Open access peer-reviewed chapter

Bioligands Acting on the Cannabinoid Receptor CB1 for the Treatment of Withdrawal Syndrome Caused by Cannabis sativa

Written By

Jaderson Vieira Ferreira, Lenir Cabral Correa, Daniel Castro da Costa and Lorane Izabel da Silva Hage-Melim

Submitted: 18 June 2018 Reviewed: 22 October 2018 Published: 19 December 2018

DOI: 10.5772/intechopen.82184

From the Edited Volume

Recent Advances in Cannabinoid Research

Edited by Willard J Costain and Robert B Laprairie

Chapter metrics overview

1,262 Chapter Downloads

View Full Metrics


Every day, the questions about Cannabis sativa ability to cause chemical dependence are closed with the considerable increase in the demand for treatment of addicts to this plant. Most drug addicts submitted to treatment have difficulty in achieving and maintaining abstinence from Cannabis due to the appearance of symptoms as irritability, anxiety, desire to consume marijuana, decreased quality and quantity of sleep, and change in appetite, weight loss, and physical discomfort, besides emotional and behavioral symptoms. The neurobiological basis for the withdrawal syndrome, that is, withdrawal of Cannabis, was established after the discovery of the endogenous cannabinoid system, identification of CB1 and CB2 cannabinoid receptors, and demonstrations of precipitated removal with antagonists of these receptors. The chapter discusses the main studies currently conducted for the treatment of withdrawal syndrome based on bioligands that act directly on the CB1 cannabinoid receptor.


  • receptor cannabinoid CB1
  • withdrawal syndrome
  • Cannabis sativa
  • drugs computer aided

1. Introduction

Cannabis sativa, commonly known as marijuana, is the illicit drug most consumed in many countries [1]. The form of Cannabis abuse is predominantly smoked, although it can be found 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 of schizophrenia [3].

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 such as abdominal pain, tremor, or sweating [6, 7, 8].

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 the CB1 cannabinoid receptor.


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].

Figure 1.

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

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

The voltage-dependent ion channels, mainly K+ 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].


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

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].


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].

Figure 2.

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

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

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

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].

Figure 4.

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

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 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].

Figure 5.

Chemical structure of SR 141716A.

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].


5. New studies on the treatment of withdrawal syndrome

There are no drugs approved for the treatment of addiction or withdrawal syndrome of Cannabis. Pharmacotherapy in these cases is focused exclusively on symptoms such as increased anxiety, insomnia, loss of appetite, migraine, and irritability. We disclose these symptoms being a result of desensitization of CB1 receptors by THC studies advancing toward the development of compounds that act selectively at this receptor. There are four main chemical classes of exogenous cannabinoid ligands under study: (a) classical cannabinoids such as Δ9-THC, AM2389, cannabinol, nabilone, HU-210, and other tricyclic terpenoid derivatives, such as Δ9-tetrahydrocannabivarin (Δ9-THCV) (Figure 6), which contains a polar benzopyran moiety attached to a hydrophilic (n-pentyl) alkyl terminus [80]; (b) the nonclassical cannabinoids CP 55,940, HU-308 (Figure 7) and other bicyclic and tricyclic analogs of Δ9-THC without the pyran ring of classical cannabinoids [81]; (c) the aminoalkylindoles WIN55,212-2, JWH-018, JWH-073, and AM1241 (Figure 8), which differ in structure, lipophilicity, and binding activity at cannabinoid receptors compared to nonclassical cannabinoids [82]; and (d) biarylpyrazole ligands such as rimonabant and AM251 antagonists, which are selective for the CB1 receptor, and SR144528 (Figure 9), which is selective for the CB2 receptor [83].

Figure 6.

Chemical structure of classical cannabinoids.

Figure 7.

Chemical structure of the non-classical cannabinoids.

Figure 8.

Chemical structure of the aminoalkylindoles.

Figure 9.

Chemical structure of the biarylpyrazole ligands such as rimonabant and AM251 antagonists.

5.1. In vivo and in vitro

It is known that because cannabinoid receptors, when bound by agonists or antagonists, have the potential to treat a variety of pathologies such as pain, neurodegeneration, obesity, tumors, chemical dependency, and immune function, it is important to develop in vitro bioassays activity determination and the function of these receptors [84]. The in vitro assays established in the studies related to CB1 and CB2 receptors involve the use of membranes or tissues containing these receptors [85]. Of particular note is the assay using radiolabeled CB1 or CB2 receptors with [3H] CP55940 (Figure 10) and bioassays with preparations of nerve-smooth muscle where the ability of the molecule under study to produce inhibition or excitation of cannabinoid receptors is verified [86].

