The endogenous cannabinoid system (ECS) is a fascinating evolutionary legacy that evolved over 600 million years ago. Fossils and genetic studies show that even primitive marine creatures such as sea squirts already produce endocannabinoids. In early vertebrates (bony fish), the differentiated endocannabinoid receptor subtypes CB-1 and CB-2 developed approximately 400 million years ago, associated with the emergence of complex neuronal networks.
The co-evolution of the endocannabinoid system and the cannabis plant
Today, almost all animal species—with the main exception of insects—have an endocannabinoid system. We now know that, as a universal regulatory system, it controls a multitude of functions to maintain a healthy balance between body and mind. The fact that this system has been preserved for millions of years indicates its central role in survival. It was only much later, around 30 million years ago , that the cannabis plant developed its characteristic phytocannabinoids—an indication that the interaction between the plant and our ECS may not be a coincidence, but the result of a co-evolutionary relationship with animals.
A historical examination of the co-evolution of humans with cannabis for at least 12,000 years suggests that today's varieties of the cultivated plant cannabis emerged through long breeding efforts with various goals. THC-rich varieties may have been bred long ago to optimize many of the plant's medicinal effects.
Many of the world's earliest pharmacopoeias (pharmacopoeias) mention cannabis, such as the famous Egyptian Ebers Papyrus from over 2,500 years ago, which describes topical (i.e., skin-acting) formulations containing cannabis for inflammation, but also formulations for gynecological applications and for eye conditions such as glaucoma, for pain management in headaches or during childbirth, as a laxative for indigestion, and for sedation in combination with opium during surgical procedures.
Cannabis has also been used by people in numerous cultures for thousands of years for a variety of other purposes: as food, for numerous products, but also for a variety of mind-altering effects for religious and spiritual rituals, for meditation, for creative purposes, or as an aphrodisiac; cannabis has also been deliberately bred for many of these purposes.
History of discovery: From the illegal plant to the medical revolution
Research into the ECS paradoxically began with an illegal plant. In the 1960s, scientists first isolated THC from cannabis and wondered: Why does the human body respond to this plant substance? In 1988, Allyn Howlett discovered the CB1 receptor in the brain, and in 1992, Raphael Mechoulam identified anandamide ("happy molecule"), the first endogenous (from the Greek "endo," inside, i.e., produced in the body) ligand that binds to and activates this receptor. Despite its enormous scientific importance, the ECS remains largely absent from almost all medical curricula worldwide—including in Europe. Broselid (2024) rightly calls this a "glaring omission" and points out that even in the current edition of the standard work "Guyton and Hall Textbook of Medical Physiology," the ECS is barely mentioned, despite being intensively researched for over 30 years. Nevertheless, in recent decades we have seen a revolutionary development in the use of medical cannabis for a variety of indications, made possible, among other things, by better regulations of the plant and its derivatives.
Key components of the ECS: receptors, molecules, enzymes
The ECS functions like the body’s own orchestra system with three main players:
Receptors
CB-1 : Dominant in the brain (hippocampus, amygdala, hypothalamus), regulates mood, pain perception and appetite.
CB-2 : Mainly found in immune cells and organs, controls, among other things, inflammatory reactions.
Interestingly, endocannabinoids also interact with non-CB receptors such as 5HT1A, the serotonin receptor.
Endocannabinoids
· Anandamide (AEA) (“inner happiness substance”): Influences, among other things, the reward system and stress resilience.
2-AG : Controls, among other things, neuroprotective processes and immune modulation.
Enzymes
· FAAH (Fatty Acid Amide Hydrolase): Breaks down anandamide
· MAGL (Monoacylglycerol Lipase): Breaks down 2-AG
Endogenous ligands such as anandamide and 2-AG are synthesized on demand by certain endogenous enzymes, then bind to the endocannabinoid receptors CB-1 or CB-2 to acutely modulate physiological processes, and are degraded within seconds to minutes by FAAH or MAGL - a dynamic cycle that ensures homeostasis.
Cannabis and the ECS: Why the plant can have such versatile effects
The endocannabinoid system controls an astonishingly broad spectrum of functions within us; it is therefore not surprising that the cannabis plant, with its plant cannabinoids so similar to endogenous cannabinoids, was used by humans so early on for such a wide variety of purposes.
The endocannabinoid system
1. Stress and emotions
It is responsible for the regulation of the stress response, anxiety modulation and resilience to stressors, influence on mood and depressive symptoms, regulation of anxiety and fear learning and helps in the attenuation of emotionally negative reactions in relation to traumatic memories - without erasing the memory itself.
2. Sleep and circadian rhythms
The ECS controls sleep-wake cycles and influences sleep quality and sleep onset behavior.
3. Pain and sensory perception
It modulates pain sensation and can reduce it, but also influences itching, temperature and touch sensation.
