Kratom and Pain Tolerance: A Randomized, Placebo-Controlled, Double-Blind Study

Abstract

Background: Kratom has a long history of traditional medicine use in Southeast Asia. Consumption of kratom products has also been reported in the US and other regions of the world. Pain relief is among many self-reported kratom effects but have not been evaluated in controlled human subject research. Methods: Kratom effects on pain tolerance were assessed in a randomized, placebo-controlled, double-blind study. During a 1-day inpatient stay, participants received a randomized sequence of kratom and placebo decoctions matched for taste and appearance. Pain tolerance was measured objectively in a cold pressor task (CPT) as time (seconds) between the pain onset and the hand withdrawal from the ice bath. Health status, vital signs, objective, and subjective indicators of withdrawal symptoms, self-reported data on lifetime kratom use patterns, and assessments of blinding procedures were also evaluated. Results: Twenty-six males with the mean (SD) age 24.3 (3.4) years were enrolled. They reported the mean (SD) 6.1 (3.2) years of daily kratom consumption. Pain tolerance increased significantly 1 hour after kratom ingestion from the mean (SD) 11.2 (6.7) seconds immediately before to 24.9 (39.4) seconds 1 hour after kratom consumption (F(2,53.7)=4.33, p=0.02). Pain tolerance was unchanged after consuming placebo drinks: 15.0 (19.0) seconds immediately before and 12.0 (8.1) seconds 1 hour after consumption of placebo (F(2,52.8)=0.93, p=0.40). No discomfort or signs of withdrawal were reported or observed during 10-20 hours of kratom discontinuation. Conclusions: Kratom decoction demonstrated a substantial and statistically significant increase in pain tolerance. Further rigorous research on kratom pain-relieving properties and a safety profile is needed.

Full text

YALE JOURNAL OF BIOLOGY AND MEDICINE 93 (2020), pp.229-238.

Kratom and Pain Tolerance: A Randomized,
Placebo-Controlled, Double-Blind Study
abaa
aaac
cda
e,*
aCentre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia; bSchool of Social Sciences, Universiti Sains Malaysia,
Penang, Malaysia; cSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia; dYale School of Public
Health, Department of Biostatistics, and Yale School of Medicine, Department of Psychiatry, New Haven, CT; eYale School of
Medicine, Departments of Psychiatry and Emergency Medicine, New Haven, CT
Background   
         
             
Methods   
      



    Results
    
      

      
              

 Conclusions   
           

Copyright © 2020 229
*To whom all correspondence should be addressed: Marek C. Chawarski, Yale School of Medicine, Department of Psychiatry,
CMHC/SAC, Room S206, 34 Park Street, New Haven, CT, 06519; Tel: +1-203-974-7602; Fax: +1-203-974-7606; Email: marek.
chawarski@yale.edu; ORCID iD: 0000-0001-6254-3092.
Abbreviations: CPT, cold pressor task; BBB, blood-brain barrier; ATS, amphetamine type stimulants; TLFB, Timeline Follow Back;
VAS, visual analogue scale; COWS, Clinical Opioid Withdrawal Scale.
Keywords: kratom, pain tolerance, plant medicine

