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Endocannabinoids as Therapeutic Targets
Archives of Medical Research 50 (2019) 518e526
REVIEW ARTICLE
Endocannabinoids as Therapeutic Targets Oscar Prospero-Garcıa,a Alejandra E. Ruiz Contreras,b Alette Ortega G omez,c Andrea Herrera-Solıs,d Monica Mendez-Dıaz,a and Grupo de Neurociencias de la Universidad Nacional Aut onoma de Mexico a
Departamento de Fisiologıa, Laboratorio de Canabinoides, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico b Laboratorio de Neurogenomica Cognitiva, Facultad de Psicologıa, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico c Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerologıa, Ciudad de Mexico, Mexico d Laboratorio Efectos Terapeuticos de los Canabinoides, Subdireccion de Investigacion Biomedica, Hospital General Dr. Manuel Gea Gonzalez, Ciudad de Mexico, Mexico Received for publication April 30, 2019; accepted September 30, 2019 (ARCMED_2019_385).
Most of the drugs of abuse affect the brain by interacting with naturally expressed molecular receptors. Marihuana affects a series of receptors including cannabinoid receptor 1 (CB1R) and CB2R, among others. Endogenous molecules with cannabinoid activity interact with these receptors naturally. Receptors, ligands, synthesizing and degrading enzymes, as well as transporters, have been described. This endocannabinoid system modulates behaviors and physiological processes, i.e. food intake, the sleep-waking cycle, learning and memory, motivation, and pain perception, among others. The rather broad distribution of endocannabinoids in the brain explains the different effects marihuana induces in its users. However, this very same anatomical and physiological distribution makes this system a useful target for therapeutic endeavors. In this review, we briefly discuss the potential of small molecules that target the endocannabinoids as therapeutic tools to improve behaviors and treat illnesses. We believe that under medical supervision, endocannabinoid targets offer new advantages for patients for controlling multiple medical disorders. Ó 2019 IMSS. Published by Elsevier Inc. Key Words: Cannabinoids, Endocannabinoids, Therapeutic properties, Sleep, Epilepsy, Pain, Learning and memory.
Marihuana affects the brain by interacting with a series of naturally expressed receptors including cannabinoid receptor 1 (CB1R) and CB2R. Endogenous molecules with cannabinoid activity interact with these receptors naturally. Similarly, receptors, ligands, synthesizing and degrading enzymes, as well as transporters, have been described. This endocannabinoid (eCB) system modulates behaviors and physiological processes, that is food intake, the sleepwaking cycle, learning and memory, motivation, and pain perception, among others. The rather broad distribution of endocannabinoids in the brain explains the different effects marihuana induces in its users. This anatomical distribution and physiological effects make this system a useful target for therapeutic endeavors. In this review, we briefly discuss
Address reprint requests to: Oscar Prospero-Garcıa, Departamento de Fisiologıa, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Apdo. Postal 70-250, Ciudad de Mexico, 04510 Mexico; Phone: (þ52) 55 255 623 2509; FAX: (þ52) 55 2585 5623 2241.; E-mail: opg@ unam.mx
how some molecules that target the eCB system under medical supervision are potential therapeutic tools to improve behaviors and treat illnesses. Since the isolation and structural description of D9tetrahydrocannabinol (THC), the main psychoactive component of marihuana (Cannabis sativa) in 1964 (1), knowledge on how marihuana causes its effects in the user has expanded exponentially. Howlett’s suggestion of the existence of a receptor to which THC binds (2), ignited the search for endogenous molecules. In 1992, Mechoulam’s group isolated anandamide (AEA) from pig brain (3). In 1994, oleamide (ODA), another endocannabinoid was isolated from the cerebrospinal fluid of sleep-deprived cats (4). In the same year, Mechoulam’s group isolated 2 arachydonoylglycerol (2-AG) from dog intestine (5) (Table 1). Few years after CB1R was cloned (6), CB2R were characterized (6,7). Enzymes that participate in the synthesis and breakdown of endocannabinoids have also been identified, and the existence of an endocannabinoid transporter has been suggested (8). All this information has led to
0188-4409/$ - see front matter. Copyright Ó 2019 IMSS. Published by Elsevier Inc. https://doi.org/10.1016/j.arcmed.2019.09.005
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Table 1. Endogenous cannabinoids (endocannabinoids) and related compounds Endocannabinoids and related compounds
Common name
N-arachidonylethanolamine 2-arachidonoyl-glycerol Cis-9,10 octadecenamide N-palmitoyl ethanolamine N-oleoyl ethanolamine 2-Arachidonoylglyceryl ether O-arachidonoylethanolamine N-Arachidonoyl-Dopamine
Anandamide 2-AG Oleamide PEA OEA Noladin ether Virodhamine NADA
expectations of cannabinoid-based therapies for treatment of several illnesses and drug-dependence (Table 2). In the following section, we discuss some evidence supporting the potential use of the facilitation or blockade of endocannabinoids to improve behaviors and illnesses.
Therapeutic Properties Ritual use of marihuana have been suggested by remains of seeds and leaves found in China next to a human skeleton which was estimated to be 10 thousand years old (9). It has been speculated that marihuana has been used to cure or control several diseases such as inflammation and pain, anxiety, depression and psychosis, fatigue and insomnia, loss of appetite and digestive disorders, such as: nausea, diarrhea, and constipation, among others (10). Both marihuana and THC have been used to lower elevated intraocular pressure (glaucoma) (11). Similarly, the manipulation of endogenous cannabinoids may be useful for the control of drug addiction (12). THC has been useful in asthma and as an analgesic (13). Many of these alleged effects are still under investigation. Comparably, Cannabidiol (CBD) seems to have properties to control epilepsy (14), and in combination with THC to control pain (15).
