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Journal of Psychoactive Drugs

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Factor Analytical Investigation of Krathom(Mitragyna speciosa Korth.) Withdrawal Syndromein Thailand

Darika Saingam Ph.D., Sawitri Assanangkornchai M.D., Ph.D., Alan F. GeaterPh.D. & Sanguan Lerkiatbundit Ph.D.

To cite this article: Darika Saingam Ph.D., Sawitri Assanangkornchai M.D., Ph.D., Alan F.Geater Ph.D. & Sanguan Lerkiatbundit Ph.D. (2016): Factor Analytical Investigation of Krathom(Mitragyna speciosa Korth.) Withdrawal Syndrome in Thailand, Journal of Psychoactive Drugs,DOI: 10.1080/02791072.2016.1156791

To link to this article: http://dx.doi.org/10.1080/02791072.2016.1156791

Published online: 25 Mar 2016.

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Factor Analytical Investigation of Krathom (Mitragyna speciosa Korth.)Withdrawal Syndrome in ThailandDarika Saingam, Ph.D.a, Sawitri Assanangkornchai, M.D., Ph.D.b, Alan F. Geater, Ph.D.c,and Sanguan Lerkiatbundit, Ph.D.d

aResearcher, Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand; bAssociate Professor,Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand; cSenior Lecturer, Epidemiology Unit,Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand; dAssociate Professor, Department of Pharmacy Administration,Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, Thailand

ABSTRACTKrathom (Mitragyna speciosa Korth.) is an addictive and illicit substance used in Thailand andother Southeast Asian countries. It has become the most commonly used substance amongvillagers. The study aimed to explore the factor structure of the krathom withdrawal syndromebased on the findings of an earlier qualitative study. The current study was divided into twostages. Cross-sectional data collections were employed in both phases. The samples comprised,respectively, 196 and 330 krathom users aged over 25 years. The characteristics of krathomwithdrawal symptoms and signs were identified and the factor structure examined using explora-tory factor analysis (EFA). Confirmatory Factor Analysis (CFA) was used to examine the constructvalidity and multivariate linear regression was used to identify factors predicting the intensity ofkrathom withdrawal symptoms. The final scale comprised 20 items with four factors: craving-fatigue syndrome; musculoskeletal system and insomnia; mood symptoms; and autonomic ner-vous system/physical sickness. Symptoms and signs of krathom withdrawal similar to those of thewithdrawal syndrome of opioid substances appear to be present in regular krathom users. Thekrathom withdrawal intensity is predicted by duration of krathom use, frequency, and dailyamount of krathom use.

ARTICLE HISTORYReceived 29 October 2015Revised 30 January 2016Accepted 1 February 2016

KEYWORDSKrathom; Mitragyna speciosakorth; withdrawal syndrome

Krathom (Mitragyna speciosa Korth.) has been used bynative villagers in Thailand and other Southeast Asiancountries for more than 100 years. In recent years,krathom use has become a global public health concernbecause of its use as a legal high in some countries.Global and local spread of krathom use has been attrib-uted to online advertisements and social networks, andeasy transportation from the cultivation areas (Schmidtet al. 2011). Reports of krathom dependence, toxicity,seizure and coma, and use as a self-treatment for opioidwithdrawal have increasingly appeared in the interna-tional literature (Boyer et al. 2008; Holler et al. 2011;McWhirter and Morris 2010; Neerman, Frost, andDeking 2013; Nelsen, Lapoint et al. 2010;Vicknasingam et al. 2010). A recent comprehensivereview (Hassan et al. 2013) found that krathom andM. speciosa preparations are consumed with specificgoals, which are to enhance tolerance for hard work oras a substitute in the self-treatment of opiate addiction.In Thailand, it is taken by chewing the leaves of theindigenous krathom tree. Our ongoing study found

that the amount of mitragynine in krathom leaf is125 mg per 100 g of krathom fresh leaves, dependingon the sources of the leaves (Chittrakarn et al. 2016). Inthe past, krathom use was predominantly practisedamong men, and restricted to those engaging in hardlabor, such as agriculturalists and unskilled laborers,because of the belief of its effect on endurance(Chittrakarn et al. 2005; Chuchuen et al. 2005). Theculture of traditional krathom use was evident in sev-eral ways, such as its use as a recreational drug in asocial gathering, as a traditional medicine, a snack towelcome guests, and a precious gift to worship godsand ancestors. Today, in Thailand, the use of a mixtureproduced from the broth of boiled krathom leaves withcola drinks and other substances, such as benzodiaze-pine and cough syrup, is very popular among adoles-cents and young adults (Saingam et al. 2013).

In the most recent National Household Survey ofSubstance Use in 2011, krathom was the most prevalentsubstance used by the Thai population. The estimatedrates of past-year and past-30-day krathom use were

CONTACT Sawitri Assanangkornchai savitree.a@psu.ac.th Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, 15 KanchanavanichRoad, Hat Yai, Songkhla 90110, Thailand.

JOURNAL OF PSYCHOACTIVE DRUGS2016, VOL. 00, NO. 00, 1–10http://dx.doi.org/10.1080/02791072.2016.1156791

© 2016 Taylor & Francis Group, LLC

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8.37 and 5.98 per 1000 people, respectively. The highestprevalence of krathom use was reported in the southernregion, with 8.6% of the adult population in the south(approximately 6,506,000) being krathom lifetime users(having used at least once) (Administrative Committeeof Substance Abuse Academic Network 2011).

The krathom leaf contains mitragynine as the prin-cipal alkaloid, which has an opioid-like activity andproduces an antinociceptive effect through an actionon the supraspinal opioid receptors and descendingnoradrenergic and serotonergic systems and a suppres-sive action on the mechanical and thermal stimuli-induced nociceptive responses (Hassan et al. 2013;Matsumoto et al. 1997; Thongpradichote et al. 1998;Tsuchiya et al. 2002). Another major alkaloid ofkrathom, 7-hydroxymitragynine, also has an antinoci-ceptive effect, which is greater than that of morphinewhen administered orally because of its being well-absorbed (Matsumoto et al. 2004). Mitragynine alsoagonizes opioid receptors in gastric secretion in invitro assays of the guinea-pig ileum and the mousevas deferens (Beckett et al. 1966; Watanabe et al.1997; Yamamoto et al. 1999). A high concentration ofmitragynine could lead to the development of toleranceand dependence, as the response to mitragynine hasbeen shown to be similar to that to chronic exposure toopioids (up-regulation of the cAMP pathway anddown-regulation of mu-opioid receptor mRNA expres-sion), which is related to tolerance and dependence(Jamil et al. 2013). In humans, regular consumptionmay escalate, lead to tolerance, and yield aversive with-drawal effects (Hassan et al. 2013).

