Melatonin in drug addiction and addiction management: Exploring an evolving multidimensional relationship

Abstract

Melatonin is a pleiotropic signalling molecule that regulates several physiological functions, and synchronises biological rhythms. Recent evidences are beginning to reveal that a dysregulation of endogenous melatonin rhythm or action may play a larger role in the aetiology and behavioural expression of drug addiction, than was previously considered. This review, using information garnered from extant literature, examines the roles played by melatonin and its receptors in addictive behaviours, addiction related changes in brain chemistry and brain plasticity; and its possible benefits in the management of drug associated withdrawal syndrome, relapse and behavioural sensitisation.

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World Journal of
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World J Psychiatr 2018 June 28; 8(2): 51-74
ISSN 2220-3206 (online)

Contents
IWJP
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W J World Journal of
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P
Volume 8 Number 2 June 28, 2018
REVIEW
51 Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment
of schizophrenia and affective disorders
Parkin GM, Udawela M, Gibbons A, Dean B
64 Melatonin in drug addiction and addiction management: Exploring an evolving multidimensional
relationship
Onaolapo OJ, Onaolapo AY

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Volume 8 Number 2 June 28, 2018
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Melatonin in drug addiction and addiction management:
Exploring an evolving multidimensional relationship
Olakunle J Onaolapo, Adejoke Y Onaolapo
Olakunle J Onaolapo, Behavioural Neuroscience/Neuroph-
armacology Unit, Department of Pharmacology and Therapeutics,
Ladoke Akintola University of Technology, Osogbo 230263,
Osun State, Nigeria
Adejoke Y Onaolapo, Behavioural Neuroscience/Neurobiology
Unit, Department of Anatomy, Ladoke Akintola University of
Technology, Ogbomosho 210211, Oyo State, Nigeria
ORCID number: Olakunle J Onaolapo (0000-0003-2142-6046);
Adejoke Y Onaolapo (0000-0001-7126-7050).
Author contributions: Onaolapo AY and Onaolapo OJ contributed
to writing sections of the review article, were also both responsible
for the critical revision, editing, and the nal approval of the nal
version
Conict-of-interest statement: None.
Open-Access: This article is an open-access article which was
selected by an in-house editor and fully peer-reviewed by external
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and
the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
Manuscript source: Invited manuscript
Correspondence to: Dr. Adejoke Y Onaolapo, MBBS, PhD,
Behavioural Neuroscience/Neurobiology Unit, Department of
Anatomy, Ladoke Akintola University of Technology, P.M.B
4000, Ogbomosho 210211, Oyo State,
Nigeria. ayonaolapo@lautech.edu.ng
Telephone: +234-80-62240434
Received: April 2, 2018
Peer-review started: April 3, 2018
First decision: May 2, 2018
Revised: May 6, 2018
Accepted: May 9, 2018
Article in press: May 10, 2018
Published online: June 28, 2018
Abstract
Melatonin is a pleiotropic signalling molecule that regu-
lates several physiological functions, and synchronises
biological rhythms. Recent evidences are beginning to
reveal that a dysregulation of endogenous melatonin
rhythm or action may play a larger role in the aetiology
and behavioural expression of drug addiction, than was
previously considered. Also, the ndings from a number
of animal studies suggest that exogenous melatonin
supplementation and therapeutic manipulation of mel-
atonin/melatonin receptor interactions may be benecial
in the management of behavioural manifestations of
drug addiction. However, repeated exogenous melatonin
administration may cause a disruption of its endogenous
rhythm and be associated with potential drawbacks that
might limit its usefulness. In this review, we examine
the roles of melatonin and its receptors in addictive beh-
aviours; discussing how our understanding of melatonin’
s modulatory effects on the brain rewards system and
crucial neurotransmitters such as dopamine has evolved
over the years. Possible indications(s) for melatonergic
agents in addiction management, and how manipulations
of the endogenous melatonin system may be of benet
are also discussed. Finally, the potential impediments to
application of melatonin in the management of addictive
behaviours are considered.
Key words: Dopamine; Drug dependence; Biological
rhythms; Neuroplasticity; Brain reward
© The Author(s) 2018. Published by Baishideng Publishing
Group Inc. All rights reserved.
Core tip: Melatonin is a pleiotropic signalling molecule
that regulates several physiological functions, and sy-
nchronises biological rhythms. Recent evidences are
beginning to reveal that a dysregulation of endogenous
melatonin rhythm or action may play a larger role in the
aetiology and behavioural expression of drug addiction,
than was previously considered. This review, using inf-
REVIEW
64 June 28, 2018
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Submit a Manuscript: http://www.f6publishing.com
DOI: 10.5498/wjp.v8.i2.64
World J Psychiatr 2018 June 28; 8(2): 64-74
ISSN 2220-3206 (online)
World Journal of
Psychiatry
W J P

ormation garnered from extant literature, examines
the roles played by melatonin and its receptors in add-
ictive behaviours, addiction related changes in brain
chemistry and brain plasticity; and its possible benets
in the management of drug associated withdrawal syn-
drome, relapse and behavioural sensitisation.