Functional properties at cannabinoid receptors Partial CB1R agonist, Weak CB2R agonist. Sleep and food intake inducer Full CB1R and CB2R agonist. Sleep and food intake inducer Weak CB1R, CB2R agonist. Sleep and food intake inducer PPAR-a agonist It inhibits the expression of FAAH TRPV1 agonist PPARa agonist. Waking and anorexia inducer CB1R agonist Partial CB2R agonist and CB1R antagonist CB1R agonist and potent TRPV1 agonist
Marihuana is classified as a schedule I substance by the U.S. Drug Enforcement Administration (DEA), indicating that marihuana is a drug with high potential for abuse. However, THC and a synthetic analog of THC (Dronabinol) have been approved by the Food and Drug Administration (FDA) for patients suffering from serious, chronic, or debilitating medical conditions. THC itself or THC analogs, as Dronabinol, are approved for treatment of the severe nausea and vomiting associated with cancer chemotherapy (16); weight loss associated with debilitating illnesses, such as HIV infection or cancer (17); spasticity associated with neurological diseases, such as multiple sclerosis and diseases accompanied by intense pain and glaucoma (18). Otherwise, any physician prescribing marihuana for diseases different from the above mentioned is committing a crime in the USA and in other countries. In Mexico, the law is so permissive that those physicians that are prescribing raw marijuana extracts to treat patients do not have to face legal charges. In the vast majority of countries, it is definitely illegal to even suggest marihuana use. On the other hand, the information indicating that California, USA, has an estimated 100,000 users of medical marihuana is absolutely fascinating. Some of them claim to use marihuana for medical conditions, but they may be faking the disease to obtain marihuana for recreational purposes.
Table 2. Synthetic cannabinoids Compound
Characteristics
CP-55940 HU-210 WIN55,212-2 JWH-133 URB597 (KDS-4103) AM251 AM404 SR144528
CB1R agonist. Highly psychoactive. 40 times more potent than THC CB1R full agonist. 100 times more potent than THC CB1R agonist CB2R agonist FAAH selective inhibitor CB1R antagonist. Potential anti-hypersomnia aid Endogenous cannabinoid reuptake inhibitor, Vanilloid receptor agonist. CB2R antagonist
Therapeutic Compound Dronabinol (Marinol)
Use THC analog. Prescribed as an appetite stimulant for patients with AIDS, chemotherapy and gastric bypass patients. Antiemetic. Potential sleep inducer and pain killer THC analog. Antiemetic and analgesic. Potential sleep inducer and pain killer CB1R Inverse agonist. Anorectic anti-obesity. Prescribed for patients with body mass index greater than 30 kg/m2 or 27 kg/m2 associated to risk factor. Potential anti-hypersomnia aid THC and CBD analog, used for neuropathic pain of multiple sclerosis
Nabilone (Cesament) Rimonabant (SR141716A, Complain, Riobant, Slimona) Sativex
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Addiction and pathology associated with marijuana abuse Some studies indicate that increasing endocannabinoids by inhibiting their breakdown enzymes prevent alcohol, nicotine or even heroin reinstatement (19e21). In contrast, some other studies relate endocannabinoids and motivation and drug dependence (12,22), that is it has been observed that CB1R blockade may prevent development of drug-seeking behavior and reinstatement in rats and mice. However, CB1R blockade in humans, may induce negative emotional effects. Regarding CB2R, its activation inhibits cocaine self-administration (23); however, CB2R KO mice do not develop nicotine-induced conditioned place preference (CPP) (24). These dissimilar effects seem to be parts of the same puzzle that are, at present time, difficult to conciliate. Further studies will shed light to this contradiction. Regarding the effects of marijuana chronic use, deleterious effects have been consistently reported. Therefore, the Diagnostic and Statistical Manual of Mental Disorders V (DSM, American Psychiatric Association, APA, 2013) includes a description of marijuana dependence syndrome (25). Marijuana tolerance and dependence (26) includes anxiety, irritability, insomnia, hyporexia, restlessness, and an intense desire for consuming marijuana (craving), after 24e74 h of abstinence. In addition, marijuana users have several brain structural changes, that is reduction in the hippocampus, amygdala, nucleus accumbens and prefrontal cortex, and a reduction of their connections, when they consume it before they were 20 years of age (27e29). Similarly, some studies have suggested a reduction in the Intelligence Quotient (IQ) (30,31), while other studies revealed that marijuana induces the first psychotic or bipolar outbreak in susceptible users (32). Due to these considerations, although marijuana derivatives may have some medicinal properties, it is advisable that their use must be subjected to strict medical supervision.
Food Intake Two or three marihuana joints increase average daily caloric intake, mostly as in between-meal snacks that cause an increase in meal size per se. An increase in body weight was also observed (33,34). THC increases food intake in satiated rats (35); however, they consume sweet more than less palatable foods (36). Free-feeding rats receiving THC increase their high-fat and high-fat sweetened food intake (37). Complementary, SR141716A (rimonabant, a CB1R antagonist) induces anorectic effects (38). Hence, cannabinoids effects on food intake occur through the activation of the CB1R. This finding opens the possibility to use these kinds of drugs as pharmacological tools in the treatment of obesity, see rimonabant in obesity (RIO) study by Van Gaal (38). Volunteers in this study developed psychiatric symptoms that led to the suspension, not only of the study,
but of the commercial availability of rimonabant. The main psychiatric symptoms rimonabant induced, according to the Food and Drug Administration report (2007), were anxiety (more than 3% with 5 mg and more than 6% with 20 mg), insomnia (almost 3% with 5 mg and more than 5% with 20 mg), depressed mood (almost 3% with 5 mg, almost 4% with 20 mg), depression (more than 2% with 5 mg and more than 3% with 20 mg), and several other minor problems were also observed. CB2R exhibits a role opposite to CB1R role. Some data support obesity leads to increased expression of the CB2R, in both adipose tissue and liver, in high-fat fed and ob/ob mice (39). While CB2R deficiency prevents body weight gain during the feeding of a high-fat diet and obesityassociated inflammation, insulin resistance and fatty liver (40). It should be noted that unlike CB1R the activation of CB2R reduces VTA DA-neurons firing, suggesting that these receptors may be a therapeutic target in obesity without affecting hedonism.
eCB System also Regulate Food Intake ODA, AEA and 2-AG increase food intake in rats (41e43), By acting on brain structures like the hypothalamus and the nucleus accumbens (44e46). Rats exhibit CPP induced by regular Lab Chow food, but CPP is stronger when they are under the effect of OLE or AEA. Such CPP is prevented by CB1 inverse agonist AM251, suggesting that OLE and AEA increase the food palatability (47). Hence, CB1R seems to mediate in part the liking phase of reward. Moreover, endocannabinoids increase its levels in a close relationship with feeding (48). AEA, AA5HT (FAAH inhibitor) and OMDM-1 (AEA reuptake inhibitor) increase AEA and 2-AG levels in the NAc, while inducing hypothalamic nuclei activation and food intake (46). All these effects were prevented by AM251 (46). This study opens a potential avenue to target endocannabinoid-breakdown molecules for treatment of eating disorders.
