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Home > Physiology > An Overview of the Endocannabinoid System
6 min

An Overview of the Endocannabinoid System

Throughout history and across civilizations there is extensive evidence of humans using cannabis for therapeutic benefit and to treat many types of ailments.  However, our ancestors did not know why these plants worked or why they were helpful but relied on anecdotal evidence and observation. Early knowledge of how cannabis works remained poorly understood until the last century. 

In the early 1990s, researchers made a significant discovery that explained the therapeutic potential of cannabis plants — a previously unknown communication system involved in the regulation of nearly every essential function in the body. This intriguing system of messengers and receptors was named the endocannabinoid system after the plant elements that led researchers to its discovery, cannabinoids.

Discovery of a previously unrecognized regulatory system

The discovery of the endocannabinoid system began when American chemist Roger Adams isolated the first cannabinoid, cannabidiol (CBD), in the 1940s. Decades later, Israeli scientist Raphael Mechoulam isolated tetrahydrocannabinol (THC), and determined THC was responsible for the psychotropic effects of cannabis, while CBD does not cause any euphoric or psychotropic effects. Although these observations were instrumental to the discovery of the endocannabinoid system, its impact was not well understood for decades.

During the 1980s, US President Ronald Reagan allocated tens of millions of dollars for researchers to prove that marijuana causes brain damage. After researchers determined that premise to be false, the Reagan administration funded additional studies that ironically led researchers to the discovery of the first endocannabinoid receptor in 1988. In turn, the discovery of the endocannabinoid receptors (CB1 and CB2) led to the discovery of the metabolic enzymes that interact with those receptors. 

The messengers of the endocannabinoid system

Locations of various endocannabinoid receptors in the human body.

If investigators had not located the receptors within the body that respond to cannabis, they may never have learned that the human body produces its own cannabinoids. Indeed, it was the discovery of the cannabinoid receptors that prompted the search for the molecules that bind with them, their ligands. 

The cannabinoid ligand anandamide was discovered in 1992, and 2-AG (2-Arachidonoylglycerol) shortly after in 1995. Today we understand that anandamide and 2-AG are the prime messengers of the endocannabinoid system. Anandamide and 2-AG are called endocannabinoids because endo means within (as opposed to phytocannabinoid- deriving from the plant). These essential neurotransmitters interact with their corresponding receptors located throughout the body to perform numerous functions. Consider the following examples:

The receptors of the endocannabinoid system

The interaction between the endocannabinoid messengers and receptors — CB1 and CB2 — regulate essential processes. 

CB1 Receptors
CB1 receptors are found throughout the body, with the highest concentration within the brain and spinal cord. The CB1 receptors in the hypothalamus regulate energy levels and metabolism, while CB1 receptors in the amygdala are responsible for regulating emotional responses and memories. CB1 receptors are also abundant in nerve endings.

CB2 Receptors
While CB2 receptors are also found throughout the body; they are most abundantly concentrated within the peripheral nervous system, the nerves extending from the brain and spinal column to other areas of the body. That means CB2 receptors regulate organ function and muscle movement. CB2 receptors also regulate the functions of the immune system. When activated, CB2 receptors reduce inflammation.

The messengers produced in the body to influence the endocannabinoid receptors are made as needed and quickly broken down by enzymes. Ideally, your body would create all the endocannabinoids needed to keep this essential communication system functioning efficiently. But under the effects of illness, injury, or environmental stress, the need for endocannabinoid messengers can exceed the supply. When the body needs more of these essential messengers than it can produce, the communication between vital processes can break down.

Endocannabinoid system balance is essential for health

All living organisms require a consistent internal environment, and the body tries to constantly maintain balance. If balance cannot be restored, the organism cannot survive. The regulatory responses enacted to re-establish balance throughout the body is a process known as homeostasis.

Many researchers today believe the endocannabinoid system is responsible for homeostasis, the processes that bring the internal environment back into balance. In fact, the endocannabinoid system is so vital to maintaining homeostasis that some researchers believe endocannabinoid deficiencies play a significant role in numerous health conditions including migraine, irritable bowel syndrome, fibromyalgia, and several neurodegenerative disorders.

