Endocannabinoid System Fundamentals

What is the ECS?

Introduction to the ECS

Introduction to the Endocannabinoid System with Dr. Ethan Russo

Evolutionary origins of the endocannabinoid system

The ECS evolved approximately 600 million years ago, well before the cannabis plant came into existence. The ECS has been found in all vertebrate animals and is important to their health and well being too.

The ECS is the body's most important homeostatic regulator. It is a circuit breaker and coordinator at a cellular level. It is tasked with the massive role of keeping our internal environment in balance, constantly making adjustments, keeping us functioning at our optimum.

Think of your body as a complex orchestra. The endocannabinoid system is the conductor keeping all of the complex and chaotic pieces working together to create the symphony that is you.

The ECS is made up of cannabinoid receptors, endocannabinoids and the enzymes that break endocannabinoids down. CB1 receptors are located predominantly in the brain and central nervous system on presynaptic neurons and CB2 receptors are predominantly attached to immune cells. All organs and physiological systems contain cannabinoid receptors, and the effects of activating these receptors is influenced by their location within those systems. However, the purpose of these receptors is always the same; to facilitate and maintain homeostasis.

The endocannabinoids are produced by the cell, on demand from the cell membrane by precursor fatty acids. Once they have been released and utilised they are broken down by the enzymes FAAH and MAGL inside the cell. Due to the predominantly local activity, it makes it difficult to reliably test endocannabinoid function on a blood test.

The ECS and Expanded Endocannabidiome Explained in Detail

Part One

Part Two

Part Three

Part Four

Clinical Endocannabinoid Deficiency

Clinical Endocannabinoid Deficiency (CECD) is a term coined by Dr Ethan Russo, a neuropharmacologist, in the early 2000s. The theory behind CECD is that many disease states are related to a deficiency of various neurotransmitters. For example, depression might be related to low serotonin, Alzheimer's disease might be related to low acetylcholine, and Parkinson's disease might be related to low dopamine levels.

The endocannabinoid system is involved in various processes within the body, including regulation of pain, sleep, stress, mood, digestion, and immune function. So, if someone has a deficiency or dysfunction of the ECS, they would start manifesting symptoms related to these core pillars of the endocannabinoid function.

The hypothesis was that patients with CECD would have a syndrome of specific symptoms that were not better diagnosed by pathogenic markers, tests or lab studies and did not have a clear diagnosis. They would also often have an overlap between comorbid states.

What Conditions Are Related to CECD and Why?

The following conditions are related to CECD:

• Irritable bowel syndrome
• Fibromyalgia
• Chronic migraines
• Endometriosis
• Anxiety
• Depression
• PTSD

The first conditions were IBS, fibromyalgia and chronic migraines because, at the time, we didn't have a clearly defined understanding of why the conditions existed, and they have similar symptoms. Each of them has stress as a significant trigger. There is a pain element out of proportion to any tissue damage or pathological process. They came in clusters and often co-existed in the same patients.

Other conditions such as Parkinson's disease, multiple sclerosis, Huntington's disease and motor neuron disease all have an implication of the endocannabinoid system in the development and worsening and progression of their disease status.

Since the original hypothesis was formulated other conditions have been added to the list of potential CECD conditions. But, whether these chronic diseases are triggered by CECD or cause ECS deficiency is yet to be determined.

However, the upregulation of the ECS in these disease states makes a significant difference to the health and wellbeing of patients with these conditions.

Research Related to CECD and Related Conditions

Patients with chronic migraines have markedly lower levels of anandamide in cerebrospinal fluid.

Women with endometriosis display lower levels of CB1 receptors in endometrial tissue. Impaired ECS functioning has been suggested to lead to unregulated growth of endometriosis tissue and significant levels of severe pain.

In children with Autism Spectrum Disorder, there are notable deficiencies of anandamide, palmitoylethanolamide, and oleoylethanolamide compared to neurotypical controls.

Fluctuations in ECS tone have been observed in patients with inflammatory bowel disease and irritable bowel syndrome. One study found a genetic variation associated with colonic transit time affecting ECS metabolism in diarrhoea-predominant IBS patients.

Research on CECD in humans is still in its early days. However, numerous studies demonstrated that rodents with a deficiency of 2-AG are more likely to display low-stress resilience and behavioural alterations analogous to mood disorders, such as increased anxiety, impaired reward pathway activation, compromised fear extinction and changes in structural plasticity.

What Causes Endocannabinoid Deficiency?

There is no clear answer to what causes CECD. While research has gotten us closer to understanding CECD and related conditions, the two main factors that contribute to CECD are genetic and environmental.