Sleep Users report, anecdotally, that marihuana induces drowsiness or sleepiness. Babor TF, et al. (49) observed that moderate to heavy marihuana use induced better sleep during the days following the consumption. Regrettably, heavy use of marihuana may trigger anxiety crises, and psychotic outbreaks, complicating its use to induce sleep (50). Both ODA and AEA increase sleep, particularly REM sleep, in rats. One single dose of either systemic ODA or intra lateral hypothalamus 2-AG increases REM sleep. Intracerebroventricular infusion of either ODA or 2-AG increases REM sleep after one single dose or after 15 d of daily administration, see review (51). Moreover, both ODA and 2-AG
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increase NREM and REM sleep in a rodent model of insomnia (52,53). Congruently, Santucci V, et al. (54) reported that SR141716A increases wakefulness. Similarly, fatty-acid amide hydrolase (FAAH)-knockout (KO) mice (FAAH hydrolyzes AEA and ODA) exhibit more NREM sleep compared to their wild type (WT) littermates (55). While CB1R-KO mice spent more time in W than their WT littermates (56,57). In humans, the FDA metaanalysis (2007) of the RIO Europe study (38) emphasized that more than 5% of the volunteers receiving rimonabant (20 mg) developed insomnia. These findings complement those obtained in animal models, and further support the notion that the facilitation of the eCB system may improve sleep in insomniac patients. Regarding Cannabidiol (CBD), it is one of the main components of Cannabis sativa, that antagonizes the binding of CB1 and CB2 receptor agonists (58). At first, it was reported that CBD decreased the latency to sleep onset, while increasing duration of non-rapid-eye-movement (NREM) sleep (59). Chagas MH, et al. 2013 (60), reported an increase in the total amount of sleep in rats during the light phase. Conversely, some other studies reported that CBD increased waking and decreased REM sleep, leaving NREM sleep unchanged (61,62). Some studies have reported that CBD (600 mg) induced sedative effects in healthy volunteers (63); while some others have shown that low doses of CBD (15 mg/d) combined with THC (15 mg/d) increased wakefulness while reducing NREM sleep stage 3 (64). An absence of effects have also been reported in healthy subjects with 300 mg of 99% pure CBD (65). Unfortunately, the experimental evidence do not support CBD sleep inducer. As an additional note, Nabilone, a synthetic CB1R agonist, has exhibited sleep-promoting effects in patients suffering from fibromyalgia, very possible by reducing pain (66).
Learning and Memory The effect of marihuana and endocannabinoids on learning and memory has been studied intensively (67e69). Hence, it is now accepted that endocannabinoids play a crucial role in the modulation of cognitive processes (70). The CB1R mediates the impairing effect induced by cannabinoids on memory. CB1R is widely expressed in memory systems, such as in the hippocampus (71). Rats under THC effects performed worse than vehicle rats in a working memory (WM) task (72). CB1R agonists reduce hippocampal neurons firing rate during encoding and delay period in WM in rats (73). In contrast, CB1R knock-out mice were able to learn the Morris water maze, albeit increasing perseverance errors after the platform position was changed (69), suggesting that CB1R participates in extinguishing memories and updating new information in WM. Congruently, SR141716A prevents THC-induced
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deficits on working and short-term memory in rats and mice (74). Terranova JP, et al. (75) described that SR141716A facilitates memory formation (76), and delays the extinction of fear conditioning (77). Cannabis users have shown an impairment in memory tasks performance (78,79). THC induces WM deficiency while reducing the activity of the dorsolateral prefrontal cortex, posterior parietal cortex, anterior cingulate and temporal cortices (80). Moreover, a reduction of BOLD signal at the posterior parietal cortex was detected in adults with early onset of cannabis use when performing a working memory task, even if subjects smoked only a few times, as long as it was at early age (81). Contrasting studies have failed to document memory deficiency in cannabis users (82,83), promoting controversy regarding cannabis effects on memory (84,85). It should be considered that THC negative effect on memory can be attenuated by CBD (86). Studies in rats have suggested that cannabis effect in memory in humans could depend on doses (87), that is THC low doses (3 mg/kg) disrupts WM performance, whereas high doses (10 mg/kg) affects spatial reference memory in mice (88). In rats, a semichronic (7d) and chronic (21d) THC administration induced hippocampal neurogenesis and upregulation of brain-derived neurotrophic factor, while inducing a better performance in short-term and long-term memory novelrecognition tasks (89). Subjects genetic variation on cognitive performance should be considered, too (90e92), that is polymorphisms of the CNR1, gene which codes for CB1R, have been associated with differential efficiency in WM and attentional control in healthy subjects (90,91). It is possible that some genotypes are less vulnerable to the deleterious effect on memory when cannabis is consumed. Endocannabinoids also participate in memory processes. In 1998, our group reported the memory-modulating properties of AEA (93). AEA impairs memory consolidation in rats in an inhibitory avoidance task, further supporting that cannabinoids regulate memory acquisition or retrieve (94). However, it is also possible that endocannabinoids modulate learning and memory by regulating the use of different strategies to solve a memory task (95). However, one eCB system important role in memory regulation is in memory extinction. For example, CB1R knockout mice exhibit a significant deficit in solving a spatial task, that is the water maze (69). The principal deficit observed in these mice is in memory extinction, that has been interpreted as an inability to substitute old strategies with newer and more adaptive ones. CB1R activation in the amygdala promotes aversive memories extinction (96) and prevents the development of post-traumatic stress disorder (PTSD)-like in rats, such as enhancement of corticosterone levels and the startle response generated by a single-prolonged stress (97). Furthermore, stressed mice increase the endocannabinoids levels in the basolateral amygdala during the extinction process, and if they are treated