Figure 10.

Chemical structure of the CP55940.

In vitro functional bioassays measure the effects of synthetic cannabinoids and their metabolites in relation to cannabinoid receptor signaling CB1/CB2, evaluating the production of cyclic ATP and elevation of intracellular calcium. In the middle of the last century, initial studies on the effects of cannabinoids used Gayer’s tests (found at the time as a useful test for the effects of THC [87]), where corneal areflexia was measured in rabbits, catatonia in mice, and increased defecation and aggressiveness in rats stressed by REM sleep deprivation [88]. In mice, high-dose catalepsy with Δ9-THC was also observed [95]. In rodents, the main bioassay is the measurement of locomotor activity, rectal temperature, and analgesia (in the tail or hot plate test) [89].

The sum of the various symptoms observed in the initial studies originated characteristic effects in laboratory animals called cannabinoid tetrad and being characterized by hypothermia, analgesia, catalepsy, and locomotor suppression [90]. This tetrad is widely used nowadays because, since the data obtained through its observation are qualitatively consistent, it is common to evaluate the dose-dependence relation of cannabinoids quickly and without any specific training of the animals, a fact that is configured as an advantage [89].

The Δ9-THC dependency/withdrawal modeling studies are based on the cannabinoid tetrad in which The triggered effects are verified with the administration of cannabinoid antagonist (usually rimonabant), and precipitation withdrawal symptoms, being, in general, the synthetic cannabinoids such as UR-144 (Figure 11), responsible to promote effects greater than that of Δ9-THC [91].

Figure 11.

Chemical structure UR-144.

Studies in rats revealed that individual enzyme activity mainly related to the genetic polymorphisms of cytochrome P450 enzymes in the phase I metabolism of cannabinoids has an important role in determining the response of an individual on the use of cannabinoids [92]. Thus, an individual may experience attenuated effects and other individual effects exacerbated by cannabinoids, depending on the liver enzyme profile that favors the formation of antagonistic or agonist metabolites, respectively [93].

Technological refinement has led to the use of new techniques and different experimental models [94] in the studies of compounds in potential for reinforcement, with the search for new targets and biomarkers [95]. Among the experimental models emerges the Danio rerio (Zebrafish), a small fish, because it has the facility of genetic manipulation and the biology of its development [96]. Zebrafish is particularly useful for measuring changes in the development of the nervous system [97], and its measures of sensorimotor plasticity, emotional function, cognition, and social interaction have been used to characterize the adverse effects of drug abuse such as Δ9-THC [98, 99] due to phylogenetic analyzes, which reveal the endocannabinoid system as highly conserved between Zebrafish and mammals [100].

Tolerance and cross-tolerance tests for cannabinoids are also performed in vivo, although studies indicate that not all effects of cannabinoids are developed during these tests, for example, adrenocorticotropic hormone (ACTH) secretion is not observed in rodents during these tests, indicating low reliability and the need for greater improvement in vivo methods used in this sense [101, 102].

5.2. In silico

There are several computational methods; among them, homology modeling is being used in cannabinoid studies [103], considering that the drugs utilized during the withdrawal syndrome of C. sativa act at a symptomatic level. The resolution of the crystalline structure of the CB1cannabinoid receptor is recent [19], and this fact favored in silico studies that evolve toward the planning of molecules that act as selective agonists of this receptor, mainly studies related to better understanding of the interaction and the relation structure-activity of synthetic cannabinoids [104]. A study can be mentioned where computational tools were used, with the objective of proposing drug candidates for the treatment of the abstinence syndrome based on the natural ligands of this receptor. A particular compound derived from marine fungi, stemphol (Figure 12) [105], presented positive predictions regarding pharmacokinetic and toxicological properties for a human CB1 receptor ligand, in addition to having a relatively simple molecular structure. Due to these computational results and the recent crystallographic elucidation of the cannabinoid CB1 receptor [20], experimental studies are being conducted for the development of candidate pharmacotherapeutic alternatives for the treatment of C. sativa withdrawal syndrome [106].

Figure 12.

Chemical structure of Stemphol.


