Pharmacology of Endocannabinoids and The

Pharmacology of Endocannabinoids
and Their Receptors 13

Gaurav Gupta, Wafa Hourani, Pran Kishore Deb, Satyendra Deka,
Pobitra Borah, Juhi Tiwari, Sacchidanand Pathak, and Puneet Kumar
Abstract
The identification of cannabinoid (CB) receptors has contributed to the state-of-the-art

on the endocannabinoid system and its elements. Endocannabinoids (eCBs) are the
endogenous agonists, derived from the conjugation of arachidonic acid with either
ethanolamine (i.e. anandamide) or glycerol (i.e. 2-arachidonoylglycerol) acting as a
lipid signaling mediator via two types of cannabinoid receptors (i.e. CB1 and CB2).
Introduction of selective CB antagonists, inhibitors of eCB transport and metabolism,
cannabinoid receptor-deficient mice and highlights on amidohydrolase have greatly
facilitated the subsequent investigation of the eCB system. Moreover, modulation of
the eCB system holds a promising therapeutic potential in the management of a myriad
of pathophysiological conditions such as anxiety or mood disorders, neuropathic pain,
multiple sclerosis, neurodegenerative diseases, osteoporosis, obesity and cancer
G. Gupta · S. Pathak
School of Pharmacy, Suresh Gyan Vihar University, Jaipur, India
W. Hourani (*)
Faculty of Pharmacy, Philadelphia University, Amman, Jordan
e-mail: [email protected]
P. K. Deb
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, Amman,
Jordan
S. Deka · P. Borah
Pratiksha Institute of Pharmaceutical Sciences, Guwahati, Assam, India
J. Tiwari
Alwar Pharmacy College, Alwar, India
P. Kumar
Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India
Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical
University, Bathinda, Punjab, India
# Springer Nature Singapore Pte Ltd. 2020 415

P. Kumar, P. K. Deb (eds.), Frontiers in Pharmacology of Neurotransmitters,
https://doi.org/10.1007/978-981-15-3556-7_13
416 G. Gupta et al.
among others. This chapter is comprehensively focused on the signal transduction and
metabolic pathways, physiological roles, pharmacology and therapeutic potential of
the endocannabinoids, with particular emphasis on cannabinoid addiction.
Keywords
Cannabinoids · Cannabinoid receptors · Biosynthesis of endocannabinoids ·

Pharmacology of endocannabinoids · Phytocannabinoids · Therapeutic potentials
of cannabinoid receptors · Addiction of cannabinoids
Abbreviations
Abh4 α/β-Hydrolase 4
2-AG 2-Arachidonoylglycerol
CB Cannabinoid
CB1R Cannabinoid 1 receptor
CB2R Cannabinoid 2 receptor
CBD Cannabidiol
CBN Cannabinol
DAG Diacylglycerol
eCBs Endocannabinoids
FAAH Fatty acid amide hydrolase
GPCRs G protein-coupled receptors
MAGL Monoacylglycerol lipase
MAPK Mitogen-activated protein kinase
NAPE N-arachidonoyl phosphatidylethanolamine
PA2 Phospholipase A2
pCBs Phytocannabinoids
PLA1 PI-explicit phospholipase A1
PLC Phospholipase C
THC Δ9-Tetrahydrocannabinol
13.1 Introduction
The medicinal use of Cannabis sativa or marijuana has a long and rich history dating
back to the sixth century B.C. and it was introduced into western medicine during the
nineteenth century (Gaoni and Mechoulam 1964). Being the oldest source of textile
fibers, cultivation of cannabis originated in Western Asia and Egypt, and later
expanded to Europe and America. Under federal laws in the United States, the
cultivation, use and possession of cannabis is illegal (1982). The legalization of
cannabis for medical and recreational use is supported by many countries, and it has
been legalized in some states of America.
Cannabis sativa is a dioecious species, that is, there is a distinct male and female
flower on separate plants, and it belongs to the Cannabinaceae family (Small et al.
2002). It is generally reported that the psychomimetic property of cannabis is
13 Pharmacology of Endocannabinoids and Their Receptors 417
Fig. 13.1 Cannabis sativa plant
associated with the female plant and the sticky resins are secreted from the glandular
hair located on the female flowers and their adjacent leaves (Fig. 13.1). A number of
constituents are found in the plant possessing their crucial role in the treatment of
various diseases, among which Δ13-tetrahydrocannabinol (THC) is the most active
constituent (Baron 2018). Cannabis sativa also consists of a hempseed fixed oil
which is found in the seed part of the plant.
This plant is therapeutically indicated in the management of nausea, pain, glau-
coma, neuralgia, cardiovascular disorder, epilepsy, inflammation, cancer, neuropsy-
chological disorder, neurodegenerative diseases, addiction, arthritis, depression and
headache (Adler and Deleo 2019; Akram et al. 2019; Alipour et al. 2019). Recent
data also suggests the use of phytocannabinoids in the management of multiple
sclerosis and HIV/AIDS symptoms.
The compounds identified or isolated from the plant have been continuously
increasing over time. Approximately 565 compounds have been identified from
C. sativa, among which approximately 120 are called cannabinoids. Cannabinoids
(CBs) are the compounds possessing the typical C21 terpenophenolic ring or its
derivatives/transformation products. CBs can be classified into two broad categories
on the basis of the location where they are found (Baron 2018). The CBs found in the
plant are known as phytocannabinoids (pCBs), whereas the CBs obtained from
animals are known as endocannabinoids (eCBs). Phytocannabinoids are either
found in the cannabis plant or in agricultural hemp (Gertsch et al. 2010). CBs are
lipophilic in nature due to which previously it was speculated that the drug directly
disrupts the cellular membrane without any specified pathway. But after the discov-
ery of some phytocannabinoids, the presence of certain receptors was observed
showing an affinity toward the CBs. CBs show their pharmacological effect by
binding with a specific cannabinoid receptor (CBR) found in the animal body, which
can be classified into two types: cannabinoid 1 receptor (CB1R) and cannabinoid
2 receptor (CB2R). These CBRs are G protein-coupled receptors (GPCRs).
Endocannabinoids are lipid-based endogenous cannabimimetic neurotransmitters
which bind to the CBR and CBR-proteins found in both the central nervous system
(CNS) and the peripheral nervous system (PNS) (Andrade et al. 2019; Borsoi et al.
2019; Breit et al. 2019). The eCBs form the endocannabinoid system, which
418 G. Gupta et al.
is involved in the maintenance of the homeostasis of the human body (Battista et al.
2012). The development of the endocannabinoid system depends upon the intake of
nutritional and dietary co-factors. The formation of eCBs occurs according to the
necessity and requirement of the body, and can bind with the receptors after being
produced. The endocannabinoids found in the human body are N-arachidonoyl-
ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG). They serve as
the endogenous agonists of CBRs and regulate the CNS as well as the PNS, thus
controlling various physiological functions of the body including the immune system.
Therefore, any changes in the endocannabinoid system will result in various disorders,
from neurodegenerative disorder to arthritis. Homeostasis is maintained due to the
constant enzymatic degradation of eCBs. Anandamide shows higher affinity but less
efficacy toward the CB1R, whereas 2-AG exhibits less affinity but high efficacy for
both the receptors (Carr et al. 2019; Chye et al. 2019; Cohen et al. 2019). The eCBs are
hydrophobic in nature and exhibit slower diffusion. The degradation of eCBs inside
the cell occurs either by oxidation or by hydrolysis. Anandamide is hydrolyzed by
fatty acid amide hydrolase into free arachidonic acid and ethanolamine, whereas 2-AG
is hydrolysed into arachidonic acid and glycerol in the presence of monoacylglycerol
lipase (MAGL). Cyclooxygenase-2 and several lipoxygenases are responsible for
hydrolysing the eCBs by the process of oxidation. Apart from maintaining homeosta-
sis, the eCBs are also responsible for recovery and repair of cells. This may confer
various properties including anti-oxidant, anti-inflammatory, anti-anxiety, anti-psy-
chotic, anti-epilepsy, anti-cancer, anti-nausea, anti-bacterial, anti-diabetic, anti-arthri-
tis, pain relief, bone stimulant, immune modulator, neuroprotective and cardio
protective activities. Some endogenous fatty acid derivatives are also found in the
body, which are known as eCB-like compounds. These substances are known to
promote the activity of classic eCBs by the entourage effect (Dale et al. 2019; Diao and
Huestis 2019; Dinis-Oliveira 2019). Apart from the above two eCBs, other reported
eCBs are noladin ether (2-arachidonylglyceryl ether), arachidonoyl dopamine and
virodhamine. The pharmacological profile and biochemical properties of these eCBs
are not known. This chapter discusses the signal transduction and metabolic pathways,
physiological roles, pharmacology and therapeutic potential of the endocannabinoids.
13.2 Cannabinoid Receptors: Signaling Pathway

and Distribution
Cannabinoid receptors are a class of cell membrane receptors that belong to the
family of rhodopsin-like G protein-coupled receptors (GPCR). There are thus two
cannabinoid receptor classes, CB1 and CB2 receptors, which are both coupled to Gi
or Go protein, via negative coupling to adenylyl cyclase (AC) and positive coupling
to the mitogen-activated protein (MAP) kinase family. CB1 receptors are also
coupled to ion channels through the Gi/o proteins. There is precisely positive
coupling to the A-type inward rectifier potassium channels with negative coupling
to N-type, P/Q-type voltage-gated calcium channels and to D-type potassium
channels (Pertwee et al. 2010). Moreover, it is presumed that CB1 also activates
adenylate cyclase types II, IV and VIII via Gsα (Rhee et al. 1998). Both receptors are
Ca+2 K+ Extracellular
CB2
Adenylyl cyclase Intracellular

α Βγ
-/+ +
Gi/Go
-
cAMP ATP
+
-
PKA AKT/PKB mTOR Raf
MEK 1/2
- + +
-/+
Gene expression EKK 1/2
Fig. 13.2 Cannabinoid receptor signaling. CB Cannabinoid receptor, mTOR Mechanistic target of
rapamycin, Akt Protein kinase B, PI3K Phosphatidylinositol-3-kinase, PKA Protein kinase A, ERK
Extracellular signal-regulated kinase
located pre-synaptically and modulate neurotransmitter release. Different impacts