Characteristic krathom dependence symptoms havebeen reported (Ahmad and Aziz 2012;Assanangkornchai 2005; Assanangkornchai et al. 2007;Saingam et al. 2013, 2014; Suwanlert 1975), such ashaving to chew krathom every day, wanting to quitbut failing to do so, tolerance (taking an increasingnumber of leaves per day), craving, and krathom takingover one’s life (e.g., not wanting to go anywhere with-out krathom and thinking of krathom all the time).Withdrawal symptoms reported by regular krathomusers upon ceasing use include muscle, bone, andjoint pains; anxiety; dysphoric mood; annoyance; rest-lessness; irritability; craving for krathom; fatigue; lazi-ness; sleepiness; yawning; watering eyes; runny nose;and sticky mouth (Ahmad and Aziz 2012;Assanangkornchai 2005; Assanangkornchai et al. 2007;McWhirter and Morris 2010; Saingam et al. 2013;Singh, Muller, and Vicknasingam 2014; Suwanlert1975; Vicknasingam et al. 2010).

Because krathom is an illegal substance, strict lawenforcement has been carried out, including fines or

incarceration of those possessing krathom and cuttingdown of krathom trees. Users are forced to stop usingit. However, the withdrawal symptoms are tremen-dously distressing and contribute to the failure of con-tinuous abstinence even with supportive treatment,whereas resumption of krathom use can alleviate thesymptoms.

Management of krathom withdrawal is one of thekey components of effective interventions to preventrelapse. The lack of research-based evidence for akrathom withdrawal syndrome is a knowledge gapthat needs to be bridged in order to develop methodsto measure the severity of the symptoms to guideclinical interventions and improve the likelihood ofcontinued abstinence.

This study was initiated to explore the factor struc-ture of the krathom withdrawal syndrome. The studyinvolved two stages: first, to examine the factor struc-ture of withdrawal symptoms using exploratory factoranalysis (EFA); and second, to examine the constructvalidity using confirmatory factor analysis (CFA) andto measure the intensity of krathom withdrawalsymptoms.

Methods

Study settings and samples

The study was conducted in rural villages in NakhonSri Thammarat province, southern Thailand, wherekrathom has been widely used in a traditional way(by chewing the krathom leaf) by villagers for morethan 100 years. Details of study settings and samplehave been reported elsewhere (Saingam et al. 2013,2014). In brief, a sample of men (women do notgenerally use krathom) aged over 25 years was ran-domly selected from the household registry of eachvillage for each stage of the study. To explorekrathom withdrawal symptoms, only current krathomusers were used, including 196 (114 regular users and82 occasional users) for EFA (stage 1) and 330 (241regular users and 89 occasional users) for CFA (stage2), with a total of 526 participants. Individuals withmajor psychiatric or physical illness, cognitiveimpairment, or impaired sensorium and those whoreported themselves co-using krathom with otherpsychoactive substances were excluded from thestudy.

A regular user was defined as an individual who hadbeen using krathom three or more days per week for aperiod of at least three months. An occasional userreferred to an individual who used krathom less thanthree days per week or one who used it at certain times

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for a specific purpose (e.g., for a medicinal purpose orin social situations).

It is suggested that the sample size needed for theEFA is 5–10 times the number of questionnaire items(Everitt 1975). Initially, 32 items of krathom withdra-wal symptoms and signs were identified so the samplesize of 196 users was considered adequate. For CFA,large samples are required to attain acceptable precisionand to prevent possible technical problems, such asiteration failure, which can occur in computer analyses.An ideal sample size to parameter ratio was suggestedto be 10–20:1 (Kline 2011; Schreiber et al. 2006). Thus,our sample of 330 users in stage 2 was deemed ade-quate for the CFA.

Materials and procedure

To identify an initial list of krathom withdrawal symp-toms and signs, we reviewed the literature related topsychoactive substance withdrawal, including cannabis,nicotine, opioid, and alcohol withdrawal (Allsop et al.2011; Elholm et al. 2010; Handelsman et al. 1987;Welsch et al. 1999). In-depth interviews were per-formed with 34 krathom users and non-users to elicitinformation regarding symptoms and signs thatoccurred upon ceasing to use or reducing the dose ofkrathom (Saingam et al. 2013). Information from theliterature and in-depth interviews were integrated toderive an initial list of 31 items of krathom withdrawalsymptoms and signs. The first drafted list of krathomwithdrawal symptoms and signs was tested on a con-venience sample of 20 krathom users and non-users (10regular, six occasional users, and four who never usedkrathom).

The list was then modified, resulting in a question-naire of 32 items. Respondents were asked to think ofthe periods when they stopped using krathom and ratethe severity of withdrawal symptoms on a Likert scaleof 0–3: not at all, a little, moderately, and extremely,and the time period after the last use that the symptomoccurred. This questionnaire, which took20–30 minutes to complete, was administered to all196 krathom users (114 regular and 82 occasionalusers) in the EFA stage.

Next, the refined list of symptoms and signs fromthe previous stage was reviewed by three experts, whowere international and Thai researchers and clinicianswith experience in working with psychoactive sub-stance users, for content and face validity, and toreceive feedback on comprehensibility and language.Item selection and refinement was done again after areview by the experts. The list was pilot tested with anew convenience sample of 20 krathom users. The

results showed that respondents required approxi-mately 10 minutes to complete the withdrawal ques-tions. Ambiguous, overlapping, and difficult items weremodified or removed, leaving 23 items. These itemswere used for data collection among 330 users (241regular and 89 occasional users) in a self-administra-tion manner.

Ethics

Institutional ethical approval was obtained from theFaculty of Medicine, Prince of Songkla University.Village health volunteers helped the researcher toaccess the respondents at their home or work place(e.g., rubber or palm plantation, rice field, or orch-ard), where the interview was done in privacy by theresearcher (DS). When an individual met eligibilitycriteria, he was informed of the purpose of the studyand assured of the confidentiality and anonymity ofthe data. Verbal consent was obtained before theinterview and written consent given during or afterthe interview. This is an acceptable practice inThailand, where villagers were reluctant to sign adocument before they were sure of the informationthey were giving. Each respondent was given a smallgift (a handkerchief or a small can of balm) uponcompletion of the interview.