Vicknasingam et al.: Kratom and pain tolerance230
INTRODUCTION
Consumption of the leaves of kratom tree (Mi-
tragyna speciosa, Rubiaceae family) has a long history
in Southeast Asia [1-3]. Whole leaves and their extracts
have been consumed for their psychoactive properties or
to self-manage or self-treat a broad range of conditions
or ailments including pain, opioid withdrawal symptoms,
and other conditions [4,5]. However, these self-reported
benecial kratom eects summarized in multiple peer-re-
viewed publications have not been evaluated in rigorous-
ly controlled clinical or laboratory research with human
participants.
An increase in consumption of kratom based prod-
ucts has been also reported in recent years in the US and
other countries due to claims of successful self-manage-
ment of pain and opioid withdrawal symptoms [6-8].
Besides these alleged therapeutic eects, issues related
to potential toxicity and fatal incidents that have been
reportedly attributed to kratom products [2,9-11], as well
as potential addictive properties of kratom or its active
compounds are frequently debated within the scientic
community and among regulatory agencies in the US and
in other countries [12].
A substantial body of animal research has been con-
ducted on mitragynine and 7-hydroxymitragynine, two of
many active compounds identied in the kratom leaves
[4]. Mitragynine was found to have unique morphine-like
or opioid receptor agonist eects on guinea-pig ileum
[13], and to have anti-nociceptive action via the supra-
spinal µ and δ opioid receptors in both in vivo and in
vitro studies [14], while 7-hydroxymitragynine has been
reported to have a high anity for µ opioid receptors us-
ing receptor-binding assays and to inhibit electrically in-
duced contraction through opioid receptors in guinea-pig
ileum [15,16]. Experimental animal model studies have
suggested possible analgesic properties of these chemical
compounds [17,18]. Two recent studies also demonstrat-
ed a possibility of mitragynine crossing the blood-brain
barrier (BBB) [19,20]. Yusof et al., additionally demon-
strated that mitragynine has a higher capacity to cross the
BBB than 7‐hydroxymitragynine, however, while in the
brain, 7‐hydroxymitragynine may be more available for
receptor binding than mitragynine [20]. While it has been
reported that mitragynine and 7-hydroxymitragynine
may act as partial agonists at opioid receptors [21], the
structural and chemical properties of both mitragynine
and 7-hydroxymitragynine are very dierent from all
known opioids [16,21,22]. Furthermore, kratom leaves
contain many additional compounds that have not been
extensively evaluated [1,21-23], and presently there is no
evidence to indicate which, if any, of these compounds
cross the blood-brain barrier or have any potential anal-
gesic or other medicinal properties.
Typically, only the kratom leaves are consumed, in-
cluding chewing the whole leaves, ingesting or smoking
dried and pulverized leaves, or drinking water extracts
based on steeping or boiling of the leaf material [2-4,24].
In Malaysia, kratom is primarily consumed as a decoc-
tion, where the leaves are boiled for several hours and
the resulting liquid is consumed several times throughout
the day [5].
To evaluate previously reported potential benecial
eects of consuming kratom leaf preparations on pain,
a randomized, placebo-controlled, double-blind, pilot
study was conducted. The study assessed changes in pain
tolerance, other physiologic responses, and changes in
potential withdrawal signs or symptoms during an initial
discontinuation of kratom use followed by consumption
of kratom or placebo decoctions in a controlled labora-
tory setting. The study enrolled individuals experienced
with kratom through their long-term, daily, habitual kra-
tom consumption who were otherwise healthy. The study
design aimed to closely approximate the frequency and
amounts of kratom consumed in natural settings, and the
process of preparing the study active decoction followed
recipes and methods observed in previous eld research
in Malaysia [2,5]. Objective pain measurements obtained
through repeated administration of a cold pressor task
(CPT) [25,26], and other objective and subjective stan-
dardized assessments were employed in the study.
METHODS
The study protocol and procedures were reviewed
and approved by the Institutional Review Board of Uni-
versiti Sains Malaysia (USM) and registered at Clinical-
Trials.gov: NCT03414099.
Study Hypothesis and Sample Size Estimation
It was hypothesized that consumption of an active
kratom decoction will result in a statistically signicant
increase in pain tolerance (the primary outcome) mea-
sured as the time dierence (in seconds) between the pain
onset after a hand immersion in ice water bath and the
hand withdrawal from the ice water bath during the CPT.
No controlled human studies on kratom related pain ef-
fects have been published to date. Consequently, no prior
data were available to estimate the potential eect size
of the hypothesized pain tolerance increase. The sample
size of 20-30 participants was determined to have > 80%
power to detect large eects (Cohen’s d’=0.6 or larger)
for the proposed within-subject pilot study comparing
kratom vs placebo at two-sided alpha level of 0.05.
Participant Screening and Enrollment
Because no prior well-controlled, clinical studies

