Endogenous Endocannabinoid System Research Articles

Cannabis and cancer: unveiling the potential of a green ally in breast, colorectal, and prostate cancer.

Cancer comes in second place on the list of causes of death worldwide. In 2018, the 5-year prevalence of breast cancer (BC), prostate cancer (PC), and colorectal cancer (CRC) were 30%, 12.3%, and 10.9%, respectively. Cannabinoids are chemicals derived from the Cannabis sativa plant; the most investigated cannabinoids are cannabinol, delta 9-tetrahydrocannabinol (Δ9-THC), and cannabidiol. In humans, the endogenous endocannabinoid system consists of endocannabinoids, cannabinoids receptors (CBs), and enzymes that degrade the endocannabinoids. In this review, we will review the most recent literature for evidence that discusses the role of cannabis in the treatment of the three types of neoplasms mentioned. Studies have proved that BC cells express CB receptors; many in-vivo studies showed that cannabinoids cause apoptosis and inhibit proliferation and migration. Also, researchers found that treating BC mice with THC and JWH-133 (CB2 receptor agonist) slowed the tumor growth. Regarding CRC, cannabidiol was found to decrease the viability of chemotherapy-resistant CRC cells and inhibit metastasis by antagonizing the G-protein-coupled receptor 55 (GPR55; a novel cannabinoid receptor) necessary for metastasis. Moreover, cannabidiol had anti-angiogenetic effects by reducing the expression of vascular endothelial growth factor (VEGF) in addition to anti-inflammatory effects. Finally, studies demonstrated that PC cells highly express CB1 and CB2 receptors and that cannabinoids are capable of inhibiting the release of exosomes and microvesicles related to cancer progression. Cannabinoids also have antiproliferative, anti-invasive, anti-fibroblastic, cell cycle arrest, and proapoptotic effects on PC cells.

Cannabis and Paternal Epigenetic Inheritance.

Cannabis is the most widely used illicit drug in Western counties and its abuse is particularly high in male adolescents and young adults. Its main psychotropic component, the cannabinoid delta-9-tetrahydrocannabinol (Δ9-THC), interferes in the endogenous endocannabinoid system. This signaling system is involved in the control of many biological activities, including the formation of high-quality male gametes. Direct adverse effects of Δ9-THC in male reproduction are well known in both animal models and humans. Nevertheless, the possibility of long-term effects due to epigenetic mechanisms has recently been reported. In this review, we summarize the main advances in the field suggesting the need to pay attention to the possible long-term epigenetic risks for the reproductive health of cannabis users and the health of their offspring.

Endocannabinoid System and Exogenous Cannabinoids in Depression and Anxiety: A Review.

Background: There is a growing liberalization of cannabis-based preparations for medical and recreational use. In multiple instances, anxiety and depression are cited as either a primary or a secondary reason for the use of cannabinoids. Aim: The purpose of this review is to explore the association between depression or anxiety and the dysregulation of the endogenous endocannabinoid system (ECS), as well as the use of phytocannabinoids and synthetic cannabinoids in the remediation of depression/anxiety symptoms. After a brief description of the constituents of cannabis, cannabinoid receptors and the endocannabinoid system, the most important evidence is presented for the involvement of cannabinoids in depression and anxiety both in human and from animal models of depression and anxiety. Finally, evidence is presented for the clinical use of cannabinoids to treat depression and anxiety. Conclusions: Although the common belief that cannabinoids, including cannabis, its main studied components-tetrahydrocannabinol (THC) and cannabidiol (CBD)-or other synthetic derivatives have been suggested to have a therapeutic role for certain mental health conditions, all recent systematic reviews that we report have concluded that the evidence that cannabinoids improve depressive and anxiety disorders is weak, of very-low-quality, and offers no guidance on the use of cannabinoids for mental health conditions within a regulatory framework. There is an urgent need for high-quality studies examining the effects of cannabinoids on mental disorders in general and depression/anxiety in particular, as well as the consequences of long-term use of these preparations due to possible risks such as addiction and even reversal of improvement.

