Search

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

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

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

Kratom (Mitragyna speciosa Korth.) is a medicinal plant, widely used in Southeast Asia chiefly for its unique medicinal properties in treating chronic pain, opioid dependence and withdrawal, and as a mood enhancer. Relevant articles describing kratom's medicinal utility was identified and reviewed. In traditional settings, laborers chew fresh leaves or ingest a kratom decoction (tea) as a stimulant that increases work performance, while those with opioid use disorder (OUD) use kratom as an affordable substitute for opioids. Though kratom is alleged to cause adverse health effects if used frequently over prolonged periods, its use has not been linked to any major health threat in traditional settings. Currently, kratom's pharmacological and long-term safety profile remains poorly elucidated and warrants further research. This paper provides a brief account of possibly overlooked medicinal potential of kratom. [ABSTRACT FROM AUTHOR]

Introduction: Kratom (Mitragyna speciosa) is a tropical plant traditionally used as an ethnomedicinal remedy for several conditions in South East Asia. Despite the increased interest in its therapeutical benefits in Western countries, little scientific evidence is available to support such claims, and existing data remain limited to kratom's chronic consumption. Objective: Our study aims to investigate (pre)clinical evidence on the efficacy of kratom as a therapeutic aid and its safety profile in humans. Methods: A systematic literature search using PubMed and the Medline database was conducted between April and November 2020. Results: Both preclinical (N = 57) and clinical (N = 18) studies emerged from our search. Preclinical data indicated a therapeutic value in terms of acute/chronic pain (N = 23), morphine/ethanol withdrawal, and dependence (N = 14), among other medical conditions (N = 26). Clinical data included interventional studies (N = 2) reporting reduced pain sensitivity, and observational studies (N = 9) describing the association between kratom's chronic (daily/frequent) use and safety issues, in terms of health consequences (e.g., learning impairment, high cholesterol level, dependence/withdrawal). Conclusions: Although the initial (pre)clinical evidence on kratom's therapeutic potential and its safety profile in humans is encouraging, further validation in large, controlled clinical trials is required. [ABSTRACT FROM AUTHOR]

