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Patterns and reasons for kratom (Mitragyna speciosa) use among current and former opioid poly-drug users
Journal Pre-proof Patterns and reasons for kratom (Mitragyna speciosa) use among current and former opioid poly-drug users Darshan Singh, Nelson Jeng Yeou Chear, Suresh Narayanan, Francisco Leon, Abhisheak Sharma, Christopher R. McCurdy, Bonnie A. Avery, Vicknasingam Balasingam PII:
S0378-8741(19)33158-7
DOI:
https://doi.org/10.1016/j.jep.2019.112462
Reference:
JEP 112462
To appear in:
Journal of Ethnopharmacology
Received Date: 7 August 2019 Revised Date:
7 October 2019
Accepted Date: 5 December 2019
Please cite this article as: Singh, D., Yeou Chear, N.J., Narayanan, S., Leon, F., Sharma, A., McCurdy, C.R., Avery, B.A., Balasingam, V., Patterns and reasons for kratom (Mitragyna speciosa) use among current and former opioid poly-drug users, Journal of Ethnopharmacology (2020), doi: https:// doi.org/10.1016/j.jep.2019.112462. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Full-Research Article
Patterns and Reasons for Kratom (Mitragyna speciosa) Use among Current and Former Opioid Poly-Drug Users
Darshan Singh1, Nelson Jeng Yeou Chear1, Suresh Narayanan2, Francisco Leon3, Abhisheak Sharma4, Christopher R. McCurdy3, Bonnie A. Avery4, Vicknasingam Balasingam1.
1. Centre for Drug Research, Universiti Sains Malaysia. 11800 Minden, Penang. Malaysia. 2. School of Social Sciences, Universiti Sains Malaysia. 11800 Minden, Penang. Malaysia. 3. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida, USA 32610. 4. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA 32610.
Running head:
Patterns and reasons for kratom use among current and former opioid poly-drug users.
Corresponding author:
Dr. Darshan Singh Centre for Drug Research, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia. Email: [email protected] Tel: 604-653 6029
Abstract Ethnopharmacological relevance: Kratom (Mitragyna speciosa) is a native medicinal plant of Southeast Asia widely reported to be used to reduce opioid dependence and mitigate withdrawal symptoms. There is also evidence to suggest that opioid polydrug users were using kratom to abstain from opioids. Aim of the study: To determine the patterns and reasons for kratom use among current and former opioid poly-drug users in Malaysia. Materials and methods: A total of 204 opioid poly-drug users (142 current users vs. 62 former users) with current kratom use history were enrolled into this crosssectional study. A validated UPLC-MS/MS method was used to evaluate the alkaloid content of a kratom street sample. Results: Results from Chi-square analysis showed that there were no significant differences in demographic characteristics between current and former opioid polydrug users except with respect to marital status. Current users had higher odds of being single (OR: 2.2: 95%CI: 1.21-4.11; p<0.009). Similarly, there were no significant differences in the duration (OR: 1.1: 0.62-2.03; p<0.708), daily quantity (OR: 1.5: 0.85-2.82; p<0.154) or frequency of kratom use between current and former opioid poly-drug users (OR: 1.1: 0.62-2.06; p<0.680). While both current and former opioid users reported using kratom to ameliorate opioid withdrawal, current users had significantly higher likelihood of using kratom for that purpose (OR: 5.4: 95%CI: 2.81-10.18; p<0.0001). In contrast, former opioid users were more likely to be using kratom for its euphoric (mood elevating) effects (OR: 1.9: 95%CI: 1.04-3.50; p<0.035). Results from the UPLC-MS/MS analysis indicated the major alkaloids present in the representative kratom street sample (of approximately 300 mL of
brewed kratom) were mitragynine, followed by paynantheine, speciociliatine and speciogynine, as well as low levels of 7-hydroxymitragynine. Conclusions: Both current and former opioid poly-drug users regularly used kratom (three glasses or about 900 mL daily or the equivalent of 170.19mg of mitragynine) to overcome opioid poly-drug use problems.
Keywords: Kratom, mitragynine, opioid poly-drug users, Malaysia.
Kratom leaf.
Graphical Abstract. UPLC-MS/MS analysis
Conclusion. • Kratom is commonly used as a substitute to illicit substances in traditional settings.
Opioid polydrug users
• Current users have higher odds of using kratom for ameliorating opioid withdrawal (OR: 5.4: 2.82-10.18; p<0.0001), while former users used kratom to experience euphoria (OR: 1.9: 1.04-3.50; p<0.035). • Both current and former opioid poly-drug users regularly used kratom (approximately 170.2mg of mitragynine) to overcome opioid poly-drug use problems.
Kratom juice.
1. Introduction The leaves from Mitragyna speciosa plant (Rubiaceae), commonly known as ketum (biak) in Malaysia or kratom in Thailand, is traditionally used for its medicinal value in Southeast Asia (Brown et al., 2017). Historically, kratom has been used in local context for its therapeutic properties - treatment of pain, diarrhoea, cough, stimulant drug for enhancing work efficiency, aphrodisiac, and as a substitute for illicit substances mainly opioid (Vicknasingam et al., 2010; Saingam et al., 2012; Tanguay, 2011; Saref et al., 2019). Because of its purported pain-relieving effects (Coe et al., 2019), unrestricted promotion on the internet (Schmidt et al., 2011), and abuse potential (FDA, 2018), some of kratom’s alkaloids have been isolated and examined for their opioid and non-opioid properties (Kruegel et al., 2016; Hiranita et al., 2019). Mitragynine and 7-hydroxymitragynine are claimed to have opioid-like effects (Kruegel et al., 2016). These alkaloids act as partial agonists at the mu-opioid receptor and competitive antagonists at the kappa and delta-opioid receptors (Kruegel et al., 2016). Since mitragynine does not recruit β-arrestin-2 mediated pathways upon receptor activation, it is considered as a safer analgesic to classical opioids (Kruegel et al., 2016). As the minor compound, 7-hydroxymitragynine (constituting only 2.0% or less of the alkaloid fraction) has a higher affinity for muopioid receptors (Matsumoto et al., 2004), and has 13 and 46-times higher potency than morphine and mitragynine, respectively (Takayama et al., 2004). However, unlike mitragynine, 7-hydroxymitragynine was reported to exert actions through βarrestin-2 mediated pathways and produce undesired effects such as tolerance and cross-tolerance to morphine (Hemby et al., 2018; Varadi et al., 2016).
The mitragynine content differs with different types of leaves and how they are ingested. It has been reported that while the mitragynine content is roughly 12% in leaves commonly found in Malaysia, it could go up to 66% in leaves found in Thailand (Takayama et al., 2004; Brown et al., 2017). The mitragynine content in kratom leaves can vary significantly depending on stage of maturity and ecosystem (Brown et al., 2017). There are significant variations in the phytochemical content of commercial kratom products (Kikura-Hanajiri et al., 2009; Lydecker et al., 2016). In most instances, users experienced a mixed pain relieving and energy increasing effects after kratom consumption, though higher (>5grams of kratom powder) intake of kratom use was reported to be beneficial in aiding cessation from opioid medication (Grundmann, 2017). It should be added although kratom is widely used in traditional, rural Southeast Asian societies (Saingam et al., 2012; Singh et al., 2016), it is currently regulated in Malaysia because of its potential for abuse. In the US, the Food and Drug Administration (FDA) has argued that kratom’s medicinal relevance has not been established and has called on the Drug Enforcement Agency (DEA) to place mitragynine and 7-hydroxymitargynine into Schedule 1 of the Control Substances Act (CSA) (Henningfield et al., 2018; Prozialeck et al., 2019). Despite the strong push for criminalization (Gauvin and Zimmermann, 2018), kratom remains widely used in US as an opioid substitute (Boyer et al., 2008; Grundmann, 2017; Smith and Lawson, 2017; Coe et al., 2019). While kratom is used for many different reasons in Southeast Asia, the focus of this study is the use of kratom among current and past opioid poly-drug users. While it is known that kratom is commonly used for reducing addiction to other drugs by opioid users, the majority rely on kratom to ameliorate withdrawal symptoms
(Vicknasingam et al. 2010; Saref et al., 2019). However, sources familiar with former opioid users also indicate that kratom is being widely used by this group to maintain their abstinence from opioids. The objective of this study was therefore to investigate the reasons for kratom use, and patterns of use, among current and former opioid poly-drug users in rural settings in Malaysia. 2. Methods 2.1 Study design, respondents and location We recruited 204 opioid poly-drug users (142 current opioid poly-drug users’ users and 62 former opioid poly-drug users) with current kratom use history (selfreported to have used kratom regularly in the last 12 months) for this cross-sectional study. A convenience sampling approach was used to recruit potential respondents. All the respondents reported to have used an opioid (heroin/morphine) with one additional substance, most commonly an amphetamine-type-stimulant (ATS) (methamphetamine). Those who regularly used opioid with methamphetamine in the last 12 months were labelled as current opioid poly-drug users. While those with previous opioid poly-drug use history were labelled as former opioid poly-drug users. Former opioid poly-drug users are those who self-reported to have abstained from illicit drug use. Respondents for this study were mainly recruited from a rural district in the northern state of Penang in Peninsular Malaysia where kratom use was reported to be prevalent among illicit drug users (Vicknasingam et al., 2010; Singh et al., 2019a).