Onaolapo OJ, Onaolapo AY. Melatonin in drug addiction and
addiction management: Exploring an evolving multidimensional
relationship. World J Psychiatr
2018; 8(2): 64-74 Available
from: URL: http://www.wjgnet.com/2220-3206/full/v8/i2/64.htm
DOI: http://dx.doi.org/10.5498/wjp.v8.i2.64
INTRODUCTION
Drug addiction or substance use disorder has been
dened as a chronic disease of the brain which is cha
racterised by uncontrollable and compulsive drugseeking
and use; and which is associated with the development
of a negative emotional state in the absence of drug
access[1,2]. There have been suggestions that drug ad
diction is both a social and a medical problem dating
as far back as recorded human history[3] and which co
ntinues to be a cause for global health concern[4]. Reports
suggest that an estimated total of 246 million people, or
approximately 1 in 20 people aged between 15 and 64
years were exposed to illicit drug in 2013; with surveys
showing that approximately 1 in 10 of these have a
drugaddiction problem[5]. Substance use disorder is ar
guably a serious public health issue, with a significant
economic and health burden on affected individuals and
their families[5]. There is also a signicant societal burden
measured in lost productivity, lawlessness, crime and
increased healthcare costs. Substanceuse disorders
have also been associated with worsening of comorbid
psychiatric and/or medical illness, risky behaviours and
increasing mortality. While the global and economic bur
den of addiction continues to increase worldwide, current
psychopharmacological therapies are falling short of the
desired goals of therapy[6,7].
Over the past few centuries, several theories (social,
biological or psychological) have been proposed to aid
in understanding the aetiology of drug addiction[8]. Also,
while the distinct aetiological bases for drug addiction are
yet unclear, advances in neuroscience have continued
to aid our understanding of the possible mechanisms
that underlie the alterations in emotional balance and
decisionmaking ability that occur with drug addiction[9].
Genetic, environmental, neurodevelopmental and socio
cultural factors have been listed as important contributors
to the development of drug addiction[10]. These factors
have also been shown to increase the susceptibility of
an individual to initiation or sustenance of drug use; and
potentiate the development of structural brain changes
that perpetuate drug use and are characteristic of drug
addiction[9,11,12].
Presently, there is a growing body of evidence ass
ociating disruptions in circadian rhythms and circadian
genes with the development and progression of drug
addiction[13,14]. Studies in human subjects have dem
onstrated circadian rhythm disruptions in individuals
with addiction, with suggestions that environmental
and/or genetic alteration of the normal sleep wake cyc
le increases vulnerability to drug use[13,15]. Studies in
rodents have also demonstrated that diurnal variations
in the behavioural responses to different addiction par
adigms exist[1618]. In rodents, an increase in cocaine
selfadministration, and the intake of drugs of abuse
have been observed at night[16,17,19,20]. There have also
been suggestions that the continued craving for drugs
of abuse is potentiated through the entrainment of the
circadian clock[16,21,22].
Melatonin is a neurohormone that is important in
the entrainment of circadian rhythms, as well as in the
modulation of behaviour and physiological functioning
in all mammals[23]. Some studies have observed a red
uction in melatonin levels, and a delay in attaining its
nocturnal peak concentration in alcoholdependent hu
mans and rodents[23]. Studies have also demonstrated
melatonin’s ability to modulate the reinforcing effects
of a number of drugs of abuse with suggestions that it
may play a crucial role in drug addiction[24]. In this review,
we examine the roles of melatonin and its receptors in
drug addiction, by discussing how our understanding
of melatonin’s modulatory effects on the brain reward
system and crucial neurotransmitters such as dopamine
has evolved over the years. Possible indications(s) for
melatonergic agents in addiction management, and
how manipulations of the endogenous melatonin syst
em may be of benefit are also discussed. Finally, the
potential impediments to application of melatonergic
agents in the management of addictive behaviours are
considered.
Neurobiological and neurochemical basis of drug
addiction
Substance dependence can be described as a disorder
which involves the motivational systems of the brain[25].
