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. Author manuscript; available in PMC: 2009 Sep 18.
Published in final edited form as: Harv Rev Psychiatry. 2009;17(2):103–119. doi: 10.1080/10673220902899680

Sex Differences in Drug-Related Stress-System Changes: Implications for Treatment in Substance-Abusing Women

Helen C Fox 1, Rajita Sinha 1
PMCID: PMC2746371  NIHMSID: NIHMS122641  PMID: 19373619

Abstract

Extensive research indicates that chronic substance abuse disrupts stress and reward systems of the brain. Gender variation within these stress-system alterations, including the impact of sex hormones on these changes, may influence sex-specific differences in both the development of, and recovery from, dependency. As such, gender variations in stress-system function may also provide a viable explanation for why women are markedly more vulnerable than men to the negative consequences of drug use. This article therefore initially reviews studies that have examined gender differences in emotional and biophysiological changes to the stress and reward system following the acute administration of drugs, including cocaine, alcohol, and nicotine. The article then reviews studies that have examined gender differences in response to various types of stress in both healthy and drug-abusing populations. Studies examining the impact of sex hormones on these gender-related responses are also reported. The implications of these sex-specific variations in stress and reward system function are discussed in terms of both comorbid psychopathology and treatment outcome.

Keywords: gender, stress, substance abuse

INTRODUCTION

Drug and alcohol dependence is now viewed as one of the most common and preventable health care problems in the United States. Although rates of substance abuse are higher in men than women,1 global studies have indicated that in the last decade, due to changing socioeconomic factors, women have become increasingly more abusive of drugs and alcohol. Hazardous, heavy episodic drinking is increasing in younger women,2 and a recent survey indicated that young adult females are consuming similar amounts of drugs and alcohol as men.3 This problem may be exacerbated by the fact that distinct gender differences, which increase addiction vulnerability for women, are observed at every phase in the drug reinforcement process, including acquisition, maintenance, and outcome.4

Preclinical models that have been used to mimic the loss of control of drinking and substance use in humans have highlighted robust variation, by sex, in factors affecting both the development of, and recovery from, dependency. For example, female rats have been shown to acquire cocaine, methamphetamine, heroin, alcohol, and nicotine self-administration more rapidly than male rats.58 They also show greater escalation and dysregulation in pattern and quantity of drug intake during extended-access regimens.9,10 Likewise, in the human literature, females report markedly different subjective effects of both psychostimulants and alcohol,11,12 and they progress to drug dependence more rapidly than men,13 through more addictive routes.14,15 Extensive research shows that the negative consequences of drinking and drug use in females appear accelerated or “telescoped,” particularly in relation to co-occurring psychopathology such as depression, phobias, and panic and eating disorders.16,17

Many interacting psychosocial and biological processes may be associated with an increased vulnerability to compulsive drug or alcohol seeking in women compared to men. The current article focuses on reviewing studies that have assessed the influence of gender and gonadal hormones on drug-related changes to stress-system function and on how these emotional and biophysiological alterations may affect co-occurring psychopathology, as well as relapse and treatment outcome, in substance-abusing women.

Association Between Stress and Substance Use

Many well-established preclinical and human models of addiction propose that chronic stress can play an integral part in the motivation to abuse drugs and to maintain alcohol abuse in addicts,1821 and that it can provide an impetus for increased alcohol consumption in social drinkers.22

In laboratory animals, experimental manipulations using various stress paradigms such as tail pinch, food deprivation, and electric foot-shock have been shown to increase the acquisition and reinstatement of stimulants, opiates, and alcohol.2325 Well-established human models of addiction such as stress-coping26 and relapse-prevention27 models also present addiction as either a maladaptive coping response to life stressors or as a biopsychosocial risk factor for individuals with poor coping strategies, whereas the tension-reduction28 and self-medication29 models emphasize the basic need to boost positive affect via either positive (mood enhancement) or negative (relief from stress) reinforcement processes.21 Furthermore, many treatment and laboratory studies have documented that stress- and negative mood–induced craving are robust predictors of treatment outcome and relapse in alcohol-dependent3033 and cocaine-dependent34,35 individuals.

Drug-Related Changes in Stress-System Engagement and Relapse

In view of the above results, both animal and human research has shown that drug-related changes to the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic adrenal medullary system (SAM), and mesolimbic dopamine (DA) stress and reward systems may underlie the pathophysiology of drug addiction.3638 For example, extensive literature has highlighted substantial interacting and overlapping neural circuitry involved in both stress and putative reward circuits.39,40 Research findings indicate that “engagement” of the stress system may serve to “prime” the brain’s reward circuits21 by modifying reward-related behavior through stimulation of mesencephalic dopaminergic transmission.41 Moreover, according to the recent allostatic model of addiction, this sustained increase in the secretion of DA may reflect a compromise in homeostasis and result in a decrease in the function of reward neurocircuitry and an increase in sensitivity of the stress-related systems,42 potentiating both the positive and negative reinforcing effects of psychostimulants, opioids, and alcohol.

Support for this stress and reward-system dysregulation has been reflected in preclinical studies showing that acute administration of both psychostimulants and alcohol mediates DA transmission, HPA function, and glucocorticoid release.4347 Furthermore, in humans, acute and chronic substance abuse and withdrawal are associated with changes in basal cortisol and ACTH tone,4850 as well as with dysregulated HPA/SAM system and cardiovascular response to both psychosocial and physiological stressors.5155

These drug-related changes to brain stress and reward systems have been associated with enhanced emotional and behavioral sensitivity to stress during protracted withdrawal—including increased reports of irritability, restlessness, depressed mood, anxiety, and high cravings.21,56,57 Studies from our own laboratory have shown that early protracted abstinence from both drug and alcohol addiction is characterized as a craving “state” comprising enhanced emotional and behavioral distress, along with robust changes in physiological and neuroendocrine markers.54,5860 Most importantly, these alterations in stress-system emotional and biophysiological markers associated with influencing the transition from controlled drug seeking to addiction61,62 are gender specific.

Prior research has assessed gender variation in emotional, physiological, and autonomic stress-system adaptations in order to better understand important differences in the stress-related craving state and compulsive drug seeking. In order to assess these findings on gender variation, we have reviewed the literature in four distinct sections reflecting the different methodological paradigms employed to compare stress-system adaptations in male and female healthy volunteers and substance abusers: (1) gender differences in stress-system changes following acute drug administration; (2) the impact of sex hormones on stress-system function following acute drug administration; (3) the impact of sex hormones on stress-system function following exposure to stress; and (4) gender differences in stress-system changes following exposure to stress.

In all four sections the literature was identified using Medline search terms “gender differences” and “sex differences” for each drug type (viz., cocaine, alcohol, d-amphetamine, and nicotine). In addition, the search terms “acute,” “administration,” “menstrual cycle,” and “stress” were selectively included for the relevant sections. The review was restricted to studies of human adult populations published in English between 1970 and 2008. Studies identified through the primary searches were also included.

GENDER DIFFERENCES IN STRESS-SYSTEM CHANGES FOLLOWING ACUTE DRUG ADMINISTRATION (TABLE 1)

TABLE 1.

Gender Differences in Stress-System Changes Following Acute Drug Administration

Study Dose regimen & route Placebo control Sample Gender differences in stress-system changes
Men vs. women
 Netter et al. (1994)63 0, 0.014, 0.028 mg/kg nicotine (oral) Y Healthy volunteers (24 M, 24 F) M > F: in serum nicotine levels
M < F: HR & BP at lower doses
 Perkins et al. (1995)64 4 × 20 mg/kg nicotine (nasal spray) 0.5 g/kg alcohol (oral) Y Smokers & social drinkers (9 M, 9 F) M, not F: alcohol decreased vigor & arousal
 Kosten et al. (1996)11 4 studies: about 2 mg/kg cocaine (inhaled) N Cocaine dependent (23 M, 11 F) M = F: plasma cocaine levels, HR, BP
M < F: “nervous”
 Evans et al. (1999)65 2 x up to six 50 mg doses cocaine across 2 days (smoked) Y Cocaine history (11 M, 9 F) M < F: plasma cocaine levels, HR, BP
M > F: “want cocaine”
 Singha et al. (2000)66 80 mg/70 kg cocaine (oral) Y Cocaine dependent (27 M, 8 F) M < F: “bad drug effects,” “anxious/nervous”
M > F: systolic BP
 Schuckit et al. (2000)67 0.75 ml/kg (for F); 0.9 ml/kg (for M) alcohol (oral) Y FH+ & FH− (alcoholism) (75 M, 38 F) FH+ males = FH− females: all subjective scales
 Gabay et al. (2003)68 10 mg amphetamine (oral) Y Healthy volunteers (63 M, 46 F) M > F: anxiety
M = F: all other subscales
 Gabay et al. (2005)69 10 mg amphetamine (oral) Y FH+ & FH− (alcoholism) (34 M, 38 F) FH+ males > FH− males: stimulant ratings
FH+ females = FH− females
 McCance-Katz et al. (2005)12 4 × 1 mg/kg cocaine (inhaled) 1 g/kg & 120 mg/kg alcohol (oral) Y Cocaine & alcohol dependent (8 M, 7 F) M < F: HR following alcohol
M < F: “feel good” following cocaine
Acheson et al. (2006)70 0, 7, or 14 mg nicotine (transdermal) Y Smokers & social drinkers (22 M, 22 F) M < F: “positive mood” (after 0 & 7 mg)
M > F: “arousal” (after 14 mg)
 Vansickel et al. (2007)71 0, 2.5, 5, 10, 15 mg amphetamine (oral) Y Healthy volunteers (14 M, 13 F) M > F: “high”, “sluggish”
M < F: “nausea”, diastolic BP
Men vs. women (follicular) vs. women (luteal)
 Lukas et al. (1996)72 0.9 mg/kg cocaine (inhaled) Y Healthy volunteers (7 M, 7 F) M > F: plasma cocaine levels & detection of cocaine effects
M = F: peak HR & subjective measures
F (follicular) > F (luteal): “how content do you feel”
 Mendelson et al. (1999)73 0.2, 0.4 mg/kg cocaine (intravenous) N Cocaine dependent (12 M, 22 F [11 follicular, 11 luteal]) M = F: plasma cocaine, HR, “feel high”
F (follicular) = F (luteal): all cardiovascular & subjective measures
 Sofuoglu et al. (1999)74 Study 1: 0.4 mg cocaine (smoked) N Cocaine history (23 M, 21 F) M & F (follicular) > F (luteal): “feel high”
Study 2: 6 × 0.4 mg cocaine (smoked) Cocaine history (11M, 12 F) M < F: “feel high,” HR, heart racing
 White et al. (2002)75 15 mg amphetamine (oral) Y Healthy volunteers (7 M, 13 F) F (follicular) > F (luteal): “feel high,” “feel drug,” “want more”
M > F (luteal): “feel drug,” “want more”
 Collins et al. (2007)76 0.06, 0.34, 0.69, 1.37 mg/kg cocaine (inhaled) N Cocaine dependent (10 M, 8 F) M = F: all subjective & cardiovascular measures
F (follicular) = F (luteal): all subjective & cardiovascular measures
Women only, follicular vs. luteal
 Justice & de Wit (1999)77 15 mg amphetamine (oral) Y Healthy volunteers (16 F) F (follicular) > F (luteal): “high,” “energetic,” “intellectually efficient,” “euphoric,” “like/want drug”
 Evans et al. (2002)78 0, 6, 12, or 25 mg cocaine (smoked) Y Cocaine history (11 F) F (follicular) > F (luteal): HR, “good drug effect,” “high,” “stimulated,” dysphoric mood
 Kouri et al. (2002)79 0.9 mg/kg cocaine (inhaled) Y Healthy volunteers (7 F) F (follicular) = F (luteal): all subjective measures
Women only, early follicular vs. late follicular
 Justice & de Wit (2000)80 15 mg amphetamine (oral) Y Healthy volunteers (19 F) F (late follicular) > F (early follicular): “unpleasant stimulation”
F (late follicular) < F (early follicular): “unpleasant sedation”
Exogenous sex hormone administration: women only, early follicular
 Justice & de Wit (2000)81 10 mg amphetamine (oral) plus either 0.8 mg estrogen or placebo (patch) Y Healthy volunteers (11 estrogen, 9 placebo) Estrogen > placebo: “pleasant stimulation”
Estrogen < placebo: “want more”
 Sofuoglu et al. (2002)82 3 × 4 mg cocaine (smoked) 200 mg progesterone (oral) Y Cocaine dependent (5 F) Progesterone < placebo: “feel the effect of last dose”
 Lile et al. (2007)83 0, 3.125, 7.5, 15 mg/70 kg amphetamine (oral) 0.25 mg estrogen (oral) Y Healthy volunteers (10 F) Estrogen > placebo: “like drug” & stimulant subscale
Exogenous sex hormone administration: men vs. women
 Sofuoglu et al. (2004)84 0.3 mg/kg cocaine (inhaled) 200 mg progesterone (oral) Y Cocaine dependent (6 M, 4 F [follicular]) Progesterone < placebo: diastolic BP, “high,” “feel the effect of last dose”
 Evans & Foltin (2006)85 6 × 0, 6, 12, or 25 mg cocaine (smoked) 150 mg progesterone (oral) Y Cocaine history (10 M, 11 F) F (follicular & progesterone) < F (luteal): “good drug effect” cluster scores, “drug quality” cluster scores, “willing to pay”

BP, blood pressure; F, female; FH, family history (+ or −); HR, heart rate; M, male.