Plant-based cannabinoids can influence endocannabinoid system function

While the body makes its own endocannabinoids, it was phytocannabinoids (plant-derived cannabinoids) that led researchers to the discovery of the endocannabinoid system. Today we understand that the phytocannabinoids in cannabis plants mimic the effects of anandamide and 2-AG and influence the receptors of the endocannabinoid system. The plant-based cannabinoids in cannabis also target receptors for other important chemical messengers, including GABA, dopamine, and serotonin. Just a few of the numerous processes regulated by endocannabinoid system function include:

  • Memory and learning
    CB1 and CB2 receptors are directly involved in the processes that regulate cognition, memory, and learning. While CB1 receptors are widely expressed in multiple areas, they are highly concentrated in regions of the brain associated with cognition and memory. These receptors are shown to control both cognitive processes and emotional behavior by modulating neuronal signaling and synaptic plasticity. Neuroplasticity is an important process in the brain which allows the brain to learn and adapt to new information.
  • Appetite regulation
    Researchers recognized decades ago that food intake is controlled by a complex process involving neurological, behavioral, and endocrine system function. Studies investigating the activation of cannabinoid receptors in the brain suggest that modulating cannabinoid receptors is essential for regulating food intake and metabolizing macronutrients and fat. There is strong evidence that modulating endocannabinoid signaling could be instrumental in the management of obesity and eating disorders.
  • Thermoregulation
    Thermoregulation is an important homeostatic process that maintains core body temperature  The body maintains a core temperature in the face of a different external environmental temperature using the sympathetic nervous system, adjusting heart rate, vasoconstriction, and respiration to help the body adjust and maintain internal balance. In addition, our body sometimes intentionally raises our core temperature to fight infection, with endocannabinoid receptors playing a role in that.
  • Immune system function
    Researchers believe endocannabinoid messengers can have both an inhibitory and stimulatory effect on the immune system by interacting with CB2 receptors. Endocannabinoids exhibit a complex regulatory effect on the immune system by inhibiting inflammation and suppressing cell activation. Researchers have hypothesized that modulating endocannabinoids could provide a “novel therapeutic” approach for the treatment of inflammation and autoimmune diseases. Researchers are also investigating the role of the endocannabinoid system for the treatment of asthma, multiple sclerosis, osteoarthritis, and some forms of cancer. Investigations into the therapeutic benefits of endocannabinoid system modulation are still in preliminary stages.
  • Female reproductive processes
    Endocannabinoids play a critical role in the modulation of the female reproductive processes. Researchers note a complex interplay between the endocannabinoid system with the hypothalamus, pituitary gland, and the ovarian axis, with CB1 receptors believed to modulate numerous complex activities. The ovarian cycles are controlled by the interaction of hormones secreted by this trio of structures. While the phytocannabinoids in cannabis are shown to potentially disrupt female reproduction by decreasing estrogen and progesterone levels, endocannabinoid system involvement in female reproduction suggests controlled modulation of the endocannabinoid system is essential for reproductive success.
  • Sleep and sleep cycles
    Sleep cycles are regulated by circadian rhythms, which are regulated by exposure to light and darkness. The endocannabinoid system also plays a role, with research showing that the activation of CB1 receptors induces sleep in laboratory settings while the endocannabinoid system also helps stabilize sleep patterns due to its effect on homeostatic recovery. The endocannabinoid system also regulates many of the processes that can interfere with restful sleep, including stress responses, anxiety, digestive disturbances, and pain perception.
  • Pain perception
    The endocannabinoid system is now understood to be one of the key systems in the regulation of pain, modulating actions at every stage of the pain processing pathway. Endocannabinoids and their corresponding receptors are found in the pain circuits of the nervous system, from the nerve endings of the peripheral nervous system to the brain. The endocannabinoid messengers produced in the body, anandamide and 2-AG, both play an essential role in analgesia and pain management. Researchers discovered that the more anandamide found in the bloodstream, the lower the level of pain perception.
  • Autonomic processes
    The autonomic nervous system regulates numerous essential functions within the body. The autonomic nervous system has two branches; sympathetic and parasympathetic. The sympathetic nervous system is responsible for the “flight or fight” response, while the parasympathetic system is credited with “rest and digest.” Some of the many processes regulated by the autonomic nervous system include heart rate, digestion, thermoregulation, respiration, pupil dilation, and blood pressure. Research suggests that deficiencies within the endocannabinoid system could lead to autonomic dysfunction which can have serious implications throughout the body. 

Supplementing the endocannabinoid system with phytocannabinoids

Given that the endocannabinoid system plays a significant and sometimes critical role in all of these processes, it can also provide avenues for breakthrough treatments and therapies for many different conditions.  

The phytocannabinoids found in cannabis plants are shown to mimic the effects of the endocannabinoid made in the body. By influencing key receptors, plant-based cannabinoids may have significant therapeutic potential, including anxiolytic, anti-inflammatory, antiemetic, antispasmodic, and anesthetic benefits. While research into each potential benefit is still in its infancy, there is growing awareness and research is growing at a breakneck speed.

While numerous people are supplementing the endocannabinoid system messengers with cannabis-derived products, particularly the non-psychoactive cannabinoid CBD, it’s important to understand that cannabis use is not ideal for everyone. If you have a medical condition or take medication, it’s essential to talk with your healthcare provider before using cannabis. 

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