Abuse liability and therapeutic potential of the Mitragyna speciosa (kratom) alkaloids mitragynine and 7‐hydroxymitragynine

Wiley

Abstract

Kratom, derived from the plant Mitragyna speciosa, is receiving increased attention as an alternative to traditional opiates and as a replacement therapy for opiate dependence. Mitragynine (MG) and 7‐hydroxymitragynine (7‐HMG) are major psychoactive constituents of kratom. While MG and 7‐HMG share behavioral and analgesic properties with morphine, their reinforcing effects have not been examined to date. 7‐HMG, but not MG, substituted for morphine self‐administration in a dose‐dependent manner in the rat self‐administration paradigm. Following the substitution procedure, re‐assessment of morphine self‐administration revealed a significant increase following 7‐HMG and a significant decrease following MG substitution. In a separate cohort, 7‐HMG, but not MG, engendered and maintained intravenous self‐administration in a dose‐dependent manner. The effects of pretreatment with nalxonaxine (NLXZ), a μ1 opiate receptor antagonist, and naltrindole (NTI), a δ opiate receptor antagonist, on 7‐HMG and morphine self‐administration were also examined. Both NLXZ and NTI reduced 7‐HMG self‐administration, whereas only NLXZ decreased morphine intake. The present results are the first to demonstrate that 7‐HMG is readily self‐administered, and the reinforcing effects of 7‐HMG are mediated in part by μ and δ opiate receptors. In addition, prior exposure to 7‐HMG increased subsequent morphine intake whereas prior exposure to MG decreased morphine intake. The present findings indicate that MG does not have abuse potential and reduces morphine intake, desired characteristics of candidate pharmacotherapies for opiate addiction and withdrawal, whereas 7‐HMG should be considered a kratom constituent with high abuse potential that may also increase the intake of other opiates.

Abuse liability and therapeutic potential of the
Mitragyna speciosa (kratom) alkaloids mitragynine
and 7-hydroxymitragynine
Scott E. Hemby1 , Scot McIntosh1, Francisco Leon2, Stephen J. Cutler3 &
Christopher R. McCurdy2
Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, High Point, NC USA1, Department of Medicinal Chemistry,
College of Pharmacy, University of Florida, Gainesville, FL USA2 and College of Pharmacy, University of South Carolina, Columbia, SC USA3
ABSTRACT
Kratom, derived from the plant Mitragyna speciosa, is receiving increased attention as an alternative to traditional opiates
and as a replacement therapy for opiate dependence. Mitragynine (MG) and 7-hydroxymitragynine (7-HMG) are
major psychoactive constituents of kratom.While MG and 7-HMG share behavioral and analgesic properties with morphine,
their reinforcing effects have not been examined to date. 7-HMG, but not MG, substituted for morphine selfadministration
in a dose-dependent manner in the rat self-administration paradigm. Following the substitution procedure,
re-assessment of morphine self-administration revealed a significant increase following 7-HMG and a significant
decrease following MG substitution. In a separate cohort, 7-HMG, but not MG, engendered and maintained intravenous
self-administration in a dose-dependent manner. The effects of pretreatment with nalxonaxine (NLXZ), a μ1 opiate
receptor antagonist, and naltrindole (NTI), a δ opiate receptor antagonist, on 7-HMG and morphine selfadministration
were also examined. Both NLXZ and NTI reduced 7-HMG self-administration, whereas only NLXZ decreased
morphine intake. The present results are the first to demonstrate that 7-HMG is readily self-administered, and
the reinforcing effects of 7-HMG are mediated in part by μ and δ opiate receptors. In addition, prior exposure to 7-HMG
increased subsequent morphine intake whereas prior exposure to MG decreased morphine intake. The present findings
indicate that MG does not have abuse potential and reduces morphine intake, desired characteristics of candidate pharmacotherapies
for opiate addiction and withdrawal, whereas 7-HMG should be considered a kratom constituent with
high abuse potential that may also increase the intake of other opiates.
Keywords 7-hydroxymitragynine, addiction, mitragynine, opiate, reinforcement, self-administration.
Correspondence to: Scott E. Hemby, Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, 802
International Avenue High Point, NC 27268, USA. E-mail: shemby@highpoint.edu
INTRODUCTION
The increasing use of kratom (Mitragyna speciosa korth;
aka thang, kakuam, thom, ketum, biak biak), a plant indigenous
to Southeast Asia, has emerged as a public health
concern in the US. Kratom has been used traditionally to
combat fatigue and increase work productivity amongst
farm populations in Southeast Asia. Kratom leaves
are chewed or made into an extract and brewed (Hassan
et al. 2013;Warner, Kaufman, & Grundmann 2016), and
consumption is reported to produce stimulation (at low
doses) and opiate-like effects (at higher doses) including
analgesia, antitussive, antidiarrheal, and anti-inflammatory
effects. Historically, kratom has also been used to reduce
the intensity and duration of opiate withdrawal symptoms
(Boyer et al. 2008; Ward et al. 2011; Cinosi et al.