ascribed to the CB receptor seem to include actuation of the PI3K/AKT pathway.
Activation of the anandamide/CB/PI3K pathway was known to be associated with
protection of rodent brain from cocaine-initiated neurotoxicity (Fig. 13.2) (Crowley
et al. 2018; Curran et al. 2019; Cyr et al. 2018; Da Silva et al. 2018; Daris et al.
2019).
However, one of the essential differences between the receptor subtypes is their
distribution, whereby the CB1 is expressed on the presynaptic peripheral and central
nerve terminals as well as in the peripheral organs. It is presumed to be distributed
throughout the brain, with the highest concentration of these receptors located in the
cerebellum (motor control and cognitive function), cerebral cortex (sensation, infor-
mation processing and cognitive function), hippocampus (short- and long-term
memory), hypothalamus (hormone release, metabolic process and sexual orienta-
tion), basal ganglia (voluntary movements control, learning and emotion), amygdala
(memory and emotions), nucleus accumbens (motor and reward system), spinal cord
(transmission of neural signals) and to a lesser extent the cardiopulmonary center of
the brainstem, which seemingly justifies its lack of respiratory depression as opposed
to the opioids (Pertwee 1997). Several pronounced effects of (-)Δ9-THC can be
accounted for by the distribution pattern of CB1 receptors within the CNS. Some of
these effects include the ability of ( )Δ9-THC to decrease motor activity, as
manifested in rodents by catalepsy and hypokinesia, to stimulate food intake, and
420 G. Gupta et al.
to produce analgesia (Pertwee et al. 2010; Matsuda et al. 1990; Herkenham et al.
1991).
CB2 receptors are predominantly associated with expression in the peripheral
cells derived from the immune system. Expression of the CB2 receptor gene
transcripts was detected in the thymus, mast cells, spleen, tonsils and blood cells
(Galiègue et al. 1995; Munro et al. 1993), where they tend to modulate inflammatory
and immunosuppressive activity and control cytokines release.
In contrast, the CB1 was also detected in several peripheral tissues including the
reproductive system, cardiovascular system and gastrointestinal tract. Recently, the
CB2 was reported to be located in the CNS, for example, in the microglial cells
(Svíženská et al. 2008). It has been demonstrated that CB2Rs expression level in the
cerebrum is much lower than CB1Rs in healthy subjects (Onaivi et al. 2008, 2006;
Nunez et al. 2004). In the brain, CB2A is the significant transcript isoform, while
both CB2A and CB2B transcripts are available in larger amounts in the peripheral
tissue such as spleen, skeletal, cardiovascular, thymus and renal systems (Jordan and
Xi 2019; Rossi et al. 2018) and in immune cells, especially cells of macrophage,
lineage thymus, tonsils, T-lymphocytes, monocytes, natural killer cells, and poly-
morphonuclear cells and B-lymphocytes (Howlett et al. 2002; Schatz et al. 1997;
Galiegue et al. 1995). This prevalent distribution of cannabinoid receptors explains
their wide therapeutic applications in almost every system in the human body.
It has been reported that the CB1 receptor conserves its identity across different
species such as mammals, amphibians and fish (Yamaguchi et al. 1996; Soderstrom
et al. 2000). In contrast, cannabinoid CB2 receptors are more varied. Mukherjee and
co-workers (2004) and Bingham et al. (2007) reported that rat CB2, mouse CB2 and
human CB2 receptors show different pharmacological profiles, although all of them
are considered CB2 receptors (Mukherjee et al. 2004; Bingham et al. 2007). There is
an 81% amino acid sequence in rodent and human CB2 receptors, contrasted with
93% amino acid identity among rodent and mouse CB2 receptors (Griffin et al.
2000).
Notwithstanding CB1 and CB2 receptors, pharmacological studies recommend
the presence of non-CB1, non-CB2 receptors interceding the impacts of
CB. Although a few proteins have been examined as contenders for a potential
“CB3” receptor, the reality is questionable and not yet established (Chen 2016).
13.3 Cannabinoid Receptor Agonists and Antagonists
13.3.1 Endocannabinoids
The extensively studied endocannbainoids (eCB) are the arachidonic acid

derivatives anandamide and 2-AG. The first putative endocannabinoid to be
identified is known as Anandamide, where ‘Ananda’ is the Sanskrit word for
‘bliss’ and ‘amide’ describes the ‘amide linkage’ in its chemical structure, which
was detected in porcine brain (Devane et al. 1992).
This ligand behaves as a CB1 and CB2 receptor partial agonist and demonstrates
higher intrinsic activity toward CB1 than CB2 (Mackie et al. 1993). Gonsiorek and
co-workers reported that anandamide and not its metabolite arachidonic acid
antagonizes hCB2 activation by 2-AG in CHO-hCB2 and anandamide can function
as an endogenous antagonist at the peripheral cannabinoid receptor. This strengthens
the hypothesis that the in vivo immunosuppressive effects of 2-AG or other
cannabinoids are dependent on the local concentration of anandamide and 2-AG
(Gonsiorek et al. 2000).
2-AG was the second endogenous cannabinoid receptor ligand to be discovered
following anandamide (Mechoulam et al. 1995) and better illustrates selective
binding toward CB1 than CB2 and functions as a full agonist. Anandamide and
2-AG show similar affinity toward hCB2. Some other substances have been found to
function as endocannabinoids. These substances comprise N-
dihomo-γ-linolenoylethanolamine, N-docosatetraenoylethanolamine,
arachidonoylethanolamine (virodhamine), oleamide, N-arachidonoyl dopamine
(NADA), Arachidonoyl-serine (ARA-S) and Noladin etherand N-oleoyl dopamine
(for a review, see Pertwee et al. 2010). Table 9.1 represents various eCBs and their
type of interaction with CB1R and CB2R, respectively.
13.3.1.1 Biosynthesis of Endocannabinoids

Two classes of eCBs have been recognized and completely contemplated. Ananda-
mide and 2-AG are bioactive lipids, having a place with the subdivisions called
monoacylglycerols and N-acylethanolamines, respectively.
As opposed to the majority of the intercellular signaling systems where
neurotransmitters are synthesized in advance and stored in vesicles for future use,
endocannabinoids are synthesized and used immediately. The endocannabinoids are
synthesized on demand in a stimulus-dependent pathway, activating the cannabinoid
receptor where it is required. The action of the cannabinoids is terminated once they
enter the cells, where they are metabolised by enzymatic hydrolysis (Varma et al.
2001).
Several mechanisms have been postulated for the synthesis of AEA from its
corresponding N-acyl phosphatidyl ethanolamine (NAPE) precursor. The most
widely studied pathway is based on NAPE-phospholipase D (PLD) interaction
(Okamoto et al. 2004; Schmid et al. 1983). However, two additional parallel
pathways have recently been proposed. One pathway involves deacylation of
NAPE by α,β-hydrolase 4 (ABHD4) followed by the cleavage of glycerolphosphate
producing anandamide (Liu et al. 2008). The other pathway involves phospholipase
C-mediated hydrolysis of NAPE-producing phosphoanandamide. The latter is then
dephosphorylated by phosphatases such as tyrosine phosphates PTPN22 and the
inositol 5ˋ phosphatase SHIP1. The functional relevance of these different pathways
has not yet been confirmed; however, it is quite certain that synthesis of AEA
depends on the tissues in which it is synthesized (Liu et al. 2008). Biosynthesis of
2-AG involves a two-step mechanism whereby the first step involves the generation
of 1-acyl-2-arachidonoylglycerol (diacylglycerol, DAG) from phosphatidylinositol
Table 13.1 Nature of endocannabinoids with receptor
422
S. No Name of eCB Chemical Name Chemical Structure CB1R CB2R
1. Anandamide N-arachidonoyl- Partial or full Low efficiency as an agonist and may act
ethanolamine agonist as an antagonist
2. 2- 2- Agonist Agonist
Arachidonoylglycerol arachidonoylglycerol
3. Noladin ether 2- More affinity Less affinity than CB1R

arachidonylglyceryl
ether
G. Gupta et al.
13
4. Arachidonoyl N-arachidonoyl Antagonist Partial Agonist
Pharmacology of Endocannabinoids and Their Receptors

dopamine dopamine
5. Virodhamine O-arachidonoyl Antagonist Agonist

ethanolamine
423
424 G. Gupta et al.
N-Acylphosphatidylethanolamine Diacylglycerol
NAPE-PLD DAGL Synthesis
N-acylethanolamine Phosphatidylethanolamine Monoacylglycerol Fatty acid
FAAH MGL
FAAH 2 ABHD6 Hydrolysis
NAAA ABHD12
Ethanolamine Glycerol Fatty acid

Fatty acid
Fig. 13.3 Schematic representation of the endocannabinoid synthesis and hydrolysis. DAGL
Diacylglycerol lipase, NAPE-PLD N-acylphosphatidylethanolamine phospholipase D, FAAH
fatty acid amide hydrolase, NAAA N-acylethanolamine-hydrolyzing acid amidase, MGL
Monoacylglycerol lipase, ABHD6 α,β-hydrolase 6, ABHD12 α,β-hydrolase 12
by PLC activity and the second step comprises the hydrolysis of DAG by
diacylglycerol (Stella et al. 1997).
13.3.1.2 Hydrolysis of Endocannabinoids

The chief pathways involving the metabolism of endocannabinoids specifically,
AEA and 2-AG, are the hydrolase and oxygenase pathways (Alexander 2016).
AEA hydrolysis is mainly mediated by fatty acid amide hydrolase (FAAH) through
the hydrolytic cleavage of the amide linkage to form arachidonic acid and ethanol-
amine (Giang and Cravatt 1997). Two other enzymes have also been identified,
namely FAAH2 and N-acylethanolamine-hydrolyzing acid amidase (NAAA). The
hydrolysis of 2-AG is mainly directed by monoacylglycerol lipase (MGL). Other
2-AG hydrolases such as ABHD12 and ABHD6 have been identified (Blankman
et al. 2007). AEA is also converted by cyclooxygenase type-2 (COX-2) to
prostamides (prostaglandin-ethanolamides) while 2-AG is converted by COX-2 to
prostaglandin glycerol esters (Fowler 2007). Biosynthesis and the hydrolysis mech-
anism of eCBs are presented in Fig. 9.3.
13.3.1.3 Pharmacodynamics of Endocannabinoids

Anandamide and 2-AG are understood as two noteworthy endogenous agonists of
CBRs. 2-AG alone is a full agonist for CB1 and CB2 and intercedes retrograde signs
at the neural connection, strongly suggesting that 2-AG is physiologically more
significant than anandamide, which is essentially a partial agonist for the CB1
receptor and CB2 receptors, but has higher affinity for the CB1R (Howlett et al.
2002). Both eCBs produce biological activity through initiation of Gi/o G proteins,
coupled to calcium channel (N-and P/Q-type) hindrance and potassium channels
opening in the cell membrane, which are associated with the regulation of synapse
discharge (either restraint of glutamate or GABA). Through hindrance of AC and a
decrease of cAMP, or through MAP kinase pathways, eCB could likewise prolong
cell action (Miller and Devi 2011; Tsuboi et al. 2018).
13.3.1.4 Physiological Role of Endocannabinoids

The eCB opened up new methodologies in the treatment of pain, obesity and
neurological diseases including multiple sclerosis and other mental disorders such
as drug addiction (Bilbao et al. 2004). Motor work, control of tremor and spasticity,
psychological capacity (e.g. learning and memory), thermogenesis, regulation of
sleep/wake cycle, adult neurogenesis, stress reaction by regulating the
hypothalamic-pituitary-adrenal axis (HPA), conceptive capacity through
hypothalamic-pituitary-gonadal pivot (HPG) and sex conduct, retinal neurotrans-
mission from the retina to the essential visual cortex (Chianese and Meccariello
2016) may improve by endocannabinoids. The well-recorded inhibitory impacts of
the CB1 receptor agonists on the arrival of GABA, glutamate, acetylcholine and
noradrenaline were investigated in different preclinical settings solely as clinical
examinations (Schlicker and Kathmann 2001; Piomelli 2003).
13.3.1.5 Pharmacology of Endocannabinoids

