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Current P SYCHIATRY CP_0806_Wilcox.FinalREV 7/19/06 1:43 PM Page 40 Current p SYCHIATRY For women only: Hormones may prevent addiction relapse Stabilizing monthly cycles can help some patients Claire Wilcox, MD Fourth-year psychiatry resident ® DowdenDepartment Health of psychiatry Media University of California, San Francisco Copyright Louann Brizendine, MD For personalClinical use professor only of psychiatry Director, Women's and teen girls' mood and hormone clinic School of medicine University of California, San Francisco omen become dependent more rapidly W 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 inter- vene more effectively. This article describes: • how women’s relapse patterns differ from men’s • why psychotherapy and hormone regula- tion may be preferred for relapse prevention in women with substance use disorders. © 2006 Nicholas Slim 40 VOL. 5, NO. 8 / AUGUST 2006 For mass reproduction, content licensing and permissions contact Dowden Health Media. CP_0806_Wilcox.Final 7/18/06 2:25 PM Page 41 CASE REPORT: WILL SHE RELAPSE AGAIN? likelihood to engage in behaviors to procure the Ms. H, age 46, is in her third month of an alcohol and drug and ultimately to relapse (Table 1, page 42).2-4 drug residential rehabilitation program. She has a 10- year history of alcohol and crack cocaine dependence EMOTIONS, STRESS TRIGGER RELAPSE and is battling cravings to use again. These feelings Ms. H. reports increased irritability and impulsivity are usually triggered by being in places or with peo- along with depressed mood—especially during the ple associated with her drug use, but this time she is 3 to 4 days preceding her menstrual period. Her committed to staying sober. periods are regular, and these mood symptoms She started smoking cigarettes in her teens and recur each month. She does not meet criteria for using drugs and alcohol in her mid 20s. She feels major depressive disorder. that her dependency has been out of control in the 10 years since her son was born. Emotional reactions play a larger role in relapse for She has tried to quit many times on her own women than for men. Women report higher lev- but has managed no more than 1 month of absti- els of craving and depressed mood during absti- nence. She often has relapsed in response to feel- nence and experience stronger urges to drink and ing anxious or depressed about being unemployed smoke when depressed. Women also are more or after arguing with her partner. likely to report substance use relapse in response to specific stressful events, MECHANISMS OF RELAPSE disappointments, or depressed Dopamine release is essential for mood.1 This is consistent with evi- encoding learned associations. Compared with men, dence that women have heightened When a drug is used in the early women experience physiologic responses to social rejection dependency state, dopamine stronger urges and social stressors.5 release produces pleasure that to drink and smoke A lower density of brain serotonin reinforces continued drug use. when depressed transporter has been associated with a Once the behavior is learned, higher risk of depression in women. environmental stimuli can trigger Because estrogen and progesterone affect dopamine and turn on the brain circuits for this expression of the serotonin transporter, familiar, highly rewarding behavior. Dopamine changes in these hormone levels might alter the also is the primary cause of long-lasting brain risk of depression.6 Thus, ovarian hormones’ effect changes that make it difficult for substance- on the serotonin system may contribute to the dependent persons such as Ms. H to control higher rate of emotionally triggered relapse in desire for the drug.2 women versus men. Early relapse—caused by dopamine’s and Menstrual cycle phases. How men and women other neurotransmitters’ effects on various brain respond to stress may contribute to differences in regions—is triggered by environmental stimuli their relapse behaviors (Table 2, page 45). such as: During the first 2 weeks of the menstrual • re-exposure to a small amount of the drug cycle—the follicular phase—women show • exposure to an environment or cues associ- lower physiologic reactivity (as seen in blood ated with past drug use pressure and catecholamine measurements) and • exposure to stressful events. lower cortisol responsiveness than men do in These effects lead from craving to increased response to psychosocial stress. Estrogen con- VOL. 5, NO. 8 / AUGUST 2006 41 CP_0806_Wilcox.FinalREV 7/19/06 1:43 PM Page 42 Substance use Table 1 3 stages of relapse and their neurobiologic components Relapse stage Key neurotransmitters