ORIGINAL ARTICLE - Long-Term Effects of Kratom (Mitragyna

Mal J Med Health Sci 16(4): 64-72, Dec 2020

Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)

ORIGINAL ARTICLE

Long-Term Effects of Kratom (Mitragyna speciosa) Use

Darshan Singh

, Suresh Narayanan

, Oliver Grundmann

, Nelson Jeng Yeou Chear

, Vikneswaran

Murugaiyah

, Shahrul Bariyah Sahul Hamid

, Nur Sabrina Mohd Yusof

, Eshal Bin Dzulkapli

, Vicknasingam

Balasingam

Centre for Drug Research, Universiti Sains Malaysia. 11800 Minden, Penang. Malaysia.

School of Social Sciences, Universiti Sains Malaysia. 11800 Minden, Penang. Malaysia.

Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1345 Center Drive, Room P6-20,

Gainesville, FL 32611, USA.

School of Pharmacy, Universiti Sains Malaysia. 11800 Minden, Penang. Malaysia.

Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200 Kepala Batas, Penang, Malaysia

ABSTRACT

Introduction: Kratom or (Mitragyna speciosa) leaves are consumed as a folk remedy and opioid substitute in the

Southeast Asian region. There is still a lack of information about the long-term or toxic-causing effects of kratom use.

Methods: A total of thirteen regular kratom users, with long-term (>20 twenty years) kratom use history were recruited

for this cross-sectional pilot study. Respondents were required to undergo a blood-test and laboratory anaysis was

conducted to determine the mitragynine content in an acquired street sample of kratom. Results: The regular, long-

term consumption of brewed kratom decoction did not cause any significant alterations in haematological, kidney,

liver, thyroid, inflammatory and gastrointestinal analytes in a cohort of kratom users who had no history of substance

misuse. However, those who had a higher intake (>3 glasses per day) of kratom exhibited higher lipid values (except

for HDL-cholesterol), and a moderate elevation of homocysteine level. Conclusion: Long-term (>20 years with a

daily intake of ≥87.54mg of mitragynine) kratom consumption was not associated with altered biochemical levels,

although prolonged and heavy use (>3 glasses daily) may result in cardiovascular risks. The latter finding, however,

requires further investigation.

Keywords: Mitragynine, Kratom, Toxicity, Haematology, Cardiotoxicity

Corresponding Author:

Darshan Singh , PhD

Email: [email protected]

Tel: +604-653 6029

INTRODUCTION

Kratom (Mitragyna speciosa) leaves are widely used in

rural Southeast Asia for its therapeutic value (1). Rural

folks traditionally use kratom to treat common health

disorders (e.g. cough, hypertension, diabetes, and pain),

while manual labourers rely on kratom to enhance work

productivity (1). Since kratom is believed to have pain

suppressing effects, it is also used as a safe alternative

to opioids (1, 2), since its most abundant alkaloid,

mitragynine has been shown to bind to opioid-receptors

(2, 3). Over the last decade, kratom has gained ground

in the US, chiefly because of its potential to reduce pain,

relieve opioid withdrawal pains, and aid in alleviating

psychological problems like anxiety and depression (2).

Its principal psychoactive alkaloids, both mitragynine

and 7-hydroxymitragynine, were reported to have

an effect on opioid receptors (3). In the West, kratom

consumption is being seen as a public health threat

on account of several kratom toxicity cases triggered

primarily in those who use kratom in combination with

other substances like ethanol, benzodiazepines, narcotics

and pain-relieving medication (acetaminophen) (4, 5). It

is unclear if mitragynine/kratom per se was responsible

for the these adverse health occurrences, or if they were

caused by the concomitant use of kratom with other

illicit drugs (5), or the consumption of unreliable kratom

products with a higher 7-hydroxymitragynine content

than is found naturally (6).

Due to the increase in kratom-related health emergencies

(5), the US Food and Drug Administration (FDA) has

expressed concern about the unapproved sales and

distribution of a variety of kratom products. It is pressing

the government to regulate kratom and its alkaloids in

the US under the Control Substances Act (CSA). Although

kratom remains legal at the Federal level, issues related

to kratom poisoning (e.g. toxicities and deaths) continue

to unfold in the US and are reported to evolve from

the use of kratom products, primarily mitragynine and

7-hydroxymitragynine (7). The latest information from

the US National Poison Data System (NPDS) indicates

that there were about 1807 kratom exposure cases

Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)

Mal J Med Health Sci 16(4): 64-72, Dec 2020

reported between 2011 and 2017 (5). In fact, two-thirds

(65%) of the exposure cases occurred between 2016

to 2017, while 51.9% of the exposure incidents were

associated with various adverse medical outcomes such

as seizures, respiratory depression, cardiac arrest, renal

failure, etc. (5).