2015; Warner et al. 2016); however, studies assessing
the clinical efficacy of kratom are limited. In Southeast
Asia, regular kratom use has been associated with physical
dependence and withdrawal symptoms (Suwanlert
1975; Saingam et al. 2013; Singh, Muller, &
Vicknasingam 2014), effects attributed in large part to
mitragynine (MG). In the United States, there is growing
concern regarding the safe use of kratom based on
reports of addiction (Sheleg & Collins 2011; Galbis-Reig
2016) and toxicity and fatalities associated with use
ORIGINAL ARTICLE doi:10.1111/adb.12639
© 2018 Society for the Study of Addiction Addiction Biology
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(McWhirter & Morris 2010; Neerman, Frost, & Deking
2013; Singh, Narayanan, & Vicknasingam 2016; Drago
et al. 2017; Fluyau & Revadigar 2017).
Various strains of kratom are widely available over the
internet as well as in various locations throughout the
country. Forecasting models indicate kratom use will continue
to increase in the United States (Stogner 2015).
Currently, kratom consumption remains legal in the majority
of states in the US. FDA’s associate commissioner for
regulatory affairs has stated that the FDA has ‘identified
Kratom as a botanical substance that poses a risk to public
health and has the potential for abuse’ (Food and Drug
Administration, 2016). Concerns about Kratom have led
the FDA to issue an import alert and public health advisory
and the DEA to include kratom on the list of Drugs
and Chemicals of Concern.
Kratom leaves contain more than 25 identified
alkaloids (Hassan et al. 2013). Mitragynine (MG) and 7-
hydroxymitrgynine (7-HMG), the main psychoactive
alkaloids of kratom, constitute approximately 60 and 2
percent of the plant’s alkaloids, respectively (Prozialeck,
Jivan, & Andurkar 2012). MG and 7-HMG are partial
agonists at the μ opiate receptor and weak antagonists
at δ and κ opiate receptors (Kruegel et al. 2016; Varadi
et al. 2016), with 7-HMG exhibiting approximately 5-fold
greater affinity at the μ opiate receptor compared to MG.
Assays of opiate receptor-mediated G-protein function reveal
similar potencies for MG and 7-HMG (Kruegel et al.
2016; Varadi et al. 2016). While both compounds exhibit
naloxone-sensitive antinociceptive activity, 7-HMG exhibits
40-fold greater potency than MG and 10-fold greater
potency than morphine in these assays (Takayama et al.
2002; Matsumoto et al. 2004). Repeated administration
of 7-HMG produces tolerance to the compound’s analgesic
effects as well as cross-tolerance to morphine’s
antinociceptive action (Matsumoto et al. 2005). Chronic
consumption of kratom as well as repeated administration
of 7-HMG induces physical dependence as determined by
naloxone-precipitated withdrawal (Matsumoto et al. 2005).
Few studies have examined the abuse/addiction potential
of MG and 7-HMG. The absence of controlled studies
in humans creates space for basic science studies to
provide critical information to help guide use and policy
decisions. The abuse liability of compounds is generally
assessed in animal models using drug discrimination,
place conditioning and/or self-administration paradigms
—all of which address different aspects of abuse. Studies
in animal models have provided considerable insight into
the behavioral effects of MG and 7-HMG as well as the potential
neurobiological mechanisms underlying those effects.
Acute administration of MG increases locomotor
activity, induces anxiolytic effects and induces conditioned
place preference (Yusoff et al. 2016), while repeated
MG administration induces locomotor
sensitization but impairs performance on a variety of
cognitive tasks (Yusoff et al. 2016; Ismail et al. 2017).
Moreover, MG and 7-HMG fully generalize to the discriminative
stimulus effects of morphine, suggesting the
potential for abuse (Harun et al., 2015).
The reinforcing effects of drugs are an important indicator
of abuse liability which is typically evaluated using
drug self-administration procedures. Inherent in the operational
definition of reinforcement is the contingency
between behavior and drug administration, an important
differentiation between self-administration and place
conditioning and drug discrimination. Drug selfadministration
is widely accepted as the gold standard
of measurements for abuse liability (Katz 1989; Hemby
1999; Lynch & Hemby 2011). In spite of the concern of
the potential abuse liability of MG and 7-HMG in
humans, no published studies to date have examined
the ability of these compounds to maintain selfadministration
in experimental subjects. To that end, we
assessed that ability of MG and 7- HMG to substitute for
morphine self-administration and to engender and maintain
self-administration in drug naïve animals. Additionally,
the contribution of μ and δ opiate receptors on the
reinforcing effects of 7-HMG was examined. Results of
these studies provide an objective assessment of the abuse
potential of MG and 7-HMG in a rodent model that recapitulates
key features of human drug taking.
MATERIALS AND METHODS
Subjects
Male Fischer 344 rats (100–130 days; Charles River,Wilmington,
MA) were housed in a temperature-controlled
vivarium on a 12-hour reversed light/dark cycle (lights
on at 6:00 PM). Rats were group-housed two per cage
with water available ad libitum. Food was restricted such
that rats were maintained at 90 percent of their free feeding
weight throughout the experiment. Experimental sessions
were conducted during the dark phase of the
light/dark cycle. All procedures were performed in accordance
with the High Point University Institutional Animal
Care and Use Committee and the National Institutes of
Health Guide for the Care and Use of Laboratory Animals
(NIH Publication No. 80-23) revised in 1996.
Chemicals
Mitragynine was isolated according to published procedures
(Ponglux et al. 1994). 7-HMG was synthesized from
mitragynine by McCurdy’s research group, Department of
BioMolecular Sciences, University of Mississippi, as previously
published (Ponglux et al. 1994; Takayama et al.
