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  • Writer's pictureTravis Cesarone

Statin drugs cause pain by depleting cannabinoid receptor genes

Updated: Jan 14, 2023

Heart disease is responsible for a substantial number of relative casualties. Combatting this, millions of people take statins to regulate their cholesterol. The drugs, unfortunately, however, cause weakness and myopathy. Doctors once thought muscular pain was psychosomatic, but statin medications likely deplete cannabinoid receptor function.

A recent study, released on Research Square before review, was co-authored by highly prolific Italian scientists. The preprint suggests that a statin drug affects enzymes in the endocannabinoidome (ECome). More troublesome, though, is that simvastatin alters genes employed to regulate cannabinoid receptors. Mapping cannabimimetic pathways manipulated by statins will help lead to therapeutic adjuvants. Redesigning existing medications to respect the endocannabinoidome is critical, considering the exorbitant costs of alternate therapies.

Statins and lipid lowering drugs

Statins reduce cholesterol by inhibiting an enzyme in the liver called HMG-CoA reductase. Overall, they lower bad cholesterol and triglycerides, increasing good cholesterol levels. Lipid regulation helps reduce the risk of cardiovascular disease. The lipidome, however, consists of endocannabinoids. And this could be why statin medications, such as simvastatin, cause pain and toxic myopathies.

HMG-CoA liberates a pathway that, in plants, is responsible for phytocannabinoid production. Whereas in animals, a unique enzyme family converts dietary Omega-3 fat into endocannabinoids. And simvastatin does affect those enzymes, dysregulating endocannabinoid tone, according to the recent preprint. But the medication also reduces cannabinoid receptor expression.

Simvastatin chemical diagram courtesy of Wikicommons.

Simvastatin stunts a cannabinoid receptor

A team of researchers tested the lipid-lowering medication known as simvastatin on special mouse cells and tissues. Cells utilized in the experiment were a type of myoblast, a stem cell that forms muscle. They further tested the drug on skeletal muscle tissue, which they extracted from sacrificed mice, and on human myoblasts.

The cholesterol-cutting drug altered genes responsible for endocannabinoid creation and degradation. Exposure to statin-based medications ultimately boosted cellular endocannabinoid expression. Contrary to standard functions, though, elevated levels of 2-AG and anandamide are likely not therapeutic without exogenous assistance.

Facilitating and treating statin toxicity

Simvastatin repressed CB1 and CB2 receptors as well as TRPV1 channels, negatively impacting the endocannabinoid system. Exogenous cannabinoid receptor blockade also progressed muscular pain and weakness induced by simvastatin. Following exposure to the medication, researchers found increased levels of micro-mRNA sequences capable of suppressing CB1 receptors.

Statins cause toxicity by downregulating CB1 receptor expression in myoblasts, according to the recent preprint. In conclusion, cholesterol-regulating statins formulated with positive modulators of the CB1 receptor could negate some toxic side effects. Further research that explores how statins affect the endocannabinoid system, causing muscular pain and weakness, is required for 200 million patients around the globe that take statin drugs.

Let us know in the comments if you or someone you know that uses statins experiences muscle pain or weakness.


  1. Hilal Kalkan, Elisabetta Panza, Ester Pagano et al. MicroRNA-mediated repression of endocannabinoid CB1 receptor expression contributes to simvastatin-induced skeletal muscle toxicity, 20 December 2022, PREPRINT (Version 1)

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