Data analysis

Descriptive analyses and EFA were performed usingR-Epicalc, R-psych, and R-nFactors packages(Chongsuvivatwong 2008; Kabacoff 2012). Based onthe descriptive analysis of the krathom withdrawalsymptoms and signs previously reported (Saingamet al. 2013), the psychometric properties of the con-struct of the krathom withdrawal syndrome wereexamined. EFA using maximum likelihood withoblique rotation was performed to explore thedimensionality of krathom withdrawal syndrome.This method was selected because the data wererelatively normally distributed and the methodallows for the computation of a wide range ofindices of goodness-of-fit of the model and permitssignificance testing of factor loadings, correlationsamong factors, and the computation of confidenceintervals for these parameters (Fabrigar et al. 1999).The number of factors retained was based on eigen-values greater than 1 and also on heuristic andpractical grounds (Kaiser 1974). Internal consistencywas calculated using Cronbachs’ alpha.

CFA was conducted to determine whether or notdata were consistent with the model suggested by the

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EFA, using LISREL version 8.80 (Joreskog and Sorbom1993). Maximum likelihood and goodness-of-fit testsfor the specified model were performed. The CFA wasrun twice, first with 330 users and second among thesubset of 241 regular users.

Finally, to test which factors predicted krathomwithdrawal intensity, the sum score of the final listwas used as the dependent variable, with indepen-dent variables being socio-demographics andamount, frequency, and duration of krathom usein a multivariate linear regression analysis.

Results

Sample characteristics

All respondents (526) were Buddhist, with a mean age of51.8 years.Mostwere agriculturists (52.5) or skilledworkers(27.8%) and had completed primary school education(70.3%). The regular users had been using krathom for anaverage of 21.5 years (SD = 15.1), whereas occasional usershad used it for 13.5 years (SD = 12.4). The average amountused by regular users was two leaves per time and 17 leavesper day, and by occasional users was one leaf per time andthree leaves per day. Frequency of krathom use per day was12.2 times by regular and 2.6 times by occasional users.

Factor structure of krathom withdrawal syndrome

The EFA of the initial 32 withdrawal symptoms andsigns was carried out on 114 regular users and 82occasional users. Four factors with eigenvalues of 4.3,4.3, 3.4, and 2.6, accounting for 46% of the total var-iance (14%, 13%, 11%, and 8%, respectively), wereobtained.

After collapsing items with similar meaning, 23items were obtained. The internal consistency of theitems within the same factor was high (i.e., 0.94, 0.95,0.95, and 0.84 for factors 1–4, respectively) and theCronbach’s alpha coefficient of the overall scalewas 0.97.

The final structure of the krathom withdrawal syn-drome included six items mostly related to craving-fatigue syndrome (factor one), seven items mostlyrelated to mood symptoms (factor two), five itemsrelated to musculoskeletal system and insomnia (factorthree), and five items related to physical sickness (factorfour; see Table 1).

Construct validity of krathom withdrawalsyndrome

The four-factor model obtained from the previous ana-lysis was submitted to confirmatory factor analysis using

the sample of 330 users. Seven out of 23 items weredeleted because the value of kurtosis was more than 10and skewness more than 3 (Schreiber et al. 2006).

As suggested by Joreskog and Sorbom (1993), a tool toincrease the goodness of fit of the model is to look at themodification index, which is an estimate or prediction ofthe decrease in chi-square that would be obtained if thatparticular path is introduced into the model.

Based on the modification indices and theoreticalgrounds, some items were moved from their currentgroup to a new group which was considered morecongruent in terms of symptom characteristics.

The resulting model for the krathom withdrawalsyndrome provided a good fit to the data. Althoughthe model chi-square indicated a significantly poorfit (chi-square = 374.74, df = 98, p < 0.001), theother principal goodness-of-fit indices indicated thatthe model was acceptable (RMSEA = 0.092 (90%CI = 0.08–0.10), NNFI = 0.98, CFI = 0.98,SRMR = 0.04) and fitted the data well. Factor load-ings of all items were in the 0.70–0.98 range withcompletely standardized solution.

To confirm the structure of withdrawal syndrome, theCFA was re-run using only the sample of 241 regularkrathom users. Three out of 23 items were deleted becauseof the value of kurtosis and skewness.

This four-factor model with 20 items yielded thefollowing results: chi-square = 570.71, df = 164,p < 0.001, RMSEA = 0.10 (90% CI = 0.09–0.11),CFI = 0.98, SRMR = 0.06, NNFI = 0.97. However, thechi-square indicated a significantly poor fit of themodel; despite the small sample size, the chi-squarewas significant, suggesting some inadequacy in the fitof the model. Nevertheless, the other goodness-of-fitindices mostly met the requirement for a robustmodel. Thus, the 20 items provided a precise measureof all four factors and were considered to provide thebest model with the items in each factor representingclearly different symptoms.

Internal consistency measures

The Cronbach’s alpha coefficients of the four factorswere .96 for craving-fatigue syndrome, .98 for muscu-loskeletal system and insomnia, .92 for mood symp-toms, .93 for autonomic nervous system/physicalsickness, and .87 for the overall scale.

Endorsement of withdrawal syndrome items amongregular and occasional users

To examine whether each item of the withdrawal symp-toms and signs could differentiate between regular and

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occasional users, the endorsement rates of the itemswere compared (Table 2). Endorsements of all itemswere significantly higher among regular users thanamong occasional users. While 30–69% of regularusers had each of these symptoms upon ceasing

krathom use, only 10% or less of the occasional usersdid so. For items 17–20, 9–17% of regular users hadexperience and these symptoms often occurred amongregular krathom users, whereas only 0–7% of occa-sional users had such experience. The mean total scores

Table 1. Krathom withdrawal scale: factor structure (based on sample of 196 krathom users in phase I study).