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with SR141716A the aversive memory extinction is delayed (74). In addition, it has been shown that CBD prevented the consolidation of aversive memories in a fear conditioning task when it is given immediately after the acquisition (98). Another line of therapeutic target that is an open window of research opportunity is cognitive function in ageing. Some studies have revealed that the systemic administration of low doses of THC (3 mg/kg) during 28 d improved learning and memory in mature (12 m) and old mice (18 m), behaving like young vehicle animals. In these aged animals, also, several synaptic, spine density and synaptic formation proteins increased (99). With all, proper doses of THC or CBD must be precisely determined to prevent adverse effects in memory, and in other cognitive functions, such as attention, perception, executive functions, and decision making (78,100). Pain Activation of the eCB system appears to reduce neuropathic pain (101e103). Several studies have documented a reduction in the perception of nociceptive stimuli in animal models (104) and pain in humans. Although results are very consistent, some controversies have arisen since the advantages of using CB1R agonists over already commercially available drugs are dubious. Since some cannabinoids, that is nabilone, marinol, have efficacy as pain relievers as some data in the clinic have shown, and may target neuropathic pain, as with opioids, the challenge remains to find pain relieving endocannabinoid modulating molecules that do not have abuse potential (66). Cancer The involvement of metabolic changes in the eCB system associated with cancer has been documented. Regrettably, poor prognosis through CB1R receptor up-regulation in malignant tissues has been describe until now (105,106). CB1R was considered a potential clinical target using direct or inverse agonists; however, as we have abovementioned these treatments interfere with normal cognitive function (107). Therefore, new indirect agonists have been developed for specific actions mediated by the activity of catalytic enzymes and/or allosteric positive modulation of endocannabinoids activity (108e110). Munson AE, et al. reported anti-proliferative actions of phytocannabinoids in animal models, documenting THC and CBD inhibition of tumor growth, long before the discovery of cannabinoid receptors and endocannabinoids (111). Nowadays, it is known that phytocannabinoids, endocannabinoids and synthetic cannabinoids exert inhibitory effects on cancer growth and spreading, in diverse cancer cell lines and animal models, albeit findings from preclinic studies remain under debate. The inhibition of tumoral pathways in which cannabinoids exert anti-
proliferative effects and cell death comprise: inhibition of mitogenic proteins, sustained stimulation of ceramide and inhibition of RAS-MAPK pathway, through pro-apoptotic proteins such as BCL-2 (112,113). It is already known that somatic or hereditary mutations on cancer, like KRAS or PI3K act like active mitogenic proteins (114,115). This genetic heterogeneity among tumoral tissues is associated to a wide range of effects through cannabinoids actions. In this context, we speculate that cannabinoids interact directly with active mutations exerting cytotoxic effects, inhibiting proliferation, migration or activating apoptotic mechanisms by increasing caspase-3 and PARP activation (116). Cannabinoids promote different cell death mechanisms as their anti-proliferative cancer actions. AEA induces late apoptosis/necrosis in different tumors; while synthetic analogs such as Meth-Anandamide induce early apoptosis and CP,55-940 induces necrosis (117). Hence, cannabinoids activate selective mechanisms that induce different patterns of cell death in different tumor cells. Further studies will clarify the utility of these findings. Phytocannabinoids, synthetic cannabinoids and endocannabinoids exert their anti-tumoral effects by a negative cross-talk between GPR55 and CB2 receptors, and a bidirectional cross-antagonism between both receptors (118). These molecular mechanisms highlight the importance of inhibiting endocannabinoids synthesizing and degrading enzymes as anti-proliferative actions demand (118e120).
Epilepsy Although a wide variety of medication is available to treat epilepsy, at least one-third of patients are drug-resistant (121), that is, the current medication cannot control their seizures. Several cultures have used cannabis to treat seizures, including the Sumerians around 1800 BCE and the Arabians in the 12th century (122,123). In the 18th century, O’Shaughnessy and Gowers reported the use cannabis to treat medication-resistant epileptics (124,125). The effects of marijuana compounds have been studied more consistently in recent times. Mounting evidence supports the anti-seizure effects of THC, CBD, cannabidavarin (CBDV), endocannabinoids, and synthetic cannabinoid receptor agonists in animal models (126). Although THC has anti-seizure effects, it can also promote them. Again, as marijuana psychotropic effects that can result in tolerance and addiction, we have to consider its therapeutic limitations. In this context, the case of Charlotte has captured the attention of the general population. Charlotte, who has Dravet syndrome, had nearly 50 seizures per day. After she began to use a CBD: THC extract, along with her prescribed antiepileptic drugs, her seizures decreased to 2 or 3 nocturnal convulsions per month (127). CBD in combination with prescribed antiepileptic drugs has exhibited anticonvulsive effects. One double-blind
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clinical trial compared CBD (200e300 mg) daily versus placebo, for 4 months, in patients suffering from generalized epilepsy secondary to a temporal focus, reported that 4 out of 8 patients had virtually no convulsions during CBD treatment, while 3 experienced partial improvements. One patient did not improve (128). The first open-label interventional trial was conducted with 162 patients (children and adults) suffering from Dravet and LennoxGastaut syndrome. CBD (Epidiolex) 2e5 mg/kg/d for 12 weeks reduced seizures by 36% (129). Another study used CBD (Epidiolex) 20 mg/kg/d to treat 120 children and young adults with Dravet syndrome and drug-resistant seizures, decreasing the frequency of convulsive seizures per month from 12.4e5.9, and 5% of patients became seizure-free during the treatment (130). One study more, included 171 children and middle-aged patients suffering from Lennox-Gastaut syndrome. CBD (20 mg/kg/d) reduced the median percentage of seizures per month to 43.9%. More studies have been conducted (131), all of them supported CBD anti-seizure effects. Regarding adverse effects, they have been somnolence, diarrhea, decreased appetite, lethargy, fatigue, vomiting, and even convulsions that became severe (129e132). Elevated transaminase was common for patients using valproate medication and high doses of CBD (133). Based on reports from the clinical trials, the FDA approved Epidiolex as a first-line CBD medication for Dravet and Lennox-Gastaut syndrome (133).
Conclusion In this context, it is clear that the eCB system can be a target to control some debilitating diseases, that is insomnia and hypersomnia, learning and memory, anxiety, cancer and epilepsy. In the meantime, we believe marijuana’s derivatives may improve the quality of life for many people suffering a terminal disease. Although cannabinoids induce dependence, see above, we believe in terminal diseases this issue should not be a concern. In other types of diseases, such as insomnia or anorexia, or pain, molecules that target the eCB system and that have no abuse potential may prove to be efficacious medical treatments.
Acknowledgment This work received support from Grant IN215218, IN217918, IA205218 from DGAPA-UNAM to OPG, AERC and MMD, respectively. The authors are grateful to Edith Monroy for reviewing the language of the manuscript. We thank Dr. George Koob, Professor, The Scripps Research Institute for his critique of an early draft of the manuscript.