Cannabidiol in the context of sleeping disorders-induced oxidative stress

Abstract Sleep disorders can be the result of psychiatric or neurological conditions, such as post-traumatic stress disorders, depression, anxiety, Alzheimer’s disease, Parkinson’s disease. At the same time, changes in sleep, known as sleep disorders, are closely related to various metabolic dysfunctions, which in turn are the result of the generation of reactive oxygen species, or otherwise known as oxidative stress. For this reason, cannabinoid derivatives are increasingly used for this purpose. Among the most used are delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). These agents interact with the endogenous endocannabinoid system, either by direct action on specific receptors, or by increasing the availability of endocannabinoids, modifying particular mental states (anxiety, depression). The results of the studies specified in this article provide promising evidence regarding the positive effects of CBD, which extend beyond the scope of sleep disorders, with possible applications also in the case of the accumulation of reactive oxygen species.

An Agathokakological Tale of Δ9-THC: Exploration of Possible Biological Targets.

Δ9-Tetrahydrocannabinol (Δ9-THC), the active phytocannabinoid in cannabis, is virtually an adjunct to the endogenous endocannabinoid signaling system. By interacting with G-proteincoupled receptors CB1 and CB2, Δ9-THC affects peripheral and central circulation by lowering sympathetic activity, altering gene expression, cell proliferation, and differentiation, decreasing leukocyte migration, modulating neurotransmitter release, thereby modulating cardiovascular functioning, tumorigenesis, immune responses, behavioral and locomotory activities. Δ9-THC effectively suppresses chemotherapy-induced vomiting, retards malignant tumor growth, inhibits metastasis, and promotes apoptosis. Other mechanisms involved are targeting cell cycle at the G2-M phase in human breast cancer, downregulation of E2F transcription factor 1 (E2F1) in human glioblastoma multiforme, and stimulation of ER stress-induced autophagy. Δ9-THC also plays a role in ameliorating neuroinflammation, excitotoxicity, neuroplasticity, trauma, and stroke and is associated with reliving childhood epilepsy, brain trauma, and neurodegenerative diseases. Δ9-THC via CB1 receptors affects nociception, emotion, memory, and reduces neuronal excitability and excitotoxicity in epilepsy. It also increases renal blood flow, reduces intraocular pressure via a sympathetic pathway, and modulates hormonal release, thereby decreasing the reproductive function and increasing glucose metabolism. Versatile medical marijuana has stimulated abundant research demonstrating substantial therapeutic promise, suggesting the possibilities of first-in-class drugs in diverse therapeutic segments. This review represents the current pharmacological status of the phytocannabinoid, Δ9-THC, and synthetic analogs in cancer, cardiovascular, and neurodegenerative disorders.

The Cannabis Spread throughout the Continents and its Therapeutic Use in History

Cannabis sativa L. (C. sativa) is a plant whose use as a therapeutic agent shares its origins with the first Far East's human societies. Cannabis has been used not only for recreational purposes but as food to obtain textile fibers, to produce hemp paper, to treat many physical and mental disorders. This review aims to provide a complete assessment of the deep knowledge of the cannabis psychoactive effects and medicinal properties in the course of history covering i.) The empirical use of the seeds and the inflorescences to treat many physical ailments by the ancient Oriental physicians' ii.) The current use of cannabis as a therapeutic agent after the discovery of its key psychoactive constituent and the human endogenous endocannabinoid system. This study was performed through a detailed analysis of the studies on the historical significance and medical applications of Cannabis sativa by using international scientific databases, historical and medical books, ancient Greek and Chinese manuscripts translations, library and statistical data from government reports and texts from the National Library of Greece (Stavros Niarchos Foundation), from the School of Health Sciences of the National and Kapodistrian University of Athens (Greece). We selected papers and texts focusing on a historical point of view about the medical importance of the plant and its applications for a therapeutic purpose in the past. Through a detailed analysis of the available resources about the origins of C. sativa, we found that its use by ancient civilizations as a source of food and textile fibers dates back over 10,000 years, while its therapeutic applications have been improved over the centuries, from the ancient East medicine of the 2nd and 1st millennium B.C. to the more recent introduction in the Western world after the 1st century A.D. In the 20th and 21st centuries, Cannabis and its derivatives have been considered as a menace and banned throughout the world, but nowadays, they are still the most widely consumed illicit drugs all over the world. Its legalization in some jurisdictions has been accompanied by new lines of research to investigate its possible applications for medical and therapeutic purposes.

Marijuana and fertility.