2002). Mitragynine and 7-HMG were analyzed by 1H
NMR, 13C NMR, elemental analysis, HPLC and HR-MS,
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and were found to be >99 percent pure. Morphine SO4
was purchased from Gallipot, Inc. (St. Paul, MN), penicillin
G procaine from Butler Company (Columbus, OH),
propofol, ketamine HCl (Ketaset), xylazine (Xylamed) from
Patterson Veterinary Supply, Inc. (Greely, CO), naltrindole
and naloxonazine from Tocris Bioscience/Biotechne
(Minneapolis, MN). Drugs were dissolved in heparinized
saline. Morphine, MG and 7-HMG were infused in a
volume of 200 μl.
Behavioral apparatus and training
Operant apparatus
Experiments were conducted in operant conditioning
chambers (ENV-008CT; Med Associates, St. Albans, VT)
enclosed in sound-attenuating cubicles (ENV-018; Med
Associates). The front panel of the operant chambers
contained a response lever (4 cm above the floor and
3 cm from the side wall), a cue light (3 cm above the
lever) and a food chute centered on the front wall
(2 cm above the floor) that was connected to a food pellet
dispenser (ENV-023; Med Associates) located behind the
front wall and a tone generator to mask extraneous
noise. A syringe pump (PHM-100; Med Associates)
holding a 20-ml syringe delivered infusions. A counterbalanced
arm containing the single channel liquid swivel
was located 8–8.5 cm above the chamber and attached
to the outside of the front panel. An IBM compatible
computer was used for session programming and data
collection (Med Associates Inc., East Fairfield, VT).
Lever training
Subjects were transferred to the operant chambers for
daily experimental sessions, and responding was engendered
and maintained by delivery of food pellets (45-mg
pellets; Noyes, Lancaster, NH) under an FR 1 schedule of
reinforcement that was gradually increased to FR3 (every
third response produced a food pellet). The lever light was
illuminated when the schedule was in effect. Completion
of the response requirement extinguished lights, delivered
food and was followed by a 20-second timeout (TO) period
during which all lights were extinguished, and responses
had no scheduled consequences. After the TO, the lights
were illuminated, and the FR schedule was again in effect.
Sessions lasted 20 minutes or until 30 food pellets were
delivered. Responding was considered stable when there
was less than 10 percent variation in the number of reinforcers
for three consecutive sessions.
Intravenous jugular surgery
After operant responding was acquired and maintained
by food, subjects surgically implanted with an
intravenous jugular catheter. Venous catheters were
inserted into the right jugular vein following administration
of ketamine (90 mg/kg; IP) and xylazine (5 mg/kg;
IP) for anesthesia as described previously (Pattison et al.
2012; Pattison et al. 2014; McIntosh et al. 2015). Catheters
were anchored to muscle near the point of entry into
the vein. The distal end of the catheter was guided subcutaneously
to exit above the scapulae through a Teflon
shoulder harness. The harness provided a point of attachment
for a spring leash connected to a single-channel
fluid swivel at the opposing end. The catheter was
threaded through the leash and attached to the swivel.
The other end of the swivel was connected to a syringe
(for saline and drug delivery) mounted on a syringe
pump. Rats were administered penicillin G procaine
(75 000 units in 0.25 ml, i.m.) and allowed a minimum
of 5 days to recover before self-administration studies
were initiated. Hourly infusions of heparinized saline
were administered through the catheter to maintain
functional catheters. The health of the rats was monitored
daily by the experimenters and weekly by institutional
veterinarians per the guidelines issued by the
Institutional Animal Care and Use Committee and the
National Institutes of Health. Infusions of propofol
(6 mg/kg; i.v.) were manually administered as needed to
assess catheter patency.
Rats were transferred to the operant chambers for
daily two-hour self-administration sessions. Before each
session, the swivel and catheter were flushed with
500 μl of heparinized saline before connecting the catheter
to the syringe via a 20 ga luer hub and 28 ga male
connector. The start of each session was indicated by
the illumination of the house light, stimulus light above
the lever and the extension of the lever. Completion of
the response requirement was followed by a 20-second
time out (FR3:TO 20 seconds) during which time the
subject received a 200-μl intravenous infusion over the
first 6 seconds, retraction of the lever, extinguishing of lever
light, generation of a tone and illumination of the
house light. At the end of the TO, the lever was extended,
lever light illuminated, tone silenced and the house light
extinguished (Hemby, Smith, & Dworkin 1996; Hemby
et al. 1999; McIntosh et al. 2015).
Experiment 1: Substitution for morphine self-administration
Self-administration was engendered using 100 μg/inf of
morphine sulfate. When responding was stable (two consecutive
sessions in which the number of reinforcers did
not vary by more than 20 percent), the dose was
changed to 50 μg/inf. Following stable responding at this
dose, saline was substituted for morphine until
responding stabilized. Following the conclusion of extinction
testing, rats were assigned to one of two groups to
kratom abuse liability 3
© 2018 Society for the Study of Addiction Addiction Biology
receive MG (n = 9; 25, 50, 100 and 150 μg/inf) or
7-HMG (n = 8; 2.5, 5, 10 and 20 μg/inf)—doses were
randomized. The dose range for MG self-administration
was based on the finding that equivalent doses of morphine
and MG induced place conditioning in rats (Yusoff
et al. 2016). The dose range for 7-HMG was based on the
finding that 7-HMG substitutes for morphine in the drug
discrimination procedure at a dose five-fold lower than
the training dose of morphine. Once responding stabilized
for a particular dose, the next dose was made available
the following session until all doses mentioned above
were assessed. After all doses had been assessed for a subject
within a group, the rat was allowed to self-administer
morphine (50 and 100 μg/inf) to determine the effect of
prior drug history on subsequent morphine intake.
