What changes occur in the endocannabinoid system due to chronic cannabis use?

Changes in the Endocannabinoid System from Chronic Cannabis Use

Chronic cannabis use causes downregulation of CB1 receptors and disrupts the endocannabinoid system's negative feedback mechanisms, leading to impaired neuronal growth, altered hippocampal structure, and dysregulated control of emesis, pain, and stress responses. 1

Receptor-Level Alterations

CB1 Receptor Changes

• THC-induced CB1 receptor activation inhibits neuronal growth and disrupts synapse formation during adolescence, with particularly severe effects when heavy use (≥20 days/month) begins in youth 1
• Chronic activation leads to loss of negative feedback control over the hypothalamic-pituitary-adrenal axis, resulting in increased vagal nerve discharges 2, 3
• Structural hippocampal changes occur specifically in regions with high CB1 receptor density among adults who initiated heavy cannabis use during adolescence 1

Receptor Distribution Context

• CB1 receptors are densely distributed in the cerebral cortex, hippocampus, basal ganglia, cerebellum, dorsal vagal complex, and peripheral nervous system 1, 3
• CB2 receptors are primarily located on immune system cells and remain less affected by chronic use 1

Functional System Dysregulation

Emesis Control Disruption

• The endocannabinoid system's control over emesis becomes dysregulated, with CB1 receptors in the dorsal vagal complex (the critical emesis control center) losing normal regulatory function 2, 3
• This dysregulation manifests as cannabinoid hyperemesis syndrome in chronic users, requiring enhanced prophylactic antiemetic therapy perioperatively 2

Gastric Motility Alterations

• Peripheral CB1 receptor activation alters gastric motility, gastric emptying, and inhibits gastric acid secretion 3
• These changes contribute to gastrointestinal symptoms in chronic users 2, 3

Neuroadaptive Changes

Endocannabinoid Tone Alterations

• Frequent cannabis use causes adaptive downregulation of brain endocannabinoid signaling 4
• This downregulation creates a state where the brain's natural endocannabinoid system (anandamide and 2-arachidonoylglycerol) functions below baseline 4

Withdrawal Manifestations

• Physical dependence develops with prolonged use, producing withdrawal symptoms within 24-72 hours of cessation including irritability, anxiety, decreased appetite, restlessness, and sleep difficulties 5, 6
• Withdrawal symptoms typically last 1-2 weeks but complete system normalization may require up to 6 months of abstinence 5

Clinical Implications

Anesthetic Considerations

• Cannabis users require higher doses of anesthetic agents to achieve adequate depth of anesthesia due to altered CB1 receptor function 1, 2
• Processed depth of anesthesia EEG monitoring (BIS) should be considered for heavy users 2

Pain Management Alterations

• Chronic users demonstrate higher postoperative analgesic requirements due to endocannabinoid system dysregulation 2
• The CB1 receptor's role in pain pathways becomes compromised with chronic THC exposure 1

Cardiovascular Effects

• Beta-adrenergic-mediated tachycardia occurs with acute use, while heavy chronic use paradoxically causes orthostatic hypotension and bradycardia 1

Critical Pitfall

The delayed expression of withdrawal symptoms due to THC's long half-life means patients and clinicians often fail to recognize the connection between cannabis cessation and subsequent symptoms, leading to underdiagnosis of cannabis-related endocannabinoid system dysfunction 6.