More than 4000 years ago, the eCB system was first reported in India, as well as the
remedial and psychotropic activity of the plant Cannabis sativa. The eCB system
involves the CB receptors and endogenous lipid ligands. Restorative uses of
antagonists of CB receptor for obesity treatment as well as control of eating conduct,
intake of food and vitality metabolism have been examined in several studies. The
excessive medicinal, religious and recreational utilization of marijuana in all ages
was clearly not adequate to start cautious and broad research up to a few decades of
20th era on CB. The endocannabinoid system is associated with a wide range of
physiological activities, a considerable number of which are identified with stress
recuperation systems and the support of homeostatic equalization. Among other
capacities, the endocannabinoid system is associated with neuroprotection, adjust-
ment of nociception, regulating motor-related activities and the control of specific
points of the memory process. Likewise, the endocannabinoid system is associated
with balancing the resistant and provocative reactions. It additionally impacts the
cardiovascular and respiratory system by controlling pulse, pressure and bronchial
capacities. Endocannabinoids are known to exhibit significant antiproliferative
activities in tumor cells (Elliott et al. 2019; Friedman et al. 2019; Goncalves et al.
2019; He et al. 2019; Henschke 2019).
In 1992, the first endogenous CB, AEA, additionally known as anandamide, was
distinguished. Later, a second endocannabinoid, 2-arachidonoyl glycerol (2-AG),
was found (Devane et al. 1992). Both these compounds are arachidonic acid
derivatives and bind to CB1 and CB2 receptors with contrast in affinities and
initiation efficacies. Neuropsychopharmacology has portrayed the eCB system
activity alongside the distinguishing proof of CB1R and CB2R and their endogenous
ligands. Nerve center, amygdaloid complex, hippocampus, mesencephalic
426 G. Gupta et al.
structures, substantia nigra, periaqueductal gray, superior colliculus and inferior

colliculus comprise a complex neural circuit that handles the dread and resistance
responses. For the control of anxiety and delirium states, substantia nigra pars
reticulata act as a key structure in the modulator circuit. Recently, eCB system in
the brain has developed as a significant subject of experiments focusing on stress-
related reactions. Endocannabinoids have a wide scope of neuronal reactions such as
perception, suffering, nervousness and anxiety-related symptoms. N-
arachidonoylethanolamide and 2-arachidonyl glycerol are the two most examined
eCBs that have been found to bind with CBRs. Both CB1R and CB2R, being the
GPCR, share similar signaling nature (Pertwee 1997). CB2R manages the
constrained restriction in the brain and furthermore controls the processes that are
not quite the same as CB1R. CB1R is associated with both glutamatergic excitatory
pathways and GABAergic inhibitory neurons. CB1R is otherwise called ‘cerebrum
type’ CBR as it is primarily located in the cerebrum, whereas CB2R is widely
distributed in immune and blood cells. Several studies conducted on striatonigral
neurons and the nigrostriatal pathway have demonstrated the presence of CB
receptors in the presynaptic terminals of striatonigral neurons (Ho et al. 2019;
Huestis et al. 2019; Khuja et al. 2019; Krebs et al. 2019).
In highly evolved creatures, the capacity of the ECS is to control a wide
assortment of physiological procedures at both central and peripheral level. How-
ever, the potential job of the endocannabinoid system in skeletal muscle tissue
remains obscure. Recently, it has been demonstrated that the muscle dimensions of
2-AG are diminished amid both myotube arrangement in vitro from C2C12
myoblasts and mouse muscle advancement in vivo. It has been additionally revealed
that in primary human myoblasts the activation of CB1 by endogenous 2-AG or
synthetic agonists, for example, arachidonoyl-2-chloroethylamide (ACEA),
invigorates myoblast expansion while checking myoblast separation. Inverse
impacts were seen with rimonabant (SR141716) or AM251, two CB1 antagonists/
reverse agonists. Several experiments showed that the activation of CB1 actuates a
commonplace GPCR-intervened signaling component, that is, the hydrolysis of
4,5-bisphosphate, along these lines causing the hindrance of myogenesis-advancing
voltage-gated potassium Kv7.4 channels (Kumar et al. 2019; Lattanzi et al. 2019).
The development of diacylglycerols and inositol trisphosphate is suggested as
occurring as an outcome of protein Gq-interceded PIP2 hydrolysis. CB ligands
likewise bind to GPR55, a vagrant GPCR, suggesting that this receptor may show
a novel focus of CB activity. CB1R is the standout among the most plentiful GPCR
in the human brain. ECBs are lipophilic and therefore cannot be stored in vesicles
such as different neurotransmitters (Lossignol 2019; Lowin et al. 2019).
Thus, the endocannabinoid signaling regulation is firmly constrained by its
synthesis, release, uptake and degradation. A few other stimuli, including layer
depolarization and expanded intracellular Ca2+ and receptor activation, can initiate
complex enzymatic machineries, which lead to the cleavage of membrane
phospholipids and finally to eCB synthesis. Significantly, various proteins are
associated with the synthesis of particular eCB, showing an autonomous inclusion
of eCB in various conditions. After synthesis, eCB can activate CB receptors, either
after the past discharge into the extracellular space or straightforwardly moving
inside the cell membrane. Endocannabinoid flagging is restricted by extremely
proficient degradation processes, including encouraging the uptake from the extra-
cellular space into the cell and enzymatic catabolism interceded by explicit intracel-
lular compounds. The molecular nature of the transporter protein(s) associated with
endocannabinoid uptake has not yet been illustrated. Nonetheless, the compounds’
capacity to degrade eCB is quite well characterized (Bara et al. 2018; Baron 2018;
Bonini et al. 2018). They are FAAH for anandamide and related eCBs, and
monoglycerollipase for 2-AG, albeit different chemicals may be in part engaged
with the degradation of this last compound. An intriguing part of endocannabinoid
function is the quick induction of their synthesis, receptor activation and degrada-
tion. The endocannabinoid framework has in this manner been proposed to act on
interest, with a firmly controlled spatial and temporal selectivity. The framework
applies its modulatory activities only when and where it is required. It represents a
significant refinement among physiological elements of the endocannabinoid frame-
work and the biological activities of exogenous CB receptor agonists, which need
such selectivity. With regard to regulation of endocrine, it is intriguing to note here
that hormonal incitement with glucocorticoids can prompt eCB synthesis in the
nerve center by quick nongenomic systems (Bonn-Miller et al. 2018; Bramness et al.
2018; Cardenia et al. 2018). It was likewise demonstrated later that phospholipase C
communicates to an intracellular event finder of membrane depolarization and
receptor incitement, prompting the combination and, potentially, the arrival of
eCB in the hippocampus. This information uncovers a novel component for activa-
tion of the endocannabinoid framework, which could be engaged with the regulation
of endocrine frameworks. This also concerns eCB degradation, which communicates
to a significant regulatory part of the movement of the endocannabinoid framework
(Citti et al. 2018; Colizzi et al. 2018).
13.3.2 Phytocannabinoids
More than 500 compounds have been identified from Cannabis sativa, which are
phytocannabinoids in nature as well as non-phytocannabinoids. A total of
104 phytocannabinoids have been isolated to date, classified into 11 chemical classes
as follows: (–)-delta-9-trans-tetrahydrocannabinol (Δ9-THC), (–)-delta-8-trans-tetra-
hydrocannabinol (Δ8-THC), cannabidiol (CBD), cannabinodiol (CBND),
cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN), cannabicyclol
(CBL), cannabielsoin (CBE), cannabitriol (CBT) and miscellaneous-type
cannabinoids (Bilbao et al. 2004). Miscellaneous cannabinoids represent compounds
that are composed of different chemical structures and these compounds tend to
differ in their psychoactive properties. In particular, the psychoactive properties of
cannabis have been attributed to the most abundant constituent, Δ9-THC, which was
initially discovered in 1964 by Ganoi and Mechoulam (Gaoni and Mechoulam
1964), while CBD is the major non-psychotropic cannabinoid found in cannabis.
The other noncannabinoid constituents that have been isolated from cannabis since
2005 belong to 8 major chemical classes, steroids, flavonoids, fatty acids,
428 G. Gupta et al.
phenanthrenes, spiroindans, xanthones, biphenyls and nitrogenous compounds

(Baron 2018).
13.3.3 Examples of Cannabinoids
13.3.3.1 Δ9-Tetrahydrocannabinol (THC)

Cannabis sativa and its subsidiary, that is, marijuana, are among the best-known
substances utilized by humans for centuries and are still among the most mishandled
substances around the world. Δ9-THC is a partial agonist at both the CB1 and CB2
receptors and the major psychoactive component of cannabis. Δ9-THC was isolated
and the structure was characterized by Gaoni and Mechoulam in 1964. Δ9-THC
induces reactions such as excess craving, decrease in the severity of sickness,
reduction of intraocular stress, euphoria and dysphoria (Volkow et al. 2014; Wang
et al. 2008; Moreira and Crippa 2009). Increasingly serious antagonistic impacts
include respiratory problems, hypertension, tachycardia, chest pain, muscle jerks,
intense renal disappointment, nervousness, disturbance, psychosis, self-destructive
ideation and intellectual impedance (Cohen and Weinstein 2018). A purified active
compound of Δ9-THC is (-)trans-Δ9-tetrahydrocannabinol (dronabinol), as of late
affirmed for the treatment of chronic pain and chemotherapy-induced nausea and
vomiting (Kowal et al. 2016; May and Glode 2016). Nabilone, a more established
commercial Δ9-THC, is used in the management of chemotherapy-induced nausea
and vomiting (Ware et al. 2008).
13.3.3.2 Cannabidiol (CBD)

Recent studies suggest that cannabidiol (CBD) might be helpful for the treatment of
various neuropsychiatric disorders. Cannabidiol does not show tranquilizing abuse
potential in experiments on mice. The researchers demonstrated that CBD, the
second most significant component of cannabis, has reduced misuse potential
(Viudez-Martinez et al. 2019).
13.3.3.3 GW405833
CB receptor, especially cerebrum CB2R, expression, shows dynamic and inducible
profiles under different neurotic conditions. GW405833 sub-atomic compound is
under preclinical investigation showing a particular CB2R agonistic activity. A
recent report revealed that CB2R agonist GW405833 secures liver cells and shows
therapeutic impact by lessening serum aminotransferase levels, and diminishes
hepatocyte apoptosis against intense concanavalin A-initiated poisonous quality
through the CB2 receptors communicated in liver resistant cells (Huang et al. 2019).
13.3.3.4 URB597 ([3-(3-carbamoylphenyl)

phenyl]-N-cyclohexylcarbamate)
The compound URB597 is an FAAH inhibitor which prompts delay in the degrada-
tion of anandamide, leading to increased centralization of anandamide accessible for
its natural movement by means of CB1 receptor. In addition, URB597 has been
exhibited to be dynamic in discouragement (Gobbi et al. 2005), inflammation (Holt

et al. 2005), neuropathy (Russo et al. 2007), and acute pain and anxiety (Kathuria
et al. 2002).
13.3.4 CB Receptor Blockers
Medications that modify the endogenous eCB levels by blocking CB receptors

intervene in downregulatory signaling and may give another medication focus to
treating different neuropsychiatric and obesity issues. Receptor blockers that have
been broadly explored include Rimonabant, Taranabent, AM4113SR141716A and
SR144528.
13.3.4.1 Rimonabant and Taranabent

Rimonabant (Sanofi-Aventis) and Taranabant (Merk pharmaceutical) can block
agonist-induced activation of cannabinoid CB1R2 stuck an aggressive way and
imbroglio with fundamentally more noteworthy partiality to cannabinoid CB1 than
cannabinoid CB2 receptors (Pertwee et al. 2010).
In spite of the fact that these mixes are lacking in their capacity to activate CB1
receptors when regulated alone, there is proof that in some CB1 receptor-containing
tissues, they can initiate inverse reactions from those evoked by a CB1 receptor
agonistic; they are CB1 receptor inverse agonists (Pertwee 2005; Fong et al. 2007).
They are suggested for the treatment of obesity by creating activity on CB1 receptors
in CNS to control hunger. Other proposed components are activities on receptors in
the GIT that may tweak satiety as a peripheral means of controlling nourishment
intake or on those communicated in the fat tissue that may improve metabolic
confusions regularly found in those who are overweight thus diminishing insulin
opposition, coronary artery disease and dyslipidemia (Kaur et al. 2013). A recent
investigation revealed knowledge on the anti-tumor adequacy of Rimonabant, firmly
recommending that it could be a novel lead compound for colorectal cancer treat-
ment (Fiore et al. 2018). Alongside the clinical preliminaries in obesity that produced
the information submitted to regulatory authorities, Rimonabant was additionally
examined in clinical preliminaries as a potential treatment for different conditions,
including diabetes, atherosclerosis and smoking cessation (Hollander et al. 2010;
Dol-Gleizes et al. 2009; Steinberg and Foulds 2007). Psychiatric adverse events such
as depression and nervousness were observed to be increasingly regular with
Rimonabant (20 mg/day), which was tested by the US Food and Drug Administra-
tion through distributed and non-distributed preliminaries (Dol-Gleizes et al. 2009).
In addition, two deaths from suicide were accounted for in patients who consumed
Rimonabant. Moreover, 10% of individuals experienced sickness and upper respira-
tory tract infections and around 1–10% of individuals suffered from unfavorable
impacts such as gastroenteritis, tension, sleeping disorder, hot flashes, loose bowels,
heavy, dry or irritated skin, tendonitis, muscle aches, fatigue and flu-like symptoms.
430 G. Gupta et al.
Rimonabant was never endorsed in the United States for the treatment of obesity.
The marketing endorsement for the drug was canceled by the European Regulatory
Authorities in 2009 (Sam et al. 2011; Moreira and Crippa 2009).
13.3.5 Therapeutic Potential of Targeting Cannabinoid Receptors
The undesired psychotropic effects of cannabinoid agonists represent a drawback in