Experiment 2: Acquisition of self-administration
Whereas substitution procedures may be more sensitive
for determining the reinforcing effects of a compound,
acquisition procedures assess only the reinforcing effects
of a single compound, without the potential confound of
prior drug associations. The ability of MG and 7-HMG to
engender and maintain responding without prior drug
history was determined in a separate cohort of rats. Rats
were assigned to one of three groups to self-administer
MG (n = 8; 100 μg/infusion), 7-HMG (n = 8;
10 μg/infusion) or morphine (n = 6; 100 μg/infusion). Following
stable responding at the initial dose, rats in the MG
group were given access to 25 and 50 μg/infusion MG,
7-HMG group was allowed to self-administer 5.0 and
2.5 μg/infusion 7-HMG, while rats in the morphine group
were allowed to self-administer 50 μg/infusion morphine.
The presentation of doses for MG and 7-HMG was
randomized following the initial dose.
Experiment 3: Selective opiate receptor antagonism of
morphine and 7-HMG self-administration
To determine the contribution of μ and δ opiate receptors
on the reinforcing effects of 7-HMG, rats that had previously
acquired morphine and 7-MHG self-administration
were administered naloxonazine (NLXZ), a selective μ1
receptor antagonist or the δ receptor antagonist
naltrindole (NTI). NLXZ (5 and 15 mg/kg, i.p.) and NTI
(0.5 and 5 mg/kg, i.p.) were administered 30 minutes
before the session. The effects of saline pretreatment
and saline extinction on responding were also assessed.
Data analysis
Experiment 1
Morphine self-administration as well as MG and 7-HMG
substitution was analyzed using a one-factor ANOVA
(Dose). Morphine self-administration before and after
MG and 7-HMG substitution was analyzed using a twoway
ANOVA (Dose × Pre/Post). Analysis of three days following
MG and 7-HMG substitution was conducted using
a two-way repeated measures ANOVA (Dose × Pre/Post)
with Sessions as the repeated measure. Experiment 2.
Acquisition of self-administration was analyzed using
one-factor ANOVA (Dose) ANOVA and number of infusions
as the dependent measure. Experiment 3. Comparisons
between baseline intake and intake following
saline pretreatment were conducted using two-tailed
paired t-test for both the morphine and 7-HMG groups.
The effects of NLXZ and NTI on morphine and 7-HMG
were analyzed independently using a one-factor ANOVA
(Antagonist Dose). Analysis of the session in which the
antagonists or saline were administered, and the following
session was conducted using a two-way repeated
measures ANOVA (Dose × Day) with Sessions as the
repeated measure. The number of infusions was the
dependent variable for analyses. Where appropriate, post
hoc analyses were conducted using Tukey’s test.
RESULTS
Substitution and reintroduction of morphine
Responding was engendered and maintained by morphine
at the doses tested [F(2,17) = 24.4, P < 0.0001].
Morphine self-administration was dose-dependent with
both morphine doses significantly greater than saline
and 50 μg greater than 100 μg/infusion (P < 0.05)
(Fig. 1a). MG was not reliably self-administered when
substituted for morphine [F(4,38) = 0.51, P = 0.73].
MG intake was not significantly different from vehicle,
suggesting that MG does not function as a reinforcer at
the doses tested (Fig. 1b). In contrast, 7-HMG substituted
for morphine with intake dependent on the dose available
[F(4,32) = 6.3, P = 0.0009]. The number of infusions
obtained for 5 and 10 μg/inf were significantly greater
than vehicle (P < 0.05), confirming that these doses of
7-HMG functioned as reinforcing stimuli. 7-HMG resulted
in an inverted ‘U’-shaped dose-effect function with maximal
intake observed at 5 and 10 μg/inf (Fig. 1c).
Following completion of the substitution protocol,
morphine self-administration was re-assessed. Morphine
intake was significantly altered by both MG
[F(1,32) = 5.5, P = 0.025] and 7-HMG
[F(1,24) = 12.92, P = 0.0015], albeit in opposite directions.
MG exposure significantly reduced morphine selfadministration
of 50 μg (P < 0.01), but not 100 μg
[Fig. 1d (top panel)]. The decrease in morphine selfadministration
(50 μg) was not observed on the first
day following MG exposure but was significantly decreased
on days two and three Fig. 1c (middle panel)].
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© 2018 Society for the Study of Addiction Addiction Biology
Intake of 100-μg morphine did not differ from saline
before or following exposure to MG [Fig. 1d (bottom
panel)].