Domain

Item Factor

How often have you had the following symptoms occurringwhen you stopped using krathom? 1 2 3 4

Factor 1Craving-fatigue syndrome 1. I feel tired, exhausted, and have no power to work. .73 .07 .17 .00

2. I feel like something is lacking in my life. .84 .06 .03 .053. I want to chew krathom, I miss krathom so much. .84 .08 .00 .054. I feel increased appetite.a .41 .05 .13 −.215. I yawn a lot, feel sleepy, and am lethargic. .77 .05 .00 .156. My mouth is dry and my saliva is sticky. .67 .10 .04 .16

Factor 2Mood symptoms 7. I feel irritable, bad-tempered, annoyed, moody, and upset. .05 1.01 −.06 −.05

8. I feel stressed and anxious. .08 .59 .00 .339. I feel uncomfortable and restless. .24 .65 .08 .0710. I feel depressed. −.09 .71 .17 .1711. I do not want to do anything. .32 .49 .16 .0212. My eyes are teary and my nose runs. .13 .42 .07 .3513. I feel nauseous and want to vomit.a −.09 .32 .03 .15

Factor 3Musculoskeletal system and insomnia 14. My muscles, joints, or bones ache. .32 .17 .53 .03

15. My hands, feet, and body are shaking. b −.07 .02 .57 .3916. My muscles and nerves are twitching. .19 −.04 .86 −.0217. I feel cramping all over the body. b −.13 .29 .56 .1718. I have insomnia at night. .34 .06 .61 .01

Factor 4Physical sickness 19. I do not feel well. It seems like I am getting a cold, my body is aching and shivering. .16 .10 .05 .77

20. I have diarrhea.a .19 −.02 .05 .3221. I have stomachache.b .20 .04 .10 .2222. I feel increased heart rate.a −.09 .27 .27 .3923. I have loss of appetite and don’t want to eat food. .20 .06 .01 .45

a,b Items removed in confirmatory factor analysis (sample size 330 of occasional and regular krathom users).b Items removed in confirmatory factor analysis (sample size 241 of regular krathom users).

Table 2. Endorsement rates to items of krathom withdrawal symptoms: comparison between regular users and occasional users(based on sample of phase I and II studies, n = 526).

I always experience the following symptoms when I stop using krathomRegular users n = 355

(%)Occasional users n = 171

(%) P-value

Craving fatigue syndrome1. I feel tired, exhausted, and have no power to work. 230 (64.8) 18 (10.5) < .0012. I do not want to do anything. 202 (56.9) 10 (5.8) < .0013. I feel like something is lacking in my life. 233 (65.6) 13 (7.6) < .0014. I want to chew krathom, I miss krathom so much. 245 (69.0) 13 (7.6) < .001Musculoskeletal system and insomnia5. My muscles, joints, or bones ache. 201 (56.6) 16 (9.4) < .0016. My muscles and nerves are twitching. 147 (41.4) 9 (5.3) < .0017. I have insomnia at night. 162 (45.6) 8 (4.7) < .001Mood symptoms8. I feel irritable, bad-tempered, annoyed, moody, and upset. 138 (38.9) 10 (5.8) < .0019. I feel stressed and anxious. 127 (35.8) 5 (2.9) < .00110. I feel uncomfortable and restless. 175 (49.3) 6 (3.5) < .00111. I feel depressed. 168 (47.3) 7 (4.1) < .001Autonomic nervous system/physical sickness12. I do not feel well. It seems like I am getting a cold, my body is aching andshivering.

177 (49.9) 11 (6.4) < .001

13. I yawn a lot, feel sleepy, and am lethargic. 240 (67.6) 15 (8.8) < .00114. My eyes are teary and my nose runs. 143 (40.3) 8 (4.7) < .00115. My mouth is dry and my saliva is sticky. 201 (56.6) 8 (4.7) < .00116. I have loss of appetite and don’t want to eat food. 108 (30.4) 5 (2.9) < .00117. I feel nauseous and want to vomit. 32 (9) 2 (1.2) < .00118. I have diarrhea. 40 (11.3) 0 (0) < .00119. I feel increased appetite. 58 (16.3) 7 (4.1) < .00120. I feel increased heart rate. 61 (17.2) 1 (.6) < .001

Note: P-values are from Chi-squared statistics.

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of withdrawal syndrome among regular and occasionalusers were 19.5 (95% confidence interval (CI) = 17.64–21.37) and 1.6 (95% CI = .72–2.57), respectively, indi-cating significantly higher numbers of symptomsamong regular users.

Onset of withdrawal symptoms after last use

Table 3 shows percentages of regular and occasional userswho reported the first appearance of each withdrawalsymptom after the last dose of krathom in four periods,within an hour, after one hour but less than half a day, afterhalf a day but less than one day, and after one day. Most ofthe symptoms occurred among regular users after the firsthour of last use but within a half day. Some occasionalusers also reported having some symptoms but theyappeared late, mostly after half a day of cessation.

Predictors of krathom withdrawal

Multivariate linear regression modeling revealed thatintensity of symptoms was greater in participants with

increased times per day and number of leaves per timeand longer duration of use, but lower in participants withhigher education. These factors had an influence on with-drawal intensity scores (with theoretical maximum valuesof 48) (Table 4).

Self-management of withdrawal symptoms

As krathom was currently difficult to find and the pricewas very high as a consequence of stricter law enforce-ment, some users had to stop using it. When faced withwithdrawal symptoms, most of them tried to treatthemselves. Only 10 regular users went to see a doctorat a hospital or a private clinic, and six purchased someanalgesic, muscle relaxant, or antispasmodic drugsfrom a pharmacy.

The withdrawal symptoms could last for one monthor up to three years in some people (Saingam et al.2013). Users who had used krathom for less thanfive years and chewed not more than five leaves perday could easily quit. However, most chewers who hadstopped relapsed when they saw their peers chewing

Table 3. Onset of withdrawal symptoms after last krathom use: Comparison between regular user and occasional user (based onsample of phase I and II study, regular users = 355, occasional users = 171).

