Cocaine-dependent Women Research Articles

Neural correlates of oxytocin and cue reactivity in cocaine-dependent men and women with and without childhood trauma.

Women with cocaine use disorder have worse treatment outcomes compared with men. Sex differences in cocaine addiction may be driven by differences in neurobiology or stress reactivity. Oxytocin is a potential therapeutic for stress reduction in substance use disorders, but no studies have examined the effect of oxytocin on neural response to drug cues in individuals with cocaine use disorders or potential sex differences in this response. The goal of this study was to examine the effect of intranasal oxytocin on cocaine cue reactivity in cocaine dependence, modulated by gender and history of childhood trauma. Cocaine-dependent men with (n = 24) or without (n = 19) a history of childhood trauma and cocaine-dependent women with (n = 16) or without (n = 8) a history of childhood trauma completed an fMRI cocaine cue reactivity task under intranasal placebo or oxytocin (40 IU) on two different days. fMRI response was measured in the right amygdala and dorsomedial prefrontal cortex (DMPFC). In the DMPFC, oxytocin reduced fMRI response to cocaine cues across all subject groups. However, in the amygdala, only men with a history of childhood trauma showed a significantly reduced fMRI response to cocaine cues on oxytocin versus placebo, while women with a history of childhood trauma showed an enhanced amygdala response to cocaine cues following oxytocin administration. Cocaine-dependent subjects with no history of childhood trauma showed no effect of oxytocin on amygdala response. Oxytocin can reduce cue reactivity in cocaine dependence, but its effect is modified by sex and childhood trauma history. Whereas men with cocaine dependence may benefit from oxytocin administration, additional studies are needed to determine whether oxytocin can be an effective therapeutic for cocaine-dependent women.

Impact of endogenous progesterone on reactivity to yohimbine and cocaine cues in cocaine-dependent women

Background and objectiveData from clinical and preclinical models of relapse suggest that progesterone attenuates cocaine-seeking behavior. In a recent study, we found that cocaine-dependent women reported greater subjective responses to cues that were preceded by a stressor than cocaine-dependent men. The objective of this study was to examine the impact of endogenous progesterone on the subjective and endocrine responses to a drug-paired cue that was preceded by a stressor in cocaine-dependent women. MethodsCocaine-dependent women with low (<4ng/ml; n=16) and high (≥4ng/ml; n=9) plasma progesterone levels received either the alpha-2 adrenergic receptor antagonist yohimbine (21.6mg) or placebo before each of two cocaine-cue exposure sessions. Participants were tested under both conditions in a counterbalanced, double-blind fashion. Data were collected after study drug administration, immediately and at 5, 30, and 60min after the cue. ResultsThe anxiety response to the cue was differentially modified by progesterone levels under the two administration conditions (condition×progesterone level interaction, F1,23=9.8, p=0.005). Progesterone levels also modified the craving response to the cue differently under the placebo condition as compared to the yohimbine condition (condition×progesterone level interaction, F1,23=13.9, p=0.001). In both cases, high progesterone levels attenuated craving and anxiety response to the cue following yohimbine administration. There was no effect of progesterone levels on salivary cortisol or dehydroepiandrosterone under the placebo condition or under the yohimbine condition. ConclusionsThese preliminary data suggest that high levels of endogenous progesterone attenuate subjective responses to drug-cues that are preceded by a stressor. Importantly, these data support a growing literature demonstrating the protective effects of progesterone on the vulnerability to cocaine relapse in women.