Repeated exposure to drugs of abuse has been linked
to the development of longlasting alterations in brain
structure and neuronal circuitry. In the last decade or
more, studies have demonstrated that repeated use
of addictive drugs can alter the neural circuitries that
are involved in reward/ motivation, learning/memory,
affect, stress response and decisionmaking[26]. These
regions which include the ventral tegmental area (VTA),
nucleus accumbens (NAc) and amygdala form a part of
the mesolimbic dopaminergic system and are important
in rewardrelated processes[27]. Adaptations in cortical
regions, including the prefrontal cortex, orbitofrontal
cortex and the anterior cingulate gyrus, which form
the mesocortical pathway, have also been implicated
in addiction[28]. Increase in dopamine release in the
mesolimbic or mesocortical brain regions have been sug
65
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gested to occur in parallel, appearing to mediate different
phases or aspects of drug addiction. The mesolimbic
regions (amygdala and hippocampus) have been linked
to mediating conditioned learning in addiction; while the
prefrontal cortex, orbitofrontal cortex and the anterior
cingulate gyrus mediate executive control and emotional
response to drugs[26].
Chronic drug use has also been associated with alt
erations in the “antireward” pathway which include the
hypothalamicpituitaryadrenal axis[29,30]. Adaptations in
stress response, involving levels of corticosterone cortisol
releasing factor and the adrenocorticotrophic hormone
have also been reported to occur with drug addiction[31,32].
Brain neurotransmitter/neuromodulator changes
also occupy a central role in the establishment, mana
gement and extinction (or otherwise) of addictive beh
aviours. In the brain, the neurochemical targets for a
number of drugs of addiction have been identied[33].
Also, while the pharmacological profiles of the drugs
of addiction are diverse, drugreceptor interactions
can largely explain the wide range of physiological and
behavioural changes that occur with drug use[26]. Also,
there have been reports that suggest that despite the
diversity of behavioural responses, drugs of addiction
may share a common reward neural circuitry. Studies
have shown that most of the addictive drugs appear
to activate the reward system, directly or indirectly
stimulating dopamine release[34,35].
Research has shown that dopaminergic (DA) neurons
that project from the VTA to the NAc play a crucial role
in the processing of stimuli associated with substance
related reward[36]. As a part of their pharmacological
effects, substances with abuse potentials stimulate the
brain reward system by increasing DA release from
the NAc[37]. Also, there are reports that drugs of abuse
induce their initial reinforcing effect by stimulating su
praphysiologic levels of DA in the NAc. These DA surges
(acting via D1 receptors) activate the striatal pathway
(direct), while inhibiting the striatocortical pathway
(indirect) through D2 receptors[10]. Repeated drug use
has also been associated with triggering neuroplastic
changes that involve the glutamatergic inputs to the
striatum and midbrain DA neurons, these alterations
enhance the ways the brain reacts to drug cues, wea
kening selfregulation, reducing sensitivity to nondrug
rewards and increasing sensitivity to stress[10].
There is also ample scientific evidence to suggest
that there are DAindependent reinforcement pathways
in the acute rewarding or pleasurable effects of ad
dictive drugs. A number of studies in animals have sh
own that alcohol, opioids, nicotine and amphetamines
may produce reinforcing effects via DAindependent
mechanisms[3840].
The involvement of some other neurochemicals and
neuromodulators such as opioids, gammaaminobutyric
acid, glutamate, noradrenaline, cannabinoids and ser
otonin in drug addiction have also been suggested[41].
Reports from brain imaging studies have demonstrated
an increase in opioid receptors density in persons ex
periencing withdrawal from alcohol[42], opioids[43] and
cocaine[44]. Studies have also shown that the cortico
striatal glutamate pathway may be important in the
initiation and/or expression of a number of addictive
behaviours; examples include conditioned place pref
erence, drug seeking behaviour and locomotor sensi
tisation[45]. The overall conclusion is that although a
number of neurotransmitters and neuromodulators are
involved in the shortterm reinforcing effects of addictive
drugs; the dopaminergic reward pathway is central
to the reinforcing properties of drugs and the initiation
of the cycle of addiction. However, other mediators
are believed to exert their inuence via dopamine mo
dulation[26,41].
The roles played by neuropeptides in addictionrela
ted behaviours have also been examined; and for the
most part, neuropeptides including signalling molecules
like substance P, endogenous opioids, and neuropeptide
Y have been studied extensively as possible therapeutic
targets for addiction management[26].
Drug addiction and circadian rhythm/gene abnormalities
There is ample scientific evidence to suggest the im
portance of chronological events like the biological
rhythms in determining response to drugs of abuse.
Earlier studies have argued that chronobiological varia
bles including time of day, sleepwake patterns and
lightdark cycles may modulate the development and
maintenance of drug addiction[46]. More recent evi
dences derived from animal models suggest and sup
port the existence of strong links between appetitive
processes and various circadian genes[47]. Also, while det
ails of the exact mechanisms are still being studied; it is
becoming more obvious that a strong relationship exists
between disturbance of circadian rhythms (as a result
of factors like alteration of normal lightdark cycle) and
the development of addiction[48].