Tetrahydrocannabinol, the active ingredient in marijuana, is a lipophilic compound with a prolonged half-life of 20–36 hours.[1][1] Tetrahydrocannabinol activates the cannabinoid receptors, which are part of the endogenous endocannabinoid system. This system is found in the hypothalamus, pituitary

Cannabis a "new" old medicine? - The challenges of its medical use in the XXI century

Cannabis sativa L. is an ancient plant, that has been used during centuries as rope, cloth, paper, oil and birdfeed and also a well-known psychoactive drug included in the lists of UN 1961 Convention and the following documents related. Likewise, it has remarkable pharmacological properties recognized by tradition that now object of scientific research. This plant produces a unique series of secondary metabolites called cannabinoids which exhibit a typical C21 terpenophenolic skeleton, responsible for its pharmacological profile. These cannabinoids interact with the endogenous endocannabinoid system, involved in the regulation of a variety of physiological and cognitive processes including fertility, pregnancy, during pre- and postnatal development, appetite, painsensation, mood and memory. Some of these pharmacological activities are so novel and interesting that justify the scientific research in these areas which is performing now. This process is expensive and takes a lot of time, and in the meantime, millions of people use cannabis herb, for medical treatments based in traditional use. Taking into consideration this fact, there are some countries have approved the medical use of cannabis, creating specific regulations. Also, the Expert Committee on Drug Dependencies, of the World Health Organization (WHO) held in June 2018 a report about the medical use of cannabis. This report recommends that a critical review of the scientific literature on the cannabis plant and its resin, extracts or tinctures should be performed and that Cannabidiol (CBD) should not be included in the lists of prohibited substances

AMP-activated kinase and the endogenous endocannabinoid system might contribute to antinociceptive effects of prolonged moderate caloric restriction in mice.

BackgroundCaloric restriction is associated with broad therapeutic potential in various diseases and an increase in health and life span. In this study, we assessed the impact of caloric restriction on acute and inflammatory nociception in mice, which were either fed ad libitum or subjected to caloric restriction with 80% of the daily average for two weeks.ResultsThe behavioral tests revealed that inflammatory nociception in the formalin test and in zymosan-induced mechanical hypersensitivity were significantly decreased when mice underwent caloric restriction. As potential mediators of the diet-induced antinociception, we assessed genes typically induced by inflammatory stimuli, AMP-activated kinase, and the endocannabinoid system which have all already been associated with nociceptive responses. Zymosan-induced inflammatory markers such as COX-2, TNFα, IL-1β, and c-fos in the spinal cord were not altered by caloric restriction. In contrast, AMPKα2 knock-out mice showed significant differences in comparison to C57BL/6 mice and their respective wild type littermates by missing the antinociceptive effects after caloric restriction. Endocannabinoid levels of anandamide and 2-arachidonyl glyceroldetermined in serum by LC-MS/MS were not affected by either caloric restriction alone or in combination with zymosan treatment. However, cannabinoid receptor type 1 expression in the spinal cord, which was not altered by caloric restriction in control mice, was significantly increased after caloric restriction in zymosan-induced paw inflammation. Since increased cannabinoid receptor type 1 signaling might influence AMP-activated kinase activity, we analyzed effects of anandamide on AMP-activated kinase in cell culture and observed a significant activation of AMP-activated kinase. Thus, endocannabionoid-induced AMP-activated kinase activation might be involved in antinociceptive effects after caloric restriction.ConclusionOur data suggest that caloric restriction has an impact on inflammatory nociception which might involve AMP-activated kinase activation and an increased activity of the endogenous endocannabinoid system by caloric restriction-induced cannabinoid receptor type 1 upregulation.

Cannabinoids for pediatric epilepsy? Up in smoke or real science?

Public interest in the use of "medical marijuana" for the treatment of childhood epilepsy has burgeoned in the last few years. This has occurred in parallel with a growing interest in "medical marijuana" in general. Physicians and pediatricians must balance their patients' desire for immediate access to these products with the tenets of evidence-based medicine. This review discusses the biochemistry of cannabis products (the phytocannabinoids) setting this in the context of the endogenous endocannabinoid system. The differing and potentially modulating effects of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are reviewed. The evidence-base supporting or not the use of cannabis products for the treatment of neurological disease and specifically epilepsy is explored. The potential for adverse effects and particularly of neurotoxicity is addressed. Finally, public health and sociocultural implications are touched upon. Specific recommendations for interested physicians are provided including advocacy for patients and for a change in the "scheduling" of cannabis in order to better foster much-needed high-quality scientific research in this important area.

Enhanced Glutamatergic Synaptic Plasticity in the Hippocampal CA1 Field of Food-Restricted Rats: Involvement of CB1 Receptors.