Sex differences in guanfacine effects on stress-induced stroop performance in cocaine dependence

AimsChronic drug abuse leads to sex-specific changes in drug cue and stress physiologic and neuroendocrine reactivity as well as in neural responses to stress and cue-related challenges and in executive function such as inhibitory control, cognitive flexibility and self control. Importantly, these functions have been associated with high risk of relapse and treatment. Alpha-2 agonism may enhance inhibitory cognitive processes in the face of stress with sex-specific effects, however this has not been previously assessed in cocaine dependence. MethodForty inpatient treatment-seeking cocaine dependent individuals (13F/27M) were randomly assigned to receive either placebo or up to 3mgs of Guanfacine. Three laboratory sessions were conducted following 3–4 weeks of abstinence, where patients were exposed to three 10-min personalized guided imagery conditions (stress, drug cue, combined stress/cue), one per day, on consecutive days in a random, counterbalanced order. The Stroop task was administered at baseline and immediately following imagery exposure. ResultsGuanfacine treated women improved their performance on the Stroop task following exposure to all 3 imagery conditions compared with placebo women (p=0.02). This improvement in cognitive inhibitory performance was not observed in the men. ConclusionsEnhancing the ability to cognitively regulate in the face of stress, drug cues and combined stress and drug cue reactivity may be key targets for medications development in cocaine dependent women.

Effects of plasma pregnanolone levels on stress response, mood and drug craving in cocaine-dependent men and women

Effects of plasma pregnanolone levels on stress response, mood and drug craving in cocaine-dependent men and women

Impact of gender on corticotropin-releasing factor and noradrenergic sensitivity in cocaine use disorder.

Responses to stress may be important in understanding gender differences in substance use disorders and may also be a target for development of treatment interventions. A growing body of both preclinical and clinical research supports important underlying gender differences in the corticotropin-releasing factor (CRF) and noradrenergic systems, which may contribute to drug use. Preclinical models have demonstrated increased sensitivity of females to CRF and noradrenergic-induced drug reinstatement compared with males, and, consistent with these findings, human laboratory studies have demonstrated greater sensitivity to corticotropin-releasing hormone (CRH) and noradrenergic stimulation in cocaine-dependent women compared with men. Furthermore, neuroimaging studies have demonstrated increased neural response to stressful stimuli in cocaine-dependent women compared with men as well as showing significant sex differences in the sensitivity of brain regions responsible for regulating the response to CRH. Development of interventions targeting the noradrenergic system and stress response in drug-dependent individuals could have important clinical implications for both women and men. © 2016 Wiley Periodicals, Inc.

Distinct behavioral and immunoendocrine parameters during crack cocaine abstinence in women reporting childhood abuse and neglect

AimTo assess plasma levels of cortisol and cytokines between cocaine-dependent women with and without childhood maltreatment (CM) history during cocaine detoxification treatment. MethodWe assessed immunoendocrine and clinical parameters of 108 crack cocaine female users during 3 weeks of inpatient detoxification treatment, and 24 healthy women to obtain reference values. Women with (CM+, n=53) or without (CM-, n=55) CM history were identified answering the Childhood Trauma Questionnaire (CTQ). Blood samples and clinical assessment were collected before lunch during the first, second and third week post-treatment admission. Flow cytometry was used to assess TNF-α, IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-17A plasma levels and ELISA assay was used to measure plasma cortisol levels. ResultsAt baseline, lower Th1 and Th17-related cytokines levels and higher Th2 cytokines levels were observed in crack cocaine users compared with reference values. Cytokines levels of cocaine dependents gradually became closer to reference values along detoxification treatment. However, when CM+ and CM- groups were compared, increased levels of IL-6, IL-4 and TNF-α across time were observed in CM+ group only. Additionally, a Th1/Th2 immune imbalance was observed within CM+ group, which was negatively correlated with the severity of the crack withdrawal. Finally, loading trauma exposure severity, immunoendocrine and clinical parameters in factor analysis, we identified three clusters of observed variables during detoxification: (1) systemic immunity and trauma exposure, (2) pro-inflammatory immunity and (3) behavior ConclusionOur results suggest the existence of an immunological phenotype variant associated with CM exposure during crack cocaine detoxification of women.