Vicknasingam et al.: Kratom and pain tolerance 231
collecting objective, physiological data on kratom safety
prole in humans were conducted, the study design in-
cluded a restrictive set of inclusion and exclusion criteria
and an extensive screening protocol to safeguard that no
participants without an extensive prior kratom experience
were exposed to kratom during the laboratory procedures
and that potential risks due to the study participation were
minimized. Consequently, a sample of individuals with a
long history of a frequent, daily kratom consumption who
were otherwise healthy, based on extensive and objective
health evaluation was targeted for the study enrollment.
Participants were recruited in areas of Penang state in
Malaysia with a high prevalence of kratom use identi-
ed in previous research. Study personnel travelled to
locations where kratom using individuals live, socialize,
buy, and consume kratom. They provided information
about the study and handed out a contact phone number
for those who were interested in study participation. Ad-
ditionally, participants who took part in the study were
asked to provide the study contact phone number to other
individuals in their communities. Those who expressed
interest in the study were briefed about objectives and
procedures and those who were interested in participa-
tion were referred to a voluntary, free health screening to
evaluate their overall health status. The health screening
was conducted by the medical personnel of an indepen-
dent ambulatory clinic who were not part of the study.
The health screening protocol included an interview, a
physical evaluation, and collection of blood and urine
samples to assess the overall health status, current and
past use of psychoactive substances, including opioids,
amphetamine type stimulants (ATS), benzodiazepines,
marijuana, ketamine, and alcohol; HIV and syphilis sta-
tus; chronic liver disease (e.g. cirrhosis, hepatitis A, B, C,
non-alcoholic fatty liver disease); coronary heart disease
and diabetes; and histories of psychological, psychiatric,
or neurological problems and pain conditions.
The study eligibility criteria were: female or male
Figure 1. The CONSORT diagram illustrating participant ow in the study.

Vicknasingam et al.: Kratom and pain tolerance232
but they could smoke cigarettes outside of the ward at the
designated area.
Blood Samples Collection
On the next day, at ~6:30 am, participants were can-
nulated for blood drawing on their non-dominant hand.
After each draw the veins were kept patent (1-2 ml of
heparinized saline, 10 units/mL). Blood samples (1 ml)
were collected 15 times. The vacutainer tubes were gently
inverted several times to prevent clotting and centrifuged
for 15 minutes at 3,000 rpm to separate the plasma from
the red blood cells. Plasma was transferred to cryovials
and stored at -20°C. The samples were analyzed using
liquid chromatography mass spectrometry (LCMS/MS)
to obtain mitragynine pharmacokinetic proles. Instru-
mentation limitations precluded measurement of other
active compounds in the kratom leaves and in the blood
samples. Mitragynine pharmacokinetic ndings from the
current study will be reported in a separate publication.
Kratom and Placebo Drinks
Kratom leaves used in preparation of the study de-
coction were obtained from a plantation. A member of
the research team travelled to the plantation and observed
the leaf collection. Ten kilograms of the freshly collect-
ed leaves were purchased. The leaves were transported
to a laboratory at the USM where they were washed
in cold water to remove particles, dust, dirt, or insects.
Subsequently, the leaves were dried for 48 hours at room
temperature (~26°C) and then dried in an oven at 37°C
for 24 hours.
Kratom drinks approximating mitragynine concen-
tration levels found in eld decoctions were prepared by
mixing the prepared leaf material with water and boiling
it on a low heat. The mixture was then strained to remove
the sediment and stored at 4°C in a locked refrigerator.
To assess mitragynine concentration, decoction was ana-
lyzed using high-performance liquid chromatography-ul-
tra violet (HPLC-UV) and high-performance liquid chro-
matography-diode array detector (HPLC-DAD) [29].
To match for taste and appearance, the placebo
decoction was prepared using the same procedures that
were used in preparation of the kratom decoction but
with botanical materials obtained from vegetables in the
Cucurbitaceae family that are frequently cultivated and
consumed in Malaysia and do not contain any known
active compounds identied in the kratom plant. To fur-
ther mask potential taste dierences, both the kratom and
placebo decoctions were avored with a sugar syrup.
All study participants consumed three decoction
drinks throughout the study day: at 7 am, 10 am, and 1
pm. Only one of the three drinks contained active kratom,
or all three drinks were placebo decoctions (PPP random-
individuals, 18-years-old or older, with at least 11 years
of education, who reported daily kratom intake during the
past 12 months. The exclusion criteria were: a positive
urine drug test for any of the tested substances (opioids,
ATS, benzodiazepines, marijuana, ketamine); a history
of signicant psychological or neurological problems,
current or past alcohol problems; history of medical con-
ditions, including liver disease (e.g. cirrhosis, hepatitis A,
B, C, non-alcoholic fatty liver disease), coronary heart
disease, diabetes, chronic pain, and psychiatric disorders;
HIV or syphilis infection.
Sixty-three individuals were contacted: one refused
to participate, one did not meet criteria for daily kratom
use, one had a history of seizure, nine had less than 11
years of education, two had high glucose levels, two test-
ed positive for tetrahydrocannabinol (THC), one tested
positive for ketamine, 14 individuals did not complete
the health screening, and six individuals were part of a
training protocol: 26 male participants were enrolled (see
Figure 1 for the CONSORT diagram). Despite extensive
outreach eorts, no females who expressed interest in
study participation were identied.
The study protocol included a training phase aimed
to train the research personnel on all laboratory and
assessment procedures planned and specied in the re-
search protocol. The current study is the rst study enroll-
ing human subjects where kratom has been administered
under placebo controlled, double-blind conditions, and
where the cold pressor task (CPT) and other assessments
were used with kratom using individuals. During the
training phase, six non-kratom users (USM students)
were engaged to test the CPT and the paper-and-pencil
assessments, and six male kratom using participants were
enrolled where the full study procedures were implement-
ed. The research personnel’s performance was evaluated
before commencing the enrollment of the randomized
study sample.
Study Procedures
Eligible participants were admitted for an overnight
stay at an inpatient USM ward). Upon arrival they signed a
voluntary written informed consent. Participants were not
allowed to bring kratom or other psychoactive substances
to the ward. Upon admission urine toxicology tests for
morphine, methamphetamine, amphetamine, THC, ben-
zodiazepine, methadone, and ketamine were performed
and all participants were interviewed about amounts and
times of kratom consumption on each day during 7 days
prior to the study admission using the Timeline Follow
Back (TLFB) method [27,28]. They were also asked
questions about their lifetime patterns of kratom use.
All participants were admitted during afternoon hours
(approximately 5 pm) and spent the night in the ward.
They were not allowed to leave the ward unaccompanied,