Rationale: Kratom (Mitragyna speciosa Korth), a native medicinal plant of Southeast Asia, is proposed to exhibit potential therapeutic value as an opioid substitute. However, studies of its negative emotional states resulting from withdrawal particularly of its main psychoactive compound, mitragynine (MG), are limited. Objectives: Using the pentylenetetrazol (PTZ) discrimination assay, this study aims to investigate the effects of MG in responding to the PTZ stimulus and to assess the generalisation effects of withdrawal from MG to the PTZ stimulus. Methods: Rats (n = 20) were trained on a tandem (FR-10, VI-15) schedule of food reinforcement to press one lever after administration of the anxiogenic compound PTZ (16 mg/kg, i.p.) and an alternate lever after vehicle. Following acute tests, training was suspended, and rats were chronically treated with MG or morphine at 8-h intervals for 9 days and withdrawal was precipitated on the tenth day using naloxone (1 mg/kg, i.p.). The rats were tested for generalisation to PTZ at 2, 8 and 24 h after the last dose of MG or morphine administration. Results: Unlike morphine that produced dose-related PTZ-like stimulus, MG at 3, 10, 30 and 45 mg/kg doses showed no substitution to the PTZ discriminative stimulus. In contrast to morphine which produced a time-dependent generalisation to the PTZ stimulus, naloxone did not precipitate withdrawal effects in MG-treated rats as they selected the vehicle lever at three withdrawal time points. Conclusion: These results demonstrate that MG produces a very different response to morphine withdrawal that is not associated with anxiogenic-like subjective symptoms. These characteristics of MG may provide further support for use as a novel pharmacotherapeutic intervention for managing opioid use disorder. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa) is a species of large tree that grows in Southeast Asia and is part of the Rubiaceae family. Its fresh leaves are harvested for their medicinal properties and used for their psychoactive effects. Kratom contains many biologically active alkaloids, including mitragynine and 7-OH-mitragynine, which are considered the two most important psychoactive components and constitute approximately 66% and 2% of the total alkaloid content. Other alkaloids are present in the plant, such as speciogynine, speciociliatine and paynantheine, but have less psychoactive activity. Over the past decade, the sale of kratom powder has increased on the Internet. This led to a significant increase in forensic cases. Given the lack of data existing in the literature, and the total absence of data in nails, the authors report a study to determine the best target alkaloids for documenting kratom consumption in this matrix. Fingernail clippings from a supposed kratom powder user were analyzed after liquid-liquid extraction, chromatography separation using a HSS C18 column and performed on an ultra-high performance liquid chromatography coupled to a tandem mass spectrometer. In the specimen, mitragynine was quantified at 229 pg/mg, speciogynine and paynantheine were both quantified at 2 pg/mg, and speciociliatine was quantified at 19 pg/mg. 7-OH-mitragynine was not detected. The interpretation of these concentrations is complex, since there is currently no reference in the literature, as this is the first identification of mitragynine and other kratom alkaloids in nails. Nevertheless, in view of the high concentration of mitragynine, the subject seems to be a repetitive user of kratom. According to the measured concentrations, it seems that mitragynine remains the best target to document kratom consumption, but the identification of the other alkaloids would enhance the specificity of the test. • Kratom contains many biologically active alkaloids, including mitragynine and 7-OH-mitragynine. • Other alkaloids are present in the plant, such as speciogynine, speciociliatine and paynanthetine. • Given the lack of data, the authors report a study to determine the best target alkaloids for documenting a kratom consumption. • According to the measured concentrations, mitragynine remains the best target to document kratom consumption. • The identification of the other alkaloids would enhance the specificity of the test. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa), an indigenous medicinal plant of Southeast Asia, is believed to be harmful. We compared the perceptions toward kratom use among kratom users and non-users in Malaysia. 356 respondents (137 kratom users and 219 non-users) were recruited for this cross-sectional study. The majority of respondents were male (60%, n = 212/356), Malays (88%), and 51% were ≥37 years old. Non-users showed higher unadjusted odds of reporting a perception that kratom use can cause addiction (OR = 6.72, CI: 3.91-11.54, p < .0001), withdrawal symptoms (OR = 7.58, CI: 4.62-12.42, p < .0001), illicit drug use problems (OR = 10.12, CI: 6.14-16.68, p < .0001), impaired social-functioning (OR = 12.05, CI: 7.24-20.05, p < .0001), and health problems (OR = 10.44, CI: 6.32-17.24, p < .0001). Similarly, non-users viewed kratom policies differently from kratom users, displaying increased odds of reporting the belief that kratom use and sales must be regulated with stringent laws (OR = 5.75, CI: 3.61-9.18, p < .0001), and kratom should be regulated instead under the Dangerous Drugs Act 1952 to overcome kratom use problems (OR = 8.26, CI: 4.94-13.82, p < .0001). Because of the disconnect in kratom use perceptions and personal experiences between kratom users and non-users, hastily criminalizing kratom without investigating carefully its scientific merits can significantly impede future kratom research. [ABSTRACT FROM AUTHOR]

Kratom, or Mitragyna, is a tropical plant indigenous to Southeast Asia, with unique pharmacological properties. It is commonly consumed by preparing the leaves into decoction or tea, or by grinding them into a powder. Recent evidence has revealed that kratom has physiological effects similar to opioids, including pain relief and euphoria, as well as stimulant properties, which together raise potential concern for dependence and addiction. Moreover, growing evidence suggests that the prevalence of kratom use is increasing in many parts of the world, raising important considerations for healthcare providers. This manuscript will discuss the most current epidemiology, pharmacology, toxicity, and management related to kratom, while seeking to provide a contemporary perspective on the issue and its role in the greater context of the opioid epidemic. [ABSTRACT FROM AUTHOR]