Plasma interleukin-6 and executive function in crack cocaine-dependent women

AimThe aim of this study was to investigate the association between plasma interleukin 6 (IL-6) levels and executive function (EF) in crack cocaine-dependent women. Methods42 crack cocaine-dependent women (CRACK) and 52 healthy women (CONTROL) were evaluated with respect to EF using the Wisconsin Card Sorting Test (WCST). Plasma IL-6 levels were quantitatively determined using the multiplexed cytometric bead assay. ResultsThe CRACK group had poor performance on WSCT scores (Non-perseverative Errors and Percent Conceptual Level Responses) and higher plasma IL-6 levels when compared with the CONTROL group. Furthermore, IL-6 was correlated with worsening of several WCST sub-scores and a linear regression model showed that IL-6 levels predicted worse cognitive flexibility within the CRACK group independently of intelligence quotient and education. ConclusionsThe results of this study indicated that low performances in EF task are associated with higher IL-6 levels in crack cocaine-dependent women. These data bolster previous works that link the cognitive decline observed in drug addicts with mechanisms of inflammation.

Effects of yohimbine and drug cues on impulsivity and attention in cocaine-dependent men and women and sex-matched controls

BackgroundDeficits in executive function have been associated with risk for relapse. Data from previous studies suggest that relapse may be triggered by stress and drug-paired cues and that there are significant sex differences in the magnitude of these responses. The aim of this study was to examine the impact of the pharmacological stressor and alpha-2 adrenergic receptor antagonist yohimbine and cocaine cues on executive function in cocaine-dependent men and women. MethodsIn a double-blind placebo controlled cross-over study, cocaine-dependent men (n=12), cocaine-dependent women (n=27), control men (n=31) and control women (n=25) received either yohimbine or placebo prior to two cocaine cue exposure sessions. Participants performed the Connors’ Continuous Performance Test II prior to medication/placebo administration and immediately after each cue exposure session ResultsHealthy controls had a significant increase in commission errors under the yohimbine condition [RR (95% CI)=1.1 (1.0–1.3), χ21=2.0, p=0.050]. Cocaine-dependent individuals exhibited a significant decrease in omission errors under the yohimbine condition [RR (95% CI)=0.6 (0.4–0.8), χ21=8.6, p=0.003]. Cocaine-dependent women had more omission errors as compared to cocaine-dependent men regardless of treatment [RR (95% CI)=7.2 (3.6–14.7), χ21=30.1, p<0.001]. Cocaine-dependent women exhibited a slower hit reaction time as compared to cocaine-dependent men [Female 354±13 vs. Male 415±14; t89=2.6, p=0.012]. ConclusionsThese data add to a growing literature demonstrating significant sex differences in behaviors associated with relapse in cocaine-dependent individuals.

Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women

ObjectivesFluctuations in progesterone levels during the menstrual cycle have been shown to affect physiological and subjective effects of cocaine. Furthermore, our laboratory has demonstrated that following drug-cue exposure, cocaine dependent women with high levels of circulating progesterone display lower diastolic and systolic blood pressure responses and report lower levels of anxiety and drug craving compared to cocaine dependent women with low levels of progesterone. In the current study we examined the role of the progesterone derived neuroactive steroid allopregnanolone (ALLO) on stress arousal, inhibitory control and drug craving in cocaine dependent subjects. MethodsPlasma levels of ALLO were measured using GC/MS in 46 treatment-seeking cocaine dependent men and women on day 5 of a 7-day treatment regimen of micronized progesterone (15M/8F) (400mg/day) or placebo (14M/9F) administered in a double blind, randomized manner. As a control, levels of the testosterone derived neurosteroid androstanediol (ADIOL) were also measured. All subjects participated in laboratory sessions on days 5–7 of progesterone/placebo administration in which they were exposed to a series of 5-min personalized guided imagery of either a stressful situation, cocaine use or of a neutral setting and dependent variables including subjective craving, mood, Stroop task as a measure of inhibitory control performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO level and levels of dependent variables compared between ALLO groups. ResultsProgesterone relative to placebo significantly increased ALLO levels with no sex differences. There were no effects of micronized progesterone on the testosterone derived ADIOL. Individuals in the high versus the low ALLO group showed decreased levels of cortisol at baseline, and a higher cortisol response to stress; higher positive mood scores at baseline and improved Stroop performance in the drug-cue and stress conditions, and reduced cocaine craving across all imagery conditions. ConclusionsAs expected, cocaine dependent individuals administered progesterone showed significantly higher ALLO plasma levels. High levels of ALLO appeared to normalize basal and stress response levels of cortisol, decrease cocaine craving and also contribute to improvements in positive emotion and Stroop performance in response to stress and drug-cue exposures. These findings suggest that the neuroactive steroid ALLO plays a significant role in mediating the positive effects of progesterone on stress arousal, cognitive performance and drug craving in cocaine dependence.

