ISSN 0006-2979, Biochemistry (Moscow), 2024, Vol. 89, No. 11, pp. 1868-1888 © The Author(s) 2024. This article is an open access publication.
1868
REVIEW
Contribution of Visceral Systems
to the Development of Substance Use Disorders:
Translational Aspects of Interaction
between Central and Peripheral Mechanisms
Danil I. Peregud
1,2,a
* and Natalia V. Gulyaeva
2,3
1
Serbsky National Medical Research Center for Psychiatry and Drug Addiction,
Ministry of Health of the Russian Federation, 119034 Moscow, Russia
2
Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485 Moscow, Russia
3
Research and Clinical Center for Neuropsychiatry of Moscow Healthcare Department, 115419 Moscow, Russia
a
e-mail: peregud_d@yahoo.com
Received May 27, 2024
Revised July 8, 2024
Accepted July 11, 2024
Abstract— Substance use disorders are associated with structural and functional changes in the neuroendo-
crine, neuromediator, and neuromodulator systems in brain areas involved in the reward and stress response
circuits. Chronic intoxication provokes emergence of somatic diseases and aggravates existing pathologies.
Substance use disorders and somatic diseases often exacerbate the clinical courses of each other. Elucidation
of biochemical pathways common for comorbidities may serve as a basis for the development of new effective
pharmacotherapy agents, as well as drug repurposing. Here, we discussed molecular mechanisms underlying
integration of visceral systems into the central mechanisms of drug dependence.
DOI: 10.1134/S0006297924110026
Keywords: psychoactive substances, dependence, brain, visceral systems, neuroendocrine mechanisms, neuro-
mediators, neuromodulators, internal diseases
Abbreviations: ACE, angiotensin-converting enzyme; ANP, atrial natriuretic peptide; BBB, blood-brain barrier;
BDNF,brain-derived neurotrophic factor; CNS,central nervous system; CVS,cardiovascular system; FGF,fibroblast growth
factor; GIT, gastrointestinal tract; GLP-1,glucagon-like peptide-1; HPA, hypothalamic-pituitary-adrenal axis; PAS, psycho-
active substance; PPAR, peroxisome proliferator-activated receptor.
* To whom correspondence should be addressed.
INTRODUCTION. PSYCHOACTIVE
SUBSTANCE DEPENDENCE IS NOT ONLY
THE CENTRAL NERVOUS SYSTEM DISEASE
At least 1% of the world’s population suffers from
substance use disorders. When taken in or adminis-
tered, psychoactive substances (PASs) affect the cen-
tral nervous system (CNS) and alter mental state, up
changes in the state of consciousness. Substance use
disorders are a heavy socioeconomic burden; their
prevalence, morbidity, as well as associated economic
losses consistently increase [1]. Disorders caused by
the use of PASs are characterized by chronic relapsing
course, loss of control, and PAS abuse despite obvious
adverse effects. The pathogenesis of these disorders
involves changes in the functioning of neuroendo-
crine, neurotransmitter, and neuromodulator systems
in specific brain areas associated with the mecha-
nisms of reinforcement and stress response [2]. Since
chronic exposure to PASs and related pathological pro-
cesses are also accompanied by the adaptive response
of CNS, substance dependence is considered as a type
of aberrant neuroplasticity [3] with the imbalance of
neurotrophins playing the key role in this process [4].
Despite a relative success in understanding the
patterns of chronic exposure to PASs, the possibilities
PERIPHERAL MEDIATORS OF SUBSTANCE USE DISORDERS 1869
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
and efficacy of pharmacotherapy in the treatment
of addiction remain quite limited. Thus, only a few
drugs have been approved by the FDA (Food and
Drug Administration) for the treatment of substance
use disorders. For example, disulfiram (acetaldehyde
dehydrogenase inhibitor), naltrexone (opioid receptor
antagonist), and acamprosate (neuromodulatory drug)
are the only therapeutic agents that have been ap-
proved for the treatment of alcohol use disorders [5].
The only drugs approved for the treatment of opioid
use disorder are naltrexone and opioids buprenorphine
and methadone used in maintenance treatment [6].
Currently, there are no drugs approved for the treat-
ment of addiction to psychostimulants (psychotropic
substances that stimulate mental and, to a lesser ex-
tent, physical activity) on the market. Pharmaceutical
agents used in the therapy of substance dependence act
primarily on the central neurotransmitter systems and
corresponding receptors. Because of a high social and
biological significance of these disorders and a limited
number of therapeutic approaches, studying biological
mechanisms involved in the formation and course of
substance use disorders at all levels (from molecules
to the entire body) remains extremely relevant.
Substance use disorders are characterized by a
recurrent or chronic course with an increase in the
dosage of used substance as a result of tolerance de-
velopment, loss of control, development of withdrawal
syndrome, compulsion to seek and take the drug, and
inability to stop using it despite obvious psychological,
physical, and social consequences [7, 8]. In fact, risky
drug consumption, addiction, and drug dependence
are integrated into a single psychopathological struc-
ture, with brain being its key substrate [9, 10]. Existing
classifications of substance use disorders typically do
not take account the contribution of physical health in
the formation of substance dependence, which is un-
doubtedly a serious omission. Substance use disorders
are considered to be diseases of the CNS by default,
thus ignoring involvement of almost all body visceral
systems in their development, which will be discussed
in this review.
PASs are xenobiotics and, therefore, also have a
significant effect on the functioning of internal organs
other than the CNS. It is not surprising that the PAS
abuse is often accompanied by comorbid diseases, for
example, cardiometabolic syndrome [11], endocrinop-
athies [12], eating disorders [13], and many others. Ap-
proximately half of subjects dependent on PASs have
at least one chronic somatic disease [14]. The risk of
developing somatic pathologies increases dramatically
in individuals with the substance use disorders [15].
The comorbidity of somatic pathologies and substance
dependence significantly increases mortality in many
diseases, including disorders of the gastrointestinal
tract(GIT) and cardiovascular system(CVS), endocrine
disorders, and pathologies associated with metabolic
disorders [16]. The prevalence of substance use disor-
ders in people with eating disorders reaches 40%, and
the prevalence of eating disorders in people with de-
pendence can reach 30%, which is considerably higher
than in the total population [17]. The comorbidity of
eating disorders with PAS dependence increases the
risk of developing somatic diseases [18]. PAS abuse is
accompanied by disturbances of circadian rhythms,
sleep structure, and sleep quality and duration in 90%
people with alcohol addiction [19] and up to 80% of
people with addiction to illicit PASs [20], which is sig-
nificantly higher than the prevalence of sleep prob-
lems in the total population. Eating and sleep dis-
orders belong to neuropsychiatric diseases and are
closely related to the physical health of an individual.