Mitragyna speciosa Korth., also known as ketum or kratom, is a tropical plant native to Southeast Asia. Mitragynine is its major active alkaloid. It is traditionally used as treatment for various conditions, including fever. The crude extract of M. speciosa leaves has been proven to have anti-inflammatory and analgesic properties. In general, M. speciosa induces a dose-dependent effect, inducing a stimulant effect at low dose and an opioid-like effect at a high dose. This study was conducted to determine the antipyretic effect of mitragynine and methanolic extract of M. speciosa (MSM) using mice as an in vivo pyretic model. Eighty mice were divided into 8 groups: 6 treatment groups (mitragynine: 5, 10, and 20 mg/kg; MSM: 50, 100, and 200 mg/kg) and 2 control groups (20% Tween 80 in 0.9% NaCl; ketoprofen 1 mg/kg). Eighteen hours after induction of pyrexia by inoculation of yeast, rectal temperature was measured every half an hour for 5 hours. Compared to the negative control group, all groups treated with either mitragynine or MSM had significant reduction of rectal temperature at different points of time. The positive control group treated with ketoprofen had significant (P < 0.001) reduction of pyrexia from 0.5 to 5.0 hours after dosing. At 200 mg/kg, MSM has led to the opioid-like effect of hypothermia, possibly due to its synergistic effect with other compounds such as 7-hydroxymitragynine or mitragynine pseudoindoxyl. This article discusses concerns pertaining to toxicity of mitragynine and MSM, and possible involvement of cyclooxygenase and microsomal prostaglandin E2 synthase pathways. In conclusion, mitragynine and MSM possess dose-dependent antipyretic properties in mice. [ABSTRACT FROM AUTHOR]

The leaves from Mitragyna speciosa (Korth.) trees, also known as kratom, are traditionally used in Southeast Asia as a mild psychotropic agent. We investigated the demographic characteristics of persons who used both kratom cocktail and benzodiazepines (BZO) in a sample drawn from a rural area in Penang, Malaysia, and the reasons for BZO use. Seventy-seven participants who currently use a kratom cocktail along with BZO were recruited through snowball sampling for this cross-sectional study. The participants were male, and the majority were Malays (99%, n = 76/77), single (57%, n = 44/77) and employed (91%, n = 70/77). BZO was used with kratom cocktail 1) to increase euphoria; 2) to reduce dependence on methamphetamine; 3) to promote sleep; 4) to ease methamphetamine-associated psychological symptoms and 5) to decrease the craving for kratom. There were no significant differences in the intake of kratom use (p = .751), BZO use duration (p = .259), frequency (p = .188) and quantity (p = .888) of BZO use in the last 7 days, and quantity of BZO use in the last 30 days (p = .337) between kratom users and kratom poly-drug users. An awareness of the health consequences of the co-use of kratom with BZO is needed to prevent untoward health incidents. [ABSTRACT FROM AUTHOR]

Background: Mitragynine is the major alkaloid of Mitragyna speciosa (Korth.) or Kratom, a psychoactive plant widely abused in Southeast Asia. While addictive effects of the substance are emerging, adverse cognitive effects of this drug and neuropharmacological actions are insufficiently understood.Aims: In the present study, we investigated the effects of mitragynine on spatial learning and synaptic transmission in the CA1 region of the hippocampus.Methods: Male Sprague Dawley rats received daily (for 12 days) training sessions in the Morris water maze, with each session followed by treatment either with mitragynine (1, 5, or 10 mg/kg; intraperitoneally), morphine (5 mg/kg; intraperitoneally) or a vehicle. In the second experiment, we recorded field excitatory postsynaptic potentials in the hippocampal CA1 area in anesthetized rats and assessed the effects of mitragynine on baseline synaptic transmission, paired-pulse facilitation, and long-term potentiation. Gene expression of major memory- and addiction-related genes was investigated and the effects of mitragynine on Ca2+ influx was also examined in cultured primary neurons from E16-E18 rats.Results/outcomes: Escape latency results indicate that animals treated with mitragynine displayed a slower rate of acquisition as compared to their control counterparts. Further, mitragynine treatment significantly reduced the amplitude of baseline (i.e. non-potentiated) field excitatory postsynaptic potentials and resulted in a minor suppression of long-term potentiation in CA1. Bdnf and αCaMKII mRNA expressions in the brain were not affected and Ca2+ influx elicited by glutamate application was inhibited in neurons pre-treated with mitragynine.Conclusions/interpretation: These data suggest that high doses of mitragynine (5 and 10 mg/kg) cause memory deficits, possibly via inhibition of Ca2+ influx and disruption of hippocampal synaptic transmission and long-term potentiation induction. [ABSTRACT FROM AUTHOR]