Impact of yohimbine and cocaine-cues on executive function in cocaine-dependent men and women

Aims:Although abuse of prescription opioids (PO) has increased dramatically amongmany age groups in the US in recent years, the rate of abuse in teens is more than 2.6 times the rate in adults. Although science-based, interactive, drug-abuse prevention programs exist focused on preventing use of non-prescription drugs in youth, no science-based, interactive program for the prevention of PO abuse among youth exists. The aims of this project were to: (1) develop 3modules (i.e. Introduction,What are PO?,Misconception that PO are safe and non-addictive) of a web-based PO abuse prevention program for high school-aged youth; and (2) conduct feedback sessions with youth to obtain reactions to beta versions of modules. Methods: To achieve aim 1, we conducted 2 focus groups and 1 interview (audiotaped: ∼ 90min) with high school-aged youth (n=12) along a continuum of exposure to opioids to determine how to best present program information to this age group. To achieve aim 2, thirty youth participated in feedback sessions to assess program acceptability and utility. Results: Focus group results reveal that youth have some accurate information about PO, but also highlight misconceptions and lack of knowledge about PO. Feedback session results demonstrate thatparticipantknowledgeaboutPO increasedsignificantly following exposure to the program (66–100%) and misconceptions were corrected (68–95%), measured by pre-post knowledge tests. Participants also rated the program highly. We are currently developing sixadditionalweb-basedmodules (developmentdata collectedwill be reported at the2015 conference) andwill conduct a randomized, controlled trial to evaluate the effectiveness of the tool. Conclusions: Results reveal the utility of including potential programusers inprogramdevelopment, andhighlight thepotential effectiveness of the tool to increase knowledge about PO. Financial support: NIDA Grant #2R42DA023731.

Gender differences in stroop performance following guanfacine versus placebo in early abstinent cocaine-dependent men and women

Gender differences in stroop performance following guanfacine versus placebo in early abstinent cocaine-dependent men and women

Behavioral incentives to promote exercise compliance in cocaine-dependent women

long time to complete, making it difficult to examine whether behavioral or pharmacological manipulations could be used to decrease choices deemed impulsive. The rapid delay-discounting procedure used in this experiment was successful at obtaining orderly discounting functions in a relatively short period of time, making this procedure potentially useful for examining effects of behavioral and pharmacological treatments on delay discounting. Financial support: This research was supported by grant R01DA-027666 to KBF from the National Institute on Drug Abuse.

