Biomedicine & Pharmacotherapy 132 (2020) 110889

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Plant-derived natural therapeutics targeting cannabinoid receptors in

metabolic syndrome and its complications: A review
Ashwani S. Patil a, Umesh B. Mahajan a, Yogeeta O. Agrawal b, Kalpesh R. Patil a,
Chandragouda R. Patil a, Shreesh Ojha c, Charu Sharma d, Sameer N. Goyal a, e, *
a
Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, 425405, Dhule, Maharashtra, India
b
Department of Pharmaceutics, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, Maharashtra, 425405, India
c
Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, United Arab Emirates
d
Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, United Arab Emirates
e
SVKM’s Institute of Pharmacy, Dhule, Maharashtra, 424 001, India

A R T I C L E I N F O A B S T R A C T

Keywords: The endocannabinoid system (ECS) is natural physiological system in the humans. The presence of the ECS
Endocannabinoids system involves different roles in body. The endocannabinoid system involves regulation of most of the centers,
Metabolic syndrome which regulates the hunger and leads to changes in the weight. In the present article, we reviewed the role of
Cannabinoid receptors
natural cannabinoid compounds in metabolic disorders and related complications. We studied variety of a plant-
Plant-derived cannabinoids
derived cannabinoids in treating the metabolic syndrome including stoutness, fatty acid liver diseases, insulin
obstruction, dementia, hypertension, lipid abnormalities, non-alcoholic steatohepatitis, endothelial damage, and
polycystic ovarian syndrome and so on. The activation of cannabinoid receptors demonstrates a significant
number of beneficial approaches concerning metabolic syndrome and reduces the pro-inflammatory cytokines on
account of aggravation, decreased oxidative stress and uneasiness, diminishes liver fibrosis, with reduces adi­
ponectin. Pre-clinical investigations of plant-derived cannabinoids resulted in promising outcomes. The different
distinctive plant-derived cannabinoids were discovered like cannabidiol (CBD), cannabinol (CBN), cannabi­
chromene (CBC), and cannabidiol (CBG). It has been observed that endogenous cannabinoids and plant-derived
cannabinoids have an advantageous impact on limiting the metabolic disorder arising due to lifestyle changes.

1. Introduction hyperactivity of endocannabinoids in the body results in depression,

ECS is known to be the natural physiological system in the human
body. ECS plays many roles in the body, it increases the brain centers for
hunger and body weight, hence can be liable for abnormalities and in­
creases the chances of physiological changes in the body. It has been
suggested that overexpression of ECS leads to the occurrence of meta­
bolic syndrome [1]. This system includes G-protein coupled receptors
called cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2). The
endocannabinoids and their receptors are found in almost all the body
organs, fluids and tissue, from which anandamide and 2-arachidonoyl­
glycerol are well known [2]. CB1 was first found in the brain after­
wards it was suggested to be in the olfactory bulb, hippocampus,
septum, amygdala, hypothalamus and cerebellum [3]. Recent studies
have shown that the ECS is involved in many diseases and disorders, the
anxiety and post-traumatic disorders [4]. The reports showed that ECS
works as epigenetic modulators activating the transcriptional action of
key genes involved in neurotransmissions [5]. Metabolic syndrome has
different physiological factors that increases the risk of cardiovascular
disease, and type 2 diabetes mellitus. The prevalence of the metabolic
syndrome in USA is, 34 % and 9.3 % of adults with diabetes mellitus.
Also, metabolic syndrome is linked to a number of cancers, including
breast, pancreatic, colon and liver cancer. Earlier Earlier review gathers
internationally generated information on metabolic syndrome, its many
definitions and its associations with life-threatening situations,
including type 2 diabetes mellitus, cardiovascular disease, and cancer
[7]. The two major components of metabolic syndrome are weight gain
and fat accumulation at intra-abdominal sites with abnormal fat in the
liver, pancreas, and heart. Psychosocial stress and our lifestyle also

* Corresponding author at: Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, and SVKM’s Institute of
Pharmacy, Dhule, 424 001, Dist: Dhule, Maharashtra, India.
E-mail address: goyal.aiims@gmail.com (S.N. Goyal).

