Evidence-Based Reviews

For women only: Hormones may prevent addiction relapse

Current Psychiatry. 2006 August;5(8):40-52

References

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Summary. Women may be more susceptible than men to emotionally triggered relapse, especially during the menstrual cycle’s luteal phase. Women may also be more susceptible than men to relapse in response to nicotine and cocaine cues.

Table 2

Substance use relapse patterns: Women versus men

Emotions and mood state play a greater role in driving relapse in women
Craving. Women have greater craving than men in response to nicotine and cocaine drug cues
Nicotine dependency. Women are more likely to relapse to cigarette use
Abstinence. Women have shorter abstinence periods after cocaine treatment
Residential treatment. Women have a better prognosis than men 6 months after residential cocaine treatment
Premenstrual hormone changes increase women’s relapse risk

Menstruation and relapse patterns

Research into a correlation between menstrual cycle phases and dependency behavior is in its infancy. Early nicotine, alcohol, and stimulant addiction studies have shown inconsistent results.

Nicotine. A naturalistic study of women smokers ages 20 to 39 showed that they smoked more cigarettes per day during the late luteal phase, but their nicotine boost and mood states were similar throughout the menstrual cycle.¹⁰

Some—but not all—studies suggest that nicotine withdrawal symptoms increase during the luteal phase.^11,12 In an outpatient study designed to assess hormonal effects on nicotine response, 30 female smokers acutely abstinent of nicotine were randomly assigned by menstrual cycle phase to receive transdermal nicotine or a placebo patch. Both premenstrual and nicotine withdrawal symptoms intensified in the women’s late luteal phase, compared with the follicular phase.¹²

Conversely, the same researchers found that menstrual cycle phase did not affect withdrawal symptoms in 21 nicotine-dependent female inpatients, even though premenstrual changes occurred in the late luteal phase.

As the authors observed, drawing conclusions can be difficult when menstrual cycle hormone withdrawal and nicotine withdrawal symptoms overlap.^12-16

Alcohol. Premenstrual syndrome (PMS) increases a woman’s risk of alcohol abuse. Alcohol and allopregnenolone—progesterone’s neuroactive metabolite—both facilitate gamma-aminobutyric acid ionotropic type A (GABAA) receptor activity. Thus, women with PMS and alcohol dependence may have a genetically more-sensitive GABAA system.¹⁷ Unfortunately, aside from one study that shows increased alcohol intake during the luteal phase, no studies have examined alcohol withdrawal, craving, and relapse across the menstrual cycle.¹⁸

Stimulants. Stimulant craving and relapse have not been examined in women at different menstrual cycle phases. Some authors speculate that women may have a higher subjective response to stimulants during the early follicular phase—when estrogen levels are higher and progesterone levels are lower—compared with the luteal phase.¹⁹

Sex hormones and relapse

Estrogen. Preclinical studies suggest that estrogen facilitates substance dependence by enhancing dopaminergic activity (Table 3).^1,20-26 Because reinstatement (the animal model of relapse) is driven partially by dopaminergic activity in the striatum, one could hypothesize that:

estrogen’s dopamine-enhancing effects facilitate dependence
women with stimulant dependence are at higher risk of relapse in the follicular phase—when estrogen levels are higher—than in the luteal phase.

Progesterone. Progesterone’s effect on dopamine release is unclear. In humans, allopregnenolone may curb relapse during the height of the luteal phase but cause anxiety when its levels drop. Thus, allopregnenolone withdrawal may promote craving and relapse late in the luteal phase.¹⁷ Allopregnenolone’s possible effect on relapse has not been confirmed in human studies, however.

Table 3

Preclinical findings: How hormones may influence addictive behavior

Hormone	Neurobiologic effect	Mechanism	Behavioral effect
Estrogen	Facilitates dopamine	Decreases inhibitory GABAB activity, regulates D2 autoreceptor expression, alters dopamine reuptake, modulates glutamate activity	Enhances reward, self-administration, sensitization,* and stimulant dependence; facilitates reinstatement^†
Progesterone	Facilitates dopamine when given intermittently; might facilitate or inhibit estrogen’s effects on dopamine	Unclear	Attenuates response to stress, anxiety, pain, aggressiveness
Allopregnenolone^‡	Facilitates GABAA	GABAA-positive allosteric modulator, such as ethanol	Enhances ethanol consumption, promotes ethanol reinstatement
GABAA/GABAB: gamma-aminobutyric acid, ionotropic types A and B
* Sensitization: Repeated exposure to psychostimulants results in drug-seeking response to subsequent exposure, which plays an important role in addiction and craving.
^† Reinstatement is the animal model of relapse.
^‡ Progesterone’s neuroactive metabolite
Source: References 1, 20-26

Treatment implications

Psychotherapy. Evidence suggests that emotions and mood states may play a larger role in triggering substance abuse relapse in women than in men. Psychotherapy and residential treatment therefore are particularly important components of women’s treatment.

In a 6-month follow-up outpatient study of cocaine dependence, women responded better than men did to behavioral treatment, even though the women had more-severe disorders at entry.^27,28

A more-recent inpatient study followed 64 men and 37 women hospitalized for treatment of cocaine dependence. Researchers compared the patients’ drug use histories, psychiatric diagnoses, and Addiction Severity Index (ASI) scores during hospitalization and their cocaine use and ASI scores 6 months later. In initial evaluations, women had significantly more-severe family and social problems. At follow-up, however, significantly more women than men were abstinent from cocaine use, and their family/social problems had diminshed.²⁸