A review proposes that cannabinoid receptor activation could counteract the dangerous calcium overload in malignant hyperthermia by reducing muscle calcium release through CB1-mediated inhibition of ryanodine receptor phosphorylation.
Anesthesiologists; endocannabinoid researchers; pharmacologists studying calcium signaling
CB1 activation inhibits the same PKA/RYR1 pathway that drives malignant hyperthermia
What the researchers found
CB1 receptor activation inhibits PKA-mediated phosphorylation of RYR1 and L-type calcium channels, potentially reducing the excessive calcium release that causes malignant hyperthermia. Preclinical studies show CB1 agonism lowers body temperature and reduces cardiovascular stress.
Why it matters
Malignant hyperthermia is life-threatening and has only one primary treatment (dantrolene), which has significant side effects. If cannabinoids can modulate the same calcium pathways, they could offer an adjunctive therapy.
The numbers in context
CB1 activation inhibits PKA-mediated phosphorylation of RYR1 and L-type calcium channels. TRPV1 antagonism or desensitization reduces sarcoplasmic reticulum calcium release.
How the study worked
Narrative review synthesizing molecular evidence linking endocannabinoid signaling to calcium homeostasis in skeletal muscle and its potential relevance to malignant hyperthermia.
What this study cannot tell us
Theoretical review based on indirect molecular evidence. No studies have tested cannabinoids specifically in malignant hyperthermia models. The proposed mechanisms need experimental validation in RYR1-mutant models.
How to read the evidence
Theoretical review proposing a novel mechanism; no direct experimental evidence in MH models yet.
When this study was published
2025 review synthesizing current molecular evidence
The bigger picture
This review connects two previously separate fields: anesthesiology/pharmacogenetics and endocannabinoid research. If validated, it could represent an entirely new therapeutic approach for a rare but deadly condition.
Questions still open
- Would cannabinoids be safe during anesthesia? Could they interfere with the triggering volatile anesthetics? What dose and timing would be needed for a protective effect?
Common questions
What is malignant hyperthermia?
Could cannabis use protect against malignant hyperthermia?
Read the original research
The endocannabinoid system & malignant hyperthermia: From molecular signaling towards clinical implications.
Progress in lipid research, 99, 101342
Citation
Dalle, Simon; Dalle, Sebastiaan. (2025). The endocannabinoid system & malignant hyperthermia: From molecular signaling towards clinical implications.. Progress in lipid research, 99, 101342. https://doi.org/10.1016/j.plipres.2025.101342
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