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

Introduction: Mitragyna speciosa (Korth.) or kratom is a native medicinal plant of Southeast Asia. Commonly used by hard labours in harsh working environment, the ingestion of brewed kratom decoction is reported to produce dose-dependent stimulant and opioid-like effects. Kratom is also regularly consumed as a pain killer and as traditional cure for common maladies such as fever and cough. However, it remains unknown whether regular consumption of kratom decoction is associated with brain abnormalities in regular users in traditional settings. Methods: A total of 14 subjects (7 regular kratom users and 7 non-kratom users) voluntarily participated in this cross-sectional study. Face-to-face interviews were conducted with kratom users to determine history of kratom use and later these respondents underwent brain magnetic resonance imaging (MRI). Results: There were no significant differences (p>0.05) in the intracranial volume (ICV), cortical volumes (frontal, parietal, temporal, occipital, or cingulate lobe), or subcortical volumes (striatum, hippocampus, or amygdala), as well as in the diffusion tensor imaging (DTI) metrics, fractional anisotropy (FA) and mean diffusivity (MD) between kratom users and the controls. Conclusion: This preliminary study showed long-term consumption of kratom decoction is not significantly associated with altered brain structures in regular kratom users in traditional settings. However, further study is needed to establish more data for kratom use and its effects. [ABSTRACT FROM AUTHOR]

Kratom, (Mitragyna Speciosa Korth.) is a plant indigenous to Southeast Asia whose leaves are cultivated for a variety of medicinal purposes and mostly consumed as powders or tea in the United States. Kratom use has surged in popularity with the lay public and is currently being investigated for possible therapeutic benefits including as a treatment for opioid withdrawal due to the pharmacologic effects of its indole alkaloids. A wide array of psychoactive compounds are found in kratom, with mitragynine being the most abundant alkaloid. The drug-drug interaction (DDI) potential of mitragynine and related alkaloids have been evaluated for effects on the major cytochrome P450s (CYPs) via in vitro assays and limited clinical investigations. However, no thorough assessment of their potential to inhibit the major hepatic hydrolase, carboxylesterase 1 (CES1), exists. The purpose of this study was to evaluate the in vitro inhibitory potential of kratom extracts and its individual major alkaloids using an established CES1 assay and incubation system. Three separate kratom extracts and the major kratom alkaloids mitragynine, speciogynine, speciociliatine, paynantheine, and corynantheidine displayed a concentration-dependent reversible inhibition of CES1. The experimental K i values were determined as follows for mitragynine, speciociliatine, paynantheine, and corynantheidine: 20.6, 8.6, 26.1, and 12.5 μM respectively. Speciociliatine, paynantheine, and corynantheidine were all determined to be mixed-type reversible inhibitors of CES1, while mitragynine was a purely competitive inhibitor. Based on available pharmacokinetic data, determined Ki values, and a physiologically based inhibition screen mimicking alkaloid exposures in humans, a DDI mediated via CES1 inhibition appears unlikely across a spectrum of doses (i.e., 2–20g per dose). However, further clinical studies need to be conducted to exclude the possibility of a DDI at higher and extreme doses of kratom and those who are chronic users. • Kratom extracts and its major alkaloids demonstrate a reversible inhibition of carboxylesterase 1, in vitro. • Using kratom products and medications metabolized by carboxylesterase 1 are unlikely to precipitate drug-drug interactions. • To exclude drug interaction risk, clinical pharmacokinetic studies with kratom at higher and chronic usage are warranted. [ABSTRACT FROM AUTHOR]

