The Complex Relationship between Depression, Diabetes, and St. Johns Wort

Patients who have type 2 diabetes are at elevated risk for developing depression, and vice versa. They sometimes self-treat with St. John’s Wort, an herbal antidepressant with an SSRI-like effect. St. John’s Wort has a hyperforin constituent—a distinct section of its molecular structure and phytochemical—that induces CYP3A4. St. John’s Wort is also a pregnane X receptor (PXR) agonist. It activates the PXR receptor and p-glycoprotein, and alters many other medications' pharmacokinetics. This is noteworthy because around 30% of drugs metabolized by the liver depend on the PRX receptor.

Now, an article published in Basic and Clinical Pharmacology and Toxicology indicates that long-term use of St. John’s Wort persistently inhibits insulin secretion in young healthy men. This is surprising since PXR agonists often enhance glucose metabolism when administered with metformin.

Ten fasting men who had no history of deranged glucose metabolism received the maximum allowable dose of St. John’s Wort (240 to 294 mg dry extract of SJW and 900 mcg total hypericin) twice daily for 21 days. They underwent an oral glucose tolerance test (OGTT) at baseline, after 21 days of St. John’s Wort exposure, and 6 weeks after treatment cessation. The researchers did not control for diet or physical activity levels.

All patients developed beta cell inhibition, and was still present 6 weeks after treatment cessation. Glucose tolerance, measured as area-under-the-curve (AUC) and 2-hour glucose—indicated that participants' beta cells were affected. Participants’ glucose AUC increased by 34% and the 2-hour glucose increased by 27 mg/dL.

Total insulin was not affected in a statistically significant way.

The study has inadequate power to detect changes in insulin sensitivity. A previous study found that rifampicin, another PXR agonist, has a similar effect on OGTT.

Recent studies have shown that combining a PXR agonist with metformin improves glucose tolerance by increasing metformin transport and subsequent beta-cell function. The authors indicate that this seemingly positive effect may outweigh the negative effect they identified in this study when patients received only St. John’s Wort.

Because of St. John’s Wort’s untoward effect on hormonal contraceptives, the researchers excluded women in this study. They also excluded patients with chronic or daily alcohol abuse, known liver disease, known hypersensitivity to St. John’s Wort, or use of systemic prescription medications.

The researchers concluded that St. John’s Wort produces persistent glucose intolerance via decreased beta-cell function. St. John’s Wort may increase risk of type 2 diabetes in the already at-risk depressed population.