It also appears that circadian phaseshifting activities
such as repeated travels across time zones may inuence
the pattern of consumption of certain substances with
addictive potentials; and this has also been demonstrated
in experimental animals[49]. Using male SpragueDawley
rats, Doyle et al[49] studied the effects of experimentally
induced chronic jet lag on methamphetamine consum
ption; and concluded that preexposure to metham
phetamine (via 2 wk of forced consumption through
drinking water) was associated with a signicantly higher
consumption of methamphetamine in phaseshifted rats
(four consecutive 6h advancing phase shifts of the light
dark cycle) during the second week following abstinence,
when compared to those with undisturbed rhythms[49].
Earlier studies in humans had observed that drug
seeking behaviours are probably linked to mutations in
certain key genes that are related to circadian rhythm
maintenance; suggesting a link between abnormalities
of circadian rhythm maintenance and addiction[47]. How
ever, the associations between these genetic alterations
and addiction have also been demonstrated in animals
by using specific experimental paradigms. In male
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sleep[55]. In heavy marijuana users, polysomnography
had shown that over two weeks of abstinence, incr
eases in wake time after sleep onset (WASO) and decr
eases in TST, sleep efciency and REM sleep had been
observed[56]. A persistence of sleep disturbances is
believed to be a risk factor for relapse[55,56]. Overall, the
relationship between circadian rhythm abnormalities/
sleep disorders and addiction/substance abuse appears
to be a complex one; with one pair increasing the pred
isposition to the other pair, and viceversa.
MELATONIN
Melatonin is an endogenouslyproduced indolamine th
at is predominantly secreted by the pineal gland, and
widely recognised as a regulator of several physiolo
gical functions. Melatonin production is controlled by
the photoperiod through the suprachiasmatic nucleus
(SCN), with production peaking at night and being at its
lowest in daytime. In mammals, melatonin is a mas
ter synchroniser of biological rhythms, a regulator of
physiological processes such as cardiac function; and
an important modulator of behaviours, body posture
and balance[5759]. Fluctuations in melatonin levels (in
a 24 h period) tune the body’s cellular activities to the
actual timeofday; and while high levels of melatonin
potentiate behaviours and physiological functions ass
ociated with darkness, low levels attenuate such be
haviours and functions[23].
In biological systems, melatonin’s effects are exerted
via interactions with melatonin receptors (MT1 and MT2),
orphan nuclear receptors, and intracellular proteins like
calmodulin[6062]. As an ampiphillic molecule, melatonin is
capable of autocrine, paracrine and endocrine signalling;
and it permeates several body compartments to exert
effects on a variety of functions such as diurnal/seasonal
rhythms, reproduction, neurobehaviour, antioxidant de
fense and general immunity.
Over the years, exogenous melatonin and melatonin
analogues have been known to have an established
role in the management of a range of sleep disorders.
However, melatonin’s therapeutic application is not
limited to the central nervous system; and research
has continued to shed light on the potential use of mela
tonergic drugs for the management of an increasing
number of disorders/diseases including respiratory ail
ments such as asthma, pneumonias, chronic obstructive
airway diseases, pleural cavity diseases, vascular pu
lmonary disease, and even lung cancer[63] Melatonin adm
inistration had also been shown to be protective against
intestinal ischaemicreperfusion injury in young male
SpragueDawley rats[64] and Wistar albino rats[65].
From the foregoing, it is obvious that due to its
unique chemical characteristics and diverse effects,
melatonin may be useful in the management of several
human diseases/disorders including those of the central
nervous system such as drug addiction. Therefore, a
better understanding of melatonin’s role in addiction
might open a new door in addiction management.
Wistar rats, a month of constant light exposure exe
rts a significant effect on voluntary consumption of
morphine, exhibition of withdrawal symptoms, plasma
concentration of melatonin [evaluated by enzyme
linked immunosorbent assay (ELISA)] and the mRNA
expression of period homolog genes (Per1, Per2) and
dopamine (D1) receptors in the striatum and prefrontal
cortex[48]. One month exposure to constant light caused
a significant decrease in melatonin concentration, an
upregulation of mRNA levels of Per2 and D1 receptor
in the striatum and prefrontal cortex, upregulation of
Per1 gene in the striatum of rats under constant light
(in comparison to those under standard light cycle),
increased morphine consumption and preference ratio,
and also a signicant increase in severity of naloxone
induced withdrawal syndrome[48]. In humans, more
studies are beginning to demonstrate that core genes
that are involved in circadian rhythm maintenance are
also important regulators of rewardrelated behaviours
which occur in response to common substances of
abuse[50]. On the other hand, substance use has been
known to cause disruptions in circadian rhythms and
affect functions such as the sleep/wake cycle; hence,
the relationship that exists between substance ab
use/addiction and circadian rhythm abnormalities is
bidirectional, such that one could lead to the other,
and vice versa. Also, abnormalities of sleep and circa
dian rhythms appear intimately linked to substance
abuse, and they could appear as either predictors or
consequences of substance abuse[47]. Documented eff
ects of substance use on sleep is not only dependent
on the class of agents, but also on the phase of usage,
with acute sleep effects, chronic sleep effects, and
sleep effects due to withdrawal or abstinence being
described. Acute ingestion of drugs such as cocaine and
amphetamine which have stimulant effects have been
associated with a light, restless and disrupted sleep[51];
while ingestion of drugs with depressant effects such as
benzodiazepines, alcohol and opiates can have an initial
sleeppromoting effect (increased daytime sleepiness
and reduced sleep latency) but sleep disruptions (incr
eased night awakenings) later in the night, as a result
of acute withdrawal effects[51,52].