Withdrawal symptoms

These symptoms appear after the last time taking krathom (%)

<1 hour 1 hour–half day half day–1 day >1 day no symptom

1. I feel tired, exhausted, and have no power to work. Reg. 39 (11.0) 151 (42.5) 33 (9.3) 7 (2.0) 125 (35.2)Occ. 2 (1.2) 7 (4.1) 7 (4.1) 2 (1.2) 153 (89.5)

2. I do not want to do anything. Reg. 38 (10.7) 139 (39.2) 24 (6.8) 1 (0.3) 153 (43.1)Occ. - 3 (1.8) 6 (3.5) 1 (0.6) 161 (94.2)

3. I feel like something is lacking in my life. Reg. 39 (11.0) 153 (43.1) 33 (9.3) 8 (2.3) 122 (34.4)Occ. 3 (1.8) 4 (2.3) 5 (2.9) 1 (0.6) 158 (92.4)

4. I want to chew krathom, I miss krathom so much. Reg. 40 (11.3) 161 (45.4) 35 (9.9) 9 (2.5) 110 (31.0)Occ. - 7 (4.1) 5 (2.9) 1 (0.6) 158 (92.4)

5. My muscles, joints, or bones ache. Reg. 34 (9.6) 136 (38.3) 26 (7.3) 5 (1.4) 154 (43.4)Occ. 1 (0.6) 7 (4.1) 7 (4.1) 1 (0.6) 155 (90.6)

6. My muscles and nerves are twitching. Reg. 7 (2.0) 62 (17.5) 73 (20.6) 5 (1.4) 208 (58.6)Occ. - 2 (1.2) 6 (3.5) 1 (0.6) 162 (94.7)

7. I have insomnia at night. Reg. - 30 (8.5) 124 (34.9) 8 (2.3) 193 (54.4)Occ. - - 7 (4.1) 1 (0.6) 163 (95.3)

8. I feel irritable, bad-tempered, annoyed, moody, and upset. Reg. 28 (7.9) 85 (23.9) 22 (6.2) 3 (0.8) 217 (61.1)Occ. - 4 (2.3) 5 (2.9) 1 (0.6) 161 (94.2)

9. I feel stressed and anxious. Reg. 26 (7.3) 77 (21.7) 23 (6.5) 1 (0.3) 228 (64.2)Occ. - 1 (0.6) 4 (2.3) - 166 (97.1)

10. I feel uncomfortable and restless. Reg. 34 (9.6) 110 (31.0) 27 (7.6) 4 (1.1) 180 (50.7)Occ. - 1 (0.6) 4 (2.3) 1 (0.6) 165 (96.5)

11. I feel depressed. Reg. 32 (9.0) 107 (30.1) 27 (7.6) 2 (0.6) 187 (52.7)Occ. - 2 (1.2) 4 (2.3) 1 (0.6) 164 (95.9)

12. I do not feel well. It seems like I am getting a cold, mybody is aching and shivering.

Reg. 30 (8.5) 119 (33.5) 24 (6.8) 4 (1.1) 178 (50.1)Occ. - 4 (2.3) 6 (3.5) 1 (0.6) 160 (93.6)

13. I yawn a lot, feel sleepy, and am lethargic. Reg. 38 (10.7) 158 (44.5) 37 (10.4) 7 (2.0) 115 (32.4)Occ. 1 (0.6) 7 (4.1) 5 (2.9) 2 (1.2) 156 (91.2)

14. My eyes are teary and my nose runs. Reg. 29 (8.2) 93 (26.2) 18 (5.1) 3 (0.8) 212 (59.7)Occ. 1 (0.6) 2 (1.2) 4 (2.3) 1 (0.6) 163 (95.3)

15. My mouth is dry and my saliva is sticky. Reg. 31 (8.7) 136 (38.3) 30 (8.5) 4 (1.1) 154 (43.4)Occ. - 4 (2.3) 3 (1.8) 1 (0.6) 163 (95.3)

16. I have loss of appetite and don’t want to eat food. Reg. 8 (2.3) 76 (21.4) 19 (5.4) 5 (1.4) 247 (69.6)Occ. - 1 (0.6) 4 (2.3) - 166 (97.1)

17. I feel nauseous and want to vomit. Reg. 4 (1.1) 13 (3.7) 3 (0.8) 12 (3.4) 323 (91.0)Occ. - 2 (1.2) - - 169 (98.8)

18. I have diarrhea. Reg. 1 (0.3) 12 (3.4) 7 (2.0) 20 (5.6) 315 (88.7)Occ. - - - - 171 (100)

19. I feel increased appetite. Reg. - 39 (11.0) 16 (4.5) 3 (0.8) 297 (83.7)Occ. 1 (0.6) 1 (0.6) 2 (1.2) 3 (1.8) 164 (95.9)

20. I feel increased heart rate. Reg. 9 (2.5) 37 (10.4) 12 (3.4) 3 (0.8) 294 (82.8)Occ. - - 1 (0.6) - 170 (99.4)

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krathom. Some users used other substances, such ascoffee, energizing drinks, hand-rolled cigarettes, alco-hol, and herbs, to reduce withdrawal symptoms. Whenkrathom was not available, other herbs that have bittertaste, such as Tinospora crispa, Cassia siamea, andAndrographis paniculata, were chewed instead. Theseherbal plants are as bitter as krathom but have nopsychoactive effect.

Discussion

Our study reveals four factors of 20 items of krathomwithdrawal syndrome, explaining craving-fatigue syn-drome, musculoskeletal system and insomnia, moodsymptoms, and autonomic nervous system/physicalsickness symptoms.

The four dimensions of krathom withdrawal pre-sented in our data are similar to the symptoms ofopioid withdrawal described in the DSM-5 (AmericanPsychiatric Association 2013). The most specific symp-toms of krathom withdrawal are fatigue and malaise,lack of will to do anything, muscle and bone pains,yawning, lacrimation and rhinorrhea, and severe crav-ing. There is some evidence that krathom could be usedas a substitute substance in people with opioid (Boyeret al. 2008; Hassan et al. 2013; Vicknasingam et al.2010), alcohol, or cocaine (Havemann-Reinecke 2011;McWhirter and Morris 2010) dependence. Mitragynineacts through opioid receptors (Thongpradichote et al.1998), but krathom has fewer harmful effects thanopioids with respect to both behavioral impairmentand the effects of prolonged use. However, withdrawalsymptoms are severely distressing and cause impair-ment in social, occupational, and other important func-tions among regular or heavy krathom users.

Craving after stopping using krathom wasreported by a high percentage of regular users(69%), and this is consistent with previous reports(Ahmad and Aziz 2012; Assanangkornchai 2005;Assanangkornchai et al. 2007; Saingam et al. 2013;Suwanlert 1975) that regular users in the first fewdays of cessation are obsessed by the desire for and

urge to use krathom. Because of being fatigued andhaving no power or will to work upon cessation ofuse, and the fact that krathom is usually used topromote functioning and is always available, regularand heavy users do not want to stop using it. Thiswas reflected among 77 regular users in our study,who never experienced withdrawal symptoms asthey never stopped using krathom. This may explainwhy we did not get 100% endorsement to allkrathom withdrawal symptoms and signs.