Kratom (Mitragyna speciosa Korth.) is a tree native to Southeast Asia with dose-dependent stimulant and opioid-like effects. Dried, powdered leaf material is among the kratom products most commonly consumed in the US and Europe, but other formulations also exist including enriched extracts, resins, tinctures, and edibles. Its prevalence in the US remains debated and the use pattern includes self-treatment of mood disorders, pain, and substance use disorders. Most of the adverse effects of kratom and its alkaloid mitragynine have been reported in the literature as case reports or part of surveys necessitating confirmation by clinical trials. Toxicities associated with kratom consumption have focused on hepatic, cardiac, and CNS effects with the potential to cause fatalities primarily as part of polydrug exposures. Kratom may also present with drug-drug interactions primarily through CYP 3A4 and 2D6 inhibition, although the clinical significance remains unknown to date. The variability in composition of commercially available kratom products complicates generalization of findings and requires further investigation by employing clinical trials. Healthcare professionals should remain cautious in counseling patients on the use of kratom in a therapeutic setting. [ABSTRACT FROM AUTHOR]

Mitragynine is the major psychoactive alkaloid of the plant kratom/ketum. Kratom is widely used in Southeast Asia as a recreational drug, and increasingly appears as a pure compound or a component of 'herbal high' preparations in the Western world. While mitragynine/kratom may have analgesic, muscle relaxant and anti-inflammatory effects, its addictive properties and effects on cognitive performance are unknown. We isolated mitragynine from the plant and performed a thorough investigation of its behavioural effects in rats and mice. Here we describe an addictive profile and cognitive impairments of acute and chronic mitragynine administration, which closely resembles that of morphine. Acute mitragynine has complex effects on locomotor activity. Repeated administration induces locomotor sensitization, anxiolysis and conditioned place preference, enhances expression of dopamine transporter- and dopamine receptor-regulating factor mRNA in the mesencephalon. While there was no increase in spontaneous locomotor activity during withdrawal, animals showed hypersensitivity towards small challenging doses for up to 14 days. Severe somatic withdrawal signs developed after 12 hours, and increased level of anxiety became evident after 24 hours of withdrawal. Acute mitragynine independently impaired passive avoidance learning, memory consolidation and retrieval, possibly mediated by a disruption of cortical oscillatory activity, including the suppression of low-frequency rhythms (delta and theta) in the electrocorticogram. Chronic mitragynine administration led to impaired passive avoidance and object recognition learning. Altogether, these findings provide evidence for an addiction potential with cognitive impairments for mitragynine, which suggest its classification as a harmful drug. [ABSTRACT FROM AUTHOR]

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-COOCH 3 (methyl ester) and 9-OCH 3 (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. [ABSTRACT FROM AUTHOR]

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

Aim of the study: Mitragyna speciosa Korth from Rubiaceae family is a tropical plant indigenous to Southeast Asia particularly in Thailand, Peninsular of Malaysia and Indonesia. The leaves have been used by natives for their opium-like effect and cocaine-like stimulant ability to combat fatigue and enhance tolerance to hard work. However there is no scientific information about the effect of mitragynine on the cognitive performances. This study is designed to examine the working memory effects of mitragynine which is extracted from Mitragyna speciosa mature leaves. Materials and methods: The cognitive effect was studied using object location task and the motor activity in open-field test. Mitragynine 5, 10 and 15mg/kg and were administered by intraperitoneal (IP) for 28 consecutive days and evaluated on day 28 after the last dose treatment. Scopolamine was used as the control positive drug. Results: In this study there is prominent effects on horizontal locomotor activity was observed. Mitragynine significantly reduced locomotor activity in open-field test compared with vehicle. In object location task mitragynine (5, 10 and 15mg/kg) did not showed any significances discrimination between the object that had changed position than the object that had remain in a constant position. Conclusion: Our results suggest that chronic administration of mitragynine can altered the cognitive behavioral function in mice. [Copyright &y& Elsevier]