6. Conclusion

Studies on cannabinoids were stimulated after the characterization and structural elucidation of Δ9-THC in the 1960s, and later on, the discovery of the cannabinoid system represented by CB1/CB2 receptors and binding substances to these receptors. Many in vitro, in vivo, and in silico trials have been developed in the last decades, and advances mainly regarding the mechanism of addiction, abuse, and withdrawal syndrome have been achieved. However, with the use of cannabinoid-based drugs and the chemical development of synthetic cannabinoids, further studies into these mechanisms are relevant, especially considering that Δ9-THC is a low-efficacy cannabinoid compared to the “new cannabinoids.”

It is expected in the future that the investigations will deepen the knowledge on the mechanisms of the cannabinoids, especially those that cause chemical dependence, both as cannabinoid system and as noncanabinoid physiological systems. In this way, it is possible to increase the knowledge about the different classes of these substances and, therefore, favor the development of new models and improvement of the tests currently used in the studies related to C. sativa.


  1. 1. Degenhardt L, Chiu WT, Sampson N, Kessler RC, Anthony JC, Angermeyer M, et al. Toward a global view of alcohol, tobacco, cannabis, and cocaine use: Findings from the WHO world mental health surveys. PLoS Medicine. 2008;5(7):1053-1067
  2. 2. Datwyler S, Weiblen GD. Genetic variation in hemp and marijuana (Cannabis sativa L.) according to amplified fragment length polymorphisms. Journal of Forensic Sciences. 2006;51(2):371-375
  3. 3. Di Forti M, Murray RM. Cannabis, skunk and spice: The evolving risk of psychosis. Schizophrenia Studies. 2014;153:S31. Available from:
  4. 4. Lachenmeier DW, Rehm J. Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach. Scientific Reports. 2015;5(1):8126. Available from:
  5. 5. Kerridge BT, Pickering R, Chou P, Saha TD, Hasin DS. DSM-5 cannabis use disorder in the National Epidemiologic Survey on Alcohol and Related Conditions-III: Gender-specific profiles. Addictive Behaviors. 2018;76:52-60. Available from:
  6. 6. Schlienz NJ, Budney AJ, Lee DC, Vandrey R. Cannabis withdrawal: A review of neurobiological mechanisms and sex differences. Current Addiction Reports. 2017;4(2):75-81. Available from:
  7. 7. D’Souza DC, Cortes-Briones JA, Ranganathan M, Thurnauer H, Creatura G, Surti T, et al. Rapid changes in cannabinoid 1 receptor availability in cannabis-dependent male subjects after abstinence from cannabis. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2016;1(1):60-67. Available from:
  8. 8. Bonnet U, Preuss U. The cannabis withdrawal syndrome: Current insights. Substance Abuse and Rehabilitation. 2017;8:9-37. Available from
  9. 9. Hesse M, Thylstrup B. The cannabis withdrawal syndrome-symptoms and time course. In: Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis, and Treatment. London: Elsevier; 2017. pp. 1066-1073. Available from:
  10. 10. Volkow ND, Swanson JM, Evins AE, DeLisi LE, Meier MH, Gonzalez R, et al. Effects of cannabis use on human behavior, including cognition,motivation, and psychosis: A review. JAMA Psychiatry. American Medical Association. 2016;73:292-297. Available from:
  11. 11. De Luca MA, Di Chiara G, Cadoni C, Lecca D, Orsolini L, Papanti D, et al. Cannabis; epidemiological, neurobiological and psychopathological issues: An update. CNS & Neurological Disorders—Drug Targets. 2017;16(5):598-609. Available from:
  12. 12. Hasin DS. US Epidemiology of Cannabis Use and Associated Problems. Neuropsychopharmacology. Vol. 43. New York: Nature Publishing Group; 2018. p. 195-212. Available from:
  13. 13. Awasthi R, An G, Donovan MD, Boles Ponto LL. Relating observed psychoactive effects to the plasma concentrations of delta-9-tetrahydrocannabinol and its active metabolite: An effect-compartment modeling approach. Journal of Pharmaceutical Sciences. 2018;107(2):745-755. Available from:
  14. 14. Dinis-Oliveira RJ. Metabolomics of Delta-9-tetrahydrocannabinol: Implications in Toxicity. Drug Metabolism Reviews. Vol. 48. London: Taylor & Francis; 2016. pp. 80-87. Available from:
  15. 15. Viera AJ, Neutze DM. Diagnosis of secondary hypertension: An age-based approach. American Family Physician. 2010;82(12):1471-1478
  16. 16. Lynch ME, Ware MA. Cannabinoids for the Treatment of Chronic Non-Cancer Pain: An Updated Systematic Review of Randomized Controlled Trials. Journal of Neuroimmune Pharmacology. Vol. 10. Washington: Springer US; 2015. pp. 293-301. Available from:
  17. 17. Panagis G. Cannabinoid reward and dependence: Focus on the main psychoactive ingredients of marijuana in preclinical studies. In: Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis, and Treatment. London: Elsevier; 2017. p. 659-670. Available from:
  18. 18. Bonnet U, Borda T, Scherbaum N, Specka M. Abstinence phenomena of chronic cannabis-addicts prospectively monitored during controlled inpatient detoxification (Part II): Psychiatric complaints and their relation to delta-9-tetrahydrocannabinol and its metabolites in serum. Drug and Alcohol Dependence. 2015;155:302-306. Available from:
  19. 19. Hua T, Vemuri K, Pu M, Qu L, Han GW, Wu Y, et al. Crystal structure of the human cannabinoid receptor CB1. Cell. 2016;167(3):750-762.e14
  20. 20. Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, et al. High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature. 2016;540(7634):1-20. Available from:
  21. 21. Song ZH, Slowey CA, Hurst DP, Reggio PH. The difference between the CB(1) and CB(2) cannabinoid receptors at position 5.46 is crucial for the selectivity of WIN55212-2 for CB(2). Molecular Pharmacology. 1999;56(4):834-840. Available from:
  22. 22. Sierra S, Luquin N, Rico AJ, Gómez-Bautista V, Roda E, Dopeso-Reyes IG, et al. Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: Changes following experimental parkinsonism. Brain Structure and Function. 2015;220(5):2721-2738. Available from:
  23. 23. Onaivi ES, Ishiguro H, Liu Q-R. Cannabinoid CB2 receptor mechanism of Cannabis sativa L. In: Cannabis sativa L—Botany and Biotechnology. Cham: Springer International Publishing; 2017. pp. 227-247. Available from:
  24. 24. Zhang P-W, Ishiguro H, Ohtsuki T, Hess J, Carillo F, Walther D, et al. Human cannabinoid receptor 1: 5′ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Molecular Psychiatry. 2004;9(10):916-931
  25. 25. Araque A, Castillo PE, Manzoni OJ, Tonini R. Synaptic functions of endocannabinoid signaling in health and disease. Neuropharmacology. 2017;124:13-24. DOI: 10.1016/j.neuropharm.2017.06.017
  26. 26. Sido JM, Nagarkatti PS, Nagarkatti M. Role of Endocannabinoid Activation of Peripheral CB1 Receptors in the Regulation of Autoimmune Disease. International Reviews of Immunology. Vol. 34. London, New York: Informa Healthcare; 2015. pp. 403-414. Available from:
  27. 27. Verdurand M, Nguyen V, Stark D, Zahra D, Gregoire MC, Greguric I, et al. Comparison of cannabinoid CB(1) receptor binding in adolescent and adult rats: A positron emission tomography study using [F]MK-9470. International Journal of Molecular Imaging. 2011;2011:548123. Available from:
  28. 28. Mallipeddi S, Janero DR, Zvonok N, Makriyannis A. Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets. Biochemical Pharmacology. 2017;128:1-11. DOI: 10.1016/j.bcp.2016.11.014
  29. 29. Howlett AC. International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacological Reviews. 2002;54(2):161-202. Available from:
  30. 30. Howlett AC. Cannabinoid inhibition of adenylate cyclase. Biochemistry of the response in neuroblastoma cell membranes. Molecular Pharmacology. 1985;27(4):429-436
  31. 31. Mu J, Zhuang SY, Hampson RE, Deadwyler SA. Protein kinase-dependent phosphorylation and cannabinoid receptor modulation of potassium A current (IA) in cultured rat hippocampal neurons. Pflügers Archiv: European Journal of Physiology. 2000;439(5):541-546. Available from:
  32. 32. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410(6824):37-40