Based on the available findings, it can be hypothesised

that kratom users in US, specifically those who co-used

kratom with other illicit substances and alcohol, have

higher possibility of experiencing adverse, but not life-

threatening, health problems (4, 5, 7). Findings from

an animal study indicated that higher mitragynine

administration has the potential to alter haematological

and biochemical parameters (8). Several studies have

also highlighted kratom's (mitragynine) association

with biochemical alterations indicative of liver injuries,

neonatal withdrawal symptoms, kratom dependence and

withdrawal, overdose, gastrointestinal and cardiovascular

(e.g. bradycardia, tachycardia, palpitation, etc.) problems

(4, 5, 7, 9, 10, 11). Researchers believe that most of the

mortality incidents in the West were caused by the toxic

effect of combining illicit substances with kratom (7),

or due to the combination of kratom with conventional

drugs that resulted in lethal herb-drug interactions (12).

About 95% of those who have passed away from kratom

use had current drug abuse histories (7).

The present study examines respondents who have a

much longer history of kratom use— more than 20 years,

as compared to a previously studied group consisting of

those who used kratom for between two and eleven years

(13). Furthermore, we also analysed cardiovascular and

gastric cancer markers. Given the unavailability of safety

data on the long-term effects of kratom use, this study

seeks to shed light on whether prolonged kratom use

(>20 years) was associated with adverse health effects.

MATERIALS AND METHODS

Study design, inclusion and exclusion criteria and

measure

Thirteen kratom users consented to participate in this

cross-sectional study. All the respondents were recruited

through purposive sampling from the northern state of

Penang. Rural dwellers in this state still maintain their

traditional kratom using habit. Respondents in this study

only used brewed kratom juice, which is commonly

obtained from illegal kratom suppliers in the community.

None of the respondents have chewed or smoked

kratom before. Respondents were eligible to participate

in the study if they were; 1) below 55 years of age, and 2)

have more than 20 years regular kratom use history. We

recruited those who were less than 55 years of age since

older respondents may be exposed to unrelated health

risks. We excluded those who had current or previous

alcohol and drug use history. All the study data were

collected from January 2019 to March 2019. A trained

research officer conducted the interviews using a semi-

structured questionnaire that collected information on

the respondent's demographic characteristics

(e.g. ethnicity, current age, marital status, etc.), and

kratom use history (e.g. duration of kratom use, first age

of kratom use, etc.). Moreover, respondents were also

asked to share the negative experiences, and any health

problems they encountered in the course of their kratom

use. We also measured the body mass index (BMI) of

each respondent, recorded their daily caloric food intake,

and documented their history of cigarette smoking. This

study was approved by the Human Ethics and Research

Committee of Universiti Sains Malaysia (USM) (USM/

JEPeM/19040224). Respondents were compensated with

RM50 (USD=13.5) for their participation. All gave their

written informed consent.

Haematological and biochemical analyses

Blood samples were analysed at a diagnostic laboratory

(PATHLAB, Malaysia). Details of the haematological and

biochemical analysis have been described in a previous

study (13). Additional tests included prothrombin time

and International Normalised Ratio (INR), cystatin C,

homocysteine, hs-C reactive protein (hsCRP), creatine

phosphokinase, apolipoproteins A1, B and Apo B/Apo

A1 ratio. The cancer antigen 19.9 (CA 19.9) test was also

done to screen for gastric cancer marker.

Study analysis

All the study data were analysed with the Statistical

Package for Social Sciences (SPSS) version 24. Descriptive

statistics were used to describe the sociodemographic

characteristics and kratom use histories of respondents.

The haematological and biochemical parameters of

respondents, and the mean scores and standard deviations

(SD) were calculated to compare with the reference range

scores. Independent t-test were computed to determine

the mean differences in the biochemical parameters

between respondents who consumed <3 glasses (low

quantity) and >3 glasses (high quantity) of kratom juice

per day. We chose to study the relationship between the

low and high dose effects of kratom use because higher

quantities of kratom use were reported to cause adverse

health effects (1). The statistical significance for all tests

was set at p<0.05.

Kratom juice analysis

Reagents and chemicals

Methanol (HPLC grade) was purchased from Merck

(Germany). Mitragynine was extracted from Mitragyna

speciosa leaves following the method described by

Sharma et al. (2019) (14). The chemical structure and

purity of mitragynine was confirmed by 1H & 13C NMR,

MS and HPLC-UV (14).

