Every function in our bodies requires a specific balance of factors in order to perform at maximum capacity. When this balance is achieved, it’s called homeostasis. The endogenous cannabinoid, or endocannabinoid system (ECS), plays a major role in survival by helping to maintain homeostasis in fish, reptiles, birds, and mammals (including humans).
Pain, stress, appetite, energy metabolism, cardiovascular function, reward and motivation, reproduction, and sleep are just a few of the functions the endogenous cannabinoid system is involved in.
The ECS consists of three main components: “messenger” molecules that our bodies synthesize, the receptors these molecules bind to, and the enzymes that break them down. This system is present throughout the entire body — it’s on immune cells in our bloodstream, on our nerves throughout our extremities, on the entire axis of the spinal cord, and in virtually every cell in our entire brain. There are even cannabinoid receptors in our skin.
The body naturally produces two known cannabinoid molecules: anandamide and 2-arachidonoylglycerol (2-AG). Because anandamide was only discovered in the 1990s, there is still a great deal of research and study to be done in order to fully understand these endocannabinoid molecules.
Anandamide and 2-AG seek out cannabinoid receptors CB1 and CB2. While these two receptors have been the most studied by scientists, there are others. Anandamide and 2-AG also activate TRPV proteins. TRPV proteins are responsible for the body’s sensations of heat and cold. For example, that heat you experience when you eat chili peppers — that’s a TRPV response.
Although the CB and TRPV receptors are the major players in the ECS, there are at least three other receptors that may eventually be considered cannabinoid receptors, once their functions are fully understood (GPR55, GPR18, and GPR119).
CB1 receptors are largely found in the central nervous system, where they regulate a wide variety of brain functions. In fact, they’re the most widely expressed protein of their kind in the brain. In the brain, the major role of the CB1 receptor is to regulate the release of other neurotransmitters, such as serotonin, dopamine, and glutamate. Think of these neurotransmitters as children waiting to enter a crosswalk after school: The endocannabinoid system acts as the crossing guard, allowing them to cross at very tightly controlled times and amounts. Although the CB1 receptor is responsible for the euphoric effects of cannabis, it’s also critically involved in the brain’s top-down control of pain.
CB2 receptors are mostly found on immune cells, which circulate throughout the body and brain via the bloodstream. They’re also found on neurons in a few select brain regions. CB2 receptors are involved in pain relief, anti-inflammation and neuroprotection.
Anandamide and 2-AG are produced by our cells in an “on demand” fashion. They are commonly referred to as “retrograde messengers” because they float backwards across the gap between two neurons, in the opposite direction of normal neuronal communication. After binding to their targets, the endogenous cannabinoids are rapidly broken down by enzymes FAAH and MAG lipase. FAAH, or fatty acid amide hydrolase, breaks down fatty acid amides like anandamide, while MAG lipase, or monoacylglycerol lipase, breaks down 2-AG.
Several pharmaceutical companies have identified these enzymes as potential targets for new classes of drugs to treat pain. The rationale is that if the endocannabinoid molecules relieve pain, then perhaps increasing their presence (by preventing their enzymatic breakdown) would be a “natural” mechanism of pain relief. Unfortunately, this approach has proven to be much more dangerous than stimulating the endocannabinoid system directly, by introducing cannabinoids from the cannabis plant.
Because our bodies already use cannabinoid molecules to regulate many functions, we’re inherently endowed with many targets the cannabis plant can activate. Phytocannabinoids (plant-derived cannabinoids) are compounds that are unique to the cannabis plant, produced by trichomes on its surface. Beyond the known and potential cannabinoid receptors mentioned above, phytocannabinoids bind to many other targets. For instance, cannabidiol (CBD) has at least 12 sites of action in the brain.
Everyone’s endocannabinoid system is unique: the rates of 2-AG and anandamide production and break down can vary wildly, and so can the levels of cannabinoid receptors in our bodies. For instance, prolonged use of cannabis causes the brain to reduce the number of CB1 receptors that are available for activation. Using human brain imaging, we can observe that just 48 hours of abstinence from cannabis is sufficient to resensitize the system and bring the expression of CB1 proteins to a level that is comparable to a non-cannabis user.
Individual differences in this system also occur due to genetic variations (mutations) in both the receptors (CB1 and CB2) and the degradation enzymes (FAAH and MAG-lipase). In the future, it may be possible for doctors to screen for the presence of these genetic variations in a simple DNA test, so patients can have some idea of what their ECS looks like before starting cannabis therapy. This type of biological screening would be incredibly useful in finding the right kind of cannabis therapy for the right patient.