https://doi.org/10.1016/j.biopha.2020.110889
Received 30 May 2020; Received in revised form 9 October 2020; Accepted 12 October 2020
Available online 28 October 2020
0753-3322/© 2020 Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
A.S. Patil et al.
Fig. 1. Different conditions or disorders included in the metabolic syndrome and its complications.
contribute to metabolic syndrome (MS) [8]. The endocannabinoid sys­
tem is regulated through the cannabinoid receptors, their transporters,
and some enzymes. The previously published reports revealed the
involvement of endocannabinoids in the growth of tumor cells. ECS has
been studied in glioma models and numerous studies showed the
expression of functional ECS components including CB1 and CB2 re­
ceptors [9] Metabolic syndrome and its complications are showed as
Fig. 1.
2. Plant-derived cannabinoids
The plant cannabis sativa, commonly known as marijuana, has long
been used for medical purposes. The active ingredients in cannabis plant
extracts (phytocannabinoids) are well investigated, for there therapeutic
and pharmaceutical applications. The most abundant phytocannabi­
noids are (− )-tetrahydrocannabinol (THC), a compound readily
extracted from Cannabis sativa, THC and cannabidiol (CBD) are key
cannabinoids [10]. Marijuana is derived from the dried flowering tops,
leaves, stems, and seeds of the CCannabis sativa (hemp) plant. Cannabis
has been used for hundreds of years for fiber (hemp), seed oils, seed,
medical treatment, and recreationally. Cannabis is one of the oldest
psychotropic drugs, various human studies are performed on cannabi­
noids (CBs), several species of Cannabis are there, and some of them are
more compatible like Cannabis sativa,Cannabis indica, and Cannabis
ruderalis. Marijuana and hashish are derived from cannabis. Now a days,
marijuana is referred to as dried leaves and flowers of the hemp plant,
whereas hashish is a viscous resin of the plant [11]. Traditionally
cannabis was used as a medication for its analgesic, tonic, antispas­
modic, and antiemetic activity [12]. Various plant-derived cannabinoids
have been found namely Cannabidiol (CBD), Cannabinol (CBN), Can­
nabichromene (CBC), (− )-tetrahydrocannabinol (THC), and Cannabi­
greol (CBG) (Fig. 2).
2.1. Cannabidiol (CBD)
CBD is well known to have anti-seizure activity, also, it has anti-
inflammatory, anti-tumor, analgesic and, anti-psychotic activity [13].
CBD does not produce the side effects that are typically seen with can­
nabinoids such as THC (WHO pre-review report 2017). Moreover, Epi­
diolex is an approved marketed CBD is containing the medicinal
product, it was reported that administration of CBD in rats, leads to a
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Biomedicine & Pharmacotherapy 132 (2020) 110889
slight increase in the blood pressure also with an increase in the heart
rate. The mechanism of the increase in the heart rate and blood pressure
is due to CBD is known to increase oxidative stress. The CBD is a major
phytocannabinoids, accounting for up to 40 % of the plant’s extract,
currently CBD is in much research due to its potential
anti-inflammatory, anticonvulsant, antioxidant, anxiolytic, and anti­
psychotic properties with numerous preclinical studies have also shown
CBD to be beneficial in these wide ranges of disorders related to meta­
bolic syndrome. CBD is also reported to reduce heroin-seeking nature
[14]. CBD is reported to have an immunomodulatory role as it relieves
the arthritis-like symptoms [15].
2.2. Cannabinol (CBN)
Various pre-clinical reports proved that, cannabinol (CBN) has
numerous therapeutic uses, it can stimulate the feeding and change the
meal pattern in rats. The ECS is well known to increase the food intake as
it is activating the hunger and related centers. It was observed as the
administration of CBN in rats showed an increase in food consumption
[16]. CBN is commonly found in the aged plant of cannabis and is a
degradation product of THC on exposure to UV light. This conversion
occurs over time if subjected to storage conditions, as a degradation
product of THC it has also shown to be a rapid metabolite of THC in
blood, CBN has shown to cause a decrease in intraocular pressure (IOP)
in rodent studies. It has shown to inhibit pro-inflammatory cytokine
such as IL-2, and transcription factors like CREB, and NF-kB [17]. CBN
has a higher affinity for CB2 receptor whereas lower for CB1 as