In contrast, 7-HMG administration significantly
increased self-administration of 50-μg morphine
(P < 0.01), and there was a trend towards increased
intake of 100-μg morphine (P = 0.054) [Fig. 1e (top
panel)]. Morphine self-administration (50 μg) was
significantly elevated for the three days following 7-
HMG exposure by 109, 110 and 95 percent, respectively
Figure 1 Substitution of MG and 7-HMG following morphine self-administration and the impact on subsequentmorphine self-administration. (a) Morphine
was reliably self-administered in a dose-dependent manner (***P< 0.001 saline versus 50 μg/inf and 50 versus 100 μg/inf, **P< 0.01 saline versus
100 μg/inf). (b) MG did not substitute for morphine (100 μg/inf) at any of the doses tested. (c) 7-HMG substituted for morphine (100 μg/inf) in a dosedependent
manner (*P< 0.05 saline versus 5 μg/inf, 10 versus 20 μg/inf, P < 0.01 saline versus 10 μg/inf). (d, e) Comparisons were made between morphine
self-administration pre-exposure and post-exposure toMG(n=9), and 7-HMG(n = 7) substitution. (d) Top panel: Comparison of morphine intake
pre-MG exposure versus post-MG exposure revealed a significant difference in self-administration (**P < 0.01, pre-MG exposure versus post-MG exposure
for 50 μg/inf). (d) Middle panel: Assessment ofmorphine self-administration for 3 days followingMGexposure revealed a decrease in intake of 50 μg/
inf morphine compared to pre-MG exposure levels (**P < 0.01 sessions 2 and 3 pre-exposure versus post-exposure to MG). (d) Bottom panel but had
no change in morphine self-administration of 100 μg/inf across the 3 days. (e) Top panel, Comparison of morphine intake pre-7-HMG exposure versus
post-7-HMG exposure revealed a significant difference in self-administration (**P<0.01, pre-7-HMG exposure versus post-7-HMG exposure for 50 μg/
infmorphine). (e) Middle panel: Substitution of 7-HMG resulted in a significant increase inmorphine self-administration (50 μg/inf) for the 3 days following
7-HMG exposure (**P < 0.01 sessions 1 and 2, *P < 0.05 session 3 pre-exposure versus post-exposure to 7-HMG). (e) Bottom panel whereas selfadministration
of 100 μg/inf of morphine was not altered by 7-HMG exposure. Data are expressed as mean ± s.e.m.
kratom abuse liability 5
© 2018 Society for the Study of Addiction Addiction Biology
[Fig. 1e (middle panel)]. Self-administration of 100-μg
morphine was also increased for the 3 days following
7-HMG exposure by 53, 75 and 41 percent, respectively
[Fig. 1e (bottom panel)]. We also determined whether
morphine self-administration was altered by forced abstinence
for an equivalent number of days to the substitution
procedure. Morphine intake was not altered by the forced
abstinence period [F(1,20) = 8, P = 0.1523], suggesting that
the amount of time between morphine self-administration
availability did not influence intake (data not shown).
Acquisition of self-administration
Following the assessment of the ability of MG and 7-HMG
to substitute for morphine self-administration, we
assessed the ability of MG and 7-HMG to engender and
maintain responding in a separate cohort of rats.
Morphine was readily self-administered at the doses
tested [F(2,17) = 24, P < 0.0001]. Self-administration
of 50 and 100 μg was greater than saline and the number
of infusions obtained for the 50 μg/inf was significantly
greater than 100 μg/inf (Fig. 2a). In contrast,
access to MG did not reliably engender or maintain selfadministration
at any of the doses tested
[F(3,31) = 2.255, P = 0.1038] as intake was not significantly
different from vehicle, indicating that MG does not
function as a reinforcer in this procedure at the doses
tested (Fig. 2b). Similar to morphine, rats selfadministered
2.5, 5 and 10 μg/infusion of 7-HMG
[F(3,31) = 6.2, P = 0.0024]—the same doses that
substituted for morphine self-administration (Fig. 2c).
The number of infusions obtained 5 and 10 μg/inf was
significantly greater than vehicle (P < 0.05), demonstrating
that these doses served as reinforcing stimuli.
Intake for 2.5 and 20 μg/inf 7-HMG did not significantly
differ from vehicle. Comparison of saline intake for all
groups revealed there was no statistically significant
difference between the groups [F(2,22) = 2.99,
P = 0.0731]. Tukey’s post hoc test revealed there was
no statistically significant difference between any of
the group pairs.