Vicknasingam et al.: Kratom and pain tolerance 233
every CPT task.
After immersing their hand in the ice bath, partic-
ipants were asked to report verbally when they rst
started feeling pain (pain onset outcome) and to keep
their hand immersed for as long as they can (for up to 5
minutes maximum). The times from when the participant
immersed his hand until he reported pain and the time
when the hand was withdrawn from the ice water bath
were recorded. The primary outcome was pain tolerance,
dened as the dierence (in seconds) between the pain
onset and the hand withdrawal from the ice bath.
For each participant, the CPT was performed repeat-
edly 10 times throughout the study: immediately before
ingesting each drink and at 1-hour intervals thereafter.
Immediately after, each CPT participant was also asked
to rate the level of unpleasantness of the CPT using a
100mm VAS scale.
Physiology and Withdrawal Assessments
Because no standardized assessments of potential
kratom withdrawal symptoms are currently available, the
Clinical Opioid Withdrawal Scale (COWS) [30] was ad-
ministered four times: before each drink and at 120-min-
ute intervals thereafter. The vital signs, including body
temperature, blood pressure, heart rate, and respiratory
rate were obtained during admission, at baseline before
the rst drink and at 120-minute intervals thereafter. The
study safety parameters were: body temperature within
36.5 – 37.5°C, systolic blood pressure 90 – 140 mm Hg,
diastolic blood pressure 60 – 90 mm Hg, and heart rate 60
– 100 beats/minute. The study protocol stipulated that if
vital signs fall out of the safety parameters range, a medi-
cal doctor will evaluate the participant. Participants were
ization sequence). The randomization sequences with the
active kratom decoction were as follows: active kratom
decoction as the rst drink followed by two placebo drinks
(KPP); active kratom decoction as the second drink in the
sequence (PKP); or active kratom decoction as the third
drink in the sequence (PPK). The assignment of kratom
and placebo drinks consumption sequences was random
for all participants. A randomization sequence generated
by the study statistician was provided to the USM study
pharmacist who prepared both the active kratom and pla-
cebo drinks. All kratom and placebo drinks were served
in non-transparent identical cups. The participants and
the study personnel were blinded about the drinks ran-
domization sequence.
Assessments of the Blinding Procedures
To assess whether participants can dierentiate be-
tween the active and placebo drinks based on taste, they
were asked to rate the kratom potency/strength of all
consumed drinks using a 100 mm visual analogue scale
(VAS) immediately after consuming each drink. The
same VAS assessment was conducted 30 minutes later
to assess whether participants can dierentiate between
the active and placebo drinks based on other subjectively
perceptible eects of kratom vs placebo.
The Cold Pressor Task (CPT)
CPT is a laboratory procedure to induce pain experi-
ence safely and without long lasting eects in laboratory
and clinical research settings [20,21]. During the CPT,
participants were asked to immerse their dominant hand
into a 10-liter ice-water bath. Water temperature was
maintained between 2.5°C and 3.5°C and recorded for
Figure 2. Hourly means of mitragynine plasma concentrations for each of the four study randomization groups. The
error bars represent 95% condence intervals.