The endogenous endocannabinoid system has a crucial role in regulating appetite and feeding behavior in mammals, as well as working memory and reward mechanisms. In order to elucidate the possible role of cannabinoid type-1 receptors (CB1Rs) in the regulation of hippocampal plasticity in animals exposed to food restriction (FR), we limited the availability of food to a 2-h daily period for 3 weeks in Sprague-Dawley rats. FR rats showed a higher long-term potentiation at hippocampal CA1 excitatory synapses with a parallel increase in glutamate release when compared with animals fed ad libitum. FR rats showed a significant increase in the long-term spatial memory determined by Barnes maze. FR was also associated with a decreased inhibitory effect of the CB1R agonist win55,212-2 on glutamatergic field excitatory postsynaptic potentials, together with a decrease in hippocampal CB1R protein expression. In addition, hippocampal brain-derived neurotrophic factor protein levels and mushroom dendritic spine density were significantly enhanced in FR rats. Altogether, our data suggest that alterations of hippocampal CB1R expression and function in FR rats are associated with dendritic spine remodeling and functional potentiation of CA1 excitatory synapses, and these findings are consistent with increasing evidence supporting the idea that FR may improve cognitive functions.

Marijuana use: neuroscience perspective.

The human behavioral repertoire includes activities that influence mood and cognition such as listening to music, watching movies, conversation, and dining, behaviors considered within the normal spectrum; however, when we choose activities that predictably and reliably alter our mood and cognition by exposing our central nervous system to exogenous molecules, we enter the potentially pathological path of addiction. We, and others around us, begin to worry as these behaviors insidiously become dominant foci in our existence. We do not clearly understand why a given individual chooses to use recreational drugs (1). As a society, we interpret and judge substance use based on our cultural prejudices, current moral and legal standards, and established norms.

Cannabis Use during Adolescent Development: Susceptibility to Psychiatric Illness

Cannabis use is increasingly pervasive among adolescents today, even more common than cigarette smoking. The evolving policy surrounding the legalization of cannabis reaffirms the need to understand the relationship between cannabis exposure early in life and psychiatric illnesses. cannabis contains psychoactive components, notably Δ9-tetrahydrocannabinol (THC), that interfere with the brain’s endogenous endocannabinoid system, which is critically involved in both pre- and post-natal neurodevelopment. Consequently, THC and related compounds could potentially usurp normal adolescent neurodevelopment, shifting the brain’s developmental trajectory toward a disease-vulnerable state, predisposing early cannabis users to motivational, affective, and psychotic disorders. Numerous human studies, including prospective longitudinal studies, demonstrate that early cannabis use is associated with major depressive disorder and drug addiction. A strong association between schizophrenia and cannabis use is also apparent, especially when considering genetic factors that interact with this environmental exposure. These human studies set a foundation for carefully controlled animal studies which demonstrate similar patterns following early cannabinoid exposure. Given the vulnerable nature of adolescent neurodevelopment and the persistent changes that follow early cannabis exposure, the experimental findings outlined should be carefully considered by policymakers. In order to fully address the growing issues of psychiatric illnesses and to ensure a healthy future, measures should be taken to reduce cannabis use among teens.

Psychopharmacology of the endocannabinoids: far beyond anandamide

The study of endocannabinoid pharmacology has proceeded from the discovery of Δ9-tetrahydrocannabinol, the main psychoactive compound in Cannabis sativa, to the identification of an endogenous endocannabinoid system that is essential for physiological modulation of neuronal functions. We have not yet achieved a complete understanding of the various roles of the endocannabinoids, but this is one of the fastest-growing fields in psychopharmacology. This review starts with a brief historical description of the discovery of the endocannabinoids and then focuses on recent pharmacological advances and recently discovered endocannabinoid mechanisms of action (e.g. functional selectivity, allosterism, and receptor trafficking). Finally, we will discuss the contention that the existence of evidence-based therapeutic applications for cannabinoids and the wide range of physiological functions affected by endocannabinoids suggests that the careful study of the endocannabinoid system may lead to the development of novel therapeutic drugs with higher societal acceptability and lower side effects profiles.