the therapeutic development of compounds for direct activation of CB1 receptors.
On the other hand, activation of CB2 receptors has no psychotropic side effects such
as hypolocomotion or catalepsy (Volkow et al. 2014). Currently, there is an
approach to developing medications that activate CB2 receptors at doses that have
little or no CB1 receptor activation. This approach appears tempting because there is
much evidence that the undesired effects induced by CB1/CB2 receptor agonists are
attributed to CB1 rather than CB2 receptor activation. This indicates that there are
important potential therapeutic applications for CB2 selective agonists. For instance,
therapies based on agonists targeting CB2 receptors have been proposed for the
treatment of a wide range of conditions. Table 13.2 represents therapeutic potentials
of cannabinoids or their derivatives.
13.3.5.1 Pain
Therapies based on agonists targeting CB2 receptors have been proposed for the
management of an array of painful conditions. Such conditions include acute pain,
nociceptive, neuropathic pain, and chronic inflammatory pain (Whiteside et al.
2007). CB2 agonists exerted analgesic effects in animal models of neuropathic
pain such as partial sciatic nerve ligation model, spinal nerve ligation model and
chemotherapy-induced neuropathy. In addition, cannabinoids also showed analgesic
effects in diverse persistent inflammatory pain models such as carrageenan, capsai-
cin, complete Freund’s adjuvant, formalin and arachidonic acid (Guindon and
Hohmann 2008). The mechanisms through which cannabinoids alleviate pain
involve decreasing the sensitivity of transient receptor potential channel vanilloid
1 (TRPV1) to noxious stimuli (Jeske et al. 2006), inhibiting NF-κB activity and
microglial production of IL-1β, IL-6 and TNFα (Klegeris et al. 2003).
In clinical trials, there were controversial findings regarding the effect of
cannabinoids in pain management, since some qualitative systematic reviews
reported that cannabinoids are no more effective than codeine in pain management
and the risks associated with their use outweigh their benefit because of their
depressant effects (Campbell et al., 2001).
13.3.5.2 Metabolic Disorders

A hypothesis proposed that when mice are exposed to cannabinoids, CB1 receptors
inhibit hypothalamic pro-opiomelanocortin (POMC) neurons which participate in
feelings of satiety resulting in the release of beta-endorphins (Koch et al. 2015). The
first human study assessing the effect of cannabinoids on appetite was reported in
Table 13.2 Summary of certain diseases that could be targeted by cannabinoids or their
derivatives
Biological Disease Targets Therapeutic Potentials
Pain • Decrease sensitivity of TRPV1 to Acute pain, nociceptive,
noxious stimuli neuropathic and chronic
• Inhibit NF-κB activity and inflammatory pain
microglial production of IL-1β,
IL-6 and TNFα
Metabolic • CB2R blockade Insulin resistance associated with
disorders obesity and obesity-associated
fatty liver
Asthma • Inhibitory effects on mast cells Immunosuppressive, anti-
and eosinophils in lung tissue inflammatory and bronchodilator
• Reduce levels of cytokines effects
involved in the immune response to
an allergen
Glaucoma • Neuroprotective and vasorelaxant Decrease intraocular pressure, and
properties via CB2R activation, hence decrease optic nerve damage
increased aqueous humor outflow due to inadequate blood supply
via enhancing the p42/44 MAP
kinase
Autoimmune • Enhance levels of anti- • Maintain normoglycemia
diseases inflammatory mediators while • Decrease inflammation
decreasing the levels of associated with rheumatoid
pro-inflammatory cytokines arthritis
• Decrease neurodegeneration in
multiple sclerosis
• Improve the symptoms of
Crohn’s, multiple sclerosis
Bone diseases • Stimulation of the CB2R • Prevent osteoclast formation
• Decrease arthritis progression
• Enhance fracture healing
Cardiovascular • CB2R activation • Diminish infract size
disorders
Gastrointestinal • Targeting the CB1 and CB2 • GastricB58 ulcers
disorders receptors • Gastroesophageal reflux
• Irritable bowel syndrome,
• Secretory diarrhea,
• Crohn’s disease,
• Paralytic ileus
• Hepatitis C
Mood and anxiety • CB2R stimulation • Bipolar disorders
disorders • Drug abuse
• Post-traumatic stress disorder
Neurodegenerative • Selective targeting of the CB2R • Multiple sclerosis
diseases • Amyotrophic lateral sclerosis
• Parkinson’s disease
• Huntington’s disease
(continued)
432 G. Gupta et al.
Table 13.2 (continued)

Biological Disease Targets Therapeutic Potentials
Cancer • Down-regulated Id-1 gene • Breast and prostate cancer
expression and increase in the • Glioblastoma, glioma
generation of reactive oxygen • Pancreatic and oral cancer
species leading to induction of • Liver and colorectal cancer
apoptosis and autophagy • Thyroid, ovarian and cervical
• Induce apoptosis via pro-caspase- cancer
3 cleavage to caspase-3 • Skin and gastric cancer
• Inhibition of angiogenesis by the
reduction of pro-angiogenic factors
VEGF, inhibiting forskolin-
induced cAMP formation and
activation of RAF1 translocation
and MAPK activity
1971 in which there was a reported increase in food intake following use of
Cannabis (Hollister 1971). Another study also presented that oral Δ9-THC doses
of up to 15 mg/day stimulated appetite and produced significant weight gain in
advanced cancer patients (Regelson et al. 1976). Later on, a more comprehensive
study demonstrated clearly that smoking Cannabis leads to a substantial increase in
food intake (Foltin et al. 1986). The expression of CB1 receptor, MAGL and FAAH
in the human pancreas was reported (Kim et al. 2011) and it was recognized that CB1
suppresses β-cell proliferation by hindering insulin secretion. As a result, CB1
receptor blockade leads to elevated β-cell mass in diabetic mice and enhanced insulin
sensitivity. Additionally, the contribution of cannabinoids to the pathogenesis of
diabetic neuropathy, retinopathy and nephropathy has been explored (Horváth et al.
2012).
CB2 receptor stimulation enhanced insulin resistance associated with obesity and
obesity-associated fatty liver and was improved in CB2 knock-out mice, suggesting
that CB2 blockade might be beneficial for the treatment of insulin resistance and fatty
liver (Deveaux et al. 2009).
13.3.5.3 Asthma
Several studies postulated that targeting cannabinoid receptors might be promising
for treating patients with asthma. Cannabinoids demonstrated immunosuppressive,
anti-inflammatory and bronchodilatory effects. In vivo models showed that
cannabinoids exerted inhibitory effects on mast cells and eosinophils in lung tissue
(Giannini et al. 2008) and reduced the levels of cytokines involved in the immune
response to an allergen (Vuolo et al. 2015). Moreover, cannabinoids demonstrated
antibacterial effects against Staphylococci and Streptococci in broth (Van Klingeren
and Ten Ham 1976). CB2 receptors also regulate the function of natural killer cells
by inhibiting cytokine production in a murine model of asthma (Ferrini et al. 2017).
In human studies, early studies found that Cannabis smoke, unlike cigarette
smoke, caused bronchodilatation rather than bronchoconstriction and, unlike
opiates, did not cause central respiratory depression (Vachon et al. 1973). Another
study also demonstrated that doses of THC provided by aerosol caused
bronchodilatation as measured by the enhancement of lung function (Hartley et al.
1978).
13.3.5.4 Glaucoma
Recent studies have demonstrated that the neuroprotective and vasorelaxant
properties of cannabinoids might be effective in reducing intraocular pressure
(Tomida et al. 2004). CB2 receptor activation increased aqueous humor outflow by
enhancing the p42/44 MAP kinase activity in cultured porcine trabecular meshwork
cells (Zhong et al. 2005). According to the American Glaucoma Society,
cannabinoids can decrease intraocular pressure briefly, and reduce blood pressure
and hence can decrease optic nerve damage due to inadequate blood supply (Jampel
2009).
13.3.5.5 Autoimmune Diseases

CB2 is primarily expressed in peripheral tissues of the immune system (leukocytes,
spleen, tonsils, thymus, bone marrow), and it has been established that cannabinoids
display immunosuppressant effects and hence can be beneficial in treating autoim-
mune diseases. They can amend immune balance by enhancing levels of anti-
inflammatory mediators while decreasing the levels of pro-inflammatory cytokines
(Nagarkatti et al. 2009). Recently, the immunomodulatory effect of THC has been
linked to its ability to affect epigenetic regulation by modifying histones (Yang et al.
2014).
In animal studies, cannabinoids produced a decreased risk of hypoglycemia along
with a significant reduction in beta-cell damage in autoimmune diabetes (Li et al.
2001). This, in turn, helps in maintaining normoglycemia (Weiss et al. 2008).
Moreover, cannabinoids were found to contribute to decreasing inflammation
associated with rheumatoid arthritis (Costa et al. 2004), as well as arresting the
neurodegeneration in multiple sclerosis (Pryce et al. 2003). In clinical studies, there
has been evidence that cannabinoids can improve the symptoms of Crohn’s disease
(Naftali et al. 2014), fibromyalgia (Schley et al. 2006) and multiple sclerosis (Collin
et al. 2007). A correlation has been established between the negative regulation of
the cAMP signaling pathway, leading to less cAMP response element-binding
protein affecting gene expression and immunomodulatory effects mediated by
cannabinoids (Kaminski 1998), suggesting that selective targeting of CB2 receptors
can cause immunosuppressive effects without eliciting psychotropic effects
(Turcotte et al. 2016).
13.3.5.6 Bone Diseases

Multiple studies have recognized the involvement of cannabinoids in osteoporosis as
CB receptors are substantially expressed in osteoblasts, osteoclasts and osteocytes. A
correlation between CB2 receptor expression and bone density, as well as polymor-
phism of the gene responsible for coding CB2 receptor and post-menopausal osteo-
porosis in humans, has been reported, and thus it has been found that stimulation of
434 G. Gupta et al.
CB2 prevents osteoclast formation (Ofek et al. 2006; Karsak et al. 2005). Other
studies involving in vivo models demonstrated that cannabinoids might improve
fracture healing (Kogan et al. 2015) and prevent the progression of arthritis (Malfait
et al. 2000).
13.3.5.7 Cardiovascular Diseases

In animal and human studies, cannabidiol has been found to exert anti-arrhythmic,
vasodilator, antioxidant and anti-inflammatory effects (Stanley et al. 2013), while
acute administration of low doses of THC before ischemia also produced
cardioprotective effects by diminishing myocardial damage (Waldman et al. 2013).
CB2 receptor stimulation has been demonstrated to diminish the infarct size of
myocardium in ischemia/reperfusion (I/R) injury by inhibiting apoptosis and
enhancing Akt phosphorylation (Li et al. 2013).
13.3.5.8 Gastrointestinal Disorders

The most commonly used indication of cannabinoids is nausea and vomiting since
former studies have revealed that THC and its analogues were effective in managing
chemotherapy-induced nausea and vomiting (Shiling et al. 1981). Paradoxically,
cannabis can be problematic if used chronically and has been reported in very few
cases to lead to cannabinoid hyperemesis syndrome (Lu and Agito 2015). Stimula-
tion of CB1 receptors has been shown to suppress gastrointestinal motility, gastric
acid secretion and intestinal secretion.
CB2 receptors are also involved in modulating the inflammatory response in the
gastrointestinal system by reducing the secretion of proinflammatory cytokines
(Wright et al. 2008). Thus, targeting cannabinoid receptors can be effective in
multiple conditions including, gastric ulcers, gastroesophageal reflux disease, irrita-
ble bowel syndrome, secretory diarrhea, Crohn’s disease, paralytic ileus and hepati-
tis C (Izzo and Camilleri 2008).
13.3.5.9 Mood and Anxiety Disorders