2.2 Study inclusion and exclusion criteria The study inclusion criteria were; 1) 18 years and above, 2) must have opioid poly-drug use history, and 3) have used kratom regularly (at least once daily) in the last 12 months. Those who met these criteria but reported significant psychological problems or who were unwilling to give written-informed consent were excluded. 2.3 Data collection The study data were collected between March 2018 and June 2018. Prior to the data collection process, we approached key-informants (e.g. former and active drug users with opioid and ATS use history) who were willing to voluntarily participate in the study. Key-informants were briefed on the study objectives and asked to refer potential respondents to the study. Eligible respondents were assured participation anonymity and data confidentiality. All the study data were collected using a semi-structured questionnaire canvassed through face-to-face interviews by a trained research assistant. The information collected included the respondents’: 1) socio-demographic characteristics such as gender, ethnicity, current age, marital status, education and employment status; 2) kratom use history including duration, frequency and quantity of daily kratom use, and 3) reasons for kratom use. All the interviews were conducted in the local Malay dialect. Each interview session lasted for about 15 to 20 minutes. 2.4 Ethics This study has been approved by the Human Ethics and Research Committee of University Sains Malaysia. As a token of appreciation, respondents were compensated with RM50 for their participation. All gave their written-informed consent.
2.5 UPLC-MS/MS analysis of kratom street sample All the respondents in this study reported consuming a brewed kratom decoction. Processed kratom decoctions can be readily bought from illegal kratom traders by regular customers in the community. Each packet (consisting approximately 300 mL of kratom juice) is usually sold for about RM5 (equivalent to USD=1.26). In order to estimate the intake of kratom alkaloids among the respondents, a packet of processed kratom decoction was purchased from a kratom trader in the study area from whom the majority of respondents usually get their kratom supply. The acquired kratom sample (300 mL) was lyophilized to remove water content, weighed and kept at -20°C prior to UPLC-MS/MS analysis (Singh et al., 2019b). 2.5.1 Chemicals and reagents The
reference
alkaloids:
mitragynine,
paynantheine,
speciogynine,
speciociliatine, corynoxine, corynoxine B, mitraphylline, corynantheidine and isocorynanthiedine (purity ≥ 98%) were extracted and purified from kratom leaves according to method described by Sharma et al. (2019). Minor alkaloid, 7hydroxymitragynine (purity ≥ 98%) was synthesized in house according to the method described by Ponglux et al. (1994). The chemical structure of the reference alkaloids was confirmed using 1H &
13
C NMR, and UPLC-QTOF-MS, and the
spectroscopic data was compared with those reported in previous studies (Sharma et al., 2019; Ponglux et al., 1994). Solvents (hexane, ethyl acetate, chloroform & methanol) for alkaloid extraction and purification were of analytical grade (Merck,
Germany). LC grade water, acetic acid, ammonium acetate, methanol and acetonitrile were purchased from Fisher Scientific (Fair Lawn, NJ, USA).
2.5.2 UPLC-MS/MS quantification of major alkaloids in lyophilized kratom street sample Method reported by Sharma et al. (2019) was applied for the quantitative analysis of lyophilized kratom street sample. In brief, Waters Acquity Class I UPLC coupled with a Xevo TQ-S Micro triple quadruple mass spectrometer (Milford, MA, USA) was used for the simultaneous quantification of kratom alkaloids. Chromatographic separation of kratom alkaloids was achieved on a Waters Acquity BEH C18 column (1.7 µm, 2.1 × 100 mm) using a gradient elution. Mobile phase consisted of acetonitrile and ammonium acetate buffer (pH 3.5, 10 mM) with a flow rate of 0.35 mL/min. Multiple reaction monitoring (MRM) with electrospray ionization (ESI) on positive mode (capillary voltage, 500 V) was implemented on the precursor ion → product ion transitions m/z 369.16 > 144.12, 385.19 > 132.09, 385.19 > 132.09, 415.19 > 190.09, 369.16 > 144.12, 399.25 > 174.16, 369.22 > 160.12, 397.16 > 174.10, 399.25 > 174.16, 399.25 > 174.16 and 180.12 > 110.03 for corynantheidine,
corynoxine,
corynoxine
isocorynantheidine,
mitragynine,
mitraphylline,
B,
7-hydroxymitragynine,
paynantheine,
speciociliatine,
speciogynine and phenacetin (internal standard), respectively. Acquisition and analysis of data from UPLC-MS/MS system was performed using MassLynx software version 4.1. 2.6 Data analysis The study data were analysed with the Statistical Package for Social Sciences (SPSS) software version 25. First, descriptive statistics were used to describe the
socio-demographic characteristics, kratom use history and the reasons for kratom use. Next, Chi-square analysis was utilised to determine if significant differences existed in the demographic characteristics, kratom use history and reasons for kratom use, between current and former opioid poly-drug users. The utility calculator available at www.Vassarstats.com was used to compute Odds Ratio (OR) and the associated 95% Confidence Intervals (CI). The statistical significance for analyses was set at p<0.05. 3. Results 3.1 Socio-demographic characteristics of current and past opioid poly-drug users The socio-demographic characteristics of both groups are shown in Table 1. Almost all respondents were males and Malays in both groups. The distribution by age, marital status and education was also similar. More than half of the respondents in both groups were between 18 to 35 years-old (53%, n=108/204), and the mean age of the sample as a whole was 35.6 years (SD=10.5). A slightly larger proportion of former users are employed (94%) as opposed to current users (89%) but the difference was not statistically significant. More than 80% of respondents in both groups are living with their family. The only significant difference between the two groups is with respect to marital status and drug use history. Current users were more likely to be single (OR: 2.2: 1.21-4.11; p<0.009), and to have had a previous drug rehabilitation history (OR: 2.1: 1.17-3.94; p<0.013), as compared to former opioid poly-drug users. INSERT TABLE 1 SOMEWHERE HERE. 3.2 Kratom use history of current opioid users
Table 2 summarises the kratom use history of current users. The respondents mean age of first kratom use in this sample was 26.7 years (SD=10.4), while their mean age of first illicit drug use was 20.4 years (SD=6.4). Fifty-two percent (n=106/204) have ≤6 years kratom use history, while 48% have used kratom for more than six years. The mean duration of kratom use was 93.7 months (SD=78.6). The majority (56%, n=114/204) used between 1 to 2 glasses of kratom daily. On average, current users consumed 2.7 glasses (SD=1.8) of kratom daily. INSERT TABLE 3 SOMEWHERE HERE. 3.3 A comparison of the kratom use history of current and former users The kratom use history of current and past opioid poly-drug users was surprisingly similar. Results from the Chi-square analyses confirmed this (Table 3). There were no significant differences in the duration (OR: 1.1: 0.62-2.03; p<0.708), quantity (OR: 1.5: 0.85-2.82; p<0.154) or frequency (OR: 1.1: 0.62-2.06; p<0.680) of daily kratom use between the two groups. INSERT TABLE 4 SOMEWHERE HERE. 3.4 Reasons for using kratom: current and former users Table 4 indicates the reasons for using kratom as reported by current and former opioid poly-drug users. The majority in both groups relied on kratom to selftreat substance use disorder (SUD). Other reasons common to both groups included using kratom to enhance energy, reduce methamphetamine use, treat psychological problems, and improve sexual performance. However, the significant difference in kratom use between the two groups was with respect to reducing opiate withdrawal symptoms and inducing euphoria. Chi-
square analysis confirmed that current users have significantly higher odds of using kratom for reducing the effects of opioid withdrawal (OR: 5.4: 2.81-10.18; p<0.0001), than former users. In contrast, former opioid users have higher odds of using kratom to induce euphoria (mood elevating effects) (OR: 1.9: 1.04-3.50; p<0.035).