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REVIEW ARTICLE
Endocannabinoids as Therapeutic Targets Oscar Prospero-Garcıa,a Alejandra E. Ruiz Contreras,b Alette Ortega G omez,c Andrea Herrera-Solıs,d Monica Mendez-Dıaz,a and Grupo de Neurociencias de la Universidad Nacional Aut onoma de Mexico a
Departamento de Fisiologıa, Laboratorio de Canabinoides, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico b Laboratorio de Neurogenomica Cognitiva, Facultad de Psicologıa, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico c Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerologıa, Ciudad de Mexico, Mexico d Laboratorio Efectos Terapeuticos de los Canabinoides, Subdireccion de Investigacion Biomedica, Hospital General Dr. Manuel Gea Gonzalez, Ciudad de Mexico, Mexico Received for publication April 30, 2019; accepted September 30, 2019 (ARCMED_2019_385).
Most of the drugs of abuse affect the brain by interacting with naturally expressed molecular receptors. Marihuana affects a series of receptors including cannabinoid receptor 1 (CB1R) and CB2R, among others. Endogenous molecules with cannabinoid activity interact with these receptors naturally. Receptors, ligands, synthesizing and degrading enzymes, as well as transporters, have been described. This endocannabinoid system modulates behaviors and physiological processes, i.e. food intake, the sleep-waking cycle, learning and memory, motivation, and pain perception, among others. The rather broad distribution of endocannabinoids in the brain explains the different effects marihuana induces in its users. However, this very same anatomical and physiological distribution makes this system a useful target for therapeutic endeavors. In this review, we briefly discuss the potential of small molecules that target the endocannabinoids as therapeutic tools to improve behaviors and treat illnesses. We believe that under medical supervision, endocannabinoid targets offer new advantages for patients for controlling multiple medical disorders. Ó 2019 IMSS. Published by Elsevier Inc. Key Words: Cannabinoids, Endocannabinoids, Therapeutic properties, Sleep, Epilepsy, Pain, Learning and memory.
Marihuana affects the brain by interacting with a series of naturally expressed receptors including cannabinoid receptor 1 (CB1R) and CB2R. Endogenous molecules with cannabinoid activity interact with these receptors naturally. Similarly, receptors, ligands, synthesizing and degrading enzymes, as well as transporters, have been described. This endocannabinoid (eCB) system modulates behaviors and physiological processes, that is food intake, the sleepwaking cycle, learning and memory, motivation, and pain perception, among others. The rather broad distribution of endocannabinoids in the brain explains the different effects marihuana induces in its users. This anatomical distribution and physiological effects make this system a useful target for therapeutic endeavors. In this review, we briefly discuss
Address reprint requests to: Oscar Prospero-Garcıa, Departamento de Fisiologıa, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Apdo. Postal 70-250, Ciudad de Mexico, 04510 Mexico; Phone: (þ52) 55 255 623 2509; FAX: (þ52) 55 2585 5623 2241.; E-mail: opg@ unam.mx
how some molecules that target the eCB system under medical supervision are potential therapeutic tools to improve behaviors and treat illnesses. Since the isolation and structural description of D9tetrahydrocannabinol (THC), the main psychoactive component of marihuana (Cannabis sativa) in 1964 (1), knowledge on how marihuana causes its effects in the user has expanded exponentially. Howlett’s suggestion of the existence of a receptor to which THC binds (2), ignited the search for endogenous molecules. In 1992, Mechoulam’s group isolated anandamide (AEA) from pig brain (3). In 1994, oleamide (ODA), another endocannabinoid was isolated from the cerebrospinal fluid of sleep-deprived cats (4). In the same year, Mechoulam’s group isolated 2 arachydonoylglycerol (2-AG) from dog intestine (5) (Table 1). Few years after CB1R was cloned (6), CB2R were characterized (6,7). Enzymes that participate in the synthesis and breakdown of endocannabinoids have also been identified, and the existence of an endocannabinoid transporter has been suggested (8). All this information has led to
0188-4409/$ - see front matter. Copyright Ó 2019 IMSS. Published by Elsevier Inc. https://doi.org/10.1016/j.arcmed.2019.09.005
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Table 1. Endogenous cannabinoids (endocannabinoids) and related compounds Endocannabinoids and related compounds
Common name
N-arachidonylethanolamine 2-arachidonoyl-glycerol Cis-9,10 octadecenamide N-palmitoyl ethanolamine N-oleoyl ethanolamine 2-Arachidonoylglyceryl ether O-arachidonoylethanolamine N-Arachidonoyl-Dopamine
Anandamide 2-AG Oleamide PEA OEA Noladin ether Virodhamine NADA
expectations of cannabinoid-based therapies for treatment of several illnesses and drug-dependence (Table 2). In the following section, we discuss some evidence supporting the potential use of the facilitation or blockade of endocannabinoids to improve behaviors and illnesses.
Therapeutic Properties Ritual use of marihuana have been suggested by remains of seeds and leaves found in China next to a human skeleton which was estimated to be 10 thousand years old (9). It has been speculated that marihuana has been used to cure or control several diseases such as inflammation and pain, anxiety, depression and psychosis, fatigue and insomnia, loss of appetite and digestive disorders, such as: nausea, diarrhea, and constipation, among others (10). Both marihuana and THC have been used to lower elevated intraocular pressure (glaucoma) (11). Similarly, the manipulation of endogenous cannabinoids may be useful for the control of drug addiction (12). THC has been useful in asthma and as an analgesic (13). Many of these alleged effects are still under investigation. Comparably, Cannabidiol (CBD) seems to have properties to control epilepsy (14), and in combination with THC to control pain (15).