As there exists an overlap in neural systems between stress response and the acute effects of many psychoactive drugs, gender-related differences in either may help identify some of the sex-specific mechanisms underlying stress-induced drug seeking. This cross-sensitization between stress response and the acute effects of drugs is related to the fact that drugs such as cocaine, alcohol, d-amphetamine, and nicotine are known to stimulate the HPA-axis stress systems in animal and humans.8688 Moreover, enhanced stress-system sensitivity and increased positive, subjective-reinforcing effects in acute drug response have been seen as markers for increased risk of problematic drug use and abuse potential.20,89,90

Preclinical data have indicated that female rats demonstrate a more sensitized biophysiological and behavioral response to acute drug administration compared to male rats. They show greater HPA-axis response to alcohol91 and greater locomotor activity following cocaine exposure compared to male rats.92 Female rats also show significantly increased locomotor activity, orofacial activity, and ACTH and cortisol levels, as well a decrease in D3 dopamine transporters, in response to nicotine compared to male rats.9395

In the human literature, findings are far more complex and largely dependent on drug, dosing pattern, route of administration, and subject population. Gender differences in stress-system adaptations to the acute administration of drugs have typically been assessed either by comparing pharmacokinetic, physiological, and subjective effects of drugs in men versus women,65,66 or by examining the effects of sex hormones on these drug-reinforcing stress-system alterations.82,83 In view of the complex interactions between hormonal status and stress, studies have either assessed the acute effects of a drug at various stages of the menstrual cycle (MC) in female subjects77,78 or examined the effects of exogenous sex hormone levels on acute drug exposure in both men and women.84,85

In relation to psychoactive stimulants, studies assessing the acute effects of cocaine on subjective and physiological response in men and women have typically been conducted in subjects who either are cocaine dependent (CD) or report a history of regular cocaine use. Although these studies have all employed different paradigms with regard to design, route of administration, and cocaine dose (Table 1), three of the four cocaine-administration studies reviewed here have shown females to demonstrate increased subjective sensitivity to physiological changes following cocaine administration. Kosten and colleagues11 collated data from the placebo phases of four different studies in 23 CD males and 11 CD females. Findings indicated that although peak plasma cocaine levels, heart rate, and blood pressure were similar across gender following intranasal cocaine administration, females showed greater self-reported “nervous” responses compared to males. Similarly, after administering cocaine orally to 27 men and 8 females, Singha and colleagues66 documented increased reports of “bad drug effects” and higher ratings of “anxious/nervous” in female CD subjects compared to men, alongside lower systolic blood pressure. Higher ratings of “feeling good” were also reported in comorbid CD and alcohol-dependent (AD) women compared to men, following persistent (4 × 1 mg/kg) intranasal cocaine administration.12

Conversely, one study by Evans and colleagues65 showed prolonged physiological effects of repeated smoked cocaine, as well as higher plasma concentrations, in females with a history of cocaine use, but no gender differences in ratings on subjective emotional visual-analog scores. Although the higher peak plasma levels of cocaine were attributed to the women effectively receiving a higher dose than the men due to weight differential,65 the lack of enhanced sensitivity observed in the CD women may have been related to variations in drug-use severity (subjects reported a cocaine history rather than met DSM-IV dependence criteria) and to differences in route of administration.

In addition to studies documenting the subjective reinforcing effects of cocaine in dependent populations, a study by Lukas and colleagues72 demonstrated that healthy, non-drug-using women are more sensitive than healthy men to stress-system cardiovascular adaptations associated with intranasal cocaine. After giving a single intranasal dose of 0.9 mg/kg cocaine to 7 male and 7 female healthy volunteers, women demonstrated significantly lower plasma cocaine levels than men, though no gender variation was observed in relation to peak heart rate or response on subjective visual-analog scales.

These findings are consistent with gender differences in stress-system sensitivity following nicotine administration in healthy smokers. Two studies administering varying levels of nicotine to men and women who were regular smokers and social drinkers indicated that females were more sensitized to both the cardiovascular and subjective effects of nicotine. After administering 0.014 and 0.028 mg/kg of nicotine to a group of healthy men and women, Netter and colleagues63 showed that although men had significantly higher serum nicotine levels compared to women, women demonstrated significantly higher heart rate and blood pressure at the lower, 0.014 mg/kg dose. Similarly, Acheson and colleagues70 showed that following administration of 0, 7, and 14 mg nicotine transdermally in males and females, females reported significantly higher positive mood compared to males following both placebo and the lower, 7 mg dose.

These findings highlight both reward system changes and a potentially sensitized response to stress in cocaine- and nicotine-dependent females. However, in marked contrast to these results, data from studies that have administered d-amphetamine and alcohol to groups of healthy men and women show different findings. In studies where a single dose of d-amphetamine has been given to groups of healthy male and female volunteers, greater drug sensitivity has been reported in males.68,69,71 Gabbay and colleagues68 found that healthy males reported significantly higher ratings of anxiety following a 10 mg/kg dose of d-amphetamine compared to healthy females. In addition, a later study by the same group indicated that males with a positive family history of alcohol abuse were significantly more sensitive to the stimulant effects of amphetamine compared to males who had no family history of alcohol abuse.69 Moreover, this difference in sensitivity was not observed in the females.69 A more recent study by Vansickle and colleagues71 also found that healthy males reported feeling more “high” than healthy females, despite demonstrating significantly lower diastolic blood pressure.

In relation to alcohol administration, findings are similar. Perkins and colleagues64 found that in males but not females, alcohol significantly reduced reported vigor and arousal compared to baseline. In addition, a study assessing the acute affects of a single dose of alcohol (adjusted for gender variations in body weight) reported no significant gender differences on all subjective scales of the Subjective High Assessment Scale.67 It is possible that some of the inconsistencies pertaining to these gender variations in subjective and physiological stress-system sensitivity may, among other factors, be related to both drug and subject sample. Whereas studies examining the effects of cocaine were largely conducted in dependent samples,11,12,65,66 studies assessing the effects of amphetamine employed either healthy volunteers68 or healthy “at risk” populations.69 Moreover, both studies examining the sex-specific effects of alcohol were conducted in samples of nonaddicted social drinkers.64,67

These differences in group dependency status may account for the disparity observed in gender-related stress-system sensitivity. For example, the alcohol literature indicates that gender differences in stress-system engagement prior to alcohol exposure may vary in addicts compared with social drinkers. Findings from social drinkers indicate, for example, that the incentive value of alcohol may be less sensitized by negative mood and stress in female social drinkers than in male social drinkers.96,97 By contrast, findings from alcoholics show that females demonstrate greater alcohol cue reactivity following negative mood induction compared to males.98 Although these studies represent different paradigms, they do reflect robust gender dissociations between nonaddicted and addicted populations in relation to stress-system function, albeit in response to stress rather than acute drug administration.

THE IMPACT OF SEX HORMONES ON STRESS-SYSTEM FUNCTION FOLLOWING ACUTE DRUG ADMINISTRATION

Complex interactions between the HPA and hypothalamic-pituary-gonadal axes may also have a salient impact on gender variation in relation to stress-system function following drug intake. For example, in animals, estradiol has been shown to have an excitatory effect on the HPA axis,99 and in humans, progesterone and estrogen both show modulating effects on the HPA axis.100,101 As such, sex hormones may influence stress-system engagement following acute drug administration and subsequently influence behavioral response to drugs,20,102 especially with regard to craving and relapse vulnerability in women. In order to examine this hypothesis, several studies have assessed the influence of the MC on acute response to drugs in groups of both healthy and substance-abusing men and women.

The majority of the research to date has indicated that MC phase appears to have a significant impact on both the subjective and pharmacokinetic effects of stimulant drugs, including cocaine, amphetamine, and methamphetamine. Drugs such as alcohol, nicotine, marijuana, and benzodiazepines have been shown to have a limited effect on the MC in both animals and humans,103 though reproductive problems such as early menopause, amenorrhea, and lutealphase dysfunction have been associated with chronic misuse of these drugs.104,105 As such, a more precise endocrine profile of MC disruption in nonstimulant drugs may still need to be elucidated.

An initial study by Justice and De Wit77 reported that the positive subjective effects of d-amphetamine such as “high”, “euphoria,” and “like drug” were potentiated in 16 healthy females during the follicular (low estrogen and low progesterone), compared to the mid-luteal (high progesterone), phase of their MC. Similarly, White and colleagues75 found that 13 normally cycling healthy women reported greater amphetamine-induced subjective stimulation in their follicular, compared to luteal, MC phase. In the same study 7 healthy males reported significantly greater subjective stimulation than females who were in the luteal, but not those who were in the follicular, phase.75 Research comparing 19 healthy women in both the early (low estradiol) and late (high estradiol) follicular phases of their MC found that most of the subjective effects of d-amphetamine were unaffected by the estradiol-related changes during the follicular phase, suggesting less of a role for estradiol in potentiating the effects of amphetamines and a potentially greater role for progesterone in masking the acute effects.80,106

Several studies support this last hypothesis. First, exogenous administration of estradiol was shown not to enhance either the subjective or pharmacokinetic effects of d-amphetamine in 20 healthy, normally cycling women81 except for an increase in subjective ratings of “pleasant stimulation” and decrease in ratings of “want more.” Second, exogenous progesterone was shown to have an attenuating effect on the subjective82,85 and physiological84 effects of smoked cocaine in follicular phase CD women. Similar subjective effects of cocaine (following smoked cocaine) were also potentiated in the follicular, compared to mid-luteal, MC phase of 11 women with a history of regular cocaine use, although ratings were dependent upon dose.78 Progesterone may attenuate the subjective effects of cocaine and amphetamine in both CD and healthy women, respectively, though the precise, sex-specific mechanisms underlying this process remain ambiguous. While Sofuoglu and colleagues84 reported that feelings of “high,” “feeling the effects” of cocaine, and diastolic blood pressure were reduced in both women and men, Evans and Foltin85 reported attenuated effects of cocaine in women only.

