Illuminating the Multifaceted Function of Endogenous Cannabinoids

Embedded in our biological makeup, humans are endowed with an endocannabinoid system (ECS), which produces and uptakes cannabinoids. The ECS was first discovered in the early 1990's, and has since been central to the study of cannabis pharmacology. The function of the ECS is complicated and still being understood, but so far we know that the ECS plays an important role in regulating a diverse array of physiological functions such as appetite, pain modulation, mood, memory, motor coordination, hormonal regulation, thermoregulation, and much more. 

The ECS consists of cannabinoid receptors, which are activated by cannabinoids fitting into them (think of a lock and key), subsequently activating the receptor. There are various types of receptors, and various types of cannabinoids, coalescing in a wide variety of possible combinations. However, receptor sites are only part of the entire ECS; in this article, we’ll look at the function of endocannabinoids (endogenous + cannabinoid = endocannabinoids), which are cannabinoids naturally produced within the body.

There are two primary endocannabinoids that we understand to have the greatest impact on the ECS: anandamide and 2-AG (2-Arachidonoylglycerol). They operate via slightly different mechanisms, but work in conjunction to promote the harmonious balance of biorhythms. 

Anandamide 

Anandamide is the most notorious endocannabinoid, its name translates to “bliss molecule” because of the characteristic effect this cannabinoid has on reward pathways and the experience of pleasure. It has a similar effect profile and molecular structure to THC, enabling it to activate the same receptors in similar ways. Like THC, anandamide has a binding affinity for CB1 receptors, which could help explain why this endocannabinoid has a similar physiological function to THC. 

In rat studies, anandamide enhances the pleasure response to sucrose and improves appetite, which may offer insight to THC’s ability to induce the munchies. For more information on the physiological mechanisms that prompt “the munchies,” glance at my article Munchie Myths & Facts. 

In addition to the experience of pleasure and reward, anandamide is understood to play an important role in pain modulation by affecting nerve conduction. Anandamide acts as a neurotransmitter, facilitating the transmission of signals between nerve cells. Anandamide deficiency is associated with heightened neuropathic pain in old mice, which may elucidate a role for THC in the prevention of chronic pain in old age. However, more research (particularly in human subjects) is necessary to draw conclusions. 

2-AG 

2-AG is an abundant endocannabinoid that plays a more subtle role in balancing physiological functions (i.e. homeostasis). Unfortunately, 2-AG isn’t as well-researched as anandamide, but several animal studies have uncovered a variety of complex mechanisms influenced by 2-AG. In particular: stress, anxiety, depression, pain, and hunger are all modulated by increasing or decreasing levels of 2-AG in the brain, although acute effects are still unclear. Based on available research, 2-AG plays a critical role in regulating hunger; as 2-AG levels rise, hunger increases, but as 2-AG levels subside, hunger decreases. 2-AG is produced more abundantly during fasting, indicating that the body uses this cannabinoid to regulate the sensation of hunger as a means of survival. 

2-AG has important effects on the experience of anxiety, particularly in regard to the stress hormone cortisol. Research is demonstrating that stressful events in which cortisol levels are elevated triggers an increase in the production of 2-AG. The exact mechanism is still being understood, but one theory is that 2-AG is a tool the body uses to maintain balance in stressful situations. Considering that stress is one of the main contributing factors of depression, it comes as no surprise that 2-AG also plays a role in mediating depression and depression-like symptoms. 

By modulating inflammation, 2-AG is able to have broad effects on the experience of pain. Cannabinoids, generally, have anti-inflammatory properties; but 2-AG in particular has been attributed to improved clinical outcomes in animal studies regarding neurodegenerative diseases such as alzheimers or parkinsons. 

Understanding the role of endocannabinoids will help us to better understand the intricate function of the human endocannabinoid system, which, in turn, progresses our understanding of how phytocannabinoids (those derived from cannabis) interact with, and modulate, the ECS. These findings have critical implications for the future of medical cannabis.