Cannabidiol is the major nonpsychoactive ingredient in cannabis. Cannabidiol demonstrates a range of effects that may be therapeutically useful, including anti-seizure, antioxidant, neuroprotective, anti-inflammatory, analgesic, anti-tumor, anti-psychotic, and anti-anxiety properties. Exact mechanism of action of cannabidiol is not known, but may include effects on the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 glycine receptors. GW Pharmaceuticals successfully developed the world’s first prescription medicine derived from the cannabis plant, Sativex® (buccal spray containing delta-9-tetrahydrocannabinol and cannabidiol) now approved in over 29 countries outside of the United States for the treatment of spasticity due to Multiple Sclerosis. GW Pharmaceuticals is developing Epidiolex® (a liquid formulation of pure plant-derived cannabidiol) for certain rare and severe early-onset, drug-resistant epilepsy syndromes.

AM-251 is a 123I radioisotope and potent CB1 receptor antagonist derivative of the CB1 cannabinoid receptor inverse agonist SR141716A, presenting a radioprobe for in vivo binding studies at the CB1 receptor with a higher affinity (Ki = 7.49 nM) for CB1 than the parent compound (Ki = 11.5 nM). AM-251 has been employed in competitive binding studies to identify CB1 affinity of different cannabimimetic agonists in vivo. AM-251 is also a potent activator of the GPR55 receptor. Daily injection of AM-251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM-251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. AM-251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome.

HU-210 is a synthetic cannabinoid. HU-210 is a highly potent cannabinoid receptor agonist. Also, it displays agonist activity at GPR55. HU-210 administration in adult rats results in a dose-dependent inhibition of plasma growth hormone, follicle stimulating hormone, and luteinizing hormone; modifications of plasma adrenocorticotropic hormone (ACTH) and corticosterone levels reveal a dose-dependent action on the pituitary-adrenal axis after acute exposure. HU-210 block beta-amyloid peptide-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-alpha release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB2-selective agonist. HU-210 induced a spatial deficit in the water maze in learning a reference memory task in numerous parameters together with alterations in hippocampal firing patterns of single principal neurons.

Palmidrol (palmitoylethanolamide, PEA) is a natural fatty acid amide found in a variety of foods, which was initially identified in egg yolk. It is an endogenous compound, locally synthesized in animal and human tissues and body fluids, to protect against perturbing inflammation. In addition to its anti-inflammatory activity, palmidrol (palmitoylethanolamide, PEA) also produces analgesia, neuroprotection, and possesses anti-epileptic properties. It also reduces gastrointestinal motility and cancer cell proliferation, as well as protecting the vascular endothelium in the ischemic heart. The physiological stimuli that regulate palmidrol (palmitoylethanolamide, PEA) levels in mammalian tissues are largely unknown, however, multiple studies indicate that this lipid accumulates during cellular stress, particularly following tissue injury. Palmidrol (palmitoylethanolamide, PEA) is a potent and selective agonist of orphan receptor GPR55.