Numerous investigators suggested that CB2 agonists can be beneficial in the man-
agement of bipolar disorders, personality disorders and drug abuse disorders
(Navarrete et al. 2012). Moreover, recent evidence demonstrated that cannabinoids
can alleviate the symptoms of post-traumatic stress disorder (Korem and Akirav
2014). CB2 receptors have also been reported to modulate the midbrain, ventral
tegmental area, and dopamine activity responsible for reward and addiction (Zhang
et al. 2014).
13.3.5.10 Neurodegenerative Diseases

The undesired psychotropic side effects of CB1 receptor agonists represent the
downside in drug discovery. Activation of CB2 receptors, however, has no psycho-
tropic side effects such as hypolocomotion and catalepsy (Volkow et al. 2014).
Moreover, CB2 receptors are present in limited amounts in the brain, and this
indicates that selective targeting of CB2 receptors could be useful in treating diseases
with neuroinflammatory or neurodegenerative components. Such diseases include
multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s
disease and inflammatory peripheral disorders (Pertwee 2010). Recent evidence

acknowledged the involvement of the endocannabinoid system in neuroprotection
induced by minocycline against brain edema, microglial stimulation and neurologi-
cal damage in traumatic brain injury in mice (Lopez-Rodriguez et al. 2013).
The down-regulation of CB2 receptors has been described in patients with
Parkinson’s disease. Hence, the activation of CB2 receptors has been postulated to
delay the progression of the disease (Javed et al. 2016).
13.3.5.11 Attention-deficit Hyperactivity Disorder (ADHD)

THC has been reported to reduce hyper impulsivity associated with ADHD by
binding to CB1 receptors and enhancing retrograde signaling inhibition in the
neuronal synapses, thus decreasing hyperactivity (Adriani et al. 2003). A clinical
case reported in Germany showed that THC improved cognitive performance in
individuals suffering from ADHD similar to stimulant medications and with limited
side effects when combined with CBD (Strohbeck-Kuehner et al. 2008). Over-
activation of mTOR signaling has been implicated in autism spectrum disorders by
inhibiting autophagy that results in autism-like behaviors (Tang et al. 2014),
suggesting that targeting mTOR signaling might provide a new therapeutics for
autism spectrum disorders.
13.3.5.12 Cancers
In addition to palliative effects, preclinical studies demonstrated that cannabinoids
exert antitumor, antiproliferative, antiangiogenic or proapoptotic effects both in vitro
and in vivo against several types of cancer. Such cancers include glioblastoma
(Guzman et al. 2006), glioma (Massi et al. 2004), pancreatic cancer (Carracedo
et al. 2006), oral cancer (Whyte et al. 2010), breast cancer (Caffarel et al. 2010),
prostate cancer (De Petrocellis et al. 2013), lung cancer (Preet et al. 2011), blood
cancer (Gustafsson et al. 2006), liver cancer (Knowles et al. 1980), colorectal cancer
(Kogan et al. 2007), thyroid cancer (Portella et al. 2003), ovarian cancer (Afaq et al.
2006), cervical cancer (Lukhele and Motadi 2016), gastric cancer (Park et al. 2011)
and skin cancer (Blázquez et al. 2006).
In breast cancer cells, cannabinoids have shown the ability to down-regulate Id-1
gene expression and increase the generation of reactive oxygen species leading to
induction of apoptosis and autophagy (Śledziński et al. 2018). In addition, the
antitumor effects of cannabinoids, phytocannabinoids, and synthetic and endoge-
nous ligands have been reported in various types of breast cancer including
hormone-dependent and hormone-independent breast cancer cell lines. These
antitumor effects include induction of apoptosis via pro-caspase-3 cleavage to
caspase-3 and cell cycle arrest, inhibition of angiogenesis by the reduction of
pro-angiogenic factors VEGF, inhibiting forskolin-induced cAMP formation, and
activation of RAF1 translocation and MAPK activity (Kisková et al. 2019).
One of the primary advantages of the potential use of cannabinoids in cancer
management is selectivity and lack of cytotoxicity to normal cells (Guzman 2003).
These effects were observed in cultured cells originating from human, mouse and
436 G. Gupta et al.
rodent tumor models. Clinical trials are needed to demonstrate the effectiveness and
safety of cannabinoids in cancer patients.
13.3.5.13 Cannabinoids and their Potential for Addiction

According to the National Institute on Drug Abuse, marijuana (cannabis) is the most
commonly used illicit substance. One of the key issues associated with the use of
cannabis is the manifestation of psychological effects. Former clinical studies
investigating the effects of marijuana were conducted by Moreau and it was
concluded that consuming large doses causes personality changes and hallucinations
(Wilkinson et al. 2014).
It has been found that the subjective effects of marijuana consumption are
partially mediated by CB1R. The effects of cannabis differ broadly depending on
many factors including the product, its route of administration, dosage form, dura-
tion of use, drug–cannabis interaction, pharmacokinetics and pharmacogenetics
properties. The acute effects of cannabis tend to be transient and dose dependent
and can be both physiological and psychological. At low doses, cannabis use can
cause difficulties in concentration and thinking, lack of coordination, temporal
distortion, restlessness, memory impairment, tachycardia and increase in blood
pressure. On the other hand, higher doses can lead to anxiety, visual hallucinations,
panic attacks and sensory distortion (Chopra and Smith 1974). These effects are
mainly attributed to the psychoactive component of cannabis, THC. CBD, on the
other hand, the nonpsychoactive constituent of cannabis, produces the opposite
effects, such as anti-anxiety, anti-psychotic, neuroprotective and bradycardia.
Due to the highly lipophilic and protein-bound nature of cannabis, it has a
prolonged half-life and the retention of THC can persist from several hours to
days depending on the amount consumed and its route of administration. Therefore,
abrupt cessation of cannabis is generally tolerated. Marijuana Abstinence Syndrome
usually commences within 48 h of cessation and can last up to 2 weeks and manifests
in the form of craving, anger or aggression, fatigue, anxiety, shakiness, sweating,
insomnia, vivid dreams, decreased appetite, irritability and depression. Substantial
clinical data is still required to confirm the safety and efficacy of cannabis consump-
tion (Abood and Martin 1992).
13.3.6 Conclusion
The underlying disclosure and ensuing thorough research of the endocannabinoid

system over the last three decades have uncovered presumably the most notable
retrograde neurotransmission system. As the fundamental mediator of the psychoac-
tive impact of THC, CB1R has gained remarkable attention over these years. Its
widespread expression and versatile functions not only increase its promising
potential as a medication focus for different illnesses, but additionally make the
undesired reactions almost inescapable. This hindrance drives specialists to give
more consideration to the science that quite a while ago disregarded CB2R and other
endo-/phyto-cannabinoids. In addition, as a neuromodulator, the crosstalk among the
endocannabinoid and other synapse systems, by means of nearby neural circuits, or

receptor heteromerization, or downstream pathway, has been accentuated. Produc-
tive investigations have been carried out, unraveling the intricacy of the entire
endocannabinoid system. It is essential to remember that the investigation of the
endocannabinoid system should be region- and condition-explicit, alongside the
consideration of other neurotransmission systems.
Even though cannabis has existed for more than 5000 years, there is anecdotal
evidence that cannabis is therapeutically beneficial for a variety of human diseases.
Nevertheless, we still have insufficient data to accept or reject the use of
cannabinoids in many clinical conditions. Few randomized controlled trials exist
and the majority of the data is based on case reports and small retrospective reviews.
The availability of a varied range of cannabinoids products, doses and routes of
administration renders it difficult to compare studies and derive appropriate
conclusions.
References
Abood M, Martin B (1992) Neurobiology of marijuana abuse. Trends Pharmacol Sci 13:201–206
Adler BL, Deleo VA (2019) Allergenic ingredients in commercial topical cannabinoid preparations.
J Am Acad Dermatol. https://doi.org/10.1016/j.jaad.2019.03.015
Adriani W, Caprioli A, Granstrem O, Carli M, Laviola G (2003) The spontaneously hypertensive-
rat as an animal model of ADHD: evidence for impulsive and non-impulsive subpopulations.
Neurosci Biobehav Rev 27:639–651
Afaq F, Sarfaraz S, Syed DN, Khan N, Malik A, Bailey HH, Mukhtar H (2006) Cannabinoid
receptors as a target for therapy of ovarian cancer. AACR Meeting, Washington, DC
Akram H, Mokrysz C, Curran HV (2019) What are the psychological effects of using synthetic
cannabinoids? A systematic review. J Psychopharmacol 33:271–283
Alexander SP (2016) Therapeutic potential of cannabis-related drugs. Prog Neuropsychopharmacol
Biol Psychiatry 64:157–166
Alipour A, Patel PB, Shabbir Z, Gabrielson S (2019) Review of the many faces of synthetic
cannabinoid toxicities. Ment Health Clin 9:93–99
Andrade AK, Renda B, Murray JE (2019) Cannabinoids, interoception, and anxiety. Pharmacol
Biochem Behav 180:60–73
Bara A, Manduca A, Bernabeu A, Borsoi M, Serviado M, Lassalle O, Murphy M, Wager-Miller J,
Mackie K, Pelissier-Alicot AL, Trezza V, Manzoni OJ (2018) Sex-dependent effects of in utero
cannabinoid exposure on cortical function. Elife 7
Baron EP (2018) Medicinal properties of cannabinoids, terpenes, and flavonoids in cannabis, and
benefits in migraine, headache, and pain: an update on current evidence and cannabis science.
Headache 58:1139–1186
Battista N, Di Tommaso M, Bari M, Maccarrone M (2012) The endocannabinoid system: an
overview. Front Behav Neurosci 6:9
Bilbao A, Cippitelli A, Bermudez-Silva FJ, Del Arco I, Navarro M, Rodríguez De Fonseca F (2004)
The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol 40:2–14
Bingham B, Jones P, Uveges A, Kotnis S, Lu P, Smith V, Sun SC, Resnick L, Chlenov M, He Y
(2007) Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2)
selective ligand AM1241 and its resolved enantiomers. Br J Pharmacol 151:1061–1070
Blankman JL, Simon GM, Cravatt BF (2007) A comprehensive profile of brain enzymes that
hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14:1347–1356
438 G. Gupta et al.
Blázquez C, Carracedo A, Barrado L, Real PJ, Fernández-Luna JL, Velasco G, Malumbres M,