  33. 33. Abbott LF, Nelson SB. Synaptic plasticity: Taming the beast. Nature Neuroscience. 2000;3(November):1178-1183
  34. 34. Augustin SM, Lovinger DM. Functional relevance of endocannabinoid-dependent synaptic plasticity in the central nervous system. ACS Chemical Neuroscience. 2018;9(9):2146-2161. Available from:
  35. 35. Auclair N, Otani S, Soubrie P, Crepel F. Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons. Journal of Neurophysiology. 2000;83(6):3287-3293
  36. 36. Lile JA, Fogel JS, Kelly TH. The role of γ-aminobutyric acid in the interoceptive effects of oral Δ9-tetrahydrocannabinol in humans. In: Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis, and Treatment. London: Elsevier; 2017. pp. 770-778. Available from:
  37. 37. Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47:345-358. Available from:
  38. 38. Volk DW, Lewis DA. The Role of Endocannabinoid Signaling in Cortical Inhibitory Neuron Dysfunction in Schizophrenia. Biological Psychiatry. Vol. 79. London: Elsevier; 2016. pp. 595-603. Available from:
  39. 39. Davies SN, Pertwee RG, Riedel G. Functions of cannabinoid receptors in the hippocampus. Neuropharmacology. 2002;42(8):993-1007
  40. 40. Beinfeld MC, Connolly K. Activation of CB1 cannabinoid receptors in rat hippocampal slices inhibits potassium-evoked cholecystokinin release, a possible mechanism contributing to the spatial memory defects produced by cannabinoids. Neuroscience Letters. 2001;301(1):69-71
  41. 41. Smith GP, Jerome C, Cishing BJ, Eterno R, Simansky KJ. Abdominal vagotomy blockes the satiety effct of cholecystokinin in the rat. Science. 1981;213(13):1036-1037
  42. 42. Zhang X, Feng ZJ, Chergui K. Induction of cannabinoid- and N-methyl-d-aspartate receptor-mediated long-term depression in the nucleus accumbens and dorsolateral striatum is region and age dependent. International Journal of Neuropsychopharmacology. 2014;18(4):1-9. Available from:
  43. 43. Demuth DG, Molleman A. Cannabinoid signalling. Life Sciences. 2006;78(6):549-563
  44. 44. Lu HC, MacKie K. An introduction to the endogenous cannabinoid system. Biological Psychiatry. 2016;79(7):516-525. DOI: 10.1016/j.biopsych.2015.07.028
  45. 45. Gómez-Gálvez Y, Palomo-Garo C, Fernández-Ruiz J, García C. Potential of the cannabinoid CB2 receptor as a pharmacological target against inflammation in Parkinson’s disease. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2016;64:200-208. DOI: 10.1016/j.pnpbp.2015.03.017
  46. 46. Di Marzo V, Stella N, Zimmer A. Endocannabinoid signalling and the deteriorating brain. Nature Reviews Neuroscience. 2015;16(1):30-42. DOI: 10.1038/nrn3876
  47. 47. Bossong MG, van Hell HH, Jager G, Kahn RS, Ramsey NF, Jansma JM. The endocannabinoid system and emotional processing: A pharmacological fMRI study with {increment}9-tetrahydrocannabinol. European Neuropsychopharmacology. 2013;23(12):1687-1697. DOI: 10.1016/j.euroneuro.2013.06.009
  48. 48. Degenhardt L, Stockings E, Patton G, Hall WD, Lynskey M. The Increasing Global Health Priority of Substance Use in Young People. The Lancet Psychiatry. Vol. 3. London: Elsevier; 2016. pp. 251-264. Available from:
  49. 49. Davis JP, Smith DC, Morphew JW, Lei X, Zhang S. Cannabis withdrawal, posttreatment abstinence, and days to first cannabis use among emerging adults in substance use treatment: A prospective study. Journal of Drug Issues. 2016;46(1):64-83. Available from:
  50. 50. Blanco C, Hasin DS, Wall MM, Flórez-Salamanca L, Hoertel N, Wang S, et al. Cannabis use and risk of psychiatric disorders. JAMA Psychiatry. 2016;73(4):388. Available from:
  51. 51. Hirvonen J, Goodwin RS, Li CT, Terry GE, Zoghbi SS, Morse C, et al. Reversible and regionally selective downregulation of brain cannabinoid CB1receptors in chronic daily cannabis smokers. Molecular Psychiatry. 2012;17(6):642-649. Available from:
  52. 52. Miller NS, Oberbarnscheidt T, Gold MS. Marijuana addictive disorders and DSM-5 substance-related disorders. Journal of Addiction Studies & Therapy. 2017;11:2-8. Available from:
  53. 53. Brezing CA, Levin FR. The Current State of Pharmacological Treatments for Cannabis Use Disorder and Withdrawal. Neuropsychopharmacology. Vol. 43. New York: Nature Publishing Group; 2018. pp. 173-194. Available from:
  54. 54. Herrmann ES, Weerts EM, Vandrey R. Sex differences in cannabis withdrawal symptoms among treatment-seeking cannabis users. Experimental and Clinical Psychopharmacology. 2015;23(6):415-421. Available from:
  55. 55. Budney AJ, Hughes JR, Moore BA, Vandrey R. Review of the validity and significance of cannabis withdrawal syndrome. American Journal of Psychiatry. 2004;161(11):1967-1977
  56. 56. De Aquino JP, Sherif M, Radhakrishnan R, Cahill JD, Ranganathan M, D’Souza DC. The psychiatric consequences of cannabinoids. Clinical Therapeutics. 2018;40(9):1448-1456. Available from:
  57. 57. Virani A, Bezchlibnyk-Butler K. Clinical Handbook of Psychotropic Drugs. 2012. 431 p. Available from:,+depression,+and+irritability%3B+decrease+in+sleep+
  58. 58. Zehra A, Burns J, Liu CK, Manza P, Wiers CE, Volkow ND, et al. Cannabis addiction and the brain: A review. Journal of Neuroimmune Pharmacology. 2018;13(4):438-452. Available from:
  59. 59. Jacobus J, Squeglia LM, Escobar S, McKenna BM, Hernandez MM, Bagot KS, et al. Changes in marijuana use symptoms and emotional functioning over 28-days of monitored abstinence in adolescent marijuana users. Psychopharmacology. 2017;234(23-24):3431-3442. Available from:
  60. 60. Hines LA, Morley KI, Strang J, Agrawal A, Nelson EC, Statham D, et al. Onset of opportunity to use cannabis and progression from opportunity to dependence: Are influences consistent across transitions? Drug and Alcohol Dependence. 2016;160:57-64. Available from:
  61. 61. Panlilio LV, Goldberg SR, Justinova Z. Cannabinoid Abuse and Addiction: Clinical and Preclinical Findings. Clinical Pharmacology and Therapeutics. Vol. 97. Hoboken: Wiley-Blackwell; 2015. pp. 616-627. Available from:
  62. 62. Crippa JAS, Hallak JEC, Machado-de-Sousa JP, Queiroz RHC, Bergamaschi M, Chagas MHN, et al. Cannabidiol for the treatment of cannabis withdrawal syndrome: A case report. Journal of Clinical Pharmacy and Therapeutics. 2013;38(2):162-164. Available from:
  63. 63. Lutz B, Marsicano G, Maldonado R, Hillard CJ. The Endocannabinoid System in Guarding Against Fear, Anxiety and Stress. Nature Reviews Neuroscience. Vol. 16. New York: Nature Publishing Group; 2015. pp. 705-718. Available from:
  64. 64. Haney M, Cooper ZD, Bedi G, Herrmann E, Comer SD, Reed SC, et al. Guanfacine decreases symptoms of cannabis withdrawal in daily cannabis smokers. Hoboken. Addiction Biology. 2018:23. DOI: 10.1111/adb.12621
  65. 65. Bedi G, Foltin RW, Gunderson EW, Rabkin J, Hart CL, Comer SD, et al. Efficacy and tolerability of high-dose dronabinol maintenance in HIV-positive marijuana smokers: A controlled laboratory study. Psychopharmacology. 2010;212(4):675-686. Available from:
  66. 66. Herrmann ES, Cooper ZD, Bedi G, Ramesh D, Reed SC, Comer SD, et al. Effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory model of relapse in cannabis users. Psychopharmacology. 2016;233(13):2469-2478. Available from:
  67. 67. Mendiguren A, Aostri E, Pineda J. Regulation of noradrenergic and serotonergic systems by cannabinoids: Relevance to cannabinoid-induced effects. Life Sciences. 2018;192(July):115-127. Available from:
  68. 68. Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW. Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacology. 2008;197(1):157-168. Available from:
  69. 69. Levin FR, Mariani JJ, Pavlicova M, Brooks D, Glass A, Mahony A, et al. Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial. Drug and Alcohol Dependence. 2016;159:53-60. DOI: 10.1016/j.drugalcdep.2015.11.025
  70. 70. Mathai DS, Holst M, Rodgman C, Haile CN, Keller J, Hussain MZ, et al. Guanfacine attenuates adverse effects of dronabinol (THC) on working memory in adolescent-onset heavy cannabis users: A pilot study. The Journal of Neuropsychiatry and Clinical Neurosciences. 2017;30(1):66-76. Available from:
  71. 71. Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, Sadler C, et al. Nabiximols as an agonist replacement therapy during cannabis withdrawal: A randomized clinical trial. JAMA Psychiatry. 2014;71(3):281-291
  72. 72. Elmes MW, Kaczocha M, Berger WT, Leung KN, Ralph BP, Wang L, et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Journal of Biological Chemistry. 2015;290(14):8711-8721. Available from:
  73. 73. Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics. Vol. 12. Washington: Springer US; 2015. pp. 825-836. Available from:
  74. 74. Burstein S. Cannabidiol (CBD) and its analogs: A review of their effects on inflammation. Bioorganic and Medicinal Chemistry. 2015;23(7):1377-1385. DOI: 10.1016/j.bmc.2015.01.059
  75. 75. Trigo JM, Lagzdins D, Rehm J, Selby P, Gamaleddin I, Fischer B, et al. Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings. Drug and Alcohol Dependence. 2016;161:298-306. Available from:
  76. 76. Hillard CJ. Cannabinoids and endocannabinoids. In: Encyclopedia of Psychopharmacology. Berlin, Heidelberg: Springer Berlin Heidelberg; 2015. pp. 329-336. Available from:
  77. 77. Becker JAJ, Kieffer BL, Le Merrer J. Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol. Addiction Biology. 2017;22(5):1205-1217. Available from:
  78. 78. Befort K. Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies. Frontiers in Pharmacology. Vol. 6. Strasbourg: Frontiers; 2015. p. 6. Available from:
  79. 79. Haney M, Ramesh D, Glass A, Pavlicova M, Bedi G, Cooper ZD. Naltrexone maintenance decreases cannabis self-administration and subjective effects in daily cannabis smokers. Neuropsychopharmacology. 2015;40(11):2489-2498. Available from:
  80. 80. Janero DR, Makriyannis A. Terpenes and Lipids of the Endocannabinoid and Transient-receptor-potential-channel Biosignaling Systems. ACS Chemical Neuroscience. Vol. 5. Washington: American Chemical Society; 2014. pp. 1097-1106. Available from:
  81. 81. Varga B, Kassai F, Szabó G, Kovács P, Fischer J, Gyertyán I. Pharmacological comparison of traditional and non-traditional cannabinoid receptor 1 blockers in rodent models in vivo. Pharmacology Biochemistry and Behavior. 2017;159(December):24-35. DOI: 10.1016/j.pbb.2017.06.012
  82. 82. Koller VJ, Ferk F, Al-Serori H, Mišík M, Nersesyan A, Auwärter V, et al. Genotoxic properties of representatives of alkylindazoles and aminoalkyl-indoles which are consumed as synthetic cannabinoids. Food and Chemical Toxicology. 2015;80:130-136. DOI: 10.1016/j.fct.2015.03.004
  83. 83. Dang D-K, Shin E-J, Mai A-T, Jang C-G, Nah S-Y, Jeong JH, et al. Genetic or pharmacological depletion of cannabinoid CB1 receptor protects against dopaminergic neurotoxicity induced by methamphetamine in mice. Free Radical Biology and Medicine. 2017;108(October):204-224. DOI: 10.1016/j.freeradbiomed.2017.03.033
  84. 84. Husni AS, McCurdy CR, Radwan MM, Ahmed SA, Slade D, Ross SA, et al. Evaluation of phytocannabinoids from high-potency Cannabis sativa using in vitro bioassays to determine structure-activity relationships for cannabinoid receptor 1 and cannabinoid receptor 2. Medicinal Chemistry Studies. 2014;23(9):4295-4300.Available from:
  85. 85. Pertwee R. Pharmacological actions of cannabinoids. European Neuropsychopharmacology. 2010;20:S205. Available from:
  86. 86. Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: An overview. International Journal of Obesity. 2006;30:S13-S18. Available from:
  87. 87. Carlini EA, Santos M, Claussen U, Bieniek D, Korte F. Structure activity relationship of four tetrahydrocannabinols and the pharmacological activity of five semi-purified extracts of Cannabis sativa. Psychopharmacologia. 1970;18(1):82-93. Available from:
  88. 88. Karniol IG, Carlini EA. Pharmacological interaction between cannabidiol and δ9-tetrahydrocannabinol. Psychopharmacologia. 1973;33(1):53-70. Available from:
