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

What Is Known About Using Them Together?

St. John's wort (Hypericum perforatum) is sold in the US as a dietary supplement, and dietary supplements are not approved by the FDA before sale; the manufacturer is responsible for evaluating safety and labeling [2]. Tretinoin is a prescription retinoid applied to the skin. Renova is a 0.02% tretinoin cream indicated only as an adjunct, alongside a comprehensive skin care and sunlight avoidance program, for the mitigation of fine facial wrinkles [1].

The two topics meet in one place in the Renova label: the drug interactions section. It says the cream should not be administered to patients who are also taking drugs known to be photosensitizers, giving thiazides, tetracyclines, fluoroquinolones, phenothiazines and sulfonamides as examples, because of the possibility of augmented phototoxicity [1]. St. John's wort is not one of the examples listed, and the label introduces them with "e.g." rather than as a closed list [1]. Separately, NCCIH warns that the herb, taken by mouth in large doses or applied to the skin, might cause severe skin reactions after sun exposure [2].

The same interactions section warns that other topical medications, medicated or abrasive soaps, shampoos, cleansers, cosmetics with a strong drying effect, and products with high alcohol concentrations may increase irritation with the cream [1].

What St. John's Wort Does to Drug Metabolism

St. John's wort activates the pregnane X receptor, which induces CYP3A4 and other cytochrome P450 enzymes and the P-glycoprotein transporter; a 2020 review links this to altered levels of digoxin, tacrolimus, indinavir, warfarin, alprazolam, simvastatin and oral contraceptives, and notes that the degree of CYP3A4 induction correlates with the hyperforin content of the product [3].

The effect is dose-dependent. 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]. Products are not interchangeable: among 42 men given one of six preparations for 14 days, midazolam AUC fell 79.4% with an extract supplying 41 mg of hyperforin a day and 21.1% with a powder supplying 0.13 mg a day, and the size of the fall tracked hyperforin dose (r = -0.765) rather than hypericin [5].

Studies of other drugs show sizable shifts too. In 11 kidney transplant patients, 600 mg of extract a day for 14 days lowered dose-corrected cyclosporine AUC by 46%, peak level by 42% and trough level by 41%, and the cyclosporine dose was raised from a median of 2.7 to 4.2 mg/kg a day, with the first adjustment needed after 3 days [6]. In a placebo-controlled study of healthy volunteers, 10 days of extract lowered digoxin AUC by 25% and trough level by 33% [7]. NCCIH's summary is that the herb can weaken the effects of many medicines, including birth control pills, cyclosporine, warfarin, some antidepressants, and certain heart, HIV and cancer drugs [2].

How Much Tretinoin Reaches the Bloodstream?

The Renova label gives the percutaneous absorption figures. Across topical formulations, transdermal absorption of tretinoin ranged from 1% to 31% of the applied dose, depending on whether it was applied to healthy skin or dermatitic skin; no percutaneous absorption study was run with Renova 0.02% itself [1]. For a 0.05% oil-in-water cream tested with radiolabeled drug in seven healthy men, absorption was less than 2% after a single application and less after 28 days of daily use [1].

Sun Sensitivity: What Each One Says

NCCIH: taken by mouth in large doses, or applied to the skin, St. John's wort might cause severe skin reactions after sun exposure [2].

The Renova label says exposure to sunlight, including sunlamps, should be avoided or minimized during use because of heightened sunburn susceptibility; that patients should use sunscreens with a minimum SPF of 15 and protective clothing; that patients with sunburn should not use the cream until fully recovered; and that people with considerable sun exposure through work, or with inherent sensitivity to sunlight, should exercise caution [1]. The same warnings section says to keep the cream out of the eyes, mouth, angles of the nose and mucous membranes, and notes that topical use may cause severe local erythema, pruritus, burning, stinging and peeling [1].

The label's directions also say not to use the cream if the patient is sunburned or has eczema or other chronic facial skin conditions, and that applying more than the recommended amount has not been shown to give faster or better results and may cause marked redness, peeling or discomfort [1].

Skin and Other Reactions Each One Can Cause

In double-blind, vehicle-controlled studies of 339 patients applying the 0.02% Renova cream to the face, almost all reported one or more local reactions such as peeling, dry skin, burning, stinging, erythema and pruritus. In 32% of all study patients, skin irritation was reported as severe, led to temporary discontinuation, or led to use of a mild topical corticosteroid. About 7% had irritation severe enough to warrant short-term use of a mild topical corticosteroid, against less than 1% of control patients, and about 4% discontinued the cream because of adverse reactions [1].

NCCIH lists diarrhea, dizziness, trouble sleeping, restlessness and skin tingling as possible side effects of the herb [2].