GuzmáN M (2006) Cannabinoid receptors as novel targets for the treatment of melanoma.
FASEB J 20:2633–2635
Bonini SA, Premoli M, Tambaro S, Kumar A, Maccarinelli G, Memo M, Mastinu A (2018)
Cannabis sativa: a comprehensive ethnopharmacological review of a medicinal plant with a
long history. J Ethnopharmacol 227:300–315
Bonn-Miller MO, Elsohly MA, Loflin MJE, Chandra S, Vandrey R (2018) Cannabis and cannabi-
noid drug development: evaluating botanical versus single molecule approaches. Int Rev
Psychiatry 30:277–284
Borsoi M, Manduca A, Bara A, Lassalle O, Pelissier-Alicot AL, Manzoni OJ (2019) Sex differences
in the behavioral and synaptic consequences of a single in vivo exposure to the synthetic
cannabimimetic WIN55,212-2 at puberty and adulthood. Front Behav Neurosci 13:23
Bramness JG, Dom G, Gual A, Mann K, Wurst FM (2018) A survey on the medical use of cannabis
in Europe: a position paper. Eur Addict Res 24:201–205
Breit KR, Zamudio B, Thomas JD (2019) Altered motor development following late gestational
alcohol and cannabinoid exposure in rats. Neurotoxicol Teratol 73:31–41
Caffarel MM, Andradas C, Mira E, Pérez-Gómez E, Cerutti C, Moreno-Bueno G, Flores JM,
García-Real I, Palacios J, Mañes S (2010) Cannabinoids reduce ErbB2-driven breast cancer
progression through Akt inhibition. Mol Cancer 9:196
Cardenia V, Gallina Toschi T, Scappini S, Rubino RC, Rodriguez-Estrada MT (2018) Development
and validation of a Fast gas chromatography/mass spectrometry method for the determination of
cannabinoids in Cannabis sativa L. J Food Drug Anal 26:1283–1292
Carr C, Vertelney H, Fronk J, Trieu S (2019) Dronabinol for the treatment of paraneoplastic night
sweats in cancer patients: a report of five cases. J Palliat Med. https://doi.org/10.1089/jpm.2018.
0551
Carracedo A, Gironella M, Lorente M, Garcia S, GuzmáN M, Velasco G, Iovanna JL (2006)
Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress–
related genes. Cancer Res 66:6748–6755
Chen C (2016) Endocannabinoid metabolism in neurodegenerative diseases. Neuroimmunol
Neuroinflammation 3:268–270
Rosanna Chianese and Rosaria Meccariello (2016) The endocannabinoid system in human physi-
ology. In: Meccariello R (ed.) Cannabinoids in health and disease. IntechOpen. https://doi.org/
10.5772/63818
Chopra GS, Smith JW (1974) Psychotic reactions following cannabis use in East Indians. Arch Gen
Psychiatry 30:24–27
Chye Y, Christensen E, Solowij N, Yucel M (2019) The endocannabinoid system and cannabidiol’s
promise for the treatment of substance use disorder. Front Psychiatry 10:63
Citti C, Palazzoli F, Licata M, Vilella A, Leo G, Zoli M, Vandelli MA, Forni F, Pacchetti B,
Cannazza G (2018) Untargeted rat brain metabolomics after oral administration of a single high
dose of cannabidiol. J Pharm Biomed Anal 161:1–11
Cohen K, Weinstein AM (2018) Synthetic and non-synthetic cannabinoid drugs and their adverse
effects-a review from public health prospective. Front Public Health 6:162–162
Cohen K, Abraham W, Aviv W (2019) Modulatory effects of cannabinoids on brain neurotrans-
mission. Eur J Neurosci. https://doi.org/10.1111/ejn.14407
Colizzi M, McGuire P, Giampietro V, Williams S, Brammer M, Bhattacharyya S (2018) Previous
cannabis exposure modulates the acute effects of delta-9-tetrahydrocannabinol on attentional
salience and fear processing. Exp Clin Psychopharmacol 26:582–598
Collin C, Davies P, Mutiboko I, Ratcliffe S (2007) Randomized controlled trial of cannabis-based
medicine in spasticity caused by multiple sclerosis. Eur J Neurol 14:290–296
Costa B, Colleoni M, Conti S, Parolaro D, Franke C, Trovato AE, Giagnoni G (2004) Oral anti-
inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute
carrageenan-induced inflammation in the rat paw. Naunyn-Schmiedeberg’s Arch Pharmacol
369:294–299
Crowley K, De Vries ST, Moreno-Sanz G (2018) Self-reported effectiveness and safety of Trokie
((R)) lozenges: a standardized formulation for the buccal delivery of cannabis extracts. Front
Neurosci 12:564
Curran HV, Hindocha C, Morgan CJA, Shaban N, Das RK, Freeman TP (2019) Which biological
and self-report measures of cannabis use predict cannabis dependency and acute psychotic-like
effects? Psychol Med 49:1574–1580
Cyr C, Arboleda MF, Aggarwal SK, Balneaves LG, Daeninck P, Neron A, Prosk E, Vigano A
(2018) Cannabis in palliative care: current challenges and practical recommendations. Ann
Palliat Med 7:463–477
Da Silva VK, De Freitas BS, Garcia RCL, Monteiro RT, Hallak JE, Zuardi AW, Crippa JAS,
Schroder N (2018) Antiapoptotic effects of cannabidiol in an experimental model of cognitive
decline induced by brain iron overload. Transl Psychiatry 8:176
Dale T, Downs J, Olson H, Bergin AM, Smith S, Leonard H (2019) Cannabis for refractory epilepsy
in children: a review focusing on CDKL5 Deficiency Disorder. Epilepsy Res 151:31–39
Daris B, Tancer Verboten M, Knez Z, Ferk P (2019) Cannabinoids in cancer treatment: therapeutic
potential and legislation. Bosn J Basic Med Sci 19:14–23
De Petrocellis L, Ligresti A, Schiano Moriello A, Iappelli M, Verde R, Stott CG, Cristino L,
Orlando P, Di Marzo V (2013) Non-THC cannabinoids inhibit prostate carcinoma growth
in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. Br J Pharmacol
168:79–102
Devane W, Hanus L, Breuer A, Pertwee R, Stevenson L, Griffin G, Gibson D, Mandelbaum A,
Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the
cannabinoid receptor. Science 258:1946–1949
Deveaux V, Cadoudal T, Ichigotani Y, Teixeira-Clerc F, Louvet A, Manin S, Tran-Van Nhieu J,
Belot MP, Zimmer A, Even P (2009) Cannabinoid CB2 receptor potentiates obesity-associated
inflammation, insulin resistance and hepatic steatosis. PLoS One 4:e5844
Diao X, Huestis MA (2019) New synthetic cannabinoids metabolism and strategies to best identify
optimal marker metabolites. Front Chem 7:109
Dinis-Oliveira RJ (2019) [The clinical toxicology perspective on the therapeutic use of cannabis and
cannabinoids]. Acta Med Port 32: 87–90
Dol-Gleizes F, Paumelle R, Visentin V, Mares AM, Desitter P, Hennuyer N, Gilde A, Staels B,
Schaeffer P, Bono F (2009) Rimonabant, a selective cannabinoid CB1 receptor antagonist,
inhibits atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol
29:12–18
Elliott J, McCoy B, Clifford T, Potter BK, Skidmore B, Wells GA, Coyle D (2019) Cost-
effectiveness of cannabinoids for pediatric drug-resistant epilepsy: protocol for a systematic
review of economic evaluations. Syst Rev 8:75
Ferrini M, Hong S, Stierle A, Stierle D, Stella N, Roberts K, Jaffar Z (2017) CB 2 receptors regulate
natural killer cells that limit allergic airway inflammation in a murine model of asthma. Allergy
72:937–947
Fiore D, Ramesh P, Proto MC, Piscopo C, Franceschelli S, Anzelmo S, Medema JP, Bifulco M,
Gazzerro P (2018) Rimonabant kills colon cancer stem cells without inducing toxicity in normal
colon organoids. Front Pharmacol 8:949
Foltin RW, Brady JV, Fischman MW (1986) Behavioral analysis of marijuana effects on food
intake in humans. Pharmacol Biochem Behav 25:577–582
Fong TM, Guan X-M, Marsh DJ, Shen C-P, Stribling DS, Rosko KM, Lao J, Yu H, Feng Y, Xiao
JC, Van Der Ploeg LHT, Goulet MT, Hagmann WK, Lin LS, Lanza TJ, Jewell JP, Liu P, Shah
SK, Qi H, Tong X, Wang J, Xu SS, Francis B, Strack AM, Macintyre DE, Shearman LP (2007)
Antiobesity efficacy of a novel cannabinoid-1 receptor inverse agonist, N-[(1S,2S)-3-
(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-
2-yl]oxy]propanamide (MK-0364), in rodents. J Pharmacol Exp Ther 321:1013–1022
Fowler C (2007) The contribution of cyclooxygenase-2 to endocannabinoid metabolism and action.
Br J Pharmacol 152:594–601
440 G. Gupta et al.
Friedman D, French JA, Maccarrone M (2019) Safety, efficacy, and mechanisms of action of
cannabinoids in neurological disorders. Lancet Neurol 18:504–512
Galiègue S, Mary S, Marchand J, Dussossoy D, CarriÈre D, Carayon P, Bouaboula M, Shire D,
Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human
immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61
Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le
Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human
immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61
Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent of
hashish. J Am Chem Soc 86:1646–1647
Gertsch J, Pertwee RG, Di Marzo V (2010) Phytocannabinoids beyond the Cannabis plant - do they
exist? Br J Pharmacol 160:523–529
Giang DK, Cravatt BF (1997) Molecular characterization of human and mouse fatty acid amide
hydrolases. Proc Natl Acad Sci U S A 94:2238–2242
Giannini L, Nistri S, Mastroianni R, Cinci L, Vannacci A, Mariottini C, Passani M, Mannaioni P,
Bani D, Masini E (2008) Activation of cannabinoid receptors prevents antigen-induced asthma-
like reaction in guinea pigs. J Cell Mol Med 12:2381–2394
Gobbi G, Bambico FR, Mangieri R, Bortolato M, Campolongo P, Solinas M, Cassano T, Morgese
MG, Debonnel G, Duranti A, Tontini A, Tarzia G, Mor M, Trezza V, Goldberg SR, Cuomo V,
Piomelli D (2005) Antidepressant-like activity and modulation of brain monoaminergic trans-
mission by blockade of anandamide hydrolysis. Proc Natl Acad Sci U S A 102:18620–18625
Goncalves J, Rosado T, Soares S, Simao AY, Caramelo D, Luis A, Fernandez N, Barroso M,
Gallardo E, Duarte AP (2019) Cannabis and its secondary metabolites: their use as therapeutic
drugs, toxicological aspects, and analytical determination. Medicines (Basel) 6. https://doi.org/
10.3390/medicines6010031
Gonsiorek W, Lunn C, Fan X, Narula S, Lundell D, Hipkin RW (2000) Endocannabinoid
2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism
by anandamide. Mol Pharmacol 57:1045–1050
Griffin G, Tao Q, Abood ME (2000) Cloning and pharmacological characterization of the rat CB
(2) cannabinoid receptor. J Pharmacol Exp Ther 292:886–894
Guindon J, Hohmann A (2008) Cannabinoid CB2 receptors: a therapeutic target for the treatment of
inflammatory and neuropathic pain. Br J Pharmacol 153:319–334
Gustafsson K, Christensson B, Sander B, Flygare J (2006) Cannabinoid receptor-mediated apopto-
sis induced by R (+)-methanandamide and Win55, 212-2 is associated with ceramide accumu-
lation and p38 activation in mantle cell lymphoma. Mol Pharmacol 70:1612–1620
Guzman M (2003) Cannabinoids: potential anticancer agents. Nature reviews cancer 3:745
Guzman M, Duarte M, Blazquez C, Ravina J, Rosa M, Galve-Roperh I, Sanchez C, Velasco G,
Gonzalez-Feria L (2006) A pilot clinical study of Δ9-tetrahydrocannabinol in patients with
recurrent glioblastoma multiforme. Br J Cancer 95:197–203
Hartley J, Nogrady S, Seaton A (1978) Bronchodilator effect of delta1-tetrahydrocannabinol. Br J
Clin Pharmacol 5:523–525
He Y, De Witte LD, Schubart CD, Van Gastel WA, Koeleman BPC, De Jong S, Ophoff RA, Hol
EM, Boks MP (2019) Liprin alfa 2 gene expression is increased by cannabis use and associated
with neuropsychological function. Eur Neuropsychopharmacol 29:643–652
Henschke P (2019) Cannabis: an ancient friend or foe? What works and doesn’t work. Semin Fetal
Neonatal Med 24:149–154
Herkenham M, Lynn AB, Johnson MR, Melvin LS, De Costa BR, Rice KC (1991) Characterization
and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic
study. J Neurosci 11:563–583
Ho C, Martinusen D, Lo C (2019) A review of cannabis in chronic kidney disease symptom
management. Can J Kidney Health Dis 6:2054358119828391
Hollander PA, Amod A, Litwak LE, Chaudhari U (2010) Effect of rimonabant on glycemic control
in insulin-treated type 2 diabetes: the ARPEGGIO trial. Diabetes Care 33:605–607
Hollister LE (1971) Hunger and appetite after single doses of marihuana, alcohol, and dextroam-
phetamine. Clin Pharmacol Ther 12:44–49
Holt S, Comelli F, Costa B, Fowler CJ (2005) Inhibitors of fatty acid amide hydrolase reduce
carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with
indomethacin and possible involvement of cannabinoid receptors. Br J Pharmacol 146:467–476
Horváth B, Mukhopadhyay P, Haskó G, Pacher P (2012) The endocannabinoid system and plant-
derived cannabinoids in diabetes and diabetic complications. Am J Pathol 180:432–442
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M,
Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacol-
ogy. Xxvii. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202
Huang Z-B, Zheng Y-X, Li N, Cai S-L, Huang Y, Wang J, Hu X-W, Wang Y, Wu J, Fan X-G
(2019) Protective effects of specific cannabinoid receptor 2 agonist GW405833 on concanavalin
A-induced acute liver injury in mice. Acta Pharmacol Sinica
Huestis MA, Blount BC, Milan DF, Newmeyer MN, Schroeder J, Smith ML (2019) Correlation of
creatinine- and specific gravity-normalized free and glucuronidated urine cannabinoid
concentrations following smoked, vaporized, and oral cannabis in frequent and occasional
cannabis users. Drug Test Anal. https://doi.org/10.1002/dta.2576
Izzo AA, Camilleri M (2008) Emerging role of cannabinoids in gastrointestinal and liver diseases:
basic and clinical aspects. Gut 57:1140–1155
Jampel H (2009) Position statement on marijuana and the treatment of glaucoma. American
Glaucoma Society, San Francisco
Javed H, Azimullah S, Haque ME, Ojha SK (2016) Cannabinoid type 2 (CB2) receptors activation
protects against oxidative stress and neuroinflammation associated dopaminergic
neurodegeneration in rotenone model of Parkinson’s Disease. Front Neurosci 10:321
Jeske NA, Patwardhan AM, Gamper N, Price TJ, Akopian AN, Hargreaves KM (2006) Cannabi-
noid WIN 55,212-2 regulates TRPV1 phosphorylation in sensory neurons. J Biol Chem
281:32879–32890
Jordan CJ, Xi ZX (2019) Progress in brain cannabinoid CB2 receptor research: from genes to
behavior. Neurosci Biobehav Rev 98:208–220
Kaminski NE (1998) Inhibition of the cAMP signaling cascade via cannabinoid receptors: a
putative mechanism of immune modulation by cannabinoid compounds. Toxicol Lett
102:59–63
Karsak M, Cohen-Solal M, Freudenberg J, Ostertag A, Morieux C, Kornak U, Essig J, Erxlebe E,
Bab I, Kubisch C (2005) Cannabinoid receptor type 2 gene is associated with human osteopo-
rosis. Human Mol Genet 14:3389–3396
Kathuria S, Gaetani S, Fegley D, ValiñO F, Duranti A, Tontini A, Mor M, Tarzia G, Rana GL,
Calignano A, Giustino A, Tattoli M, Palmery M, Cuomo V, Piomelli D (2002) Modulation of
anxiety through blockade of anandamide hydrolysis. Nat Med 9:76
Kaur R, Singh P, Kaur A, Mahajan D, Kaur H (2013) Effect of rimonabant on the components of
metabolic syndrome: a randomized, controlled study done on Punjabi population. J Pharm
Negat Results 4:46–53
Khuja I, Yekhtin Z, Or R, Almogi-Hazan O (2019) Cannabinoids reduce inflammation but inhibit
lymphocyte recovery in murine models of bone marrow transplantation. Int J Mol Sci 20. https://
doi.org/10.3390/ijms20030668
Kim W, Doyle ME, Liu Z, Lao Q, Shin Y-K, Carlson OD, Kim HS, Thomas S, Napora JK, Lee EK
(2011) Cannabinoids inhibit insulin receptor signaling in pancreatic β-cells. Diabetes
60:1198–1209
Kisková T, Mungenast F, Suváková M, Jäger W, Thalhammer T (2019) Future aspects for
cannabinoids in breast cancer therapy. Int J Mol Sci 20:1673
Klegeris A, Bissonnette CJ, Mcgeer PL (2003) Reduction of human monocytic cell neurotoxicity
and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol
139:775–786
Knowles BB, Howe CC, Aden DP (1980) Human hepatocellular carcinoma cell lines secrete the
major plasma proteins and hepatitis B surface antigen. Science 209:497–499
442 G. Gupta et al.
Koch M, Varela L, Kim JG, Kim JD, Hernández-NuñO F, Simonds SE, Castorena CM, Vianna CR,
Elmquist JK, Morozov YM (2015) Hypothalamic POMC neurons promote cannabinoid-
induced feeding. Nature 519:45–50
Kogan NM, Schlesinger M, Peters M, Marincheva G, Beeri R, Mechoulam R (2007) A cannabinoid
anticancer quinone, HU-331, is more potent and less cardiotoxic than doxorubicin: a compara-
tive in vivo study. J Pharmacol Exp Ther 322:646–653
Kogan NM, Melamed E, Wasserman E, Raphael B, Breuer A, Stok KS, Sondergaard R, Escudero
AV, Baraghithy S, Attar-Namdar M (2015) Cannabidiol, a major non-psychotropic cannabis
constituent enhances fracture healing and stimulates lysyl hydroxylase activity in osteoblasts. J
Bone Miner Res 30:1905–1913
Korem N, Akirav I (2014) Cannabinoids prevent the effects of a footshock followed by situational
reminders on emotional processing. Neuropsychopharmacology 39:2709–2722
Kowal M, Hazekamp A, Grotenhermen F (2016) Review on clinical studies with cannabis and
cannabinoids 2010-2014
Krebs MO, Kebir O, Jay TM (2019) Exposure to cannabinoids can lead to persistent cognitive and
psychiatric disorders. Eur J Pain. https://doi.org/10.1002/ejp.1377
Kumar A, Premoli M, Aria F, Bonini SA, Maccarinelli G, Gianoncelli A, Memo M, Mastinu A
(2019) Cannabimimetic plants: are they new cannabinoidergic modulators? Planta
249:1681–1694
Lattanzi S, Trinka E, Russo E, Striano P, Citraro R, Silvestrini M, Brigo F (2019) Cannabidiol as
adjunctive treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syn-
drome. Drugs Today (Barc) 55:177–196
Li X, Kaminski NE, Fischer LJ (2001) Examination of the immunosuppressive effect of Δ
9-tetrahydrocannabinol in streptozotocin-induced autoimmune diabetes. Int Immunopharmacol
1:699–712
Li Q, Wang F, Zhang Y-M, Zhou J-J, Zhang Y (2013) Activation of cannabinoid type 2 receptor by
JWH133 protects heart against ischemia/reperfusion-induced apoptosis. Cell Physiol Biochem
31:693–702
Liu J, Wang L, Harvey-White J, Huang BX, Kim H-Y, Luquet S, Palmiter RD, Krystal G, Rai R,
Mahadevan A (2008) Multiple pathways involved in the biosynthesis of anandamide. Neuro-
pharmacology 54:1–7
Lopez-Rodriguez AB, Siopi E, Finn DP, Marchand-Leroux C, Garcia-Segura LM, Jafarian-
Tehrani M, Viveros M-P (2013) CB1 and CB2 cannabinoid receptor antagonists prevent
minocycline-induced neuroprotection following traumatic brain injury in mice. Cereb Cortex
25:35–45
Lossignol D (2019) Cannabinoids: a new approach for pain control? Curr Opin Oncol. https://doi.
org/10.1097/CCO.0000000000000523
Lowin T, Schneider M, Pongratz G (2019) Joints for joints: cannabinoids in the treatment of
rheumatoid arthritis. Curr Opin Rheumatol 31:271–278
Lu M, Agito MD (2015) Cannabinoid hyperemesis syndrome: marijuana is both antiemetic and
proemetic. Cleve Clin J Med 82:429–434
Lukhele ST, Motadi LR (2016) Cannabidiol rather than Cannabis sativa extracts inhibit cell growth
and induce apoptosis in cervical cancer cells. BMC Complement Altern Med 16:335
Mackie K, Devane WA, Hille B (1993) Anandamide, an endogenous cannabinoid, inhibits calcium
currents as a partial agonist in N18 neuroblastoma cells. Mol Pharmacol 44:498–503
Malfait A, Gallily R, Sumariwalla P, Malik A, Andreakos E, Mechoulam R, Feldmann M (2000)
The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in
murine collagen-induced arthritis. Proc Natl Acad Sci U S A 97:9561–9566
Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio MP, Parolaro D (2004) Antitumor effects of
cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther
308:838–845
Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bronner TI (1990) Structure of a cannabinoid
receptor and functional expression of the cloned cDNA. Nature 346:561
May MB, Glode AE (2016) Dronabinol for chemotherapy-induced nausea and vomiting unrespon-
sive to antiemetics. Cancer Manag Res 8:49–55
Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A,
Almog S, Martin BR, Compton DR (1995) Identification of an endogenous 2-monoglyceride,
present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90
Miller LK, Devi LA (2011) The highs and lows of cannabinoid receptor expression in disease:
mechanisms and their therapeutic implications. Pharmacol Rev 63:461–470
Moreira FA, Crippa JAS (2009) The psychiatric side-effects of rimonabant. Braz J Psychiatry
31:145–153
Mukherjee S, Adams M, Whiteaker K, Daza A, Kage K, Cassar S, Meyer M, Yao BB (2004)
Species comparison and pharmacological characterization of rat and human CB 2 cannabinoid
receptors. Eur J Pharmacol 505:1–9
Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for
cannabinoids. Nature 365:61
Naftali T, Mechulam R, Lev LB, Konikoff FM (2014) Cannabis for inflammatory bowel disease.
Dig Dis 32:468–474
Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M (2009) Cannabinoids as novel anti-
inflammatory drugs. Future Med Chem 1:1333–1349
National Research Council (US) Committee on Substance Abuse and Habitual Behavior 1982) An
analysis of Marijuana Policy [Online]. Accessed https://www.ncbi.nlm.nih.gov/books/
NBK217602/
Navarrete F, Pérez-Ortiz JM, Manzanares J (2012) Cannabinoid CB2 receptor-mediated regulation
of impulsive-like behaviour in DBA/2 mice. Br J Pharmacol 165:260–273
Nunez E, Benito C, Pazos MR, Barbachano A, Fajardo O, Gonzalez S, Tolon RM, Romero J (2004)
Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain:
an immunohistochemical study. Synapse 53:208–213
Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V,
Shohami E (2006) Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad
Sci U S A:103, 696–701
Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (2004) Molecular characterization of a
phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305
Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, Meozzi PA, Myers L, Mora Z, Tagliaferro P,
Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Iwasaki S, Arinami T, Teasenfitz L, Uhl
GR (2006) Discovery of the presence and functional expression of cannabinoid CB2 receptors
in brain. Ann N Y Acad Sci 1074:514–536
Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, Perchuk A, Mora Z, Tagliaferro PA,
Gardner E, Brusco A, Akinshola BE, Hope B, Lujilde J, Inada T, Iwasaki S, Macharia D,
Teasenfitz L, Arinami T, Uhl GR (2008) Brain neuronal CB2 cannabinoid receptors in drug
abuse and depression: from mice to human subjects. PLoS One 3:e1640
Park JM, Xian XS, Choi MG, Park H, Cho YK, Lee IS, Kim SW, Chung IS (2011) Antiproliferative
mechanism of a cannabinoid agonist by cell cycle arrest in human gastric cancer cells. J Cell
Biochem 112:1192–1205
Pertwee R (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther
74:129–180
Pertwee RG (2005) The therapeutic potential of drugs that target cannabinoid receptors or modulate
the tissue levels or actions of endocannabinoids. AAPS J 7
Pertwee R (2010) Receptors and channels targeted by synthetic cannabinoid receptor agonists and
antagonists. Curr Med Chem 17:1360
Pertwee R, Howlett A, Abood ME, Alexander S, Di Marzo V, Elphick M, Greasley P, Hansen HS,
Kunos G, Mackie K (2010) International Union of Basic and Clinical Pharmacology. LXXIX.
Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588–631
Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci
4:873–884
444 G. Gupta et al.
Portella G, Laezza C, Laccetti P, De Petrocellis L, Di Marzo V, Bifulco M (2003) Inhibitory effects