Mental health and physical health are closely in-
terrelated [21], which is clearly evident, in particular,
for affective spectrum disorders. It has been proven
that the development of stress-induced mental disor-
ders, e.g., psychotic depression, is based on the close
interaction between the central and peripheral mecha-
nisms [22]. This example is especially important if we
consider development of substance dependence, since
psychopathological addiction is formed as a way to
achieve a feeling of well-being against the background
of chronic stress and mental tension [23]. In other
words, psychopathological addiction in some way is
an attempt of adaptation to stress. Indeed, an imbal-
ance in the stress response systems often accompanies
the development of a pathological pattern of PAS in-
take [2]. Stress response systems and their mediators
(corticosteroids) play a key role in both development
of brain pathology under chronic stress and forma-
tion of depressive phenotype [24, 25]. The risk of de-
veloping depression increases significantly in chronic
somatic pathologies. In turn, depression is an indepen-
dent risk factor for increased morbidity and mortality
in many somatic diseases. Moreover, effective therapy
of depression not only contributes to the restoration
of mental health, but also improves the clinical prog-
nosis of concomitant somatic diseases [26].
Therefore, substance use disorders and comor-
bid somatic diseases aggravate each other’s clinical
course. Chronic substance abuse is a risk factor in
somatic pathologies and vice versa. Identification of
their common molecular mechanisms can help in the
development and implementation of new effective
methods of pharmacological correction of the corre-
sponding comorbidities.
The main goal of our review was conceptual
analysis of the relationship between peripheral sys-
tems and central biochemical mechanisms underlying
substance use disorders. This article is a traditional
critical review of the published articles. The search
queries included the following keywords: [name of the
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compound/mediator or process AND PAS dependence
OR substance use disorder] in the Russian-language
resource Scientific Electronic Library (eLIBRARY.ru)
and English-language MEDLINE (PubMed) and Google
Scholar databases. The search was conducted among
the reports published within the last 5 years; some
significant studies that had been published before
that, were also included. The discussed peripheral
mediators were grouped by their anatomical location
and belonging to a particular organ system or by in-
volvement in a corresponding physiological process
(although classification by systems and organs is rath-
er conventional, since all described biologically active
molecules exhibit pleiotropic effects).
MEDIATORS OF CARDIOVASCULAR SYSTEM
AND WATER-SALT BALANCE
Endothelin is synthesized in many types of en-
dothelial cells, vascular smooth muscle cells, macro-
phages, fibroblasts, and brain neurons [27]. Endothe-
lin acts through the activation of the subtypeA (ETA)
andB (ETB) transmembrane G protein-coupled recep-
tors (GPCRs). Stimulation of ETA receptors is accom-
panied by vasoconstriction and inflammation, while
stimulation of ETB receptors typically has the opposite
effect [27]. Activation of endothelin receptors located
in the brain ensures their involvement in many patho-
physiological processes of the CNS. ETA receptors mod-
ify the antinociceptive effect of opiates, as well as the
development of tolerance [28]. It was suggested that
the blockade of ETA receptors potentiates the antino-
ciceptive activity of opiates and reduces development
of desensitization and tolerance by restoring the as-
sociation of Gi proteins with the opioid receptors and
preventing their desensitization mediated by β-arres-
tin [28]. Administration of the ETA receptor antagonist
BQ123 to the brain ventricles attenuated oxycodone
and morphine withdrawal syndrome in mice, which
indicates endothelin involvement in the mechanisms
of dependence formation [29]. Despite an obvious po-
tential of endothelin receptor antagonists for treating
opioid dependence and appearance of approved anti-
hypertensive drugs with such pharmacological activity
on the market, no clinical studies have been conduct-
ed so far.
Atrial natriuretic peptide (ANP) is a hormone
produced by cardiomyocytes in response to myocardi-
al strain. By binding to a receptor with the guanylate
cyclase activity, ANP stimulates formation of cGMP,
which mediates biological functions of this peptide.
ANP produces a pleiotropic effect, including relaxation
of vascular smooth muscles, regulation of water-salt
balance due to its influence on sodium excretion,
suppresses the renin-angiotensin-aldosterone system,
stimulates lipolysis and lipid oxidation, and regulates
insulin sensitivity [30]. In general, increased ANP
plasma levels are associated with a reduced risk of
cardiometabolic syndrome. Beside regulating the wa-
ter-salt balance, ANP is also integrated in the activities
of the hypothalamic-pituitary-adrenal (HPA) axis and
immune system [31]. Despite the fact that preclinical
studies have demonstrated ANP involvement in the
development of mental disorders, there are almost
no studies dedicated to this topic, although their rele-
vance has been well recognized. Alcohol intoxication
leads to electrolyte imbalance accompanied by chang-
es in the content of substances regulating electrolyte
homeostasis in blood plasma during withdrawal syn-
drome. In the acute withdrawal phase, the activity of
renin and the plasma levels of aldosterone increase
and then return to the initial values as the symptoms
of withdrawal reduce [32]. It has been shown that
in patients with alcohol-related psychosis, the level
of ANP increases at the onset the psychosis. In mice
maintained on an alcohol-liquid diet, intracerebroven-
tricular injection of ANP attenuated, whereas injection
of an antiserum against ANP intensified the severity
of handling-induced convulsions (a symptom of al-
cohol withdrawal) [32]. In patients with alcohol de-
pendence, the level of ANP in the blood plasma after
two weeks of abstinence under stationary conditions
correlated negatively with alcohol craving, severity of
perceived stress, and anxiety. Moreover, the ANP level
was found to be a reliable predictor of anxiety and
stress [33]. Therefore, ANP is only a peripheral mark-
er of clinical manifestations of alcohol addiction, but
might also exhibit the central activity in the case of
alcohol withdrawal syndrome.
The renin-angiotensin system is involved in the
CVS functioning through the regulation of vascular
tone and water-salt balance. Angiotensin also partici-
pates in the mechanisms of PAS dependence develop-
ment. Using a pharmacological approach and function-
al MRI, it was demonstrated that angiotensin regulates
the functional activity of human brain via activation
of type 1 receptors [34]. Several signaling cascades trig-
gered by the activation of type 1 angiotensin II recep-
tor, are integrated into the HPA axis and participate
in the stress response, which can explain angioten-
sin participation in the mechanisms of addiction [35].
It is known that the angiotensin system is able to
alter the motivation for alcohol consumption in ro-
dents [36]. Early experiments on rodents showed that
captopril and enalapril, which are angiotensin-convert-
ing enzyme (ACE) inhibitors that suppress formation
of active angiotensin II and are used in the therapy
of hypertension, reduced voluntary alcohol consump-
tion without affecting hemodynamic parameters [37].
Interestingly, ACE involved in proteolytic maturation
of angiotensin in the nucleus accumbens mediates the
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BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
degradation of endogenous opioid peptides, which
underlies the interaction of opioid, glutamate, and
dopaminergic neurotransmitter systems [38]. More-
over, systemic administration of captopril reduced
the activity of dopaminergic striatal neurons and at-
tenuated the reinforcing properties of fentanyl [38].
It is believed that such pharmacological agents can
be repurposed for the pharmacotherapy of substance
use disorders. The role of angiotensinII in the CNS in
alcohol consumption has been studied in detail [39].
