Oral Micronized Progesterone and Cannabis: Full Interaction Profile

Does cannabis interact with oral micronized progesterone?

The Prometrium label does not mention cannabis, so it gives no interaction rating or dose adjustment for the combination [1]. What can be described is what the label says about progesterone itself, one small trial in which oral progesterone was given to women who use cannabis heavily, and where the effects of the two overlap [1][4].

What the Prometrium label covers

Prometrium is micronized progesterone in 100 mg and 200 mg oral capsules, with two labeled uses: prevention of endometrial hyperplasia in postmenopausal women with a uterus who are taking conjugated estrogens tablets, and treatment of secondary amenorrhea [2]. The labeled dose for endometrial protection is 200 mg at bedtime for 12 days sequentially per 28-day cycle alongside daily conjugated estrogens; for secondary amenorrhea it is 400 mg at bedtime for 10 days [2]. The label's dosing and its trials use conjugated estrogens, not estradiol [2]. The capsules contain peanut oil, and peanut allergy is a labeled contraindication [2].

The label says micronization increases oral bioavailability and describes the drug as chemically identical to progesterone of human ovarian origin, synthesized from a plant-source starting material [1].

What the label says about interactions

The label has no separate drug-interactions section, and its interaction content consists of two items [1].

The first is an in-vitro result. Progesterone metabolism by human liver microsomes was inhibited by ketoconazole at an IC50 below 0.1 micromolar; the label calls ketoconazole a known CYP3A4 inhibitor and says such inhibitors 'may increase the bioavailability of progesterone,' adding that 'the clinical relevance of the in vitro findings is unknown' [1]. The label does not name CYP3A4 inducers [1].

The second is a human study of conjugated estrogens. Giving Prometrium 200 mg for 12 days with conjugated estrogens 0.625 mg to 29 postmenopausal women raised total estrone (Cmax 3.68 to 4.93 ng/mL) and total equilin (2.27 to 3.22 ng/mL) and lowered circulating 17-beta estradiol (Cmax 0.037 to 0.030 ng/mL); conjugated estrogen half-life was unchanged [1].

Cannabis is not part of either item [1].

Metabolism: what is stated and what is left open

Progesterone is metabolized primarily in the liver, largely to pregnanediols and pregnanolones, which are conjugated and excreted in bile and urine [1]. The label does not state which enzyme carries out the main metabolism; CYP3A4 appears only inside the in-vitro ketoconazole sentence [1].

Absorption is fairly quick. Maximum serum concentrations are reached within 3 hours of an oral dose [1]. In postmenopausal women after five daily doses, mean Cmax was 38.1 ng/mL at a mean Tmax of 2.3 hours on 200 mg/day, and the variability between women was wide: the standard deviation, 37.8, was about the size of the mean itself [1]. At 100 mg/day the mean Cmax was 17.3 ng/mL [1].

The 2019 trial: oral progesterone in women who use cannabis

The closest human data is a randomized, placebo-controlled feasibility trial by Sherman and colleagues, published in 2019 in Pharmacology Biochemistry and Behavior [4]. Eight heavy cannabis-using women in the early follicular phase of the menstrual cycle received micronized progesterone 200 mg twice daily (n=3) or matching placebo (n=5) for five days while abstaining from cannabis [4]. Adherence was high, 100% by self-report and 98% by video capture, and salivary progesterone levels differed between groups over time (P<0.027) [4].

The authors reported an indication of reduced cannabis craving in the progesterone group (P=0.07) [4]. The trial's primary outcomes were adherence and salivary hormone levels, with cannabis withdrawal severity as an exploratory outcome, and the groups were three and five women [4]. Participants were abstaining from cannabis, so the trial was not designed to show what happens to a progesterone dose when someone uses cannabis.

Drowsiness, dizziness and coordination

This is the part of the overlap a patient would actually notice, and the label is direct about progesterone's side. Prometrium 'may cause transient dizziness and drowsiness and should be used with caution when driving a motor vehicle or operating machinery,' and the label directs that it be taken as a single daily dose at bedtime [2]. The patient leaflet says to take it at bedtime because some women become very drowsy or dizzy [1].

During initial therapy, a few women have had extreme dizziness or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk and shortness of breath [1]. Dizziness is also a recorded adverse reaction: 24% of women on 400 mg/day versus 4% on placebo in the secondary amenorrhea trial, and 15% versus 9% on placebo in the 3-year trial of 200 mg plus conjugated estrogens, a comparison that cannot separate progesterone from estrogen because the active arm took both [1].

Cannabis touches the same functions. Experimental studies show THC impairs cognition, psychomotor function and actual driving performance in a dose-related manner; doses up to 300 micrograms per kg produced impairment equivalent to a blood alcohol concentration of 0.05 g/dL or higher [3]. Regular users develop partial tolerance, with the strongest tolerance in cognitive measures and blunted but not absent intoxication and cardiac effects [5].

The label's caution describes progesterone alone, and the driving data describe THC alone [2][3]. Drowsiness, dizziness and slowed reactions are where the two meet.