How it Works: The Endocannabinoid System
We just beginning to understanding this complex system, here’s what we’ve got so far.
The endocannabinoid system is a signalling system of receptors found on the surface of certain cells, and then the molecules that bind to them. These molecules are called ligands or endocannabinoids. In addition, there are a collection of enzymes responsible for assembling or degrading the endocannabinoids.
In the 1980s, research into the effect of endocannabinoids on the human brain discovered that there was a specific binding site for them. In the early 1990s, the two major cannabinoid receptors were identified and cloned. These are called CB1 and CB2 and they are both G protein-coupled receptors. Since this discovery, researchers have learned more about the endocannabinoid system and mechanisms for its involvement in various diseases. As a result, cannabis, or cannabinoids, have become the focus in developing new therapies, and the medical use of cannabis has become a target of public policy.
The first type of cannabinoid receptor, CB1, is found primarily in the brain and on tissues associated with the central nervous system, such as neurons in the spinal cord. However, it has also been found in peripheral organs like the pancreas, digestive tract, and liver.
In the brain, CB1 receptors are present in high densities in certain structures, like the substantia nigra, basal ganglia, cerebellum, and hippocampus. Other areas of the brain have much lower densities, like the brainstem, which contributes to cannabis’ safety record (can’t overdose).
CB1 receptors are thought to be responsible for the psychoactive effects of cannabis. These receptors also play an important role during brain development and in several signalling pathways in the brain. These pathways are responsible for cognition, neuronal growth, and the regulation of reward and mood systems. Activation of the CB1 receptor is therefore not only responsible for the euphoric high associated with THC, but also for a variety of therapeutic benefits like treating anxiety, pain, and post-traumatic stress disorder (PTSD).
The CB1 receptor is activated by endogenous ligands, but also by the most famous of the cannabinoids found in the cannabis plant, delta-9-tetrahydrocannabinol (THC). THC binds strongly to the CB1 receptor, which is likely the reason for its psychoactive effects. Cannabidiol (CBD) can bind to the CB1 receptor, but not very strongly; its affinity for the receptor is low.
Another cannabinoid found in the Cannabis plant, delta-9-tetrahydrocannabivarin (THCV) is also known to bind strongly to the CB1 receptor, although THCV blocks the binding site on the CB1 receptor, inhibiting its activation.
In the brain, the CB1 receptor is often found in neural synapses. Unlike the receptors associated with most neurotransmitters, the CB1 receptor is often found in the presynapse neuron. Endocannabinoids are made and released from the postsynaptic neuron. When the CB1 receptor is activated, it often prevents further release of neurotransmitters, so it seems that the endocannabinoid system functions as a negative feedback loop. For example, it can prevent the release of glutamate, which is thought to be the mechanism behind the neuroprotective effects of cannabis against excitotoxicity. However, CB1 activation has been shown to increase the release of dopamine, which is thought to contribute to addiction.
The CB2 receptor is primarily expressed by immune cells. Some scientists hypothesize that the CB2 receptor evolved as a defense mechanism for the body since it is involved in suppressing inflammatory responses and in neuroprotective responses to brain injury. The CB2 receptor is also thought to be involved in the pain relieving property of cannabis. THC and CBD both bind to the CB2 receptor, although again, CBD has a low affinity for it. THCV also inhibits the CB2 receptor. Many researchers have developed synthetic cannabinoid molecules that can bind specifically to the CB2 receptor and not to the CB1 receptor in order to obtain therapeutic effects of CB2 activation without causing psychoactive side effects.
The low affinity of CBD for both the cannabinoid receptors has caused some researchers to hypothesize that there must be other unidentified receptors in the endocannabinoid system.
Other G protein-coupled receptors have been identified as cannabinoid-like. In addition, there are other receptors, like the transient receptor potential vanilloid type 1 receptor (TRPV1) ion channel, that can also be activated by cannabinoids like CBD, so there may be some crossover between the endocannabinoid and other signaling systems. CBD is also thought to inhibit the activity of fatty acid amide hydrolase (FAAH), the enzyme responsible for breaking down endocannabinoid anandamide. As a result, CBD can contribute to elevated levels of anandamide, which targets the cannabinoid receptors with higher affinity than CBD but without psychoactive effects of THC.
In many ways, we are just at the beginning of a steep learning curve when it comes to the inner-workings of the endocannabinoid system. It is complex and its mysteries will lead to important healing practices in the future.