The endocannabinoid system & malignant hyperthermia: From molecular signaling towards clinical implications

Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disorder triggered by volatile anaesthetics and depolarizing muscle relaxants. MH is characterized by excessive calcium release from the sarcoplasmic reticulum, often due to ryanodine receptor 1 (RYR1) mutations, leading to hypermetabolism, muscle rigidity and hyperthermia. While the RYR1 antagonist dantrolene remains the primary pharmacological treatment, its side effects necessitate exploration of alternative treatment options. Emerging evidence implicates the endocannabinoid system in muscle calcium homeostasis, suggesting its potential role in MH management. The endocannabinoid system comprises endogenous ligands (e.g. anandamide), cannabinoid receptors (e.g. cannabinoid receptor 1, CB1), and can modulate the calcium dynamics. CB1 activation inhibits PKA-mediated phosphorylation of RYR1 and L-type calcium channels, reducing myoplasmic calcium and muscle contractility, a mechanism that could counteract MH pathophysiology. In addition, antagonism or desensitization of the calcium channel transient receptor potential vanilloid 1 lowers calcium release from the sarcoplasmic reticulum. Preclinical studies demonstrate that CB1 agonism lowers body temperature and attenuates cardiovascular stress, aligning with MH therapeutic goals. This review synthesizes molecular insights linking endocannabinoid signaling to MH, highlighting its unexplored potential as an adjunctive therapy. Future research should validate these mechanisms in MH-specific models, including RYR1-mutant human myotubes, to translate ECS modulation into clinical practice.