Sample collection and preparation

In traditional settings, kratom traders typically use fresh

and matured kratom (Mitragyna speciosa) leaves to

produce kratom juice for local consumption. Unlike

in the US where users have a liking for using red and

Mal J Med Health Sci 16(4): 64-72, Dec 2020

green-veined kratom powder, local kratom traders

usually combine both the green and red-veined leaves

to prepare kratom juice. On average, respondents in this

study consumed about three packets of kratom decoction

daily (approximately 1,120 mL). It was previously shown

that the major alkaloid detected in local kratom tea/

juice was mitragynine, followed by paynantheine,

speciogynine and speciociliatine (13). Mitragynine is the

major psychoactive alkaloid of kratom. To estimate the

amount of mitragynine consumed by our respondents,

we purchased a sample packet of street kratom. The

acquired sample was measured and freeze-dried to

evaporate off the water content. The alkaloid content of

the lyophilized powder was then pre-concentrated with

methanol prior to GC-MS analyses (13).

Quantification of mitragynine content using a

validated GC-SIM-MS method

Mitragynine content of the acquired kratom juice/

tea (methanol extract, 20 mg/mL) was estimated using

a validated gas chromatography-mass spectrometry

(GC-MS) method with a selective ion monitoring (SIM)

mode as described in a previous study (13). Detection of

mitragynine (kratom juice) was done by comparing the

retention time (16.8 min) and the major product ion (m/z

214) of the analyte with that of mitragynine standard (>

98% purity) (Figure 1).

RESULTS

The demographic characteristics and kratom use

history of respondents

The demographic characteristics and kratom use

history of respondents are shown in Table I. The sample

consisted only of Malay males (100%, n=13/13). The

mean age of respondents was 45.1 years. The majority

were married (85%, n=11/13), and had completed

upper secondary education (69%, n=9/13). None were

unemployed. The mean age of first kratom use was 27.5

years (SD=4.2), and their mean duration of kratom use

was 20.4 years. Respondents consumed, on average, 4

glasses of kratom juice daily (Table I). Forty-six percent

(n=6/13) consumed >3 glasses of kratom juice daily,

while 54% (n=7/13) used <3 glasses of kratom per day.

The mean BMI of the respondents were 27.2 (SD=4.5),

and their mean intake of daily calories was 2,084.7

(SD=320.6). Almost all (n=12/13) had current history of

cigarette smoking, and their mean duration of smoking

was 26.6 years (SD=2.4).

Haematology blood test findings

There were no significant alterations in the haematology

parameters of the respondents. Only subtle alterations

were observed for RDW value and prothrombin time as

shown in Table I.

Table I: Respondents socio-demographic characteristics and kratom

use history

n (%)

Gender

Male

13 (100)

Ethnicity

Malay

13 (100)

Mean age 45.1 years (SD=6.6)

Marriage

Single

Married

2 (15)

11 (85)

Education

9 years

≥11 years

4 (31)

9 (69)

Employment

Employed 13 (100)

Kratom use history

Mean age of first kratom use

Mean duration of kratom use

Mean frequency of daily kratom use

Mean quantity of daily kratom use

27.5 years (SD=4.2)

20.4 years (SD=0.7)

5.6 times (SD=2.4)

4 glasses (SD=2.5)

Daily quantity of kratom use

≤3 glasses

>3 glasses

7 (54)

6 (46)

Mean BMI 27.2 (SD=4.5)

Mean calories daily 2084.7 calories (SD=320.6)

Mean smoking duration 26.6 years (SD=2.4)

Smoker

Yes

12 (92)

1 (8)

Health problems since kratom use

No 13 (100)

Blood group

O RH

AB RH

A RH

B RH

7 (54)

1 (8)

2 (15)

3 (23)

Figure 1: (A) GC-SIM-MS chromatogram of the purchased

kratom juice sample (methanol extract); (B) GC-SIM-MS

chromatogram of mitragynine standard (75 µg/mL).

Mal J Med Health Sci 16(4): 64-72, Dec 2020

Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)

Biochemical test findings

Results from the blood chemistry analyses indicated that

there were no significant alterations in the kidney, liver or

thyroid functions, rheumatoid factor, and CA 19.9 level

(Table II). However, the lipid profile and apolipoprotein

parameters were found to be altered. It was apparent that

the level of total cholesterol, LDL, triglycerides, hs-CRP

and homocysteine levels were higher than the reference

range, although the HDL remained at the normal range

(Table II).

