The endocannabinoid system (ECS) is a complex cell-signaling network found throughout the animal kingdom that functions as a homeostatic regulator. This system maintains internal stability by modulating a wide range of physiological processes, including mood, memory, appetite, and immune response. Surveying the presence of the ECS across different animal phyla reveals that the core machinery of the ECS is ancient and highly conserved, appearing in nearly all major animal groups.
Defining the Endocannabinoid System Components
The presence of a functional ECS in any animal is determined by the identification of three main molecular components. The first component consists of the cannabinoid receptors, primarily Cannabinoid Receptor Type 1 (CB1) and Type 2 (CB2), which are G protein-coupled receptors located on cell surfaces. The second component is the group of endogenous ligands, known as endocannabinoids, which are lipid-derived signaling molecules that bind to these receptors; the two most studied are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The final component includes the specific enzymes responsible for the synthesis and rapid degradation of these ligands, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Identifying the functional orthologs—genes or proteins in different species that evolved from a common ancestor—for all three components establishes the existence of a true ECS.
Evolutionary Origins of the System
The core elements of the ECS are ancient, with precursors appearing very early in animal evolution. Evidence suggests that the ability to synthesize endocannabinoids is an old phenomenon, potentially dating back to the common unicellular ancestor of animals and plants. For example, the freshwater polyp Hydra vulgaris, one of the first animals to evolve a neural network, possesses an ECS that regulates its feeding response.
The full system, including a CB1-like receptor, is found in basal chordates, such as the sea squirt Ciona intestinalis, which are marine invertebrates closely related to vertebrates. This suggests that the complete receptor-ligand-enzyme signaling system originated in a deuterostomian invertebrate, a group that includes all vertebrates. The CB1 receptor is highly conserved across many phyla, indicating its biological importance has been preserved over hundreds of millions of years.
Presence and Conservation in Vertebrates
The endocannabinoid system is fully present and highly conserved across all major vertebrate classes, from fish to mammals. This includes mammals, birds, reptiles, amphibians, and bony fish, all of which possess orthologs for the CB1 and CB2 receptors, the endocannabinoid ligands, and the synthesis and degradation enzymes. The functional completeness of the ECS throughout the subphylum Vertebrata underscores its role in regulating complex physiological functions.
In bony fish, such as the zebrafish (Danio rerio) and puffer fish (Takifugu rubripes), genes encoding orthologs of both CB1 and CB2 receptors are found, sometimes in duplicate copies due to ancient whole-genome duplication events. Amphibians like the African clawed frog (Xenopus laevis) and various reptile species, including turtles, also possess CB1 receptor genes structurally similar to their mammalian counterparts. Birds, such as chickens and zebra finches, exhibit a complete ECS, with CB1 receptors playing a conserved role in functions like locomotor activity and neural plasticity. Across all these groups, the CB1 receptor’s function as a retrograde messenger that modulates neurotransmitter release has remained consistent across the vertebrate lineage.
Endocannabinoid Signaling in Invertebrate Phyla
While the full, integrated ECS is a hallmark of vertebrates, components of the system are distributed unevenly across invertebrate phyla. Many invertebrates, including sea urchins, leeches, and mussels, possess endocannabinoid-like systems. These species often contain the enzymes for endocannabinoid biosynthesis and inactivation, such as FAAH and MAGL, suggesting the production and breakdown of the lipid messengers is common.
However, the canonical CB1 and CB2 receptors are frequently absent in many non-chordate invertebrates, particularly in the large phylum Arthropoda, which includes insects. For instance, the fruit fly (Drosophila melanogaster) and other insects generally lack the full set of CB1/CB2 receptors, though they can still produce endocannabinoid ligands like 2-AG. This fragmented presence suggests that while the signaling molecules are widespread, the sophisticated, integrated signaling network mediated by the cannabinoid receptors largely evolved in the lineage leading to chordates and vertebrates. The system’s components in invertebrates often serve roles including control of reproduction, feeding behavior, and neuroimmune modulation.