compared to THC. CBN is found to potentiate the effect of THC in
humans, whereas it antagonizes the effects of preclinically in rats and
mice.
2.3. Cannabichromene (CBC)
CBC is a non-psychoactive cannabinoid and alters the activity of
proteins involved in the nociceptive mechanism including transient re­
ceptor potential (TRP) channels of vanilloid type-1 (TRPV1) and of
ankyrin type-1 (TRPA1) [18]. CBC is the second most to produce
anti-nociception and anti-inflammatory effects in animals and is the
second most abundant phytocannabinoids in some strains of marijuana
in the United States. It is specifically more plentiful in freshly harvested
dry-type cannabis material. Recent reports showed it’s antimicrobial,
A.S. Patil et al.
Fig. 2. Molecular structure of Cannabinoids based on their functional groups [21].
anti-inflammatory, analgesic and anti-depressant like activity in animal
studies [19].
2.4. Cannabigreol (CBG)
Cannabigreol is known to kill or slow bacterial growth, reduce
inflammation inhibits cell growth in cancer cells, and promote bone
growth. It acts as a low-affinity antagonist at the CB1 receptor. CBG
pharmacological activity at the CB2 receptor is currently unknown.
Some studies demonstrate for the first time that the non-psychoactive
plant cannabinoid CBG can stimulate appetite in pre-satiated rats,
CBG predominantly stimulated feeding behavior by decreasing the la­
tency to feed and increasing the frequency of feeding rather than by
increasing individual meal size or duration [20] (Fig. 2).
3. Cannabinoid receptors
The endocannabinoids are highly lipophilic and hence, they
reasonably interact with the cell membranes. CB1 and CB2 are the
Fig. 3. Different effects of cannabinoids on the human body and reported effects [30–32].
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Biomedicine & Pharmacotherapy 132 (2020) 110889
cannabinoid receptors. CB1 is largely found in the brain, whereas CB2 is
found in immune cells and few in nervous tissue. Activation of CB1 and
CB2 receptors further communicate with GPCRs and ion channels. CB1
cannabinoid receptor shows an important role in the molecular and
cellular mechanisms involved in brain development. CB1 receptors play
a key role in cortical development and essential role in adult brain
function, neuropsychiatric disorder including the balance of neuronal
excitation and inhibition activity [22]. Both the receptors are distinc­
tively present in the body tissues, mainly, the CB1 receptor was found in
rat cerebral cortex, and is predominately expressed in the central ner­
vous system. The subtypes of this receptor are also expressed in vascular
endothelium, small intestine, peripheral tissue, and testis, etc. [23].
Whereas the CB2 receptor was initially identified in promyelocytic
leukemia cell line HL60 [23]. The degradation of endocannabinoids is
attained utilizing two specific enzymes, the fatty acid amide hydrolase
(FAAH) and the monoacylglyceride lipase (MAGL) enzymes. FAAH de­
grades anandamide, whereas the MAGL degrades 2-AG [24]. CB1 re­
ceptor activity is linked to the management of different neural cell types
development, including neurons and glial cells. CB1 antagonists increase
A.S. Patil et al.
Fig. 4. Effects of cannabinoid receptor on different organs in the human body with their activities.
cardiac contractile performance without disturbing peripheral vascular
resistance. The role of CB1 in hypertension can be considered thera­
peutically, activation of CB1 by any means that is by plant or synthetic
agonists is unacceptable because of its psychotropic effects [25].
4. Cannabinoid receptor expressions
Majorly the CB1 receptor is found in peripheral tissues whereas, the
expression of these receptors is in the adipocytes, liver, pancreas and
skeletal muscle, the expression of the CB1 receptor is found to be low.
CB2 receptors are expressed in immune cells mainly those derived from
macrophages [26]. The CB1 receptors are expressed in embryonic
development in initial stages also present in trophoblast stem cells. With
neuronal cell differentiation, the expression of CB1 increases, the
imbalance in the CB1 expression is due to changes in the neuronal
markers [22]. There are some studies which say that the CB1 and CB2
are not limited for the central nervous system (CNS) rather it has an
expression on heart that is it modulates heart rate and blood pressure,
CB1 receptor activation increases the release of pro-inflammatory cy­