Differences in the haematology and bio-chemical

parameters between those who consumed lower (<3

glasses) and higher (>3 glasses) quantity of kratom juice

It has been reported that those who consumed kratom

regularly over prolonged periods may experience weight

loss, decreased appetite and libido, fatigue, etc. (1).

Therefore, we investigated the dose-response effects

of kratom use on haematological and biochemical

parameters. Since chronic kratom use was associated

with gastrointestinal discomfort and elevation in

lipid profile (13), we attempted to determine whether

higher intake of kratom was associated with altered

haematological and biochemical parameters. We found

there was a significant increase beyond the reference

range particularly for RDW and prothrombin time

among those who consumed <3 glasses of kratom per

day, relative to those who consumed >3 glasses of

kratom (Table III). However, there were no significant

alterations in the kidney parameters of the respondents,

except for the cystatin value which appeared higher than

the reference range among those who consumed >3

glasses of kratom juice per day. No significant changes

in the glucose, liver function, thyroid function and CA

19.9 levels were detected between those who reported

consuming more than or less than 3 glasses per day.

However, our results indicated that respondents who

consumed >3 glasses of kratom on a regular basis had

substantial elevations in total cholesterol, LDL, Apo

B, Apo B/A1 ratio when compared to the individual

reference range parameters. There were also elevations

in homocysteine and triglyceride levels, but interestingly

the values turn out to be high among those who reported

consuming lower (<3 glasses) quantity of daily kratom

use. However, hs-CRP was above the reference range

for both groups.

Estimation of mitragynine content in the kratom sample

In this study, approximately 360 mL of kratom tea/juice

was lyophilized to yield 4.39 g of water extract and

subsequently extracted with methanol to yield 3.1 g of

methanolic extract. Based on GC-SIM-MS quantification,

the mitragynine content in the methanol extract (20 mg/

mL) was 0.1883 ± 0.01 mg/mL which is equivalent to

29.18 mg in 3.1 g of methanol extract (0.94% (w/w)).

The mitragynine content in the street sample was found

to be around 29.18 mg per glass (360mL of kratom tea/

juice). It can, therefore, be inferred that the respondents

ingested approximately 87.54 mg of mitragynine per

Table II: Respondents biochemical profile.

Scores

(n=13)

Mean ± (SD)

Unit

Reference

Range

Haematology

ESR

RBC

Haemoglobin

PCV (HCT)

MCV

MCH

MCHC

RDW value

Platelet count

WBC

7.5 (4.2)

5.5 (.74)

15.1 (.94)

41.6 (11.4)

82.5 (10.1)

27.8 (3.4)

33.8 (.90)

15.0 (1.9)*

326.6 (74.4)

9.8 (2.5)

MM/HR

X10^12/L

G/DL

X10^9/L

X10^/L

0-10

4.5-6.5

13.0-18.0

40-54

76-96

27-32

32-36

11.5-14.5

150-400

4.0-11.0

Differential count

Neutrophil

Lymphocyte

Monocyte

Eosinophil

Basophil

50.2 (9.5)

36.1 (7.7)

8.6 (2.4)

4.9 (3.2)

0.31 (.48)

40-75

20-45

2-10

0-6

0-2

Prothrombin time

Patient time

Control time

INR

14.4 (2.9)*

14.0 (.00)

1.1 (.13)

Seconds

9.8-12.1

Diabetes screen

Glucose 5.6 (1.4) mmol/L Fasting 3.9-

5.6

Kidney function test

Urea

Creatinine

Calcium

Inorganic phosphate

Uric acid

Sodium

Potassium

Chloride

Cystatin C

2.9 (.81)

87.5 (10.5)

2.3 (.09)

1.3 (.26)

0.38 (.10)

145.4 (2.3)

4.5 (.36)

101.4 (1.6)

0.97 (.16)*

mmol/L

mg/L

1.7-8.4

62-115

2.12-2.52

0.78-1.65

0.20-0.42

137-150

3.5-5.3

96-108

0.50-0.96

Microalbumin

Urine microalbumin

Urine creatinine

Microalb: creat ratio

6.70 (5.0)

11.5 (7.1)

0.76 (1.2)

mg/L

nmol/L

mg/MMOL <3.4

Lipid profile

Total cholesterol

HDL

LDL

Triglycerides

Total/HDL ratio

Hs-C reactive protein

5.8 (1.1)*

1.3 (.25)*

3.6 (.91)*

2.2 (1.8)*

4.6 (1.4)

