Does St. John's Wort (Hypericum perforatum) increase cholesterol levels?

St. John's Wort and Cholesterol Levels

St. John's Wort can increase cholesterol levels, particularly when used concomitantly with cholesterol-lowering medications like statins, by reducing their effectiveness through induction of CYP450 enzymes.

Mechanism of Action

St. John's Wort (Hypericum perforatum) is a potent inducer of several metabolic pathways that can affect cholesterol levels:

• Acts as a strong inducer of cytochrome P450 3A4 (CYP3A4) enzymes 1
• Functions as a P-glycoprotein (P-gp) inducer, affecting drug metabolism 1
• These effects can persist for a period after discontinuation due to the long half-lives of constituents like hypericin 2

Effects on Cholesterol Levels

Direct Evidence

• Clinical studies show St. John's Wort significantly increases LDL cholesterol levels in patients taking statins:
  • Increased LDL cholesterol from 2.30 mmol/L to 2.72 mmol/L in patients on simvastatin (p<0.0001) 3
  • Increased total cholesterol from 4.56 mmol/L to 5.08 mmol/L in the same population (p<0.0001) 3
  • Similar effects observed with atorvastatin, where LDL cholesterol increased from 2.34 mmol/L to 2.66 mmol/L (p=0.004) 4

Mechanism of Cholesterol Elevation

The cholesterol-raising effect occurs primarily through:

1. Reducing the effectiveness of statins by accelerating their metabolism through CYP3A4 induction
2. Potentially altering the metabolism of endogenous cholesterol precursors

Clinical Implications

For Patients on Statins

• St. John's Wort should not be given to patients with hypercholesterolemia who are on treatment with simvastatin 3
• If St. John's Wort treatment is considered necessary for patients on atorvastatin, there may be a need for increasing the statin dose 4

For Patients Not on Statins

Interestingly, some animal studies suggest St. John's Wort might have hypolipidemic effects when used alone:

• Lowered total cholesterol and LDL cholesterol in normal rats 5
• Prevented hypercholesterolemia in ovariectomized rats 6

However, these findings in animal models have not been confirmed in humans, and the clinical evidence points toward cholesterol elevation, particularly when used with statins.

Recommendations for Clinical Practice

• Avoid St. John's Wort in patients with hypercholesterolemia, especially those taking statins
• If discontinuing St. John's Wort, allow at least 2 weeks for its enzyme-inducing effects to diminish 1, 2
• Monitor lipid profiles more frequently in patients who insist on taking St. John's Wort
• Consider alternative treatments for depression in patients with cardiovascular risk factors or hypercholesterolemia

Other Important Considerations

St. John's Wort has numerous other drug interactions that clinicians should be aware of:

• Reduces effectiveness of oral anticoagulants 1
• Decreases serum levels of digoxin 1
• Interacts with many other medications metabolized by CYP3A4 1

These interactions make St. John's Wort particularly problematic for patients with multiple comorbidities requiring polypharmacy.