What Are Endocannabinoids?

WRITTEN BY KIMBERLY MA AND DR. SWATHI

Due to findings over the last few decades on the medical potential of natural compounds like cannabidiol (CBD) and cannabigerol (CBG), cannabinoid products have taken off. The versatile therapeutic uses for cannabinoids products are attributed to their ability to affect many different organ systems within the body. So, how exactly do these compounds work at so many different sites? Answer: Through the endocannabinoid system!

What is the endocannabinoid system? 

Cannabinoids stimulate a vast network of receptors distributed throughout our body known as the endocannabinoid system (ECS). This network is involved in both cognitive and physiological processes. Some of these processes include regulation of mood, appetite, inflammation, and more. There are two main types of receptors which are CB1 and CB2 receptors. CB1 is primarily located in the brain and central nervous system while CB2 is more dispersed in peripheral organs. Both receptors can respond to exogenous cannabinoids that come from external sources such as the cannabis plant, like CBG, CBD, and trans-Δ9 -tetrahydrocannabinol (THC). However, receptors in the ECS can also respond to compounds known as endocannabinoids.

Summary of ECS Components 

• CB1 and CB2 Receptors 
• Other non-cannabinoid receptors 
• Endocannabinoids (AEA and 2-AG)
• Exogenous cannabinoids (CBD, CBG, and THC)
• Enzymes that facilitate metabolism or degradation processes 
  

What are Endocannabinoids? 

Endocannabinoids are cannabinoids that are synthesized through normal physiological processes within the body. They are synthesized on “demand,” or when the body requires them. Therefore, they are not stored in reserves for future use and are rapidly degraded by enzymes immediately following their effects.  The two main endogenous cannabinoids are N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG). Both endocannabinoids are capable of activating CB1 and CB2 receptors; but, AEA has a higher affinity for CB2 and 2-AG has a higher affinity for CB1.

N-arachidonoylethanolamine (AEA)

AEA, also referred to as anandamide, was the first endocannabinoid to be discovered and therefore is the most studied. Anandamide, which is derived from the Sanskrit word “ananda” translates to “internal bliss,” which emphasizes its role in producing euphoric, analgesic, anxiolytic and antidepressant effects. In fact, the intoxicating compound from cannabis, (also known as THC), exerts its effects on the body by mimicking endogenous anandamide. Research has aimed to study how altering concentrations (either increasing or decreasing) of cannabinoids like AEA can have different therapeutic effects on various disorders. So what kind of research has been done on it?

• Substance use disorders like nicotine, alcohol, or opioid use disorders, all have an effect on the endocannabinoid system. Recent studies have shown that AEA has the ability to attenuate cravings while reducing symptoms of withdrawal such as anxiety, pain, and stress in these conditions.
• Heart conditions like hypertension (high blood pressure) can be reduced by AEA expression throughout several organ systems. AEA has a variety of mechanisms that have been shown to cause vasorelaxation in a number of different vascular beds dispersed in the body, resulting in a reduction of high blood pressure. 
• Liver diseases (like cirrhosis) are often related to other conditions like alcohol abuse or portal hypertension. In disease state livers, cannabinoid receptor expressions are upregulated causing a proportional increase in AEA. 
• Brain function and related diseases ranging from memory formation to parkinson’s disease, all have the ECS in common. AEA is involved in numerous processes including memory formation and the regulation of stress, anxiety, and inflammation. At present, there is ongoing research to investigate how enhanced ECS tone or cannabinoid receptors as therapeutic targets can be used in future therapies. It has been proposed that AEA has a neuroprotective role in the progression of certain neurodegenerative diseases.
  

2-arachidonoylglycerol (2-AG)

2-AG was the second endocannabinoid to be discovered following AEA. Due to its higher affinity for CB1 receptors, 2-AG works primarily in the brain and central nervous system. Its release helps to modulate a wide range of neurophysiological functions including cognition, emotion, energy levels, pain sensations, and inflammatory responses. Like AEA, there is ongoing research exploring the role of 2-AG in future pharmacologic therapies. Here are a couple of physiological functions that have been linked to 2-AG in recent research.

• Food intake and metabolism has been well linked to the CB1 receptor and the ECS as a whole. Studies have shown that fasting results in increased levels of 2-AG in the brain leading to increased appetite and conservation of energy.
• Neuroinflammation is regulated by 2-AG through a number of different processes. One of its main physiological roles in the brain is to help support normal inflammatory responses and fever generation following prostaglandin synthesis. 
• Stress has also been correlated with low concentrations of endocannabinoids. Replenishing low levels of 2-AG (and AEA) represent a therapeutic approach to treating anxious and stress-related mood disorders. 
• Occasional pain has long been treated with cannabinoids. Both CB1 and CB2 receptor stimulation results in analgesic effects that play a role in inflammatory pain, neuropathic pain, gastrointestinal pain, and chemotherapy related pain.

It's important to note that while AEA has a higher affinity for CB1 receptors and 2-AG has a higher affinity for CB2 receptors, that both endocannabinoids have the ability to stimulate both types of receptors. Therefore, many of the physiological functions that are associated with one of these ligands are likely associated with the other as well.

So, why are endocannabinoids and the ECS important? 

The ECS and its components have had growing evidence in their role of regulating more and more physiological processes within the body, thus making it an excellent potential drug target. Many studies have suggested that altering activity (through either agonism or inhibition) within the ECS holds promise in aiding conditions related to inflammation,  and more. Future research that can contribute towards expanding our knowledge of the various components that comprise the ECS, such as endocannabinoids, will help to understand the best location to target therapeutically; ultimately this will translate to better therapies with reduced side effect profiles. 

References

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