tokines in macrophages and responsible for the increase in the inflam­
mation [27]. CB1 and CB2 both are GPCR that regulate secondary
messenger and signaling molecules such as adenylate cyclase,
mitogen-activated protein kinase (MAPK), and other members form
nuclear factor family like (NF-κB), and also play an essential role in
regulating membrane ion channels [28]. The essential roles of these
receptors and interconnected ligands in embryonic stem cells are not
fully known, it is also suggested that the antagonists of these receptors
are involved in promoting the embryonic stem cell death in murine
models, and treatment with exogenous cannabinoids ligands increased
the hematopoietic differentiation of embryonic stem cells [29] (Fig. 3).
5. Involvement of CB receptors in different abnormalities
5.1. Central obesity
Obesity, the increase in abdominal fat, leads to an increase in insulin
resistance, decreased glucose metabolism, hypertension, and heart-
related abnormalities. According to the world health organization, the
prevalence of obesity was doubled between the years 1980 and 2014.
The risk number for women is more than men. The normal waist
circumference (WC) criteria were defined by WHO and given as follows,
WC ≥ 90 cm in men and 80 cm or more in women.
Fasting TG ≥ 150 mg/dL or drug treatment for elevated TG.
HDL cholesterol <40 mg/dL in men and less than 50 mg/ dL in
women or drug treatment for low HDL cholesterol.
BP ≥ 130/85 mmHg or taking antihypertensive medication; and
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Biomedicine & Pharmacotherapy 132 (2020) 110889
fasting glucose ≥100 mg/ dL or taking antidiabetic medication [33].
Whereas, studies have shown the role of ECS in regulating energy bal­
ance, glucose and lipoprotein metabolism. Transition to this system via
endocannabinoid-receptor blockade has resulted in improvement in the
clinical trial studies related to obesity risk [34].
5.2. Lipid abnormality
MS involves a cluster of cardiovascular risk factors which comprises
of insulin resistance, glucose intolerance, elevated blood pressure, low
levels of high-density lipoprotein (HDL), and elevated triglyceride (TG)
levels. Patients suffering from dyslipidemia have the risk of cardiovas­
cular death. Dyslipidemia is one of the disease in the MS, Patients with
abdominal obesity, show a high atherogenic lipid profile and can lead to
premature death [36]. Endocannabinoids mimic the action of insulin on
glucose uptake in human adipose cells, which is a concern with CB1
receptors, phosphatidylinositol 3-kinase, an increase in intracellular
calcium and relevant during adipogenesis [37].
The CB1 and CB2 were also been found in the human lungs and
bronchial tissues. It plays an important role in the immune system. It has
been reported that CB receptor activation leads to activate the immune
system and racing the pathogenic events. In LPS induced lung inflam­
mation model in mouse, cannabinoids are shown to be effective as they
reduced the level of tumor necrosis factor-alpha (TNF-α) and reduction
of neutrophils in bronchoalveolar lavage fluid (BALF) [38]. CB1 and CB2
receptors have a role in vasodilation of mesenteric and other vascular
beds and vasodilation in coronary and cerebral circulation. The endo­
cannabinoid system (ES) is present in peripheral tissues, selectively in
adipose tissue. Fat cells act as a target for ES in glucose uptake and li­
poprotein lipase (LPL) activity, lipogenesis, and adipogenesis, stimu­
lated by CB1 receptors [39] (Fig. 4).
5.3. Non-alcoholic steatohepatitis (NASH) / non-alcoholic fatty liver
diseases (NAFLD)
NASH is a condition characterized by deposition of fat, inflamma­
tion, and necrosis of hepatocytes, which progresses to liver cirrhosis and
cancer. The CB1 and CB2 receptors demonstrated to have a role in liver
injury and can relieve liver abnormalities [40]. NASH can be related to
insulin resistance and metabolic syndrome. The prevalence of NASH in
lean persons is 16.5 % and in the person with MS is 75 % [41]. NASH is
correlated with abdominal obesity, i.e. a component of MS. Central
obesity, fat mass, and increased visceral fat, including the excessive
body fats are associated with MS. In recent cohort researches, it has been
found that 23 % of patients with NASH were suffering from hyper­
triglyceridemia, 10 % were having low HDL cholesterol and 18 % were
A.S. Patil et al. Biomedicine & Pharmacotherapy 132 (2020) 110889

