**4. Treatment of withdrawal syndrome**

Although there are more than 160 million *Cannabis* users in the world, no pharmacological therapy currently available is considered adequate for the treatment of symptoms caused during the withdrawal syndrome. The known effects of withdrawal syndrome, which occur when drug use is deprived and disappear with the reintroduction of Δ9-THC [60], favor the recurrence of use by users attempting to stop. The main compounds that have activity on the cannabinoid receptor and mechanisms related to *Cannabis* withdrawal syndrome are as follows*.*

#### **4.1. Agonist compounds**

The involvement of the CB1 receptor with the development of dependence, as well as the expression of withdrawal symptoms, has already been evidenced in several animal experiments. Therefore, it is suggested that treatment with low doses of CB1 receptor agonists could reduce the severity of withdrawal symptoms [61]. Low doses of Δ9-THC were tested to improve withdrawal symptoms; however, these doses exhibited reinforcing properties in chronic *Cannabis* users, eliminating THC as a viable treatment [62].

The endocannabinoids AEA and 2-AG, which are low and high efficiency agonists for the CB1 receptor, respectively, as well as fatty acid amide hydrolase (FAAH) enzymes responsible for the degradation of AEA and monoacylglycerol lipase (MAGL) responsible for the degradation of 2-AG were proposed as mediating mechanisms of *Cannabis* withdrawal but lack further enlightening studies [6, 63].

#### *4.1.1. Synthetic cannabinoids*

These synthetic cannabinoid agonists present themselves as promising molecules, providing ample reduction in *Cannabis* withdrawal symptoms (mood, sleep, and food intake), both in the laboratory and in clinical settings. Unlike the isomer of THC and derived from the *Cannabis* plant, dronabinol, the synthetic cannabinoid nabilone (**Figure 2**) has potential to reduce self-administration of *Cannabis,* presenting as more promising for treatment [64].

Nabilone has more predictable side effects, and it is well tolerated among *Cannabis* users, better bioavailability, and longer duration of action than dronabinol, allowing the end of abstinence with a single daily dose [65]. In addition, nabilone produces non-*Cannabis* urinary biomarkers that allow monitoring of abstinence through the use of standard urine toxicology during nabilone maintenance, but this consistently decreases *Cannabis* self-administration in the laboratory, ensuring that testing occurs in a clinical setting [66].

#### *4.1.2. α2a adrenergic receptor agonist*

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 dur-

Although there are more than 160 million *Cannabis* users in the world, no pharmacological therapy currently available is considered adequate for the treatment of symptoms caused during the withdrawal syndrome. The known effects of withdrawal syndrome, which occur when drug use is deprived and disappear with the reintroduction of Δ9-THC [60], favor the recurrence of use by users attempting to stop. The main compounds that have activity on the cannabinoid receptor and mechanisms related to *Cannabis* withdrawal syndrome are as follows*.*

The involvement of the CB1 receptor with the development of dependence, as well as the expression of withdrawal symptoms, has already been evidenced in several animal experiments. Therefore, it is suggested that treatment with low doses of CB1 receptor agonists could reduce the severity of withdrawal symptoms [61]. Low doses of Δ9-THC were tested to improve withdrawal symptoms; however, these doses exhibited reinforcing properties in

The endocannabinoids AEA and 2-AG, which are low and high efficiency agonists for the CB1 receptor, respectively, as well as fatty acid amide hydrolase (FAAH) enzymes responsible for the degradation of AEA and monoacylglycerol lipase (MAGL) responsible for the degradation of 2-AG were proposed as mediating mechanisms of *Cannabis* withdrawal but lack

These synthetic cannabinoid agonists present themselves as promising molecules, providing ample reduction in *Cannabis* withdrawal symptoms (mood, sleep, and food intake), both in the laboratory and in clinical settings. Unlike the isomer of THC and derived from the *Cannabis* plant, dronabinol, the synthetic cannabinoid nabilone (**Figure 2**) has potential to reduce self-administration of *Cannabis,* presenting as more promising for treatment [64].

Nabilone has more predictable side effects, and it is well tolerated among *Cannabis* users, better bioavailability, and longer duration of action than dronabinol, allowing the end of abstinence with a single daily dose [65]. In addition, nabilone produces non-*Cannabis* urinary

chronic *Cannabis* users, eliminating THC as a viable treatment [62].

ing the abstinence period, suggesting reliable studies of *Cannabis* abstinence [58, 59].

**4. Treatment of withdrawal syndrome**

**4.1. Agonist compounds**

160 Recent Advances in Cannabinoid Research

further enlightening studies [6, 63].

*4.1.1. Synthetic cannabinoids*

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].