Transgenic rats with the downregulated expression
of angiotensin II and lower dopamine content in the
ventral tegmental area demonstrated reduced volun-
tary alcohol consumption compared to the wild-type
animals [39]. Experiments in knockout mice showed
that alcohol consumption depended on type1, but not
type2 angiotensin receptors [39]. A single administra-
tion of angiotensin II receptor antagonist telmisartan
to brain ventricles reduced alcohol consumption in al-
cohol-preferring rats without affecting food and water
intake [40]. Administration of valsartan, another an-
giotensin II receptor antagonist, during morphine in-
toxication prevented development of tolerance to the
antinociceptive effect of morphine and lessened the
severity of withdrawal syndrome [41]. Candesartan,
an antagonist of type 1 angiotensin receptor, attenuat-
ed the reinforcing properties of methamphetamine in
the rat self-administration model [42]. Moreover, de-
spite the fact that both ACE inhibitors and angiotensin
receptor blockers are widely used in the treatment of
hypertension, we failed to find the data on clinical
studies of their effectiveness in PAS use disorders in
the analyzed publications.
Aldosterone is a steroid hormone produced by
the adrenal gland in response to the stimulation with
angiotensin, extracellular potassium, and adrenocorti-
cotropic hormone (ACTH). By binding to mineralocor-
ticoid receptors (nuclear receptors acting as transcrip-
tion factors) in distal nephrons, aldosterone increased
the reabsorption of sodium and water and stimulated
potassium efflux, thus modulating the water-salt bal-
ance and blood pressure [43]. Mineralocorticoid re-
ceptors are also expressed in the brain, in particular
in the hippocampus, amygdala, and prefrontal cortex,
i.e., brain regions involved in the cognitive functions
and formation of addiction [44]. Animal studies have
shown that exposure to PASs alters the content of al-
dosterone and expression of its receptors in the brain.
The blockade of mineralocorticoid receptors attenuat-
ed the reinforcing properties of PASs and alleviated
the symptoms of withdrawal [45]. It is believed that
antagonists of mineralocorticoid receptors are prom-
ising agents in the treatment of alcohol dependence.
Thus, in primates, expression of the mineralocorticoid
receptor mRNA in the amygdala correlated negatively
with alcohol consumption, while the level of aldoste-
rone in the plasma increased after alcohol intake [44].
Similarly, downregulation of the mineralocorticoid re-
ceptor mRNA in the amygdala of rats was associated
with an increase in anxiety-like behavior during acute
withdrawal and compulsive alcohol consumption [44].
In patients dependent on alcohol, plasma aldosterone
levels correlated positively with the amount of alcohol
consumed, as well as severity of cravings and anx-
iety [44]. Spironolactone (mineralocorticoid receptor
antagonist) reduced alcohol consumption in mice.
Moreover, retrospective analysis of pharmacoepide-
miological records showed that administration of spi-
ronolactone to alcohol drinkers was also accompanied
by a decrease in the level of alcohol consumption [46].
Steroid antagonists of mineralocorticoid receptor (e.g.,
spironolactone) have been approved for the treatment
of hypertension and heart failure. At the same time,
there are no reports on the clinical studies of their
efficacy against substance use disorders.
Vasopressin is an antidiuretic hormone involved
in the regulation of vascular tone and water-salt
balance, which determines its influence on blood
pressure [47]. Vasopressin peptide is expressed in the
hypothalamus and acts as a hormone and neurotrans-
mitter in the brain. Several subtypes of vasopressin
receptors have been discovered, all of them being
GPCRs [47]. Subtype V1a receptors are expressed in
blood vessels, adrenal glands, and kidneys and stim-
ulate vasoconstriction, aldosterone and glucocorticoid
secretion, and renin production. Central V1a receptors
contribute to the regulation of the sympathetic ner-
vous system. Vasopressin receptors of the V1b subtype
are expressed in the hypothalamus, pituitary gland,
and limbic structures and play a key role in the stress
reactivity. Through activation of V1b receptors, vaso-
pressin potentiates the action of corticoliberin by stim-
ulating ACTH secretion of by the pituitary gland and
activation of the HPA axis. Subtype V1b receptor an-
tagonists are promising compounds for suppression of
the HPA axis activity in the development of substance
dependence, in particular, on alcohol. For example, se-
lective V1b receptor antagonist SSR149415 inhibited
alcohol intake in rats [48, 49]. In mice, SSR149415 sup-
pressed conditioned place preference associated with
morphine administration [50]. Another V1b receptor
antagonist, ABT-436, suppressed the activity of HPA
axis in humans by decreasing cortisol levels in the
blood serum [51]. In phase II clinical trials, ABT-436
increased the duration of abstinence without affect-
ing the alcohol craving, the greatest effect being ob-
served in the subgroup with a higher baseline stress
level [52]. ABT-436 is among the most promising can-
didates for developing agents for treatment of alcohol
use disorders [53].
Oxytocin. Another neuropeptide hormone that
has to be mentioned is oxytocin. Assigning oxytocin
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and vasopressin to compounds associated with the
CVS functioning might seem controversial, but, con-
sidering an incredible pleiotropic action of both hor-
mones, they can be attributed to the regulators of any
body system. Both oxytocin and vasopressin are pro-
duced in the hypothalamus. Along with the regulation
of various aspects of brain functioning and behavior,
oxytocin controls many body systems [54, 55], includ-
ing CVS [56]. Metabotropic receptors for oxytocin are
expressed in the limbic structures and regulate the
reinforcing effect of various stimuli (including PASs),
stress sensitivity, and socialization [57]. The neurobi-
ological activity of oxytocin is realized through direct
or indirect action on the dopamine and serotonergic
neurotransmitter systems and HPA axis [58].
According to the data of preclinical studies, stim-
ulation of oxytocin receptors has a protective effect
in substance dependence. It reduces the severity of
anxiety and depressive-like behavior, attenuates re-
inforcing properties of PASs, and reduces the risk of
relapse during withdrawal [57, 58]. Injectable oxyto-
cin is used in obstetrics for labor induction. Oxytocin
(mostly as nasal spray) has been actively investigat-
ed for the therapy of mental disorders, in particular,
those associated with substance use. Oxytocin attenu-
ates manifestations of the PAS withdrawal syndrome,
including its affective component, and can suppress
cravings and consumption of PASs [59].
MEDIATORS OF METABOLISM
AND EATING BEHAVIOR
PASs alter fundamental processes of energy me-
tabolism. Chronic morphine intoxication in mice
downregulated expression of subunits of pyruvate
and NADH dehydrogenase complexes and lactate de-
hydrogenase 2, reduced ATP synthesis, and impaired
glycolysis in the hippocampus, while systemic and in-
trahippocampal administration of D-glucose attenuat-
ed symptoms of morphine withdrawal [60]. Based on
these results, Jiang and Ma [61] suggested, although
with a certain degree of skepticism, that hypoglycemia
may be one of the causes of physical dependence on
opiates. Interestingly, the effect of morphine on ener-
gy metabolism can be direct, as morphine has been
shown to bind to creatine kinase B and inhibit its ac-
tivity both in vitro and in vivo [62].