5.3 (3.3)*

mmol/L

mg/L

<5.2

>1.04

<2.6

<1.7

<5.0

<4.7

Apolipoproteins

Apolipoprotein A1

Apolipoprotein B

Apo B/APO A1 ratio

Homocysteine

1.3 (.17)

1.3 (.25)

1.0 (.25)

19.2 (13.8)*

g/L

μmol/L

0.94-1.78

0.63-1.33

<1.00

5.0-15.0

Liver function test

Total protein

Albumin

Globulin

A/G ratio

Total bilirubin

Alkaline phosphatase

SGOT (AST)

SGPT (ALT)

GGT

CPK (Total)

75.2 (3.7)

41.5 (3.3)

33.7 (4.1)

1.3 (.23)

9.5 (2.10)

89.6 (12.7)

30.6 (6.2)

28.1 (10.1)

40.3 (14.8)

162.9 (76.6)

g/L

μmol/L

IU/L

U/L

64-83

30-50

20-50

1.2-2.5

<17

39-117

0-40

0-53

<73

39-308

Thyroid screen

Thyroxine (T4)

Rheumatoid factor

111.4 (29.8)

17.3 (25.6)

nmol/L

IU/ML

64.0-167.0

0-35

Tumour marker

CA 19.9 9.4 (5.7) U/ML <37.0

*Denotes values are higher than the reference range.

Mal J Med Health Sci 16(4): 64-72, Dec 2020

Table III: Differences in the biochemical parameters of between those who consumed ≤3 glasses and >3 glasses of kratom daily

≤3 glasses

(n=7)

Mean ± (SD)

>3 glasses

(n=6)

Mean ± (SD)

Difference t df

P-value

Reference Range

Haematology

ESR

RBC

Haemoglobin

PCV (HCT)

MCV

MCH

MCHC

RDW value

Platelet count

WBC

7.1 (4.3)

5.5 (1.03)*

14.5 (.72)

37.5 (14.6)

80.9 (13.3)

27.0 (4.5)

33.4 (.98)

15.4 (2.6)*

356.4 (69.8)

9.10 (2.4)

8.0 (4.6)

5.4 (.23)

15.8 (.63)

46.3 (2.2)

84.5 (4.9)*

28.8 (1.2)*

34.3 (.52)

14.6 (.82)

291.8 (68.7)

9.7 (2.7)

0.9

0.1

1.3

8.8

3.6

1.8

0.9

0.8

64.6

0.6

0.349

0.072

3.455

1.455

0.630

0.963

2.032

0.726

1.675

0.215

0.782

0.014

0.863

0.105

0.031

0.008

0.153

0.012

0.576

0.911

0-10

4.5-6.5

13.0-18.0

40-54

76-96

27-32

32-36

11.5-14.5

150-400

4.0-11.0

Differential count

Neutrophil

Lymphocyte

Monocyte

Eosinophil

Basophil

49.0 (10.20)

36.9 (9.0)

10.3 (1.5)

3.7 (1.7)

.14 (.38)

51.5 (9.30)

35.2 (6.6)

6.7 (1.8)

6.2 (4.2)*

.50 (.55)*

2.5

1.7

3.6

2.5

0.36

0.459

0.380

4.023

1.432

1.387

0.894

0.702

0.545

0.012

0.042

40-75

20-45

2-10

0-6

0-2

Prothrombin time

Patient time

Control time

INR

15.5 (3.20)**

14.0 (.00)

1.1 (.2)

13.1 (1.10)**

14.00 (.00)

1.0 (.1)*

2.4

0.1

1.554

1.683

0.166

0.000

9.8-12.1

Diabetes screen

Glucose 5.6 (1.9) 5.6 (.70) 0 0.000 11 0.106 Fasting 3.9-5.6

Kidney function test

Urea

Creatinine

Calcium

Inorganic phosphate

Uric acid

Sodium

Potassium

Chloride

Cystatin C

3.2 (.93)

84.0 (10.1)

2.24 (.10)

1.3 (.30)

.40 (.10)

144.7 (2.6)

4.50 (.27)

101.14 (2.1)

0.88 (.14)

2.6 (.60)

91.5 (10.4)

2.30 (.12)*

1.3 (.30)

.40 (.10)

146.2 (1.6)

4.60 (.47)

101.7 (.8)

