**2. Physiology**

#### **2.1. Cannabinoid receptor type 1 (CB1)**

After the use of *Cannabis*, THC interacts with the CB1 cannabinoid receptor, inducing conformational changes in this receptor, the interaction with the residue of amino acid TRP356 and its surroundings being the activation trigger for the signaling [19]. Also, the binding site of the CB1 receptor comprises the amino acid residues Phenylalanine 174 (PHE174), Leucine 193 (LEU193), and Serine 383 (SER383) (**Figure 1**) that must be in contact or proximity to the preferred THC docking position [20].

The morphological differences between CB1 and CB2 cannabinoid receptors indicate that most cannabinoid compounds interact differently in both receptors [21], and the location of

**Figure 1.** Amino acid residues present at the cannabinoid receptor binding site CB1.

in paste form called hashish, mixed with crack, or as *skunk*, which is a polymorphic form of marijuana [2] cultivated in special appearance and 7–25 times stronger than common marijuana causing greater psychotropic effects, as well as adverse effects such as triggering

Studies have found moderate evidence that there is a link between *Cannabis* use and in relation to the development of dependence and substance abuse such as alcohol and tobacco among other illicit drugs [4], and after a long discussion about the relevance of recent *Cannabis* withdrawal syndrome, this condition was added to the fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [5]. This syndrome appears within 24 h after cessation of *Cannabis* use, reaches a peak in about days 2–6, and can last from 1 or 2 weeks. It affects 55–89% of regular *Cannabis* users. The *Cannabis* withdrawal syndrome is clinically defined by irritability, anger, nervousness, anxiety, sleep difficulties, decreased appetite or weight loss, restlessness, and mood depression, in addition to various physical symptoms

The evidence of *Cannabis* withdrawal syndrome is based on behavioral observations in animal studies [9], clinical observation of patients [10], or epidemiological surveys [11, 12]. However, the biological correlates of this phenomenon remain obscure, challenging the validity of the syndrome. This lack of knowledge is partly explained by the interindividual variability of delta 9-tetrahydrocannabinol (THC) metabolism [13] and the complexity of plasma-tissue exchanges [14]. In the last decades, many studies have been dedicated to discover and understand the diverse effects of cannabinoids on the organism whether therapeutic (with the relief of chronic pains and muscle spasms related to multiple sclerosis) [15, 16] or derived from the psychoactivity of *C. sativa*, originating the dependence and consequently the withdrawal syndrome [17]. These symptoms include physical discomforts such as headaches and stomach psychological symptoms accompanied by irritability, anxiety, sleep disturbances, decreased appetite/weight loss, restlessness, or depressed mood [18]. The chapter discusses the main studies currently conducted for the treatment of *Cannabis* withdrawal syndrome, that is, molecules which have their activity associated with some kind of interaction by structural complementarity beside

After the use of *Cannabis*, THC interacts with the CB1 cannabinoid receptor, inducing conformational changes in this receptor, the interaction with the residue of amino acid TRP356 and its surroundings being the activation trigger for the signaling [19]. Also, the binding site of the CB1 receptor comprises the amino acid residues Phenylalanine 174 (PHE174), Leucine 193 (LEU193), and Serine 383 (SER383) (**Figure 1**) that must be in contact or proximity to the

The morphological differences between CB1 and CB2 cannabinoid receptors indicate that most cannabinoid compounds interact differently in both receptors [21], and the location of

of schizophrenia [3].

156 Recent Advances in Cannabinoid Research

such as abdominal pain, tremor, or sweating [6–8].

the CB1 cannabinoid receptor.

**2.1. Cannabinoid receptor type 1 (CB1)**

preferred THC docking position [20].

**2. Physiology**

CB1 receptors in the central nervous system is directly associated with the behavioral effects produced by cannabinoids [22, 23]. CB1 gene polymorphisms have been observed and their importance is still unknown, but it is suggested that they are linked to increased susceptibility to *C. sativa* dependence and neuropsychiatric disorders [24].

CB1 cannabinoid receptors are present in areas associated with motor control, emotional response, learning, memory, goal-oriented behaviors, energy homeostasis, and higher cognitive functions, among others [25]. In peripheral organs and tissues, CB1 receptors are expressed in low density and have potential implication to regulate inflammation and autoimmune diseases [26]. Unlike the standard of others neuroreceptor systems, levels of CB1 receptors in rats are increased in the transition from adolescence to adult age, a fact that suggests the propensity to search for cannabinoid compounds at this stage of life [27].

The CB1 receptor is a subfamily member of the G protein-coupled receptors (GPCRs) [28] and is predominantly present in the presynaptic terminal, although small amounts are present in peripheral nerves and its function seems to modulate the release of neurotransmitters such as dopamine, noradrenaline, glutamate, and serotonin in the synaptic cleft [29].

The inhibition of adenylate cyclase by psychoactive cannabinoids in more densely populated regions of CB1 receptors was initially identified in N18TG2 neuroblastoma cells and thereafter in many other preparations [30]. This inhibition causes modulation of intracellular cAMP concentration, thereby regulating protein kinase A (PKA) phosphorylation, fact that may result in large changes on cellular activity, such as regulation of K<sup>+</sup> channels undergoing PKA action in hippocampus [31].