Table 1 6. Metabolic syndrome: signaling and their regulation by

Specific CB-1 and CB-2 receptor agonists and antagonists [45,46]. cannabinoids
Specific CB-1 receptor agonists Specific CB-2 Cannabinoid receptor
receptor agonists antagonists MS is a multifaceted disease condition, which includes cardiac ab­
AM-411 AM-1241 SR141716A (RIO; CB1 normalities as cardiometabolic disease conditions, abnormalities in in­
antagonist, inverse agonist) sulin metabolism and obesity. The MS is also known as insulin
CP55940 HU-308 AM251 (CB1 antagonist, syndrome, as it has been known to prone to insulin resistance. Also, it
inverse agonist) includes an increase in abdominal fats, hyperglycemia, problems in lipid
Win 55212-2 HU-910 SR147778 (CB1 antagonist,
inverse agonist)
metabolism and many more. The MS leads to an increase in the oxidative
Δ9-tetrahydrocannabinol L-759633 AM281 (CB1 antagonist, stress and superoxide generations and increases the apoptosis by
inverse agonist) increasing the activation of pro-apoptotic proteins as caspase 9 and
Arachidonoylethanolamide L-759656 SR144528 (CB2 antagonist, caspase 3. The activation of apoptotic factors responsible for apoptosis
(AEA) [47] inverse agonist)
of cells [68]. The endocannabinoids are well known to increase the
AM251 JWH-015 LY 320135 (CB1
antagonist) activation of caspases and leading to activation of the apoptotic path­
Levonantradol JWH-133 AM 630 (CB2 antagonist, ways, therefore blockade of CB1 receptor in the endocannabinoid sys­
partial CB1 agonist) tem was found to be beneficial to reduce the apoptosis and reduces
obesity [26].
Previously published data suggest that the free fatty acid and
having lipid abnormalities [33]. The ECS has potential mechanistic and
decreased level of adiponectin is responsible for insulin resistance and
therapeutic roles in NAFLD
obesity. Obesity brings with the generation of atherosclerotic plaques.
The levels of adiponectin and fatty acids ultimately responsible for
5.4. Hypertension
developing the plaques in the coronary artery and atherosclerosis. It
leads to the development of risk for heart failure and further compli­
Hypertension is the most common cause of mortality in both devel­
cations. Whereas, it has been described that cannabinoids like Δ9-
oped and developing countries. It is one of the foremost risk factors for
tetrahydrocannabinol, a psychoactive compound, interacting with the
cardiac complications. The world’s one-fourth population suffering from
cannabinoid receptor and having biological effects to reduce the risk of
hypertension, the leading cause of the MS. It leads to an increase in the
atherosclerosis and further complications. The cannabinoid receptors
chances of kidney failure and heart problems. The MS was observed in
are well studies in response to their effects of atherosclerosis and related
about one-third of the patients, who is with hypertension but not dia­
cardiac complications [69–71].
betes [42].
Previous studies reported that the activation of CB1 receptor leads to
Tetrahydrocannabinol (THC) is the essential psychoactive ingredient
activate the mitogen-activated protein kinases (MAPK) pathways, with
of marijuana, lowers blood pressure and heart rate in rodent studies
activation of c-Jun and P38 leads activate the cell survival and cell
whereas hypotension has been reported after chronic marijuana use in
proliferation pathways lead to the death of cells. The activation of MAPK
humans, and it has also been found that endogenous cannabinoid li­
and c-Jun is taught via GPCR and PI3K. The activation of PI3K is
gands like arachidonoyl ethanolamine (anandamide) and 2-arachido­
responsible for the activation of AKT. AKT directly phosphorylates the
noylglyerol (2-AG) reduces blood pressure and heart rate in animals.
tuberous sclerosis complex (TCS)-2 complex on the different sites. This
However, an elevation in the hypotensive efficacy of cannabinoids has
phosphorylation of the TSC1-TCS2 complex responsible for the dysre­
been observed in spontaneously hypertensive rats (SHR) [43]. It was
gulation of free fatty acids and result in obesity [72]. Inhibition of these
observed that the endocannabinoids are involved in the regulation of
signaling pathways shown to have beneficial effects in the reduction of
blood flow and blood pressure, mainly in hypertension in rodents. Also,
obesity and further lipid dysregulation. The inhibition of mTOR path­
the externally administered 2-AG reduces cardiac contraction, vascular
ways shown to have beneficial effects on lipid and free fatty acid
tone and arterial blood pressure [44] (Tables 1–3).
metabolism [73].
The PPAR-gamma, a nuclear receptor family, shown to be activated
by the endocannabinoid system via activation of the receptors. The

Table 2
Endocannabinoid system and its elements [21,48].
Natural Endogenous Synthetic