of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on
signals involved in angiogenesis and metastasis. FASEB J 17:1771–1773
Preet A, Qamri Z, Nasser MW, Prasad A, Shilo K, Zou X, Groopman JE, Ganju RK (2011)
Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non–small cell lung
cancer growth and metastasis. Cancer Prev Res 4:65–75
Pryce G, Ahmed Z, Hankey DJ, Jackson SJ, Croxford JL, Pocock JM, Ledent C, Petzold A,
Thompson AJ, Giovannoni G (2003) Cannabinoids inhibit neurodegeneration in models of
multiple sclerosis. Brain 126:2191–2202
Regelson W, Butler J, Schulz J, Kirk T, Peek L, Green M, Zalis M (1976) Delta-9-THC as an
effective antidepressant and appetite-stimulating agent in advanced cancer patients. In: Braude
MC, Szara S (eds). The pharmacology of marihuana. Raven press, New york, pp. 763-776.
Rhee MH, Bayewitch M, Avidor-Reiss T, Levy R, Vogel Z (1998) Cannabinoid receptor activation
differentially regulates the various adenylyl cyclase isozymes. J Neurochem 71:1525–1534
Rossi F, Punzo F, Umano GR, Argenziano M, Miraglia Del Giudice E (2018) Role of cannabinoids
in obesity. Int J Mol Sci 19
Russo R, Loverme J, La Rana G, Compton TR, Parrott J, Duranti A, Tontini A, Mor M, Tarzia G,
Calignano A, Piomelli D (2007) The fatty acid amide hydrolase inhibitor URB597
(cyclohexylcarbamic acid 3’-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after
oral administration in mice. J Pharmacol Exp Ther 322:236–242
Sam AH, Salem V, Ghatei MA (2011) Rimonabant: from RIO to Ban. J Obes 2011:432607–432607
Schatz AR, Lee M, Condie RB, Pulaski JT, Kaminski NE (1997) Cannabinoid receptors CB1 and
CB2: a characterization of expression and adenylate cyclase modulation within the immune
system. Toxicol Appl Pharmacol 142:278–287
Schley M, Legler A, Skopp G, Schmelz M, Konrad C, Rukwied R (2006) Delta-9-THC based
monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and
pain relief. Curr Med Res Opin 22:1269–1276
Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid
receptors. Trends Pharmacol Sci 22:565–572
Schmid P, Reddy P, Natarajan V, Schmid H (1983) Metabolism of N-acylethanolamine
phospholipids by a mammalian phosphodiesterase of the phospholipase D type. J Biol Chem
258:9302–9306
Shiling DJ, Stillman RC, Chang AE, Goldberg NH, Seipp CA, Barofsky I, Rosenberg SA (1981) A
prospective evaluation of delta-9-tetrahydrocannabinol as an antiemetic in patients receiving
adriamycin and cytoxan chemotherapy. Cancer 47:1746–1751
Śledziński P, Zeyland J, SŁomski R, Nowak A (2018) The current state and future perspectives of
cannabinoids in cancer biology. Cancer Med 7:765–775
Small E, Pocock T, Cavers PB (2002) The biology of Canadian weeds. 119. Cannabis sativa L. Can
J Plant Sci 83:217–237
Soderstrom K, Leid M, Moore FL, Murray TF (2000) Behavioral, pharmacological, and molecular
characterization of an amphibian cannabinoid receptor. J Neurochem 75:413–423
Stanley CP, Hind WH, O’sullivan SE (2013) Is the cardiovascular system a therapeutic target for
cannabidiol? Br J Clin Pharmacol 75:313–322
Steinberg MB, Foulds J (2007) Rimonabant for treating tobacco dependence. Vasc Health Risk
Manag 3:307–311
Stella N, Schweitzer P, Piomelli D (1997) A second endogenous cannabinoid that modulates long-
term potentiation. Nature 388:773–778
Strohbeck-Kuehner P, Skopp G, Mattern R (2008) Cannabis improves symptoms of ADHD.
Cannabinoids 3:1–3
Svíženská I, Dubový P, Šulcová A (2008) Cannabinoid receptors 1 and 2 (CB1 and CB2), their
distribution, ligands and functional involvement in nervous system structures—a short review.
Pharmacol Biochem Behav 90:501–511
Tang G, Gudsnuk K, Kuo S-H, Cotrina ML, Rosoklija G, Sosunov A, Sonders MS, Kanter E,
Castagna C, Yamamoto A (2014) Loss of mTOR-dependent macroautophagy causes autistic-
like synaptic pruning deficits. Neuron 83:1131–1143
Tomida I, Pertwee R, Azuara-Blanco A (2004) Cannabinoids and glaucoma. Br J Ophthalmol

