Sex Hormones Shape How the Body Responds to THC Dependence and Withdrawal | Research

The takeaway

In rats, estrogen and progesterone promoted the development of THC dependence and withdrawal, while testosterone appeared protective, helping explain why women may experience more severe cannabis withdrawal.

Read this if you are curious about why cannabis affects men and women differently.

Estrogen and progesterone promoted dependence; testosterone was protective

What the researchers found

Researchers removed the gonads of male and female rats and selectively replaced hormones to isolate their effects on THC dependence. After twice-daily THC dosing for nearly a week, withdrawal was triggered with a CB1 antagonist.

Females with intact ovaries developed greater tolerance to THC-induced hypothermia than males. When hormones were replaced in gonadectomized animals, progesterone increased tolerance to THC's locomotor effects, while estradiol and progesterone together increased withdrawal-related chewing.

In males, testosterone replacement decreased withdrawal-related licking behavior, suggesting a protective effect. Overall, estradiol appeared to play a broader role than testosterone in modulating THC's behavioral effects.

Why it matters

Women report greater cannabis withdrawal symptoms than men, and this study provides a biological mechanism: female sex hormones (estrogen and progesterone) appear to promote THC dependence development, while testosterone may protect against it.

The numbers in context

30 mg/kg THC twice daily for 6.5 days; sham females showed greater tolerance than sham males; progesterone increased tolerance to locomotor suppression; testosterone decreased withdrawal-related licking

How the study worked

Adult rats were gonadectomized or sham-operated, with hormone replacement in half of gonadectomized animals. THC (30 mg/kg) or vehicle was given twice daily for 6.5 days. Withdrawal was precipitated with rimonabant on day 7. Measured somatic signs, startle amplitude, and temperature.

What this study cannot tell us

Rat study using supraphysiological THC doses. Gonadectomy and hormone replacement create an artificial hormonal environment. Human hormonal interactions are more complex. Limited behavioral measures of withdrawal.

How to read the evidence

Well-controlled animal study isolating hormonal effects, but high THC doses and artificial hormonal conditions limit direct human translation.

When this study was published

Published in 2015. Sex differences in cannabis pharmacology remain an active research area.

The bigger picture

Sex differences in cannabis response are not just behavioral or cultural but have hormonal underpinnings. This has implications for treatment: cannabis cessation support may need to account for menstrual cycle effects and hormonal status.

Questions still open

Do hormonal contraceptives affect cannabis dependence risk in women? Would cannabis withdrawal symptoms vary across the menstrual cycle? Could testosterone-based interventions reduce withdrawal severity?

Common questions

Do women get more addicted to cannabis than men?

This animal study suggests female sex hormones promote the development of THC dependence, which aligns with human research showing women report more severe withdrawal symptoms. However, addiction involves many factors beyond hormones.

Does the menstrual cycle affect cannabis response?

This study did not directly test that, but the finding that estrogen and progesterone modulate THC dependence suggests that hormonal fluctuations during the menstrual cycle could influence cannabis effects and withdrawal severity.

Read the original research

The impact of gonadal hormones on cannabinoid dependence.

Experimental and clinical psychopharmacology, 23(4), 206-16

View on PubMed ↗Publisher’s paper ↗

Citation

Marusich, Julie A; Craft, Rebecca M; Lefever, Timothy W; Wiley, Jenny L. (2015). The impact of gonadal hormones on cannabinoid dependence.. Experimental and clinical psychopharmacology, 23(4), 206-16. https://doi.org/10.1037/pha0000027