Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years

Abstract

The cannabis derivative marijuana is the most widely used recreational drug in the Western world, that is consumed by an estimated 83 million individuals (~3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the USA and worldwide. Compelling research evidence and the FDA cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ 9tetrahydrocannabinol (THC) and other plant-derived cannabinoids (phytocannabinoids). Of note, our body has a complex endocannabinoid system (ECS) -made of receptors, metabolic enzymes and transporters -that is also regulated by phytocannabinoids. The first endocannabinoid to be discovered 30 years ago was anandamide (N-arachidonoyl-ethanolamine); since then, distinct elements of ECS have been the target of drug design programs aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here, a critical review of our knowledge of the goods and bads of ECS as a therapeutic target are presented, in order to define the benefits of ECS-active phytocannabinoids and ECS-oriented synthetic drugs for human health. Significance Statement -The endocannabinoid system plays important roles virtually everywhere in our body and is either involved in mediating key processes of central and peripheral diseases or represents a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of the components of this complex system, and in particular of key receptors (like CB 1 R and CB 2 R) and metabolic enzymes (like FAAH and MAGL), will advance our understanding of endocannabinoid signaling and activity at molecular, cellular, and system levels providing new opportunities to treat patients.

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

“…In addition to direct radical-scavenging, the antioxidant effects of CBD are achieved through specific receptor-mediated pathways. There is an endocannabinoid system in the human body that is responsible for pain, sleep, appetite, and immune response ( Maccarrone et al, 2023 ). CBD may also exert antioxidant effects through binding with endocannabinoid receptors CB 1 and CB 2 .…”

Preclinical Evaluation of the Reversible Monoacylglycerol Lipase PET Tracer (R)‐[11C]YH132: Application in Drug Development and Neurodegenerative Diseases

“…The ECS is a complex cell signaling system that involves diverse physiological processes within the central nervous system (CNS), including brain plasticity, learning and memory, neuronal development, cellular fate, nociception, and inflammation. [1,2] Monoacylglycerol lipase (MAGL) is a membrane-bound soluble hydrolase localized in the axon terminal and is recognized as a predominant guardian in endocannabinoid signaling. MAGL degrades 85 % of brain 2-AG into glycerol and arachidonic acid, a major arachidonate precursor pool for neuroinflammatory prostaglandins.…”

Multiple triggers converge to preferential effector coupling in the CB2R through a complex allosteric communication network

“…The cannabinoid receptor 2 (CB 2 R) is a GPCR that plays a crucial role in numerous physiological processes including immune response and inflammation 2 . This makes the CB 2 R a promising therapeutic target for a variety of diseases, such as chronic pain, neuroinflammation, and cancer 3,4 . Currently, the only FDA approved drugs acting on CB 2 R are phytocannabinoids including Δ9-THC or its synthetic analogues.…”

“…Currently, the only FDA approved drugs acting on CB 2 R are phytocannabinoids including Δ9-THC or its synthetic analogues. However, these compounds are non-selective agonist of cannabinoid receptors and cause psychoactive effects via CB1R 4 . Additionally, they also cause adverse cardio-vascular liability in a dose-dependent matter 5 via CB1R.…”