Evaluating the hematological and clinical-chemistry parameters of kratom (Mitragyna speciosa) users in Malaysia
Graphical abstract
Introduction
Mitragyna speciosa (Korth.) from the Rubiaceae family is a tropical medicinal tree of Southeast Asia (Suwanlert, 1975, Saingam et al., 2012, Vicknasingam et al., 2010, Singh et al., 2016). M. speciosa is known locally as ‘Ketum’ or ‘Biak’ in Malaysia, and as ‘Kratom’ in Thailand. Kratom has been traditionally used in Southeast Asia for its medicinal value, and as a psychostimulant drug (Assanangkornchai et al., 2007, Saingam et al., 2012, Hassan et al., 2013, Singh et al., 2016). Kratom leaves can be freshly chewed, smoked or consumed orally as an herbal concoction. About 44 alkaloids have been isolated from M. speciosa leaves (Shellard, 1974, Adkins et al., 2011), and mitragynine was found to be the major alkaloid. A minor constituent 7-hydroxymitragynine has been studied and reported to have unique opioid like-effects (Suhaimi et al., 2016, Kruegel and Grundmann, 2017). Kratom was shown to produce dose-dependent psychotropic effects; it acts as a stimulant at lower doses, and has sedative effects at higher doses (Grewal, 1932b, Kruegel and Grundmann, 2017). However, it was not found to produce intense euphoria, depressive effects on respiration, or constipation (Prozialeck, 2016, Varadi et al., 2016, Pinney Associates, 2016).
Kratom has gained popularity as an ingredient of so-called ‘legal high’ preparations in the US and Europe (Warner et al., 2016, Grundmann, 2017). In most Western countries, kratom can be easily purchased through the internet, unlike Southeast Asia where it is illegally sold in the community (Boyer et al., 2008, Schmidt et al., 2011, Cinosi et al., 2015, Grundmann, 2017). In Western countries, kratom extracts are used as a natural alternative to self-treat a variety of problems, such as pain, anxiety, alcohol and illicit drug dependence, and opioid withdrawal symptoms (Boyer et al., 2008, Swogger et al., 2015, Warner et al., 2016, Grundmann, 2017).
Some of the case-reports that have emerged from European Union and the United States have indicated that kratom use is harmful (toxic) and can result in death (Kronstrand et al., 2011, Singh et al., 2016, Anwar et al., 2016, Domingo et al., 2017). However, the reported fatal cases may have resulted from the co-administration of kratom with other substances, using adulterated kratom products, or pre-existing medical conditions (Kronstrand et al., 2011, Lydecker et al., 2016, Griffin et al., 2016). No clear conclusions on toxicity and mortality risk can therefore be drawn at the current stage.
Kratom use is associated with dependence and withdrawal symptoms in regular users (Vicknasingam et al., 2010, Singh et al., 2014, Saingam et al., 2016). Regular and chronic kratom use is associated with seizure, coma, tongue numbness, vomiting and nausea, dry skin, hyperpigmentation, constipation, psychosis, weight loss, insomnia, frequent urination, tremor, jaundice and pruritus, intrahepatic cholestasis, hypothyroidism, changes in heart rate, dehydration, palpitation, and anorexia (Singh et al., 2016, Fluyau and Revadigar, 2017, Kruegel and Grundmann, 2017). The self-reported withdrawal symptoms of kratom use are clearly linked to kratom because it is widely used in its unadulterated form (Ahmad and Aziz, 2012, Lee, 1957, Saingam et al., 2012, Singh et al., 2014, Singh et al., 2015, Suwanlert, 1975, Vicknasingam et al., 2010). However, a recent study by Smith and Lawson (2017) indicate that in the case of individuals with extensive substance misuse history, kratom is not preferred to illicit drugs, and they were not dependent on it.
Findings from several animal studies have shown that M. speciosa extracts and its principal alkaloid mitragynine to be toxic, and can cause significant changes in various blood parameters (Reanmongkol et al., 2007, Harizal et al., 2010, Kamal et al., 2012; Sabetghadam et al., 2013; Ilmie et al., 2015; Suhaimi et al., 2016). In addition, mitragynine and 7-hydroxymitragynine may cause herb-drug interaction by inhibiting UGT2B7 activity (Haron and Ismail, 2015), CYP2D6 and CYP3A4 (Hanapi et al., 2013, Kong et al., 2011), or with drugs that are P-gylcoprotein substrates (Manda et al., 2014). Information on the long-term effects of kratom use in humans is limited and warrants further investigation. Previous surveys describing the effects and side-effects of regular kratom use depended on self-reports. No objective clinical measures were used to determine the severity of self-reported side-effects of kratom use (Suwanlert, 1975, Vicknasingam et al., 2010, Saingam et al., 2012).
