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

Does St. John's wort change tirzepatide levels?

The Zepbound label says tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the fatty diacid and amide hydrolysis, not by CYP enzymes, and that it has low in vitro potential to inhibit or induce CYP enzymes [1]. St. John's wort acts mainly by inducing CYP3A4 and P-glycoprotein [3]. Median time to peak concentration is 24 hours, absolute bioavailability is 80%, about 99% is albumin bound, and the half-life is roughly 5 days [1]. Zepbound is given as a once-weekly subcutaneous injection [1].

How strong is the enzyme induction?

St. John's wort activates the pregnane X receptor, which switches on CYP3A4 and other cytochrome P450 enzymes plus P-glycoprotein [3]. The size of the effect depends on the dose and the product, and specifically on its hyperforin content [3][10]. Measured in people:

• 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 [4].
• In 42 men given one of 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 [10]. The effect correlated with hyperforin dose, not hypericin [10].
• In 12 volunteers taking 300 mg three times daily for 14 days, alprazolam exposure fell by half and its half-life dropped from 12.4 to 6.0 hours [11].

The milligram amount on a label says little on its own; across products, the hyperforin dose is what tracked the size of the effect [10].

What happens with birth control pills?

The Zepbound label says use may reduce the efficacy of oral hormonal contraceptives because of delayed gastric emptying, which is largest after the first dose and diminishes over time. It advises a non-oral method or an added barrier method for 4 weeks after starting and for 4 weeks after each dose escalation; non-oral hormonal contraceptives should not be affected [1]. In the label's study of a single 5 mg dose with a combined pill, peak levels of ethinyl estradiol, norgestimate and norelgestromin fell 59%, 66% and 55%, and total exposure fell 20% to 23% [1].

St. John's wort acts on the same pill by a different route. In a randomized trial of 18 women using a pill with 0.02 mg ethinyl estradiol and 0.15 mg desogestrel, adding 300 mg of extract twice daily produced intracyclic bleeding in 13 of 17 (77%) and three times daily in 15 of 17 (88%), against 6 of 17 (35%) on the pill alone. Exposure to the active progestin metabolite fell 43.9% and 41.7%, ethinyl estradiol levels were unchanged, and there was no evidence of ovulation [2]. A systematic review of four such studies found more breakthrough bleeding in three, increased follicular growth with probable ovulation in one, and lower hormone exposure in three [12]. The Sprintec (norgestimate and ethinyl estradiol) label names products containing St. John's wort among those that may lower combined-pill concentrations and says to continue back-up contraception for 28 days after the inducer is stopped [13].

Which other prescriptions are affected?

The Zepbound label says to monitor oral medicines that depend on threshold concentrations for effect, and those with a narrow therapeutic index such as warfarin, when given with Zepbound [1]. St. John's wort has separately been shown to lower exposure to several oral medicines:

• Warfarin: in 12 healthy men given a single 25 mg dose, 14 days of St. John's wort raised S-warfarin clearance by 29% and lowered the INR area under the curve to 0.79 of baseline (90% CI 0.70 to 0.95) [5]. The warfarin label lists St. John's wort among botanicals that may decrease its effect [14].
• Cyclosporine: in 11 kidney transplant recipients, 600 mg a day of extract for 14 days lowered dose-corrected cyclosporine exposure by 46%, peak by 42% and trough by 41%. The cyclosporine dose was raised from a median of 2.7 to 4.2 mg/kg/day, with the first adjustment 3 days after starting the herb [6].
• Digoxin: in a placebo-controlled study, 10 days of extract at 900 mg a day lowered digoxin exposure by 25%, trough by 33% and peak by 26% [7].
• Rivaroxaban: after 2 weeks of extract in 12 volunteers, exposure fell to 0.76 of baseline and factor Xa inhibition to 0.80 [15].
• Amitriptyline: in 12 patients, adding extract lowered amitriptyline exposure by 22% and nortriptyline by 41% [8].

NCCIH's list of medicines the herb can weaken includes antidepressants, birth control pills, cyclosporine, some anti-seizure drugs, some heart, HIV and cancer drugs, warfarin and certain statins including simvastatin [9].

What about antidepressants and other serotonin-affecting drugs?

NCCIH says that taking St. John's wort with certain antidepressants or other drugs that affect serotonin may lead to increased serotonin-related side effects, which can be serious [9].

What the Zepbound label actually flags

The label's interaction section covers two things: insulin and insulin secretagogues such as sulfonylureas, where a lower dose may be considered to reduce hypoglycemia risk, and oral medicines generally, where delayed gastric emptying may change absorption, with specific advice on oral contraceptives [1]. St. John's wort is not named in that section [1].

For someone taking both, the practical points are which oral contraceptive is in use and whether a non-oral or barrier method covers the 4-week windows after starting Zepbound and after each dose escalation [1], and whether a narrow-therapeutic-index oral drug such as warfarin is on the medication list, given that St. John's wort lowers warfarin's effect [5][14].