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Abstract

Recent widespread policy changes have legalized or decriminalized Cannabis for medicinal and/or nonmedicinal use in over half of the United States. These policy changes will decrease the perception of harms, increase the availability and use of the drug, and thus bring concomitant increases in negative outcomes. This increased risk can be mitigated by a better understanding of its acute effects. Cannabis and its main psychoactive constituent, ∆9-tetrahydrocannabinol (THC), can produce serious unwanted effects including anxiety, especially in women. Yet, because women have been historically underrepresented in Cannabis research, relatively little is known about sources of variability in women. One potential source is menstrual cycle phase and circulating ovarian hormones. In rodents, responses to THC differ in males and females, and sensitivity to THC depends on circulating estradiol levels. In humans, women are more susceptible than men to adverse responses to THC, but little is known about how cycle phase or hormone levels affect drug effects. Here, we compare responses to oral THC between the early and late follicular phase of the menstrual cycle. Then we analyze significant drug effects as a function of circulating ovarian hormone levels. The primary outcome measures were cardiovascular (heart rate, blood pressure, temperature, heart rate variability), biochemical, (salivary cortisol) and subjective (i.e., ratings of feeling drug, liking the drug, and anxiety) drug effects. Sixty women were randomly assigned to two groups, who were tested either the early follicular phase (days 1 – 5) when estrogen levels are low, or late follicular phase (days 9 – 14) when estrogen levels are higher. After recording baseline measurements and drawing blood for ovarian hormone analysis, oral THC (7.5 mg and 15 mg or 15 mg only) and placebo were administered in a double-blind counter-balanced order. Drug effects were monitored continuously and recorded six times across the four-hour long experimental sessions. We hypothesized women would experience greater stress-related responses to THC during the late follicular compared to the early follicular phase. THC dose dependently increased HR and salivary cortisol. These effects were similar between the early and late follicular groups. THC also increased ratings of “feeling” a drug effect, anxiety, and confusion. Faster onset of subjective effects occurred during the early follicular phase compared to the late follicular phase. To determine whether circulating hormone levels mediated these phase differences, or otherwise independently modulated the acute effects of oral THC, we incorporated a continuous repeated measure of circulating hormone levels. We hypothesized estradiol would significantly affect drug effects across time whereas progesterone would not. The acute effects of THC were highly robust. Hormone levels did not significantly affect baseline cardiovascular, biochemical, or subjective measures, nor any drug effect across time. These findings suggest ovarian hormone levels do not i) underlie the previously reported menstrual cycle phase differences in response to Cannabis, or ii) modulate acute responses to THC in naturally cycling women. This study deepens our understanding of estrogen-cannabinoid interactions and their potential downstream biological effects, providing critical information regarding hormonal mechanisms underlying female-specific individual differences in responses to acute THC.

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