Can I Take St. John's Wort with Wegovy?

Is there a direct interaction between St. John's wort and Wegovy?

Semaglutide is a peptide, and the body handles it differently from most pills. The Wegovy label describes breakdown by proteolytic cleavage of the peptide backbone and beta-oxidation of the fatty acid side chain, not by CYP enzymes, and says semaglutide has very low potential to inhibit or induce CYP enzymes [1]. It is more than 99% bound to albumin, has an elimination half-life of about a week, and about 3% of a dose is excreted unchanged in urine [1].

The Wegovy drug interactions section covers two things: low blood sugar when Wegovy is used with insulin or an insulin secretagogue such as a sulfonylurea, and delayed gastric emptying that can affect absorption of oral medicines [1]. St. John's wort is not named there [1].

No study that tested St. John's wort and semaglutide together was identified. Any prediction rests on how each is handled by the body and on studies of St. John's wort with other medicines, so it does not prove the combination is safe.

Why St. John's wort changes so many drug levels

St. John's wort (Hypericum perforatum) is sold in the US as a dietary supplement, so it is not FDA-approved before sale, and it is not an approved treatment for depression [2]. It activates the pregnane X receptor, which induces CYP3A4 and other cytochrome P450 enzymes as well as the P-glycoprotein transporter. The extent of CYP3A4 induction correlates with the product's hyperforin content [3][5].

The size of the effect depends on dose. In 11 healthy volunteers, 14 days of St. John's wort raised oral midazolam clearance 1.96-fold at 300 mg a day, 3.86-fold at 900 mg a day and 5.62-fold at 1,800 mg a day [6]. In 42 men given six products for 14 days, midazolam exposure fell 79.4% with an extract supplying 41 mg of hyperforin a day, 47.9% with a powder supplying 12 mg a day and 21.1% with a powder supplying 0.13 mg a day; the change correlated with hyperforin dose, not hypericin [5]. A separate low-hyperforin powder cut midazolam exposure 11.3%, which those authors judged not clinically relevant [7].

Which other medicines matter if you take Wegovy

Combined birth control pills. The Sprintec label says products containing St. John's wort may lower combined oral contraceptive levels, potentially reducing effectiveness or increasing breakthrough bleeding, and says to use an alternative or back-up method and continue it for 28 days after the inducer is stopped [8]. In 18 women using a pill containing ethinyl estradiol 0.02 mg and desogestrel 0.15 mg, adding 300 mg of St. John's wort extract twice or three times daily produced intracyclic bleeding in 77% and 88% of women versus 35% on the pill alone, and lowered 3-ketodesogestrel exposure by 43.9% and 41.7%; ethinyl estradiol was unchanged and there was no evidence of ovulation [9]. A review of four studies found more breakthrough bleeding in three and probable ovulation in one [10]. Semaglutide is a different case: the semaglutide labels carry no oral contraceptive switching advice, and a tablet interaction study found no clinically significant effect on ethinyl estradiol or levonorgestrel [1].

Warfarin. In 12 healthy men given a single 25 mg dose, 14 days of St. John's wort raised S-warfarin apparent clearance 29% and R-warfarin 23% and lowered the INR area under the curve to 0.79 of baseline (90% CI 0.70 to 0.95) [11]. The warfarin label lists St. John's wort among botanicals that may decrease its effect [12].

Digoxin and rivaroxaban. Ten days of an extract at 900 mg a day lowered digoxin exposure 25%, trough 33% and peak 26% in a placebo-controlled study, with no change after the first dose [13]. Two weeks of extract lowered rivaroxaban exposure to 0.76 of baseline and factor Xa inhibition to 0.80 in 12 volunteers [14].

Cyclosporine. In 11 kidney transplant patients, 600 mg a day of extract for 14 days lowered dose-corrected cyclosporine exposure 46%, peak 42% and trough 41%, and the dose was raised from a median 2.7 to 4.2 mg/kg a day, with the first adjustment needed after 3 days [4]. Acute rejection in two heart transplant patients linked to the interaction was reported in 2000 [15].

Antidepressants. NCCIH says combining St. John's wort with certain antidepressants or other drugs that affect serotonin may cause increased serotonin-related side effects, which can be serious [2]. The Zoloft label lists St. John's wort among serotonergic drugs that raise serotonin syndrome risk [16]. A case report described possible serotonin syndrome after buspirone plus St. John's wort [17], and a case series described central serotonergic syndrome in five elderly patients who combined prescription antidepressants with the herb [18]. St. John's wort also lowers amitriptyline levels: in 12 patients, amitriptyline exposure fell 22% and nortriptyline 41% [19].

What the Wegovy label flags for other medicines

Insulin and sulfonylureas are the label's first concern. The label says to consider reducing the insulin or secretagogue dose when starting Wegovy [1]. In a weight trial in adults with type 2 diabetes and BMI 27 or higher, glucose below 54 mg/dL occurred in 6.2% on Wegovy 2.4 mg versus 2.5% on placebo, and adding Wegovy to insulin has not been evaluated [1]. The second concern is absorption. Because Wegovy delays gastric emptying, the label advises increased clinical or laboratory monitoring for oral medicines with a narrow therapeutic index or that need clinical monitoring, and clinical pharmacology trials with semaglutide 1 mg injection found no effect on absorption of the oral medicines tested [1].

Side effects the two can share

Wegovy's label reports nausea in 44% versus 16% on placebo, diarrhea 30% versus 16%, vomiting 24% versus 6%, constipation 24% versus 11% and dizziness 8% versus 4% in pooled trials of 2,116 adults on 2.4 mg and 1,261 on placebo lasting up to 68 weeks [1]. In those pooled trials, 6.8% of patients stopped treatment because of adverse reactions versus 3.2% of placebo-treated patients [1]. NCCIH lists diarrhea, dizziness, trouble sleeping, restlessness and skin tingling among St. John's wort side effects, and says large oral doses or skin application may cause severe skin reactions after sun exposure [2]. Diarrhea and dizziness appear on both lists [1][2].

Pregnancy and contraception

The Wegovy label says weight loss offers no benefit in pregnancy and may cause fetal harm, and that people using it for weight reduction should stop at least 2 months before a planned pregnancy because of the long half-life [1]. NCCIH says St. John's wort may be unsafe in pregnancy because it may increase the risk of birth defects, and that breastfed infants of mothers taking it can experience colic, drowsiness and lethargy [2]. For anyone relying on a combined pill, the contraceptive interaction is the practical link between the two.

Putting it together

NCCIH says St. John's wort can weaken the effects of many medicines, including birth control pills, warfarin, cyclosporine, some antidepressants, digoxin and certain statins [2]. For Wegovy itself, the interactions the label describes are delayed gastric emptying that can change absorption of oral medicines and low blood sugar with insulin and sulfonylureas [1]. The St. John's wort concern lies with whatever else is in the regimen: a combined pill, warfarin, digoxin, cyclosporine or a serotonergic antidepressant [2][8][11].