3.5
UPLC-MS/MS analysis of major alkaloids in an acquired kratom street sample A total of 300 mL (one packet which is equivalent to one glass) of kratom
street sample was lyophilized to yield 1.5 g of powdered extract. A validated analytical method as described in our previous study (Sharma et al., 2019) was used for the quantitative analysis of kratom alkaloids in lyophilized extract. Test sample was analyzed along with the freshly prepared calibration and quality control standards. The analytical results showed that mitragynine (3.80%, w/w) was the predominant alkaloid found in lyophilized kratom extract. Other mitragynine’s isomers – paynanthiene (0.39%, w/w), speciogynine (0.26%, w/w) and speciociliatine (0.29%, w/w) appeared as minor alkaloids. Other analysed kratom alkaloidscorynantheidine, corynoxine, corynoxine B, isocorynantheidine, mitraphylline and 7hydroxymitragynine (most potent but addictive opioid agonist) were below lower limit of quantification (< 1 ng/mL or 0.01 %, w/w). A total of 300 mL of the kratom decoction (1.5 g of lyophilized extract) was equivalent to the intake of 56.73 mg of mitragynine, 5.82 mg of paynanthiene, 4.33 mg of speciociliatine and 3.88 mg of speciogynine. Multiple reaction monitoring (MRM) chromatograms of mitragynine (13.75 min), paynanthiene (13.41 min), speciociliatine (18.03 min), speciogynine (15.46 min) and 7-hydroxymitragynine (4.80 min) are shown in Figure 1.
INSERT FIGURE 1 SOMEWHERE HERE.
4. Discussion This study described patterns and reasons for kratom use among current and former opioid poly-drug users in Malaysia. We found current opioid poly-drug users have significantly higher odds of using kratom for reducing opioid withdrawal symptoms while past opioid poly-drug users have higher odds of using kratom to induce euphoria. There was also no statistically significant difference in the quantity, or frequency of use between the two groups. The laboratory findings based on a typical street sample of kratom tea (brew) consumed suggests that approximately 170mg of mitragynine is ingested per day (or the equivalent of 3 glasses), as the therapeutic dose for managing the opioid polydrug use problems (by current opioid users) and to experience euphoria in order to abstain from opioid use (by former users). Despite the lack of clinical studies to support kratom’s efficacy as a novel alternative to opioid treatment (Henningfield et al., 2018), data from survey findings indicate that kratom is generally used in Southeast Asia and US for managing pain and opioid withdrawal (Saref et al., 2019; Prozialeck et al., 2019; Coe et al., 2019). Our findings are consistent with the claims in these studies.
The implications of these findings are important. The fact that current opioid poly-drug users are relying on kratom to mitigate opioid withdrawal symptoms suggests that it has the potential to replace methadone which is currently being used for a similar purpose. However, methadone maintenance therapy has several disadvantages with respect to opioid users in more rural settings. There is a monetary cost involved in travelling to government established methadone therapy centres to benefit from the service. Second, there is also stigma attached to being seen at these centres. Third, not all rural opioid users are aware of the availability of methadone maintenance therapy. Fourth, there is considerable misconception regarding the use of methadone. Finally, being present at these centres is still viewed with fear and suspicion since one can be arrested as opioid use is still an offence. Kratom, on the other hand, is cheap, easily available, avoids stigma as a drug user (Vicknasingam et al., 2010; Saingam et al., 2012; Singh et al., 2014; Singh et al., 2015), and has been a trusted general remedy for generations (Tanguay, 2011; Saingam et al., 2012; Singh et al., 2016). Kratom use, particularly among men, is not viewed with concern in rural communities (Assanangkornchai et al., 2007; Saingam et al., 2012; Ahmad and Aziz, 2012). The finding is consistent with that of a recent study that found kratom initiation was associated with significant decreases in the prevalence and severity of the adverse side-effects associated with opioid us (Saref et al., 2019). The second finding that former opioid poly-drug users continue to use kratom, but primarily for its mood elevating effects to prevent their return to opioid use. This suggests that kratom has the potential to aid out-of-treatment opioid poly-drug users to abstain from illicit drug use. Once again, this is in line with previous studies that show kratom has been used as a harm reduction tool, especially among people
addicted to opioids and other drugs such as cannabis and methamphetamine (Swogger et al., 2015; Swogger and Walsh, 2018). A recent internet survey among kratom users in the US elicited responses indicating that kratom was very helpful in alleviating pain, reducing prescription opioids or heroin use, and relieving withdrawal symptoms (Coe et al., 2019).
While both kratom and opioids are addictive, kratom was found to be less addictive than opioid/heroin, amphetamine and Suboxone (Smith and Lawson, 2018). Furthermore, many field studies have shown that those using kratom, even over long periods, continue to work and function usefully in society as opposed to long-term users of opioids (Singh et al., 2015). Kratom can cause severe dependence (Suwanlert, 1975; Singh et al., 2014), but so does tobacco and alcohol. While not denying its potential for abuse, in our sample we found no significant differences in the kratom use patterns among current and former opioid poly-drug users. Thus, the finding does not indicate that opioid poly-drug users are abusing kratom, since their patterns of use (duration, quantity and frequency) do not differ significantly from the kratom use patterns of former users. Kratom’s main alkaloid mitragynine is reported to be responsible for almost all the adverse kratom related cases (Post et al., 2019; Olsen et al., 2019; Eggleston et al., 2019). However, recently Hemby et al. (2018) and Yue et al. (2018) found mitragynine has limited abuse potential and therefore it can be used to reduce morphine intake. To date, mitragynine’s role in pain alleviation remains questionable. Recently, Kruegel et al. (2019) found mitragynine is being converted to a much more
potent mu-opioid receptor agonist 7-hydroxymitragynine. However, in our laboratory findings, 7-hydroxymitragynine appeared in negligible levels in the processed kratom tea sample. This might suggest that kratom’s therapeutic effects in managing opioid poly-drug may be due to the synergistic effects of other major kratom alkaloids such as mitragynine, paynantheine, speciogynine and speciociliatine. Given its complex pharmacological effect the role of other alkaloids deserves to be further investigated as has been done with the effects of mitragynine. The other interesting finding from the study is that more than two-thirds (73%) of both current and past opioid poly-drug users were relying on, or had relied on, kratom to reduce dependence on methamphetamine. This warrants further research although there are two reasons that can be put forth tentatively. First, since methamphetamine use is associated with psychological problems (Degenhardt et al., 2010), kratom is perhaps being used to overcome the anxiety and depressive symptoms (Idayu et al., 2011; Grundmann, 2017; Singh et al., 2019a). Second, because kratom is reported to have stimulant effects, drug users could be substituting methamphetamine with kratom for its stimulant effects. This is because mitragynine, as well as other unknown alkaloids in kratom leaves are reported to produce opioid and non-opioid like effects (Raffa et al., 2018; Hiranita et al., 2019). Finally, although respondents in this cohort used kratom concurrently with illicit substances, none reported any adverse health incidents. There are some limitations in this study. First, all the respondents were largely recruited from the northern states of Peninsular Malaysia and their responses were based solely on their self-report which could have been exposed to recall and social desirability biases, thus our findings cannot be generalised. Second, we did not
screen the respondents for illicit drug use, though former opioid poly-drug users claimed to have abstained from illicit drug use. Since drug use has been criminalised and individuals testing positive for illicit drugs can face legal problems, respondents were reluctant to participate if it involved drug screening. Finally, although we made attempts to recruit female participants, none of the identified female opioid poly-drug users reported kratom use. Kratom is more common among males as compared to females, as females generally use kratom to treat common ailments (Saingam et al., 2012). In conclusion, we found current opioid poly-drug users commonly use kratom to manage their opioid poly-drug use problem, while former users rely on kratom to help them abstain from using opioids. Acknowledgment We thank Higher Institutions Centre of Excellence (HICoE) for their financial support. The PhD study of Nelson Jeng Yeou Chear was supported by the Institute of Postgraduate Studies, Universiti Sains Malaysia (USM) under USM Fellowship Scheme. We also thank Nur Sabrina Yusof and Muhamad Eshal Dzulkapli for coordinating the field work and sample preparation. Disclosure/Conflict of Interest All the authors declared that there is no conflict of interest. Author contributions Singh, Narayanan and Chear designed the study methodology, analysed the data.
[email protected];
[email protected];
[email protected]:
Singh
and
Narayanan wrote the original draft; [email protected]; [email protected]: Singh, Narayanan, McCurdy and Balasingam reviewed and edited the manuscript.
[email protected]; [email protected]; [email protected]; [email protected]: Chear,
Leon,
Sharma
[email protected];
and
Avery
performed
[email protected];
the
kratom
juice
analysis.
[email protected];
[email protected].