Functional properties at cannabinoid receptors Partial CB1R agonist, Weak CB2R agonist. Sleep and food intake inducer Full CB1R and CB2R agonist. Sleep and food intake inducer Weak CB1R, CB2R agonist. Sleep and food intake inducer PPAR-a agonist It inhibits the expression of FAAH TRPV1 agonist PPARa agonist. Waking and anorexia inducer CB1R agonist Partial CB2R agonist and CB1R antagonist CB1R agonist and potent TRPV1 agonist
Marihuana is classified as a schedule I substance by the U.S. Drug Enforcement Administration (DEA), indicating that marihuana is a drug with high potential for abuse. However, THC and a synthetic analog of THC (Dronabinol) have been approved by the Food and Drug Administration (FDA) for patients suffering from serious, chronic, or debilitating medical conditions. THC itself or THC analogs, as Dronabinol, are approved for treatment of the severe nausea and vomiting associated with cancer chemotherapy (16); weight loss associated with debilitating illnesses, such as HIV infection or cancer (17); spasticity associated with neurological diseases, such as multiple sclerosis and diseases accompanied by intense pain and glaucoma (18). Otherwise, any physician prescribing marihuana for diseases different from the above mentioned is committing a crime in the USA and in other countries. In Mexico, the law is so permissive that those physicians that are prescribing raw marijuana extracts to treat patients do not have to face legal charges. In the vast majority of countries, it is definitely illegal to even suggest marihuana use. On the other hand, the information indicating that California, USA, has an estimated 100,000 users of medical marihuana is absolutely fascinating. Some of them claim to use marihuana for medical conditions, but they may be faking the disease to obtain marihuana for recreational purposes.
Table 2. Synthetic cannabinoids Compound
Characteristics
CP-55940 HU-210 WIN55,212-2 JWH-133 URB597 (KDS-4103) AM251 AM404 SR144528
CB1R agonist. Highly psychoactive. 40 times more potent than THC CB1R full agonist. 100 times more potent than THC CB1R agonist CB2R agonist FAAH selective inhibitor CB1R antagonist. Potential anti-hypersomnia aid Endogenous cannabinoid reuptake inhibitor, Vanilloid receptor agonist. CB2R antagonist
Therapeutic Compound Dronabinol (Marinol)
Use THC analog. Prescribed as an appetite stimulant for patients with AIDS, chemotherapy and gastric bypass patients. Antiemetic. Potential sleep inducer and pain killer THC analog. Antiemetic and analgesic. Potential sleep inducer and pain killer CB1R Inverse agonist. Anorectic anti-obesity. Prescribed for patients with body mass index greater than 30 kg/m2 or 27 kg/m2 associated to risk factor. Potential anti-hypersomnia aid THC and CBD analog, used for neuropathic pain of multiple sclerosis
Nabilone (Cesament) Rimonabant (SR141716A, Complain, Riobant, Slimona) Sativex
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Addiction and pathology associated with marijuana abuse Some studies indicate that increasing endocannabinoids by inhibiting their breakdown enzymes prevent alcohol, nicotine or even heroin reinstatement (19e21). In contrast, some other studies relate endocannabinoids and motivation and drug dependence (12,22), that is it has been observed that CB1R blockade may prevent development of drug-seeking behavior and reinstatement in rats and mice. However, CB1R blockade in humans, may induce negative emotional effects. Regarding CB2R, its activation inhibits cocaine self-administration (23); however, CB2R KO mice do not develop nicotine-induced conditioned place preference (CPP) (24). These dissimilar effects seem to be parts of the same puzzle that are, at present time, difficult to conciliate. Further studies will shed light to this contradiction. Regarding the effects of marijuana chronic use, deleterious effects have been consistently reported. Therefore, the Diagnostic and Statistical Manual of Mental Disorders V (DSM, American Psychiatric Association, APA, 2013) includes a description of marijuana dependence syndrome (25). Marijuana tolerance and dependence (26) includes anxiety, irritability, insomnia, hyporexia, restlessness, and an intense desire for consuming marijuana (craving), after 24e74 h of abstinence. In addition, marijuana users have several brain structural changes, that is reduction in the hippocampus, amygdala, nucleus accumbens and prefrontal cortex, and a reduction of their connections, when they consume it before they were 20 years of age (27e29). Similarly, some studies have suggested a reduction in the Intelligence Quotient (IQ) (30,31), while other studies revealed that marijuana induces the first psychotic or bipolar outbreak in susceptible users (32). Due to these considerations, although marijuana derivatives may have some medicinal properties, it is advisable that their use must be subjected to strict medical supervision.
Food Intake Two or three marihuana joints increase average daily caloric intake, mostly as in between-meal snacks that cause an increase in meal size per se. An increase in body weight was also observed (33,34). THC increases food intake in satiated rats (35); however, they consume sweet more than less palatable foods (36). Free-feeding rats receiving THC increase their high-fat and high-fat sweetened food intake (37). Complementary, SR141716A (rimonabant, a CB1R antagonist) induces anorectic effects (38). Hence, cannabinoids effects on food intake occur through the activation of the CB1R. This finding opens the possibility to use these kinds of drugs as pharmacological tools in the treatment of obesity, see rimonabant in obesity (RIO) study by Van Gaal (38). Volunteers in this study developed psychiatric symptoms that led to the suspension, not only of the study,
but of the commercial availability of rimonabant. The main psychiatric symptoms rimonabant induced, according to the Food and Drug Administration report (2007), were anxiety (more than 3% with 5 mg and more than 6% with 20 mg), insomnia (almost 3% with 5 mg and more than 5% with 20 mg), depressed mood (almost 3% with 5 mg, almost 4% with 20 mg), depression (more than 2% with 5 mg and more than 3% with 20 mg), and several other minor problems were also observed. CB2R exhibits a role opposite to CB1R role. Some data support obesity leads to increased expression of the CB2R, in both adipose tissue and liver, in high-fat fed and ob/ob mice (39). While CB2R deficiency prevents body weight gain during the feeding of a high-fat diet and obesityassociated inflammation, insulin resistance and fatty liver (40). It should be noted that unlike CB1R the activation of CB2R reduces VTA DA-neurons firing, suggesting that these receptors may be a therapeutic target in obesity without affecting hedonism.
eCB System also Regulate Food Intake ODA, AEA and 2-AG increase food intake in rats (41e43), By acting on brain structures like the hypothalamus and the nucleus accumbens (44e46). Rats exhibit CPP induced by regular Lab Chow food, but CPP is stronger when they are under the effect of OLE or AEA. Such CPP is prevented by CB1 inverse agonist AM251, suggesting that OLE and AEA increase the food palatability (47). Hence, CB1R seems to mediate in part the liking phase of reward. Moreover, endocannabinoids increase its levels in a close relationship with feeding (48). AEA, AA5HT (FAAH inhibitor) and OMDM-1 (AEA reuptake inhibitor) increase AEA and 2-AG levels in the NAc, while inducing hypothalamic nuclei activation and food intake (46). All these effects were prevented by AM251 (46). This study opens a potential avenue to target endocannabinoid-breakdown molecules for treatment of eating disorders.
