What is the pathophysiology of Cannabis Hyperemesis Syndrome (CHS)?

Pathophysiology of Cannabis Hyperemesis Syndrome

Central Mechanism: Endocannabinoid System Dysregulation

The pathophysiology of CHS centers on chronic overstimulation of CB1 receptors in the central nervous system, particularly in the dorsal vagal complex, which disrupts the normal negative feedback control of the hypothalamic-pituitary-adrenal axis and leads to paradoxical increased vagal nerve discharges that trigger vomiting. 1

Receptor Systems Involved

CB1 Receptor Activation

• Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, activates two G-protein-coupled membrane receptors: CB1 and CB2 1, 2
• CB1 receptors are densely distributed in the dorsal vagal complex of the brain, which is the critical neurocircuit controlling emesis 1, 3
• CB1 receptors are also located throughout the gut in myenteric and submucosal neurons, as well as in epithelial cells 1
• The predominant receptors mediating nausea and vomiting in CHS are central CB1 receptors, where cannabinoids normally exert effects on anxiety, depression, gastrointestinal secretions, emesis, and appetite control 1

TRPV1 Receptor Involvement

• THC also binds to transient receptor potential vanilloid type 1 (TRPV1) channels, which are considered important in CHS due to their effects on the vagus nerve and gut functions 1, 2
• This TRPV1 involvement explains why topical capsaicin and hot water bathing provide symptomatic relief, as both activate these receptors 1, 4, 3

The Paradoxical Effect

Loss of Negative Feedback

• The endocannabinoid system normally exerts constant negative feedback on the hypothalamic-pituitary-adrenal axis 1
• Chronic stimulation of CB receptors leads to loss of this feedback mechanism, resulting in increased vagal nerve discharges that contribute to vomiting 1, 3
• This represents a biphasic effect: low doses of cannabinoids have antiemetic properties, while chronic high doses produce emesis 5

Peripheral Effects

• Activation of peripheral CB1 receptors affects gastric motility and emptying, as well as more distal gut motility 1
• Inhibition of gastric acid secretion may also occur through peripheral CB1 receptor activation 1, 2

Classification as Gut-Brain Disorder

• CHS is classified as a disorder of gut-brain interaction in the Rome IV classification of functional gastrointestinal disorders since 2016 1, 2
• This classification reflects the complex interplay between central nervous system dysregulation and peripheral gastrointestinal effects 1

Duration and Dose Dependency

• The syndrome typically develops after prolonged cannabis use, with a mean duration of 6.6 years before symptom onset 1, 2
• Daily or near-daily use (>4 times per week) is characteristic of patients who develop CHS 1, 4, 2
• The total THC dose and duration of exposure are critical factors, not the route of administration (smoking, vaping, or edibles all carry equal risk) 3

Stress and Allostasis

• The endocannabinoid system is an important regulator of stress response and allostasis, which can be overwhelmed by excessive cannabis use 6
• Acute CHS episodes may be precipitated by stress or fasting in chronic cannabis users who have pre-existing abnormal hypothalamic-pituitary-adrenal axis feedback 6

Key Pathophysiologic Features

• Dysregulation of multiple neurotransmitter systems occurs with chronic high-dose THC exposure 5
• Thermoregulation disruption may explain the characteristic hot water bathing behavior seen in 71-92% of patients 1, 4, 5
• The pathophysiology shares similarities with cyclic vomiting syndrome and chemotherapy-related anticipatory nausea, suggesting overlapping mechanisms involving stress and anxiety responses 5