The Structural Basis of Endocannabinoid Oxygenation by Cyclooxygenase-2

The cyclooxygenases (COX-1 and COX-2) oxygenate arachidonic acid (AA) in the committed step of prostaglandin biogenesis. Substitutions of I434V, H513R, and I523V constitute the only differences in residues lining the cyclooxygenase channel between COX-1 and COX-2. These changes create a hydrophobic pocket in COX-2, with Arg-513 located at the base of the pocket, which has been exploited in the design of COX-2-selective inhibitors. Previous studies have shown that COX-2, but not COX-1, can oxygenate endocannabinoid substrates, including 2-arachidonoyl glycerol (2-AG). To investigate the isoform-specific structural basis of endocannabinoid binding to COX-2, we determined the crystal structure of the 2-AG isomer 1-arachidonoyl glycerol (1-AG) in complex with wild type and R513H murine (mu) COX-2 to 2.2 and 2.35 Å, respectively, and R513H muCOX-2 in complex with AA to 2.45 Å resolution. The 2,3-dihydroxypropyl moiety of 1-AG binds near the opening of the cyclooxygenase channel in the space vacated by the movement of the Leu-531 side chain, validating our previous hypothesis implicating the flexibility of the Leu-531 side chain as a determinant for the ability of COX-2 to oxygenate endocannabinoid substrates. Functional analyses carried out to compliment our structural findings indicated that Y355F and R513H muCOX-2 constructs had no effect on the oxygenation of 1-AG and 2-AG, whereas substitutions that resulted in a shortened side chain for Leu-531 had only modest effects. Both AA and 1-AG bind to R513H muCOX-2 in conformations similar to those observed in the co-crystal structures of these substrates with wild type enzyme.

Cannabinoid Receptor 1 Influences Chromatin Remodeling in Mouse Spermatids by Affecting Content of Transition Protein 2 mRNA and Histone Displacement

Marijuana smokers and animals treated with Δ9-tetrahydrocannabinol, the principal component of marijuana, show alterations of sperm morphology suggesting a role for cannabinoids in sperm differentiation and/or maturation. Because the cannabinoid receptor 1 (CNR1) activation appears to play a pivotal role in spermiogenesis, the developmental stage where DNA is remodeled, we hypothesized that CNR1 receptors might also influence chromatin quality in sperm. We used Cnr1 null mutant (Cnr1-/-) mice to study the possible role of endocannabinoids on sperm chromatin during spermiogenesis. We demonstrated that CNR1 activation regulated chromatin remodeling of spermatids by either increasing Tnp2 levels or enhancing histone displacement. Comparative analysis of wild-type, Cnr1+/-, and Cnr1-/- animals suggested the possible occurrence of haploinsufficiency for Tnp2 turnover control by CNR1, whereas histone displacement was disrupted to a lesser extent. Furthermore, flow cytometry analysis demonstrated that the genetic loss of Cnr1 decreased sperm chromatin quality and was associated with sperm DNA fragmentation. This damage increased during epididymal transit, from caput to cauda. Collectively, our results show that the expression/activity of CNR1 controls the physiological alterations of DNA packaging during spermiogenesis and epididymal transit. Given the deleterious effects of sperm DNA damage on male fertility, we suggest that the reproductive function of marijuana users may also be impaired by deregulation of the endogenous endocannabinoid system.

Pleiotropic Effects of Rimonabant: Clinical Implications

Abdominal obesity (high waist circumference) is more strongly associated with cardiovascular disease and type 2 diabetes than generalized adiposity (high body mass index). Recent research has highlighted the role of chronic overactivation of the endogenous endocannabinoid system, acting through its CB(1) receptor, as a key factor involved in the development of abdominal obesity and related cardiometabolic risk abnormalities such as insulin resistance, low HDL-cholesterol, hypertriglyceridemia, inflammation and low adiponectin. Evidence suggests that these cardiometabolic risk factors/markers are not optimally managed by current treatments. Improving the nutrition and physical activity/exercise habits of patients remains the cornerstone of management of elevated global cardiometabolic risk. Antagonism of the endocannabinoid system provides a novel strategy to target several unaddressed cardiometabolic risk markers/factors. Randomized trials of rimonabant in patients with overweight or obesity and/or type 2 diabetes have demonstrated marked and significant improvements in body weight, waist circumference, glycemic control (in patients with type 2 diabetes), features of atherogenic dyslipidemia, insulin resistance, adipose tissue-derived cytokines (leptin and adiponectin) and C-reactive protein (a marker of systemic inflammation). Further analyses suggested that about half of the improvements of several cardiometabolic risk markers were independent from concomitant weight loss. Blood pressure also improved with rimonabant treatment, this effect being consistent with the blood pressure lowering effect of weight loss. The tolerability and safety of rimonabant have been extensively studied and most transient side effects include some gastrointestinal side effects, anxiety, mood changes and incidence of depressive disorders, particularly in patients with previous history of depression. Rimonabant is a useful option for patients with abdominal obesity and with related cardiometabolic risk abnormalities such as an atherogenic dyslipidemia and/or type 2 diabetes.