88:708–713
Tsuboi K, Uyama T, Okamoto Y, Ueda N (2018) Endocannabinoids and related
N-acylethanolamines: biological activities and metabolism. Inflamm Regen 38:28
Turcotte C, Blanchet M-R, Laviolette M, Flamand N (2016) The CB 2 receptor and its role as a
regulator of inflammation. Cell Mol Life Sci 73:4449–4470
Vachon L, Fitzgerald MX, Solliday NH, Gould IA, Gaensler EA (1973) Single-dose effect of
marihuana smoke: bronchial dynamics and respiratory-center sensitivity in normal subjects. N
Engl J Med 288:985–989
Van Klingeren B, Ten Ham M (1976) Antibacterial activity of Δ 9-tetrahydrocannabinol and
cannabidiol. Antonie Van Leeuwenhoek 42:9–12
Varma N, Carlson GC, Ledent C, Alger BE (2001) Metabotropic glutamate receptors drive the
endocannabinoid system in hippocampus. J Neurosci 21:188
Viudez-Martinez A, Garcia-Gutierrez MS, Medrano-Relinque J, Navarron CM, Navarrete F,
Manzanares J (2019) Cannabidiol does not display drug abuse potential in mice behavior.
Acta Pharmacol Sin 40:358–364
Volkow ND, Baler RD, Compton WM, Weiss SR (2014) Adverse health effects of marijuana use. N
Engl J Med 370:2219–2227
Vuolo F, Petronilho F, Sonai B, Ritter C, Hallak JE, Zuardi AW, Crippa JA, Dal-Pizzol F (2015)
Evaluation of serum cytokines levels and the role of cannabidiol treatment in animal model of
asthma. Mediators Inflamm 2015
Waldman M, Hochhauser E, Fishbein M, Aravot D, Shainberg A, Sarne Y (2013) An ultra-low dose
of tetrahydrocannabinol provides cardioprotection. Biochem Pharmacol 85:1626–1633
Wang T, Collet J-P, Shapiro S, Ware MA (2008) Adverse effects of medical cannabinoids: a
systematic review. CMAJ:178, 1669–1678
Ware MA, Daeninck P, Maida V (2008) A review of nabilone in the treatment of chemotherapy-
induced nausea and vomiting. Ther Clin Risk Manag 4:99–107
Weiss L, Zeira M, Reich S, Slavin S, Raz I, Mechoulam R, Gallily R (2008) Cannabidiol arrests
onset of autoimmune diabetes in NOD mice. Neuropharmacology 54:244–249
Whiteside GT, Lee G, Valenzano KJ (2007) The role of the cannabinoid CB2 receptor in pain
transmission and therapeutic potential of small molecule CB2 receptor agonists. Curr Med
Chem 14:917–936
Whyte DA, Al-Hammadi S, Balhaj G, Brown OM, Penefsky HS, Souid A-K (2010) Cannabinoids
inhibit cellular respiration of human oral cancer cells. Pharmacology 85:328–335
Wilkinson ST, Radhakrishnan R, D’souza DC (2014) Impact of cannabis use on the development of
psychotic disorders. Curr Addict Rep 1:115–128
Wright K, Duncan M, Sharkey K (2008) Cannabinoid CB2 receptors in the gastrointestinal tract: a
regulatory system in states of inflammation. Br J Pharmacol 153:263–270
Yamaguchi F, Macrae AD, Brenner S (1996) molecular cloning of two cannabinoid type 1-like
receptor genes from the puffer fishfugu rubripes. Genomics 35:603–605
Yang X, Hegde VL, Rao R, Zhang J, Nagarkatti PS, Nagarkatti M (2014) Histone modifications are
associated with Δ9-tetrahydrocannabinol-mediated alterations in antigen-specific T cell
responses. J Biol Chem 289:18707–18718
Zhang H-Y, Gao M, Liu Q-R, Bi G-H, Li X, Yang H-J, Gardner EL, Wu J, Xi Z-X (2014)
Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-
related behavior in mice. Proc Natl Acad Sci U S A 111:E5007–E5015
Zhong L, Geng L, Njie Y, Feng W, Song Z-H (2005) CB2 cannabinoid receptors in trabecular
meshwork cells mediate JWH015-induced enhancement of aqueous humor outflow facility.
Invest Ophthalmol Vis Sci 46:1988–1992

Pharmacology of Endocannabinoids and The

Uploaded by

Copyright:

Available Formats

Pharmacology of Endocannabinoids and The

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Pharmacology of Endocannabinoids and The

Uploaded by

Copyright:

Available Formats

Pharmacology of Endocannabinoids

and Their Receptors 13

The identiﬁcation of cannabinoid (CB) receptors has contributed to the state-of-the-art

# Springer Nature Singapore Pte Ltd. 2020 415

Cannabinoids · Cannabinoid receptors · Biosynthesis of endocannabinoids ·

Fig. 13.1 Cannabis sativa plant

13.2 Cannabinoid Receptors: Signaling Pathway

Adenylyl cyclase Intracellular

located pre-synaptically and modulate neurotransmitter release. Different impacts

13.3 Cannabinoid Receptor Agonists and Antagonists

The extensively studied endocannbainoids (eCB) are the arachidonic acid

13.3.1.1 Biosynthesis of Endocannabinoids

3. Noladin ether 2- More afﬁnity Less afﬁnity than CB1R

Pharmacology of Endocannabinoids and Their Receptors

5. Virodhamine O-arachidonoyl Antagonist Agonist

NAPE-PLD DAGL Synthesis

N-acylethanolamine Phosphatidylethanolamine Monoacylglycerol Fatty acid

Ethanolamine Glycerol Fatty acid

13.3.1.2 Hydrolysis of Endocannabinoids

13.3.1.3 Pharmacodynamics of Endocannabinoids

13.3.1.4 Physiological Role of Endocannabinoids

13.3.1.5 Pharmacology of Endocannabinoids

structures, substantia nigra, periaqueductal gray, superior colliculus and inferior

phenanthrenes, spiroindans, xanthones, biphenyls and nitrogenous compounds

13.3.3 Examples of Cannabinoids

13.3.3.1 Δ9-Tetrahydrocannabinol (THC)

13.3.3.2 Cannabidiol (CBD)

13.3.3.4 URB597 ([3-(3-carbamoylphenyl)

exhibited to be dynamic in discouragement (Gobbi et al. 2005), inﬂammation (Holt

13.3.4 CB Receptor Blockers

Medications that modify the endogenous eCB levels by blocking CB receptors

13.3.4.1 Rimonabant and Taranabent

13.3.5 Therapeutic Potential of Targeting Cannabinoid Receptors

The undesired psychotropic effects of cannabinoid agonists represent a drawback in

13.3.5.2 Metabolic Disorders

Table 13.2 (continued)

13.3.5.5 Autoimmune Diseases

13.3.5.6 Bone Diseases

13.3.5.7 Cardiovascular Diseases

13.3.5.8 Gastrointestinal Disorders

13.3.5.9 Mood and Anxiety Disorders

13.3.5.10 Neurodegenerative Diseases

disease and inﬂammatory peripheral disorders (Pertwee 2010). Recent evidence

13.3.5.11 Attention-deficit Hyperactivity Disorder (ADHD)

13.3.5.13 Cannabinoids and their Potential for Addiction

The underlying disclosure and ensuing thorough research of the endocannabinoid

endocannabinoid and other synapse systems, by means of nearby neural circuits, or

Blázquez C, Carracedo A, Barrado L, Real PJ, Fernández-Luna JL, Velasco G, Malumbres M,

Portella G, Laezza C, Laccetti P, De Petrocellis L, Di Marzo V, Bifulco M (2003) Inhibitory effects

Tomida I, Pertwee R, Azuara-Blanco A (2004) Cannabinoids and glaucoma. Br J Ophthalmol

You might also like