom tree parts.
... Although there is no federal ban on kratom, a number of states, the District of Columbia, and smaller jurisdictions have banned its use [24]. Kratom is easily purchased online without adequate safeguards for product purity [25]. For example, in Sweden, it was found that one kratom-containing product available online, Krypton, also contained the active metabolite of tramadol, O-desmethyltramadol, which was believed to have contributed to nine deaths [26]. ...
Context: Kratom, or Mitragyna speciosa, is a plant indigenous to Southeast Asia that has gained national attention in the United States for its increased use in the self-management of opioid withdrawal and pain, as well as for concerns about its safety.
Methods: This study analyzes exposures to kratom reported to poison control centers (PCCs) in the United States during 2011–2017 from the National Poison Data System (NPDS).
Discussion: From 2011 through 2017, 1807 kratom exposures were reported to United States PCCs. Almost two-thirds (65.0%) of these exposures occurred during 2016–2017. Most exposures occurred among adults ≥20 years (88.9%), males (70.8%), at a residence (86.1%), and were intentional (74.3%). Among first-ranked kratom exposures, 31.8% resulted in admission to a health care facility (HCF) and 51.9% in a serious medical outcome. Multiple-substance exposures were associated with greater odds of admission to a HCF (OR: 2.80; 95% CI: 2.21–3.55) and a serious medical outcome (OR: 2.25; 95% CI: 1.77–2.85) compared with single-substance exposures. There were 11 deaths associated with kratom exposure, including two that occurred after exposure to kratom only. Among kratom-only exposures, 86.1% resulted in one or more clinical effects. The most common clinical effects were agitation/irritability (22.9%) and tachycardia (21.4%). There were seven neonatal exposures, including five experiencing withdrawal.
Conclusions: Kratom is associated with a variety of serious medical outcomes, especially when used with other substances. More research is needed to define the human response to kratom. Increased regulation of kratom products would help guarantee product quality and safety. Individuals who choose to use kratom should be educated about its potential risks, including the dangers of using it in combination with other substances.