Phytocannabinoids Endocannabinoids Endocannabinoid-related Cannabinoid receptor agonist

compounds

Δ9-tetrahydrocannabinol N-arachidonoylethanolamide (AEA - anandamide; CB1-CB2 Fatty acid derivatives Classical Non-classical
(THC) partial agonist) cannabinoids cannabinoids
Δ8- 2-arachidonoylglycerol (2-AG; CB1 complete agonist, CB2 Oleamide Delta (8)-THC (CB1- CP-55 940 (complete
Tetrahydrocannabinols agonist) CB2 agonist) CB1-CB2 agonist)
(THC)
Cannabidiol O-arachidonoyl-ethanolamine (rhodamine; CB2 partial Oleoylethanolamide (OEA) HU-210 (CB1-CB2 JWH-015 (CB2 agonist)
agonist, CB1 antagonist, inverse agonist) N-arachidonoyl- agonist)
dopamine (CB1 agonist)
Cannabigerol THC: Δ9-Tetrahydrocannabinol [28] 2-oleoylglycerol O-1184 (CB1 agonist, L-768242 (CB2 agonist)
CB2 inverse agonist)
Cannabichromene Anandamide Stearoylethanolamide O-1057 (complete Aminoalkylindoles (WIN
CB1-CB2 agonist) 55212)
Cannabicyclol Arachidonic acid Palmitoylethanolamide O-1317 CP-55940
(PEA)
Cannabielsoin Lysophosphatidylinositol 2-palmitoylglycerol JWH-130 Diarylpyrazole AM251
Cannabinol Docosatetraenoylethanolamide Linoleoylethanolamide JWH-138 CP47497
Cannabinodiol Oleamide 2-linoleoylglycerol AMG-41 GPR18
Cannabielsoin RVD-Hpα Archidonoyl-amino acid AMG-731 GPR55

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A.S. Patil et al. Biomedicine & Pharmacotherapy 132 (2020) 110889

