The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana's psychoactive ingredient Δ9-tetrahydrocannabinol (Δ9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors. For centuries, in addition to its recreational actions, several contradictory claims regarding the effects of Cannabis use in sexual functioning and behavior (e.g. aphrodisiac vs anti-aphrodisiac) of both sexes have been accumulated. The identification of Δ9-THC and later on, the discovery of the ECS have opened a potential therapeutic target for sexual dysfunctions, given the partial efficacy of current pharmacological treatment. In agreement with the bidirectional modulation induced by cannabinoids on several behavioral responses, the endogenous cannabinoid AEA elicited biphasic effects on sexual behavior as well. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of several aspects of sexuality in preclinical and human studies, highlighting their therapeutic potential.

• Keywords
• Cannabinoid CB1 receptor, Endocannabinoids, Sexual behavior, Δ(9)-THC,
• MeSH
• Endocannabinoids metabolism   MeSH
• Cannabinoids metabolism   MeSH
• Humans MeSH
• Cannabinoid Receptor Modulators metabolism   MeSH
• Receptors, Cannabinoid metabolism   MeSH
• Sexual Behavior physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Endocannabinoids MeSH
• Cannabinoids MeSH
• Cannabinoid Receptor Modulators MeSH
• Receptors, Cannabinoid MeSH

BACKGROUND: n-3 polyunsaturated fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduce the risk of cardiovascular disease and can ameliorate many of obesity-associated disorders. We hypothesised that the latter effect will be more pronounced when DHA/EPA is supplemented as phospholipids rather than as triglycerides. METHODOLOGY/PRINCIPAL FINDINGS: In a 'prevention study', C57BL/6J mice were fed for 9 weeks on either a corn oil-based high-fat obesogenic diet (cHF; lipids ∼35% wt/wt), or cHF-based diets in which corn oil was partially replaced by DHA/EPA, admixed either as phospholipids or triglycerides from marine fish. The reversal of obesity was studied in mice subjected to the preceding cHF-feeding for 4 months. DHA/EPA administered as phospholipids prevented glucose intolerance and tended to reduce obesity better than triglycerides. Lipemia and hepatosteatosis were suppressed more in response to dietary phospholipids, in correlation with better bioavailability of DHA and EPA, and a higher DHA accumulation in the liver, white adipose tissue (WAT), and muscle phospholipids. In dietary obese mice, both DHA/EPA concentrates prevented a further weight gain, reduced plasma lipid levels to a similar extent, and tended to improve glucose tolerance. Importantly, only the phospholipid form reduced plasma insulin and adipocyte hypertrophy, while being more effective in reducing hepatic steatosis and low-grade inflammation of WAT. These beneficial effects were correlated with changes of endocannabinoid metabolome in WAT, where phospholipids reduced 2-arachidonoylglycerol, and were more effective in increasing anti-inflammatory lipids such as N-docosahexaenoylethanolamine. CONCLUSIONS/SIGNIFICANCE: Compared with triglycerides, dietary DHA/EPA administered as phospholipids are superior in preserving a healthy metabolic profile under obesogenic conditions, possibly reflecting better bioavalability and improved modulation of the endocannabinoid system activity in WAT.

• MeSH
• Analysis of Variance MeSH
• Adipose Tissue, White metabolism   MeSH
• Biological Availability MeSH
• Diet, High-Fat * MeSH
• Endocannabinoids * MeSH
• Phospholipids metabolism   MeSH
• Immunohistochemistry MeSH
• Liver drug effects   metabolism   MeSH
• Muscle, Skeletal metabolism   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Eicosapentaenoic Acid metabolism   MeSH
• Docosahexaenoic Acids metabolism   MeSH
• Metabolomics MeSH
• Microscopy MeSH
• Cannabinoid Receptor Modulators metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Obesity diet therapy   prevention & control   MeSH
• Fatty Acids, Omega-3 administration & dosage   metabolism   pharmacology   MeSH
• Body Weight MeSH
• Triglycerides metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Endocannabinoids * MeSH
• Phospholipids MeSH
• Eicosapentaenoic Acid MeSH
• Docosahexaenoic Acids MeSH
• Cannabinoid Receptor Modulators MeSH
• Fatty Acids, Omega-3 MeSH
• Triglycerides MeSH