1.1 (.13)**

0.6

7.5

0.06

1.5

0.1

0.56

0.22

1.259

1.316

0.900

0.043

0.759

1.175

0.555

0.568

2.399

0.195

0.886

0.044

0.967

0.916

0.448

0.167

0.315

0.972

1.7-8.4

62-115

2.12-2.52

0.78-1.65

0.20-0.42

137-150

3.5-5.3

96-108

0.50-0.96

Microalbumin

Urine microalbumin

Urine creatinine

Microalb: create ratio

8.3 (5.2)

12.8 (6.4)

1.03 (1.6)

4.9 (4.4)

10.0 (8.1)

0.45 (.24)

3.4

2.8

0.58

1.251

0.704

0.879

0.757

0.502

0.109 <3.4

Lipid profile

Total cholesterol

HDL

LDL

Triglycerides

Total/HDL ratio

Hs-C reactive protein

5.3 (.89)**

1.3 (.31)**

3.1 (.80)**

2.2 (2.2)**

4.2 (1.4)

5.3 (3.4)**

6.5 (1.0)**

1.3 (.18)**

4.1 (.82)**

1.2 (1.5)

5.1 (1.3)

5.2 (3.6)**

1.2

0.9

0.1

2.247

0.005

1.833

0.056

1.110

0.044

0.839

0.353

0.893

0.196

0.860

0.847

<5.2

>1.04

<2.6

<1.7

<5.0

<4.7

Apolipoproteins

Apolipoprotein A1

Apolipoprotein B

Apo B/APO A1 ratio

Homocysteine

1.30 (.20)

1.14 (.20)

.90 (.20)

21.2 (18.2)**

1.30 (.15)

1.41 (.24)**

1.12 (.30)**

16.4 (3.7)**

0.27

0.22

4.8

0.217

2.201

1.851

0.572

0.661

0.878

0.158

0.119

0.94-1.78

0.63-1.33

<1.00

5.0-15.0

Liver function test

Total protein

Albumin

Globulin

A/G ratio

Total bilirubin

Alkaline phosphatase

SGOT (AST)

SGPT (ALT)

GGT

CPK (Total)

75.0 (3.8)

43.1 (3.4)

31.9 (3.3)

1.4 (.22)

10.4 (2.5)

87.4 (14.1)

33.6 (4.2)

33.0 (11.60)

41.6 (17.3)

173.7 (75.30)

75.3 (3.10)

39.5 (1.6)

35.8 (4.0)

1.1 (.16)

8.5 (3.4)

92.7 (11.40)

27.2 (6.7)

22.3 (3.5)

38.8 (12.7)

150.2 (83.1)

0.3

3.6

3.9

0.3

1.9

5.3

6.4

10.7

2.8

23.5

0.154

2.364

1.950

2.198

1.178

0.729

2.106

2.159

0.320

0.536

0.900

0.236

0.603

0.325

0.475

0.608

0.144

0.078

0.465

0.545

64-83

30-50

20-50

1.2-2.5

<17

39-117

0-40

0-53

<73

39-308

Thyroid screen

Thyroxine (T4)

Rheumatoid factor

120.5 (24.4)

22.0 (33.7)

100.7 (34.1)

11.8 (11.7)

19.8

10.2

1.218

0.699

0.093

0.101

64.0-167.0

0-35

Tumour marker

CA 19.9 7.5 (4.4) 11.3 (6.7) 3.8 1.175 11 0.210 <37.0

*Denotes differences between those who consumed ≤3 or >3 glasses of kratom daily at (p<0.05).

**Denotes values are higher than the reference range.

Mal J Med Health Sci 16(4): 64-72, Dec 2020

Malaysian Journal of Medicine and Health Sciences (eISSN 2636-9346)

day, corresponding to an average of three glasses of

kratom juice.

DISCUSSION

Although kratom leaves have customarily been used

for its broad therapeutic values such as relieving pain,

elevating mood, and as an affordable substitute for opioids

in Southeast Asia, several studies from the West have

emerged linking kratom consumption with poisoning and

death (4, 5, 7). Kratom use for the self-treatment of pain

first was identified in the US in 2007 (1). Subsequently

large scale surveys have shown that kratom was being

used to self-treat chronic pain, opioid withdrawal and

dependence, as well as psychological problems (1, 2).