Vicknasingam et al.: Kratom and pain tolerance234
MCH using the SAS 9.4 and SPSS 24 (IBM Corp. Re-
leased 2016. IBM SPSS Statistics for Windows, Version
24.0. Armonk, NY: IBM Corp.) statistical packages.
RESULTS
Between May and August 2018, 26 male Malay par-
ticipants were enrolled. Their mean (SD) age was 24.3
(3.4) years. They reported the mean (SD) of 6.1 (3.2)
years history of daily kratom consumption and consum-
ing kratom drinks multiple times during each of the seven
days prior to their study participation.
The mean (SD) score on the COWS at baseline at ~
7 am (before the kratom or placebo drinks were given)
was 0.5 (0.8). The remaining COWS scores collected
throughout the study day were: 0.4 (0.6), 0.4 (0.6), and
0.5 (0.5) respectively. One participant had one diastolic
blood pressure reading of 58 mm Hg while receiving
placebo and one of 57 mm Hg when he received kratom.
One participant who received only placebo drinks had
one diastolic blood pressure reading of 95 mm Hg. One
participant had one diastolic blood pressure reading of 58
mm Hg on the night of admission. One participant had
one diastolic blood pressure reading of 93 mm Hg at ~8
hours after receiving the kratom drink. A medical doctor
evaluated each of these participants and concluded that it
was safe for them to continue with the study.
The means of mitragynine plasma concentrations for
all randomization groups are shown in Figure 2.
Twenty participants received one kratom and two pla-
cebo drinks: seven received the active kratom decoction
in rst dosing sequence (~ at 7 am, KPP), seven received
the active kratom decoction in second dosing sequence (~
also asked to report any discomfort or unusual symptoms.
Upon the study completion, urine samples were
tested for morphine, amphetamine type stimulants (ATS),
methadone, benzodiazepines, THC, and ketamine. Each
participant received RM350 (~80 USD) as a compensa-
tion for time spent in the study.
DATA ANALYSES
CPT data were log-transformed to correct for skew-
ness and were analyzed using the mixed models with
drink type (kratom vs placebo), time following drink
administration (0, 1, 2 hours), dosing sequence (rst,
second, or third) and the interaction between drink type
and time as within-subject eects and randomization se-
quence (KPP, PKP, PPK, and PPP) as the between-subject
factors. Random subject eects and the autoregressive
structure of the errors were used to model the correlation
of repeated observations within individuals. Best-t-
ting variance-covariance structure for each model was
selected using Akaike’s Information Criterion (AICC).
Signicant interaction eects were followed by post-hoc
F-tests of simple eects and t-tests of pairwise compari-
sons, whereas signicant main eects were explained by
performing all pairwise least square mean comparisons
corresponding to the Fisher’s Least Signicant Dier-
ence (LSD) approach [31].
The CPT unpleasantness assessments were analyzed
using the same analytical approach described above.
The results of VAS evaluating the maintenance of the
blinding procedures were compared between the kratom
and placebo drinks using an analysis of variance method
(t-tests). All analyses were performed by authors RG and
Figure 3. The means of pain tolerance, in seconds, immediately before the drink consumption and at 1 and 2 hours
after consumption for kratom and placebo drinks. The error bars represent 95% condence intervals.

