Endocannabinoid System Balance

Many of us realise the important of balance in our lives. Balancing work and play is critical for physical and mental health. Nutritional scientists have shown that balancing Omega-6 fats (which are generally, but not always, pro-inflammatory and therefore considered the bad guys) with Omega-3 fats (the good guys) can impact a multitude of health outcomes. For example, replacing Omega-6 rich processed foods (e.g., French Fries, potato chips, and pastries) with Omega-3 rich healthy alternatives (e.g., salmon steak, sardines and fresh leafy vegetables) improves cardiovascular health, brain health and metabolic wellness. A similar analogy can be used when discussing endocannabinoids (first defined in 1995 as 'endogenous substances capable of binding to and functionally activating the cannabinoid receptors') and endocannabinoid tone/balance.

What is the Endocannabinoid System (ECS)? 

The ECS is a group of specialised lipids (an important part of living cells, together with carbohydrates and proteins, the main constituents of plant and animal cells; cholesterol and triglycerides are lipids), their receptors and the enzymes (catalysts for organic biochemical reactions) that produce and degrade them. Through direct and indirect actions, endocannabinoids are known to modulate and influence a variety of physiological systems, including appetite, pain, inflammation, thermo-regulation, intra-ocular pressure, sensation, muscle control, energy balance, metabolism, sleep health, stress responses, motivation/reward, mood and memory.

What are Cannabinoid Receptors? 

Cannabinoid receptors are an important class of cell membrane receptors that are known to have a serpentine shape. Receptors are akin to locks and the ligand compounds that bind to them are akin to keys in a lock and key system. They have around seven sections that pass through the outer cell membrane. Cannabinoid receptors are also coupled to G-proteins, where a lot of the signalling 'magic' happens when a molecule or compound binds to the outer portion of these receptors. The three main ligands that bind to cannabinoid receptors are all lipophilic (fatty or fat-loving compounds) and include endocannabinoids (synthesised within the body), phytocannabinoids (plant-derived, such as from cannabis) and synthetic cannabinoids.

Cannabinoid receptors are further divided into two main subtypes, known as CB1 and CB2. Although they have some similarity, they are mostly differentiated by what tissue or organ system they are associated with in the body. CB1 is found mostly in the brain, with some presence in the lungs, kidney, liver, fat deposits, heart, muscle and bone. CB1 receptors are mostly associated with the psychoactive and euphoric aspects of Tetrahydrocannabinol (THC). However, CB2 receptors are mostly found within the immune system and blood cells and secondarily in lesser density within the nervous system, liver, gut, muscle and bone.

How Do Cannabinoid Receptors Contribute to the Balance of the Endocannabinoid System (ECS)?
Endocannabinoid tone/balance is the relative contributions of CB1 versus CB2 activity at any given time. Research is accumulating that shows CB1 dominance is associated with increased perception of stress, anxiety, paranoia, augmented appetite, and decreased nausea, vomiting and pain, as well as enhanced immune surveillance, the latter of which has been demonstrated in certain cancer models. In contrast, CB2 dominance is associated with decreased inflammation and tissue injury in conjunction with improvements in metabolic health, insulin signalling/sensitivity, satiety and energy balance.

Using this information, some scientists are zeroing in on specific CB1 blockers that could improve many of the symptoms of metabolic syndrome. Metabolic syndrome is a cluster of risk factors that increase the risk of heart disease, stroke, and diabetes. Specifically, it includes increased blood pressure, high blood sugar, excess body fat around the waist and abnormal cholesterol levels. Some research in this area has already demonstrated that peripheral CB1 inhibition reduces blood pressure and blood sugar and improves cholesterol levels, as well as leads to visceral fat loss resulting in a lower risk for cardiovascular disease and type II diabetes.

What Does a Balanced Endocannabinoid System (ECS) Look Like?
Recent biochemical and behavioural findings demonstrate that optimal activation of CB1 receptors promotes antidepressant-like neurochemical changes and behavioural effects consistent with anti-depressant/anti-stress activity in rodents. These findings reinforce the importance of a balanced ECS.

The ECS is known to control the proliferation, differentiation, survival and immune competence of the often-neglected integumentary organ system (consisting of the skin, hair, nails and exocrine glands; skin is only a few millimetres thick yet is the largest organ in the body). Targeting and manipulating endocannabinoid balance with the intent to normalise unwanted skin cell growth and skin inflammation might be beneficial for a variety of human skin conditions (psoriasis, eczema, acne, dermatitis, systemic sclerosis). Drawing comparisons between the Omega-6:Omega-3 essential polyunsaturated fatty acid (PUFA) balance and the CB1:CB2 endocannabinoid tone is even more appropriate as dietary PUFA intake has been shown to influence the levels of anandamide (derivative of arachidonic acid that occurs naturally in the brain and in some foods [chocolate] and binds to the same brain receptors as cannabinoids [THC]) and 2-AG (the two most prominent endocannabinoids in humans). Therefore, the balance of Omega-6 and Omega-3 PUFA is an important modifier for the activation and suppression of cannabinoid signalling in cells.

To illustrate this point, Hutchins-Weise et al published findings from a rodent model of immobilisation-disuse atrophy in combination with fish oil supplementation. The increased Omega-3 levels from fish oil consumption caused significant changes in the ECS (increased CB2 receptors, but decreased levels of 2-AG and CB1 activity) of the mice by sensitising muscle to counter the effects of immobilisation and hind-limb suspension.

What Happens When the Endocannabinoid System Becomes Imbalanced?

Keep in mind that balance is critical, as research has shown if we tip the scales too heavily in the direction of CB1 inhibition there may be an associated decrease in fertility with increased risk of depression, mood disturbance, and immuno-suppression. An over-abundance of CB1 signalling has been associated with increased psychoactivity, systemic inflammation, cardiovascular risk, diabetes and obesity. In contrast, CB2 over-activation and dominance could lead to decreased immune function and diminished wound healing.

adapted from Is Your Endocannabinoid System in Balance?