Mitogen-activated protein kinases (MAP kinases) are important signal transduction enzymes involved in cell regulation to physiological functions of gene expression control, proliferation, and programmed cell death (apoptosis) [32]. Studies confirm a positive connection of CB1 receptors with MAP kinase, so that, *in vivo*, acute administration of Δ9-THC and CB1 cannabinoid receptor agonists (CP-55940, WIN 55,212-2, anandamide (AEA), and 2-O-arachidonoylglycerol (2-AG)) stimulates the MAP kinase of guinea pigs. Synaptic plasticity is considered as the capacity of rearrangement by the neural networks, constitutes an important mechanism to recover or adapt in case of injury, and provides the basis for most models of learning, memory, and development in neural circuits [33]. Brain-derived neurotrophic factor (BDNF) and Krox-24 gene have been recognized for their importance in synaptic plasticity and are prevented by the activation of MAP kinase [34], including studies that indicate that cannabinoid receptors alter this physiological process and may favor the induction of long-term depolarization (LTD) [35].

THC, as well as other CB1 receptor agonists, has inhibitory effects on the release of GABA and glutamate. Excitatory effects on dopamine (DA) are also evident, leading to an increase in the

Bioligands Acting on the Cannabinoid Receptor CB1 for the Treatment of Withdrawal…

http://dx.doi.org/10.5772/intechopen.82184

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The chemical dependence on *C. sativa* develops in about 10% of the people who experience the plant, being more common and on higher levels of use at an early age [48]. Withdrawal syndrome was recognized and added to DSM-5 in 2014, mainly due to the increase with the number of treatment episodes to chronic users of *Cannabis* in the last years [49]. These treatments involve psychosocial approaches, but only 20% of patients achieve definitive abstinence [50],

Studies using positron emission tomography revealed a significantly lower availability of CB1 receptors between *Cannabis* smokers and nonsmokers, in which the level of downregulation correlated with the time of *Cannabis* use [46]. Interestingly, after a 30-day abstinence period, there was an increase in CB1 receptor availability to levels comparable to healthy

For the diagnosis of *C. sativa* withdrawal, it is necessary to have criteria such as (1) the development in specific syndrome of the substance due to cessation or reduction in use; (2) the syndrome causes clinically significant distress or impairment in social, occupational, or other important areas of functioning; and (3) the symptoms are not due to a general medical condi-

Following the recognition by the ICD-10 (International Statistical Classification of Diseases and Related Health Problems) system of *Cannabis* withdrawal, the demand for treatment of *Cannabis* abuse has grown in several countries and a large proportion of adults and adolescents who participate in the outpatient treatments have difficulty in achieving and maintain-

Experimental studies on *Cannabis* withdrawal in humans began in the 1970s and showed moderate withdrawal symptoms (such as transient nervousness) following cessation of marijuana use and more robust symptoms (restlessness, sleep problems, poor appetite, and disorientation). In the 1980s, new withdrawal symptoms were reported as decreased appetite/weight loss, hostility, irritability, mild nausea, lack of cooperation, restlessness, sleep EEG changes (increased REM sleep), and sleep/insomnia difficulties. These symptoms started within 5–6 h of the last dose and decreased by 96 h with a reduction in weight and sleep. Changes in EEG

More recent studies have demonstrated *Cannabis* withdrawal syndrome associated with significantly increased outcomes of anxiety, depression, and irritability; decrease in sleep quality and quantity indices; and decreased food intake [56]. Symptoms such as stomach pain and decreased assessments of contentment, friendliness, language, sociability, and energy were also reported. Most of the mood symptoms begin within 48 h after cessation and appear to peak at day 3 or 4 of the withdrawal phases, and it is interesting to note that studies of oral

THC use have not reported sleep disturbances during the withdrawal phases [57].

manifesting a clear need to develop effective treatments for this pathology.

tion and are not better accounted for by another mental disorder [52].

level of extracellular DA [42].

controls [6, 51].

ing *Cannabis* withdrawal [53].

**3.1. Symptoms of withdrawal syndrome**

(i.e., increase in REM) are also observed [54, 55].

The voltage-dependent ion channels, mainly K<sup>+</sup> and Ca2+, are modulated by CB1 receptors, suggesting that the release of gamma-aminobutyric acid (GABA), a neurotransmitter responsible for CNS inhibition, is mediated by the opening of these channels [36], thus influencing cognitive processes such as learning and memory [37].

Cerebral cortex neurons expressing the G-protein coupled receptors, called CCK receptors, are responsible for the release of the neuropeptide cholecystokinin (CCK) [38], whose action on the hypothalamus produces the sensation of satiety, and also express the CB1 receptors [39]. Activation of CB1 receptors also activates CCK receptors, thus inhibiting the release of CCK [40] and negatively influencing satiety [41].

Rich areas in CB1 receptors reveal a high expression of N-methyl d-aspartate (NMDA) receptors, a class of receptors involved in glutamate neurotransmission and therefore important in movement control and memory formation [42]. Cannabinoid substances have shown dual effects on NMDA receptor activity, influencing memory acquisition and learning mechanisms [43].

#### **2.2. Cannabinoid receptor type 2 (CB2)**

The main and most well-known location of CB2 receptors on human beings is in nonneuronal tissues, mainly in the immune system and hematopoietic cells. The exclusively peripheral location of the CB2 receptors was already questioned when, in 2006, their existence was confirmed in the nervous system, principally in neuronal, glial, and endothelial cells in the brain, although in lower proportions than the CB1 receptors [44]. As CB2 receptors has an important role in neuroinflammatory responses, neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease become the subject of pharmaceutical studies in this regard [45], where the concentration of these receptors seems to be increased in specific brain regions related to these pathologies [46].

As with CB1 receptors, CB2 receptors are also coupled to G protein although their action seems to be part of a general protection system since its activation has no association with psychoactive effects. Agonist molecules of these receptors are being tested in neuropsychiatric, cardiovascular, and hepatic pathologies [47].
