Endocannabinoid System

Summary

The endocannabinoid system (ECS) is a unique signalling system distributed throughout the body. Its components interact to send messages across the system to produce specific outcomes. The ECS is primarily responsible for maintaining a stable state in the body, known as homeostasis, but is also involved in other processes including, organ system development and regulation, memory formation and sleep regulation. When abnormalities occur in the ECS, this is known as dysregulation and it may contribute to a number of pathological conditions such as chronic pain, psychiatric disorders and neurodegenerative diseases. According to the clinical endocannabinoid deficiency (CED) theory, the development of pain-specific conditions may be linked to endocannabinoid deficiencies.

What is the endocannabinoid system (ECS)?

The endocannabinoid system (ECS) is an ancient lipid-signalling system found in all mammals. The system is expressed throughout the body, such as the nervous system, and in other body tissues. It consists of three main components: the endocannabinoids, cannabinoid receptors and enzymes, which are found in different concentrations across the ECS. The interaction of these components is the basis for cannabinoid signalling and maintaining homeostasis in the body.

Endocannabinoids

Endocannabinoids are a class of lipid compounds produced by the body that bind to specific sites, such as cannabinoid receptors. When bound to these receptors, they produce effects similar to those of the phytocannabinoids found in cannabis, such as tetrahydrocannabinol (THC).

The two main endocannabinoids in the ECS are 2-arachidonoylglycerol (2-AG) and anandamide (AEA). They play an important role in activating cannabinoid signalling, which is a process that transmits signals (or messages) across the ECS to produce specific outcomes.

2-AG and AEA are present in small concentrations in the brain and other body tissues to regulate different processes:

  • 2-AG is primarily involved in regulating inflammation, stress, sleep, weight gain and balance;
  • AEA may be involved in reducing anxiety and relieving pain, although more research is required to establish its effects.

Phytocannabinoids, Endocannabinoids and Synthetic Cannabinoids

Cannabinoids produced by the cannabis plant are called phytocannabinoids (phyton = “plant”) while cannabinoids created naturally in the body are called endocannabinoids (endo = “within”). Synthetic cannabinoids are manufactured in laboratories to mimic natural cannabinoid behaviour and are produced legally and illicitly. All three types of cannabinoids produce effects such as euphoria, pain relief or changes in memory function when they bind and activate cannabinoid receptors.

 

Cannabinoid Receptors

Cannabinoids bind to cannabinoid receptors to activate cannabinoid signalling and to produce changes in cell response and behaviour. There are two main cannabinoid receptors in the ECS:

  • Cannabinoid 1 (CB₁) receptors – highest concentrations are found primarily in the central nervous system (CNS);
  • Cannabinoid 2 (CB₂) receptors – highest concentrations are found primarily in the immune system;

Enzymes

Enzymes are proteins involved in accelerating chemical reactions within cells. In the ECS, enzymes can be divided into two main classes based on their function:

  • Enzymes that synthesize endocannabinoids, such as 
    • N-acyltransferase (NAT)
    • Phospholipase D (PLD)
    • Phospholipase C (PLC)
    • Diacylglycerol-lipase (DAGL)
  • Enzymes that break down endocannabinoids, such as
    • Fatty acid amide hydrolase (FAAH)
    • Monoacylglycerol lipase (MAGL)

The endocannabinoid synthesizing and degrading enzymes play a significant role in controlling and maintaining endocannabinoid production, which is a highly regulated process. The synthesizing enzymes only produce endocannabinoids “on demand” in response to cellular requirements to initiate cannabinoid signalling. Once the endocannabinoids have fulfilled their functions, they are broken down immediately by degrading enzymes to terminate the cannabinoid signalling process.

Signal termination is important to ensure biological activities are properly regulated since prolonged signalling activity can have deleterious effects (e.g. hallucinations, impaired memory and problems with coordination).

What are the functions of the ECS?

The primary responsibility of the ECS is to maintain homeostasis – a balanced state in the body that is required for optimum function. To keep systems throughout the body in balance, the ECS affects a wide range of physiological and pathophysiological processes, including:

  • Nervous system and bone development
  • Immune system and cardiovascular function
  • Inflammation and pain
  • Appetite and digestion
  • Reproduction
  • Memory formation
  • Mood and stress

Changes in ECS functioning, also known as dysregulation, may contribute to a number of pathological conditions. Changes in AEA and 2-AG concentrations for instance, has been observed in the following:

  • Immunological disorders
  • Cardiovascular disorders
  • Cancer
  • Neurodegenerative disorders (e.g. Alzheimer’s disease, multiple sclerosis)
  • Eating disorders
  • Pain and inflammation

The dysregulation of the ECS can result in protective or harmful outcomes.

For example, it has been observed that the number of cannabinoid receptors increases in response to stress. This plays a protective role in neuropathic pain and multiple sclerosis by reducing symptoms and slowing down disease progression. In other diseases such as liver fibrosis, these same changes can be harmful, as they are associated with the development of scar tissue and disease progression.

What is clinical endocannabinoid deficiency (CED)?

Clinical endocannabinoid deficiency (CED) is a theory that suggests low levels of endocannabinoids may be associated with diseases characterized by high pain sensitivity, such as:

  • Migraines and headaches
  • Irritable bowel syndrome (IBS)
  • Fibromyalgia (condition that causes pain all over the body)
  • Depression

Although current research on CED is limited, this theory provides the groundwork for the development of different management strategies for pain-specific conditions. The ideal approach to treat these conditions would be a multimodal approach that may include cannabinoid therapy, as well as life-style and dietary modifications.