Sleep Users report, anecdotally, that marihuana induces drowsiness or sleepiness. Babor TF, et al. (49) observed that moderate to heavy marihuana use induced better sleep during the days following the consumption. Regrettably, heavy use of marihuana may trigger anxiety crises, and psychotic outbreaks, complicating its use to induce sleep (50). Both ODA and AEA increase sleep, particularly REM sleep, in rats. One single dose of either systemic ODA or intra lateral hypothalamus 2-AG increases REM sleep. Intracerebroventricular infusion of either ODA or 2-AG increases REM sleep after one single dose or after 15 d of daily administration, see review (51). Moreover, both ODA and 2-AG
Cannabinoids and Medicine
increase NREM and REM sleep in a rodent model of insomnia (52,53). Congruently, Santucci V, et al. (54) reported that SR141716A increases wakefulness. Similarly, fatty-acid amide hydrolase (FAAH)-knockout (KO) mice (FAAH hydrolyzes AEA and ODA) exhibit more NREM sleep compared to their wild type (WT) littermates (55). While CB1R-KO mice spent more time in W than their WT littermates (56,57). In humans, the FDA metaanalysis (2007) of the RIO Europe study (38) emphasized that more than 5% of the volunteers receiving rimonabant (20 mg) developed insomnia. These findings complement those obtained in animal models, and further support the notion that the facilitation of the eCB system may improve sleep in insomniac patients. Regarding Cannabidiol (CBD), it is one of the main components of Cannabis sativa, that antagonizes the binding of CB1 and CB2 receptor agonists (58). At first, it was reported that CBD decreased the latency to sleep onset, while increasing duration of non-rapid-eye-movement (NREM) sleep (59). Chagas MH, et al. 2013 (60), reported an increase in the total amount of sleep in rats during the light phase. Conversely, some other studies reported that CBD increased waking and decreased REM sleep, leaving NREM sleep unchanged (61,62). Some studies have reported that CBD (600 mg) induced sedative effects in healthy volunteers (63); while some others have shown that low doses of CBD (15 mg/d) combined with THC (15 mg/d) increased wakefulness while reducing NREM sleep stage 3 (64). An absence of effects have also been reported in healthy subjects with 300 mg of 99% pure CBD (65). Unfortunately, the experimental evidence do not support CBD sleep inducer. As an additional note, Nabilone, a synthetic CB1R agonist, has exhibited sleep-promoting effects in patients suffering from fibromyalgia, very possible by reducing pain (66).
Learning and Memory The effect of marihuana and endocannabinoids on learning and memory has been studied intensively (67e69). Hence, it is now accepted that endocannabinoids play a crucial role in the modulation of cognitive processes (70). The CB1R mediates the impairing effect induced by cannabinoids on memory. CB1R is widely expressed in memory systems, such as in the hippocampus (71). Rats under THC effects performed worse than vehicle rats in a working memory (WM) task (72). CB1R agonists reduce hippocampal neurons firing rate during encoding and delay period in WM in rats (73). In contrast, CB1R knock-out mice were able to learn the Morris water maze, albeit increasing perseverance errors after the platform position was changed (69), suggesting that CB1R participates in extinguishing memories and updating new information in WM. Congruently, SR141716A prevents THC-induced
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deficits on working and short-term memory in rats and mice (74). Terranova JP, et al. (75) described that SR141716A facilitates memory formation (76), and delays the extinction of fear conditioning (77). Cannabis users have shown an impairment in memory tasks performance (78,79). THC induces WM deficiency while reducing the activity of the dorsolateral prefrontal cortex, posterior parietal cortex, anterior cingulate and temporal cortices (80). Moreover, a reduction of BOLD signal at the posterior parietal cortex was detected in adults with early onset of cannabis use when performing a working memory task, even if subjects smoked only a few times, as long as it was at early age (81). Contrasting studies have failed to document memory deficiency in cannabis users (82,83), promoting controversy regarding cannabis effects on memory (84,85). It should be considered that THC negative effect on memory can be attenuated by CBD (86). Studies in rats have suggested that cannabis effect in memory in humans could depend on doses (87), that is THC low doses (3 mg/kg) disrupts WM performance, whereas high doses (10 mg/kg) affects spatial reference memory in mice (88). In rats, a semichronic (7d) and chronic (21d) THC administration induced hippocampal neurogenesis and upregulation of brain-derived neurotrophic factor, while inducing a better performance in short-term and long-term memory novelrecognition tasks (89). Subjects genetic variation on cognitive performance should be considered, too (90e92), that is polymorphisms of the CNR1, gene which codes for CB1R, have been associated with differential efficiency in WM and attentional control in healthy subjects (90,91). It is possible that some genotypes are less vulnerable to the deleterious effect on memory when cannabis is consumed. Endocannabinoids also participate in memory processes. In 1998, our group reported the memory-modulating properties of AEA (93). AEA impairs memory consolidation in rats in an inhibitory avoidance task, further supporting that cannabinoids regulate memory acquisition or retrieve (94). However, it is also possible that endocannabinoids modulate learning and memory by regulating the use of different strategies to solve a memory task (95). However, one eCB system important role in memory regulation is in memory extinction. For example, CB1R knockout mice exhibit a significant deficit in solving a spatial task, that is the water maze (69). The principal deficit observed in these mice is in memory extinction, that has been interpreted as an inability to substitute old strategies with newer and more adaptive ones. CB1R activation in the amygdala promotes aversive memories extinction (96) and prevents the development of post-traumatic stress disorder (PTSD)-like in rats, such as enhancement of corticosterone levels and the startle response generated by a single-prolonged stress (97). Furthermore, stressed mice increase the endocannabinoids levels in the basolateral amygdala during the extinction process, and if they are treated