There are reports that chronic use of substances may
alter sleep quality and quantity in ways that are similar
across different substances[53]. Extended sleep onset
latency (SOL), a reduction in total sleep time (TST),
increased frequency of nighttime awakenings, reduced
slowwave sleep (SWS) and rapid eye movement (REM)
sleep have all been described[47]. However, withdrawal
from alcohol or stimulants may be associated with di
stinct timerelated changes in pattern of TST and REM
sleep[51,54]. Acute withdrawal from substance use may
also be associated with sleep disturbances such as
extended SOL, reduced TST, and reduced SWS[51]. Also,
sleep disturbances such as REM sleep disturbances may
continue weeks into abstinence; and polysomnographic
evidences in cocainedependent participants still show
increased SOL, and decreased TST, SWS, and REM
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Melatonin and drug addiction
The roles played by circadian rhythm/gene abnorm
alities in the development or entrainment of addiction–
related behaviours, or in potentiating changes in neu
rohormone, neuromodulator or neurotransmitter levels
which result in the development of addiction are well
documented[24]. Melatonin’s role in the entrainment
of circadian rhythms is also welldocumented. Obse
rvations that alcohol consumption altered the circadian
profile of melatonin production in alcoholdependent
humans and alcohol drinking rodents[66,67] have also
increased interests in the importance of melatonin in
addiction[23].
Studies by Uz et al[68], and Kurtuncu et al[69] dem
onstrated loss of diurnal variation in cocaineinduced
locomotor sensitisation and cocaineinduced place
preference respectively, in melatonindeficient pine
alectomised mice, suggesting that the cocaineinduced
diurnal variations were mediated by melatonin[68,69].
There have also been reports suggesting that (drug
induced) hypothermic responses to injections of mor
phine, nicotine or ethanol varied with the lightdark
cycle[70]. There have been suggestions that disturbances
in sleep observed after months of abstinence in humans
with alcoholdependence could be linked to delayed
peak of melatonin’s nocturnal rise and lower melatonin
levels[68,71]. Studies in rodents have also demonstrated
similar alterations[67], further buttressing the role of the
melatonergic system in drug addiction.
The effects of exogenous melatonin in modulating
behavioural responses to specic drugs of abuse have
also been studied. Vengeliene et al[23] demonstrated that
administration of melatonin modulates alcoholseeking
or wanting and/or relapselike drinking behaviours[23].
Results of in vitro electrophysiological studies have also
shown that in cerebellar neurons, nicotinestimulated
currents decreased with application of increasing con
centrations of melatonin[72]. Markus et al[73] also reported
nocturnal elevations of melatoninmediated nicotine
induced glutamate release by cerebellar neurons[73].
Finally, studies have demonstrated that melatonin is
able to modulate the reinforcing or relapsing effects of
certain drugs of abuse[23,24].
Melatonin receptors and drug addiction
Melatonin exerts its effects on behaviours and ph
ysiological functions largely via the melatonin (MT) re
ceptors 1 and 2[74,75]. Also, while research has continued
to demonstrate the possible roles that melatonin may
play in drug addiction, including modulation of the
development of dopaminergic behaviours, like drug
seeking behaviours or psychostimulantinduced diurnal
locomotor sensitisation; the contributions of melatonin
receptors, especially as it relates to specic drugs, are
still being evaluated[23]. Research has demonstrated the
presence of the MT1 receptor subtype in a number of
brain regions, including areas like the prefrontal cortex,
hippocampus, nucleus accumbens and amygdala wh
ich have been associated with regulating the effects
of addictive drugs or behaviours[76,77]. Uz et al[76] stu
died the expression pattern of MT1 receptors in the
dopaminergic system of the human and rodent brain,
and observed the presence of MT1 receptor in these
regions of the postmortem human brain; while in the
mouse brain, they observed a diurnal variation (high
protein levels and low mRNA at night) in the expression
of the mouse MT1 receptor in the dopaminergic sy
stem[76]. A few studies have also observed an incr
ease in melatonin receptorrelated cyclic AMP in the
mesolimbic dopaminergic system[62]. In another stu
dy, prolonged treatment with antidepressants and
cocaine was associated with alteration in the content
of melatonin receptor mRNA, with the effects of these
drugs on MT1/MT2 mRNAs being brain regionspe
cific[78]; however, prolonged cocaine use did not alter
MT2 receptor expression[78,79]. There have been reports
suggesting that genetic deletion of MT1 and MT2 rece
ptors abolished the development and expression of
methamphetamineinduced locomotor sensitisation[79],
and methamphetamineinduced reward[80] in melatonin
expressing C3H/HeN mice. Uz et al[68] however reported
that MT1, and not MT2 receptor was required for
cocaineinduced locomotor sensitisation in rodents.