Vicknasingam et al.: Kratom and pain tolerance 235
consuming the active kratom drinks than after consum-
ing the placebo drinks across all timepoints (see Figure
4). There was also a signicant dosing sequence eect
(F(2,47.9)=6.88, p=0.002). Pain onset was longer during
the rst dosing sequence than during the second and
third sequences (t(52.5)=3.16, p=0.003 and t(40.2)=3.43,
p=0.001 respectively). There were no dierential changes
in the pain onset after ingestion of active kratom versus
placebo drinks.
The mean (SD) rating of unpleasantness of the CPT
decreased from 57.8 (24.7) mm immediately after (0
hour) to 52.1 (21.3) mm at 1 hour after consumption of
the active kratom drinks. For the placebo drinks, the cor-
responding mean (SD) ratings were 58.8 (19.0) mm at 0
hour and 59.4 (21.6) mm 1 hour (see Figure 5). There was
a signicant main eect of time (F(2,108)=4.70, p=0.01)
and a signicant dosing sequence eect (F(2,45.4)=5.89,
p=0.005). The mean CPT unpleasantness ratings went
down from baseline to 1 hour (p=0.25) and then signi-
cantly up at 2 hours (p=0.003). The dierence at 1 hour
after the drink consumption between kratom and placebo
on the unpleasantness rating was statistically signicant
(p=0.05). The mean CPT unpleasantness ratings were sig-
nicantly higher during second and third dosing sequenc-
es than during the rst dosing sequence (t(54.7)=3.03,
p=0.004 and t(30.2)=3.17, p=0.004 respectively).
DISCUSSION
The current study found that in the enrolled cohort of
kratom experienced individuals with long-term histories
of daily kratom consumption, pain tolerance increased
at 10 am, PKP), six received the active kratom decoction
in third dosing sequence (~ at 1 pm, PPK). The remaining
six participants received three placebo drinks (PPP).
The means (SD) of the reported strengths on the
VAS for the active kratom and placebo drinks were 57
(27) mm versus 52 (26) mm respectively when evaluated
immediately upon consumption (p=0.5) and 58 (23) mm
vs 46 (24) mm respectively when evaluated 30 minutes
after the drinks consumption (p=0.09).
Pain tolerance increased signicantly from the mean
(SD) 11.2 (6.7) seconds when measured immediately
before kratom consumption to the mean (SD) 24.9 (39.4)
seconds at 1 hour after consuming the kratom drinks. In
contrast, the mean (SD) pain tolerance was 15.0 (19.0)
seconds when measured immediately before consuming
the placebo drinks and 12.0 (8.1) seconds at 1 hour after
consuming the placebo drinks (see Figure 3).
There was a signicant interaction between the
drink type and time after consumption (F(2,65.5)=3.20,
p=0.05) with signicant changes in pain tolerance after
kratom consumption. After consuming the active kratom
drinks, pain tolerance was signicantly higher at 1 hour
compared to 0 hour (t(68.3)=2.77, p=0.007) and com-
pared to 2 hours (t(50)=2.06, p=0.04), with no signicant
dierences between 0 hour and 2 hours (t(51.8)=1.04,
p=0.30). After consuming the placebo drinks, none of the
pairwise dierences of the three timepoints were signif-
icant (all p-values > 0.20). The pain tolerance dierence
at 1 hour after the drink consumption between kratom and
placebo was not statistically signicant (p=0.12).
Pain onset showed a signicant main eect of kratom
vs placebo (F(1,48.1)=8.68, p=0.005), it was longer after
Figure 4. The means of pain onset, in seconds, immediately before the drink consumption and at 1 and 2 hours after
consumption for kratom and placebo drinks. The error bars represent 95% condence intervals.