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

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

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

improve both. In contrast, lofexidine decreased self-administration of *Cannabis* in the laboratory after abstinence but worsened the performance of psychomotor tasks [68].

and high dose use. Due to this property on the endocannabinoid system, CBD has several pharmacological effects, including anxiolytic, antipsychotic, neuroprotective, antiinflammatory, and antiemetic actions, favoring its use in the treatment of *Cannabis* withdrawal syndrome [73, 74]. Comparative studies of the use of nabiximols and dronabinol concluded that they did not produce significant cognitive or psychomotor adverse effects and showed a similar or lower reinforcement potential than dronabinol at lower doses [71, 75]. However, high doses of both drugs exhibited some potential for a booster. This fact highlights the need for careful monitoring related to drug administration during future studies and clinical practice for treatment of

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

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

163

The use of CB1 cannabinoid receptor antagonists is more related to the treatment of *C. sativa* dependence than to the treatment of withdrawal syndrome triggered by the withdrawal of this use in chronic users, as much as characteristic symptoms of withdrawal syndrome such as insomnia, dysphoria, and anxiety manifesting with the use of the CB1 receptor antagonist, rimonabant (also known as SR 141716A) (**Figure 5**) [8]. For this reason, the rimonabant, previously used in the treatment of obesity, was removed from the market in 2008, but it is useful in inducing signs of withdrawal in *Cannabis*-dependent individuals. One of the explanations is that the neural circuits involved with the serotonergic, noradrenergic, and dopaminergic

It is important to mention that the endogenous opioid system also contributes to the dependence of *Cannabis* because it also has G protein-coupled membrane receptors [78], and users of opioid-dependent *Cannabis* are less likely to experience withdrawal symptoms. Opioid receptor antagonists, such as naltrexone, reduce self-administration of *C. sativa* and their sub-

systems have been shown to be sensitive to CB1 receptor antagonists [76, 77].

dependence and abstinence from *Cannabis* with nabiximols.

jective positive effects in chronic plant users [79].

**Figure 5.** Chemical structure of SR 141716A.

**4.2. Antagonists**

#### *4.1.3. Nabiximols*

Nabiximols are used to treat muscle spasticity associated with multiple sclerosis. These produce little intoxication, tolerance, or abstinence. They are oral spray medications containing THC, cannabidiol (CBD), and various terpenoids (**Figure 4**) derived from *C. sativa* plants. Once CBD attenuated the paranoia and euphoria associated with THC studies, nabiximols were used to treat *Cannabis* withdrawal and observed that they attenuated abstinence symptoms and improved patient compliance to treatment, as well as reducing irritability and depression of the users [71].

The indirect CBD agonist, which has a relatively low affinity for CB1 and CB2 receptors, inhibits AEA reuptake and hydrolysis while maintaining CB1 receptor stimulation, thus potentiating endocannabinoid transmission and emerging as an alternative treatment for the abstinence syndrome of *C. sativa* [72]. It is a compound with no significant adverse effects even with chronic

**Figure 4.** Chemical structure of nabiximols and terpenoids derived from *C. sativa* plants.

and high dose use. Due to this property on the endocannabinoid system, CBD has several pharmacological effects, including anxiolytic, antipsychotic, neuroprotective, antiinflammatory, and antiemetic actions, favoring its use in the treatment of *Cannabis* withdrawal syndrome [73, 74].

Comparative studies of the use of nabiximols and dronabinol concluded that they did not produce significant cognitive or psychomotor adverse effects and showed a similar or lower reinforcement potential than dronabinol at lower doses [71, 75]. However, high doses of both drugs exhibited some potential for a booster. This fact highlights the need for careful monitoring related to drug administration during future studies and clinical practice for treatment of dependence and abstinence from *Cannabis* with nabiximols.

#### **4.2. Antagonists**

The use of CB1 cannabinoid receptor antagonists is more related to the treatment of *C. sativa* dependence than to the treatment of withdrawal syndrome triggered by the withdrawal of this use in chronic users, as much as characteristic symptoms of withdrawal syndrome such as insomnia, dysphoria, and anxiety manifesting with the use of the CB1 receptor antagonist, rimonabant (also known as SR 141716A) (**Figure 5**) [8]. For this reason, the rimonabant, previously used in the treatment of obesity, was removed from the market in 2008, but it is useful in inducing signs of withdrawal in *Cannabis*-dependent individuals. One of the explanations is that the neural circuits involved with the serotonergic, noradrenergic, and dopaminergic systems have been shown to be sensitive to CB1 receptor antagonists [76, 77].

It is important to mention that the endogenous opioid system also contributes to the dependence of *Cannabis* because it also has G protein-coupled membrane receptors [78], and users of opioid-dependent *Cannabis* are less likely to experience withdrawal symptoms. Opioid receptor antagonists, such as naltrexone, reduce self-administration of *C. sativa* and their subjective positive effects in chronic plant users [79].

**Figure 5.** Chemical structure of SR 141716A.

**Figure 4.** Chemical structure of nabiximols and terpenoids derived from *C. sativa* plants.

improve both. In contrast, lofexidine decreased self-administration of *Cannabis* in the labora-

Nabiximols are used to treat muscle spasticity associated with multiple sclerosis. These produce little intoxication, tolerance, or abstinence. They are oral spray medications containing THC, cannabidiol (CBD), and various terpenoids (**Figure 4**) derived from *C. sativa* plants. Once CBD attenuated the paranoia and euphoria associated with THC studies, nabiximols were used to treat *Cannabis* withdrawal and observed that they attenuated abstinence symptoms and improved patient compliance to treatment, as well as reducing irritability and

The indirect CBD agonist, which has a relatively low affinity for CB1 and CB2 receptors, inhibits AEA reuptake and hydrolysis while maintaining CB1 receptor stimulation, thus potentiating endocannabinoid transmission and emerging as an alternative treatment for the abstinence syndrome of *C. sativa* [72]. It is a compound with no significant adverse effects even with chronic

tory after abstinence but worsened the performance of psychomotor tasks [68].

*4.1.3. Nabiximols*

depression of the users [71].

162 Recent Advances in Cannabinoid Research