  89. 89. Järbe TUC, Gifford RS. “Herbal Incense”: Designer Drug Blends as Cannabimimetics and Their Assessment by Drug Discrimination and Other In Vivo Bioassays. Life Sciences. Vol. 97. London: Pergamon; 2014. pp. 64-71. Available from:
  90. 90. Gurney SMR, Scott KS, Kacinko SL, Presley BC, Logan BK, Grove W. Pharmacology, toxicology, and adverse effects of synthetic cannabinoid drugs pharmacology, toxicology, and adverse effects of synthetic cannabinoid drugs. Forensic Science Review. 2014;26(1):53-78. Available from:
  91. 91. Kaizaki-Mitsumoto A, Hataoka K, Funada M, Odanaka Y, Kumamoto H, Numazawa S. Pyrolysis of UR-144, a synthetic cannabinoid, augments an affinity to human CB1 receptor and cannabimimetic effects in mice. The Journal of Toxicological Sciences. 2017;42(3):335-341. Available from:
  92. 92. Zelasko S, Arnold WR, Das A. Endocannabinoid Metabolism by Cytochrome P450 Monooxygenases. Prostaglandins and Other Lipid Mediators. Vol. 116-117. London: Elsevier; 2015. pp. 112-123. Available from:
  93. 93. Tai S, Fantegrossi WE. Synthetic cannabinoids: Pharmacology, behavioral effects, and abuse potential. Current Addiction Reports. 2014;1(2):129-136. Available from:
  94. 94. Doke SK, Dhawale SC. Alternatives to animal testing: A review. Saudi Pharmaceutical Journal: SPJ: The Official Publication of the Saudi Pharmaceutical Society. 2015;23(3):223-229. Available from:
  95. 95. Anderson DC, Kodukula K. Biomarkers in pharmacology and drug discovery. Biochemical Pharmacology. 2014;87(1):172-188. DOI: 10.1016/j.bcp.2013.08.026
  96. 96. Kamstra JH, Aleström P, Kooter JM, Legler J. Zebrafish as a model to study the role of DNA methylation in environmental toxicology. Environmental Science and Pollution Studies. 2015;22(21):16262-16276
  97. 97. Bailey J, Oliveri A, Levin ED. Zebrafish model systems for developmental neurobehavioral toxicology. Birth Defects Studies Part C—Embryo Today: Reviews. 2013;99(1):14-23
  98. 98. Oltrabella F, Melgoza A, Nguyen B, Guo S. Role of the endocannabinoid system in vertebrates: Emphasis on the zebrafish model. Development Growth and Differentiation. 2017;59(4):194-210
  99. 99. Krug RG, Clark KJ. Elucidating cannabinoid biology in zebrafish (Danio rerio). Gene. 2015;570(2):168-179. DOI: 10.1016/j.gene.2015.07.036
  100. 100. Klee EW, Schneider H, Clark KJ, Cousin MA, Ebbert JO, Hooten WM, et al. Zebrafish: A model for the study of addiction genetics. Human Genetics. 2012;131(6):977-1008. Available from:
  101. 101. Hillard CJ. Endocannabinoids and the endocrine system in health and disease. In: Endocannabinoids. Cham: Springer; 2015. pp. 317-339. Available from:
  102. 102. Panlilio LV, Justinova Z. Preclinical Studies of Cannabinoid Reward, Treatments for Cannabis Use Disorder, and Addiction-Related Effects of Cannabinoid Exposure. Neuropsychopharmacology. Vol. 43. New York: Nature Publishing Group; 2018. pp. 116-141. Available from:
  103. 103. Singh P, Ganjiwale A, Howlett AC, Cowsik SM. In silico interaction analysis of cannabinoid receptor interacting protein 1b (CRIP1b)—CB1 cannabinoid receptor. Journal of Molecular Graphics and Modelling. 2017;77:311-321. Available from:
  104. 104. Paulke A, Proschak E, Sommer K, Achenbach J, Wunder C, Toennes SW. Synthetic cannabinoids: In silico prediction of the cannabinoid receptor 1 affinity by a quantitative structure-activity relationship model. Toxicology Letters. 2016;245:1-6. Available from:
  105. 105. Xu J, Liu P, Li X, Gan L, Wang P. Novel stemphol derivatives from a marine fungus Pleospora sp. Natural Product Studies. 2018;32:1-7. Available from:
  106. 106. Ferreira JV, Chaves GA, Marino BLB, Sousa KPA, Souza LR, Brito MFB, et al. Cannabinoid type 1 receptor (CB1) ligands with therapeutic potential for withdrawal syndrome in chemical dependents of Cannabis sativa. ChemMedChem. 2017;12(16):1408-1416

Written By

Jaderson Vieira Ferreira, Lenir Cabral Correa, Daniel Castro da Costa and Lorane Izabel da Silva Hage-Melim

Submitted: 18 June 2018 Reviewed: 22 October 2018 Published: 19 December 2018