Vaginal Estradiol and Cannabis: Full Interaction Profile

Does cannabis interact with vaginal estradiol?

The Estradiol Vaginal Cream, 0.01% label says that systemic absorption may occur with its use and that the warnings, precautions and adverse reactions of oral estrogen treatment should be taken into account [1]. It also states that estrogens are metabolized partly by CYP3A4 [1].

The oral tablet and patch labels name the drugs that act on that enzyme. Inducers such as St. John's wort, phenobarbital, carbamazepine and rifampin may lower estrogen concentrations, possibly reducing effect or changing the bleeding pattern; inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may raise them and cause side effects [3][4]. Cannabis, THC and CBD are not on those lists.

What the vaginal cream label warns about

• The boxed warning is titled endometrial cancer, cardiovascular disorders, breast cancer and probable dementia. For estrogen-alone therapy it describes the increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens [1].
• The label calls for adequate diagnostic measures, including endometrial sampling when indicated, to rule out malignancy in women with undiagnosed persistent or recurring abnormal genital bleeding [1].
• Contraindications include undiagnosed abnormal genital bleeding, known or suspected breast cancer or a history of it, estrogen-dependent neoplasia, active DVT or PE or a history of these, active arterial thromboembolic disease or a history of it, known liver dysfunction or disease, protein C, protein S or antithrombin deficiency, and known or suspected pregnancy [1].

Estradiol, THC and the endocannabinoid system

A 2023 trial gave 60 healthy women who used cannabis occasionally oral THC 7.5 mg and 15 mg, or placebo, during the early follicular phase when estradiol is low or the late follicular phase when it is higher [2]. THC slowed response time, increased commission errors and lowered accuracy on a Go/No Go task, and the impairment was not related to circulating estradiol levels [2].

Reviews of sex differences rely mainly on animal data. One review identifies estradiol as the hormone that contributes most to the sexually dimorphic effects of cannabinoids in adults, while noting that a sexually dimorphic endocannabinoid system has not yet been firmly established in humans [5]. Another reports that female rodents are generally more sensitive than males to the effects of THC [6].