Table 3 essential function in the inflammatory response. G protein-coupled re­

Marketed drug preparations of cannabinoid, medicinal use, and properties. ceptor 55 (GPR55) is majorly expressed in hypothalamus, nucleus
Name of drug Medicinal /Therapeutic use Properties related to cannabis accumbens, caudate nucleus, striatum and putamen of the brain, as well
as in the peripheral system, co-localizing with the cannabinoid receptors
Sativex Treatment of neuropathic Sativex contains two
pain and spasticity in cannabinoids, THC (Δ -9- in diverse tissues. GPR55 has been suggested in different pathophysio­
patients with Multiple tetrahydrocannabinol) and CBD logical conditions such as cancer, pain, metabolic disorder etc. In-vivo
Sclerosis (MS) [49] (cannabidiol) [44] studies for GPR55 resulted the increases insulin secretion, reduces in­
Epidiolex Treatment of Epilepsy It is a plant-derived, purified testinal contractions and activates immunocytes which helps in boosting
prescription cannabidiol,
indicated for the treatment of
the immunity [78]. Further, GPR18 is also another orphan ECS receptor,
seizures in patients 2 years and however activation of this receptor protects against hypothalamic
older [50]. inflammation, improves glucose tolerance and helps in reducing obesity.
Activation of GPR18 reduces viability of proinflammatory macrophages
Dronabinol / Appetite stimulant for AIDS Synthetic Delta-9 THC [52]
via apoptotic mechanisms, and the macrophages seem to be important in
Marinol patients, analgesic to ease
neuropathic pain in multiple development of obesity. Thus, activation of GPR18 may play a protec­
sclerosis patients [51] tive role against obesity [79] (Fig. 5).
Nabilone / Treatment of nausea and A synthetic cannabinoid similar
Cesamet vomiting in patients to THC [54] 7. Conclusion
undergoing cancer treatment
[53]
Dexanabinol Neuroprotective for use after Synthetic non-psychotropic A metabolic disorder is a group of diseases, which includes type-II
cardiac surgery, following cannabinoid that blocks NMDA diabetes, obesity, atherosclerosis, and cardiometabolic disorders. The
Traumatic Brain Injury (TBI), receptors and COX-2 cytokines westernized lifestyle and stress conditions are the major cause of these
possible future use as an anti- and chemokines [56]
metabolic disorders. The complexity of metabolic syndrome is
cancer drug [55]
CT-3(ajulemic Anti-inflammatory Synthetic, more potent analog increasing day by day as the stress and generation of superoxide’s, ab­
acid) properties may help relieve of THC metabolite THC-11-oic normalities in lipid metabolism, and increases in insulin resistance. The
pain from arthritis [57] acid [58] pharmacological therapy for metabolic syndrome is not a complete cure
Cannabinol Anti-inflammatory; Synthetic chemical that but the primary treatment and prevention of metabolic syndrome are
(formerly treatment of chronic pain specifically binds to the brain’s
considered worldwide is the modification of lifestyle. The endocanna­
PRS-211, [59] secondary cannabinoid receptor
375) (CB2) [60] binoid system involved in the major metabolic pathways and can be
HU 308 Treatment of hypertension; Synthetic chemical that useful for treating disease conditions like metabolic diseases. There is
anti-inflammatory [61] specifically binds to the brain’s the number of cannabinoids derived from the plants, which assumes to
secondary cannabinoid receptor
have a beneficial and pivotal role in the metabolic syndrome. There are
(CB2) [62]
HU 331 Treatment of memory, Synthetic chemical compound so many distinctive plant-derived cannabinoids that have been discov­
weight loss, appetite, composed of central ered previously like CBD, CBN, CBC, and cannabigreol. The previous
neurodegeneration, tumor cannabinoid (CB1), peripheral reports suggest that these phytocannabinoids have distinctive properties
surveillance, analgesia, and cannabinoid (CB2), and non-CB to modulate the cannabinoid system and restores the abnormalities
inflammation [63] receptor-mediated
arising due to metabolic syndrome. Hyperactivity of ECS causing
pharmacology [21]
Rimonabant / Anti-obesity (appetite A synthetic chemical that blocks changes in different molecular pathways, which might be reducing the
Acomplia reducer) [64] endocannabinoids from being severity of the metabolic syndrome. However, the levels of natural
received in the brain, and, as a expression of endocannabinoids in the human body are normal and
result, suppresses appetite [65]
control the normal functioning of different body activities. ECS controls
Taranabant / Anti-obesity (appetite Targets receptors in the brain
MK-0364 reducer) [66] linked to appetite; acts as a
vitality by balancing the glucose and lipids, the main pathways for
(Aronne et al, 2012) Cannabinoid receptor type 1 progression of metabolic syndrome.
(CB1) inverse agonist, blocking In this review, we conclude that in near future, there will be a need to
cannabinoid receptors in the study the involvement of endocannabinoid system in the regulation of
brain, which suppresses
various metabolic activities including the regulation of different
appetite [67]
signaling pathways related to oxidative stress, cardiometabolic diseases,
and metabolic syndrome. In future perspectives, it needs to study for the
usefulness of phytocannabinoids in various ailments.
anandamide and 2-arachidonoyl-glycerol (2-AG), arachidonic acid ac­
tivates PPAR-gamma [74].
Author contributions
It is studied that endocannabinoids anandamide (AEA) induces the
cell death of tumor cells via increasing the cytosolic Ca2+ activity,
All the authors provided important intellectual content, reviewed the
which leads to shrinking of cells and cell membranes disarrangement of
content and approved the final version for the manuscript. Conceptu­
mature erythrocytes [75]. Decreased in the level of actin induces accu­
alized the idea and revised manuscript: SO, SG CS and CP. Proofread and
mulation of aggregates of F-actin and increases the ROS level in the
extensive editing: SO, SG, YA, CS, UM and CP. Performed the literature
cytosol, the endocannabinoid 2 AG controls the actin dynamics by p38
search: AP, UM, YA and SG. The first draft of the manuscript: AP and
MAPK- heat shock protein (HSP), distribution in smooth muscle cells
UM.
[76]. The pro-inflammatory cytokines are involved in the process of
inflammation as a messenger. The activation and release of these cyto­
Declaration of Competing Interest
kines lead to produces inflammation and dysregulation of various
metabolic activities. The activation of the cannabinoid receptor or
The authors declare that they have no known competing financial
cannabinoid system leads to reduce the release of pro-inflammatory
interests or personal relationships that could have appeared to influence
cytokines and has beneficial effects on the inflammatory disease con­
the work reported in this paper.
ditions [77]. CB2 receptor agonist has been proved for their
anti-inflammatory activates because they are expressed predominately
in immune cells suggesting endocannabinoids signaling system has an

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Biomedicine & Pharmacotherapy 132 (2020) 110889

Fig. 5. Molecular mechanisms for metabolic syndrome and the role of cannabinoids.
A.S. Patil et al. Biomedicine & Pharmacotherapy 132 (2020) 110889

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