Furthermore, the report of muscle, joint, and bonepains (56.6%) and muscle and nerve twitching (41.4%)among regular users upon cessation of use may beexplained by its pharmacological properties. This isalso in keeping with a previous study in Malaysia,which found that common physiological symptoms ofkrathom withdrawal included muscle spasms and pain(Singh, Muller, and Vicknasingam 2014). As bothmitragynine and 7-hydroxymitragynine have antinoci-ceptive effects (Chittrakarn et al. 2010), the reverse ofthese effects could be expected. As found in a qualita-tive study, these symptoms were more likely causativefor re-starting using krathom to alleviate these with-drawal symptoms.

Data from a qualitative study indicated that theregular users and occasional users differed clearly interms of their patterns of krathom use and the symp-toms and signs of prolonged use and those after stop-ping use (Saingam et al. 2013). The current studysupports this. It was shown that the severity of with-drawal symptoms was different between regular users,who were probably dependent on krathom, and thosewho occasionally used krathom for functional, social,or medicinal purposes. These findings are of clinicalimportance as the intensity of withdrawal syndromecan be used to differentiate those in need of clinicalintervention to help relieve distressing symptoms andmaintain abstinence.

This study shows that the intensity of krathom with-drawal syndrome was associated independently withpatterns of krathom use and the structure of the syn-drome was in accordance with the international

Table 4. Factors associated with intensity of krathom withdrawal symptoms.Factor Coef 95% CI P-value

Education .003—Illiterate and primary school (Ref.) 0 -—Secondary school and high school −2.36 −5.82, 1.09—Vocational and diploma vocational certificate −4.21 −7.74, -.68—Bachelor degree or higher −4.07 −8.19, .05Duration of krathom use (years) .197 .12, .27 <.001Number of times of krathom use per day .604 .45, .76 <.001Number of krathom leaves per time 6.55 4.88, 8.23 <.001

Note: multivariate linear regression model.

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diagnostic criteria for psychoactive substance withdra-wal. This adds weight to the reliability of the bio-beha-vioral aspects of krathom dependence syndrome andconfirms that krathom use is similar to that of othersubstances in producing dependence syndrome(Saingam et al. 2014).

The findings reported here suggest that regularkrathom use leads to the development of a krathomdependence syndrome, and cessation of use resulted indistressing withdrawal symptoms. Overall, the currentstudy supports previous findings of the addictionpotential of mitragynine in animal and human studies(e.g., Singh, Muller, and Vicknasingam 2014; Yusoffet al. 2014).

This study has some limitations. Although thesample sizes were large, the numbers of heavy userswere limited. With larger and more diverse samples,the factor analyses and model fitting may yield moresignificant results (Schreiber et al. 2006). In addition,some symptoms which were reported to occur amongheavy users, such as nausea and vomiting, diarrhea,stomach ache, and increasing heart rate, might pos-sibly appear in the list. This study did not use bio-chemical tests to confirm the self-report of non-useof other psychoactive substances. In addition, wefound that most krathom users co-used krathomwith coffee, tea, tobacco, and betel nut. This mayinfluence withdrawal symptoms reported by therespondents.

All participants in this study used krathom by chew-ing its fresh leaves—a pattern differing from that inother countries such as Malaysia, the USA, and someEuropean countries, where use is commonly in theforms of drinking, smoking, or adding its leaves tofood (Ahmad and Aziz 2012; Hassan et al. 2013;Singh, Muller, and Vicknasingam 2014). Therefore,our findings of withdrawal syndrome may be limitedlyapplied to users in other countries.

It is important to explore krathom withdrawal symp-toms among other diverse communities and samples,including those using different methods such as tea infu-sion. Early time course of withdrawal symptoms aftercessation was investigated, yet onset of symptoms andlong-term time course should be established in order tosupport sustainable krathom cessation. These results willhelp develop guidelines to inform health professionalshow to recognize levels of krathom withdrawal. Optionsof support for users wanting to cease krathom use shouldbe tested in future research. Finally, the concurrent valid-ity of these self-reported findings using objective mea-sures (e.g., biochemical), along with further exploration ofpredictors of severe krathom withdrawal syndrome,should be considered in future research.

This study examined the characteristics and structure ofthe withdrawal syndrome of krathom. Symptoms and signsof krathomwithdrawal similar to withdrawal syndromes ofopioid substances appear to be present in regular krathomusers. The krathom withdrawal intensity is predicted byduration of krathom use, frequency, and quantity ofkrathom use per day. The applicability of the krathomwithdrawal syndrome to guide clinical intervention forkrathom users who want to quit should be pursued infuture research. In addition, this instrument is appropriateto use in the clinical setting and it should be used, togetherwith the Krathom Dependence Scale (Saingam et al. 2014),to provide better validity and efficiency to diagnose orscreen krathom users for those needing treatment.

Acknowledgments

The authors wish to thank the village health volunteers whoacted as assistant researchers, the Director of the Mae ChaoYu Hua Health Center, and all staff for help in coordinatingthe fieldwork. Ms. Walailuk Jitpiboon’s help with the dataprocessing and analysis is highly appreciated. Appreciation isalso expressed to the experts who have kindly reviewed theinstruments, Professor John B. Saunders and Professor ManitSrisurapanont.

Funding

This study was supported by the Research Chair Grant to Dr.Sawitri Assanangkornchai from the National Science andTechnology Development Agency, Ministry of Science andTechnology, Thailand (P-10-10307). The Epidemiology Unit,Prince of Songkla University, is partially supported by theNational Science and Technology Development Agency,Ministry of Science and Technology, Thailand, and the ThaiHealth Promotion Foundation.

References

Administrative Committee of Substance Abuse AcademicNetwork. 2011. Status of substance use in 2011: Nationalhousehold survey, estimation of population related withsubstance abuse. Hat Yai, Thailanda: Prince of SongklaUniversity.

Ahmad, K., and K. Aziz. 2012. Mitragyna speciosa use in thenorthern states of Malaysia: A cross-sectional study.Journal of Ethnopharmacology 141 (1):446–50.doi:10.1016/j.jep.2012.03.009.

Allsop, D. J., M. M. Norberg, J. Copeland, S. Fu, and A. J.Budney. 2011. The Cannabis Withdrawal Scale develop-ment: Patterns and predictors of cannabis withdrawal anddistress. Drug and Alcohol Dependence 119 (1–2):123–29.doi:10.1016/j.drugalcdep.2011.06.003.

