The flowering plant Cannabis sativa, known most commonly as marijuana, is one of the first plants to be used for therapeutic and recreational use and even the occasional religious ceremony. Records of medicinal use date back as far as 5,000 years in China with therapeutic uses such as pain relief, mood stabilization, and reduced nausea documented during this time. However, scientific research didn’t begin until the early 20th century when the major constituents of cannabis, phytocannabinoids, were first characterized. The first of these plant cannabinoids, Cannabinol (CBN) and Cannabidiol (CBD), were isolated approximately 80 years ago. The versatility of cannabis’s effects didn’t begin to be unveiled until the isolation and partial synthesis of the phytocannabinoid ∆9-tetrahydrocannabinol (THC) about 30 years later. From the approximate 550 total compounds currently identified in cannabis, 144 are phytocannabinoids, and THC is considered the primary psychoactive component of the plant.

With further identification and understanding of phytocannabinoids, the idea of the presence or absence of cannabinoid receptors (CBRs) became a debated topic in the field. The discovery and synthesis of THC paved the way for the construction of high potency synthetic cannabinoids with similar structures to natural phytocannabinoids. The availability and use of these synthetic cannabinoids directed research to answering the question of the existence of endogenous CBRs. Evidence of their presence was first demonstrated by the ability of cannabinoids to inhibit cAMP formation, a Gi/Go protein pathway that is turned on through GPCR surface proteins. This was followed by the successful cloning of the first CBR, cannabinoid receptor 1 (CB1R), from mammalian brain, followed closely by the identification of a second CBR, eventually named cannabinoid receptor 2 (CB2R), which was cloned from immune tissue.

With these newly discovered CBRs, ligands that are naturally expressed in the body, N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG), that bind these surface proteins were isolated and named endogenous cannabinoids or endocannabinoids. These two originally identified molecules remain the best studied endocannabinoids in the field. They are endogenous lipids whose precursors are present in the cell membrane and when needed can be released from the lipid bilayer, converted into endocannabinoids through enzyme reactions, and released into the extracellular space as neuromodulators. The efficacy of each endogenous CBR agonist varies. 2-AG has high efficacy for both CB1R and CB2R while anandamide has low efficacy for CB1R and extremely low efficacy for CB2R. These endocannabinoids, their corresponding CBRs, and relevant enzymes comprise the endocannabinoid system. This system remains a research field of high interest in terms of further exploration of canonical, noncanonical, and adjacent signaling pathways and the potential development of these pathways for therapeutic and medical use.