4. Appetite, nutrition and metabolism
The ECS controls appetite, food intake and metabolism, regulates energy balance and fat metabolism.
5. Cognition and memory
The ECS modulates learning and memory and influences cognitive flexibility and synaptic plasticity. In my book "Elevated: Cannabis as a Tool for Mind Enhancement" (2023), I hypothesized that it might be involved in the control of a variety of other mental abilities, such as pattern recognition and empathic understanding.
6. Immune function and inflammation
The ECS regulates immune responses and controls autoimmunity; for example, it reduces the pathogenic (diseased) immune reaction in multiple sclerosis.
7. Motor skills and movement coordination
The ECS controls fine motor skills and muscle tone and prevents spasticity or tremor, for example.
8. Reproduction and development
It controls sperm motility, egg maturation, and embryo implantation, but also regulates neural networking in the fetus. Postnatally, it plays a role in breastfeeding; for example, it increases 2-AG levels, which promotes mother-child bonding and infant feeding.
9. Homeostasis and cell protection
The endocannabinoid system maintains internal balance (homeostasis), provides protection against oxidative stress and regulates mitochondrial metabolism.
10. Additional functions
The ECS also plays a role in circulatory regulation and influences social interactions and many other functions such as reward and addictive behavior.
Clinical studies confirm several millennia-old observations about the versatile therapeutic applications of cannabis: For example, medical cannabis-based medicines reduce spasticity in multiple sclerosis, and medical cannabis products alleviate chronic pain. At the same time, ECS mechanisms partially explain side effects such as "munchies" or temporary memory impairment (hippocampus).
Conclusion
The ECS is revolutionizing our understanding of health as a dynamic balance. The fact that many physicians and the public are still unfamiliar with this system, discovered in the 1990s, underscores the urgency of adapting medical education in particular. New findings about this system also partially confirm the experiences of thousands of cannabis users and patients who consciously or unconsciously modulate this system with herbal ingredients.
The many effects of different cannabis strains and products can therefore be partly explained by the interaction of plant cannabinoids with a powerful and incredibly versatile system that has evolved to be a key system to enable us to achieve a healthy balance.
Ultimately, knowledge about our ECS reveals to us how deeply rooted our biology is with the plant world - a realization that changes not only medicine but also our self-image.
Sources
1. Alger, BE (2013). Getting high on the endocannabinoid system. Cerebrum, 2013, 14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997295/
2. Baron, E. P., Lucas, P., Eades, J., & Hogue, O. (2018). Medicinal cannabis: Educational deficits in medical training. Cannabis and Cannabinoid Research, 3(1), 57-67. https://doi.org/10.1089/can.2018.0020
3. Broselid, S. (2024). The endocannabinoidome: A pivotal physiological regulator and therapeutic target. Medical Cannabis Clinicians' Society UK.
Chiurchiù, V., van der Stelt, M., Centonze, D., & Maccarrone, M. (2017). The endocannabinoid system and its therapeutic exploitation in multiple sclerosis. Progress in Neurobiology, 160, 82-100. https://doi.org/10.1016/j.pneurobio.2017.10.007
Elphick, M.R. (2012). The evolution and comparative neurobiology of endocannabinoid signaling. Philosophical Transactions of the Royal Society B: Biological Sciences, 367(1607), 1687-1698. https://doi.org/10.1098/rstb.2011.0394
Guyton, A.C., & Hall, J.E. (2020). Textbook of medical physiology (14th ed.). Elsevier.
Livingston, S.J., Quilichini, T.D., & Page, J.E. (2020). Cannabis glandular trichomes: A cellular metabolite factory. Frontiers in Plant Science, 11, 958. https://doi.org/10.3389/fpls.2020.00958
Lu, H.C., & Mackie, K. (2021). Review of the endocannabinoid system. Biological Psychiatry, 89(6), 520-529. https://doi.org/10.1016/j.biopsych.2020.09.005
Marincolo, S. (2023). Elevated: Cannabis as a Tool for Mind Enhancement. Hilaritas Press
McPartland, JM, & Pruitt, P.L. (1999). Coevolution between cannabinoid receptors and endocannabinoid ligands. Gene, 397(1-2), 126-135. https://doi.org/10.1016/j.gene.2007.04.017
Russo, E. B. (2020). Propagation of cannabis for clinical research: An evolutionary perspective. Frontiers in Plant Science, 11, 958. https://doi.org/10.3389/fpls.2020.00958
Silva, L.R., Ferreira, A.S., & Costa, P. (2024). Knowledge and attitudes about medical cannabis and the endocannabinoid system among nurses and nursing students in Portugal. Journal of Cannabis Research, 6(1), 45-57. https://doi.org/10.1186/s42238-024-00215-1
Volteface. (2022). Medical cannabis in the UK: The need for education and training. https://volteface.me