In another study by Hutchinson et al[81], this time co
mparing the differences in locomotor sensitisation obs
erved following a single dose of methamphetamine in
low melatoninexpressing C57BL/6 wildtype and MT1
knockout mice, to melatoninprocient C3H/HeN mice;
it was reported that methamphetamine pretreatment
induced locomotor sensitisation during the light per
iod in C3H and C57 wildtype mice. A diminution in
magnitude of sensitisation in C57 mice in the dark per
iod, and a complete abrogation in the MT1 receptor
knockout (MT1KO) mice was observed; buttressing the
role of MT1 receptors in the possible management of
drug addiction[81]. On the other hand, MT2 receptors
have been linked to the modulation of hippocampal
dependent longterm potentiation; with a few studies
demonstrating loss of longterm potentiation in tra
nsgenic mice decient of MT2 receptors[82]. There were
also reports of loss of experience–dependent short
term latency to enter the closed arm on the second
day of elevated plus maze exposure; a feature which
suggests that MT2 receptors may play an important
role in modulating memory processes and hippocampal
synaptic plasticity[82]. These properties may prove useful
in the management of addictionrelated neuroplasticity.
MELATONIN AND THE PHARMACOLOGIC
MANAGEMENT OF DRUG ADDICTION
Information garnered from years of research into the
aetiopathogenesis of addiction point to the conclusion
that drugdependence is a multifactorial behavioural
and biological disorder, which is amenable to medical
treatment. The current treatment protocol for drug
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use disorders involves the use of psychosocial and
pharmacological interventions[5]. The main goals of
management include: (1) reduction of drug use and
drug craving; (2) improvement of general wellbeing
and functioning of the individual; and (3) decreasing
the risk of the development of complications and/or
recurrence[5]. However, currentlyavailable treatment
options remain inadequate, with varying addiction
relapse rates, depending on the drugs involved[83,84].
Thankfully, advances in science and research are ope
ning new vistas for possible therapeutic interventions,
and as such, current research interests are directed
at developing or discovering new treatments options
like the use of melatonin (a regulator of the circadian
rhythm and potent antioxidant) that could be benecial
in reducing craving/withdrawal period and preventing
relapse.
The ability of melatonin to mitigate different as
pects of addiction neurobiology has been examined
extensively. Studies have reported the efcacy of mela
tonin supplementation in the control of drugseeking
behaviour, opiate withdrawal/ relapse[24], behavioural
sensitisation[84,85], regulation of the sleep and or circadian
rhythm disorders[86], neuroplasticity, and prevention of:
Mitochondrialinduced autophagy, apoptosis, oxidative
stress and neurotoxic injury[84] in brain areas linked to
reward and emotionality.
Melatonin, withdrawal syndrome and relapse
Prolonged use or abuse of drugs (such as opioids) by
humans have been linked to the development of physical
dependence and/or addiction, which is usually associated
with alterations in brain biochemistry and hormone levels;
and disruption of the sleep/wake cycle[8789]. Also, sudden
clearance or reduction in the plasma concentration
of opioids of abuse results in withdrawal symptoms,
including circadian rhythm disturbances like insomnia,
jitteriness and restlessness[90,91]. Studies in animals
have reported that chronic morphine administration
resulted in a reduction in total activity within a 24 h
period, and a dampening of the circadian amplitude in
locomotor activity rhythm[92,93]. Abrupt withdrawal of
morphine administration in rats has also been associated
with sustained disruption of the circadian rhythms in
locomotor activity, and alterations in plasma melatonin,
βendorphin, corticosterone, adenocorticothrophic hor
mone, and orexin concentrations[9395]. Studies have also
reported evidence of anxietyrelated behaviour following
cocaine withdrawal[96].