Antagonist effects on 7-HMG and morphine
self-administration
The effects of the selective μ opiate receptor antagonist
NLXZ and the δ receptor antagonist NTI on morphine
(50 μg/inf) and 7-HMG (5 μg/inf) self-administration
were examined. The selection was based on doses that
maintained the highest intake for morphine and 7-HMG
self-administration, respectively. NLXZ pretreatment attenuated
morphine self-administration [F(2,15) = 76,
P < 0.0001] [Fig. 3a (left panel)]. Both 5 and
15 mg/kg NLXZ produced a significant decrease in the
number of infusions for morphine (P < 0.05); however,
there was no significant difference in the number of infusions
between the doses. Morphine intake was significantly
decreased the day of NLXZ pretreatment for both
doses (P < 0.001) and returned to control levels the
following session [Fig. 3a (right panel)]. Pretreatment
with NLXZ also significantly reduced 7-HMG selfadministration
[F(2,22) = 39, P < 0.0001] [Fig. 3b (left
panel)]. Both NLXZ doses significantly reduced 7-HMG
Figure 2 Acquisition of intravenous self-administration with 7-
HMG but not MG. (a) Rats acquired morphine self-administration,
and intake was dose dependent. (b) Rats did not acquire self-administration
of MG at any of the doses tested. (c) However, a separate
cohort of rats acquired self-administration of 7-HMG. n = 8 rats. Data
are expressed as mean ± s.e.m. *P < 0.05, **P < 0.01, #P < 0.0001
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© 2018 Society for the Study of Addiction Addiction Biology
Figure 3 Selective μ and δ opiate receptor antagonist pretreatment alters 7-HMG self-administration. Effects of NLXZ on morphine (50 μg/
inf) and 7-HMG (5 μg/inf) self-administration. Baseline drug intake was not significantly different than intake following saline pretreatment for
morphine analysis or 7HMG analysis. (a) Left panel NLXZ significantly reduced the number of morphine infusions compared to saline pretreatment
(#P < 0.0001, saline versus 5 and 15 mg/kg NLXZ). (a) Right panel There was a significant interaction between NLXZ doses and sessions
with infusions on the day of pretreatment significantly less than following saline pretreatment for the 15 mg/kg NLXZ dose (***P < 0.001). (b)
Left panel NLXZ decreased 7-HMG self-administration, the effect was dose dependent (#P < 0.0001, *P < 0.05) and (b) right panel There was
a significant interaction between NLXZ doses and sessions with infusions on day of pretreatment significantly less than following saline pretreatment
for both NLXZ doses. We also examined the effects of NTI on morphine (50 μg/inf) and 7-HMG (5 μg/inf) self-administration. Baseline
drug intake was not significantly different than intake following saline pretreatment for morphine analysis and 7HMG analysis. (c) Left panel NTI
did not significantly alter morphine self-administration at either dose tested. (c) Right panel No significant interaction of NTI dose and session was
observed. (d) Left panel Pretreatment with NTI decreased 7-HMG self-administration in a dose-dependent manner (**P < 0.01, saline versus
5.0 mg/kg NTI, 0.5 versus 5.0 mg/kg NTI) and (d) right panel There was a significant interaction between NTI doses and sessions although
Bonferroni’s post hoc analysis did not reveal any significant differences between saline and NTI pretreatment for either day. Data are expressed
as mean ± s.e.m.
kratom abuse liability 7
© 2018 Society for the Study of Addiction Addiction Biology
intake compared to saline (P < 0.0001), although intake
following 15 mg/kg was significantly less than following
5 mg/kg (P < 0.05). For both doses, 7-HMG intake was
significantly reduced the day of NLXZ pretreatment
(P < 0.001) and returned to control levels the following
session [Fig. 3b (right panel)]. Comparison of baseline intake
was not significantly different than intake following
saline pretreatment for the morphine [t = 2.5, df = 5,
P = 0.057] or 7-HMG groups [t = 0.03, df = 7,
P = 0.98]; therefore, the number of infusions following
saline was used for comparison with NLXZ.
NTI pretreatment produced differential effects on morphine
and 7-HMG self-administration. Neither 0.5 nor
5.0 mg/kg NTI significantly altered morphine selfadministration
[F(2,17) = 0.88, P = 0.434] [Fig. 3c
(left panel)]. Morphine intake following either dose of
NTI did not differ significantly from saline pretreatment
the day of or the day following pretreatment [Fig. 3c (right
panel)]. In contrast, 5.0 mg/kg NTI pretreatment significantly
altered 7-HMG self-administration [F(2,23) = 11,
P < 0.0007] [Fig. 3d (left panel)]. The effect of NTI on
7-HMG intake was dose dependent as intake following
the 5 mg/kg dose was significantly lower than saline
(P < 0.05) as well as the 0.5 g/kg dose (P < 0.05).
7-HMG intake was significantly reduced the day of
5.0 mg/kg NTI pretreatment (P < 0.05) and returned
to control levels the following session [Fig. 3 (right
panel)]. For naltrindole (NTI), comparison of baseline intake
was not significantly different than intake following
saline pretreatment for the morphine [t = 0.13, df = 5,
P = 0.90] or 7-HMG groups [t = 0.94, df = 7, P = 0.38].
DISCUSSION
The present study provides the first characterization of
the reinforcing effects of MG and 7-HMG in an animal
model of human drug consumption. Using the intravenous
self-administration procedure, the study demonstrates
7-HMG, but not MG, substitute for morphine
self-administration and engender and maintain selfadministration
in drug-naïve rats. Under both the
substitution and acquisition self-administration procedures,
7-HMG self-administration exhibited an inverted
‘U’ dose–effect curve, typical of other drugs of abuse
under similar experimental conditions, wherein low to
moderate doses increase responding and higher doses
decrease responding (Wilson, Hitomi, & Schuster 1971;
Pickens 1978). In both self-administration procedures,
7-HMG maintained intake above levels observed for
saline, indicating the compound serves as a reinforcing
stimulus within the range of the doses examined.
Previous studies have shown MG induces a conditioned
place preference (Sufka et al. 2014; Yusoff et al. 2016;
Yusoff et al. 2017) and both MG and 7-HMG generalize
to the discriminative stimulus effects of morphine (Harun
et al. 2015). Both procedures provide valuable information
about the abuse liability of compounds such as the
motivational effects of contextual cues associated with a
drug (place conditioning) and whether a compound
shares subjective effects with a known drug of abuse
(drug discrimination). Self-administration is used to examine
the reinforcing effects of drugs, a key feature
influencing the potential risk for abuse. With regard to
opioids, findings from studies using rat selfadministration
models are highly consistent with clinical
measures of abuse liability and have proven to be a reliable
predictor of abuse liability in humans (O’Connor
et al. 2011). While MG shares a similar mechanism of action
with morphine, the present results demonstrate a
difference in the reinforcing effects and thus the abuse
potential between the two compounds. The discrepancy
between the present finding and those of aforementioned
place conditioning and drug discrimination studies are
intriguing and warrant further assessment of routes of
administration as well as non-human primate and human
abuse potential studies. The self-administration of
7-HMG along with the shared subjective effects of morphine
(Harun et al. 2015) indicate that 7-HMG has a significant
potential to be abused. Additional studies are
needed to examine the ability of 7-HMG selfadministration
to induce physical dependence and
withdrawal, and the effects of 7-HMG on relapse to
morphine, other opiates and other drug classes. The
present findings along with the results of additional studies
will provide critical information as to whether the
compounds warrant control under the Controlled
Substances Act.