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Kruegel, A.C., Uprety, R., Grinnell, S.G., Langreck, C., Pekarskaya, E.A., Rouzic, V.L., Ansonoff, M., Gassaway, M.M., Pintar, J.E., Pasternak, G.W., Javitch, J.A., Majumdar, S., & Sames, D. (2019). 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of its Analgesic Effects. ACS, Cent. Sci, 5, 992-1001. Kruegel, A. C., Gassaway, M. M., Kapoor, A., Váradi, A., Majumdar, S., Filizola, M., Javitch, J. A., & Sames, D. (2016). Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. Journal of the American Chemical Society, 138(21): 6754-6. Lydecker, A. G., Sharma, A., McCurdy, C. R., Avery, B. A., Babu, K. M., Boyer, E. W. (2016). Suspected Adulteration of Commercial Kratom Products with 7Hydroxymitragynine. J. Med. Toxicol, 12(4), 341-349. Matsumoto, K., Horie, S., Ishikawa, H., Takayama, H., Aimi, N., Ponglux, D., & Watanabe, K. (2004). Antinociceptive effect of 7-hydroxymitargynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa. Life Sciences, 74, 2143-2155. Olsen, E.O., O’Donnell, J., Mattson, C.L., Schier, J.G., & Wilson, N. (2019). Notes from the Field. Unintentional Drug Overdose Deaths with Kratom Detected – 27 States, July 2016 – December 2017. MMWR Morb Mortal Wkly Rep, Vol. 68, No14. 326-327. Post, S., Spiller, H. A., Chounthirath, T., Smith, G. A. (2019). Kratom exposure reported to United States poison control centers: 2011-2017. Clin. Toxicol. DOI: 10.1080/15563650.2019.1569236. Prozialeck, W. C., Avery, B. A., Boyer, E. W., Grundmann, O., Henningfield, J. E., Kruegel, A. C.,… Singh, D. (2019). Kratom policy: The challenge of balancing therapeutic potential with public with public safety. Int. J. Drug Policy, 70.
Raffa, R. B., Pergolizzi Jr, J. V., Taylor, Jr. R., Ossipov, M. H., NEMA Research Group. (2018). Natur’s first “atypical opioid”: Kratom and mitragynines. J Clin Pharm Ther, 43: 437-441. Saref, A., Suraya, S., Singh, D., Grundmann, O., Narayanan, S., Swogger, M. T., Prozialeck, W. C., Boyer, E., Chear, N. J. Y., Balasingam, V. 2019. Selfreported prevalence and severity of opioid and kratom (Mitragyna speciosa Korth.) side effects. Journal of Ethnopharmacology, 238. Saingam, D., Assanangkornchai, S., Geater, A.F., Balthip, K. (2012). Pattern and consequences of krathom (Mitragyna speciosa Korth.) use among male villagers in southern Thailand: a qualitative study. Int. J. Drug Policy, 24 (4), 351-358. Schmidt, M.M., Sharma, A., Schifano, F., & Feinmann, C. (2011). “Legal highs” on the net – Evaluation of UK-based Websites, products and product information. Forensic Science International, 206, 92-97. Singh, D., C. P. Muller, & B. Vicknasingam. (2014). Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users. Drug Alcohol Depend, 139:132-137. Singh, D., Muller, C.P., Vicknasingam, B., & Mansor, S.M. (2015). Social functioning of kratom (Mitragyna speciosa) users in Malaysia. J Psychoactive Drugs, 47: 125-131. Singh, D., Narayanan, S., & Vicknasingam, B. (2016). Traditional and non-traditional uses of Mitragyna (Kratom): A survey of the literature. Brain Res. Bull, 126(1), 41-46. Smith, K.E., & Lawson, T. (2017). Prevalence and motivations of kratom use in a sample of substance users enrolled in a residential treatment program. Drug Alcohol Depend,180, 340-348. Suwanlert, S. (1975). A study of kratom eaters in Thailand. Bull. Narcot, 27 (3), 2127. Swogger, M. T., & Walsh, Z. (2018). Kratom use and mental health: A systematic review. Drug Alcohol Depend, 183, 134-140. Swogger, M.T., Hart, E., Erowid, F., Erowid, E., Trabold, N., Yee, K., Parkhurst, K.A., Priddy, B. M., & Walsh, Z. (2015). Experiences of Kratom Users: A Qualitative Analysis. Journal of Psychoactive Drugs, 47 (5), 360-367. Takayama, H. (2004). Chemistry and Pharmacology of Analgesic Indole Alkaloids from the Rubiaceous Plant, Mitragyna speciosa. Chem, Pharm. Bull, 52, 916928. Tanguay, P. (2011). Kratom in Thailand: Decriminalisation and community control? Series on legislative reform of drug policies, vol. 13, International Drug Policy Consortium (IDPC).
Vicknasingam, B., Narayanan, S., Goh, T.B., & Mansor, S.M. (2010). The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. Int. J. Drug Policy, 21 (4), 283-288. Yue, K., Kopajtic, T. A., Katz, J. l. (2018). Abuse liability of mitragynine assessed with a self-administration procedure in rats. Psychopharmacology. https://doi.org/10.1007/s00213-018-4974-9.
Table 1: Differences in the demographic characteristics between current and former opioid poly-drug users.
n=
%
Gender Male 203 99 Female 1 1 Ethnicity Malay 191 94 Non-Malay 13 6 Mean age Age 18-35 years 108 53 >36 years 96 47 Marriage Single 129 63 Married 75 37 Education 9 years 91 45 11 years 113 55 Employment Employed 185 91 Unemployed 19 9 Accommodation Family 179 88 Renting/friends 25 12 Drug rehabilitation history Yes 109 53 No 95 47 *Denotes P-value at <0.05.
Current Users (n=142) n= %
Former Users (n=62) n= %
142 100 0 0
61 1
99 1
OR:95%CI
P-Value
-
0.304
134 94 57 92 1.5: 0.46-4.68 8 6 5 8 35.6 years (SD=10.5)
0.539
74 68
52 48
34 28
55 45
1.1: 0.61-2.03
0.718
98 44
69 31
31 31
50 50
2.2: 1.21-4.11
0.009*
69 73
49 51
22 40
35 65
1.7: 0.93-3.18
0.083
127 89 15 11
58 4
94 6
1.7: 0.54-5.39
0.354
126 89 16 11
53 9
86 14
1.3: 0.56-3.22
0.517
84 58
25 37
40 60
2.1: 1.17-3.94
0.013*
59 41
Table 2: Current kratom use history. n= % 26.7 years (SD=10.4) 20.4 years (SD=6.4) 93.7 months (SD=78.6) 2.7 glasses (SD=1.8)
Mean age of first kratom use Mean age of first illicit drug use Mean duration of kratom use Mean quantity of daily kratom use Kratom use duration ≤6 years >6 years Daily quantity of kratom use 1-2 glasses >3 glasses Daily frequency of kratom use 1-2 times >3 times
106 52 98 48 114 56 90 44 113 55 91 45
Table 3: Kratom use history between current and former opioid poly-drug users.
Kratom use duration ≤6 years >6 years Daily quantity of kratom use 1-2 glasses >3 glasses Daily frequency of kratom use 1-2 times >3 times
Current Users (n=142) n= %
Former Users (n=62) n= %
75 67
53 47
31 31
84 58
59 41
80 62
56 44
OR:95%CI
P-Value
50 50
1.1: 0.62-2.03
0.708
30 32
48 52
1.5: 0.85-2.82
0.154
33 29
53 47
1.1: 0.62-2.06
0.680
Table 4: Kratom use reasons between current and former opioid poly-drug users.
n=
%
Treat SUD Yes 180 88 No 24 12 Ameliorate opiate withdrawal Yes 128 63 No 76 37 Treat psychological problems Yes 102 50 No 102 50 Euphoric Yes 99 48 No 105 52 Enhance energy Yes 171 84 No 33 16 Improve sexual performance Yes 98 48 No 106 52 Reduce methamphetamine use Yes 149 73 No 55 27 *Denotes P-value at <0.05.
Current Users (n=142) n= %
Former Users (n=62) n= %
125 88 17 12
55 7
106 75 36 25
71 71 62 80
OR:95%CI
PValue
89 11
1.1: 0.42-2.72
0.887
22 40
35 65
5.4: 2.81-10.18
<.0001*
50 50
31 31
50 50
1: 0.55-1.82
0.560
44 56
37 25
60 40
1.9: 1.04-3.50
0.035*
116 82 26 18
55 7
89 11
1.8: 0.72-4.31
0.210
64 78
45 55
34 28
55 45
1.5: 0.81-2.69
0.199
101 71 41 29
48 14
77 23
1.4: 0-69-2.79
0.351
A
B
C
D
E
Figure 1: MRM chromatograms of kratom street sample and the detected alkaloids mitragynine (A), paynantheine (B), speciociliatine (C), speciogynine (D) and 7hydroxymitragynine (E).