Insulin is synthesized by pancreatic β-cells; its
key function is regulation of energy metabolism, par-
ticularly, carbohydrate metabolism, by stimulation of
glucose transport into the cells. In addition to regu-
lating energy metabolism in almost all organs and
tissues, insulin also crosses the blood-brain barrier
(BBB) and participates in the regulation of cognitive
functions and eating behavior [63]. Central insulin re-
sistance, which typically accompanies peripheral insu-
lin resistance, disrupts synaptogenesis, neurogenesis,
and many aspects of neuroplasticity. A decrease in the
sensitivity of insulin receptor to insulin is associated
with morphological and functional disturbances in the
CNS, formation of affective (depressive) phenotype,
and impaired cognitive abilities [63].
Antidiabetic drugs, especially BBB-penetrating
metformin, have a potential in the treatment of mental
disorders, including those associated with substance
use. Metformin normalizes blood glucose levels by in-
hibiting gluconeogenesis in the liver, reduces glucose
absorption in the GIT, stimulates glucose uptake by pe-
ripheral tissues, and improves insulin sensitivity [64].
Metformin is a biguanidine compound; its mechanism
of action is based on the ability to inhibit mitochon-
drial complex I, reduce production of reactive oxygen
species, and exhibit the anti-inflammatory properties.
Metformin reduces the severity of neuroinflammation
and stimulates neuroplasticity and excitability of neu-
rons. Its neurotropic effects are based on the abili-
ty to activate AMPK (AMP-activated protein kinase)
and CREB (cAMP responsive element binding protein)
transcription factor, leading to the upregulation of
BDNF (brain-derived neurotrophic factor) expression
followed by the stimulation of neurogenesis and anti-
depressant effect [64].
Competitive administration of metformin and
morphine interfered with the formation of tolerance to
the anti-nociceptive effect and morphine dependence
in rats [65]. Metformin administration prevented de-
velopment of anxiety- and depressive-like behavior,
as well as memory and learning impairments during
chronic methamphetamine intoxication in rats (which
was accompanied by CREB activation and increased
BDNF levels in the hippocampus) [66]. Metformin in-
jection to the nucleus accumbens reduced cocaine
self-administration [67]. Nevertheless, no controlled
clinical trials on the effect of metformin or other
drugs normalizing glucose level in PAS dependence
have been conducted so far.
Cholecystokinin is a peptide hormone produced
by the small intestine mucosa in response to stimula-
tion by food proteins and lipids. By binding to GPCRs,
it regulates appetite and satiety, stimulates gallblad-
der contractions, and promotes secretory activity of
the stomach and pancreas, thus participating in di-
gestion [68]. Cholecystokinin is also synthesized in the
CNS, where it is colocalizes and interacts functional-
ly with the dopamine, GABA, serotonin, and opioid
systems in limbic structures and modulates positive
reinforcement and emotional state [69].
In animal models, administration of cholecys-
tokinin receptor agonists or antagonists modified
consumption of different classes of PASs, but the
results of these studies remain contradictory [69].
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Russian scientists synthesized and characterized orig-
inal tetra- [70] and dipeptide [71] analogues of chole-
cystokinin that reduced alcohol consumption and alle-
viated alcohol and morphine withdrawal syndromes.
Nevertheless, only a few works suggested the pros-
pects for the clinical use of cholecystokinin recep-
tor ligands. RPR102681, an antagonist of the CCK-B
(CCK2) cholecystokinin receptor, stimulated dopamine
release in the ventral striatum and reduced cocaine
self- administration in rodents. In a clinical study, ad-
ministration of RPR102681 caused a trend toward re-
duction in cocaine craving [72].
Ghrelin is a peptide hormone produced pri-
marily by enteroendocrine cells in the stomach. Ac-
ylated ghrelin interacts with the corresponding GPCR
(GHSR1a, growth hormone secretagogue receptor 1a),
which is expressed in the CNS and peripheral or-
gans and tissues, such as intestine, pancreas, adrenal
glands, and adipose tissue [73, 74]. The main function
of ghrelin is regulation of eating behavior. It also plays
an important role in energy homeostasis by controlling
the intake and consumption of nutrients and partici-
pating in the basic metabolism of glucose and lipids
[75]. Ghrelin is a stress-reactive molecule that closely
interacts with the HPA axis in stress response [76].
Ghrelin has become a focus of attention as a
promising pharmacological target in the treatment
of substance use disorders. For example, systemic
administration of the ghrelin receptor antagonists
JMV2959 and HM-04 or inverse agonists PF-5190457
and PF-6870961 attenuated alcohol consumption re-
gardless of sex [77]. Similarly, systemic administration
of a JMV2959 reduced conditioned place preference
and self-administration of fentanyl, which was accom-
panied by a decrease in the extracellular dopamine
content in the nucleus accumbens [78]. According to
preclinical studies, ghrelin stimulated craving for and
consumption of PASs, apparently, due to its ability to
influence the dopaminergic system by inducing forma-
tion of heterodimers of ghrelin receptors with the D1
and D2 dopamine receptors [79, 80]. In many clinical
studies, ghrelin modifies alcohol craving. Intravenous
administration of ghrelin to alcohol-abusing patients
stimulated alcohol cravings [81], while oral admin-
istration of PF-5190457 reduced the stimulus-driven
cravings [82]. The clinical effect of ghrelin might be
due to its ability to influence the cytokine profile.
Combined intravenous administration of ghrelin (but
not PF-5190457) during intravenous self-administration
of alcohol reduced the level of interleukin-6 (IL-6) but
increased the content of IL-10 in alcohol abusers with
alcohol dependence [83]. The effect of PF-05190457 on
alcohol craving was investigated in phase 2 clinical
trial (https://clinicaltrials.gov/study/NCT02707055).
Unfortunately, due to the COVID-19 pandemic, the
study was terminated. In the case of chronic intox-
ication, ghrelin plays a decisive role in the develop-
ment of alcoholic liver disease by decreasing insulin
secretion and directly affecting the transport, de novo
synthesis, and esterification of fatty acids, which re-
sults in hepatic steatosis [84]. Therefore, development
and introduction of ghrelin antagonists in the clinical
practice for the treatment of alcohol use disorders
is important for the treatment of both alcohol de-
pendence and concomitant liver pathologies. Ghrelin
receptor antagonists are among the most promising
drugs in the treatment of disorders associated with
the consumption of alcohol [53] and opioids [85].
Glucagon-like peptide-1 (GLP-1) in an incretin
hormone that is expressed in the intestine and pan-
creas. It is secreted in response to food intake and
regulates satiety. The physiological activity of GLP-1 is
mediated through the activation of peripheral GLP-1
GPCRs, resulting in the suppression of intestinal peri-
stalsis, stimulation of insulin secretion, and inhibi-
tion of glucagon secretion, which normalizes glucose
levels [86, 87]. GLP-1 can penetrate the BBB and is
also expressed in the brain stem. GLP-1 receptors are
expressed in brain structures associated with rein-
forcement circuits [86, 87].