Progress in understanding the molecular mechanisms of cannabis action was made after discovery of cannabinoid receptors in the brain and the finding of endogenous metabolites with affinity to them. Activation of cannabinoid receptors on synaptic terminals results in regulation of ion channels, neurotransmitter release and synaptic plasticity. Neuromodulation of synapses by the cannabinoids is proving to have a wide range of functional effects, making them potential targets as medical preparations in a variety of illnesses, including some mental disorders and neurodegenerative illnesses. Cannabis contains a large amount of substances with affinity for the cannabinoid receptors. The endocannabinoids are a family of lipid neurotransmitters that engage the same membrane receptors targeted by tetrahydrocannabinol and that mediate retrograde signal from postsynaptic neurons to presynaptic ones. Discovery of endogenous cannabinoids and studies of the physiological functions of the cannabinoid system in the brain and body are producing a number of important findings about the role of membrane lipids and fatty acids in nerve signal transduction. Plant, endogenous and synthetic cannabinoids are using in these studies. The role of lipid membranes in the cannabinoid system follows from the fact that the source and supply of endogenous cannabinoids are derived from arachidonic acid, an important membrane constituent. The study of structure-activity relationships of molecules which influence the cannabinoid system in the brain and body is crucial in search of medical preparations with the therapeutic effects of the phytocannabinoids without the negative effects on cognitive function attributed to cannabis.

• MeSH
• Cannabis chemistry   MeSH
• Endocannabinoids * MeSH
• Cannabinoids chemistry   pharmacology   MeSH
• Plants, Medicinal chemistry   MeSH
• Humans MeSH
• Cannabinoid Receptor Modulators metabolism   MeSH
• Receptors, Cannabinoid drug effects   metabolism   MeSH
• Signal Transduction physiology   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Endocannabinoids * MeSH
• Cannabinoids MeSH
• Cannabinoid Receptor Modulators MeSH
• Receptors, Cannabinoid MeSH

In the last 25 years data has grown exponentially dealing with the discovery of the endocannabinoid system consisting of specific cannabinoid receptors, their endogenous ligands, and enzymatic systems of their biosynthesis and degradation. Progress is being made in the development of novel agonists and antagonists with receptor subtype selectivity which should help in providing a greater understanding of the physiological role of the endocannabinoid system and perhaps also in a broad number of pathologies. This could lead to advances with important therapeutic potential of drugs modulating activity of endocannabinoid system as hypnotics, analgesics, antiemetics, antiasthmatics, antihypertensives, immunomodulatory drugs, antiphlogistics, neuroprotective agents, antiepileptics, agents influencing glaucoma, spasticity and other "movement disorders", eating disorders, alcohol withdrawal, hepatic fibrosis, bone growth, and atherosclerosis. The aim of this review is to highlight distribution of the CB1 and CB2 receptor subtypes in the nervous system and functional involvement of their specific ligands.

• MeSH
• Cannabinoids therapeutic use   MeSH
• Humans MeSH
• Ligands MeSH
• Cannabinoid Receptor Modulators metabolism   MeSH
• Nervous System metabolism   MeSH
• Receptor, Cannabinoid, CB1 agonists   antagonists & inhibitors   metabolism   MeSH
• Receptor, Cannabinoid, CB2 agonists   antagonists & inhibitors   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Cannabinoids MeSH
• Ligands MeSH
• Cannabinoid Receptor Modulators MeSH
• Receptor, Cannabinoid, CB1 MeSH
• Receptor, Cannabinoid, CB2 MeSH