A subsequent study comparing the effects of cocaine in 23 CD men compared to 21 CD women in both the follicular and luteal MC phases demonstrated that the subjective effects of drugs, such as “feeling high,” were potentiated in women during the follicular phase, though comparable to men.74 Conversely, women in the high-progesterone, luteal MC phase were shown to report attenuated effects compared to men.

Notably, the above studies assessed the subjective and physiological reinforcing effects of smoked cocaine. In three studies examining the effects of intranasal76,79 and intravenous73 cocaine, no MC influence was observed in either CD subjects or healthy volunteers, suggesting that the impact of gender and MC phase on acute stimulant administration may vary as a function of route of administration.76

In summary, these studies broadly indicate that females may have a sensitized subjective response to the acute administration of cocaine. Moreover, high progesterone levels during the mid-luteal phase may serve to “mask” some of the positive subjective effects of cocaine in CD women.

THE IMPACT OF SEX HORMONES ON STRESS-SYSTEM FUNCTION FOLLOWING EXPOSURE TO STRESS

Studies in our laboratory have further investigated the impact of sex hormones on stress-system function during a period of high stress and also following personalized stress-related imagery exposure. In an initial study, we assessed daily levels of salivary cortisol, estradiol, and progesterone at waking in a group of 12 CD women following admission to inpatient treatment, comparing them to a group of 10 healthy control women, across one complete 28-day MC.55 Weekly measures of negative emotion were also collected in all women, and cocaine-craving measures were collected in the CD women only. Findings indicated that levels of waking cortisol and progesterone, but not estradiol, were significantly higher in the CD women compared to controls. Significantly lower E2/P ratios were also observed in the CD women, largely as a result of high waking levels of progesterone. CD women also reported significantly higher overall negative emotion. Although ratings of cocaine craving did not change in CD women as a function of MC phase, craving did correlate positively with negative mood in the follicular and luteal phases. Increased levels of progesterone in early-abstinent CD females may represent compensatory adaptations to an enhanced HPA-driven distressed state and is consistent with the possibility that progesterone may reduce the positive effects of d-amphetamine and cocaine.82,84,85

In a follow-up study to assess the effects of MC phase more systematically on stress and cue-related cocaine craving, we compared the reactions of three groups of CD women to stress, drug-cue, and neutral imagery exposure using our standard procedures.107 The groups included five women with high progesterone levels to match the mid-luteal MC phase (P = 11.8 ng/ml, SD = 2.9; E = 69.1 pg/ml, SD = 43.2); five women with high estradiol levels and low progesterone levels to match the late follicular MC phase (P = 0.44 ng/ml, SD = .21; E = 112.46 pg/ml, SD = 118.3); and nine women with moderate levels of estradiol and progesterone (P = 2.7 ng/ml, SD = 2.85; E = 60.19 pg/ml, SD = 66.9) corresponding to the early luteal MC phase.

Findings indicated that the CD women with high progesterone levels reported significantly lower stress, cue-induced cocaine craving, and cue-induced anxiety, as well as had decreased cue-induced blood pressure, compared to the women with high estradiol levels and low progesterone levels. These findings also corroborate previous human studies that show intramuscular progesterone treatment to significantly attenuate epinephrine and heart rate responses to mental stress.108 Most importantly, findings confirm the acute-administration studies and demonstrate that increased progesterone levels are able to regulate selective aspects of the stress- and cue-induced craving state in mid-luteal CD women.

GENDER DIFFERENCES IN STRESS-SYSTEM CHANGES FOLLOWING EXPOSURE TO STRESS (TABLE 2)

TABLE 2.

Gender Differences in Stress-System Changes Following Stress or Drug Cue

Study Stressor/cue Sample Gender differences in stress-system response
Frankenhaeusr et al. (1976)109 Stroop & repeated venipuncture Healthy volunteers (6 M, 6F) F < M: epinephrine
Frankenhaeuser et al. (1978)110 Examination stress Healthy volunteers (19 M, 30 F) F < M: epinephrine, MHPG, “success & confidence”
F < M: “discomfort & failure”
Collins & F)rankenhaeuser (1978 )111 Stroop Healthy volunteers (6 M, 6 F) F < M: HR in control condition
F < M: epinephrine, plasma cortisol, HR
Jorgensen & Housten (1981)112 Stroop, mental arithmetic (serial 7s), shock avoidance FH+ (hypertension) (14 M, 16 F)
FH− (hypertension) (13 M, 15 F)
F FH+ > F FH−: systolic BP
M FH+ = M FH−: systolic BP
Hastrup & Light (1984)113 Unsignaled shock-avoidance reaction time and cold pressor task Healthy volunteers (12 M, 24 F [follicular & luteal]) F (follicular) < F (luteal) & M:
HR & BP on shock test only
Frankenhaeuser et al. (1986)114 Examination stress Healthy volunteers F< M HMPG
Tersman et al. (1991)115 Mental arithmetic and cold pressor task Healthy volunteers (15 M, 15 F [luteal & follicular]) F < M: systolic BP
F > M: HR in metal arithmetic
F (luteal) > F(follicular): glucocorticoid response after cold pressor task
Kirschbaum et al. (1992)116 Trier Social Stress Test, CRH challenge; physical exercise Study 1: Healthy volunteers (19 M, 13 F)
Study 2: Healthy volunteers (23 M, 14 F)
Study 3: Healthy volunteers (22 M, 26 F)
F < M: ACTH, plasma cortisol following Trier Social Stress Test
F = M: ACTH, plasma cortisol, CRH, & physical exercise
Allen et al. (1993)117 Math task, mirror tracing, Stroop, isometric handgrip Healthy volunteers (22 M, 22 F) F < M: systolic BP, diastolic BP
F > M: HR
Rubonis et al. (1994)98 Beverage cue followed by mood induction Alcohol dependent (38 M, 19 F) F > M: “urge reactivity” following negative mood
Kirschbaum et al. (1995)118 Trier Social Stress Test Healthy volunteers (19 M, 29 F) F < M: plasma cortisol
Kudielka et al. (1998)119 Trier Social Stress Test Healthy volunteers (postmen) (34 M, 36 F) F < M: ACTH, plasma cortisol, salivary cortisol
Sinha et al. (1998)120 0.85 g/kg ethanol followed by public speech Social drinkers (61 M, 54 F)
Willner et al. (1998)96 25 ml low-alcohol beer, followed by musical depression induction Social drinker (72 M, 72 F) F < M: “craving” following alcohol consumption
F < M: liking for alcohol reinforcers after negative mood
Kirschbaum et al. (1999)121 Trier Social Stress test & 0.25 mg & ACTH 1–24 challenge Healthy volunteers (20 M, 19 F [follicular], 20 F [luteal], 21F [taking oral contraceptive]) Trier Social Stress Test
F < M: ACTH
M = F (follicular) > F(luteal) = F(taking oral contraceptive): salivary cortisol
ACTH challenge
F (luteal) > M > F (follicular) > F (taking oral contraceptive): salivary cortisol
Earle et al. (1999)122 Harassment Healthy volunteers (28 M, 32 F) F < M: plasma cortisol, diastolic BP
F > M: HR, “hostility”
Matthews et al. (2001)123 Mental arithmetic & public speaking Healthy volunteers (31 M, 31 F) F < M: diastolic BP
F < M: systolic BP, diastolic BP, epinephrine during recovery
Seeman et al. (2001)124 30-minute cognitive challenge Healthy volunteers (9 M, 17 F [younger]; 7 M, 7 F) [older]) F < M: salivary cortisol in younger adults
F > M: salivary cortisol in older adults
Stroud et al. (2002)125 Achievement stress (math & verbal) & rejection stress (social interaction) Healthy volunteers (24 M, 26 F) F < M: salivary cortisol following achievement stress
F > M: salivary cortisol following rejection stress
Traustadottir et al. (2003)126 Matt Stress Test Reactivity Protocol, Stroop, cold pressor task, interpersonal stressor, anagram test, mental arithmetic Healthy volunteers (8M, 8 F) (55–75 years old) F < M: plasma cortisol, diastolic BP
F = M: HR, systolic BP, ACTH
Zimmer et al. (2003)127 Pain (cold pressor task modified) Healthy volunteers (39 M, 37 F) F < M: salivary cortisol
F = M: “pain intensity.” “unpleasantness”
Kudielka et al. (2004)128 Trier Social Stress Test Healthy volunteers (28 children; 34 young adults; 26 older adults) F < M: HR in children and young adults
F = M: HR in older adults
Back et al. (2005)16 Cold pressor task & mental arithmetic task Cocaine dependent (18 M, 21 F) F > M: “stress,” “nervousness,” “pain”
F < M: skin conductance, HR
Brady et al. (2006) 33 Cold pressor task Alcohol dependent (19 M, 15 F)
PTSD (12 M, 18 F)
Alcohol dependent & PTSD (16 M, 12F)
F < M ACTH, w/greater ACTH blunting in alcohol-dependent Fs
Fox et al. (2006)129 Personalized stress and cue imagery Cocaine dependent (25 M, 25 F) F < M: basal systolic BP, plasma cortisol, ACTH
F< M: systolic BP, plasma cortisole, ACTH in response to stress & cue
F > M: basal HR, prolactin
Nesic & Duka (2006)97 Public speech followed by alcohol cue Heavy social drinkers (16 M, 16 F) F < M: alcohol consumption
Stressed F < nonstressed F: skin conductance
Fox et al. (2007)60 Personalized stress and cue imagery Alcohol dependent (21 M, 21 F) Social drinkers (21 M, 21 F) Alcohol-dependent F > alcohol- dependent M, social-drinking
F, social-drinking M: “sadness,” “anxiety,” “anger,” “fear,” “behavioral arousal”
Back et al. (2008)130 Trier Social Stress Test & CRH challenge Healthy volunteers (21 M, 25 F) F < M: basal ACTH & BP
F > M: ACTH & BP response
F smokers < F nonsmokers: plasma cortisol
Chaplin et al. (2008)131 Personalized stress and cue imagery Social drinkers (27 M, 27 F) F > M: “sadness” & “anxiety” following stress
M > F: diastolic BP following stress

BP, blood pressure; F, female; FH, family history (+ or −); HR, heart rate; M, male; MHPG, 3-methoxy-4-hydroxy-phenylethylene glycol; PTSD, posttraumatic stress disorder.

To date, preclinical studies have been fairly consistent in demonstrating a more extensive response to various stress paradigms in female, compared to male, laboratory rats. Female rats show significantly greater corticosterone and ACTH levels than male rats, both at baseline132 and in response to stressors such as footshock and restraint stress.43,133,134 Female rats also show longer activation of the HPA axis135 and demonstrate greater behavioral sensitivity (locomotor activity, vocalizations, and flinching) to stressors compared to male rats.136 In relation to catecholaminergic markers, norepinephrine response to controlled, compared with uncontrolled, stress is also greater in female rats, and footshock initiates greater neural activity in monoaminergic brain regions of female, versus male, rats.137,138 Studies that have examined the effects of both stress and drug administration on behavioral sensitivity have shown maternal separation to facilitate behavioral sensitization to alcohol in female, but not male, rats.139 Similarly, following restraint stress and nicotine exposure, female rats show increases in horizontal activity and decreases in feeding and body weight to a greater extent than male rats.94,140

In humans the broader picture is far more complex. In general, gender-specific emotional and biophysiological responsivity to stress has been shown to vary in relation to both the nature of the substance being abused and the type of stressor. In drug abusers this responsivity may be associated with drug-related neuroadaptations to the stress and sex hormonal systems.