Experiments in animals have shown that stim-
ulation of central GLP-1 receptors suppressed the
reinforcing properties of alcohol, opioids, and psy-
chostimulants, as well as reduced the motivation to
consume them and symptoms of dependence [86, 87].
Among the mechanisms of action of GLP-1 receptor
agonists that underlie their modifying effect on the
activity of PASs, we should mention the relationship
of GLP-1 with the stress reactivity system and abili-
ty of hypothalamic neurons to express corticoliberin
[88], aswell as the ability of these compounds to mod-
ulate the activity of dopaminergic and glutamatergic
neurons in limbic structures [86]. The GLP-1 receptor
agonist exenatide, which is used in diabetes therapy,
reduced alcohol consumption in a subgroup of obese
individuals [89]. Exenatide reduced alcohol-dependent
activation of the ventral striatum and availability of
dopamine transporter [89]. Severely obese patients
consuming alcohol and treated with semaglutide or
tirzepatide (GLP-1 receptor agonists) for diabetes or
obesity for at least 30 days reported decrease in alco-
hol intake, which was accompanied by reduction of
the symptoms of alcohol use disorder according to the
AUDIT (Alcohol Use Disorder Identification Test) scores
compared to values in the control group (people that
had not received the drugs) and before the treatment
[90]. Treated patients noted a subjective decrease in
alcohol cravings, which can be considered as an in-
direct evidence of the efficacy of these drugs against
alcohol dependence [90]. Retrospective analysis of pa-
tients treated with semaglutide for weight loss also
showed a significant reduction in alcohol use disorder
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BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
symptoms based on the AUDIT score [91]. The effica-
cy of GLP-1 receptor activation by agonists, especially
semaglutide, has been demonstrated in independent
studies in rodents and primates, so that the use of these
drugs in the clinic seems extremely promising [92].
Leptin is a peptide hormone secreted by the ad-
ipose tissue. It regulates food intake by influencing
appetite; moreover, leptin is involved in the regula-
tion of reinforcement-related behavior associated with
various stimuli [93]. Leptin acts through a receptor
belonging to class I cytokine receptors expressed in
the hypothalamus, hippocampus, and amygdala. In
the ventral tegmental area, leptin attenuated the fir-
ing rate of dopaminergic neurons projecting to the
nucleus accumbens [93].
The data obtained on the studies of the effect
of alcohol on the leptin blood levels in animals are
contradictory. In mice bearing mutations in the genes
encoding leptin or its receptor, leptin administration
stimulated alcohol intake [93]. In contrast, leptin ad-
ministration attenuated motivation for cocaine use in
rats [94]. Injection of leptin receptor antagonist into
the ventricles or local knockout of leptin receptors in
the mesolimbic structures increased dopamine levels
and stimulated cocaine-associated conditioned place
preference [95]. Leptin peripheral levels in patients
with alcohol dependence varied significantly, as well
as the relationship between the leptin levels and clin-
ical manifestations of alcohol dependence, especially,
alcohol craving [93].
Neurotensin is a peptide produced in the CNS
and GIT. Neurotensin is difficult to attribute to any
body system, since it exhibits its biological activity in
nervous tissue, CVS, adipose tissue, and GIT. Among
others, it regulates food and water intake, body tem-
perature, blood pressure, metabolism, energy balance,
and sleep-wake cycle [96]. Neurotensin also plays an
important role in the mechanisms of reinforcement
and formation of adaptive response to stress. The pos-
itive reinforcing properties of neurotensin are due to
the activation of the high-affinity NTSR1 (neurotensin
receptor 1) GPCR in the structures of the mesocortico-
limbic system [96].
The influence of neurotensin on the reward cir-
cuits and, therefore, mechanisms of psychostimulant
and alcohol preference, as well as on the motivation
for drug and alcohol consumption, is based on its abil-
ity to interact with the dopaminergic system through
the formation of NTSR1 heterocomplexes with D2
dopamine receptor [97, 98]. Neurotensin interaction
with the dopaminergic system indirectly modulates
the activity of glutamatergic and GABAergic systems.
Russian scientists synthesized and characterized a di-
peptide analogue of neurotensin capable of attenuat-
ing morphine withdrawal syndrome in rodents, which
was accompanied by changes in the dopamine metab-
olism [99]. The results of studies in rodents are often
contradictory [97, 98]. Despite the efficacy of neu-
rotensin receptor ligands (especially, NTSR1 ligands)
in modulation of PAS consumption demonstrated in
preclinical studies, no clinical studies on this topic
have been conducted yet.
Fibroblast growth factor (FGF) family includes
23 secreted proteins. In humans, FGFs are produced
by keratinocytes, fibroblasts, chondrocytes, endothe-
lial cells, smooth muscle cells, and mast cells and
display a wide range of biological activities. Impair-
ments in the functioning of these factors are associat-
ed with metabolic disorders, cardiovascular diseases,
and oncogenesis. It is known that at least two mem-
bers of this family, FGF2 [100] and FGF21 [101], are
involved in substance use disorders. FGF2 has a para-
crine mechanism of action; it binds to FGF receptors
(FGFRs) with the tyrosine kinase activity, participates
in cell migration and proliferation, regulates vascular
tone and angiogenesis, and displays the anti-apoptotic
and anti-inflammatory properties [100]. FGF2 is also
expressed in the brain, where it exhibits the neuro-
protective properties, participates in neurogenesis and
memory formation, and regulates stress reactivity
and emotional background by activating FGFR1 [102].
FGF21, on the contrary, is an endocrine regulator.
Beside FGFR, it requires the Klotho transmembrane
protein for its activity. Klotho regulates insulin sensitiv-
ity and increases FGF21 affinity for the receptor [100].
FGF21 is expressed in liver, adipose tissue, and pan-
creas and is involved in fat and glucose metabolism.
In rodents, FGF2 influenced the sensitivity to
amphetamine and cocaine self-administration. At the
same time, FGF2 expression in dopaminergic neurons
is affected by psychostimulants. Moreover, in these
experiments, FGF2 participated in the morphologi-
cal changes of neurons of the ventral tegmental area
[100]. Systemic administration of FGF2 or its injection
into the striatum in rodents stimulated alcohol con-
sumption, while the knockout of the Fgf 2 gene or inhi-
bition of FGFR1 reduced the reinforcing properties of
alcohol and motivation to consume it [103-105]. Using
systemic and central administration of FGF21 or its
analogue (PF-05231023), as well as the tissue-specific
deletion of FGF21 in the liver, it was shown that FGF21
expressed in the liver in response to alcohol intoxi-
cation, is involved in the negative feedback that sup-
presses subsequent alcohol intake through the Klotho
coreceptor in the basolateral amygdala, as well as in
the regulation of dopaminergic neurons activity in
the nucleus accumbens [106]. According to the clinical
data, alcohol drinking is accompanied by the upregu-
lation of circulating FGF21 [107, 108]. Transgenic mice
with an increased level of circulating FGF21 showed
attenuation of the morphine antinociceptive toler-
ance development, reduced morphine dependence,
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BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
and reduced preference for morphine in the con-
ditioned place preference test [109]. Therefore, the
blockade of FGF2 signaling attenuates addictive prop-
erties of alcohol and psychostimulants, while FGF21
stimulation suppresses formation of alcohol and opi-
oid dependences. However, no clinical studies have
been conducted to verify the effects of FGF2 or FGF21
in the consumption of alcohol and PASs. Because FDA
has approved erdafitinib and pemigatinib (FGFR in-
hibitors) for the therapy of malignancies with the
activating mutations in FGFR2 and FGFR3, this might
raise the question of potential repurposing of these
drugs in pharmacotherapy for the treatment of sub-
stance dependence.
