The endogenous cannabinoid system (ECS) is a fascinating evolutionary legacy that developed more than 600 million years ago. Fossils and genetic studies show that even primitive marine creatures such as sea squirts produce endocannabinoids. In early vertebrates (bony fish), the distinct endocannabinoid receptor subtypes CB-1 and CB-2 then evolved around 400 million years ago, alongside the emergence of complex neural 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 wide range of functions to keep body and mind in balance. The fact that this system has been preserved over millions of years points to its central role in survival. Only much later, around 30 million years ago, did the cannabis plant develop its characteristic phytocannabinoids. This suggests that the interaction between the plant and our ECS may be no coincidence but the result of a co-evolutionary relationship with animals.
A look at the shared history of humans and cannabis, going back at least 12,000 years, suggests that today's varieties of the cultivated plant arose from long breeding efforts with different goals. THC-rich varieties may have been bred for medicinal purposes a very long time ago.
Many of the world's earliest pharmacopoeias (books of remedies) mention cannabis, for example the famous Egyptian Ebers Papyrus, written more than 2,500 years ago. It describes topical (applied to the skin) cannabis preparations for inflammation, as well as preparations for gynaecological use, for eye conditions such as glaucoma, for headaches or during childbirth, as a laxative for digestive complaints, and for sedation in combination with opium during surgery.
Beyond that, people in many cultures have used cannabis for thousands of years for many other purposes: as food, for countless products, but also for its mind-altering effects in religious and spiritual rituals, for meditation, for creative purposes or as an aphrodisiac. For many of these purposes, too, cannabis was deliberately bred.
A history of discovery: from illegal plant to medical revolution
Research into the ECS began, paradoxically, with an illegal plant. In the 1960s scientists first isolated THC from cannabis and asked themselves: 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 ("bliss molecule"), the first endogenous (from the Greek "endo", within, i.e. produced in the body) ligand that binds to and activates this receptor. Despite its enormous scientific importance, the ECS is still largely missing from almost all medical curricula worldwide (Europe included). Broselid (2024) rightly calls this a "glaring omission" and points out that even the current edition of the standard work "Guyton and Hall Textbook of Medical Physiology" barely mentions the ECS, although it has been studied intensively for more than 30 years. Even so, recent decades have seen a revolutionary development in the use of medical cannabis, made possible in part by better regulation of the plant and its derivatives.
Key components of the ECS: receptors, molecules, enzymes
The ECS works like the body's own orchestra with three main players:
Receptors
· CB-1: Dominant in the brain (hippocampus, amygdala, hypothalamus), regulates mood, pain perception and appetite.
· CB-2: Found mainly in immune cells and organs, controls inflammatory responses among other things.
Interestingly, endocannabinoids also interact with non-CB receptors such as 5HT1A, the serotonin receptor.
Endocannabinoids
· Anandamide (AEA) ("inner bliss substance"): influences the reward system and stress resilience, among other things.
· 2-AG: Controls neuroprotective processes and immune modulation, among other things.
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 produced "on demand" by specific enzymes in the body, bind to the endocannabinoid receptors CB-1 or CB-2 to modulate physiological processes acutely, and are broken down again within seconds to minutes by FAAH or MAGL. A dynamic cycle that contributes to homeostasis.
Cannabis and the ECS: why the plant can have such varied effects
The endocannabinoid system controls an astonishingly broad range of functions in us. So it is hardly surprising that people used the cannabis plant, with plant cannabinoids so similar to the body's own, so early and for so many purposes.
The endocannabinoid system
1. Stress and emotions
It is involved in regulating the stress response, modulating anxiety and resilience to stressors, influences mood, regulates fear learning and is involved in dampening negative emotional reactions to traumatic memories, without erasing the memory itself.
2. Sleep and circadian rhythms
The ECS controls sleep-wake cycles and influences sleep quality and falling asleep.
3. Pain and sensory perception
It modulates and can dampen pain perception, but also influences itching, temperature and touch perception.
4. Appetite, nutrition and metabolism
The ECS controls appetite, food intake and metabolism, and 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 put forward the hypothesis that it may be involved in controlling many other mental abilities, such as pattern recognition or empathic understanding.
6. Immune function and inflammation
The ECS regulates immune responses and is involved in controlling autoimmunity. Its role in the pathogenic (disease-causing) immune response in multiple sclerosis is one area being studied.
7. Motor control and coordination
The ECS is involved in controlling fine motor skills and muscle tone. Researchers are therefore studying its role in spasticity or tremor, for example.
8. Reproduction and development
It controls sperm motility, egg maturation and embryo implantation, and also regulates neural networking in the foetus. After birth it plays a role in breastfeeding; for example, it raises 2-AG levels, which supports mother-child bonding and infant feeding.
9. Homeostasis and cell protection
The endocannabinoid system maintains internal balance (homeostasis), offers protection against oxidative stress and regulates mitochondrial metabolism.
10. Other functions
Among other things, the ECS also plays a role in regulating circulation and influences social interaction and many other functions such as reward and addictive behaviour.
Clinical studies have taken up some observations about cannabis that are thousands of years old: for example, cannabis-based medicines have been studied for spasticity in multiple sclerosis, and medical cannabis products for chronic pain. At the same time, ECS mechanisms partly explain side effects such as the "munchies" or temporary memory lapses (hippocampus).
Conclusion
The ECS is fundamentally changing our understanding of health as a dynamic balance. The fact that many doctors and the public still do not know about this system, discovered back in the 1990s, shows how urgently medical training in particular needs to adapt. New findings about this system also partly confirm the experiences of thousands of cannabis users and patients who, knowingly or not, influence this system with plant compounds.
The many effects of different cannabis strains and products can therefore partly be traced back to the interaction of plant cannabinoids with a powerful and incredibly versatile system that evolved as a key system for our inner balance.
Ultimately, knowing about our ECS shows us how deeply our biology is rooted in the plant world: an insight that changes not only medicine but also how we see ourselves.
Sources
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