In addition to abuse liability assessments, we also
explored the impact of exposure to MG and 7-HMG to
subsequent morphine intake following completion of the
substitution procedure. Exposure to less than 2 mg of
MG over a 2-week period (when examining the ability
of MG to substitute for morphine) significantly reduced
subsequent morphine self-administration up to 3 days
following the last administration of MG. These findings
raise the possibility that MG may contribute to the
reported reduction in opiate intake in dependent individuals.
Buprenorphine, a μ receptor partial agonist like MG,
also reduced morphine (Harrigan & Downs 1981) as well
as heroin self-administration (Mello, Bree, & Mendelson
1983) when administered continuously or intravenously
twice daily but the effects on intake were acute. The
effects of MG on morphine intake in the present study
are intriguing but should be interpreted with caution
for several reasons including the lack of morphine dosedependent
effects, the absence of a MG dose-effect determination
on morphine and other commonly abused
opiates, and the need to assess the effect of MG on animal
8 Scott E. Hemby et al.
© 2018 Society for the Study of Addiction Addiction Biology
models of opiate relapse and withdrawal. The finding that
MG, in contrast to buprenorphine which has abuse liability
(Jones et al., 2017), does not appear to have abuse liability
and reduces morphine intake is intriguing and
warrants further investigation to determine the efficacy
of MG as a potential pharmacotherapy for opiate addiction.
Comparison of MG with buprenorphine as well as
methadone, on the self-administration of morphine as
well as other opiates, is needed to determine the therapeutic
potential and potency of MG. The effects of 7-
HMG on morphine intake are opposite to those observed
with MG. An average total intake of approximately
700 μg of 7-HMG over a 2 to 3-week period (when examining
substitution for morphine) induced a significant elevation
in subsequent morphine self-administration over
3 days following the last exposure to the compound, indicative
of tolerance to morphine. Previous reports indicate
that kratom users develop tolerance, increasing
intake over time (Suwanlert 1975; Hassan et al. 2013).
While tolerance to the analgesic effects of 7-HMG has
been reported (Matsumoto et al. 2005; Matsumoto et al.
2008), no published studies to date report tolerance or
cross-tolerance to morphine (or other opiates) intake.
The increase in morphine intake in the present study
could reflect a compensatory response to withdrawal
from 7-HMG; however, this is unlikely as no overt signs
of withdrawal were observed. Additional studies are warranted
to determine if the observed increase in morphine
intake following 7-HMG self-administration is related to a
change in the reinforcing effects of morphine, a decrease
in the adverse effects or a combination of the two. The
demonstration that 7-HMG has significant abuse potential
and increases the intake of morphine and possibly
other opiates has significant potential clinical relevance.
The present study utilized two variations of the intravenous
self-administration procedure to determine abuse
liability of MG and 7-HMG: substitution and acquisition
of self-administration. The substitution procedure
assessed the ability of MG and 7-HMG to substitute for
morphine in rats with a history of morphine selfadministration
and provided a clinically relevant evaluation
given the potential for cross-generalization of opiates,
the use of kratom to reduce intake of and
withdrawal from other opiates, and the use of kratom
as an affordable substitute for heroin (Boyer, Babu, &
Macalino 2007; Boyer et al. 2008; Vicknasingam et al.
2010). The ability of 7-HMG to substitute for morphine
in the present study suggests that the reinforcing effects
may be mediated by similar neural mechanisms such as
μ and δ opiate receptors. The effects of NLXZ on 7-HMG
and morphine self-administration may reflect nonspecific
effects on responding; however, we do not consider
this a viable interpretation inasmuch as NLXZ doses
within this range do not affect responding maintained by
saccharin or food (Liu & Jernigan 2011; Peana et al.
2011). The present results confirm and extend previous
studies of the effects of NLXZ on opiates including decreasing
heroin self-administration (Negus et al. 1993),
decreasing morphine-induced place conditioning in rats
(Piepponen et al. 1997) and attenuating the discriminative
stimulus effects of morphine (Suzuki et al. 1995).
These results indicate that the reinforcing effects of morphine
7-HMG are mediated in part by μ opiate receptors.