COMPONENTS OF THE IMMUNE SYSTEM
An important aspect in PAS activity and formation
of dependence is the effect they exert on the immune
system and neuroimmune communication. Ingeneral,
resident CNS macrophages respond to pro-inflamma-
tory stimuli. TLRs (Toll-like receptors) trigger cascades
leading to the activation of transcription factors, pri-
marily NF-κB (nuclear factor κB), and subsequent
expression of proinflammatory cytokines by the mi-
croglia [110]. In response to cytokines, astrocytes re-
duce expression of the glutamate transporter, result-
ing in the impaired functioning of the glutamatergic
system [110]. Hence, the microglia and astrocytes
can control the excitability of glutamatergic neurons.
Thedisturbances in the balance between the pro- and
anti- inflammatory systems can cause neuroinflamma-
tion development that often accompanies PAS abuse.
Immune mechanisms play an important role in the
development of diseases comorbid with chronic PAS
abuse, such as affective mental disorders, pain syn-
drome, and infectious process [111].
Studies in animals deficient by the key mediators
of immune response, such as TLRs, TNFs (tumor ne-
crosis factors), IL-1 (interleukin 1), and IL-6, showed
that these molecules can modify the addictive proper-
ties of PASs or manifestations of the withdrawal syn-
drome [111]. Preclinical studies have demonstrated
that the neuroimmune system modulators, e.g., phos-
phodiesterase inhibitors and ligands of peroxisome
proliferator-activated receptors (PPARs), can modify
the course and symptoms of dependence [110, 111].
It is important that these agents demonstrate their
activity in clinical studies as well [110, 111].
cAMP and cGMP. As secondary mediators, cAMP
and cGMP play an important role in the immune
system signaling, while isoform-specific inhibitors of
phosphodiesterases (enzymes breaking the phospho-
diester bond in cyclic nucleotides) exhibit the immu-
nomodulatory activity and suppress the inflammatory
response [112]. The non-selective phosphodiesterase
inhibitor ibudilast, which is approved in some coun-
tries for the treatment of asthma, acts as an immu-
nosuppressor that inhibits the activation of microglia
[113]. Ibudilast efficiently reduced alcohol intake in
many rodent models [114]. In a clinical study, ibudi-
last attenuated alcohol cravings and normalized mood
[115], as well as reduced the volume of alcohol con-
sumed, which, according to MRI, was accompanied
by a decrease in the activity of the ventral striatum
[116]. Systemic administration of ibudilast potentiated
the analgesic effect of morphine and oxycodone and
attenuated the symptoms of withdrawal syndrome in
rats [117]. In clinical studies in patients with opioid
dependence, ibudilast weakened the reinforcing prop-
erties of oxycodone and attraction to heroin, but po-
tentiated the antinociceptive effect of oxycodone [118],
and also partially attenuated the symptoms of opioid
withdrawal syndrome [119]. At the same time, ibudi-
last did not affect the amount of methamphetamine
consumed in a 12-week clinical study involving pa-
tients undergoing outpatient treatment for addiction
[120]. Promising results have been demonstrated for
the anti-alcohol properties of apremilast (phosphodi-
esterase 4 inhibitor) that has been approved for the
treatment of psoriasis. Apremilast reduced motiva-
tion to consume alcohol in a mouse model, presum-
ably through modification of dopaminergic neurons
in the nucleus accumbens, and decreased alcohol
consumption by dependent patients in phase 2 clin-
ical trial [121].
PPAR family of transcription factors exhibits a
wide range of biological activities by controlling ex-
pression of proteins regulating metabolism and in-
flammatory and immune responses [122, 123]. PPARα
isoform stimulates endocytosis, esterification, and
transport of fatty acids and regulates the genes of
lipoprotein metabolism. PPARδ stimulates lipid and
glucose catabolism. PPARγ promotes fatty acid up-
take and triglyceride formation, thus providing insulin
sensitivity and glucose metabolism. PPAR agonists are
widely used in the clinic. Thus, glitazones (PPARγ ago-
nists) are used for the treatment of insulin resistance.
Fibrates (PPARα agonisms) are the therapeutic agents
in dyslipidemia [122, 123]. Due to the PPAR involve-
ment in essential metabolic processes (e.g., oxidative
phosphorylation), These receptors are expressed in
almost all tissues and organs.
Due to their involvement in the key processes,
such as oxidative stress and inflammation, PPARs also
participate the development of CNS pathologies. Many
PPAR agonists approved for the use in clinic, penetrate
the BBB and show central activity, which opens up
the prospects in their repurposing for the treatment
of brain diseases [124]. PPAR isoforms are expressed
in the dopaminergic neurons of limbic structures
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BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
involved in the dependence formation; hence, PPAR
agonists can modify the activity of these neurons,
which makes their investigation a relevant topic in
the studies of addictions [125]. Agonists of PPARα and
PPARγ isoforms were found to attenuate motivation
and PAS consumption and to reduce the symptoms of
withdrawal in experimental models [125]. It should
be noted that most studies have been conducted in
alcohol consumption models, in which agonists of
both isoforms suppressed voluntary and operant in-
take [125]. Despite their potential, PPARα agonists are
unlikely to be effective in the treatment of alcohol
dependence, since fenofibrate had no effect on alco-
hol intake and alcohol craving in a clinical trial [126].
Atthe same time, in a small sample of diabetic alcohol
drinkers, pioglitazone helped to reduce alcohol con-
sumption [127]. In contrast, in another clinical trial
(which had been terminated), pioglitazone stimulated
rather than inhibited alcohol cravings [128]. There-
fore, results of clinical studies do not allow to make
unambiguous conclusions regarding the effectiveness
of PPARα agonists.
Intestinal microflora (microbiota) makes a sig-
nificant contribution to the development of inflam-
matory response in organs and tissues, including
the CNS. Regarding communication between the GIT
and the brain in the formation of the PAS dependence,
it should be taken into account that chronic PAS con-
sumption affects the microbiome, which in turn af-
fects the brain [129]. As xenobiotics, many classes of
drugs (including PASs) have a direct impact on the
intestinal bacteria [130, 131]. PAS, such as opiates and
opioids, indirectly affect the peripheral nervous sys-
tem and regulate intestinal peristalsis, which can also
alter the microbiota composition [132]. The most stud-
ied mechanism by which intestinal microbiota affects
the CNS is production of neuroactive metabolites, pri-
marily short-chain fatty acids (SCFAs), which enter the
portal circulation and reach the brain [133]. Also, lipo-
polysaccharides, which are pro-inflammatory factors,
can enter the bloodstream due to impaired intestinal
permeability [134]. SCFAs affect the microglia and im-
mune cells by activating the corresponding receptors.