Abstract: Mitragynine is the primary active alkaloid extracted from the leaves of Mitragyna speciosa Korth, a plant that originates in South-East Asia and is commonly known as kratom in Thailand. Kratom has been used for many centuries for their medicinal and psychoactive qualities, which are comparable to that of opiate-based drugs. Kratom abuse can lead to a detectable content of mitragynine residue in urine. Ultra trace amount of mitragynine in human urine was determined by a high performance liquid chromatography coupled to an electrospray tandem mass spectrometry (HPLC-ESI/MS/MS). Mitragynine was extracted by methyl t-butyl ether (MTBE) and separated on a HILIC column. The ESI/MS/MS was accomplished using a triple quadrupole mass spectrometer in positive ion detection and multiple reactions monitoring (MRM) mode. Ajmalicine, a mitragynine''s structure analog was selected as internal standard (IS) for method development. Quality control (QC) performed at three levels 0.1, 1 and 5ng/ml of mitragynine in urine gave mean recoveries of 90, 109, and 98% with average relative standard deviation of 22, 12 and 16%, respectively. The regression linearity of mitragynine calibration ranged from 0.01 to 5.0ng/ml was achieved with correlation coefficient greater than 0.995. A detection limit of 0.02ng/ml and high precision data within-day and between days analysis were obtained. [Copyright &y& Elsevier]

Introduction: Mitragyna speciosa Korth or also known as kratom is a psychoactive plant indigenous to the Southeast Asia region which exhibits potential therapeutic values as an opioid substitute. Mitragynine (MG), the major alkaloid of M. speciosa Korth has been shown to contribute to the various opioid-like pharmacological effects. Previous studies lend support for the roles of the dopamine D1 receptor in the rewarding properties of various drugs of abuse, including opioid. However, the role of the dopamine D1 receptor in mediating MG reward has not been fully characterised. Methods: Using the conditioned place preference (CPP) model as a paradigm for measuring drug reward, the present study was conducted to evaluate the roles of the dopamine D1 receptor in the acquisition and expression of MG-induced CPP. Firstly, we examined the effects of the selective dopamine D1- type receptor antagonist SCH- 23390 on the acquisition of MG-induced CPP. Rats were pre-treated systemically with a selective dopamine D1-type receptor antagonist (SCH-23390; 0, 0.1 and 0.3 mg/kg, i.p.) prior to MG (10 mg/kg, i.p.) conditioning sessions. Next, we tested the effects of the dopamine D1 receptor in the expression of MG-induced CPP when the rats were administered dopamine D1 receptor antagonist (SCH-23390; 0, 0.1 and 0.3 mg/kg, i.p.) prior to CPP test. Results: The results showed that SCH-23390 at 0.1 mg/kg dose was able to suppress the acquisition of MG-induced CPP. This effect was already evident for SCH-23390 at a dose of 0.1 mg/kg which, by itself, did not produce a conditioned place aversion (CPA) effect. In contrast, SCH-23390 at any doses had no effect on the expression of MG-induced CPP. Conclusion: The findings of the present study suggested the role of the dopamine D1-like receptor in mediating the acquisition of the rewarding effects of MG, but not the expression as indexed by CPP. [ABSTRACT FROM AUTHOR]

Introduction: Drug addiction changes the normal structure and functions of the brain, which may lead to memory deficit that requires urgent interventions. Mitragynine, the major indole alkaloid from Mitragyna speciosa has been used as a recreational drug and ‘herbal high’ preparation in Southeast Asia and Western countries due to its opium and coca-like effects. However, there are insufficient data regarding the effects of long-term exposure to mitragynine on addiction and cognitive behavior. Thus, in this study, effects of repeated exposure to mitragynine on withdrawal signs and cognitive functions were evaluated. Methods: Animals were treated (intraperitoneally) daily with mitragynine (1, 5, 10 and 30 mg/kg) for 14 days. Twenty-four (24) hours after the last dose, animals were examined for behavioral signs using global withdrawal scoring and the effect on cognitive behavior was determined using passive avoidance task. Results: One way ANOVA revealed that, mitragynine at the doses of 5, 10 and 30 mg/kg produced a significant (P < 0.01) and dose dependent increase in the behavioral “counted signs” and a non-dose dependent increase at all the doses tested (1, 5, 10 and 30 mg/kg) in “checked signs” (squeaking on touch and hostility on handling) as compared to control. A significant (P < 0.01) dose dependent increase in the mean aggregate withdrawal signs was found in all the doses tested when compared to vehicle. At the doses of 5, 10 and 30 mg/kg, mitragynine significantly (P < 0.001) reduced the step through latency as compared to control in passive avoidance task. Conclusion: Data from this study showed that mitragynine at high dose possessed abuse liability leading to cognitive decline. However, mitragynine at lower dose (1mg/kg) was found to be safe without cognitive decline. Hence, the use of mitragynine at high dose as a “herbal high” is justified. [ABSTRACT FROM AUTHOR]