Brain regions involved Early relapse triggered by: • exposure to a small amount Dopamine Ventral tegmental area of the drug Nucleus accumbens core Prefrontal cortex • environmental cues that Dopamine Basolateral amygdala re-trigger learned associations Nucleus accumbens core • stressful events and Norepinephrine, Extended amygdala disappointments corticotropin-releasing Bed nucleus of the stria factor terminalis Craving Multiple, undetermined Prefrontal cortex circuitry involving the anterior cingulate and orbitofrontal cortices Relapse Glutamate, dopamine Prefrontal cortex Nucleus accumbens core Ventral pallidum Source: References 2-4 tributes to this effect by attenuating sympatho- may also be more susceptible than men to relapse adrenal responsiveness.5 in response to nicotine and cocaine cues. During the latter 2 weeks of the menstrual cycle—the luteal phase—the ovulating woman’s MENSTRUATION AND RELAPSE PATTERNS hypothalamic-pituitary-adrenal (HPA) axis Research into a correlation between menstrual response increases and increases her sensitivity to cycle phases and dependency behavior is in its stress. In this phase, progesterone’s presence infancy. Early nicotine, alcohol, and stimulant reverses estrogen’s effect and makes the brain addiction studies have shown inconsistent results. more reactive to emotions and stressors. Nicotine. A naturalistic study of women smokers Higher stress responsiveness is associated ages 20 to 39 showed that they smoked more cig- with increased cocaine craving.7,8 A 20-year litera- arettes per day during the late luteal phase, but ture review of the role of substance abuse in their nicotine boost and mood states were similar depression indicates that HPA axis responsive- throughout the menstrual cycle.10 ness of depressed women exceeds that of Some—but not all—studies suggest that depressed men.9 nicotine withdrawal symptoms increase during Summary. Women may be more susceptible than the luteal phase.11,12 In an outpatient study men to emotionally triggered relapse, especially designed to assess hormonal effects on nicotine during the menstrual cycle’s luteal phase. Women response, 30 female smokers acutely abstinent of continued on page 45 42 Current VOL. 5, NO. 8 / AUGUST 2006 p SYCHIATRY CP_0806_Wilcox.Final 7/18/06 2:25 PM Page 45 Current p SYCHIATRY continued from page 42 nicotine were randomly assigned by menstrual Table 2 cycle phase to receive transdermal nicotine or a Substance use relapse patterns: placebo patch. Both premenstrual and nicotine Women versus men withdrawal symptoms intensified in the women’s late luteal phase, compared with the follicular Emotions and mood state play a greater role in driving relapse in women phase.12 Conversely, the same researchers found that Craving. Women have greater craving menstrual cycle phase did not affect withdrawal than men in response to nicotine and symptoms in 21 nicotine-dependent female inpa- cocaine drug cues tients, even though premenstrual changes Nicotine dependency. Women are occurred in the late luteal phase. more likely to relapse to cigarette use As the authors observed, drawing conclu- sions can be difficult when menstrual cycle hor- Abstinence. Women have shorter abstinence periods after cocaine treatment mone withdrawal and nicotine withdrawal symp- toms overlap.12-16 Residential treatment. Women have Alcohol. Premenstrual syndrome (PMS) increases a a better prognosis than men 6 months woman’s risk of alcohol abuse. Alcohol and allo- after residential cocaine treatment pregnenolone—progesterone’s neuroactive meta- Premenstrual hormone changes increase bolite—both facilitate gamma-aminobutyric acid women’s relapse risk ionotropic type A (GABAA) receptor activity. Thus, women with PMS and alcohol dependence may have a genetically more-sensitive GABAA system.17 • estrogen’s dopamine-enhancing effects Unfortunately, aside from one study that shows facilitate dependence increased alcohol intake during the luteal phase, no • women with stimulant dependence are at studies have examined alcohol withdrawal, crav- higher risk of relapse in the follicular ing, and relapse across the menstrual cycle.18 phase—when estrogen levels are higher— Stimulants. Stimulant craving and relapse have than in the luteal phase. not been examined in women at different men- Progesterone. Progesterone’s effect on dopamine strual cycle phases. Some authors speculate that release is unclear. In humans, allopregnenolone women may have a higher subjective response to may curb relapse during the height of the luteal stimulants during the early follicular phase— phase but cause anxiety when its
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