S0378-8741(19)33158-7
DOI:
https://doi.org/10.1016/j.jep.2019.112462
Reference:
JEP 112462
To appear in:
Journal of Ethnopharmacology
Received Date: 7 August 2019 Revised Date:
7 October 2019
Accepted Date: 5 December 2019
Please cite this article as: Singh, D., Yeou Chear, N.J., Narayanan, S., Leon, F., Sharma, A., McCurdy, C.R., Avery, B.A., Balasingam, V., Patterns and reasons for kratom (Mitragyna speciosa) use among current and former opioid poly-drug users, Journal of Ethnopharmacology (2020), doi: https:// doi.org/10.1016/j.jep.2019.112462. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Full-Research Article
Patterns and Reasons for Kratom (Mitragyna speciosa) Use among Current and Former Opioid Poly-Drug Users
Darshan Singh1, Nelson Jeng Yeou Chear1, Suresh Narayanan2, Francisco Leon3, Abhisheak Sharma4, Christopher R. McCurdy3, Bonnie A. Avery4, Vicknasingam Balasingam1.
1. Centre for Drug Research, Universiti Sains Malaysia. 11800 Minden, Penang. Malaysia. 2. School of Social Sciences, Universiti Sains Malaysia. 11800 Minden, Penang. Malaysia. 3. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida, USA 32610. 4. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA 32610.
Running head:
Patterns and reasons for kratom use among current and former opioid poly-drug users.
Corresponding author:
Dr. Darshan Singh Centre for Drug Research, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia. Email: [email protected] Tel: 604-653 6029
Abstract Ethnopharmacological relevance: Kratom (Mitragyna speciosa) is a native medicinal plant of Southeast Asia widely reported to be used to reduce opioid dependence and mitigate withdrawal symptoms. There is also evidence to suggest that opioid polydrug users were using kratom to abstain from opioids. Aim of the study: To determine the patterns and reasons for kratom use among current and former opioid poly-drug users in Malaysia. Materials and methods: A total of 204 opioid poly-drug users (142 current users vs. 62 former users) with current kratom use history were enrolled into this crosssectional study. A validated UPLC-MS/MS method was used to evaluate the alkaloid content of a kratom street sample. Results: Results from Chi-square analysis showed that there were no significant differences in demographic characteristics between current and former opioid polydrug users except with respect to marital status. Current users had higher odds of being single (OR: 2.2: 95%CI: 1.21-4.11; p<0.009). Similarly, there were no significant differences in the duration (OR: 1.1: 0.62-2.03; p<0.708), daily quantity (OR: 1.5: 0.85-2.82; p<0.154) or frequency of kratom use between current and former opioid poly-drug users (OR: 1.1: 0.62-2.06; p<0.680). While both current and former opioid users reported using kratom to ameliorate opioid withdrawal, current users had significantly higher likelihood of using kratom for that purpose (OR: 5.4: 95%CI: 2.81-10.18; p<0.0001). In contrast, former opioid users were more likely to be using kratom for its euphoric (mood elevating) effects (OR: 1.9: 95%CI: 1.04-3.50; p<0.035). Results from the UPLC-MS/MS analysis indicated the major alkaloids present in the representative kratom street sample (of approximately 300 mL of
brewed kratom) were mitragynine, followed by paynantheine, speciociliatine and speciogynine, as well as low levels of 7-hydroxymitragynine. Conclusions: Both current and former opioid poly-drug users regularly used kratom (three glasses or about 900 mL daily or the equivalent of 170.19mg of mitragynine) to overcome opioid poly-drug use problems.
Keywords: Kratom, mitragynine, opioid poly-drug users, Malaysia.
Kratom leaf.
Graphical Abstract. UPLC-MS/MS analysis
Conclusion. • Kratom is commonly used as a substitute to illicit substances in traditional settings.
Opioid polydrug users
• Current users have higher odds of using kratom for ameliorating opioid withdrawal (OR: 5.4: 2.82-10.18; p<0.0001), while former users used kratom to experience euphoria (OR: 1.9: 1.04-3.50; p<0.035). • Both current and former opioid poly-drug users regularly used kratom (approximately 170.2mg of mitragynine) to overcome opioid poly-drug use problems.
Kratom juice.
1. Introduction The leaves from Mitragyna speciosa plant (Rubiaceae), commonly known as ketum (biak) in Malaysia or kratom in Thailand, is traditionally used for its medicinal value in Southeast Asia (Brown et al., 2017). Historically, kratom has been used in local context for its therapeutic properties - treatment of pain, diarrhoea, cough, stimulant drug for enhancing work efficiency, aphrodisiac, and as a substitute for illicit substances mainly opioid (Vicknasingam et al., 2010; Saingam et al., 2012; Tanguay, 2011; Saref et al., 2019). Because of its purported pain-relieving effects (Coe et al., 2019), unrestricted promotion on the internet (Schmidt et al., 2011), and abuse potential (FDA, 2018), some of kratom’s alkaloids have been isolated and examined for their opioid and non-opioid properties (Kruegel et al., 2016; Hiranita et al., 2019). Mitragynine and 7-hydroxymitragynine are claimed to have opioid-like effects (Kruegel et al., 2016). These alkaloids act as partial agonists at the mu-opioid receptor and competitive antagonists at the kappa and delta-opioid receptors (Kruegel et al., 2016). Since mitragynine does not recruit β-arrestin-2 mediated pathways upon receptor activation, it is considered as a safer analgesic to classical opioids (Kruegel et al., 2016). As the minor compound, 7-hydroxymitragynine (constituting only 2.0% or less of the alkaloid fraction) has a higher affinity for muopioid receptors (Matsumoto et al., 2004), and has 13 and 46-times higher potency than morphine and mitragynine, respectively (Takayama et al., 2004). However, unlike mitragynine, 7-hydroxymitragynine was reported to exert actions through βarrestin-2 mediated pathways and produce undesired effects such as tolerance and cross-tolerance to morphine (Hemby et al., 2018; Varadi et al., 2016).
The mitragynine content differs with different types of leaves and how they are ingested. It has been reported that while the mitragynine content is roughly 12% in leaves commonly found in Malaysia, it could go up to 66% in leaves found in Thailand (Takayama et al., 2004; Brown et al., 2017). The mitragynine content in kratom leaves can vary significantly depending on stage of maturity and ecosystem (Brown et al., 2017). There are significant variations in the phytochemical content of commercial kratom products (Kikura-Hanajiri et al., 2009; Lydecker et al., 2016). In most instances, users experienced a mixed pain relieving and energy increasing effects after kratom consumption, though higher (>5grams of kratom powder) intake of kratom use was reported to be beneficial in aiding cessation from opioid medication (Grundmann, 2017). It should be added although kratom is widely used in traditional, rural Southeast Asian societies (Saingam et al., 2012; Singh et al., 2016), it is currently regulated in Malaysia because of its potential for abuse. In the US, the Food and Drug Administration (FDA) has argued that kratom’s medicinal relevance has not been established and has called on the Drug Enforcement Agency (DEA) to place mitragynine and 7-hydroxymitargynine into Schedule 1 of the Control Substances Act (CSA) (Henningfield et al., 2018; Prozialeck et al., 2019). Despite the strong push for criminalization (Gauvin and Zimmermann, 2018), kratom remains widely used in US as an opioid substitute (Boyer et al., 2008; Grundmann, 2017; Smith and Lawson, 2017; Coe et al., 2019). While kratom is used for many different reasons in Southeast Asia, the focus of this study is the use of kratom among current and past opioid poly-drug users. While it is known that kratom is commonly used for reducing addiction to other drugs by opioid users, the majority rely on kratom to ameliorate withdrawal symptoms
(Vicknasingam et al. 2010; Saref et al., 2019). However, sources familiar with former opioid users also indicate that kratom is being widely used by this group to maintain their abstinence from opioids. The objective of this study was therefore to investigate the reasons for kratom use, and patterns of use, among current and former opioid poly-drug users in rural settings in Malaysia. 2. Methods 2.1 Study design, respondents and location We recruited 204 opioid poly-drug users (142 current opioid poly-drug users’ users and 62 former opioid poly-drug users) with current kratom use history (selfreported to have used kratom regularly in the last 12 months) for this cross-sectional study. A convenience sampling approach was used to recruit potential respondents. All the respondents reported to have used an opioid (heroin/morphine) with one additional substance, most commonly an amphetamine-type-stimulant (ATS) (methamphetamine). Those who regularly used opioid with methamphetamine in the last 12 months were labelled as current opioid poly-drug users. While those with previous opioid poly-drug use history were labelled as former opioid poly-drug users. Former opioid poly-drug users are those who self-reported to have abstained from illicit drug use. Respondents for this study were mainly recruited from a rural district in the northern state of Penang in Peninsular Malaysia where kratom use was reported to be prevalent among illicit drug users (Vicknasingam et al., 2010; Singh et al., 2019a).
