The endocannabinoid system (ECS) is a key modulatory signaling pathway [1]. Which, I’ve heard, is a very common phrase in the scientific community, and is simply a fancy way of saying it does a whole lot of stuff. So what exactly does it modulate, and what does that mean?
The ECS is made up of two major receptors, called CB1 and CB2. CB1 receptors are found primarily in the central nervous system, and CB2 receptors are found in the immune system.
Activation of ECS receptors [1]These receptors are actually found on the presynaptic cell (normally receptors are found on the postsynaptic cell), making them a part of retrograde signalling [1].
The ligands of this system are endogenous cannabinoids, which are produced on demand. An increase of intracellular calcium triggers arachidonoyl ethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) to be synthesized from the phospholipid bilayer [1].
Starting at the phospholipid bilayer, the enzymes NAPE and PLD are used to make AEA. The enzyme FAAH is used to degrade AEA into AA.
From the phospholipid bilayer, the enzyme PLC is used to make DAG, then the enzyme DAGL is used to make 2-AG. The enzyme MAGL is used to degrade 2-AG into AA.
Once synthesized, these eCB bind to CB1 and CB2 (GPCR receptors), and inhibit adenylyl cyclase. This decreases levels of cyclic-AMP, inhibits calcium channels, and inhibits neurotransmitter release. Overall, when the receptors are activated, they decrease signaling in other pathways [1].
Roles
As we said earlier, the ECS modulates a whole bunch of stuff. Another way of saying that, is the ECS regulates a lot of cellular processes. This means it has a lot of roles, and can change cellular communication and processes in relation to them all. These are some of the processes the ECS modulates:
Endocannabinoids, such as THC, are often used to treat central nervous system diseases including multiple sclerosis, Huntington’s disease, Alzheimer’s disease, epilepsy, anxiety, and depression. THC can be helpful with reducing pain and inflammation, regulating mood, and providing a neuroprotective role against neurodegeneration [1]. However, the ECS is an incredibly complicated system, and long term use of THC does have potential side effects and risks. This can include:
Apathy and passivity, as well as a decrease in motivation and goal-oriented behaviors. This may be due to altered neurocognitive functioning and reward salience [2].
Alterations in learning and memory, and disruptions of long-term potentiation. This is due to changes in glutamatergic neurotransmission signaling [3].
Excitotoxicity due to increased glutamate receptor expression [3].
Neurodegeneration due to too much calcium [3].
Inflammatory cytokine production and inflammationDesensitization [4].due to activation of microglia and astrocytes [3].
Downregulation, receptors permanently being removed, and desensitization, the uncoupling of the G-protein from the receptor. These processes are related to tolerance [4].
Research and Regulations
The gist of it is we do not know enough about the ECS and endocannabinoids work. We need more research in order to be prepared with a more complete explanation of risks and benefits. However, marijuana (the cannabis plant that contains more than 60 active synthetic ligands for CB1 and CB2, including THC), is a schedule 1 drug. This classification is defined with “no currently accepted medical use and a high potential for abuse” despite proven therapeutic benefits [5]. This means in order to study cannabis, there are a lot of regulations and paperwork involved, restricting the amount of research that can be done [6].
With this lack of understanding of the risks, there needs to be more regulations on marijuana. Regulations, not criminalization. For example, making sure kids and their developing brains don’t have access without a medical prescription. Or regulating the marketing and packaging, so colorful bags of gummy bears don’t catch the eyes of an eight year old, who then ends up ingesting 100mg of THC.
People need to be able to make informed decisions, taking into consideration the short-term and long-term impacts on their health. The scientific community needs to be able to do more research, then communicate the results to the public in a way that educates them, but doesn’t tell them what to do. People who rely on endocannabinoids for their medical purposes have a right to understand all the benefits as well as risks. And the general public has the right to be informed to aid in their decision making as well.
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] Rovai, L., Maremmani, A. G. I., Pacini, M., Pani, P. P., Rugani, F., Lamanna, F., Schiavi, E., Mautone, S., Dell’Osso, L., & Maremmani, I. (2013). Negative dimension in psychiatry. Amotivational syndrome as a paradigm of negative symptoms in substance abuse. Rivista Di Psichiatria, 48(1), 1–9. https://doi.org/10.1708/1228.13610
[3] Chowdhury, K. U., Holden, M. E., Wiley, M. T., Suppiramaniam, V., & Reed, M. N. (2024). Effects of Cannabis on Glutamatergic Neurotransmission: The Interplay between Cannabinoids and Glutamate. Cells, 13(13), 1130. https://doi.org/10.3390/cells13131130
[4] Piscura, M. K., Henderson-Redmond, A. N., Barnes, R. C., Mitra, S., Guindon, J., & Morgan, D. J. (2023). Mechanisms of cannabinoid tolerance. Biochemical Pharmacology, 214, 115665. https://doi.org/10.1016/j.bcp.2023.115665
[5] U.S. Department of Justice. (n.d.). Drug scheduling. United States Drug Enforcement Administration. https://www.dea.gov/drug-information/drug-scheduling
[6] Medications: Research on schedule I drugs. National Alliance on Mental Illness. (2024, July 23). https://www.nami.org/advocacy/policy-priorities/improving-health/medications-research-on-schedule-i-drugs/#:~:text=Federal%20law%20prohibits%20the%20manufacture,studying%20any%20Schedule%20I%20drugs.