Background: Kratom (Mitragyna speciosa Korth.) has been used in Southeast Asia for hundreds of years to increase energy, for relaxation, and to diminish opioid withdrawal. Kratom use has recently spread to Western countries. Kratom could potentially be used for the treatment of opioid withdrawal and pain, but more insight is needed into its abuse potential. Therefore, we investigated the rewarding properties of the primary kratom alkaloid mitragynine and its active metabolite 7-hydroxymitragynine, and morphine as a reference drug in male and female rats. These compounds have agonist activity at mu-opioid receptors.Methods: The compounds were tested in an intracranial self-stimulation (ICSS) procedure, which allows for the evaluation of the rewarding/aversive and sedative effects of drugs. Rewarding doses of drugs decrease the brain reward thresholds, and aversive drug doses have the opposite effect.Results: Mitragynine, 7-hydroxymitragynine, and morphine affected the brain reward thresholds. A high dose of 7-hydroxymitragynine (3.2 mg/kg) increased the brain reward thresholds, whereas an intermediate dose of morphine (10 mg/kg) decreased the reward thresholds. 7-Hydroxymitragynine and morphine affected the response latencies. Five mg/kg of morphine increased response latencies. 7-Hydroxymitragynine tended to increase the response latencies, but the post hoc analyses did not reveal a significant effect. There were no sex differences in the effects of mitragynine, 7-hydroxymitragynine, and morphine on the reward thresholds and the response latencies.Conclusions: These initial findings indicate that mitragynine and 7-hydroxymitragynine are not rewarding in the ICSS procedure. The present results suggest that these kratom alkaloids do not have abuse potential. [ABSTRACT FROM AUTHOR]

• Sexual satisfaction and sexual performance of long-term daily uses of kratom in Malaysia have been evaluated. • Daily consumption of kratom decoction is reported to improve sexual functioning among adult males. • No relationships between the years of use or current daily quantity of kratom consumption have been found. Kratom leaves from Mitragyna speciosa (Korth.) trees are believed to have medicinal value, and have a long-history of folk medicine use for self-treatment of a broad range of indications. In Southeast Asia, traditional uses of kratom include as an aphrodisiac and a sexual performance enhancer. The study evaluated sexual functioning in a cohort of long-term male kratom users in the state of Penang, Malaysia. A field face-to-face survey, including the Malay version of the Brief Male Sexual Function Inventory (BMSFI) called Mal-BMSFI was conducted between January and December of 2017. The mean (SD) age of the cohort (N = 92) was 37.0 (11.2) years, and the mean (SD) duration of kratom use was 9.14 (5.5) years. All participants reported consuming kratom decoction, with an average amount of 1200 ml daily. Seventy-two participants (78%) reported using kratom to enhance sexual performance, and 71 of them (71/72, 99%) reported experiencing improved sexual performance. Of those who reported not using kratom to enhance sexual performance, 7/20 (35%) also experienced improved sexual performance after kratom use. The reported enhancements of sexual performance included: more energy during sex (75/92), delayed ejaculation (71/92), help to maintain erection (70/92), longer climax (51/92), increased sexual desire (44/92), and reduced sex organ sensitivity (43/92). The mean (SD) Mal-BMSFI score was 33.9 (7.1) and 78/92 (85%) reported overall high satisfaction with their sex life in the past 30 days. In conclusion long-term daily, male users of kratom decoction in Malaysia reported improved sexual functioning attributed to their kratom consumption. [ABSTRACT FROM AUTHOR]