2.2 Study inclusion and exclusion criteria The study inclusion criteria were; 1) 18 years and above, 2) must have opioid poly-drug use history, and 3) have used kratom regularly (at least once daily) in the last 12 months. Those who met these criteria but reported significant psychological problems or who were unwilling to give written-informed consent were excluded. 2.3 Data collection The study data were collected between March 2018 and June 2018. Prior to the data collection process, we approached key-informants (e.g. former and active drug users with opioid and ATS use history) who were willing to voluntarily participate in the study. Key-informants were briefed on the study objectives and asked to refer potential respondents to the study. Eligible respondents were assured participation anonymity and data confidentiality. All the study data were collected using a semi-structured questionnaire canvassed through face-to-face interviews by a trained research assistant. The information collected included the respondents’: 1) socio-demographic characteristics such as gender, ethnicity, current age, marital status, education and employment status; 2) kratom use history including duration, frequency and quantity of daily kratom use, and 3) reasons for kratom use. All the interviews were conducted in the local Malay dialect. Each interview session lasted for about 15 to 20 minutes. 2.4 Ethics This study has been approved by the Human Ethics and Research Committee of University Sains Malaysia. As a token of appreciation, respondents were compensated with RM50 for their participation. All gave their written-informed consent.
2.5 UPLC-MS/MS analysis of kratom street sample All the respondents in this study reported consuming a brewed kratom decoction. Processed kratom decoctions can be readily bought from illegal kratom traders by regular customers in the community. Each packet (consisting approximately 300 mL of kratom juice) is usually sold for about RM5 (equivalent to USD=1.26). In order to estimate the intake of kratom alkaloids among the respondents, a packet of processed kratom decoction was purchased from a kratom trader in the study area from whom the majority of respondents usually get their kratom supply. The acquired kratom sample (300 mL) was lyophilized to remove water content, weighed and kept at -20°C prior to UPLC-MS/MS analysis (Singh et al., 2019b). 2.5.1 Chemicals and reagents The
reference
alkaloids:
mitragynine,
paynantheine,
speciogynine,
speciociliatine, corynoxine, corynoxine B, mitraphylline, corynantheidine and isocorynanthiedine (purity ≥ 98%) were extracted and purified from kratom leaves according to method described by Sharma et al. (2019). Minor alkaloid, 7hydroxymitragynine (purity ≥ 98%) was synthesized in house according to the method described by Ponglux et al. (1994). The chemical structure of the reference alkaloids was confirmed using 1H &
13
C NMR, and UPLC-QTOF-MS, and the
spectroscopic data was compared with those reported in previous studies (Sharma et al., 2019; Ponglux et al., 1994). Solvents (hexane, ethyl acetate, chloroform & methanol) for alkaloid extraction and purification were of analytical grade (Merck,
Germany). LC grade water, acetic acid, ammonium acetate, methanol and acetonitrile were purchased from Fisher Scientific (Fair Lawn, NJ, USA).
2.5.2 UPLC-MS/MS quantification of major alkaloids in lyophilized kratom street sample Method reported by Sharma et al. (2019) was applied for the quantitative analysis of lyophilized kratom street sample. In brief, Waters Acquity Class I UPLC coupled with a Xevo TQ-S Micro triple quadruple mass spectrometer (Milford, MA, USA) was used for the simultaneous quantification of kratom alkaloids. Chromatographic separation of kratom alkaloids was achieved on a Waters Acquity BEH C18 column (1.7 µm, 2.1 × 100 mm) using a gradient elution. Mobile phase consisted of acetonitrile and ammonium acetate buffer (pH 3.5, 10 mM) with a flow rate of 0.35 mL/min. Multiple reaction monitoring (MRM) with electrospray ionization (ESI) on positive mode (capillary voltage, 500 V) was implemented on the precursor ion → product ion transitions m/z 369.16 > 144.12, 385.19 > 132.09, 385.19 > 132.09, 415.19 > 190.09, 369.16 > 144.12, 399.25 > 174.16, 369.22 > 160.12, 397.16 > 174.10, 399.25 > 174.16, 399.25 > 174.16 and 180.12 > 110.03 for corynantheidine,
corynoxine,
corynoxine
isocorynantheidine,
mitragynine,
mitraphylline,
B,
7-hydroxymitragynine,
paynantheine,
speciociliatine,
speciogynine and phenacetin (internal standard), respectively. Acquisition and analysis of data from UPLC-MS/MS system was performed using MassLynx software version 4.1. 2.6 Data analysis The study data were analysed with the Statistical Package for Social Sciences (SPSS) software version 25. First, descriptive statistics were used to describe the
socio-demographic characteristics, kratom use history and the reasons for kratom use. Next, Chi-square analysis was utilised to determine if significant differences existed in the demographic characteristics, kratom use history and reasons for kratom use, between current and former opioid poly-drug users. The utility calculator available at www.Vassarstats.com was used to compute Odds Ratio (OR) and the associated 95% Confidence Intervals (CI). The statistical significance for analyses was set at p<0.05. 3. Results 3.1 Socio-demographic characteristics of current and past opioid poly-drug users The socio-demographic characteristics of both groups are shown in Table 1. Almost all respondents were males and Malays in both groups. The distribution by age, marital status and education was also similar. More than half of the respondents in both groups were between 18 to 35 years-old (53%, n=108/204), and the mean age of the sample as a whole was 35.6 years (SD=10.5). A slightly larger proportion of former users are employed (94%) as opposed to current users (89%) but the difference was not statistically significant. More than 80% of respondents in both groups are living with their family. The only significant difference between the two groups is with respect to marital status and drug use history. Current users were more likely to be single (OR: 2.2: 1.21-4.11; p<0.009), and to have had a previous drug rehabilitation history (OR: 2.1: 1.17-3.94; p<0.013), as compared to former opioid poly-drug users. INSERT TABLE 1 SOMEWHERE HERE. 3.2 Kratom use history of current opioid users
Table 2 summarises the kratom use history of current users. The respondents mean age of first kratom use in this sample was 26.7 years (SD=10.4), while their mean age of first illicit drug use was 20.4 years (SD=6.4). Fifty-two percent (n=106/204) have ≤6 years kratom use history, while 48% have used kratom for more than six years. The mean duration of kratom use was 93.7 months (SD=78.6). The majority (56%, n=114/204) used between 1 to 2 glasses of kratom daily. On average, current users consumed 2.7 glasses (SD=1.8) of kratom daily. INSERT TABLE 3 SOMEWHERE HERE. 3.3 A comparison of the kratom use history of current and former users The kratom use history of current and past opioid poly-drug users was surprisingly similar. Results from the Chi-square analyses confirmed this (Table 3). There were no significant differences in the duration (OR: 1.1: 0.62-2.03; p<0.708), quantity (OR: 1.5: 0.85-2.82; p<0.154) or frequency (OR: 1.1: 0.62-2.06; p<0.680) of daily kratom use between the two groups. INSERT TABLE 4 SOMEWHERE HERE. 3.4 Reasons for using kratom: current and former users Table 4 indicates the reasons for using kratom as reported by current and former opioid poly-drug users. The majority in both groups relied on kratom to selftreat substance use disorder (SUD). Other reasons common to both groups included using kratom to enhance energy, reduce methamphetamine use, treat psychological problems, and improve sexual performance. However, the significant difference in kratom use between the two groups was with respect to reducing opiate withdrawal symptoms and inducing euphoria. Chi-
square analysis confirmed that current users have significantly higher odds of using kratom for reducing the effects of opioid withdrawal (OR: 5.4: 2.81-10.18; p<0.0001), than former users. In contrast, former opioid users have higher odds of using kratom to induce euphoria (mood elevating effects) (OR: 1.9: 1.04-3.50; p<0.035).
