Web Box 3.4 Sex Hormones and Drug Abuse

Surveys have shown that use and abuse of illicit drugs are generally more common in men than in women. This gender difference can be seen, for example, in the results of the National Survey on Drug Use and Health, which is carried out every year by the federal government’s Substance Abuse and Mental Health Services Administration (SAMHSA, 2019). Nevertheless, even though there are more male than female drug users, other findings suggest greater vulnerability of females to drug abuse. Depending on the drug, women may show a greater rate of escalation of drug use, more drug craving, greater difficulty quitting drug use, and greater susceptibility to relapse compared to men (NIDA, 2020).

Gender differences in drug use and abuse are likely related to a variety of different factors, some cultural and others biological. Particularly relevant to this discussion is the potential role of sex hormones in drug sensitivity. We focus here on the effects of the female gonadal hormones estradiol and progesterone on responses to cocaine and nicotine, as this has been an active area of research for many years.

Fewer women than men are users of cocaine or tobacco (SAMHSA, 2019), which is consistent with the overall gender difference in drug use mentioned previously. However, Evans and Foltin (2010) note that despite the difference in the sheer numbers of women and men who become cocaine-dependent, there is evidence that women who do take cocaine progress to dependence more rapidly than men and also relapse more quickly after treatment. Could this greater vulnerability in women be related to sex hormones? This issue has been addressed in various studies examining the subjective effects of cocaine administered in a laboratory setting to experienced cocaine users recruited for research purposes. The first and most basic question concerns whether men and women differ in the subjective effects produced by taking the drug. The answer is mainly no; women overall respond to cocaine in a similar manner to men (Evans and Foltin, 2010). However, when we say “overall,” we mean that there is no gender difference when the stage of the menstrual cycle is not controlled in the experiment. Before going further, it is important to briefly discuss the stages of the menstrual cycle and the hormonal changes that occur at each stage.

The human menstrual cycle has a period of approximately 28 days that consists of two main stages: follicular and luteal. During the follicular stage, a single follicle containing an immature egg (oocyte) in the woman’s ovary begins to mature in preparation for ovulation. As shown in Figure 1, circulating progesterone levels are low during this phase, whereas estradiol levels are beginning to rise. Because of positive feedback on the pituitary gland, the high estradiol levels eventually trigger a surge of LH that acts on the follicle to trigger ovulation. After releasing the egg (ovum), the follicle changes into a corpus luteum and begins to secrete large amounts of progesterone. If the egg is not fertilized, progesterone levels subsequently decline, menstruation occurs, and the cycle begins again.


A graph depicts the different phases of menstruation. The horizontal axis representing the day of menstrual cycle ranges from 1 to 28. Days 1 to 13 are marked as follicular phase, days 13 to 15 are marked as ovulation, and days 15 to 28 is marked as luteal phase. A curve for Estradiol remains constant from days 1 to 9, gradually increases between the days 9 to 13, decreases when it reaches day 17, again gradually increases and declines within the days of 17 and 28. A curve for LH remains constant from day 1 to 12, steeply rises and falls between day 13 and 15 and remains constant for the rest of the days. A curve for Progesterone gradually increases and decreases between days 13 and 28. A curve for FSH increase and decrease between days 4 and 6, 7 and 9, 13 and 15.

Figure 1 Changes in circulating hormone levels during the menstrual cycle.

 

Research on the effects of menstrual cyclicity, hormones, and drug sensitivity has focused on estradiol and progesterone rather than LH or FSH for two reasons. First, large changes in the levels of the two pituitary hormones LH and FSH are relatively short-lived, occurring primarily around the time of ovulation, whereas more sustained changes in estradiol and progesterone occur as a function of stage of the cycle. Second, LH and FSH have relatively little effect on the brain (in contrast to the gonads, of course), whereas estrogen and progestin receptors are present in significant numbers of neurons, and activation of those receptors alters neuronal activity. When Evans and Foltin tested the positive subjective effects of different doses of smoked cocaine (6, 12, or 25 mg) on women during either the midfollicular phase (6–10 days after the beginning of menstruation) or the midluteal phase (7–12 days following the LH surge), the intensity of the drug effect at 12- mg and 25-mg doses was significantly lower during the luteal compared to the follicular phase (Evans and Foltin, 2010; Figure 2, top). A subsequent study examining the influence of intravenously administered nicotine similarly found that the subjective drug “high” in women was lower during the luteal compared to the follicular phase (DeVito et al., 2014; Figure 2, bottom). Men tested under the same conditions showed a similar response to women in the follicular phase. One of the major hormonal differences between the luteal and follicular phases is the higher levels of circulating progesterone in the luteal phase. This difference may play a key role in the menstrual cycle–dependent changes in the effects of cocaine and nicotine, as researchers have demonstrated that progesterone administration reduces the subjective responses to both drugs (Sofuoglu et al., 2004, 2009).

