The endocannabinoid system, explained

The endocannabinoid system (ECS) is a complex cell signalling system that plays a very important role in the human body, maintaining homeostasis.

Human cannabinoid receptors.

Back in the 1960s Professor Raphael Mechoulam became interested in researching the bioactivity of the cannabis plant and eventually isolated many of its active compounds. In particular, cannabinoids such as delta-9-tetrahydrocannabinol (THC), then later cannabidiol (CBD) and many others.

It took another 30 years, however, for researchers studying animal models to discover a receptor for endocannabinoid system (ECS) compounds in the brains of rodents – a discovery that opened a whole world of inquiry into why the ECS receptors exist and the purpose of their physiology.

We now know that most animals – from fish to birds to mammals – have an ECS. We also know that humans make their own cannabinoids that interact with this system. Other compounds that interact with the ECS are found in a variety of foods and plants, beyond the cannabis species.

As a system of the body, the ECS is not an isolated structural system like the nervous system or cardiovascular system. Instead, the ECS is a set of receptors broadly distributed throughout the body that are acted on by a set of ligands we now collectively call endocannabinoids (for endogenous cannabinoids). The two verified receptors are simply known as CB1 and CB2, although there are others that have been proposed. PPAR and TRP channels also mediate some functions. Likewise, there are two well-documented endocannabinoids: anadamide and 2-arachidonoyl glycerol (or 2-AG).

Also important to the ECS are the enzymes that synthesise and break down the endocannabinoids. Endocannabinoids are believed to be synthesised on an as-needed, basis. The primary enzymes involved are diacylglycerol lipase and N-acyl-phosphatidylethanolamine-phospholipase D, which respectively synthesise 2-AG and anandamide. The two primary degrading enzymes are fatty acid amide hydrolase (FAAH), which breaks down anandamide, and monoacylglycerol lipase (MAGL), which breaks down 2-AG. Modulation of these two enzymes can up-regulate or down-regulate the ECS.

How does the ECS work in humans?

The ECS is the primary homeostatic regulatory system of the body. It can readily be viewed as the body’s internal adaptogenic system, constantly working to maintain a vast range of functions in equilibrium. Endocannabinoids broadly work as neuromodulators and, as such, they regulate a wide scope of physiological processes – from fertility to pain. Some of the better-known functions impacted by the ECS are as follows:

Nervous system

In the central nervous system (CNS), general stimulation of the CB1 receptors will inhibit the release of glutamate and GABA. In the CNS, the ECS plays a role in memory formation and learning, promotes neurogenesis in the hippocampus, and regulates neuronal excitability.

The ECS also plays a role in how the brain will respond to trauma and inflammation. In the spinal cord, the ECS modulates pain signaling and promotes natural analgesia. In the peripheral nervous system, where CB2 receptors dominate, the ECS acts primarily in the sympathetic nervous system to regulate functions of the digestive, urinary, and reproductive tracts.

Stress and Mood

The ECS has multiple impacts on stress responses and emotional regulation, including initiation of the physiological response to acute stress and adaptation over time to more long-term emotions such as fear and anxiety.

A healthy functioning endocannabinoid system is critical to how humans modulate between a pleasurable level of arousal in contrast to a level that is excessive and unpleasant. The ECS also plays a role in memory formation and perhaps especially in how the brain imprints memories from stress or trauma.

Because the ECS modulates the release of dopamine, noradrenaline, serotonin, and cortisol, it can also broadly influence emotional response and behaviors.

Digestive System

The digestive system is populated with both CB1 and CB2 receptors that regulate several important aspects of GI health. It is believed that the ECS might be the “missing link” in explaining the gut-brain-immune connection that plays an important role in the functional health of the digestive system.

The ECS is a regulator of gut immunity, possibly by limiting the immune system from destroying healthy flora, and also through the modulation of cytokine signaling. The ECS modulates the natural inflammatory response in the digestive system, which has important implications for a broad range of health concerns. Gastric and overall GI motility also seems to be partly regulated by the ECS.

Appetite and Metabolism

The ECS, particularly the CB1 receptors, plays a role in appetite, metabolism, and regulation of body weight. Stimulation of the CB1 receptors increases food-seeking behavior, enhances sense of smell, and regulates energy balance.

Both animals and humans that are obese have ECS dysregulation that can lead this system to become hyperactive, which contributes to both overeating and reduced energy expenditure. Circulating levels of anandamide and 2-AG have been found to be elevated in obesity, which might be in part due to decreased production of the FAAH degrading enzyme.

Immune Health and Inflammatory Response

The organs and cells of the immune system are rich with endocannabinoid receptors. Cannabinoid receptors are expressed in the thymus gland, spleen, tonsils, and bone marrow – as well as on T- and B-lymphocytes, macrophages, mast cells, neutrophils, and natural killer cells.

The ECS is considered to be the primary driver of immune system balance and homeostasis. Although not all of the functions of the ECS in the immune system are known, the ECS appears to regulate cytokine production and to have a role in preventing overactivity in the immune system.

Inflammation is a natural part of the immune response, and it plays a normal role in acute insults to the body (including injury and infection); however, when it is not kept in check it can become chronic and contribute to a cascade of adverse health issues. By keeping the immune response in check, the ECS helps maintain a balanced inflammatory response throughout the body.

Other areas of health regulated by the ECS:

• Bone health

• Fertility

• Skin health

• Arterial and respiratory health

• Sleep and circadian rhythm

When you think about it, a health disorder is simply a disruption of stable internal systems. The disruption causes those systems to become unstable, leading our immune system to break down.

Enter, medicinal cannabis

Medicinal cannabis is a term that refers to regulated, high-quality and standardised products made from crude cannabis extracts, or dried cannabis flower. Cannabinoid medicines, using compounds such as CBD and THC, target the ECS to best support its healthy function.

Pharmaceutical preparations of cannabis use active components of cannabis in medical formulations, which maximise the therapeutic benefit and minimise side effects. Medical preparations, such as sublingual solutions, capsules or mouth sprays, mean the concentration can be standardised and the dose controlled.

Helius cultivates cannabis and produces high-quality, standardised cannabinoid medicines

In New Zealand, there are vaporisers available (as registered as medical devices) that allow patients to inhale dry cannabis flower as a whole-plant medicine. In the future, new measured dose aerosol devices and inhalers are expected too.

Many medicinal cannabis products contain a combination of THC and CBD. Some products contain CBD only and others contain predominantly THC. Some are isolates (a single isolated cannabinoid), while others contain full-spectrum cannabinoids. In the future there will also be medicinal cannabis products that deliver minor cannabinoids, such as THCV and CBN.

There are different rules relating to the availability of cannabis products in other countries, such as the United States. Those that are available without a prescription overseas will require a prescription in New Zealand. For example, products labelled as containing CBD cannot be sold as dietary supplements in New Zealand. Products containing CBD, THC and any other cannabinoids, can only be legally obtained as a prescription medicine.

Since the Medicinal Cannabis Scheme was enacted in April 2020, any doctor in New Zealand can now prescribe medicinal cannabis, for any condition, as they see fit. You can read more about accessing medicinal cannabis here.

For more information about how cannabis medicines work, including their potential benefits and risks, visit the New Zealand's medicinal cannabinoid information service, mcinfo.com.