Vicknasingam et al.: Kratom and pain tolerance236
No adverse eects were observed in the study. All
participants completed all study tasks and procedures,
and none reported any discomfort or unusual symptoms.
None of the participants reported withdrawal symptoms
either using spontaneous self-report or had signicant
withdrawal symptoms based on the COWS scores. All
urine toxicology screens conducted at the end of the test-
ing day were negative.
All participants reported long histories of daily
kratom consumption, with high frequency of daily con-
sumption and substantial amounts consumed. It is not
possible to quantify these reports into markers that could
be used to approximate amounts of plant material or ac-
tive ingredients consumed. However, despite the reported
long duration and high levels of daily kratom consump-
tion, during documented kratom discontinuation lasting
from 10 to 20 hours, no participant reported or displayed
discomfort, symptoms, or signs of potential withdrawal
symptoms.
A substantial amount of misinformation has been
published in literature and disseminated in media reports,
creating a misconception that kratom is simply a danger-
ous opioid. Kratom is a plant that contains many alka-
loids and other potentially active substances [1,21,23].
Psychoactive eects of consuming plant material are
likely to result from synergistic interactions among many
substances, including possible competing agonist and
antagonist eects on opioid and other receptors [21].
Limitations
The enrolled cohort of participants resulted from
the relatively restrictive inclusion/exclusion criteria of
signicantly 1 hour after active kratom drinks were con-
sumed in laboratory settings. The ratings of unpleasant-
ness of the CPT task decreased signicantly 1 hour after
consuming the active kratom drinks. The assessments of
the blinding procedures indicated that participants were
not able to distinguish between the placebo and the active
kratom drinks based either on taste or other perceptual,
subjective eects.
These study ndings provide the rst objectively
measured evidence obtained in a controlled research
with human subjects that are preliminarily supporting or
conrming previously published reports of kratom pain
relieving properties based on self-reports collected in
observational studies.
Because of laboratory assessment and instrumenta-
tion limitations, only mitragynine could be measured in
the collected plasma samples and in the prepared drinks.
Consequently, mitragynine concentration levels were
used as approximate markers to ensure that the study ac-
tive kratom decoction approximated the strength of drinks
that are typically consumed in natural settings, and the
patterns of mitragynine plasma concentrations obtained
from the study participants were used as a verication
of the randomization procedures and to document that
no additional kratom was consumed during the study. As
seen in Figure 2, the mitragynine plasma proles peaks
match the corresponding randomization sequences.
Large individual dierences in pain responses, illus-
trated by the 95% CI error bars in Figure 3, and in mi-
tragynine plasma levels, Figure 2, were observed. There
were no measurable or discernible relationships between
the mitragynine plasma proles and pain responses pro-
les.
Figure 5. The means of CPT unpleasantness immediately before the drink consumption and at 1 and 2 hours after
consumption for kratom and placebo drinks. The error bars represent 95% condence intervals.

Vicknasingam et al.: Kratom and pain tolerance 237
chemicals or contaminated with pathogens [9,11,33,34].
Acknowledgments: The research was supported in part
by the Ministry of Education of Malaysia under the HICoE
Programme: 311.CDADAH.4401009.
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the current study and may not be representative of other
groups of kratom users. Therefore, the generalizability of
the study ndings may be limited. However, the current
study was aimed to objectively detect a signal under
controlled laboratory conditions rather than to obtain a
broadly generalizable evidence. Further research with
larger and more diverse samples, including research
enrolling kratom naïve participants is needed to obtain
more generalizable evidence of kratom’s pain relieving
properties.
The study was not able to enroll female participants
despite strong outreach eorts. Kratom use among
females in Malaysia is culturally restricted and less
prevalent than among males and previous research in
Malaysia encountered similar challenges in enrolling
female participants [5,32]. The sample size was too small
to evaluate potential factors contributing to the observed
large data variability.
Instrumentation limitations precluded measurement
of other active compounds in kratom leaves and in blood
samples. Consequently, the full biochemical composition
of the study kratom decoction and preparations consumed
in natural settings are unknown. Further research is need-
ed in this area.
The study design, including the lack of kratom specif-
ic and validated methods to assess withdrawal symptoms
and the lack of a control, kratom-naïve group precluded
longer range evaluations of potential kratom withdrawal
symptoms that could emerge later than 10-20 hours after
kratom discontinuation, and precluded evaluations of
addictive potential of kratom.
CONCLUSIONS
The ndings of increased pain tolerance resulting
from consuming kratom decoction should be interpreted
cautiously. These ndings should be replicated in larger
and more diverse samples to provide rigorous assessment
of the observed eects. Extensive controlled studies
are needed to fully evaluate currently debated potential
benecial and harmful eects of kratom and to determine
its potential future therapeutic value for pain or other
conditions. The study ndings should not be interpreted
as endorsing the use of kratom products for self-treatment
of pain or other conditions. Furthermore, in the current
study, kratom decoction was prepared under strictly con-
trolled laboratory conditions using botanical materials
inspected and identied using precise botanical markers
by scientists with extensive experience studying the
kratom plant. Products that are labeled as “kratom” or
“containing kratom” that are purchased online or in stores
are typically not prepared under such strictly controlled
conditions. There have been reports of such products
being adulterated with psychoactive substances or other

Vicknasingam et al.: Kratom and pain tolerance238
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