Evidence-Based Reviews

For women only: Hormones may prevent addiction relapse

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Stabilizing monthly cycles can help some patients.



Women become dependent more rapidly than men after initial cocaine, opioid, or alcohol use and may be more sensitive to drugs’ adverse health effects.1 And although men and women relapse to substance use at similar rates, ovulating women may be particularly vulnerable to relapse at certain times of the month.

Understanding the hormonal influences that increase women’s relapse risk can help you intervene more effectively. This article describes:

  • how women’s relapse patterns differ from men’s
  • why psychotherapy and hormone regulation may be preferred for relapse prevention in women with substance use disorders.

Case report: will she relapse again?

Ms. H, age 46, is in her third month of an alcohol and drug residential rehabilitation program. She has a 10-year history of alcohol and crack cocaine dependence and is battling cravings to use again. These feelings are usually triggered by being in places or with people associated with her drug use, but this time she is committed to staying sober.

She started smoking cigarettes in her teens and using drugs and alcohol in her mid 20s. She feels that her dependency has been out of control in the 10 years since her son was born.

She has tried to quit many times on her own but has managed no more than 1 month of abstinence. She often has relapsed in response to feeling anxious or depressed about being unemployed or after arguing with her partner.

Mechanisms of relapse

Dopamine release is essential for encoding learned associations. When a drug is used in the early dependency state, dopamine release produces pleasure that reinforces continued drug use. Once the behavior is learned, environmental stimuli can trigger dopamine and turn on the brain circuits for this familiar, highly rewarding behavior. Dopamine also is the primary cause of long-lasting brain changes that make it difficult for substance-dependent persons such as Ms. H to control desire for the drug.2

Early relapse—caused by dopamine’s and other neurotransmitters’ effects on various brain regions—is triggered by environmental stimuli such as:

  • re-exposure to a small amount of the drug
  • exposure to an environment or cues associated with past drug use
  • exposure to stressful events.
These effects lead from craving to increased likelihood to engage in behaviors to procure the drug and ultimately to relapse (Table 1).2-4

Table 1

3 stages of relapse and their neurobiologic components

Relapse stageKey neurotransmittersBrain regions involved
Early relapse triggered by:
• exposure to a small amount of the drugDopamineVentral tegmental area
Nucleus accumbens core
Prefrontal cortex
• environmental cues that re-trigger learned associationsDopamineBasolateral amygdala
Nucleus accumbens core
• stressful events and disappointmentsNorepinephrine, corticotropin-releasing factorExtended amygdala
Bed nucleus of the stria terminalis
CravingMultiple, undeterminedPrefrontal cortex circuitry involving the anterior cingulate and orbitofrontal cortices
RelapseGlutamate, dopaminePrefrontal cortex
Nucleus accumbens core
Ventral pallidum
Source: References 2-4

Emotions, stress trigger relapse

Ms. H. reports increased irritability and impulsivity along with depressed mood—especially during the 3 to 4 days preceding her menstrual period. Her periods are regular, and these mood symptoms recur each month. She does not meet criteria for major depressive disorder.

Emotional reactions play a larger role in relapse for women than for men. Women report higher levels of craving and depressed mood during abstinence and experience stronger urges to drink and smoke when depressed. Women also are more likely to report substance use relapse in response to specific stressful events, disappointments, or depressed mood.1 This is consistent with evidence that women have heightened physiologic responses to social rejection and social stressors.5

A lower density of brain serotonin transporter has been associated with a higher risk of depression in women. Because estrogen and progesterone affect expression of the serotonin transporter, changes in these hormone levels might alter the risk of depression.6 Thus, ovarian hormones’ effect on the serotonin system may contribute to the higher rate of emotionally triggered relapse in women versus men.

Menstrual cycle phases. How men and women respond to stress may contribute to differences in their relapse behaviors (Table 2).

During the first 2 weeks of the menstrual cycle—the follicular phase—women show lower physiologic reactivity (as seen in blood pressure and catecholamine measurements) and lower cortisol responsiveness than men do in response to psychosocial stress. Estrogen contributes to this effect by attenuating sympathoadrenal responsiveness.5

During the latter 2 weeks of the menstrual cycle—the luteal phase—the ovulating woman’s hypothalamic-pituitary-adrenal (HPA) axis response increases and increases her sensitivity to stress. In this phase, progesterone’s presence reverses estrogen’s effect and makes the brain more reactive to emotions and stressors.

Higher stress responsiveness is associated with increased cocaine craving.7,8 A 20-year literature review of the role of substance abuse in depression indicates that HPA axis responsiveness of depressed women exceeds that of depressed men.9


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