ReviewNeurobiology of Kratom and its main alkaloid mitragynine
Introduction
Mitragyna speciosa Korth (M. speciosa) is a medicinal herb originated from the Rubiaceae (coffee) family. It is a naturally occurring plant in tropical and sub-tropical regions of Southeast Asia and Africa. This plant is also known as Ketum or biak-biak in Malaysia and Kratom, Kakuam, Kraton, Ithang or Thom in Thailand (Jansen and Prast, 1988, Matsumoto et al., 1996a, Matsumoto et al., 1996b, Ponglux et al., 1994, Boyer et al., 2008, Ingsathit et al., 2009, Adkins et al., 2011, Gong et al., 2012, Hassan et al., 2013, Saingam et al., 2014). Today, it is one of several psychoactive herbal products that are widely available over the Internet and its use is being spread around the world (Adkins et al., 2011). This plant has been widely used throughout Southeast Asian countries as a herbal drug for decades, as early as the late 1800 (Nelson et al., 2014) such as for the treatment of muscle pain, diarrhea, cough, and to enhance productivity. It is used to reduce intake of more expensive opiates and as alternative to other opioid-replacement medications. It mitigates opioid withdrawal symptoms and can develop euphoric or pleasure effect (Assanangkornchai et al., 2007a, Assanangkornchai et al., 2007b, Chan et al., 2005, Hassan et al., 2013, Vicknasingam et al., 2010, Ahmad and Aziz, 2012). In animal models, mitragynine has shown to elicit reward behaviour (Sufka et al., 2014, Yusoff et al., 2016) and it is effective in ameliorating morphine withdrawal effects (Khor et al., 2011). However, prolonged consumption of this plant preparation may develop tolerance. Therefore, increasing dosage is required to achieve the desired effects (Hassan et al., 2013). In addition, aversive withdrawal effects upon abstaining from consumption have been documented (for review see: Hassan et al., 2013). Withdrawal symptoms include hostility, aggression, aching of muscles and bones, jerky movements of the limbs, anorexia, weight loss, insomnia, and psychosis (Hassan et al., 2013, Singh et al., 2014, Yusoff et al., 2016). Here, we aim to provide an overview about the latest findings of Kratom and its main alkaloid, mitragynine on its physicochemical properties as well as its psychological, pharmacological and behavioural activities based on published reports. The review shall contribute to a more comprehensive understanding about Kratom in regards to its potential medical application, legal status and future research needs.
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Preparations and consumption
The fresh leaves of M. speciosa can be chewed. The dried leaves can be smoked or taken as tea by brewing the powder with hot water and some sugar or honey to mask the bitter taste of the brew (Tanguay, 2011, Hassan et al., 2013). Extraction of the alkaloids is facilitated by the addition of lemon juice. Other than that, the fresh leaves can be chewed alone with removal of the veins before eating, or taken together with the betel nut (Areca catechu) (Scholz and Eigner, 1983, Hassan et al., 2013
Epidemiology and legal status
In Southern Thailand, the lifetime prevalence for M. speciosa use among high school students was approximately 2.3–4.9% in 2002–2004 (Assanangkornchai et al., 2007a). The prevalence among 12–65 years old in the year 2007 was 3.76% and a year before was 4.73% (Assanangkornchai et al., 2007b, Assanangkornchai et al., 2008). However, the use of M. speciosa is no longer restricted to Southeast Asia. It has been reported that the use of M. speciosa substance has spread to Japan (Kikura-Hanajiri et
Medicinal use
Over years, M. speciosa leaves have been traditionally used to treat muscle pain, intestinal infections, coughing and diarrhea (Suwanlert, 1975, Jansen and Prast, 1988, Said et al., 1991, Watanabe et al., 1997, Prozialeck et al., 2012) particularly in Malaysia and Thailand. Apart from that, M. speciosa may also possess analgesic, antipyretic, anti-depressant and anxiolytic effects. They can also improve the immune system, lower blood pressure, act as antiviral, antidiabetic as well as
Phytochemistry
Isolation and chemical characterization of constituents from M. speciosa started as early as 1960s (Beckett et al., 1965, Beckett et al., 1966, Zacharias et al., 1965). Since then, a number of alkaloids have been isolated from M. speciosa. Investigation of the young leaves of Thai M. speciosa showed the presence of mitragynine and its analogues, speciogynine, paynantheine and speciociliatine. A new alkaloid, 7α-hydroxy-7H-mitragynine (7-hydroxymitragynine) has also been isolated from the plant (
Pharmacokinetics
A bioavailability study found that mitragynine and 7-hydroxy-mitragynine have moderate permeability across human colonic adenocarcinoma (Caco-2) and Madin Darby Canine Kidney (MDCK)-transfected with the MDR1 gene (MDR-MDCK) monolayers with no significant efflux. However, another minor constituent, mitraphylline showed a significant efflux mediated by P-glycoprotein in both Caco-2 and MDR-MDCK monolayers (Manda et al., 2014). Using equilibrium dialysis, these compounds exhibited plasma protein
Detection of breakdown products of mitragynine
The exposure or abuse of M. speciosa can be confirmed by the presence of mitragynine and its metabolites in urine samples. This compound can be detected by gas chromatography coupled with mass spectrometry (GC–MS) (Kaewklum et al., 2005), liquid chromatography with linear ion trap mass-spectrometry (Philipp et al., 2009, Philipp et al., 2010a, Philipp et al., 2010b, Arndt et al., 2011) or with electrospray tandem mass spectrometry (Lu et al., 2009, Le et al., 2012). Another study did a
Toxicology
The toxicology of mitragynine and analogues have been reviewed recently (Ramanathan and Mansor, 2015). In animal models, mitragynine showed a relatively low toxicity (Macko et al., 1972, Sabetghadam et al., 2013b). Azizi et al. (2010) reported that oral doses of total alkaloid extract of M. speciosa at 200 mg/kg caused lethality in rats. Janchawee et al. (2007) also reported that a single dose of mitragynine (200 mg/kg) given orally caused death in rats.
Another study demonstrated that oral
Receptor interactions
Previous studies have suggested that mitragynine acts as an opioid receptor agonist with high affinity to μ-opioid receptors (Yamamoto et al., 1999, Watanabe et al., 1997). Mitragynine pseudoindoxyl, its derivative compound also demonstrates potent opioid agonistic properties in vitro (Yamamoto et al., 1999). Mitragynine exhibited its antinociceptive effects via supraspinal μ- and δ-opioid receptors in both in vivo and in vitro studies (Babu et al., 2008, Thongpradichote et al., 1998, Tohda et
Authors’ contributions
F.W.S., N.H.M.Y., R.H, S.M.M, C.P.M. and Z.H. wrote the paper. All authors read and approved the manuscript.
Acknowledgements
This work was supported by the Higher Education Centre of Excellence (HiCoE) special funding (311/CDADAH/4401009), the Fundamental Research Grant Scheme (203/CDADAH/6711469) and International Research Collaboration Fund (IReC) (1002/CDADAH/910410). This work was further supported by funds of the Friedrich- Alexander-University of Erlangen-Nuremberg (Germany).
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These authors contributed equally.