They can also act as substrates for histone modifica-
tion, as well as regulators of activity of enzymes, for
example, histone deacetylases [135].
Studies in animal, early phases of clinical trials,
and retrospective analysis have shown that PASs af-
fect the microbiota composition, which can be import-
ant in the formation of drug dependence. At the same
time, manipulating the composition of the microbio-
ta using antibiotics or its transplantation can modify
the course or manifestation of dependence [129, 135].
Despite the fact that the nature of microbiota inter-
actions with the brain under the influence of PASs
depends on many factors, which can be seen from di-
verse and often contradictory study results, the modu-
lation of the microbiota or its metabolites has serious
prospects of becoming a part of substance dependence
treatment program in the future [129, 135].
CIRCADIAN RHYTHMS
Circadian rhythms and sleep are controlled by the
central mechanisms. Dysregulation of these mecha-
nisms affects somatic health, resulting in a wide range
of internal diseases [136]. In this regard, we decided
to discuss this topic in the review, especially since dis-
turbances in the quality and duration of sleep often
accompany the PAS abuse. Sleep disorders increase
the risk of relapse, aggravate the course of substance
use disorders, and worsen physical health [137, 138].
Melatonin (N-acetyl-5-methoxytryptamine) is se-
creted by the pituitary gland and regulates circadian
rhythms by binding to the MT1 and MT2 GPCRs in the
suprachiasmatic nucleus. Administration of melatonin
reduced the consumption of alcohol, opiates, and co-
caine in rodent models [139]. Melatonin is involved in
the mechanisms of dependence at the cellular and sys-
temic levels through the modulation of the glutamate,
dopamine, and GABA neurotransmitter systems. It also
possesses pronounced anti-inflammatory properties
[139]. In contrast to numerous experimental studies,
the clinical studies are much less common and the
effect of melatonin in these studies strongly depends
on the pharmacological class of PAS. For example,
in heroin-dependent patients undergoing substitu-
tion therapy, melatonin significantly improved sleep
quality, as well as reduced anxiety and depression,
which was accompanied by a reduction in the insulin
serum levels and decrease in the insulin resistance
[140]. At the same time, clinical studies have failed
to show the effectiveness of melatonin in the treat-
ment of sleep disorders associated with alcohol depen-
dence [141].
Orexins regulate the sleep-wake cycle and eating
behavior, i.e., processes often disrupted in individu-
als with substance dependence. Orexins A and B are
peptides produced by neurons in the lateral hypothal-
amus that act through binding to the cognate Ox1R
and Ox2R GPCRs expressed in various brain regions.
Unlike classical neurotransmitter systems involved in
the reinforcement, orexins do not participate directly
in the regulation of primary reinforcement. Orexins
regulate motivation to consume PASs, which is a key
symptom of addiction, by influencing the neuronal
plasticity in limbic structures upon chronic intoxica-
tion [142]. In animal models, both non-selective and
subtype-selective Ox1R and Ox2R antagonists reduced
the reinforcing properties of stimulants (alcohol and
opiates), thereby reducing consumption and risk
PERIPHERAL MEDIATORS OF SUBSTANCE USE DISORDERS 1877
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
of relapse [143]. Thus, SB-408124 (Ox1R antagonist)
blocked alcohol-induced conditioned place preference
in rats [144]. Non-selective Ox1R and Ox2R antagonists,
such as suvorexant, have been approved for the treat-
ment of insomnia. These drugs also have a potential in
the reduction of cravings in the comorbidity of sleep
disorders and alcohol dependence [145]. In a clinical
study, suvorexant ameliorated sleep disturbance and
relieved symptoms of depression and opiate with-
drawal syndrome [146, 147]. Hence, orexin receptors
are promising pharmacological targets in the therapy
of sleep disorders and comorbid substance use disor-
ders. Antagonists or negative allosteric modulators of
orexin receptors are believed to be among the most
promising drugs in the treatment of disorders asso-
ciated with the use of alcohol [53] and opioids [85].
CONCLUSION
Realize that everything
connects to everything else.
Leonardo da Vinci (1452-1519)
A body can function in a changing environment
due to the maintenance of metabolic homeostasis
achieved through cooperation between the CNS and
internal organs. Myriads of hormones, peptides, and
neurotransmitters in a whimsical ensemble ensure the
functioning of systems and organs, as well as commu-
nication between them. All compounds described in
our review have the following fundamental charac-
teristics: (i) pleiotropic action, i.e., ability to influence
different body systems and exert different effects;
(ii) interaction with signaling systems and participa-
tion in the metabolic events that also involve other
described compounds; (iii) close relationship with the
main neurohumoral body system regulating stress
response and adaptive processes. This is why an im-
balance in the mediators in one part of the system,
which might reach a critical level when the compen-
sation is no longer possible, leads to a development
of a complex disorder. Substance use disorders are a
psychopathological phenomenon mostly affecting me-
socorticolimbic structures and stress response circuit,
whereas interaction with internal organs regulates
these processes.
According to the analyzed data, the main effect
of visceral system mediators with the pleiotropic
functions on the PAS-associated mechanisms is their
involvement in the limbic reinforcement system and
stress response circuit originating in the hypothalam-
ic-pituitary system. The reward system has a central
location, while the system responsible for the stress
sensitivity is connected with internal organs via hor-
monal communication. In addition to the HPA axis,
which has been repeatedly mentioned here, axes link-
ing the hypothalamic-pituitary system with the activ-
ity of thyroid gland and gonads might be essential in
the substance dependence. Due to the complexity of
the subject, we opted not to discuss this topic in the
current article. Interested readers can refer to the
comprehensive reviews [12, 148, 149].
Therefore, PASs themselves, as well as cycles of
intoxication and withdrawal, directly or indirectly dis-
rupt neurochemical and hormonal homeostasis, which
aggravates the course of chronic somatic diseases.
In turn, this promotes pathological dependence, thus
forming a vicious circle exacerbating both substance
use disorders and concomitant comorbidities. Figure 1
shows interactions between some visceral and CNS
mediators, which, according to the published reports,
have an effect in substance use disorders.
An important direction in the development of
clinical psychopharmacotherapy of substance use
disorders should be design and introduction of new
drugs, as well as repurposing, i.e., the use of drugs
that had been approved for the treatment of other
class of diseases [53, 85, 150, 151]. The review describes
Fig. 1. Interaction of visceral systems and CNS in PAS use
disorders. When exposed to PASs, hormones, peptides, neu-
rotransmitters, and growth factors produced in the brain
and/or peripheral organs and tissues, have a pleiotropic ef-
fect by participating in the pathology development in inter-
nal organs, on one hand, and modulating the reinforcement
and stress response systems as components of the central
mechanism of substance dependence, on the other hand.
