Simvastatin Interactions

Grapefruit blocks the intestinal CYP3A4 enzyme that simvastatin depends on, raising simvastatin blood levels and increasing the risk of muscle damage (myopathy and rhabdomyolysis).

Red yeast rice contains monacolin K, which is chemically identical to the prescription statin lovastatin. Adding it to simvastatin stacks two statins with the same mechanism and metabolism, adding to the risk of muscle injury, rhabdomyolysis, and liver problems.

St. John's wort induces the CYP3A4 enzyme and the P-glycoprotein transporter that simvastatin depends on, sharply increasing the drug's first-pass breakdown. In a controlled crossover study of healthy volunteers, two weeks of St. John's wort substantially lowered the amount of active simvastatin reaching the bloodstream, weakening its cholesterol-lowering effect.

Pomelo (Citrus maxima) contains furanocoumarins that inhibit intestinal CYP3A4, the enzyme that breaks down simvastatin during first-pass absorption. With that enzyme suppressed, more simvastatin reaches the bloodstream, raising the risk of muscle-related side effects. This is the same mechanism behind the well-established grapefruit-simvastatin interaction, since pomelo is the parent species of grapefruit and shares its furanocoumarins.

Simvastatin blocks HMG-CoA reductase, the enzyme upstream of both cholesterol and coenzyme Q10 (CoQ10) synthesis, so it lowers circulating CoQ10 alongside cholesterol. This depletion is a plausible contributor to statin-associated muscle symptoms, and some randomized trials suggest CoQ10 supplements modestly ease those symptoms — though the evidence is mixed.

Simvastatin is activated and cleared by the CYP3A4 enzyme. A human study found that repeated berberine inhibits CYP3A4, which could raise simvastatin levels and increase the risk of muscle-related side effects. Some animal data suggest berberine can also induce CYP3A4 over time, so the net effect on statin exposure is hard to predict. There are no published human case reports of myopathy from this specific combination, so the concern is mechanistic and moderate.

Simvastatin is cleared mainly by the liver enzyme CYP3A4, and CBD inhibits that same enzyme. Combining them is expected to raise simvastatin exposure, which could increase the risk of muscle pain and, rarely, more serious muscle injury. This is a predicted, mechanism-based interaction rather than one confirmed by a direct human study.

Blood orange (Citrus sinensis var.) is a sweet orange and does not contain the furanocoumarins (such as bergamottin and 6',7'-dihydroxybergamottin) that drive the grapefruit-statin interaction. Reviews of citrus furanocoumarin content place blood orange among the sweet oranges that are essentially free of clinically significant CYP3A4-inhibiting compounds, so it is not expected to meaningfully affect simvastatin levels.