The first human studies in healthy populations examining variations in response to stress between men and women were conducted by Marianne Frankenhaeuser’s group in Stockholm during the 1970s. A series of refined studies using student samples assessed gender differences in response to examination and cognitive stress, and indicated fairly consistently that women demonstrated a reduced epinepherine response compared to men,109,110 as well as lower cortisol and heart rate.111 In one study, 19 student males were compared to 30 student females in response to examination stress. Findings showed a reduced catecholamine response to examination stress in females, along with lower ratings of “success and confidence.”110 These findings were pioneering in showing that females may be more emotionally sensitive than males to catecholamine response and also that females may be less affected by achievement challenges. The latter is consistent with a later study by Stroud and colleagues125 that compared self-reported affect and salivary cortisol responses in 24 healthy males and 26 healthy females randomly assigned to either an achievement stress (a mathematical and a verbal challenge) or social rejection situation (two social interaction challenges). Although no significant gender variation was reported in mood ratings, men showed significantly greater cortisol responses to the achievement challenges, whereas women showed greater cortisol responses to the social rejection.

Despite these potential interactions between gender and stress type, findings from young healthy population samples have typically shown that males demonstrate higher heart rate,115,117,123,128 blood pressure response,113,117,122,123 and HPA-axis sensitivity116,119,121 across a range of laboratory challenge studies compared to healthy females. These challenges have included public speaking, mental arithmetic,116,119,121 pain,119 cognitive challenge,124 harassment,122 and mirror-drawing tasks.117 Exceptions have included studies employing physical exercise as a stressor, where no gender variations have been documented.116,141 Furthermore, although consistency in response to psychological stress has been shown in some studies employing elderly populations,119,124,126 others have highlighted sex-specific differences. A reanalysis of five independent studies from the same laboratory populations indicated increased plasma, but not salivary, cortisol levels in elderly women compared to elderly men and a suggestion that the heightened HPA sensitivity documented in younger adult males may decrease with age.142

Notably, despite young adult males displaying increased physiological, stress-related activity compared to females, females have tended to report significantly higher levels of distress. This finding is consistent with data from several of the studies mentioned previously in relation to stress-system changes following the acute administration of psychoactive drugs. In all cases, a more sensitized emotional response to biophysiological stress-system activity following either stress or acute drug administration may predispose women to specific risk factors for addictive disorders. Recently, several studies have assessed stress and drug-cue responses within addicted populations and have highlighted important gender variations in autonomic and affective functioning.

Consistent with research on healthy volunteers, studies comparing male and female cocaine abusers have indicated that CD males may have a significantly higher HPA-axis drive than CD women. In a study conducted in our laboratory, we found that 25 CD women demonstrated significantly lower ACTH, cortisol, and blood pressure drive compared to 25 CD men, despite similar ratings of subjective anxiety following exposure to personalized, individually calibrated stress, drug-cue, and neutral imagery.129

One of the limitations of the above study was the exclusion of a healthy control group, making it difficult to assess whether CD males demonstrated a hyper–HPA response compared to healthy males, or whether CD females demonstrated a hypo-response compared to healthy females. In a subsequent study using an identical paradigm, however, we examined the impact of both gender and drug group on emotional and cardiovascular response to stress imagery in 40 CD individuals and 40 social drinkers.60 Findings indicated that the CD males demonstrated an enhanced change from baseline heart rate response to stress compared to both the social-drinking males and CD females. Consistent with the emotional sensitivity to stress-system engagement shown in healthy females following stress and acute administration of cocaine, findings indicated that females in general (36 total [CD or social drinkers]) reported significantly higher levels of anxiety and sadness following exposure to stress compared to males (44 total [same groups]).

In relation to gender variation in adrenal sensitivity, extended analyses from Fox and colleagues129 found that ACTH and cortisol were correlated in the 25 CD males, but not in CD females, following both stress and drug cue. This low ACTH and cortisol conformity may also highlight a failure of the adrenal cortex to respond normally to ACTH stimulation when the HPA system is challenged under psychologically stressful conditions. Previous research has interpreted a lack of synchrony between ACTH and cortisol as reflecting a potential disturbance in the regulation of cortisol secretion and disruption in hormonal release patterns—which could increase vulnerability to neuroendocrine dysfunction.143,144 Further alterations in adrenal responsiveness were evident in that CD females did not demonstrate the hypersensitivity to ACTH in relation to the production of glucocorticoids typically observed in normal, healthy females.145 Again, although a healthy control group was not included in this study, previous studies using healthy volunteers have tended to show higher levels of basal ACTH, but not cortisol, in males,146148 suggesting a different set-point to cortisol feedback in healthy females. This sensitivity was not demonstrated in CD women.129

In addition, several studies have reported similar gender-specific changes in both emotional and behavioral set-point following exposure to stress in alcohol-dependent females. Employing an identical personalized imagery paradigm to that used with CD subjects, we compared a group of AD and social-drinking males and females across three imagery conditions (stress, alcohol cue, and neutral/relaxing) and assessed emotional and behavioral response at baseline, immediately following imagery exposure, and at various time-points. Similar to CD females, 21 early-abstinent AD females reported significantly higher ratings of stress-induced sadness, anxiety, anger, fear, and behavioral arousal compared to 21 AD males as well as to 21 social-drinking males and females.149

In relation to HPA-axis markers, a recent study by Brady and colleagues33 demonstrated gender-related basal and response differences to the cold pressor task in three groups of individuals (AD, posttraumatic stress syndrome [PTSD], and comorbid AD and PTSD). Forty-five females showed significantly lower levels of ACTH compared to 47 males (across all three groups), and 12 females with either AD or PTSD showed greater ACTH blunting following stress exposure compared to 16 males meeting the same diagnostic criteria.

In addition, findings from a recent study by Back and colleagues130 indicated that, similar to AD women, stress-induced HPA-axis response was more reduced in female than in male smokers. The study involved male and female smokers and nonsmokers being exposed to both the Trier Social Stress Test118 and a corticotrophin-releasing hormone challenge. Female smokers demonstrated significantly lower basal cortisol levels compared to female non-smokers, as well as a blunted cortisol response to both the physiological and psychosocial stressor compared to female nonsmokers. Importantly, these variations in smoking-related adaptations were not observed between the male smokers and nonsmokers, and may have some role in explaining why women have markedly greater difficulty than men in quitting smoking.150152

THE IMPLICATIONS OF GENDER DIFFERENCES IN STRESS-SYSTEM CHANGES

Although methodological complications regarding drug type, stressor type, and subject sample make it difficult to formulate detailed conclusions concerning gender variation in stress-system changes, there are some broad consistencies. First, an enhanced emotional sensitivity to biophysiological stress-system changes is typically observed in female substance abusers compared to males, particularly following the acute administration of cocaine and nicotine. Inconsistencies following the administration of amphetamine may reflect the character of the samples, which included nonaddicted subjects. Second, following exposure to both stress and drug cue, cocaine- and alcohol-dependent females typically report an enhanced emotional response relative to their biophysiological stress-system arousal. Third, a dsyregulated HPA-axis response is documented in both CD and AD females. In CD females, a low conformity in stress- and drug cue–related ACTH and cortisol response, as well as potential alterations in cortisol feedback, may be indicative of adrenal cortex failure to respond normally to ACTH stimulation under challenging situations. Similarly, a blunted cortisol response to stress in alcohol- and nicotine-dependent women may represent an important risk factor for relapse. HPA-axis hyporeactivity to social stress, alcoholcue exposure, and alcohol consumption has been associated with greater craving and with a return to early drinking in alcoholics,153155 and has also been deemed a risk marker for the development of substance use disorders in individuals with a positive family history for alcoholism.156 Fourth, MC changes marked by fluctuations in sex hormones can influence these stress-system adaptations in substance-abusing women.

Findings relating to enhanced emotional sensitivity in substance-abusing women may be largely reflective of trends in the general population,17,157,158 as healthy and socially drinking females also report increased stress-related anxiety and negative affect following stress.122,131 In drug-abusing women, enhanced emotional sensitivity to a stress-related craving state, along with differences in adrenal response, may increase risk of relapse vulnerability and also highlight dissociations in risk for comorbid disorders between men and women.

Increased anxiety, anger, fear, and sadness reported by AD females150 have been significantly associated with stress-induced alcohol craving in alcoholics,58,59 and increased stress-related anxiety and sadness have been significantly associated with stress-related cocaine craving in cocaine abusers.60 Furthermore, meta-analyses of international longitudinal surveys have shown that emotionally driven, internalizing disorders such as depression are predictive of drinking in women but not in men.159 Similarly, affective problems such as low self-esteem, guilt,160 stigmatization,161 and social withdrawal162 have all been highlighted as risk factors in these populations.

Findings from our laboratory studies are consistent with the fact that women generally surpass men in the number of psychiatric problems related to their drug/alcohol use, despite men having significantly higher consumption levels and dependence problems.2,145 Moreover, the National Comorbidity Survey found greater prevalence of anxiety, depression, panic disorder, and phobia in female alcohol abusers compared to males,163 and almost twice the prevalence of anxiety disorder has been reported in treatment-seeking CD women compared to men.164 As such, allostasis of stress-related HPA and SAM systems, increased emotional intensity, and the potential for comorbid affective disorders in drug/alcohol-abusing women may therefore interact as unique risk factors in alcohol- and drug-abusing women.

Similarly, fluctuations in sex hormones across the MC may influence neuroadaptations in stress response and drug craving in several ways—and in so doing have relevant treatment implications. First, the positive effects of cocaine may be potentiated in women during the follicular phase of their cycle to the same levels as men.74,106 Although follicular estradiol has been shown to play a lesser role in altering response to stimulants in humans, the equivalent hedonic experience in women compared to men may highlight the follicular phase as a period of increased allostatic susceptibility. Of particular note in this context is that CD females may potentially experience greater emotional intensity in response to HPA arousal,131,165 as observed in our laboratory studies.60,129

Second, while increased levels of progesterone and decreased levels of E2/P across the MC in CD women may initially reflect a neuroadaptive response to enhanced, stress-induced HPA and negative affect, the persistence of distress and repeated adaptations may lead to depleted progesterone and allopregnanolone levels.166 These changes could further predispose women to increased anxiety, negative emotion, and lowered tolerance to stress, which in turn may increase vulnerability to relapse.

Third, the attenuating effects of progesterone suggest that the late luteal (premenstrual) MC phase, which is characterized by endogenous progesterone withdrawal,167 could represent a phase of increased vulnerability to stress and to cue-related craving. These progesterone-related mechanisms may serve to increase anxiety168 and insensitivity to the potentiating effects of GABA-modulatory drugs such as alcohol169 in substance-abusing women. It is notable that in our study we found that E2/P ratios in the late luteal phase of 12 CD women were significantly associated with increased cocaine craving.55

In summary, studies reviewed in this article have shown that substance-abusing women may show increased emotional sensitivity to stress-system changes compared to men, alongside sex-specific differences in HPA- and SAM-system responses. Moreover, these unique neuroadaptations in affect and autonomic function may influence relapse vulnerability, comorbid affective disorders, and treatment outcome. Findings also indicate that stress- and reward-system alterations may be mediated by sex hormones or MC phase, suggesting that women may be more susceptible to stress and cue-related craving during the follicular phase, when progesterone levels are low. Such compounded problems may, in turn, highlight the necessity for appropriately tailored, gender-specific treatment programs emphasizing the development of assertiveness training and coping skills for affective disorders, guilt, and low self-esteem.160,170

