The Endocannabinoid System: Master of Body Balance

A Quick Overview of the ECS

Overview of the Endocannaboinoid System provided by CFH, Ltd.’s Clinical Science Director, Dr. Karen Hufnagl

What Is It?

• Master regulatory system – maintains homeostasis and balance in the whole body
• Extensive system with a web of receptors throughout the body
• Modulates and influences every single system in the body
• Functions as a pleiotropic signaling system – a single signal generates multiple responses in numerous tissues containing receptors
• Not discovered until the late 1980s/early 1990s

Comprised Of:

• Endocannabinoids – signaling molecules
• Receptors
• Enzymes that synthesize endocannabinoids
• Enzymes that degrade endocannabinoids
  • FAAH (Fatty Acid Amide Hydroxylase)
  • Monoacylglycerol lipase (MGL)

Endocannabinoids (neurotransmitters)

• 2 main endocannabinoids; total of 6 have been discovered so far
• Anandamide [AEA]

Partial agonist at both the CB1 and CB2 receptors; greater affinity for CB1 receptors

• 2-arachidonoylglycerol [2-AG]

Full agonist at both CB1 and CB2 receptors but with lower affinity than anandamide

• Synthesized and released from postsynaptic neurons through a retrograde signaling system – diffuse backward across the synaptic cleft binding to endocannabinoid receptors on the presynaptic side
• Arachidonic acid derivatives that are synthesized “on demand” based on cellular metabolic needs
• Modulate the release of neurotransmitters – help keep the body from being too over-stimulated or too relaxed
  • Indirect effects on receptors:
    • Serotonin
    • NMDA
    • Opiate
    • GABA
• Multiple signal mechanisms – act on cannabinoid receptors other than CB1/CB2 (i.e., TRP receptors)

Receptors

• CB1
• CB2
• Peroxisome proliferator-activated receptor-γ (PPAR-γ)
• TRPV1 receptor
• GPR55, GPR18, GPR119 (G-protein coupled receptors)

G-protein coupled receptors, TRPV1, and PPAR-γ functionally interact with CB1 receptor signaling

CB1 Receptors

• Primarily located in the central and peripheral nervous system
• Important role in cognition, memory, learning, emotion, mood, motor activity, pain and motivation
• Exist to a lesser degree in many peripheral organs (such as adrenal gland, adipose tissue, heart, liver, lung, prostate, uterus, ovary, testis, bone marrow, thymus, tonsils)
• Located pre-synaptically

CB2 Receptors

• Primarily in peripheral organs/tissues (including bone, GI tract, etc.) and immune system
• Modulate cytokine release (impacts pain, inflammation, immune function)
• Recently, CB2 receptors have been discovered in the brain as well – including pain pathways
• Located pre-synaptically

Endocannabinoid System Functions

• Hippocampal neurogenesis
  • Memory
• Appetite regulation
• Homeostasis of energy balance and metabolism
• Regulation of the HPA axis
  • Stress response
  • Emotion regulation
• Modulation of the immune system
  • Including gut immunity
• Female reproduction – anandamide regulates timing of embryonic implantation and uterine receptivity…if levels are either too high or too low, risk of miscarriage increases.
• Autonomic nervous system regulation
  • Including gut motility, heart rate, breathing, etc.
• Analgesia (pain relief)
• Inflammation
• Thermoregulation
• Sleep
• Cardiovascular function
• Physical exercise effects – aerobic exercise (70-80% MHR) increases plasma anandamide levels – responsible for the “Runner’s high”.
• On-demand regulation of other neurotransmitter systems