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Key points
- Variability in estrogen levels may explain some of the gender differences in addiction across substances: estrogen fuels addiction.
- Progesterone treatment in post-partum women may reduce relapse risk for some substances.
- More studies of how hormone therapy might be used in relapse prevention for substance use disorders are needed.
Female hormones—namely progesterone and estrogen—are underrecognized contributors to addictive behavior in women.
Women are more vulnerable to developing addictions than men. In particular, women develop substance use disorders (SUD) faster than men, going more quickly from first use to heavy use, and then to a full-fledged use disorder. This is termed the telescoping effect, and it appears to hold true for a variety of substances including alcohol, cannabis, opioids, stimulants, and nicotine.
In preclinical studies—meaning studies in animal models—female rodents develop addiction-like behaviors more rapidly than males, too.
The degree of drug-induced high, amount of drug use, and relapse risk appear to change across the menstrual cycle in women, too, as hormone levels fluctuate.
How are these hormones likely influencing women’s behavior, and what kinds of things should we think about when treating our female patients with SUD?
Estrogen
In animal models, it’s more feasible to manipulate hormone levels and parse the effects of the different hormones on behavior than in humans.
Studies in animal models (mostly rodents) across substances show that estrogen (17ß-estradiol) accelerates several facets of addictive behavior: the amount the female rodents use, their motivation for the drug (willingness to work for more drug), the vulnerability to relapse (for example, to engage in drug-seeking behavior after a period of abstinence in response to a stress-cue or drug-cue), and withdrawal severity.
Some studies have even shown that estrogen may cause more medical complications during drug withdrawal in animal models too, especially from opioids, including slower weight regain, infection risk due to suppression of the immune system, and vulnerability to other illnesses.
Women report feeling more drug-related high during the estrogen surge portion of the menstrual cycle (which occurs right before ovulation), too, relative to other time periods in the month, supporting what is seen in animal models.
Therefore, estrogen seems to enhance the high and speed up the rate at which someone progresses to addiction. It's not surprising that estrogen seems to fuel addictive behavior from a physiologic perspective. Reward and conditioning are both highly dependent on dopamine release, and estrogen is known to enhance dopamine activity in key areas of the brain.
Progesterone
By contrast, progesterone and/or its downstream metabolite allopregnanolone, seem to dampen addictive behaviors. Interestingly, allopregnanolone is an agonist at (meaning it activates) the GABA receptor in the brain, and through that mechanism, it may have a calming effect that could be protective against severe withdrawal and relapse vulnerability.
During the luteal phase of the menstrual cycle—the week or so that precedes menses—and post-partum, progesterone levels are dropping which physiologically mimics alcohol withdrawal and may fuel more use. During high progesterone states, by contrast, use, craving, and relapse risk are dampened.
Treatment implications
Since estrogen seems to fuel addiction via its effects on the dopamine system, and since higher progesterone may be protective, is there a way to use hormone therapy as a component of substance use disorder treatment in women?
In animal studies, blocking estrogen with tamoxifen slows the onset of addiction and the severity of addictive behaviors. Furthermore, administering allopregnanolone or progesterone protects against the development and expression of all kinds of addictive behaviors and relapse.
Crazily enough, there is very little definitive human research on the topic. Probably the strongest clinical data comes from two recent studies in post-partum women, where researchers found that progesterone administered for two to three months at doses of 25-200 mg twice daily reduced cocaine use and relapse, and nicotine relapse, with few side effects reported. However, whether progesterone might be effective for women who are not post-partum, or for the subgroups of women that experience peri-ovulatory or pre-menstrual cravings, has also not been well-studied in extended (weeks-long) clinical trials as of yet, and should be.
In the meantime, considering some of the treatments for premenstrual dysphoric disorder (PMDD) might help women with SUD who report intense mood and craving fluctuations across the cycle. Stabilizing the hormone levels might be key for these women. These treatments include oral contraceptives which stabilize the estrogen fluctuations and reduce the extent of the precipitous drop in progesterone after ovulation and before menses. Selective serotonin reuptake inhibitors (SSRI) are often used to treat the mood symptoms in PMDD (given sometimes just during the two weeks before menses) or post-partum depression, too, and could be of use in women with SUD and PMDD or even just in women with relapse sensitivity during particular phases of their cycle.
However, unlike in SUD, in PMDD models, allopregnanolone is believed to cause, not protect against, symptoms. So, clearly, what works in SUD may not end up working in PMDD and vice versa. More research is needed.
Conclusion
Progesterone and estrogen play a role in addictive behavior, and studies to determine how hormones might be used in treatment to support women in early recovery are needed. In the meantime, for women who seem especially sensitive to fluctuations in hormone levels, collaborating with primary care providers about the initiation of birth control or other forms of hormone replacement, and having a low threshold for trying an SSRI in women, might be helpful.