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References

  • 1.Substance Abuse and Mental Health Services Administration. Results from the 2004 National Survey on Drug Use and Health: national findings [Office of Applied Studies NSDUH Series H-28; DHHS pub. no. SMA 05–4062] Rockville, MD: SAMHSA; 2005. [Google Scholar]
  • 2.Wilsnack S. Patterns and trends in women’s drinking: recent findings and some implications for prevention. In: Howard J, Martin S, Mail P, Hilton M, Taylor E, editors. Women and alcohol: issues for prevention research [National Institute on Alcohol Abuse and Alcoholism research monograph no. 32 NIH pub. no. 96–3817] Bethesda, MD: Department of Health and Human Services, Public Health Service, National Institutes of Health, NIAAA; 1996. pp. 19–63. [Google Scholar]
  • 3.Substance Abuse and Mental Health Services Administration. Overview of findings from the 2006 National Survey on Drug Use and Health [Office of Applied Studies NHSAA Series H-21; DHHS pub. no. SMA 03–3774] Rockville, MD: SAMHSA; 2007. [Google Scholar]
  • 4.Quinones-Jenab V. Why are women from Venus and men from Mars when they abuse cocaine? Brain Res. 2006;1126:200–3. doi: 10.1016/j.brainres.2006.08.109. [DOI] [PubMed] [Google Scholar]
  • 5.Lynch WJ, Carroll ME. Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology (Berl) 1999;144:77–82. doi: 10.1007/s002130050979. [DOI] [PubMed] [Google Scholar]
  • 6.Donny EC, Caggiula AR, Rowell PP, et al. Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding. Psychopharmacology (Berl) 2000;151:392–405. doi: 10.1007/s002130000497. [DOI] [PubMed] [Google Scholar]
  • 7.Carroll KM, Sinha R, Nich C, Babuscio T, Rounsaville BJ. Contingency management to enhance naltrexone treatment of opioid dependence: a randomized clinical trial of reinforcement magnitude. Exp Clin Psychopharmacol. 2002;10:54–63. doi: 10.1037//1064-1297.10.1.54. [DOI] [PubMed] [Google Scholar]
  • 8.Hu M, Crombag HS, Robinson TE, Becker JB. Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology. 2004;29:81–5. doi: 10.1038/sj.npp.1300301. [DOI] [PubMed] [Google Scholar]
  • 9.Lynch WJ, Arizzi MN, Carroll ME. Effects of sex and the estrous cycle on regulation of intravenously self-administered cocaine in rats. Psychopharmacology (Berl) 2000;152:132–9. doi: 10.1007/s002130000488. [DOI] [PubMed] [Google Scholar]
  • 10.Lynch W. Sex differences in vulnerability to drug self-administration. Exp Clin Psychopharmacol. 2006;14:34–41. doi: 10.1037/1064-1297.14.1.34. [DOI] [PubMed] [Google Scholar]
  • 11.Kosten TR, Kosten TA, McDougle CJ, et al. Gender differences in response to intranasal cocaine administration to humans. Biol Psychiatry. 1996;39:147–8. doi: 10.1016/0006-3223(95)00386-X. [DOI] [PubMed] [Google Scholar]
  • 12.McCance-Katz EF, Hart CL, Boyarsky B, Kosten T, Jatlow P. Gender effects following repeated administration of cocaine and alcohol in humans. Subst Use Misuse. 2005;40:511–28. doi: 10.1081/ja-200030693. [DOI] [PubMed] [Google Scholar]
  • 13.Hernandez-Avila CA, Rounsaville BJ, Kranzler HR. Opioid-, cannabis- and alcohol-dependent women show more rapid progression to substance abuse treatment. Drug Alcohol Depend. 2004;74:265–72. doi: 10.1016/j.drugalcdep.2004.02.001. [DOI] [PubMed] [Google Scholar]
  • 14.McCance-Katz EF, Carroll KM, Rounsaville BJ. Gender differences in treatment-seeking cocaine abusers—implications for treatment and prognosis. Am J Addict. 1999;8:300–11. doi: 10.1080/105504999305703. [DOI] [PubMed] [Google Scholar]
  • 15.Sinha R, Rounsaville BJ. Sex differences in depressed substance abusers. Clin Psychiatry. 2002;63:616–27. doi: 10.4088/jcp.v63n0715. [DOI] [PubMed] [Google Scholar]
  • 16.Back SE, Brady KT, Jackson JL, Salstrom S, Zinzow H. Gender differences in stress reactivity among cocaine-dependent individuals. Psychopharmacology (Berl) 2005;180:169–76. doi: 10.1007/s00213-004-2129-7. [DOI] [PubMed] [Google Scholar]
  • 17.Brady KT, Sinha R. Co-occurring mental and substance use disorders: the neurobiological effects of chronic stress. Am J Psychiatry. 2005;162:1483–93. doi: 10.1176/appi.ajp.162.8.1483. [DOI] [PubMed] [Google Scholar]
  • 18.Wills TA, Shiffman S. Coping and substance abuse: a conceptual framework. In: Shiffman S, Wills TA, editors. Coping and substance use. Orlando: Academic; 1985. pp. 3–24. [Google Scholar]
  • 19.Childress AR, Ehrman R, McLellan AT, MacRae J, Natale M, O’Brien CP. Can induced moods trigger drug-related responses in opiate abuse patients? J Subst Abuse Treat. 1994;11:17–23. doi: 10.1016/0740-5472(94)90060-4. [DOI] [PubMed] [Google Scholar]
  • 20.Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology. 2001;24:97–129. doi: 10.1016/S0893-133X(00)00195-0. [DOI] [PubMed] [Google Scholar]
  • 21.Sinha R. How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berl) 2001;158:343–59. doi: 10.1007/s002130100917. [DOI] [PubMed] [Google Scholar]
  • 22.de Wit H, Soderpalm AH, Nikolayev L, Young E. Effects of acute social stress on alcohol consumption in healthy subjects. Alcohol Clin Exp Res. 2003;27:1270–7. doi: 10.1097/01.ALC.0000081617.37539.D6. [DOI] [PubMed] [Google Scholar]
  • 23.Higley JD, Hasert MF, Suomi SJ, Linnoila M. Nonhuman primate model of alcohol abuse: effects of early experience, personality, and stress on alcohol consumption. Proc Natl Acad Sci U S A. 1991;88:7261–5. doi: 10.1073/pnas.88.16.7261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Kosten TA, Miserendino MJ, Kehoe P. Enhanced acquisition of cocaine self-administration in adult rats with neonatal isolation stress experience. Brain Res. 2000;875:44–50. doi: 10.1016/s0006-8993(00)02595-6. [DOI] [PubMed] [Google Scholar]
  • 25.Shalev U, Marinelli M, Baumann MH, Piazza PV, Shaham Y. The role of corticosterone in food deprivation-induced reinstatement of cocaine seeking in the rat. Psychopharmacology (Berl) 2003;168:170–6. doi: 10.1007/s00213-002-1200-5. [DOI] [PubMed] [Google Scholar]
  • 26.Shiffman S. Relapse following smoking cessation: a situational analysis. J Consult Clin Psychol. 1982;50:71–86. doi: 10.1037//0022-006x.50.1.71. [DOI] [PubMed] [Google Scholar]
  • 27.Marlatt GA, Gordon JR. Relapse prevention: maintenance strategies in the treatment of addictive behaviors. New York: Guilford; 1985. [Google Scholar]
  • 28.Conger JJ. Reinforcement theory and the dynamics of alcoholism. Q J Stud Alcohol. 1956;17:296–305. [PubMed] [Google Scholar]
  • 29.Khantzian EJ. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatry. 1985;142:1259–64. doi: 10.1176/ajp.142.11.1259. [DOI] [PubMed] [Google Scholar]
  • 30.O’ Malley SS, Jaffe AJ, Chang G, et al. Six-month follow-up of naltrexone and psychotherapy for alcohol dependence. Arch Gen Psychiatry. 1996;53:217–24. doi: 10.1001/archpsyc.1996.01830030039007. [DOI] [PubMed] [Google Scholar]
  • 31.Cooney NL, Litt MD, Morse PA, Bauer LO, Gaupp L. Alcohol cue reactivity, negative-mood reactivity, and relapse in treated alcoholic men. J Abnorm Psychol. 1997;106:243–50. doi: 10.1037//0021-843x.106.2.243. [DOI] [PubMed] [Google Scholar]
  • 32.Litt MD, Cooney NL. Inducing craving for alcohol in the laboratory. Alcohol Res Health. 1999;23:174–8. [PMC free article] [PubMed] [Google Scholar]
  • 33.Brady KT, Waldrop AE, McRae AL, et al. The impact of alcohol dependence and posttraumatic stress disorder on cold pressor task response. J Stud Alcohol. 2006;67:700–6. doi: 10.15288/jsa.2006.67.700. [DOI] [PubMed] [Google Scholar]
  • 34.Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ. Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Arch Gen Psychiatry. 2006;63:324–31. doi: 10.1001/archpsyc.63.3.324. [DOI] [PubMed] [Google Scholar]
  • 35.Paliwal P, Hyman SM, Sinha R. Craving predicts time to cocaine relapse: further validation of the Now and Brief versions of the cocaine craving questionnaire. Drug Alcohol Depend. 2008;93:252–9. doi: 10.1016/j.drugalcdep.2007.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Volkow ND, Fowler JS, Wang GJ, et al. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse. 1993;14:169–77. doi: 10.1002/syn.890140210. [DOI] [PubMed] [Google Scholar]
  • 37.Volkow ND, Fowler JS, Wang GJ. Imaging studies on the role of dopamine in cocaine reinforcement and addiction in humans. J Psychopharmacol. 1999;13:337–45. doi: 10.1177/026988119901300406. [DOI] [PubMed] [Google Scholar]
  • 38.Shalev U, Grimm JW, Shaham Y. Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev. 2002;54:1–42. doi: 10.1124/pr.54.1.1. [DOI] [PubMed] [Google Scholar]
  • 39.Shaham Y, Shalev U, Lu L, De Wit H, Stewart J. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 2003;168:3–20. doi: 10.1007/s00213-002-1224-x. [DOI] [PubMed] [Google Scholar]
  • 40.Sinha R. The role of stress in addiction relapse. Curr Psychiatry Rep. 2007;9:388–95. doi: 10.1007/s11920-007-0050-6. [DOI] [PubMed] [Google Scholar]
  • 41.Piazza PV, Le Moal M. Glucocorticoids as a biological substrate of reward: physiological and pathophysiological implications. Brain Res Brain Res Rev. 1997;25:359–72. doi: 10.1016/s0165-0173(97)00025-8. [DOI] [PubMed] [Google Scholar]
  • 42.Koob GF, Le Moal M. Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci. 2005;8:1442–4. doi: 10.1038/nn1105-1442. [DOI] [PubMed] [Google Scholar]
  • 43.Rivier C. Gender, sex steroids, corticotropin-releasing factor, nitric oxide, and the HPA response to stress. Pharmacol Biochem Behav. 1999;64:739–51. doi: 10.1016/s0091-3057(99)00148-3. [DOI] [PubMed] [Google Scholar]
  • 44.Shaham Y, Erb S, Stewart J. Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Brain Res Rev. 2000;33:13–33. doi: 10.1016/s0165-0173(00)00024-2. [DOI] [PubMed] [Google Scholar]
  • 45.Stewart J. Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking. J Psychiatry Neurosci. 2000;25:125–36. [PMC free article] [PubMed] [Google Scholar]
  • 46.Lee S, Schmidt ED, Tilders FJ, Rivier C. Effect of repeated exposure to alcohol on the response of the hypothalamic-pituitary-adrenal axis of the rat: I. Role of changes in hypothalamic neuronal activity. Alcohol Clin Exp Res. 2001;25:98–105. [PubMed] [Google Scholar]
