Humans have used cannabis for centuries, but only in the last 50 years or so has any scientific understanding emerged as to how cannabis works within the human body. While the discovery of the first plant cannabinoids took place in the 1940s, it was not until 1964 that THC produced by the cannabis plant was first characterised and synthesised by Gaoni and Mechoulam in Israel.
The discovery of THC in 1964 sparked the search for its mechanism of action. Initially, it was postulated that THC and other cannabinoids increased cell membrane permeability. Eventually, however, the permeability hypothesis was disproved, which led to the search for a protein receptor molecule in the body with which THC might interact. The first cannabinoid (CB) receptors in the body were not found until the late 1980s. These receptors comprised a new series of homeostatic regulatory mechanisms within the body, which was named the endocannabinoid system.
Role of the Endocannabinoid System
The endocannabinoid system is a very complex regulatory system, broad in its function, and found within all complex animals, from fish to humans. It regulates diverse functions such as memory, digestion, motor function, immune response and inflammation, appetite, pain, blood pressure, bone growth, and the protection of neural tissues. The endocannabinoid system comprises three principal elements: endocannabinoid receptors; specialised molecules called endocannabinoids that interact with those receptors; and enzymes that either synthesise or metabolise these endocannabinoids.
Endocannabinoid Receptors
The two primary subtypes of classical cannabinoid receptors in the endocannabinoid system are CB1 and CB2. These receptors are distributed throughout the central nervous and immune systems and within many other tissues, including the brain, gastrointestinal system, reproductive and urinary tracts, spleen, endocrine system, heart, and circulatory system. Many of the physiological effects of cannabis were first believed to be caused by the interaction of phytocannabinoids with the CB1 and CB2 receptors.
Because the THC family of cannabinoids are the only compounds that robustly activate the CB1 receptor, some have even suggested that its name be changed from CB1 to the THC receptor. It is now known that cannabinoid interactions extend beyond the CB1 and CB2 receptors, however, and interact with other CB-type and related receptors and ion channels.
These include the so-called orphan CB receptors GPR55, GPR18, and GPR119; the transient receptor potential vanilloid-type channel (TRPV1, associated with pain transmission and typically activated by temperatures over 109ºF/43ºC, hot peppers or horseradish, and also known as the capsaicin receptor); and the peroxisome proliferator-activated nuclear receptors (PPAR-alpha and – gamma regulate important metabolic functions involving fatty acid storage, glucose metabolism, and development and progression of malignancies).
Of these, other CB-type receptors, the orphan or candidate cannabinoid receptors are becoming increasingly important to the understanding of the endocannabinoid system. These receptors are so-called “orphans” because their endogenous ligands (molecules that bind to larger molecules, such as receptors) have not been conclusively identified.
The orphan CB receptors have the following functions:
- GPR55 is a receptor linked to energy homeostasis and metabolic dysregulation associated with diabetes and obesity.
- GPR18 regulates disparate physiological functions ranging from intraocular pressure to cellular migration, including endometriosis and some forms of metastatic disease.
- GPR30 responds to estrogen with rapid signalling.
- GPR119 functions as a “fat sensor” to reduce food intake and weight gain.
Endocannabinoid Activity
The CB1 receptor is expressed throughout the brain, where endocannabinoids and CB1 combine to form a “circuit breaker,” which modulates the release of both inhibitory and excitatory neurotransmitters across the synapse. It is the activation of the CB1 receptor that is responsible for the psychoactive effects of cannabis since THC mimics an endocannabinoid by binding to this receptor.
The list of brain functions that are affected by the endocannabinoid system is enormous:
Decision-making, cognition, emotions, learning, and memory, as well as regulation of bodily movement, anxiety, stress, fear, pain, body temperature, appetite, sense of reinforcement or reward, blood-brain permeability, and motor control. One brain region that does not express many CB1 receptors is the brain stem, responsible for respiration and circulation, which is a primary reason why cannabis overdoses do not cause respiratory depression and death, both of which are possible with opioid overdoses. Until a few years ago, it was believed that CB2 receptors were only primarily found in immune and blood cells, tonsils, and the spleen.
From these sites, CB2 receptors controlled the release of cytokines (immunoregulatory proteins) linked to inflammation and general immune function throughout the body. Recently, with the advent of better probes and methods, CB2 expression has been identified in key regions of the brain, including the hippocampus. CB2 has been shown to modulate midbrain reward circuitry, such as the self-administration of cocaine. In the hippocampus, CB2 receptors appear to modulate self-activity and information flow between brain networks, potentially assisting in the selection of inputs that may guide complex behaviours.
Targeting the Endocannabinoid System with Drugs
The endocannabinoid system as a target for drug delivery goes well beyond the use of cannabis. Cannabinoid-based medicines can either enhance or interfere with the endocannabinoid system’s balancing act, by targeting receptors, the endocannabinoids, or the enzymes that synthesize or degrade those endocannabinoids. However, designing drugs that interact safely with the endocannabinoid system is difficult, and drugs that antagonize or interfere with the function of cannabinoid receptors have met with decidedly mixed success.
Regardless, the positives outweigh the negatives in that regard and with ongoing research our dosing and titrations will only get better.
Have you ever heard of the Endocannabinoid system? Let us know your thoughts below.
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