**3. Chemical dependence and withdrawal syndrome**

THC is a partial agonist of CB1 and CB2 receptors, although it is the interaction with CB1 receptors that is responsible for the psychoactive effects of *C. sativa* [40, 41]. CB1 receptors are found at high densities in the ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, amygdala, and cerebellum, whereas CB2 receptors are primarily located in immune cells [24, 41].

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 level of extracellular DA [42].

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

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 controls [6, 51].

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

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 maintaining *Cannabis* withdrawal [53].

#### **3.1. Symptoms of withdrawal syndrome**

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

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

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

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 learn-

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

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 neuropsychiat-

THC is a partial agonist of CB1 and CB2 receptors, although it is the interaction with CB1 receptors that is responsible for the psychoactive effects of *C. sativa* [40, 41]. CB1 receptors are found at high densities in the ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, amygdala, and cerebellum, whereas CB2 receptors are primarily located in

and Ca2+, are modulated by CB1 receptors,

induction of long-term depolarization (LTD) [35]. The voltage-dependent ion channels, mainly K<sup>+</sup>

158 Recent Advances in Cannabinoid Research

cognitive processes such as learning and memory [37].

CCK [40] and negatively influencing satiety [41].

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

specific brain regions related to these pathologies [46].

**3. Chemical dependence and withdrawal syndrome**

ric, cardiovascular, and hepatic pathologies [47].

ing mechanisms [43].

immune cells [24, 41].

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

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].

The symptoms reached the highest levels of aggression on days 3 and 7 of abstinence and lasted until day 28, being reported for up to 6 months after cessation of use, showing an effect transient. Among chronic and daily users, the appetite decreased after day 9 of abstinence, anxiety occurred between days 1 and 11, irritability was greatest on days 1–14, and the mood was lower on days 3–9 and was higher on days 1–10. Daily users have higher levels of anxiety, irritability, nervousness, restlessness, tremors, difficulty sleeping, stomach pain, strange dreams, excessive sweating, negative mood, physical symptoms, and decreased appetite during the abstinence period, suggesting reliable studies of *Cannabis* abstinence [58, 59].

biomarkers that allow monitoring of abstinence through the use of standard urine toxicology during nabilone maintenance, but this consistently decreases *Cannabis* self-administration in

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

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Preclinical data have demonstrated that abstinence of cannabinoid is associated with adrenergic hyperactivity [67], and that α2 receptors agonists decrease the withdrawal symptoms of THC. Therefore, the α2a adrenergic receptor agonist, lofexidine (**Figure 3**), has been tested, and its use has improved sleep during the abstinence period and decreased *Cannabis* relapse [68] but is poorly tolerated even at less frequent doses and at lower target dose (0.6 mg three times a day), with 40% of patients presenting dizziness and fatigue [69]. Another α2-adrenergic agonist, guanfacine hydrochloride (**Figure 3**), which improves memory performance in humans, was tested on the hypothesis that nocturnal administration of this drug would reduce *Cannabis* withdrawal while producing little evidence of sedation or hypotension. Daily administration of the compound significantly reduced irritability, produced small but significant decreases in blood pressure and heart rate, however was well tolerated, producing no sedation, dizziness, or altered food intake observed with lofexidine. Due to these results, guanfacine hydrochloride stands out as one of the

first non-cannabinoid agonists to reduce *cannabis* abstinence-related irritability [64, 70].

**Figure 2.** Chemical structure of isomer of THC, dronabinol and synthetic cannabinoid, and nabilone.

**Figure 3.** Chemical structure of α2a adrenergic receptor agonist.

Despite reductions in certain withdrawal symptoms, guanfacine did not reduce self-administration of *Cannabis* and did not worsen abstinence-related anorexia and weight loss but did not

the laboratory, ensuring that testing occurs in a clinical setting [66].

*4.1.2. α2a adrenergic receptor agonist*