  • 47.Mantsch JR, Cullinan WE, Tang LC, et al. Daily cocaine self-administration under long-access conditions augments restraint-induced increases in plasma corticosterone and impairs glucocorticoid receptor-mediated negative feedback in rats. Brain Res. 2007;1167:101–11. doi: 10.1016/j.brainres.2007.05.080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Dai X, Thavundayil J, Gianoulakis C. Response of the hypothalamic-pituitary-adrenal axis to stress in the absence and presence of ethanol in subjects at high and low risk of alcoholism. Neuropsychopharmacology. 2002;27:442–52. doi: 10.1016/S0893-133X(02)00308-1. [DOI] [PubMed] [Google Scholar]
  • 49.Adinoff B, Ruether K, Krebaum S, Iranmanesh A, Williams MJ. Increased salivary cortisol concentrations during chronic alcohol intoxication in a naturalistic clinical sample of men. Alcohol Clin Exp Res. 2003;27:1420–7. doi: 10.1097/01.ALC.0000087581.13912.64. [DOI] [PubMed] [Google Scholar]
  • 50.Adinoff B, Junghanns K, Kiefer F, Krishnan-Sarin S. Suppression of the HPA axis stress-response: implications for relapse. Alcohol Clin Exp Res. 2005;29:1351–5. doi: 10.1097/01.ALC.0000176356.97620.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Wand GS, Dobs AS. Alterations in the hypothalamic-pituitary-adrenal axis in actively drinking alcoholics. J Clin Endocrinol Metab. 1991;72:1290–5. doi: 10.1210/jcem-72-6-1290. [DOI] [PubMed] [Google Scholar]
  • 52.al’Absi M, Bongard S, Lovallo WR. Adrenocorticotropin responses to interpersonal stress: effects of overt anger expression style and defensiveness. Int J Psychophysiol. 2000;37:257–65. doi: 10.1016/s0167-8760(00)00108-2. [DOI] [PubMed] [Google Scholar]
  • 53.Junghanns K, Backhaus J, Tietz U, et al. Impaired serum cortisol stress response is a predictor of early relapse. Alcohol Alcohol. 2003;38:189–93. doi: 10.1093/alcalc/agg052. [DOI] [PubMed] [Google Scholar]
  • 54.Sinha R, Talih M, Malison R, Cooney N, Anderson GM, Kreek MJ. Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states. Psychopharmacology (Berl) 2003;170:62–72. doi: 10.1007/s00213-003-1525-8. [DOI] [PubMed] [Google Scholar]
  • 55.Fox HC, Hong KA, Paliwal P, Morgan PT, Sinha R. Altered levels of sex and stress hormones assessed daily over a 28-day cycle in early abstinent cocaine dependent females. Psychopharmacology (Berl) 2008;195:527–36. doi: 10.1007/s00213-007-0936-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Kampman KM, Volpicelli JR, McGinnis DE, et al. Reliability and validity of the Cocaine Selective Severity Assessment. Addict Behav. 1998;23:449–61. doi: 10.1016/s0306-4603(98)00011-2. [DOI] [PubMed] [Google Scholar]
  • 57.Kampman KM, Alterman AI, Volpicelli JR, et al. Cocaine withdrawal symptoms and initial urine toxicology results predict treatment attrition in outpatient cocaine dependence treatment. Psychol Addict Behav. 2001;15:52–9. doi: 10.1037/0893-164x.15.1.52. [DOI] [PubMed] [Google Scholar]
  • 58.Sinha R, Fox HC, Hong KA, Bergquist KL, Bhagwagar Z, Siedlarz KM. Enhanced negative emotion and alcohol craving, and altered physiological responses following stress and cue exposure in alcohol dependent individuals. Neuropsychopharmacology. 2008;33:796–805. doi: 10.1038/npp.2008.78. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Fox HC, Berquist KL, Hong KI, Sinha R. Stress-induced and alcohol cue-induced craving in recently abstinent alcohol dependent individuals. Alcohol Clin Exp Res. 2007;31:395–403. doi: 10.1111/j.1530-0277.2006.00320.x. [DOI] [PubMed] [Google Scholar]
  • 60.Fox HC, Hong KA, Siedlarz KM, Sinha R. Enhanced sensitivity to stress and drug/alcohol craving in abstinent cocaine dependent individuals compared to social drinkers. Neuropsychopharmacology. 2008;33:796–805. doi: 10.1038/sj.npp.1301470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Koob GF, Ahmed SH, Boutrel B, et al. Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2004;27:739–49. doi: 10.1016/j.neubiorev.2003.11.007. [DOI] [PubMed] [Google Scholar]
  • 62.Weiss F. Neurobiology of craving, conditioned reward and relapse. Curr Opin Pharmacol. 2005;5:9–19. doi: 10.1016/j.coph.2004.11.001. [DOI] [PubMed] [Google Scholar]
  • 63.Netter P, Müller MJ, Neumann A, Kamradik B. The influence of nicotine on performance, mood, and physiological parameters as related to smoking habit, gender, and suggestibility. Clin Investig. 1994;72:512–8. doi: 10.1007/BF00207480. [DOI] [PubMed] [Google Scholar]
  • 64.Perkins KA, Sexton JE, DiMarco A, Grobe JE, Scierka A, Stiller RL. Subjective and cardiovascular responses to nicotine combined with alcohol in male and female smokers. Psychopharmacology (Berl) 1995;119:205–12. doi: 10.1007/BF02246162. [DOI] [PubMed] [Google Scholar]
  • 65.Evans SM, Haney M, Fischman MW, Foltin RW. Limited sex differences in response to “binge” smoked cocaine use in humans. Neuropsychopharmacology. 1999;21:445–54. doi: 10.1016/S0893-133X(98)00120-1. [DOI] [PubMed] [Google Scholar]
  • 66.Singha AK, McCance-Katz EF, Petrakis I, Kosten TR, Oliveto A. Sex differences in self-reported and physiological response to oral cocaine and placebo in humans. Am J Drug Alcohol Abuse. 2000;26:643–57. doi: 10.1081/ada-100101900. [DOI] [PubMed] [Google Scholar]
  • 67.Schuckit MA, Smith TL, Kalmijn J, Tsuang J, Hesselbrock V, Bucholz K. Response to alcohol in daughters of alcoholics: a pilot study and a comparison with sons of alcoholics. Alcohol Alcohol. 2000;35:242–8. doi: 10.1093/alcalc/35.3.242. [DOI] [PubMed] [Google Scholar]
  • 68.Gabbay FH. Variations in affect following amphetamine and placebo: markers of stimulant drug preference. Exp Clin Psychopharmacol. 2003;11:91–101. doi: 10.1037//1064-1297.11.1.91. [DOI] [PubMed] [Google Scholar]
  • 69.Gabbay FH. Family history of alcoholism and response to amphetamine: sex differences in the effect of risk. Alcohol Clin Exp Res. 2005;29:773–80. doi: 10.1097/01.alc.0000164380.16043.4f. [DOI] [PubMed] [Google Scholar]
  • 70.Acheson A, Mahler SV, Chi H, de Wit H. Differential effects of nicotine on alcohol consumption in men and women. Psychopharmacology (Berl) 2006;186:54–63. doi: 10.1007/s00213-006-0338-y. [DOI] [PubMed] [Google Scholar]
  • 71.Vansickel AR, Lile JA, Stoops WW, Rush CR. Similar discriminative stimulus effects of D-amphetamine in women and men. Pharmacol Biochem Behav. 2007;87:289–96. doi: 10.1016/j.pbb.2007.05.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Lukas SE, Sholar M, Lundahl LH, et al. Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers. Psychopharmacology (Berl) 1996;125:346–54. doi: 10.1007/BF02246017. [DOI] [PubMed] [Google Scholar]
  • 73.Mendelson JH, Mello NK, Sholar MB, Siegel AJ, Kaufman MJ, Levin JM. Cocaine pharmacokinetics in men and in women during the follicular and luteal phases of the menstrual cycle. Neuropsychopharmacology. 1999;21:294–303. doi: 10.1016/S0893-133X(99)00020-2. [DOI] [PubMed] [Google Scholar]
  • 74.Sofuoglu M, Dudish-Poulsen S, Nelson D, Pentel PR, Hatsukami DK. Sex and menstrual cycle differences in the subjective effects from smoked cocaine in humans. Exp Clin Psychopharmacol. 1999;7:274–83. doi: 10.1037//1064-1297.7.3.274. [DOI] [PubMed] [Google Scholar]
  • 75.White TL, Justice AJ, de Wit H. Differential subjective effects of D-amphetamine by gender, hormone levels and menstrual cycle phase. Pharmacol Biochem Behav. 2002;73:729–41. doi: 10.1016/s0091-3057(02)00818-3. [DOI] [PubMed] [Google Scholar]
  • 76.Collins SL, Evans SM, Foltin RW, Haney M. Intranasal cocaine in humans: effects of sex and menstrual cycle. Pharmacol Biochem Behav. 2007;86:117–24. doi: 10.1016/j.pbb.2006.12.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Justice AJ, de Wit H. Acute doses of d-amphetamine during the follicular and luteal phases of the menstrual cycle in women. Psychopharmacology (Berl) 1999;145:67–75. doi: 10.1007/s002130051033. [DOI] [PubMed] [Google Scholar]
  • 78.Evans SM, Haney M, Foltin RW. The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women. Psychopharmacology (Berl) 2002;159:397–406. doi: 10.1007/s00213-001-0944-7. [DOI] [PubMed] [Google Scholar]
  • 79.Kouri EM, Lundahl LH, Borden KN, McNeil JF, Lukas SE. Effects of oral contraceptives on acute cocaine response in female volunteers. Pharmacol Biochem Behav. 2002;74:173–80. doi: 10.1016/s0091-3057(02)00992-9. [DOI] [PubMed] [Google Scholar]
  • 80.Justice AJ, de Wit H. Acute effects of d-amphetamine during the early and late follicular phases of the menstrual cycle in women. Pharmacol Biochem Behav. 2000;66:509–15. doi: 10.1016/s0091-3057(00)00218-5. [DOI] [PubMed] [Google Scholar]
  • 81.Justice AJ, de Wit H. Acute effects of estradiol pretreatment on the response to d-amphetamine in women. Neuroendocrinology. 2000;71:51–9. doi: 10.1159/000054520. [DOI] [PubMed] [Google Scholar]
  • 82.Sofuoglu M, Babb DA, Hatsukami DK. Effects of progesterone treatment on smoked cocaine response in women. Pharmacol Biochem Behav. 2002;72:431–5. doi: 10.1016/s0091-3057(02)00716-5. [DOI] [PubMed] [Google Scholar]
  • 83.Lile JA, Kendall SL, Babalonis S, Martin CA, Kelly TH. Evaluation of estradiol administration on the discriminative-stimulus and subject-rated effects of d-amphetamine in healthy pre-menopausal women. Pharmacol Biochem Behav. 2007;87:258–78. doi: 10.1016/j.pbb.2007.04.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Sofuoglu M, Mitchell E, Kosten TR. Effects of progesterone treatment on cocaine responses in male and female cocaine users. Pharmacol Biochem Behav. 2004;78:699–705. doi: 10.1016/j.pbb.2004.05.004. [DOI] [PubMed] [Google Scholar]
  • 85.Evans SM, Foltin RW. Exogenous progesterone attenuates the subjective effects of smoked cocaine in women, but not in men. Neuropsychopharmacology. 2006;31:659–74. doi: 10.1038/sj.npp.1300887. [DOI] [PubMed] [Google Scholar]
  • 86.Deutch AY, Roth RH. The determinants of stress-induced activation of the prefrontal cortical dopamine system. Prog Brain Res. 1990;85:367–402. doi: 10.1016/s0079-6123(08)62691-6. discussion 402–3. [DOI] [PubMed] [Google Scholar]
  • 87.Sorg BA, Steketee JD. Mechanisms of cocaine-induced sensitization. Prog Neuropsychopharmacol Biol Psychiatry. 1992;16:1003–12. doi: 10.1016/0278-5846(92)90117-w. [DOI] [PubMed] [Google Scholar]