NTI, the selective δ opiate receptor antagonist, attenuated
7-HMG in a dose-dependent manner. The lack of
effect of NTI on morphine self-administration is
supported by previous studies, which indicates that NTI
does not alter morphine place conditioning (Suzuki
et al. 1994; Piepponen et al. 1997) or the discriminative
stimulus effects of morphine (Stevenson et al. 2000). In
contrast, NTI and naltrindole-50-isothiocyanate have
been shown to attenuate the reinforcing effects of heroin
(Negus et al. 1993; Martin et al. 2000); however, δ opiate
receptors are not considered to directly mediate heroin
reinforcement. The reinforcing effects of heroin are mediated
via μ opiate receptors which bind the major heroin
metabolites, morphine and 6-monoacetylmorphine,
neither of which bind to the δ receptor with appreciable
affinity. The difference in the effects of NTI between the
Negus et al. study is likely attributable to the finding that
only the 10 and 17 mg/kg doses of NTI were effective in
attenuating heroin self-administration—compared with
0.5 and 5 mg/kg in the present study. Given that the
5 mg/kg NTI dose slightly decreased morphine selfadministration,
higher doses of NTI may have significantly
attenuated intake. The significant attenuation of
the reinforcing effects of 7-HMG by NTI reflects involvement
of δ opiate receptors in the reinforcing effects of this
compound. Given that 7-HMG is a weak δ opiate receptor
antagonist, the finding that antagonism of the δ receptor
partially attenuates the reinforcing effects of this compound
seems counterintuitive. However, two potential
mechanisms may account in part for the finding. Martin
et al. suggested that morphine-induced activation of μ
opiate receptors in the pallidum stimulates release of
met-enkephalin that then binds to δ opiate receptors to
exert reinforcing effects (Martin et al. 2000). Because
7-HMG is a partial μ opiate receptor agonist, the compound
may exert effects similar to morphine via this
mechanism. An alternative hypothesis suggests that
chronic μ opiate receptor stimulation results in δ opiate
receptor recruitment and μ opiate receptor desensitization.
However, the dose-dependent effect of NLXZ on
7-HMG indicates that μ receptors were not de-sensitized.
The manner in which δ opiate receptors are involved in
7-HMG reinforcement remains to be determined. Nonetheless,
results from the present study indicate that both
μ and δ opiate receptors contribute to the reinforcing
kratom abuse liability 9
© 2018 Society for the Study of Addiction Addiction Biology
effects of 7-HMG. Current pharmacotherapies for opiate
addiction including methadone, buprenorphine and naloxone
do not bind appreciably to δ opiate receptors and
therefore may be less effective in treating kratom abuse.
The current results are the first demonstration of selfadministration
of MG and 7-HMG in the preclinical literature;
however, several issues related to study design and
methodology deserve to be addressed. First, food was
restricted for all subjects in the present study in order to
enhance acquisition and maintenance of selfadministration
in both the substitution and acquisition
procedures. Previous studies have demonstrated that food
restriction facilitates the acquisition of opiate selfadministration
and increases intake during the maintenance
phase as well as enhances drug seeking (Piazza &
Le Moal 1998). The absence of MG acquisition or substitution
under food restriction conditions provides confidence
that administration of this alkaloid is not
reinforcing even under conditions that enhance the probability
of intake. Nonetheless, negative results in selfadministration
procedures are difficult to interpret and
may be due to multiple experimental variables that are
not optimal for the drug being investigated including,
but not limited to, the schedule of reinforcement, response
contingencies, selected doses, rate of infusion,
route of administration and drug availability. For example,
the lack of MG self-administration may be attributed
in part to the route of administration. Kratom is administered
orally by humans whereas intravenous administration
was used in the present study—routes which would
yield different rates of onset of drug effects, drug levels,
duration of effect and metabolism. The concern is mitigated
to some extent by the finding that 7-HMG, a structurally
similar compound from the same plant, is readily
self-administered intravenously using the same procedure.
Thus, the relevance of the current findings using
the intravenous self-administration is not diminished, although
future studies need to address the abuse liability
of MG and 7-HMG using voluntary oral consumption
methods (food and liquid). Another caveat to the present
experimental design is the use of one versus two levers in
the self-administration procedure. The determination of
reinforcement is based on the statistical comparison of intake
maintained by doses of a drug versus a negative control,
which is vehicle in the present study. Alternatively,
comparisons can be made between the rates of
responding on an ‘active’ versus the ‘inactive’ lever. In either
case, drugs that engender and/or maintain
responding at levels that exceed responding maintained
by the negative control are considered to be selfadministered
(function as reinforcing stimuli) (O’Connor
et al. 2011).
In summary, the present findings from the rodent selfadministration
model indicate that MG, the main kratom
alkaloid, does not have abuse or addiction potential and
reduces morphine intake—desired characteristics of
candidate pharmacotherapies for opiate addiction and
withdrawal. In contrast, 7-HMG should be considered a
kratom constituent with high abuse potential that may
also increase the intake of other opiates. Although
7-HMG constitutes only 2 percent of the alkaloid content
of kratom, purified extracts of 7-HMG are widely available
on the internet and are consumed for their euphoric
effects. Additional danger is posed by adulteration or
the presence of high concentrations of 7-HMG in
commercially available kratom products (Lydecker et al.
2016) which may increase the abuse liability.
Acknowledgements
The study was supported by funding from the High Point
University, Fred Wilson School of Pharmacy. Additional
support was provided by an Institutional Development
Award (IDeA) P20GM104932 from the National
Institutes of Health.
Conflict of Interest
The authors have no competing financial interests.
Authors Contribution
S.E.H., S.J.C. and C.R.M. jointly conceived the study; S.E.
H. designed the experiments; J.F., S.J.C. and C.R.M.
isolated, purified and prepared salts of mitragynine and
7-hydroxymitragynine; S.M. and S.E.H. performed the
experiments, collected the data and analyzed the data;
S.E.H. wrote and revised the manuscript and S.M., S.J.C.
and C.R.M. edited the manuscript.
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