Some of the genetic factors include:

• Expression and density of CB1 and CB2 receptors in the body
• An individual's genetics in relation to the production of certain enzymes (ie FAAH)

The likelihood is that CECD can arise in two ways. One is with people predisposed to having an endocannabinoid deficiency and then are exposed to a stressor or trauma and develop a related condition. The second is where an individual develops a medical condition and can't manage the condition well enough. As a result, there is a decline in the ECS's ability to keep up with demand and the patient may then be diagnosed with CECD.

How Do You Test for Endocannabinoid Deficiency?

Unfortunately, there is no test or specific way to diagnose CECD.

There is no endocannabinoid gland. Instead, the cell wall releases endocannabinoids. They act locally and are taken back inside that cell and broken down locally. And, there is no endocannabinoid deficiency blood test. So, measuring levels of endocannabinoids in the blood is difficult.

The best indicator of endocannabinoid dysfunction is increase of cell receptors. An increase of receptors shows that the body is trying to hold on to as many of the endocannabinoids that are being produced.

Without doing invasive testing such as tissue biopsies or lumbar punctures, it's impossible to discern an endocannabinoid deficiency from pathological or laboratory processes.

Diagnosing an endocannabinoid deficiency, it will boil down to patient history more than anything else. Dr Jim Connell said:

When patients are getting health issues in multiple areas that may seem unrelated but may have a common link through the ECS processes, this is where you may begin to suspect CECD.

Let's take an example. When treating someone with chronic pain, you're often not just treating pain. You're treating their pain, sleep, anxiety and aiming to improve their overall wellbeing.

The ability to potentially manage all of this with one medicine, cannabis, is what makes it such a valuable tool for you and these patients.

Clinical Endocannabinoid Deficiency Explained & Reconsidered

Clinical Endocannabinoid Deficiency Reconsidered

Nurturing the ECS

The ECS is very important to maintain good health but for it to be able to do its job properly then it needs to be cared for and supported. This is even more important when the ECS has continual demands placed on it in the case of chronic disease, otherwise it becomes downregulated, and the disease state is able to continue unchecked.

1. Nutrition

1. Eat whole foods and minimize packaged, processed and refined products
2. Eat healthy fats especially omega 3 containing fats as these are essential for production of endocannabinoids
   • Sources include walnuts, hemp seeds, chia seeds, flax seeds, fish, wild/lean meat, pasture raised eggs
3. Eat the rainbow and increase the diversity of plant based foods
4. Cook with spices especially those rich in β-caryophyllene, a natural CB2 agonist great for inflammation
5. Dark chocolate has been shown to increase ECS levels by blocking the reuptake of anandamide
6. Slow down! Eat slowly and mindfully, try and eat with people that bring you joy.

2. Exercise

1. Runner's high is related to surge of anandamide
2. Aerobic exercise has been proven to increase ECS function
3. Exercise you enjoy is important, forced exercise doesn't have the same effect. Try things like dancing, walks in nature, yoga, gardening etc

3. Reduce Stress

1. Take time to savour the moment. Use your senses to explore your environment
2. Breathing exercises, meditation and mindfulness on a regular basis. Only needs to be for a few minutes at a time. Can be incorporated into mundane everyday tasks.
3. Try adult colouring in or other creative outlets to allow your mind to disengage with fear and worry

4. Sleep Hygiene Practices

Good sleep hygiene is essential for supporting endocannabinoid system health. Prioritise consistent sleep and wake times, limit screen exposure before bed, and create an environment conducive to restful sleep.

5. Connection

1. Social connection is important
2. Hug those close to you
3. Pets can help humans connect
4. Connect with nature

6. Do Things That Bring You Joy

1. Much of the endorphin response to joyous activity is mediated by the ECS
2. If it is a guilty pleasure i.e. chocolate, movies, wine — savour the moment, maximise the pleasure and do them in moderation

7. Singing

1. Especially in a choir has been proven to up-regulate the ECS
2. Sing in the shower or the car

Endocannabinoid-Enhancing Foods and Activities

Additional Resources

The following research articles and resources provide deeper exploration of the endocannabinoid system:

• Circulating endocannabinoids: from whence do they come and where are they going?
• CB1 and CB2 Receptor Pharmacology
• Beyond Cannabis: Plants and the Endocannabinoid System
• Endocannabinoid System – Signalling at the Synapse
• Cannabinoid receptors in the human brain
• Endocannabinoid System and Skin
• Endocannabinoid System: Inflammation and Tissue Injury
• Endocannabinoid system components: Overview and tissue distribution
• The endocannabinoid system: an osteopathic perspective
• Endocannabinoids in synaptic plasticity and neuroprotection

Recommended Podcast Episodes:

The Endocannabinoid System Demystified (Knox Sisters)