Endocannabinoid system, the complex of specific cannabinoid receptors (CB1 and CB2 subtypes) and their endogenous agonistic ligands (endocannabinoids) plays, besides others, an important role in the central and peripheral regulation of food intake, fat accumulation, and lipid and glucose metabolism. Alterations of these functions are associated with endocannabinoid system hyperactivity. The cannabinoid receptor CB1 antagonist rimonabant normalizes the over activated endocannabinoid system which contributes to the regulation of energy homeostasis, and improves lipid and glucose metabolism--decreases body weight, waist circumference, intra-abdominal obesity and triglycerides, increases HDL-C, improves insulin sensitivity according to HOMA index. Results of the international multicentric clinical trials confirm that rimonabant is well tolerated and show antiatherogenic effects (increased adiponectin, decreased marker of inflammation CRP and improvement of LDL profile) as well as decreased percentage of subjects with NCEP/ATPIII (National Cholesterol Education Program Adult Treatment Panel III) defined metabolic syndrome. Thus, the CB1 cannabinoid receptor antagonist rimonabant is suggested to be a prospective drug decreasing cardiometabolic risk factors.

• MeSH
• Cannabinoid Receptor Antagonists MeSH
• Endocannabinoids * MeSH
• Cardiovascular Diseases metabolism   MeSH
• Humans MeSH
• Lipid Metabolism * MeSH
• Cannabinoid Receptor Modulators antagonists & inhibitors   metabolism   MeSH
• Piperidines therapeutic use   MeSH
• Pyrazoles therapeutic use   MeSH
• Receptors, Cannabinoid metabolism   MeSH
• Rimonabant MeSH
• Risk Factors MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Cannabinoid Receptor Antagonists MeSH
• Endocannabinoids * MeSH
• Cannabinoid Receptor Modulators MeSH
• Piperidines MeSH
• Pyrazoles MeSH
• Receptors, Cannabinoid MeSH
• Rimonabant MeSH

• MeSH
• Endocannabinoids * MeSH
• Cardiovascular Diseases metabolism   MeSH
• Humans MeSH
• Lipid Metabolism MeSH
• Cannabinoid Receptor Modulators metabolism   MeSH
• Receptors, Cannabinoid metabolism   MeSH
• Risk Factors MeSH
• Check Tag
• Humans MeSH
• Publication type
• Comment MeSH
• Editorial MeSH
• Names of Substances
• Endocannabinoids * MeSH
• Cannabinoid Receptor Modulators MeSH
• Receptors, Cannabinoid MeSH

Development of the metabolic syndrome results from the interaction of genetic and environmental factors. Metabolic syndrome together with smoking represents risk factors for the development of cardiovascular complications. They may result from the hyperstimulation of the endocannabinoid system. The CB1 receptor has been assumed to play an important role in the endocannabionoid system. It is abundantly expressed in the brain, and in other parts of human body such as in the fat tissue. Rimonabant is a selective blocker of cannabinoid-1 (CB1) receptors and participates in the regulation of impaired endocannabinoid system. In the overweight humans, it stimulates sustained reduction of the body weight, girth size and it improves lipid and glucose metabolism. Rimonabant also reduces nicotine self-administration and may be effective not only as an aid for smoking cessation but also in the prevention of body weight increase related to the smoking cessation as it was documented in Rio-Lipids and Stratus-us studies.

• MeSH
• Cannabinoid Receptor Antagonists * MeSH
• Endocannabinoids * MeSH
• Weight Loss MeSH
• Smoking metabolism   MeSH
• Arachidonic Acids metabolism   MeSH
• Humans MeSH
• Metabolic Syndrome metabolism   therapy   MeSH
• Cannabinoid Receptor Modulators antagonists & inhibitors   metabolism   MeSH
• Smoking Cessation * MeSH
• Piperidines therapeutic use   MeSH
• Polyunsaturated Alkamides MeSH
• Pyrazoles therapeutic use   MeSH
• Rimonabant MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• anandamide MeSH Browser
• Cannabinoid Receptor Antagonists * MeSH
• Endocannabinoids * MeSH
• Arachidonic Acids MeSH
• Cannabinoid Receptor Modulators MeSH
• Piperidines MeSH
• Polyunsaturated Alkamides MeSH
• Pyrazoles MeSH
• Rimonabant MeSH