The Endocannabinoid System Explained

The endocannabinoid system (ECS) is a complex cell-signaling system that regulates many of our most crucial bodily functions such as sleep, mood, memory, motor control, appetite, pain perception, body temperature, immune responses and reproduction. The main function of the ECS is to help us maintain homeostasis – a state of equilibrium in the body where everything functions optimally to maintain physiological, cognitive and emotional balance.

The ECS consists of three core components: cannabinoid receptors, endocannabinoids and the enzymes responsible for their synthesis and degradation. Two major cannabinoid receptors have been identified, namely cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 receptors are primarily located in the central nervous system (brain and spinal cord), while CB2 receptors are most prevalent in the peripheral nervous system (the rest of the body). 

Cannabinoids can either be classified as endocannabinoids or phytocannabinoids, depending on their origin. The term “endo” is short for “endogenous”, which means “originating in the body”, while “phyto” stands for “plant”, ie. “originating in the cannabis plant”.  All humans and most animals have an ECS and are able to produce endocannabinoids on demand as needed to help maintain homeostasis, even if they have never used cannabis in their life. The two main endocannabinoids identified thus far are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Once the endocannabinoids have done their jobs, they are degraded by two metabolic enzymes:  fatty acid amide hydrolase (FAAH) and monoacylglycerol acid lipase (MAGL), which breaks down AEA and 2-AG, respectively. 

Both endocannabinoids and phytocannabinoids are able to bind to human cannabinoid receptors with great specificity, much like a lock and key. Endocannabinoids (eg. AEA and 2-AG) and phytocannabinoids (eg. THC and CBD) can be thought of as the “keys”, and the cannabinoid receptors (eg. CB1 and CB2) as the “locks”. Each of these “chemical keys” has a unique molecular structure, which can only unlock specific receptors in the body. Once unlocked, it can modulate the release of neurotransmitters and influence various physiological processes in the body. 

Endocannabinoids and phytocannabinoids are often referred to as “retrograde messengers” due to their unique ability to communicate backwards. Neurotransmitters normally only travel from presynaptic (sending) neurons to postsynaptic (receiving) neurons. However, endocannabinoids and phytocannabinoids are able to communicate in the opposite direction, enabling them to deliver feedback to a presynaptic cell (negative feedback loop). For example, if a neuron is firing messages too quickly, endocannabinoids or phytocannabinoids can instruct it to slow down by traveling backwards and activating CB1 receptors on the presynaptic neuron. This bidirectional communication is fundamental to the ECS’s ability to to maintain homeostasis. 

A theory known as clinical endocannabinoid deficiency (CED) suggests that low endocannabinoid levels or ECS dysfunction can contribute to the development of certain conditions which do not have a clear underlying cause. The theory is based on the concept that many brain disorders are associated with neurotransmitter deficiencies, eg. acetylcholine in Alzheimer’s disease, dopamine in parkinson’s disease and serotonin / norepinephrine in depression. The CED theory hypothesizes that a comparable deficiency in endocannabinoids  might manifest similarly in certain disorders such as migraine, fibromyalgia and irritable bowel syndrome (IBS). A 2016 review on this topic concluded that migraine, fibromyalgia, IBS and other treatment-resistant pain syndromes may be suitably treated with exogenous phytocannabinoids (ie. cannabis). 

Beyond drug interventions, lifestyle approaches such as aerobic exercise have also demonstrated beneficial effects on endocannabinoid function. This is because exercise increases the levels of AEA (also known as our “bliss hormone”), which causes people to experience what is known as a “runners high” – a feeling of euphoria along with reduced anxiety and pain. This feeling of euphoria or “high” that people get after prolonged exercise is similar to the “high” caused by cannabis, since both AEA and THC bind to CB1 receptors in the brain. 

It is important to note, however, that endocannabinoids and phytocannabinoids are not equal. Endocannabinoids have very specific effects, are tightly controlled (produced in the right place, at the right time and in the right amounts) and are highly responsive to the environment. Phytocannabinoids (eg. THC) on the other hand, are not specific, can have multiple effects at once, and do not respond to the environment. In addition, constant activation of cannabinoid receptors by THC can cause them to “downregulate” and reduce their sensitivity to cannabis. This is why chronic users often become “tolerant” to the effects of cannabis, and need to consume higher doses of THC to achieve similar effects. If this sounds familiar, you might consider taking a break from cannabis to help reset your ECS. On average, a break of about 4 weeks is required for your cannabinoid receptor function to return to normal.

Even though the ECS has evolved more than 600 million years ago, it was only discovered very recently by scientists investigating the effects of THC in the early 1990s. Research on the ECS is therefore still in its infancy, and we still have a lot to learn about how it works. However, from what we do know so far, it is clear that the ECS plays a major role in homeostasis and overall health, by helping our bodies to stay in balance. Since cannabinoid receptors are located throughout the entire body, it is not surprising that cannabis, which contains over 400 different chemical “keys”, can unlock so many therapeutic effects. In the next blog post, we will talk more about all the health benefits of cannabis, as well as the risks that you need to be aware of.

For more information on the endocannabinoid system, you can watch the following TED talks:

• Demystifying the endocannabinoid system | Dr. Ruth Ross
• The endocannabinoid system and the revolution of one | Dr. Rachel Knox