  • 88.Sarnyai Z, Mello NK, Mendelson JH, Erös-Sarnyai M, Mercer G. Effects of cocaine on pulsatile activity of hypothalamic-pituitary-adrenal axis in male rhesus monkeys: neuroendocrine and behavioral correlates. J Pharmacol Exp Ther. 1996;277:225–34. [PubMed] [Google Scholar]
  • 89.Fischman MW, Foltin RW. Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br J Addict. 1991;86:1563–70. doi: 10.1111/j.1360-0443.1991.tb01749.x. [DOI] [PubMed] [Google Scholar]
  • 90.Schoedel KA, Sellers EM. Assessing abuse liability during drug development: changing standards and expectations. Clin Pharmacol Ther. 2008;83:622–6. doi: 10.1038/sj.clpt.6100492. [DOI] [PubMed] [Google Scholar]
  • 91.Ogilvie KM, Rivier C. Gender difference in hypothalamic-pituitary-adrenal axis response to alcohol in the rat: activational role of gonadal steroids. Brain Res. 1997;766:19–28. doi: 10.1016/s0006-8993(97)00525-8. [DOI] [PubMed] [Google Scholar]
  • 92.Carroll ME, Anderson MM, Morgan AD. Higher locomotor response to cocaine in female (vs. male) rats selectively bred for high (HiS) and low (LoS) saccharin intake. Pharmacol Biochem Behav. 2007;88:94–104. doi: 10.1016/j.pbb.2007.07.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Harrod SB, Mactutus CF, Bennett K, et al. Sex differences and repeated intravenous nicotine: behavioral sensitization and dopamine receptors. Pharmacol Biochem Behav. 2004;78:581–92. doi: 10.1016/j.pbb.2004.04.026. [DOI] [PubMed] [Google Scholar]
  • 94.Faraday MM, Blakeman KH, Grunberg NE. Strain and sex alter effects of stress and nicotine on feeding, body weight, and HPA axis hormones. Pharmacol Biochem Behav. 2005;80:577–89. doi: 10.1016/j.pbb.2005.01.015. [DOI] [PubMed] [Google Scholar]
  • 95.Harrod SB, Booze RM, Welch M, Browning CE, Mactutus CF. Acute and repeated intravenous cocaine-induced locomotor activity is altered as a function of sex and gonadectomy. Pharmacol Biochem Behav. 2005;82:170–81. doi: 10.1016/j.pbb.2005.08.005. [DOI] [PubMed] [Google Scholar]
  • 96.Willner P, Field M, Pitts K, Reeve G. Mood, cue and gender influences on motivation, craving and liking for alcohol in recreational drinkers. Behav Pharmacol. 1998;9:631–42. doi: 10.1097/00008877-199811000-00018. [DOI] [PubMed] [Google Scholar]
  • 97.Nesic J, Duka T. Gender specific effects of a mild stressor on alcohol cue reactivity in heavy social drinkers. Pharmacol Biochem Behav. 2006;83:239–48. doi: 10.1016/j.pbb.2006.02.006. [DOI] [PubMed] [Google Scholar]
  • 98.Rubonis AV, Colby SM, Monti PM, Rohsenow DJ, Gulliver SB, Sirota AD. Alcohol cue reactivity and mood induction in male and female alcoholics. J Stud Alcohol. 1994;5:487–94. doi: 10.15288/jsa.1994.55.487. [DOI] [PubMed] [Google Scholar]
  • 99.McCormick CM, Mathews IZ. HPA function in adolescence: role of sex hormones in its regulation and the enduring consequences of exposure to stressors. Pharmacol Biochem Behav. 2007;86:220–33. doi: 10.1016/j.pbb.2006.07.012. [DOI] [PubMed] [Google Scholar]
  • 100.Lindheim SR, Legro RS, Morris RS, et al. The effect of progestins on behavioral stress responses in postmenopausal women. J Soc Gynecol Investig. 1994;1:79–83. doi: 10.1177/107155769400100116. [DOI] [PubMed] [Google Scholar]
  • 101.Roca CA, Schmidt PJ, Rubinow DR. Gonadal steroids and affective illness. Neuroscientist. 1999;5:227–37. [Google Scholar]
  • 102.Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dys-regulation. Science. 1997;278:52–8. doi: 10.1126/science.278.5335.52. [DOI] [PubMed] [Google Scholar]
  • 103.Terner JM, de Wit H. Menstrual cycle phase and responses to drugs of abuse in humans. Drug Alcohol Depend. 2006;84:1–13. doi: 10.1016/j.drugalcdep.2005.12.007. [DOI] [PubMed] [Google Scholar]
  • 104.Mello NK. Effects of alcohol abuse on reproductive function in women. Recent Dev Alcohol. 1988;6:253–76. doi: 10.1007/978-1-4615-7718-8_14. [DOI] [PubMed] [Google Scholar]
  • 105.Teoh SK, Lex BW, Mendelson JH, Mello NK, Cochin J. Hyper-prolactinemia and macrocytosis in women with alcohol and polysubstance dependence. J Stud Alcohol. 1992;53:176–82. doi: 10.15288/jsa.1992.53.176. [DOI] [PubMed] [Google Scholar]
  • 106.Evans SM. The role of estradiol and progesterone in modulating the subjective effects of stimulants in humans. Exp Clin Psychopharmacol. 2007;15:418–26. doi: 10.1037/1064-1297.15.5.418. [DOI] [PubMed] [Google Scholar]
  • 107.Sinha R, Fox HC, Paliwal P, Hong KA, Morgan PT, Bergquist KL. Sex steroid hormones, stress response and drug craving in cocaine dependent women: implications for relapse susceptibility. Exp Clin Psychopharmacol. 2007;15:445–52. doi: 10.1037/1064-1297.15.5.445. [DOI] [PubMed] [Google Scholar]
  • 108.Del Rio G, Velardo A, Menozzi R, et al. Acute estradiol and progesterone administration reduced cardiovascular and catecholamine responses to mental stress in menopausal women. Neuroendocrinology. 1998;67:269–74. doi: 10.1159/000054322. [DOI] [PubMed] [Google Scholar]
  • 109.Frankenhaeuser M, Dunne E, Lundberg U. Sex differences in sympathetic adrenal medullary reactions induced by different stressors. Psychopharmacology. 1976;47:1–5. doi: 10.1007/BF00428693. [DOI] [PubMed] [Google Scholar]
  • 110.Frankenhaeuser M, von Wright MR, Collins A, von Wright J, Sedvall G, Swahn CG. Sex differences in psychoneuroendocrine reactions to examination stress. Psychosom Med. 1978;40:334–43. doi: 10.1097/00006842-197806000-00006. [DOI] [PubMed] [Google Scholar]
  • 111.Collins A, Frankenhaeuser M. Stress responses in male and female engineering students. J Human Stress. 1978;4:43–8. doi: 10.1080/0097840X.1978.9934986. [DOI] [PubMed] [Google Scholar]
  • 112.Jorgensen RS, Houston BK. Family history of hypertension, gender, and cardiovascular reactivity and stereotypy during stress. J Behav Med. 1981;4:175–89. doi: 10.1007/BF00844269. [DOI] [PubMed] [Google Scholar]
  • 113.Hastrup JL, Light KC. Sex differences in cardiovascular stress responses: modulation as a function of menstrual cycle phases. J Psychosom Res. 1984;28:475–83. doi: 10.1016/0022-3999(84)90081-3. [DOI] [PubMed] [Google Scholar]
  • 114.Frankenhaeuser M, Lundberg U, Rauste von Wright M, von Wright J, Sedvall G. Urinary monoamine metabolites as indices of mental stress in healthy males and females. Pharmacol Biochem Behav. 1986;24:1521–5. doi: 10.1016/0091-3057(86)90478-8. [DOI] [PubMed] [Google Scholar]
  • 115.Tersman Z, Collins A, Eneroth P. Cardiovascular responses to psychological and physiological stressors during the menstrual cycle. Psychosom Med. 1991;53:185–97. doi: 10.1097/00006842-199103000-00008. [DOI] [PubMed] [Google Scholar]
  • 116.Kirschbaum C, Wust S, Hellhammer D. Consistent sex differences in cortisol responses to psychological stress. Psychosom Med. 1992;54:648–57. doi: 10.1097/00006842-199211000-00004. [DOI] [PubMed] [Google Scholar]
  • 117.Allen MT, Stoney CM, Owens JF, Matthews KA. Hemodynamic adjustments to laboratory stress: the influence of gender and personality. Psychosom Med. 1993;55:505–17. doi: 10.1097/00006842-199311000-00006. [DOI] [PubMed] [Google Scholar]
  • 118.Kirschbaum C, Pirke KM, Hellhammer DH. Preliminary evidence for reduced cortisol responsivity to psychological stress in women using oral contraceptive medication. Psychoneuroendocrinology. 1995;20:509–14. doi: 10.1016/0306-4530(94)00078-o. [DOI] [PubMed] [Google Scholar]
  • 119.Kudielka BM, Hellhammer J, Hellhammer DH, et al. Sex differences in endocrine and psychological responses to psychosocial stress in healthy elderly subjects and the impact of a 2-week dehydroepiandrosterone treatment. J Clin Endocrinol Metab. 1998;83:1756–61. doi: 10.1210/jcem.83.5.4758. [DOI] [PubMed] [Google Scholar]
  • 120.Sinha R, Robinson J, O’Malley S. Stress response dampening: effects of gender and family history of alcoholism and anxiety disorders. 1998;137:311–20. doi: 10.1007/s002130050624. [DOI] [PubMed] [Google Scholar]
  • 121.Kirschbaum C, Kudielka BM, Gaab J, Schommer NC, Hellhammer DH. Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamuspituitary-adrenal axis. Psychosom Med. 1999;61:154–62. doi: 10.1097/00006842-199903000-00006. [DOI] [PubMed] [Google Scholar]
  • 122.Earle TL, Linden W, Weinberg J. Differential effects of harassment on cardiovascular and salivary cortisol stress reactivity and recovery in women and men. J Psychosom Res. 1999;46:125–41. doi: 10.1016/s0022-3999(98)00075-0. [DOI] [PubMed] [Google Scholar]
  • 123.Matthews KA, Gump BB, Owens JF. Chronic stress influences cardiovascular and neuroendocrine responses during acute stress and recovery, especially in men. Health Psychol. 2001;20:403–10. [PubMed] [Google Scholar]
  • 124.Seeman TE, Singer B, Wilkinson CW, McEwen B. Gender differences in age-related changes in HPA axis reactivity. Psychoneuroendocrinology. 2001;26:225–40. doi: 10.1016/s0306-4530(00)00043-3. [DOI] [PubMed] [Google Scholar]
  • 125.Stroud LR, Salovey P, Epel ES. Sex differences in stress responses: social rejection versus achievement stress. Biol Psychiatry. 2002;52:318–27. doi: 10.1016/s0006-3223(02)01333-1. [DOI] [PubMed] [Google Scholar]
  • 126.Traustadóttir T, Bosch PR, Matt KS. Gender differences in cardiovascular and hypothalamic-pituitary-adrenal axis responses to psychological stress in healthy older adult men and women. Stress. 2003;6:133–40. doi: 10.1080/1025389031000111302. [DOI] [PubMed] [Google Scholar]
  • 127.Zimmer C, Basler HD, Vedder H, Lautenbacher S. Sex differences in cortisol response to noxious stress. Clin J Pain. 2003;19:233–9. doi: 10.1097/00002508-200307000-00006. [DOI] [PubMed] [Google Scholar]
  • 128.Kudielka BM, Schommer NC, Hellhammer DH, Kirschbaum C. Acute HPA axis responses, heart rate, and mood changes to psychosocial stress (TSST) in humans at different times of day. Psychoneuroendocrinology. 2004;29:983–92. doi: 10.1016/j.psyneuen.2003.08.009. [DOI] [PubMed] [Google Scholar]
  • 129.Fox HC, Garcia M, Kemp K, Milivojevic V, Kreek MJ, Sinha R. Gender differences in cardiovascular and corticoadrenal response to stress and drug cues in cocaine dependent individuals. Psychopharmacology (Berl) 2006;185:348–57. doi: 10.1007/s00213-005-0303-1. [DOI] [PubMed] [Google Scholar]