3.5
UPLC-MS/MS analysis of major alkaloids in an acquired kratom street sample A total of 300 mL (one packet which is equivalent to one glass) of kratom
street sample was lyophilized to yield 1.5 g of powdered extract. A validated analytical method as described in our previous study (Sharma et al., 2019) was used for the quantitative analysis of kratom alkaloids in lyophilized extract. Test sample was analyzed along with the freshly prepared calibration and quality control standards. The analytical results showed that mitragynine (3.80%, w/w) was the predominant alkaloid found in lyophilized kratom extract. Other mitragynine’s isomers – paynanthiene (0.39%, w/w), speciogynine (0.26%, w/w) and speciociliatine (0.29%, w/w) appeared as minor alkaloids. Other analysed kratom alkaloidscorynantheidine, corynoxine, corynoxine B, isocorynantheidine, mitraphylline and 7hydroxymitragynine (most potent but addictive opioid agonist) were below lower limit of quantification (< 1 ng/mL or 0.01 %, w/w). A total of 300 mL of the kratom decoction (1.5 g of lyophilized extract) was equivalent to the intake of 56.73 mg of mitragynine, 5.82 mg of paynanthiene, 4.33 mg of speciociliatine and 3.88 mg of speciogynine. Multiple reaction monitoring (MRM) chromatograms of mitragynine (13.75 min), paynanthiene (13.41 min), speciociliatine (18.03 min), speciogynine (15.46 min) and 7-hydroxymitragynine (4.80 min) are shown in Figure 1.
INSERT FIGURE 1 SOMEWHERE HERE.
4. Discussion This study described patterns and reasons for kratom use among current and former opioid poly-drug users in Malaysia. We found current opioid poly-drug users have significantly higher odds of using kratom for reducing opioid withdrawal symptoms while past opioid poly-drug users have higher odds of using kratom to induce euphoria. There was also no statistically significant difference in the quantity, or frequency of use between the two groups. The laboratory findings based on a typical street sample of kratom tea (brew) consumed suggests that approximately 170mg of mitragynine is ingested per day (or the equivalent of 3 glasses), as the therapeutic dose for managing the opioid polydrug use problems (by current opioid users) and to experience euphoria in order to abstain from opioid use (by former users). Despite the lack of clinical studies to support kratom’s efficacy as a novel alternative to opioid treatment (Henningfield et al., 2018), data from survey findings indicate that kratom is generally used in Southeast Asia and US for managing pain and opioid withdrawal (Saref et al., 2019; Prozialeck et al., 2019; Coe et al., 2019). Our findings are consistent with the claims in these studies.
The implications of these findings are important. The fact that current opioid poly-drug users are relying on kratom to mitigate opioid withdrawal symptoms suggests that it has the potential to replace methadone which is currently being used for a similar purpose. However, methadone maintenance therapy has several disadvantages with respect to opioid users in more rural settings. There is a monetary cost involved in travelling to government established methadone therapy centres to benefit from the service. Second, there is also stigma attached to being seen at these centres. Third, not all rural opioid users are aware of the availability of methadone maintenance therapy. Fourth, there is considerable misconception regarding the use of methadone. Finally, being present at these centres is still viewed with fear and suspicion since one can be arrested as opioid use is still an offence. Kratom, on the other hand, is cheap, easily available, avoids stigma as a drug user (Vicknasingam et al., 2010; Saingam et al., 2012; Singh et al., 2014; Singh et al., 2015), and has been a trusted general remedy for generations (Tanguay, 2011; Saingam et al., 2012; Singh et al., 2016). Kratom use, particularly among men, is not viewed with concern in rural communities (Assanangkornchai et al., 2007; Saingam et al., 2012; Ahmad and Aziz, 2012). The finding is consistent with that of a recent study that found kratom initiation was associated with significant decreases in the prevalence and severity of the adverse side-effects associated with opioid us (Saref et al., 2019). The second finding that former opioid poly-drug users continue to use kratom, but primarily for its mood elevating effects to prevent their return to opioid use. This suggests that kratom has the potential to aid out-of-treatment opioid poly-drug users to abstain from illicit drug use. Once again, this is in line with previous studies that show kratom has been used as a harm reduction tool, especially among people
addicted to opioids and other drugs such as cannabis and methamphetamine (Swogger et al., 2015; Swogger and Walsh, 2018). A recent internet survey among kratom users in the US elicited responses indicating that kratom was very helpful in alleviating pain, reducing prescription opioids or heroin use, and relieving withdrawal symptoms (Coe et al., 2019).
While both kratom and opioids are addictive, kratom was found to be less addictive than opioid/heroin, amphetamine and Suboxone (Smith and Lawson, 2018). Furthermore, many field studies have shown that those using kratom, even over long periods, continue to work and function usefully in society as opposed to long-term users of opioids (Singh et al., 2015). Kratom can cause severe dependence (Suwanlert, 1975; Singh et al., 2014), but so does tobacco and alcohol. While not denying its potential for abuse, in our sample we found no significant differences in the kratom use patterns among current and former opioid poly-drug users. Thus, the finding does not indicate that opioid poly-drug users are abusing kratom, since their patterns of use (duration, quantity and frequency) do not differ significantly from the kratom use patterns of former users. Kratom’s main alkaloid mitragynine is reported to be responsible for almost all the adverse kratom related cases (Post et al., 2019; Olsen et al., 2019; Eggleston et al., 2019). However, recently Hemby et al. (2018) and Yue et al. (2018) found mitragynine has limited abuse potential and therefore it can be used to reduce morphine intake. To date, mitragynine’s role in pain alleviation remains questionable. Recently, Kruegel et al. (2019) found mitragynine is being converted to a much more
potent mu-opioid receptor agonist 7-hydroxymitragynine. However, in our laboratory findings, 7-hydroxymitragynine appeared in negligible levels in the processed kratom tea sample. This might suggest that kratom’s therapeutic effects in managing opioid poly-drug may be due to the synergistic effects of other major kratom alkaloids such as mitragynine, paynantheine, speciogynine and speciociliatine. Given its complex pharmacological effect the role of other alkaloids deserves to be further investigated as has been done with the effects of mitragynine. The other interesting finding from the study is that more than two-thirds (73%) of both current and past opioid poly-drug users were relying on, or had relied on, kratom to reduce dependence on methamphetamine. This warrants further research although there are two reasons that can be put forth tentatively. First, since methamphetamine use is associated with psychological problems (Degenhardt et al., 2010), kratom is perhaps being used to overcome the anxiety and depressive symptoms (Idayu et al., 2011; Grundmann, 2017; Singh et al., 2019a). Second, because kratom is reported to have stimulant effects, drug users could be substituting methamphetamine with kratom for its stimulant effects. This is because mitragynine, as well as other unknown alkaloids in kratom leaves are reported to produce opioid and non-opioid like effects (Raffa et al., 2018; Hiranita et al., 2019). Finally, although respondents in this cohort used kratom concurrently with illicit substances, none reported any adverse health incidents. There are some limitations in this study. First, all the respondents were largely recruited from the northern states of Peninsular Malaysia and their responses were based solely on their self-report which could have been exposed to recall and social desirability biases, thus our findings cannot be generalised. Second, we did not
screen the respondents for illicit drug use, though former opioid poly-drug users claimed to have abstained from illicit drug use. Since drug use has been criminalised and individuals testing positive for illicit drugs can face legal problems, respondents were reluctant to participate if it involved drug screening. Finally, although we made attempts to recruit female participants, none of the identified female opioid poly-drug users reported kratom use. Kratom is more common among males as compared to females, as females generally use kratom to treat common ailments (Saingam et al., 2012). In conclusion, we found current opioid poly-drug users commonly use kratom to manage their opioid poly-drug use problem, while former users rely on kratom to help them abstain from using opioids. Acknowledgment We thank Higher Institutions Centre of Excellence (HICoE) for their financial support. The PhD study of Nelson Jeng Yeou Chear was supported by the Institute of Postgraduate Studies, Universiti Sains Malaysia (USM) under USM Fellowship Scheme. We also thank Nur Sabrina Yusof and Muhamad Eshal Dzulkapli for coordinating the field work and sample preparation. Disclosure/Conflict of Interest All the authors declared that there is no conflict of interest. Author contributions Singh, Narayanan and Chear designed the study methodology, analysed the data.
[email protected];
[email protected];
[email protected]:
Singh
and
Narayanan wrote the original draft; [email protected]; [email protected]: Singh, Narayanan, McCurdy and Balasingam reviewed and edited the manuscript.
[email protected]; [email protected]; [email protected]; [email protected]: Chear,
Leon,
Sharma
[email protected];
and
Avery
performed
[email protected];
the
kratom
juice
analysis.
[email protected];
[email protected].
