What are Endocannabinoids
Endocannabinoids (eCBs) are naturally produced in the body and are lipid-based neurotransmitters. The primary endocannabinoids are arachidonoyl ethionamides (AEA) and 2-archidonoyl glycerol (2-AG) which are agonists to CB1 and CB2 but bind to both receptors. However, CB1 has a higher binding affinity than CB2. eCBs are produced as the body needs them by an increase in intracellular calcium and are degraded through fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). FAAH breaks down AEA and MAGL breaks down 2-AG. The benefits of the endocannabinoid system are that it aids in mood, pain, perception, and learning and memory.
CB1 and CB2 Receptors
CB1 receptors are found primarily in the central nervous system (CNS) and CB2 receptors are primarily in the peripheral nervous system (PNS). CB1 receptor accounts for being the most abundant GPCR in the CNS but is also located on peripheral nerve terminals. Besides binding AEA and 2-AG THC, the main ingredient in cannabis sativa (marijuana), binds at CB1. CB2 receptors can be found in the CNS but are mainly located in cells and tissues of the immune system. CB2 receptors in the CNS are localized to microglia and modulate inhibitory plasticity. Additionally, CB1 and CB2 receptors operate independently from each other.
Receptor Activation
Following activation of CB1 there is a rapid decrease in the levels of cAMP via adenylate cyclase inhibition. This decrease occurs through activation resulting in potassium channel conductance and a decrease in calcium voltage operated channels. Ultimately resulting in a decrease in neurotransmitter release. However, prolonged exposure can result in tolerance and a decrease in the ability of the receptors to activate the endocannabinoid pathway. AEA and 2-AG can bind and activate CB receptors but so can THC and CBD from marijuana.
AEA, 2-AG, THC, and CBD are the only agonists that can bind to CB receptors. However, there are ways to enhance endocannabinoid levels and receptor activation. Both dark chocolate and black truffles contain anandamide (naturally produced endocannabinoid), caffeine, olive oil, exercise, and omega-3 fatty acids upregulate CB receptors. Lastly, cold exposure increases endocannabinoid levels and flavonoids found in tea and wine inhibit the breakdown of endocannabinoids.
Endocannabinoids and Pain
The activation of the endocannabinoid system is associated with pain reduction. However, natural endocannabinoids may not be able to provide the level of activation required of the endocannabinoid system which is when cannabinoids of THC and CBD are introduced. Research has linked cannabis to control and manage pain associated with Alzheimer’s disease (AD), Huntington’s disease (HD), and multiple sclerosis (MS). In MS eCB system activation reduced pain and spasms and provided neuroprotective and anti-inflammatory effects. In HD CB1 receptor activation is reduced, resulting in reduced motor performance. Therefore, enhanced activation of remaining CB1 receptors may help the degradation of the receptors. In AD CB receptor activation is thought to produce a neuroprotective effect and protect individuals against amyloid beta plaque toxicity and reduced tau phosphorylation.
Conclusion
Endocannabinoids are naturally produced in the body and are agonist to CB1 and CB2 receptors, as are phytocannabinoids, THC and CBD. The activation of the endocannabinoid system has been linked to pain reduction, mood stabilization, and memory and learning. Research has begun investigating the therapeutic effects of endocannabinoids on diseases such as HD, MS, and AD.
References
[1] Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid receptors in the central nervous system: Their signaling and roles in disease. Frontiers in Cellular Neuroscience, 10. https://doi.org/10.3389/fncel.2016.00294
[2] De Pietro, MaryAnn, CRT (2021). What to know about endocannabinoids and the endocannabinoid system. Medical News Today. https://www.medicalnewstoday.com/articles/endocannabinoid
[3] Fallis, Jordan (2023). 26 powerful ways to boost your endocannabinoid system. Optimal Living Dynamics. https://www.optimallivingdynamics.com/blog/how-to-stimulate-and-support-your-endocannabinoid-system#:~:text=Medium%20and%20high%2Dintensity%20exercise,68%2C%2072%2C%2074)