 

A set of two graphs depicting the different phases for cocaine and nicotine. In the first graph for Cocaine, the horizontal axis represents the smoke cocaine dose in milligrams, ranging from 6 to 25. The vertical axis represents the good drug effect, ranging from 0 to 35 in increments of 5. The data for the follicular phase and luteal phase in the order of cocaine dose and the corresponding effect is as follows: 6 - 3, 2; 12 - 15, 10; and 25 - 32, 26. In the second graph for Nicotine, the horizontal axis represents the minutes post-four nicotine dose ranging in three sections, each from 0 to 10. The vertical axis represents the subjective drug high ranging between 0 and 6. The curves for Saline are as follows: A pair of curves for men and women in follicular phase decreases from y value of 2 to 1 between the x values of 1 and 10. A curve for the women in luteal phase increases from the y value of 1 to 2 within the x values of 1 and 10. The curves for 0.5 NIC are as follows: A pair of curves for men and women in follicular phase steeply rises and falls from the y value of 1 to 4.5 within the x values of 0 and 10. A curve for the women in luteal phase steeply rises and falls from the y value of 1.2 to 2.8 within the x values of 0 and 10. The curves for 1.0 NIC are as follows: A pair of two curves for men and women in follicular phase rises and falls from 1.5 to 5 within the x values of 0 and 10. A curve for women in luteal phase rises and falls from the y value of 1.2 to 3 within the x values of 0 and 10.

Figure 2 Effects of the menstrual cycle on the subjective responses to smoked cocaine and IV nicotine brain (Top) The positive subjective response to smoking 6, 12, or 25 mg of cocaine (measured as “Good Drug Effect”) was significantly greater when women were tested during the follicular phase of their menstrual cycle than during the luteal phase. (Bottom) In a separate study, the subjective “high” produced by two different intravenous (IV) doses of nicotine (NIC; 0.5 mg/70 kg or 1.0 mg/70 kg) was again significantly greater when women were tested during the follicular phase. Men’s response was similar to that of women who were in the follicular phase of the cycle. (Top, after Evans and Foltin, 2010; bottom, after DeVito et al., 2014.)

 

The findings discussed here do not explain why men are more likely than women to use psychoactive drugs, nor do they account for unexpected observations such as the more rapid progression to dependence in cocaine-using women. Nevertheless, the research clearly shows that hormones such as progesterone can influence the subjective responses to drugs of abuse. It is even possible that administering exogenous progesterone could be helpful in the treatment of substance use disorders (Peltier and Sofuoglu, 2018).

References

DeVito, E., Herman, A.I., Waters, A.J., Valentine, G.W., and Sofuoglu, M. (2014). Subjective, physiological, and cognitive responses to intravenous nicotine: Effects of sex and menstrual cycle phase. Neuropsychopharmacology, 39, 1431–1440.

Evans, S.M., and Foltin, R.W. (2010). Does the response to cocaine differ as a function of sex or hormonal status in human and nonhuman primates? Horm. Behav., 58, 13–21.

NIDA. (2020). Substance Use in Women. Retrieved from https://www.drugabuse.gov/publications/research-reports/substance-use-in-women on April 26, 2020.

Peltier, M.R., and Sofuoglu, M. (2018). The role of exogenous progesterone in the treatment of males and females with substance use disorders: A narrative review. CNS Drugs, 32, 421–435.

Sofuoglu, M., Mitchell, E., and Kosten, T.R. (2004). Effects of progesterone treatment on cocaine responses in male and female cocaine users. Pharmacol. Biochem. Behav., 78, 699–705.

Sofuoglu, M., Mitchell, E., and Mooney, M. (2009). Progesterone effects on subjective and physiological responses to intravenous nicotine in male and female smokers. Hum. Psychopharmacol., 24, 599–564.

Substance Abuse and Mental Health Services Administration. (2019). Results from the 2018 National Survey on Drug Use and Health: Detailed tables. Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/ on April 26, 2020.

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