What Are Endocannabinoids?
Endocannabinoids are lipid-based neurotransmitters produced endogenously by the human body that activate cannabinoid receptors (CB1 and CB2) to maintain physiological homeostasis across multiple organ systems. 1
Core Components of the Endocannabinoid System
The endocannabinoid system (ECS) consists of four key elements that work together as an intricate cell-signaling network 1:
- Endogenous cannabinoids (endocannabinoids): The two primary endocannabinoids are anandamide (arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), both derived from arachidonic acid 1, 2
- Cannabinoid receptors: Two G-protein-coupled membrane receptors—CB1 and CB2—that bind both endogenous and exogenous cannabinoids 1
- Transport proteins: Specific uptake systems that move endocannabinoids into cells 2
- Degrading enzymes: Fatty acid amide hydrolase and monoacylglycerol lipase that break down endocannabinoids after use 3, 2
Receptor Distribution and Function
CB1 receptors are densely concentrated in the central nervous system, particularly in the dorsal vagal complex, and throughout the gastrointestinal tract in myenteric and submucosal neurons. 1 These receptors control anxiety, depression, gastrointestinal secretions, emesis, appetite, motor control, cognition, emotional responses, and motivated behavior 1, 2.
CB2 receptors are located predominantly in inflammatory cells (immunocytes and macrophages), epithelial cells, and to a lesser extent in sensory neurons. 1 They primarily mediate effects on inflammation and nociception 1.
Physiological Regulation Mechanism
Endocannabinoids function as "on-demand" signaling molecules rather than being stored in vesicles like classical neurotransmitters 4, 3:
- They are synthesized from lipid precursors in cell membranes when needed 3, 2
- They act as retrograde messengers in GABAergic and glutamatergic synapses, traveling backward across synapses to modulate neurotransmitter release 2
- They exert constant negative feedback on the hypothalamic-pituitary-adrenal axis to maintain homeostasis 1
- After signaling, they are rapidly degraded by specific enzymes, ensuring tight temporal control 3, 2
Homeostatic Functions
The ECS maintains balance across numerous physiological processes 1, 5:
- Temperature regulation, mood, and immune system function 5
- Energy input and output, feeding behavior, and appetite 5, 2
- Pain sensation and nociception 5, 6
- Memory, learning, cognition, and neurogenesis 5
- Fertility, pregnancy, and pre- and post-natal development 5
- Autonomic nervous system and microcirculation modulation 2
Clinical Significance
Endocannabinoid levels are transiently elevated as an adaptive reaction to restore homeostasis when acutely disrupted by pathological conditions. 4 Alterations in endocannabinoid levels have been documented in pain states, neurological and neurodegenerative diseases, gastrointestinal disorders, and inflammatory conditions 4.
However, in chronic conditions, dysregulation of the ECS can contribute to disease progression rather than resolution 4. This dual nature makes the ECS a target for both agonists (to enhance signaling) and antagonists (to block excessive signaling) in therapeutic drug development 4, 6.
Distinction from Exogenous Cannabinoids
While endocannabinoids are produced naturally by the body, exogenous cannabinoids like Δ9-tetrahydrocannabinol (THC) from cannabis plants act on the same receptors 1. THC is a partial agonist at both CB1 and CB2 receptors, whereas cannabidiol (CBD) is a negative allosteric modulator that does not directly activate these receptors. 1
The key difference is that endocannabinoids are tightly regulated through synthesis and degradation mechanisms, while exogenous cannabinoids bypass these controls and can lead to receptor dysregulation with chronic use 1.