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Kruegel, A.C., Uprety, R., Grinnell, S.G., Langreck, C., Pekarskaya, E.A., Rouzic, V.L., Ansonoff, M., Gassaway, M.M., Pintar, J.E., Pasternak, G.W., Javitch, J.A., Majumdar, S., & Sames, D. (2019). 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of its Analgesic Effects. ACS, Cent. Sci, 5, 992-1001. Kruegel, A. C., Gassaway, M. M., Kapoor, A., Váradi, A., Majumdar, S., Filizola, M., Javitch, J. A., & Sames, D. (2016). Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. Journal of the American Chemical Society, 138(21): 6754-6. Lydecker, A. G., Sharma, A., McCurdy, C. R., Avery, B. A., Babu, K. M., Boyer, E. W. (2016). Suspected Adulteration of Commercial Kratom Products with 7Hydroxymitragynine. J. Med. Toxicol, 12(4), 341-349. Matsumoto, K., Horie, S., Ishikawa, H., Takayama, H., Aimi, N., Ponglux, D., & Watanabe, K. (2004). Antinociceptive effect of 7-hydroxymitargynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa. Life Sciences, 74, 2143-2155. Olsen, E.O., O’Donnell, J., Mattson, C.L., Schier, J.G., & Wilson, N. (2019). Notes from the Field. Unintentional Drug Overdose Deaths with Kratom Detected – 27 States, July 2016 – December 2017. MMWR Morb Mortal Wkly Rep, Vol. 68, No14. 326-327. Post, S., Spiller, H. A., Chounthirath, T., Smith, G. A. (2019). Kratom exposure reported to United States poison control centers: 2011-2017. Clin. Toxicol. DOI: 10.1080/15563650.2019.1569236. Prozialeck, W. C., Avery, B. A., Boyer, E. W., Grundmann, O., Henningfield, J. E., Kruegel, A. C.,… Singh, D. (2019). Kratom policy: The challenge of balancing therapeutic potential with public with public safety. Int. J. Drug Policy, 70.
Raffa, R. B., Pergolizzi Jr, J. V., Taylor, Jr. R., Ossipov, M. H., NEMA Research Group. (2018). Natur’s first “atypical opioid”: Kratom and mitragynines. J Clin Pharm Ther, 43: 437-441. Saref, A., Suraya, S., Singh, D., Grundmann, O., Narayanan, S., Swogger, M. T., Prozialeck, W. C., Boyer, E., Chear, N. J. Y., Balasingam, V. 2019. Selfreported prevalence and severity of opioid and kratom (Mitragyna speciosa Korth.) side effects. Journal of Ethnopharmacology, 238. Saingam, D., Assanangkornchai, S., Geater, A.F., Balthip, K. (2012). Pattern and consequences of krathom (Mitragyna speciosa Korth.) use among male villagers in southern Thailand: a qualitative study. Int. J. Drug Policy, 24 (4), 351-358. Schmidt, M.M., Sharma, A., Schifano, F., & Feinmann, C. (2011). “Legal highs” on the net – Evaluation of UK-based Websites, products and product information. Forensic Science International, 206, 92-97. Singh, D., C. P. Muller, & B. Vicknasingam. (2014). Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users. Drug Alcohol Depend, 139:132-137. Singh, D., Muller, C.P., Vicknasingam, B., & Mansor, S.M. (2015). Social functioning of kratom (Mitragyna speciosa) users in Malaysia. J Psychoactive Drugs, 47: 125-131. Singh, D., Narayanan, S., & Vicknasingam, B. (2016). Traditional and non-traditional uses of Mitragyna (Kratom): A survey of the literature. Brain Res. Bull, 126(1), 41-46. Smith, K.E., & Lawson, T. (2017). Prevalence and motivations of kratom use in a sample of substance users enrolled in a residential treatment program. Drug Alcohol Depend,180, 340-348. Suwanlert, S. (1975). A study of kratom eaters in Thailand. Bull. Narcot, 27 (3), 2127. Swogger, M. T., & Walsh, Z. (2018). Kratom use and mental health: A systematic review. Drug Alcohol Depend, 183, 134-140. Swogger, M.T., Hart, E., Erowid, F., Erowid, E., Trabold, N., Yee, K., Parkhurst, K.A., Priddy, B. M., & Walsh, Z. (2015). Experiences of Kratom Users: A Qualitative Analysis. Journal of Psychoactive Drugs, 47 (5), 360-367. Takayama, H. (2004). Chemistry and Pharmacology of Analgesic Indole Alkaloids from the Rubiaceous Plant, Mitragyna speciosa. Chem, Pharm. Bull, 52, 916928. Tanguay, P. (2011). Kratom in Thailand: Decriminalisation and community control? Series on legislative reform of drug policies, vol. 13, International Drug Policy Consortium (IDPC).
Vicknasingam, B., Narayanan, S., Goh, T.B., & Mansor, S.M. (2010). The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. Int. J. Drug Policy, 21 (4), 283-288. Yue, K., Kopajtic, T. A., Katz, J. l. (2018). Abuse liability of mitragynine assessed with a self-administration procedure in rats. Psychopharmacology. https://doi.org/10.1007/s00213-018-4974-9.
Table 1: Differences in the demographic characteristics between current and former opioid poly-drug users.
n=
%
Gender Male 203 99 Female 1 1 Ethnicity Malay 191 94 Non-Malay 13 6 Mean age Age 18-35 years 108 53 >36 years 96 47 Marriage Single 129 63 Married 75 37 Education 9 years 91 45 11 years 113 55 Employment Employed 185 91 Unemployed 19 9 Accommodation Family 179 88 Renting/friends 25 12 Drug rehabilitation history Yes 109 53 No 95 47 *Denotes P-value at <0.05.
Current Users (n=142) n= %
Former Users (n=62) n= %
142 100 0 0
61 1
99 1
OR:95%CI
P-Value
-
0.304
134 94 57 92 1.5: 0.46-4.68 8 6 5 8 35.6 years (SD=10.5)
0.539
74 68
52 48
34 28
55 45
1.1: 0.61-2.03
0.718
98 44
69 31
31 31
50 50
2.2: 1.21-4.11
0.009*
69 73
49 51
22 40
35 65
1.7: 0.93-3.18
0.083
127 89 15 11
58 4
94 6
1.7: 0.54-5.39
0.354
126 89 16 11
53 9
86 14
1.3: 0.56-3.22
0.517
84 58
25 37
40 60
2.1: 1.17-3.94
0.013*
59 41
Table 2: Current kratom use history. n= % 26.7 years (SD=10.4) 20.4 years (SD=6.4) 93.7 months (SD=78.6) 2.7 glasses (SD=1.8)
Mean age of first kratom use Mean age of first illicit drug use Mean duration of kratom use Mean quantity of daily kratom use Kratom use duration ≤6 years >6 years Daily quantity of kratom use 1-2 glasses >3 glasses Daily frequency of kratom use 1-2 times >3 times
106 52 98 48 114 56 90 44 113 55 91 45
Table 3: Kratom use history between current and former opioid poly-drug users.
Kratom use duration ≤6 years >6 years Daily quantity of kratom use 1-2 glasses >3 glasses Daily frequency of kratom use 1-2 times >3 times
Current Users (n=142) n= %
Former Users (n=62) n= %
75 67
53 47
31 31
84 58
59 41
80 62
56 44
OR:95%CI
P-Value
50 50
1.1: 0.62-2.03
0.708
30 32
48 52
1.5: 0.85-2.82
0.154
33 29
53 47
1.1: 0.62-2.06
0.680
Table 4: Kratom use reasons between current and former opioid poly-drug users.
n=
%
Treat SUD Yes 180 88 No 24 12 Ameliorate opiate withdrawal Yes 128 63 No 76 37 Treat psychological problems Yes 102 50 No 102 50 Euphoric Yes 99 48 No 105 52 Enhance energy Yes 171 84 No 33 16 Improve sexual performance Yes 98 48 No 106 52 Reduce methamphetamine use Yes 149 73 No 55 27 *Denotes P-value at <0.05.
Current Users (n=142) n= %
Former Users (n=62) n= %
125 88 17 12
55 7
106 75 36 25
71 71 62 80
OR:95%CI
PValue
89 11
1.1: 0.42-2.72
0.887
22 40
35 65
5.4: 2.81-10.18
<.0001*
50 50
31 31
50 50
1: 0.55-1.82
0.560
44 56
37 25
60 40
1.9: 1.04-3.50
0.035*
116 82 26 18
55 7
89 11
1.8: 0.72-4.31
0.210
64 78
45 55
34 28
55 45
1.5: 0.81-2.69
0.199
101 71 41 29
48 14
77 23
1.4: 0-69-2.79
0.351
A
B
C
D
E
Figure 1: MRM chromatograms of kratom street sample and the detected alkaloids mitragynine (A), paynantheine (B), speciociliatine (C), speciogynine (D) and 7hydroxymitragynine (E).