American Psychiatric Association. 2013. Diagnostic and sta-tistical manual of mental disorders: DSM-V, 5th ed.Washington, DC: American Psychiatric Association.

Assanangkornchai, S. 2005. Pattern of krathom use, krathomaddiction and its impact on health. In Krathom plant in

8 D. SAINGAM ET AL.

Dow

nloa

ded

by [

Lib

rary

Ser

vice

s C

ity U

nive

rsity

Lon

don]

at 0

9:13

29

Mar

ch 2

016

Thai society: Culture, behavior, health, science, laws, eds. S.Assanangkornchai, A. Sirivongs, and N. Ayudhya, 130–43.Bangkok: Ministry of Justice.

Assanangkornchai, S., A. Muekthong, N. Sam-Angsri, and U.Pattanasattayawong. 2007. The use of Mitragynine speciosa(“Krathom”), an addictive plant, in Thailand. SubstanceUse and Misuse 42 (14):2145–57. doi:10.1080/10826080701205869.

Beckett, A. H., E. J. Shellard, J. D. Phillipson, and C. M. Lee.1966. The Mitragyna species of Asia. VI. Oxindole alka-loids from the leaves of Mitragyna speciosa Korth. PlantaMedica 14 (3):266–76. doi:10.1055/s-0028-1100054.

Boyer, E. W., K. M. Babu, J. E. Adkins, C. R. McCurdy, and J.H. Halpern. 2008. Self-treatment of opioid withdrawalusing kratom (Mitragynia speciosa Korth). Addiction 103(6):1048–50. doi:10.1111/add.2008.103.issue-6.

Chittrakarn, S., S. Assanangkornchai, E. Kumarnsit, J.Wungsintaweekul, P. Penjamras, W. Udomuksorn, andD. Saingam. 2016. Pharmacokinetic study and effects ofkratom (Mitragyna speciosa Korth.) on electroencephalo-gram in healthy volunteers: An on-going research.Songkhla: Prince of Songkla University.

Chittrakarn, S., N. Keawpradub, K. Sawangjaroen, S.Kansenalak, and B. Janchawee. 2010. The neuromuscularblockade produced by pure alkaloid, mitragynine andmethanol extract of kratom leaves (Mitragyna speciosaKorth.). Journal of Ethnopharmacology 129 (3):344–49.doi:10.1016/j.jep.2010.03.035.

Chittrakarn, S., P. Keawwongsri, E. Kumarnsit, K.Sawangjaroen, and N. Keawpradub. 2005. Botanicaldescription and pharmacological activity. In Krathomplant in Thai society: Culture, behavior, health, science,laws, eds. S. Assanangkornchai, A. Sirivongs, and N.Ayudhya, 97–112. Bangkok, Thailand: Ministry of Justice.

Chongsuvivatwong, V. 2008. Analysis of epidemiological datausing R and Epicalc. Songkhla, Thailand: EpidemiologyUnit, Prince of Songkla University.

Chuchuen, C., B. Petcharat, S. Jitpiromsri, C. Phantusena, T.Intanont, and U. Pattanasattayawong. 2005. Definition,social and culture implication, and life style in communityrelated to krathom use. In Krathom plant in Thai society:Culture, behavior, health, science, laws, eds. S.Assanangkornchai, A. Sirivongs, and N. Ayudhya, 19–95.Bangkok, Thailand: Ministry of Justice.

Elholm, B., K. Larsen, N. Hornnes, F. Zierau, and U. Becker.2010. A psychometric validation of the Short AlcoholWithdrawal Scale (SAWS). Alcohol and Alcoholism 45(4):361–65. doi:10.1093/alcalc/agq033.

Everitt, B. S. 1975. Multivariate analysis: The need for dataand other problems. The British Journal of Psychiatry126:237–40. doi:10.1192/bjp.126.3.237.

Fabrigar, L. R., D. T. Wegener, R. C. MacCallum, and E. J.Strahan. 1999. Evaluating the use of exploratory factoranalysis in psychological research. Psychological Methods4:272–99. doi:10.1037/1082-989X.4.3.272.

Handelsman, L., K. J. Cochrane, M. J. Aronson, R. Ness, K. J.Rubinstein, and P. D. Kanof. 1987. Two new rating scalesfor opiate withdrawal. The American Journal of Drug andAlcohol Abuse 13 (3):293–308. doi:10.3109/00952998709001515.

Hassan, Z., M. Muzaimi, V. Navaratnam, N. H. Yusoff, F. W.Suhaimi, R. Vadivelu, B. K. Vicknasingam, D. Amato, S.

Von Horsten, N. I. Ismail, N. Jayabalan, A. I. Hazim, S. M.Mansor, and C. P. Muller. 2013. From Kratom to mitra-gynine and its derivatives: Physiological and behaviouraleffects related to use, abuse, and addiction. Neuroscienceand Biobehavioral Reviews 37 (2):138–51. doi:10.1016/j.neubiorev.2012.11.012.

Havemann-Reinecke, U. 2011. P01-50-Kratom and alcoholdependence: Clinical symptoms, withdrawal treatmentand pharmacological mechanisms: A case report. TheJournal of the. European Psychiatric Association 26(Suppl. 1):50. doi:10.1016/S0924-9338(11)71761-8.

Holler, J. M., S. P. Vorce, P. C. McDonough-Bender, J.Magluilo Jr., C. J. Solomon, and B. Levine. 2011. A drugtoxicity death involving propylhexedrine and mitragynine.Journal of Analytical Toxicology 35 (1):54–59. doi:10.1093/anatox/35.1.54.

Jamil, M. F., M. F. Subki, T. M. Lan, M. I. Majid, and M. I.Adenan. 2013. The effect of mitragynine on cAMP forma-tion and mRNA expression of mu-opioid receptorsmediated by chronic morphine treatment in SK-N-SHneuroblastoma cell. Journal of Ethnopharmacology 148(1):135–43. doi:10.1016/j.jep.2013.03.078.

Joreskog, K. G., and D. Sorbom. 1993. Structural equationmodeling with the SIMPLIS command language. Mahwah,NJ: Lawrence Erlbaum Associates.

Kabacoff, R. I. 2012. Principal components and factor analysis.http://www.statmethods.net/advstats/factor.html (accessedApril 12, 2012).