The possible effects of melatonin on withdrawal
symptoms have also been examined; and while there
is a dearth of clinical trials, studies in rodents have dem
onstrated its effectiveness. Zhdanova and Giorgetti[96]
assessed the effects of melatonin supplementation on
cocaineinduced anxietylike behaviour and nucleus
accumbens cyclic adenine monophosphate (AMP)
levels in rats. In their study, melatonin (200 ng/mL)
was administered in drinking water (at night) to gr
oups of rats that had been exposed to repeated co
caine administration (15 mg/kg i.p.), or during its
withdrawal. Results showed that melatonin caused
a reduction in anxietylike behaviour in a defensive
withdrawal paradigm, 48 h after the last injection of
cocaine[96]. Melatonin pretreatment also attenuated the
augmentation of cAMP levels in the nucleus accumbens
following acute administration of cocaine. These results
suggest that a lowdose nighttime melatonin treatment
was effective in militating against symptoms of cocaine
withdrawal in rats[96]. Bondi et al[97] conducted a single
centre, randomised, doubleblind, placebocontrolled,
parallelgroup trial to assess the effect of melatonin
(5 mg) compared to placebo as adjuvant treatment
(alongside behavioural and pharmacotherapy) on we
ekly selfreported severity of depression, anxiety, stress,
and insomnia complaints in recovering substance
use disorder subjects males (aged 18 years or older
) who were at a residential program. Results showed
no significant differences were observed for baseline
characteristics; although the frequency of reported
adverse events was higher in the melatonin group[97]. The
authors were of the opinion although the diversity of
medication regimens and behavioural interventions pro
vided increase the complexity of assessing melatonin’s
efcacy with regards to the measured outcome, there
is insufcient evidence to demonstrate melatonin’s be
nets as an adjuvant in addiction recovery[97].
The use of melatonin for its antioxidant effects
during recovery from drug abuse has also been studied.
The naloxoneinduced heroine withdrawal syndrome
has been associated with derangement in antioxidant
enzymes and bioelements which are essential for
the maintenance of life[98]. Cemek et al[98] examined
the effect of melatonin supplementation on the levels
of antioxidant enzymes and bio elements in naloxone
induced heroine withdrawal syndrome and reported
a reversal in heroine withdrawal related alteration in
glutathione, catalase levels, and the levels of bio ele
ments (iron, manganese, magnesium, aluminium,
calcium and copper). The researchers concluded that
exogenous melatonin could be effective in militating
bio element and antioxidant enzyme derangements in
heroine withdrawal syndrome[98].
A very powerful challenge to drug addiction trea
tment is the high incidence of drug use relapse during
abstinence[99]. However, years of extensive clinical and
preclinical research on druguse relapse[100,101] have do
ne little to reduce relapse rates[83,102]. Reports from a
number of studies have reported that druguse relapse
is usually triggered by acute exposure to the selfadm
inistered drug[103], stress[102], the presence of drug
related cues and contexts[104], and protracted periods
of withdrawal or exposure to cure that have been
previously associated with withdrawal[105]. Extensive
research work has led to the identification of possible
cellular, neurotransmitter, and/or receptor mediated
mechanisms that increase the risk of relapse to drug
use with the intent of identifying novel pharmacological
treatment options[106108]. Takahashi et al[24] assessed
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the effects of melatonin supplementation (administered
at either 25 or 50 mg/kg body weight) on cocaine self
administration and relapselike behaviours in male Sp
ragueDawley rats (which had been exposed to long
term cocaine selfadministration training). Behavioural
parameters measured included the motivation for co
caine selfadministration in the break point test, relapse
like behaviour in the cueinduced reinstatement test,
sucrose preference and distance travelled in the open
eld. Results showed a reduction in the cocaineseeking
behaviour and the desire to selfadminister cocaine. The
researchers concluded that melatonin supplementation
could be benecial in reducing relapse[24].
Melatonin, addiction-related behavioural sensitisation,
neuroplasticity and neurotoxicity
Chronic intermittent use of cocaine and a number of
other psychostimulants have been associated with
the development of a progressive, longlasting enha
ncement of psychomotor effects which have been ref
erred to as cocaine or psychostimulant sensitisation.