Mediators have a negative (–) or stimulating (+) effect on
various factors in the formation of PAS dependence (right
panel). The HPA, hypothalamic-pituitary-thyroid, and hypo-
thalamic-pituitary-gonadal axes, as well as immune system
and intestinal microbiota, coordinate the process (left panel).
The figure was created using Servier Medical Art (Servier)
templates licensed under Creative Commons Attribution 3.0
unported license
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BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
Table 1. Promising pharmacological groups of drugs in the treatment of substance use disorders
Pharmacological
group
Efficacy in the context of PAS action Indications
for approved
drugs
Group
representatives
PAS
Test models
Clinical trials
Endothelin receptor
antagonists
BQ123 opiates/opioids
potentiation of analgesia,
attenuation of tolerance
and withdrawal syndrome[28]
– hypertension
ACE inhibitors
captopril,
enalapril
alcohol suppression of intake[37]
– hypertension
captopril opiates/opioids reinforcement attenuation [38]
Angiotensin receptor
antagonists
telmisartan alcohol suppression of intake[40]
– hypertensionvalsartan opiates/opioids
attenuation of tolerance
and withdrawal syndrome[41]
candesartan psychostimulants reinforcement attenuation [42]
Mineralocorticoid
receptor antagonists
spironolactonum alcohol suppression of intake [46] –
hypertension
heart failure
Vasopressin V1b
receptor antagonists
SSR149415,
ABT-436
alcohol suppression of intake[48, 49]
suppression
of intake [52]
–
SSR149415 opiates/opioids reinforcement attenuation [50] –
Oxytocin receptor
agonists
oxytocin
alcohol,
opiates/opioids,
psychostimulants
reinforcement attenuation,
reduced relapse risk [57, 58]
suppression
of craving
and intake,
attenuation
of withdrawal
syndrome [59]
labor induction
Hypoglycemic agents
(biguanides)
metformin
opiates/opioids
attenuation of tolerance
and withdrawal
syndrome [65]
– type 2 diabetes
psychostimulants
suppression of intake,
attenuation of intoxication
[66, 67]
PERIPHERAL MEDIATORS OF SUBSTANCE USE DISORDERS 1879
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
Table 1 (cont.)
Pharmacological
group
Efficacy in the context of PAS action Indications
for approved
drugs
Group
representatives
PAS
Test models
Clinical trials
Ghrelin receptor
antagonists
JMV2959,
HM-04
alcohol suppression of intake[77]
-–
JMV2959 opiates/opioids reinforcement attenuation [78]
Ghrelin receptor
inverse agonists
PF-5190457,
PF-6870961
alcohol suppression of intake[77]
suppression
of craving[82]
–
GLP-1 receptor agonists
exenatide,
semaglutide,
tirzepatide
alcohol,
opiates/opioids,
psychostimulants
suppression of intake[86, 87]
suppression
of alcohol craving
and alcohol
intake[90, 91]
type 2 diabetes,
obesity
FGF21 receptor agonists FGF21, PF05231023
alcohol suppression of intake [106]
––
opiates/opioids
attenuation of reinforcement, toler-
ance, and withdrawal
syndrome [109]
Phosphodiesterase
inhibitors
ibudilast
alcohol suppression of intake [114]
suppression
of alcohol craving
and alcohol in-
take [115,116]
asthma
opiates/opioids
analgesia potentiation, attenuation
of withdrawal syndrome[117]
analgesia
potentiation,
suppression
of craving,
attenuation
of withdrawal
syndrome
[118, 119]
apremilast alcohol suppression of intake [121]
suppression
of intake[121]
psoriasis
PPARα and PPARγ
agonists
fibrates, glitazones alcohol suppression of intake [125]
results regarding
intake are
inconsistent
[126-128]
metabolic
syndrome
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main mediators of peripheral systems involved in the
central biochemical mechanisms of substance use dis-
orders. The comorbidity of somatic pathologies and
chemical dependence, which is due to the existence
of common biological mechanisms, can be the basis
for the development and introduction into clinical
practice of new effective tools of pharmacological
correction. At the same time, potential repurposing
of many drugs already used in the pharmacothera-
py of addiction based on the existence of common
pathogenetic mechanisms, can be fundamentally im-
portant, since it allows to reduce the stage of safety
trials and introduce these drugs in a short time and
with minimal funding into clinical practice for a new
therapeutic application. The most promising pharma-
cological targets, whose involvement in the formation
of drug dependence was described in this review, are
summarized in Table 1.
PAS consumption is not necessarily comorbid with
somatic pathologies, although it significantly increases
the risk of developing such pathologies and vice versa.
Creation of a high-tech methodological base for geno-
typing allows to analyze the data at a genome-wide
level and makes possible identification of genetic and
epigenetic markers of comorbid pathologies. This can
be used in addiction medicine for identification of risk
groups, prognostics and diagnostics, and identification
of individuals responsive to pharmacotherapy [8].
Due to the science development, an incredibly
large amount of experimental data have been accu-
mulated, which determines the need for their analy-
sis and creation of new concepts of physiological and
pathological processes. Indeed, considering the mul-
tifactorial nature, polygeny, and pleiotropy of media-
tors involved in the mechanisms providing formation
of pathological dependence, it seems that implemen-
tation of new effective therapeutic methods has no
prospects. Nevertheless, modern tools of data analysis
inspire some hope. For example, the use of integra-
tive bioinformatic approaches has led to the identi-
fication of protein kinase mTOR (mammalian target
of rapamycin) as one of the most promising targets
in the treatment of addictions and repurposing of
already approved drugs [152]. mTOR inhibitors are
used in cancer chemotherapy. mTOR is a key mole-
cule regulating fundamental physiological processes;
there is also evidence of mTOR involvement in the
mechanisms of PAS action [153].
Keeping with the general trend in modern medi-
cine, drug treatment in addiction medicine should also
use a personalized approach, in particular, include
clinical examination of patients for detection of co-
morbid somatic diseases. It has been repeatedly noted
that in order to increase the efficiency of treatment
of substance use disorders, it is necessary to take into
account somatic pathologies in the patient’s anamne-
sis and to integrate therapeutic programs aimed at
improving both mental and somatic health [21, 154].
Contributions. D.I.P. and N.V.G. developed the
study concept, searched for and analyzed published
data; D.I.P wrote the original version of the article;
N.V.G. edited the manuscript.
Funding. This work was supported by the Serbsky
National Medical Research Center for Psychiatry and
Drug Addiction, Ministry of Health of the Russian
Federation, within the framework of the State Task
(project no.122031000267-0).
Ethics declaration. This work does not describe
any studies involving humans or animals as subjects
performed by any of the authors. The authors of this
work declare that they have no conflicts of interest.
Open access. This article is licensed under a Cre-
ative Commons Attribution4.0 International License,
which permits use, sharing, adaptation, distribution,
and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s)
and the source, provide a link to the Creative Com-
mons license, and indicate if changes were made.
Theimages or other third party material in this article
are included in the article’s Creative Commons license,
unless indicated otherwise in a credit line to the mate-
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Commons license and your intended use is not permit-
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use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license,
visit http://creativecommons.org/licenses/by/4.0/.
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