Despite this, the FDA has kept alleging that kratom's

main alkaloids, mitragynine and 7-hydroxymitragynine,

had a role in the majority of kratom fatalities in the US

(7). In fact, the link between mitragynine and the reported

death rates has been poorly elucidated, since 71% of

the fatalities were reported as accidental (including

misadventure), while 9% were classified as intentional

(suicide) (7). A recent study estimated that the risk of

overdose death is >1000 times greater for opioids than for

kratom (15). In fact, the majority who have encountered

adverse health problems were those who had current

histories of drug use problem, chiefly opioid abuse (7,

15). Meanwhile, in Southeast Asia, traditional kratom

use has, thus far, not been associated with any major

health concerns, although it has been placed under the

Poisons Act 1952 in Malaysia (1). While previous studies

have documented the side-effects of kratom, and its use

as an opioid substitute among heroin users in Malaysia

(1), the safety of long-term consumption remains poorly

investigated. Our preliminary findings show that regular,

long-term kratom use was not associated with altered

biochemical parameters in a small sample of non-drug

using kratom users. This suggests that long-term (>20

years) kratom use may not adversely affect the studied

parameters. Our findings are in line with an earlier study

indicating that kratom use was not harmful (13). However,

more data and clinical investigations of kratom use are

needed to establish its therapeutic value and safety.

In comparison to other haematological parameters, only

the red cell distribution (RDW) value was found to be

raised above the reference range. RDW is commonly

used as a marker for detecting iron deficiency anaemia,

as well as a predictor for inflammatory diseases such as

chronic heart failure (18, 19). A previous study reported

that elevation in RDW value was associated with

increased risk of cardiovascular problems; however,

other factors like poor nutritional intake and age-related

diseases could have played a role in the elevation of

RDW value (16, 19). Similarly, an increase in RDW

value can also arise from defects in red cell production,

or because of increased haemolysis (16). Though there

were significant differences in the RBC, MCV and MCH

values of those who consumed low (<3 glasses) and

higher (>3 glasses) quantities of kratom juice, all values

of the parameters were within the normal reference

range. Only the RDW value was slightly raised beyond

the reference value for those who consumed a lower

quantity of kratom juice (<3 glasses) on a daily basis

(p<0.012). The elevated RDW value can be a sign of

cardiovascular risk or marker for inflammatory cytokines

(16). However, the increase in the prevalence of anaemia

with advancing age can also be partially attributed to

the cytokines that inhibit the proliferation of erythroid

progenitor cells (19).

In the West, users appeared prone to develop liver

and kidney impairments even after using kratom for

short durations (5, 7). This is in contrast to our findings

that suggest that even long-term kratom consumption

appears not to affect liver and kidney functions. Despite

the non-significant differences in the cystatin C level

between those who consumed either more or less

quantity of kratom juice (p<0.972), we found cystatin C

levels were slightly raised beyond the reference range.

A previous study indicated that elevation of cystatin

C level was linked with hypertension, coronary heart

disease, rheumatoid arthritis and older age (20). Based

on this, an inference of a possible link between long-

term kratom use and increased cardiovascular risk might

be made. Confirmation of this link, however, requires

more controlled-clinical studies.

Besides the RDW and cystatin C levels, we found that

long-term kratom users had elevated lipid profiles. The

lipid profile (total cholesterol, LDL and triglycerides) of

respondents were markedly raised beyond the reference

range, regardless of the quantity of kratom consumed.

The hs-CRP, homocysteine and apolipoproteins such as

apolipoprotein B were higher among respondents who

consumed more than 3 glasses of kratom daily. The

elevation in total cholesterol, LDL, triglycerides, hs-CRP,

homocysteine, apolipoprotein B and apolipoprotein B/

APO A1 ratio may be indicative of elevated cardiovascular

risk. Our findings were in line with an earlier study that

also noted the elevation in LDL cholesterol with a higher

intake of kratom juice (13). In another animal model

study, the intake of kratom crude extracts of 100, 500 and

1000mg/kg was associated with a significant increase

in triglycerides and cholesterol parameters in rats (21).

Given its lipid-altering effects, long-term kratom use may

potentially increase the cardiovascular risk among users.

In Asian societies people conceive opium consumption as

having positive effects on cardiometabolic diseases (e.g.

hypertension and dyslipidaemia) (22). It was reported

that opiate use is associated with significant elevation in

lipid profile (23). The mechanism behind this elevation

remains poorly delineated, but the problem was shown

to occur from both the decreased in hepatic clearance of

LDL cholesterol from plasma, as well as the increase in

hepatic synthesis of triglycerides (24). The findings from

a review article indicated that opium (opioids) use is

Mal J Med Health Sci 16(4): 64-72, Dec 2020

linked with coronary artery disease (CAD) (22), although

opium was reported to have both positive and negative

cardiovascular effects (25). Opium addiction was found

to have harmful effects on one or more lipid parameters

leading to hypercholesterolemia (26).