The metabolic implications of long term cannabis use in patients with psychosis

The aim of this paper is to summarise the effects of cannabis use on appetite and energy balance, and to subsequently investigate the possible implications this may have in patients with psychosis, in whom a high prevalence of cannabis use has been reported. A narrative review based on the recent literature regarding cannabis use in the general population and patients with psychosis. The short-term abilities of cannabis to increase appetite and body weight, through actions on the endogenous endocannabinoid system, have been well characterised throughout the literature. The long term effects of cannabis use are however unclear and only a minority of studies have been conducted in the general population with overall conflicting results. In terms of the effects of cannabis in patients with psychosis, there has only been one study to date that has investigated this and interestingly found cannabis use to be associated with increased body weight and blood glucose levels, thus providing evidence that cannabis use may be an important contributing factor to the reduced life expectancy, as is currently observed in this vulnerable patient group. It is clear from the literature that patients with psychosis are at a high risk of metabolic and cardiovascular disease in comparison to the general population. However the contribution of cannabis use to this risk is as of yet undetermined and further long term studies are need to confirm current findings and evaluate hypothesised mechanisms.

Role of systemic endocannabinoid CB-1 receptor antagonism in the acquisition and expression of fructose-conditioned flavor–flavor preferences in rats

Rats learn to prefer a flavor mixed into a fructose–saccharin solution over a different flavor mixed into a saccharin-only solution which is considered to be a form of flavor–flavor conditioning. Fructose-conditioned flavor preferences are impaired by systemic dopamine D1 and to a lesser degree, D2 receptor antagonism as well as by NMDA, but not opioid, receptor antagonism. Given the emerging role of the endocannabinoid system in mediating hedonically-driven food intake, the present study examined whether systemic administration of the inverse CB-1 receptor agonist, AM-251 would alter fructose-conditioned flavor preferences. In Experiment 1, food-restricted rats were trained over 10 sessions (30 min/day) to drink a fructose–saccharin solution mixed with one flavor (CS+/Fs) and a less-preferred saccharin-only solution mixed with another flavor (CS−/s). Subsequent two-bottle tests with the two flavors in saccharin (CS+/s, CS−/s) occurred 15 min following counterbalanced pairs of AM-251 doses of 0, 0.1, 1 or 3 mg/kg. Preference for CS+/s over CS−/s following vehicle treatment (74%) was significantly reduced by the 0.1 (67%) and 1 (65%) AM-251 doses, whereas CS+/s, but not CS−/s intake was significantly reduced by the 1 and 3 mg/kg AM-251 doses. In Experiment 2, rats received systemic injections of AM-251 (1 mg/kg) or vehicle prior to the 10 CS+/Fs and CS−/s training sessions. In subsequent two-bottle tests (drug-free) the AM-251 and control groups displayed similar preferences for the CS+ flavor (66% vs. 69%). Experiment 3 demonstrated that AM-251 significantly decreased chow intake (24 h), and 1-h intakes of fructose–saccharin and saccharin-only solutions in ad libitum-fed rats. These data indicate that functional CB-1 receptor antagonism significantly reduces the expression, but not the acquisition of fructose-conditioned flavor–flavor preferences. The endogenous endocannabinoid system is therefore implicated in the maintenance of this form of learned flavor preferences.

Targeted modulators of the endogenous cannabinoid system: Future medications to treat addiction disorders and obesity

The endogenous endocannabinoid system encompasses a family of natural signaling lipids ("endocannabinoids") functionally related to (9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana (cannabis), along with proteins that modulate the endocannabinoids, including enzymes, transporters, and receptors. The endocannabinoid system's ubiquitous regulatory actions in health and disease underscore its importance to mammalian (patho)physiology and suggest discrete targets through which it may be modulated for therapeutic gain. Medications based on the endocannabinoid system are an important focus of contemporary translational research, particularly with respect to substance abuse and obesity, two prevalent disorders with a pathogenic component of endocannabinoid system hyperactivity. Pressing health care needs have made the rational design of targeted CB1 cannabinoid-receptor modulators a promising route to future medications with significant therapeutic impact against psychobehavioral and metabolic disturbances having a reward-supported appetitive component.