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with SR141716A the aversive memory extinction is delayed (74). In addition, it has been shown that CBD prevented the consolidation of aversive memories in a fear conditioning task when it is given immediately after the acquisition (98). Another line of therapeutic target that is an open window of research opportunity is cognitive function in ageing. Some studies have revealed that the systemic administration of low doses of THC (3 mg/kg) during 28 d improved learning and memory in mature (12 m) and old mice (18 m), behaving like young vehicle animals. In these aged animals, also, several synaptic, spine density and synaptic formation proteins increased (99). With all, proper doses of THC or CBD must be precisely determined to prevent adverse effects in memory, and in other cognitive functions, such as attention, perception, executive functions, and decision making (78,100). Pain Activation of the eCB system appears to reduce neuropathic pain (101e103). Several studies have documented a reduction in the perception of nociceptive stimuli in animal models (104) and pain in humans. Although results are very consistent, some controversies have arisen since the advantages of using CB1R agonists over already commercially available drugs are dubious. Since some cannabinoids, that is nabilone, marinol, have efficacy as pain relievers as some data in the clinic have shown, and may target neuropathic pain, as with opioids, the challenge remains to find pain relieving endocannabinoid modulating molecules that do not have abuse potential (66). Cancer The involvement of metabolic changes in the eCB system associated with cancer has been documented. Regrettably, poor prognosis through CB1R receptor up-regulation in malignant tissues has been describe until now (105,106). CB1R was considered a potential clinical target using direct or inverse agonists; however, as we have abovementioned these treatments interfere with normal cognitive function (107). Therefore, new indirect agonists have been developed for specific actions mediated by the activity of catalytic enzymes and/or allosteric positive modulation of endocannabinoids activity (108e110). Munson AE, et al. reported anti-proliferative actions of phytocannabinoids in animal models, documenting THC and CBD inhibition of tumor growth, long before the discovery of cannabinoid receptors and endocannabinoids (111). Nowadays, it is known that phytocannabinoids, endocannabinoids and synthetic cannabinoids exert inhibitory effects on cancer growth and spreading, in diverse cancer cell lines and animal models, albeit findings from preclinic studies remain under debate. The inhibition of tumoral pathways in which cannabinoids exert anti-
proliferative effects and cell death comprise: inhibition of mitogenic proteins, sustained stimulation of ceramide and inhibition of RAS-MAPK pathway, through pro-apoptotic proteins such as BCL-2 (112,113). It is already known that somatic or hereditary mutations on cancer, like KRAS or PI3K act like active mitogenic proteins (114,115). This genetic heterogeneity among tumoral tissues is associated to a wide range of effects through cannabinoids actions. In this context, we speculate that cannabinoids interact directly with active mutations exerting cytotoxic effects, inhibiting proliferation, migration or activating apoptotic mechanisms by increasing caspase-3 and PARP activation (116). Cannabinoids promote different cell death mechanisms as their anti-proliferative cancer actions. AEA induces late apoptosis/necrosis in different tumors; while synthetic analogs such as Meth-Anandamide induce early apoptosis and CP,55-940 induces necrosis (117). Hence, cannabinoids activate selective mechanisms that induce different patterns of cell death in different tumor cells. Further studies will clarify the utility of these findings. Phytocannabinoids, synthetic cannabinoids and endocannabinoids exert their anti-tumoral effects by a negative cross-talk between GPR55 and CB2 receptors, and a bidirectional cross-antagonism between both receptors (118). These molecular mechanisms highlight the importance of inhibiting endocannabinoids synthesizing and degrading enzymes as anti-proliferative actions demand (118e120).
Epilepsy Although a wide variety of medication is available to treat epilepsy, at least one-third of patients are drug-resistant (121), that is, the current medication cannot control their seizures. Several cultures have used cannabis to treat seizures, including the Sumerians around 1800 BCE and the Arabians in the 12th century (122,123). In the 18th century, O’Shaughnessy and Gowers reported the use cannabis to treat medication-resistant epileptics (124,125). The effects of marijuana compounds have been studied more consistently in recent times. Mounting evidence supports the anti-seizure effects of THC, CBD, cannabidavarin (CBDV), endocannabinoids, and synthetic cannabinoid receptor agonists in animal models (126). Although THC has anti-seizure effects, it can also promote them. Again, as marijuana psychotropic effects that can result in tolerance and addiction, we have to consider its therapeutic limitations. In this context, the case of Charlotte has captured the attention of the general population. Charlotte, who has Dravet syndrome, had nearly 50 seizures per day. After she began to use a CBD: THC extract, along with her prescribed antiepileptic drugs, her seizures decreased to 2 or 3 nocturnal convulsions per month (127). CBD in combination with prescribed antiepileptic drugs has exhibited anticonvulsive effects. One double-blind
Cannabinoids and Medicine
clinical trial compared CBD (200e300 mg) daily versus placebo, for 4 months, in patients suffering from generalized epilepsy secondary to a temporal focus, reported that 4 out of 8 patients had virtually no convulsions during CBD treatment, while 3 experienced partial improvements. One patient did not improve (128). The first open-label interventional trial was conducted with 162 patients (children and adults) suffering from Dravet and LennoxGastaut syndrome. CBD (Epidiolex) 2e5 mg/kg/d for 12 weeks reduced seizures by 36% (129). Another study used CBD (Epidiolex) 20 mg/kg/d to treat 120 children and young adults with Dravet syndrome and drug-resistant seizures, decreasing the frequency of convulsive seizures per month from 12.4e5.9, and 5% of patients became seizure-free during the treatment (130). One study more, included 171 children and middle-aged patients suffering from Lennox-Gastaut syndrome. CBD (20 mg/kg/d) reduced the median percentage of seizures per month to 43.9%. More studies have been conducted (131), all of them supported CBD anti-seizure effects. Regarding adverse effects, they have been somnolence, diarrhea, decreased appetite, lethargy, fatigue, vomiting, and even convulsions that became severe (129e132). Elevated transaminase was common for patients using valproate medication and high doses of CBD (133). Based on reports from the clinical trials, the FDA approved Epidiolex as a first-line CBD medication for Dravet and Lennox-Gastaut syndrome (133).
Conclusion In this context, it is clear that the eCB system can be a target to control some debilitating diseases, that is insomnia and hypersomnia, learning and memory, anxiety, cancer and epilepsy. In the meantime, we believe marijuana’s derivatives may improve the quality of life for many people suffering a terminal disease. Although cannabinoids induce dependence, see above, we believe in terminal diseases this issue should not be a concern. In other types of diseases, such as insomnia or anorexia, or pain, molecules that target the eCB system and that have no abuse potential may prove to be efficacious medical treatments.
Acknowledgment This work received support from Grant IN215218, IN217918, IA205218 from DGAPA-UNAM to OPG, AERC and MMD, respectively. The authors are grateful to Edith Monroy for reviewing the language of the manuscript. We thank Dr. George Koob, Professor, The Scripps Research Institute for his critique of an early draft of the manuscript.
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