Apolipoprotein A 1 and B, and hs-CRP (also known as

a highly sensitive C-reactive protein/CRP) have been

recognised as novel cardiovascular risk factors (28).

Notably, we found kratom users in this study had elevated

hs-CRP. The elevation of hs-CRP is reported to increase

mortality risk (e.g. heart attack and stroke) (28, 29). The

hs-CRP has opsonizing properties, where it can increase

the risk of endothelial dysfunction (28). Perhaps, elevation

in hs-CRP may indicate that kratom users could be at risk

of developing atherosclerosis and myocardial infarction.

This is because hs-CRP is reported to play an important

role in several aspects of atherogenesis (e.g. release of

proinflammatory cytokines, promotion of endothelial

dysfunction, prevent nitric oxide production, etc.) (29).

However, this alteration in hs-CRP parameter needs to

be further investigated through proper clinical studies.

Elevation in LDL and apolipoprotein B are associated

with coronary heart disease (30). We found kratom users

in this cohort had an altered LDL and apolipoprotein B.

Indeed, the elevation in apolipoprotein B was associated

with higher kratom intake (>3 glasses), and may serve

as a risk factor for coronary heart disease. Our results

also indicated that kratom users in this cohort had

hyperhomocysteinemia. It has shown that the elevation

in homocysteine levels can be related to various health

conditions such as cardiovascular risk, neurological

and psychiatric diseases (31). In fact, the prevalence of

hyperhomocysteinemia is shown to be common among

patients with heart diseases or high blood pressure (32).

Despite the elevated cardiovascular risk, we found HDL

cholesterol level was above the reference range among

kratom users in this study, while apolipoprotein A was

within the normal reference range.

We also found there were no alterations in the thyroid

function and rheumatoid factor parameters of the

respondents. It appears that regular kratom consumption

in the form of a decoction did not impair their thyroid

function. Since kratom use was associated with

gastrointestinal discomfort like constipation, we also

determined whether long-term kratom use can cause a

severe gastrointestinal problem. CA 19.9 is usually used

as a prognostic indicator in diagnosing gastric cancer

(33). Respondents' CA 19.9 markers for gastric cancer

were either negative or within the normal range. Thus,

we found no link between regular kratom consumption

and elevated risk of gastric cancer.

This study has a few limitations. First, our sample size was

relatively small and consisted only of male respondents

who were recruited through purposive sampling from

one particular state without a control group. We decided

not to recruit a control-group because the aim of the

study was to determine the long-term (>20 years) effects

of kratom use. We tried to recruit more long-term kratom

users; however, most were excluded from the study since

they had existing medical problems such as diabetes and

hypertension, as well as previous illicit drug use history.

Due to the small sample size, our findings cannot be

generalised. Second, although all the respondents were

long-term users (>20 years), some of the alterations in the

haematological and biochemical parameters, specifically

in the lipid profile (total cholesterol, LDL, triglycerides,

hs-CRP and apolipoproteins B) could have been caused

by other factors such as respondent's history of cigarette

smoking, diet and lifestyle, and not kratom use per se. As

such, it is vital that future studies attempt to determine

the long-term effects of kratom use in regular users

through a longitudinal clinical study. Finally, although

the respondents self-reported the absence of pre-existing

medical problems, we could not conclusively rule this

out. This may have affected our findings.

CONCLUSION

Notwithstanding the vast evidence highlighting kratom's

utility as a safe substitute to opioids, the popular notion

that kratom is an opioid has compelled regulatory

agencies to consider banning kratom use. In fact, though

kratom consumption has been implicated in some deaths

in the US, it has not been conclusively demonstrated

that kratom was primarily or solely responsible for

them (34). A recent study clearly pinpointed that 80%

of kratom-related deaths occurred among those with

history of substance misuse, and 90% had no evidence

of a history of supervised pain care, suggesting strongly

that the majority of the deaths were caused by the used

of multiple drugs and not just kratom (35). Our findings

are among the first to show in a cohort of non-drug using

kratom users, that prolonged kratom use (>20 years with

an average daily intake of ≥87.54mg of mitragynine), in

the form of a brewed solution, was not associated with

significant alterations in haematological and biochemical

profile. However, there were indications that kratom use

may increase cardiovascular risk, especially when used

in large quantity for an extended period of time; this

possible link necessitates further investigation.

ACKNOWLEDGEMENTS

This study was financially supported by the Ministry of

Higher Education Malaysia under the Higher Institution

Centres of Excellence (HICoE) grant.

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