  • 130.Back SE, Waldrop AE, Saladin ME, et al. Effects of gender and cigarette smoking on reactivity to psychological and pharmacological stress provocation. Psychoneuroendocrinology. 2008;33:560–8. doi: 10.1016/j.psyneuen.2008.01.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 131.Chaplin T, Hong K-I, Bergquist K, Sinha R. Gender differences in response to emotional stress: an assessment across subjective, behavioral, and physiological domains and relations to alcohol craving. Alcohol Clin Exp Res. 2008;32:1242–50. doi: 10.1111/j.1530-0277.2008.00679.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 132.Atkinson HC, Waddell BJ. Circadian variation in basal plasma corticosterone and adrenocorticotropin in the rat: sexual dimorphism and changes across the estrous cycle. Endocrinology. 1997;138:3842–8. doi: 10.1210/endo.138.9.5395. [DOI] [PubMed] [Google Scholar]
  • 133.Handa RJ, Burgess LH, Kerr JE, O’Keefe JA. Gonadal steroid hormone receptors and sex differences in the hypothalamopituitary-adrenal axis. Horm Behav. 1994;28:464–76. doi: 10.1006/hbeh.1994.1044. [DOI] [PubMed] [Google Scholar]
  • 134.Yoshimura S, Sakamoto S, Kudo H, Sassa S, Kumai A, Okamoto R. Sex-differences in adrenocortical responsiveness during development in rats. Steroids. 2003;68:439–45. doi: 10.1016/s0039-128x(03)00045-x. [DOI] [PubMed] [Google Scholar]
  • 135.Heinsbroek RP, van Haaren F, Feenstra MG, Boon P, van de Poll NE. Controllable and uncontrollable footshock and monoaminergic activity in the frontal cortex of male and female rats. Brain Res. 1991;14:247–55. doi: 10.1016/0006-8993(91)90939-s. [DOI] [PubMed] [Google Scholar]
  • 136.van Haaren F, Meyer ME. Sex differences in locomotor activity after acute and chronic cocaine administration. Pharmacol Biochem Behav. 1991;39:923–7. doi: 10.1016/0091-3057(91)90054-6. [DOI] [PubMed] [Google Scholar]
  • 137.Heinsbroek RP, van Haaren F, Feenstra MG, van Galen H, Boer G, van de Poll NE. Sex differences in the effects of inescapable footshock on central catecholaminergic and serotonergic activity. Pharmacol Biochem Behav. 1990;37:539–50. doi: 10.1016/0091-3057(90)90025-d. [DOI] [PubMed] [Google Scholar]
  • 138.Heinsbroek RP, Van Haaren F, Van de Poll NE, Steenbergen HL. Sex differences in the behavioral consequences of inescapable footshocks depend on time since shock. Physiol Behav. 1991;49:1257–63. doi: 10.1016/0031-9384(91)90360-z. [DOI] [PubMed] [Google Scholar]
  • 139.Kawakami SE, Quadros IM, Takahashi S, Suchecki D. Long maternal separation accelerates behavioural sensitization to ethanol in female, but not in male mice. Behav Brain Res. 2007;184:109–16. doi: 10.1016/j.bbr.2007.06.023. [DOI] [PubMed] [Google Scholar]
  • 140.Faraday MM, Elliott BM, Phillips JM, Grunberg NE. Adolescent and adult male rats differ in sensitivity to nicotine’s activity effects. Pharmacol Biochem Behav. 2003;74:917–31. doi: 10.1016/s0091-3057(03)00024-8. [DOI] [PubMed] [Google Scholar]
  • 141.Kraemer RR, Blair S, Kraemer GR, Castracane VD. Effects of treadmill running on plasma beta-endorphin, corticotropin, and cortisol levels in male and female 10K runners. Eur J Appl Physiol Occup Physiol. 1989;58:845–51. doi: 10.1007/BF02332217. [DOI] [PubMed] [Google Scholar]
  • 142.Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol. 2005;69:113–32. doi: 10.1016/j.biopsycho.2004.11.009. [DOI] [PubMed] [Google Scholar]
  • 143.Galard R, Gallart JM, Catalan R, Schwartz S, Arguello JM, Castellanos JM. Salivary cortisol levels and their correlation with plasma ACTH levels in depressed patients before and after the DST. Am J Psychiatry. 1991;148:505–8. doi: 10.1176/ajp.148.4.505. [DOI] [PubMed] [Google Scholar]
  • 144.Roelfsema F, Pincus SM, Veldhuis JD. Patients with Cushing’s disease secrete adrenocorticotropin and cortisol jointly more asynchronously than healthy subjects. J Clin Endocrinol Metab. 1998;83:688–92. doi: 10.1210/jcem.83.2.4570. [DOI] [PubMed] [Google Scholar]
  • 145.Kajantie E, Phillips DI. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology. 2006;31:151–78. doi: 10.1016/j.psyneuen.2005.07.002. [DOI] [PubMed] [Google Scholar]
  • 146.Horrocks PM, Jones AF, Ratcliffe WA, et al. Patterns of ACTH and cortisol pulsatility over twenty-four hours in normal males and females. Clin Endocrinol (Oxf) 1990;32:127–34. doi: 10.1111/j.1365-2265.1990.tb03758.x. [DOI] [PubMed] [Google Scholar]
  • 147.Roelfsema F, van den Berg G, Frolich M, Veldhuis JD, van Eijk A, Buurman MM, Etman BH. Sex-dependent alteration in cortisol response to endogenous adrenocorticotropin. J Clin Endocrinol Metab. 1992;77:234–40. doi: 10.1210/jcem.77.1.8392084. [DOI] [PubMed] [Google Scholar]
  • 148.Dorn LD, Burgess ES, Susman EJ, et al. Response to oCRH in depressed and nondepressed adolescents: does gender make a difference? J Am Acad Child Adolesc Psychiatry. 1996;35:764–73. doi: 10.1097/00004583-199606000-00016. [DOI] [PubMed] [Google Scholar]
  • 149.Fox HC, Sinha R. Gender differences in neurobiological response to stress and alcohol cues: implications for treatment and relapse. Paper presented at the annual meeting of the Research Society of Alcoholism; Chicago, IL. July; 2007. [Google Scholar]
  • 150.Ward AS, Haney M, Fischman MW, Foltin RW. Binge cocaine self-administration in humans: intravenous cocaine. Psychopharmacology (Berl) 1997;132:375–81. doi: 10.1007/s002130050358. [DOI] [PubMed] [Google Scholar]
  • 151.Wileyto EP, Patterson F, Niaura R, et al. Recurrent event analysis of lapse and recovery in a smoking cessation clinical trial using bupropion. Nicotine Tob Res. 2005;7:257–68. doi: 10.1080/14622200500055673. [DOI] [PubMed] [Google Scholar]
  • 152.Green JP, Lynn SJ, Montgomery GH. Gender-related differences in hypnosis-based treatments for smoking: a follow-up meta-analysis. Am J Clin Hypn. 2008;50:259–71. doi: 10.1080/00029157.2008.10401628. [DOI] [PubMed] [Google Scholar]
  • 153.O’Malley SS, Krishnan-Sarin S, Farren C, Sinha R, Kreek MJ. Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamopituitary-adrenocortical axis. Psychopharmacology (Berl) 2002;160:19–29. doi: 10.1007/s002130100919. [DOI] [PubMed] [Google Scholar]
  • 154.Breese GR, Chu K, Dayas CV, et al. Stress enhancement of craving during sobriety: a risk for relapse. Alcohol Clin Exp Res. 2005;29:185–95. doi: 10.1097/01.alc.0000153544.83656.3c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 155.Junghanns K, Tietz U, Dibbelt L, et al. Attenuated salivary cortisol secretion under cue exposure is associated with early relapse. Alcohol Alcohol. 2005;40:80–5. doi: 10.1093/alcalc/agh107. [DOI] [PubMed] [Google Scholar]
  • 156.Sorocco KH, Lovallo WR, Vincent AS, Collins FL. Blunted hypothalamic-pituitary-adrenocortical axis responsivity to stress in persons with a family history of alcoholism. Int J Psychophysiol. 2006;59:210–7. doi: 10.1016/j.ijpsycho.2005.10.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 157.Brebner J. Gender and emotions. Pers Individ Dif. 2003;34:387–94. [Google Scholar]
  • 158.Fischer AH, Mosquera PMR, van Vianen AEM, Manstead ASR. Gender and culture differences in emotion. Emotion. 2004;4:87–94. doi: 10.1037/1528-3542.4.1.87. [DOI] [PubMed] [Google Scholar]
  • 159.Fillmore KM, Golding JM, Leino EV. Patterns and trends in women’s and men’s drinking. In: Wilsnack RW, Wilsnack SC, editors. Gender and alcohol: individual and social perspectives. New Brunswick, NJ: Rutgers Center of Alcohol Studies; 1997. pp. 21–48. [Google Scholar]
  • 160.Reed BG. Drug misuse and dependency in women: the meaning and implications of being considered a special population or minority group. Int J Addict. 1985;20:13–62. doi: 10.3109/10826088509074828. [DOI] [PubMed] [Google Scholar]
  • 161.Bepko C. Disorders of power: women and addiction in the family. In: McGoldrick M, Anderson CM, Walsh F, editors. Women in families: a framework for family therapy. New York: Norton; 1991. pp. 406–26. [Google Scholar]
  • 162.Turnbull JE, Gomberg ES. The structure of drinking-related consequences in alcoholic women. Alcohol Clin Exp Res. 1991;15:29–38. doi: 10.1111/j.1530-0277.1991.tb00516.x. [DOI] [PubMed] [Google Scholar]
  • 163.Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC. Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry. 1997;54:313–21. doi: 10.1001/archpsyc.1997.01830160031005. [DOI] [PubMed] [Google Scholar]
  • 164.Rounsaville BJ, Anton SF, Carroll K, Budde D, Prusoff BA, Gawin F. Psychiatric diagnoses of treatment-seeking cocaine abusers. Arch Gen Psychiatry. 1991;48:43–51. doi: 10.1001/archpsyc.1991.01810250045005. [DOI] [PubMed] [Google Scholar]
  • 165.Young EA. The role of gonadal steroids in hypothalamic-pituitary-adrenal axis regulation. Crit Rev Neurobiol. 1995;9:371–81. [PubMed] [Google Scholar]
  • 166.Girdler SS, Klatzkin R. Neurosteroids in the context of stress: implications for depressive disorders. Pharmacol Ther. 2007;116:125–39. doi: 10.1016/j.pharmthera.2007.05.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 167.Moran MH, Goldberg M, Smith SS. Progesterone withdrawal. II: insensitivity to the sedative effects of a benzodiazepine. Brain Res. 1998;807:91–100. doi: 10.1016/s0006-8993(98)00781-1. [DOI] [PubMed] [Google Scholar]
  • 168.Smith SS, Gong QH, Li X, et al. Withdrawal from 3alpha-OH-5alpha-pregnan-20-One using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor alpha4 subunit in association with increased anxiety. J Neurosci. 1998;18:5275–84. doi: 10.1523/JNEUROSCI.18-14-05275.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 169.Gulinello M, Gong QH, Li X, Smith SS. Short-term exposure to a neuroactive steroid increases alpha4 GABA(A) receptor subunit levels in association with increased anxiety in the female rat. Brain Res. 2001;910:55–66. doi: 10.1016/s0006-8993(01)02565-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 170.Kauffman E, Dore MM, Nelson-Zlupko L. The role of women’s therapy groups in the treatment of chemical dependence. Am J Orthopsychiatry. 1995;65:355–63. doi: 10.1037/h0079657. [DOI] [PubMed] [Google Scholar]

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