Studies have demonstrated that behavioural sensi
tisation to psychostimulants is associated with an inc
rease in nitric oxide synthase[109]. While examining the
effect of melatonin on cocaineinduced behavioural
sensitisation in rats, Sircar[85] reported that: (1) acute
or repeated melatonin injections on its own did not
affect locomotor behaviour in rats; (2) acute melatonin
preexposure augmented the acute locomotor effects
of cocaine; and (3) repeated melatonin preexposure
prevented the development of cocaine induced be
havioural sensitisation, while a single injection of me
latonin did not halt behavioural sensitisation in rats
already sensitised to cocaine. Sircar[85] concluded
that while melatonin supplementation increased co
caine’s acute behavioural effects and prevented the
development of cocaine’s behavioural sensitisation,
it had no effect in militating fullydeveloped cocaine
behavioural sensitisation[85]. Itzhak et al[110] studied
the effects of melatonin supplementation on the de
velopment of methamphetamine (METH)induced
behavioural sensitisation and reported that pre
treatment with melatonin at 10 mg/kg body weight
prevented the development of METHinduced depletion
of dopamine and/or its metabolites and depletion of
dopamine transporter binding sites. It also attenuated
METHinduced behaviours and diminished METH
induced hyperthermia, although it did not reverse fully
developed METH–induced behavioural sensitisation[110].
Feng et al[84] also examined the effects of melatonin
on morphineinduced behavioural sensitisation and
reported that pretreatment with melatonin prevented
the development of morphineinduced behavioural se
nsitisation and analgesic tolerance; effects which were
dosedependent[84].
The development of longlasting addictionrelated
behavioural dysfunction and structural deficits in the
brain have been linked to alterations in the methylation
processes for purine metabolism/serotonin pathways[111],
oxidative stressinduced autophagy[84], mitochondrial
mediated apoptosis[112,113], alteration in mitochondrial
DNA copy number in distinct brain regions[81], and
neurotoxicity[84,114]. Li et al[95] also reported that protr
acted opiate withdrawal in rats was associated with the
disruption of the circadian rhythm of hormones (adr
enocorticotropin, orexin and corticosterone), leading
to the induction of neurobiological changes which may
worsen the risk of relapse[95].
Feng et al[84] examined the ability of melatonin to
militate against the deleterious effects of opiate ad
diction and reported that melatonin was able to reve
rse morphine induced mitochondrial dysfunction and
oxidative stress, in cultured cells. They also demonstrated
that melatonin reversed morphineinduced autophagy
and changes in mitochondrial DNA copy number in
cultured cells and neurons[84]. In vivo studies using a
mouse model of morphine addiction demonstrated th
at melatonin also counteracted morphine–induced au
tophagic effects and decrease in mitochondrial DNA copy
number in the hippocampus[84].
Melatonin in the management of drug-addiction related
sleep and circadian rhythm disorders
Sleep and circadian rhythm disorders have been well
dened in a number of substances use disorders, including
those of marijuana[115], alcohol[52,116,117], nicotine[118], be
nzodiazepines[86,119] and cocaine[51]. Also, results from
a number of rodent studies have reported interactions
between alcohol and homeostatic mechanisms[120] and/or
circadian systems[121123]. Treatment options for insomnias
in drug addiction are limited, largely because traditional
hypnotics that target benzodiazepine receptors are ass
ociated with abuse potential, withdrawal effects, and
the potential for overdose. Melatonin supplement has
been found particularly valuable in the management
of circadian rhythm disorders[124], in the treatment of
insomnias in subjects with chronic schizophrenia[125],
in the elderly[126,127], and among children with sleep
onset insomnia[128]. However, its benefits in addiction
related sleep and/or circadian rhythm disorders are
still being evaluated. A doubleblind crossover control
study that examined melatonin’s ability in militating
sleep difficulties associated with benzodiazepine (BDZ)
withdrawal reported that while melatonin did not increase
the likelihood of BDZ discontinuation, it improved sleep
quality, especially in subjects who continued to use
BDZ[86].
Its use in alcohol addicts have been supported
by studies that have reported low plasma melatonin
levels in this group of substance users[66,129]. Other
studies have examined the efficacy of melatonin
analogs in militating addictionrelated sleep disorders.
Brower et al[116] examined the ability of the melatonin
receptor agonist ramelteon to attenuate insomnia in
recovering alcoholics, and reported an improvement
in sleep quality and quantity. Another study using ag
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omelatine (a melatonergic agonist at MT1 and MT2 rec
eptors, and a 5HT2C antagonist approved for use as
an antidepressant) reported improved sleep in alcohol
dependent subjects with insomnia; with participants
reporting improved subjective sleep quality after 6 wk
of administration[130].
CONCLUSION
To date, melatonin and its analogs have continued to
show promise in the management of drug addiction.
However, the use of melatonin may be limited by its
short halflife and an additive sedative effect when used
alongside BDZs and other drugs such as morphine;
also, its safety in the younger age groups are still being
debated. Despite these, evidences from both animal
and human studies continue to show the potentials
of melatonin and its analogs in the management of
drug addiction. Therefore, research must continue to
focus on the applications of melatonergic agents in
drug addiction management, especially, beyond their
established use for associated sleep disorders.
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P- Reviewer: Leon J, Talas ZS S- Editor: Ji FF L- Editor: A
E- Editor: Tan WW
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