Similarly, it is not known whether regular kratom consumption has a direct effect on the hematological and clinical-chemistry parameters of users. The objective of the present study was therefore to investigate the biochemical parameters of regular kratom users in traditional settings in Malaysia.
Section snippets
Study design, subjects and settings
A total of 77 subjects (n=58 regular kratom users, and n=19 healthy controls) were recruited for this cross-sectional study. We used the snowball sampling technique to recruit potential subjects for the study. Subjects for the kratom using group and healthy controls were recruited from the same study area, located in the northern state of Penang, Malaysia, bordering southern Thailand. In Malaysia, kratom is commonly ingested in the form of brewed tea/juice, unlike in Thailand where traditional
Subjects socio-demographic characteristics
The subject's socio-demographic characteristics are shown in Table 1. Subjects were all males, majority were Malays (96%). The healthy controls mean age in this study was 28.91 years (SD=5.6), while kratom users mean age was 25.63 years (SD=7.0). More than half were >28 years-old (n=44/77), while 92% had 11 years of education. Seventy-five percent (n=58/77) of the subjects were single, 86% were employed, and 58% earned a monthly income of RM>1001. For the kratom using group, about 41% (n=24/58)
Discussion
To the best of our knowledge, this study is the first to evaluate the effects of kratom (Mitragyna speciosa) on the hematological profile, and clinical-chemistry parameters in regular kratom users in traditional setting in Malaysia. Besides its detailed pharmacological characterisation (Hassan et al., 2013, Kruegel and Grundmann, 2017), information on the adverse effects of kratom use is inadequately delineated in humans. This study provides data from a larger sample of regular users who have
Acknowledgments
We would like to thank all the study subjects who have participated in this study. We would also like to thank Dr. Sitharthan Naidu (Clinic Tanah Melayu) for his kind assistance in handling all the blood-test procedures, Mr. Azlan Abdul Rahim, Mr. Mohamad Hafifi Jamri, and Mr. Muhammad Eshal Dzulkapli for coordinating the field work, Mr. Nizuwan Bin Azman for statistical advice, and Mrs. Nur Sabrina Mohd Yusof for conducting the laboratory analysis. This work was supported by a Higher
Author contributions
Singh and Mansor, designed the study, analysed the study data and wrote the manuscript; [email protected], [email protected] Müller, Murugaiyah, Hamid, Balasingam, and Avery revised the manuscript; Christian. [email protected], [email protected], [email protected], [email protected], [email protected]. Chear performed the experiments; [email protected].
Conflict of interest
The authors declare that they have no conflict of interest.
Disclosure/Conflict of interest
The authors reported no biomedical financial interests or potential conflicts of interest.
References (53)
- et al.
Mitragyna speciosa use in the northern states of Malaysia: cross-sectional study
J. Ethnopharmacol.
(2012) - et al.
Cholinesterase inhibitory activities and chemical constituents of Stenochlaena palustris at two stages of maturity
J. Food Drug Anal.
(2016) - et al.
Mitragynine concentrations in two fatalities
Forensic Sci. Int
(2017) Patterns of Kratom use and health impact in the US-Results from an online survey
Drug Alcohol Depend.
(2017)- et al.
Acute toxicity study of the standardized methanolic extract of Mitragyna speciosa Korth in rodent
J. Ethnopharmacol.
(2010) - et al.
From Kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction
Neurosci. Biobehav. Rev.
(2013) - et al.
Subchronic exposure to mitragynine, the principal alkaloid of Mitragyna speciosa, in rats
J. Ethnopharmacol.
(2013) - et al.
“Legal highs” on the net – Evaluation of UK-based Websites, products and product information
Forensic Sci. Int.
(2011) - et al.
Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users
Drug Alcohol Depend.
(2014) - et al.
Traditional and non-traditional uses of Mitragynine (Kratom): a survey of the literature
Brain Res. Bull.
(2016)