Kaiser, H. F. 1974. An index of factorial simplicity.Psychometrika 39:31–36. doi:10.1007/BF02291575.

Kline, R. B. 2011. Principles and practice of structuralequation modeling, 3rd ed. New York: The GuilfordPress.

Matsumoto, K., S. Horie, H. Ishikawa, H. Takayama, N.Aimi, D. Ponglux, and K. Watanabe. 2004.Antinociceptive effect of 7-hydroxymitragynine in mice:Discovery of an orally active opioid analgesic from theThai medicinal herb Mitragyna speciosa. Life Sciences 74(17):2143–55. doi:10.1016/j.lfs.2003.09.054.

Matsumoto, K., M. Mizowaki, H. Takayama, S. Sakai, N.Aimi, and H. Watanabe. 1997. Suppressive effect of mitra-gynine on the 5-methoxy-N,N-dimethyltryptamine-induced head-twitch response in mice. Pharmacology,Biochemistry, and Behavior 57 (1–2):319–23. doi:10.1016/S0091-3057(96)00314-0.

McWhirter, L., and S. Morris. 2010. A case report of inpatientdetoxification after kratom (Mitragyna speciosa) depen-dence. European Addiction Research 16 (4):229–31.doi:10.1159/000320288.

Neerman, M. F., R. E. Frost, and J. Deking. 2013. A drugfatality involving kratom. Journal of Forensic Sciences 58(Suppl. 1):S278–9. doi:10.1111/1556-4029.12009.

Nelsen, J. L., Lapoint, J., Hodgman, M. J., and Aldous, K. M..2010. Seizure and coma following Kratom (Mitragyninaspeciosa Korth) exposure. Journal of medical toxicology 6(4):424–6. doi:10.1007/s13181-010-0079-5.

Saingam, D., S. Assanangkornchai, A. F. Geater, and Q.Balthip. 2013. Pattern and consequences of krathom(Mitragyna speciosa Korth.) use among male villagers insouthern Thailand: A qualitative study. The InternationalJournal on Drug Policy 24 (4):351–58. doi:10.1016/j.drugpo.2012.09.004.

JOURNAL OF PSYCHOACTIVE DRUGS 9

Dow

nloa

ded

by [

Lib

rary

Ser

vice

s C

ity U

nive

rsity

Lon

don]

at 0

9:13

29

Mar

ch 2

016

Saingam, D., S. Assanangkornchai, A. F. Geater, and S.Lerkiatbundit. 2014. Validation of Krathom (Mitragynaspeciosa Korth.) Dependence Scale (KDS): A dependencescreen for internationally emerging psychoactive sub-stance. Substance Abuse 35:276–83. doi:10.1080/08897077.2014.924464.

Schmidt, M. M., A. Sharma, F. Schifano, and C. Feinmann.2011. “Legal highs” on the net-evaluation of UK-basedwebsites, products and product information. ForensicScience International 206 (1–3):92–97. doi:10.1016/j.forsciint.2010.06.030.

Schreiber, J. B., A. Nora, F. K. Stage, E. A. Barlow, and J.King. 2006. Reporting structural equation modeling andconfirmatory factor analysis results: A review. The Journalof Educational Research 99:323–38. doi:10.3200/JOER.99.6.323-338.

Singh, D., C. P. Muller, and B. K. Vicknasingam. 2014. Kratom(Mitragyna speciosa) dependence, withdrawal symptoms andcraving in regular users. Drug and Alcohol Dependence139:132–37. doi:10.1016/j.drugalcdep.2014.03.017.

Suwanlert, S. 1975. A study of kratom eaters in Thailand.Bulletin on Narcotics 27:21–27.

Thongpradichote, S., K. Matsumoto, M. Tohda, H.Takayama, N. Aimi, S. Sakai, and H. Watanabe. 1998.Identification of opioid receptor subtypes in antinocicep-tive actions of supraspinally-administered mitragynine inmice. Life Sciences 62 (16):1371–78. doi:10.1016/S0024-3205(98)00075-7.

Tsuchiya, S., S. Miyashita, M. Yamamoto, S. Horie, S. Sakai,N. Aimi, H. Takayama, and K. Watanabe. 2002. Effect ofmitragynine, derived from Thai folk medicine, on gastric

acid secretion through opioid receptor in anesthetized rats.European Journal of Pharmacology 443 (1–3):185–88.doi:10.1016/S0014-2999(02)01588-1.

Vicknasingam, B., S. Narayanan, G. T. Beng, and S. M.Mansor. 2010. The informal use of ketum (Mitragynaspeciosa) for opioid withdrawal in the northern states ofpeninsular Malaysia and implications for drug substitutiontherapy. The International Journal on Drug Policy 21(4):283–88. doi:10.1016/j.drugpo.2009.12.003.

Watanabe, K., S. Yano, S. Horie, and L. T. Yamamoto. 1997.Inhibitory effect of mitragynine, an alkaloid with analgesiceffect from Thai medicinal plant Mitragyna speciosa, onelectrically stimulated contraction of isolated guinea-pigileum through the opioid receptor. Life Sciences 60(12):933–42. doi:10.1016/S0024-3205(97)00023-4.

Welsch, S. K., S. S. Smith, D. W. Wetter, D. E. Jorenby, M. C.Fiore, and T. B. Baker. 1999. Development and validationof the Wisconsin Smoking Withdrawal Scale. Experimentaland Clinical Psychopharmacology 7 (4):354–61.doi:10.1037/1064-1297.7.4.354.

Yamamoto, L. T., S. Horie, H. Takayama, N. Aimi, S. Sakai, S.Yano, J. Shan, P. K. Pang, D. Ponglux, and K. Watanabe.1999. Opioid receptor agonistic characteristics of mitragy-nine pseudoindoxyl in comparison with mitragyninederived from Thai medicinal plant. Mitragyna Speciosa.General Pharmacology 33 (1):73–81.

Yusoff, N. H., F. W. Suhaimi, R. K. Vadivelu, Z. Hassan, A.Rumler, A. Rotter, D. Amato, H. C. Dringenberg, S. M.Mansor, V. Navaratnam, and C. P. Muller. 2014. Abuse poten-tial and adverse cognitive effects of mitragynine (kratom).Addiction Biology 21 (1):98–110. doi:10.1111/adb.12185.

10 D. SAINGAM ET AL.

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