Progesterone treatment for cocaine-dependent women: A pilot treatment trial

Aims: This study evaluated the efficacy of oral micronized progesterone (PROG) for reducing cocaine use in women. Methods: A 10-week double-blind treatment trial compared PROG (up to 400mg/day, b.i.d.) to placebo (PBO) in cocaine-dependent women who were cocaine abstinent before randomization. Voucher incentives for attendance were used to enhance retention. Primary outcome measures included time to relapse, days of consecutive cocaine abstinence and retention. Response to a laboratory stressor, the Trier Social Stress Test (TSST) and treatment outcome was also explored. Results: Out of 227 women assessed, 25 women entered the trial, with 10 stratified to the PBOGroup and 11 to the PROGGroup. Thirteen women (62%) completed the entire 10-week trial. Five patients (2 in the PROG group and 3 in the PBO group) did not relapse, i.e., remained cocaine abstinent, during the trial. Two other women, one in each group, also did not relapse, but did not complete the trial. For the remainingwomen, themean number of days to relapse was 2.0 for the PROG group and 2.3 for the PBO group (p>0.05). Themean number of consecutive days of abstinence was 7.5 for the PROG group and 9.0 days for the PBO group (p>0.05). Among the 14 women who completed the TSST before randomization, increases in heart rate (r=−.33), anxiety scores (r=−.37) and cocaine craving (r=−.34) in response to stress were negatively correlated with the percentage of cocaine negative urines. Conclusions: PROG was well tolerated, but due to the small sample size it was not possible to adequately determine if PROG may be an effective treatment for cocaine-dependent women. Although cocaine-abstinence rates were low, they could be potentially improved using voucher incentives contingent on cocaine abstinence. Lastly, the preliminary findings showing that increased stress reactivity was related to low rates of cocaine abstinence suggest that stress-reduction techniques could improve treatment outcome. Financial support: NIDA grants RO1 DA022218 (SME), K24 DA029647 (FRL) and KO1 DA022282 (SCR). Medication was provided by the Women’s International Pharmacy.

Hypoactive bold response to general emotional stimuli among cocaine-dependent women

Hypoactive bold response to general emotional stimuli among cocaine-dependent women

Effects of plasma allopregnanolone levels on drug craving in cocaine-dependent men and women

Effects of plasma allopregnanolone levels on drug craving in cocaine-dependent men and women

Multisite, randomized, double-blind, placebo-controlled pilot clinical trial to evaluate the efficacy of buspirone as a relapse-prevention treatment for cocaine dependence.

To evaluate the potential efficacy of buspirone as a relapse-prevention treatment for cocaine dependence. A randomized, double-blind, placebo-controlled, 16-week pilot trial was conducted at 6 clinical sites between August 2012 and June 2013. Adult crack cocaine users meeting DSM-IV-TR criteria for current cocaine dependence who were scheduled to be in inpatient/residential substance use disorder (SUD) treatment for 12-19 days when randomized and planning to enroll in local outpatient treatment through the end of the active treatment phase were randomized to buspirone titrated to 60 mg/d (n = 35) or placebo (n = 27). All participants received psychosocial treatment as usually provided by the SUD treatment programs in which they were enrolled. Outcome measures included maximum days of continuous cocaine abstinence (primary), proportion of cocaine use days, and days to first cocaine use during the outpatient treatment phase (study weeks 4-15) as assessed by self-report and urine drug screens. There were no significant treatment effects on maximum continuous days of cocaine abstinence or days to first cocaine use. In the female participants (n = 23), there was a significant treatment-by-time interaction effect (χ²₁ = 15.26, P < .0001), reflecting an increase in cocaine use by those receiving buspirone, relative to placebo, early in the outpatient treatment phase. A similar effect was not detected in the male participants (n = 39; χ²₁ = 0.14, P = .70). The results suggest that buspirone is unlikely to have a beneficial effect on preventing relapse to cocaine use and that buspirone for cocaine-dependent women may worsen their cocaine use outcomes. ClinicalTrials.gov identifier: NCT01641159.

Yohimbine administration and cue-reactivity in cocaine-dependent individuals.

Preclinical studies suggest that stress potentiates cue-induced cocaine seeking and that this effect is more pronounced in females. These findings have not been characterized in clinical populations. The objectives of this study were to examine the impact a pharmacological stressor, alpha-2 adrenergic receptor antagonist yohimbine, on the subjective, endocrine, and physiologic responses to drug-paired cues cocaine-dependent men and women. In a double-blind placebo-controlled cross-over study, cocaine-dependent men (n = 32), cocaine-dependent women (n = 30), control men (n = 32), and control women (n = 25) received either yohimbine or placebo prior to two cocaine cue exposure sessions. Yohimbine increased ratings of anxiety both before (p < 0.001) and after (p = 0.035) cues, and the post-cue increase in anxiety was more pronounced in women (p = 0.001). Yohimbine also significantly increased craving, compared with placebo (p < 0.05), following the cue presentation, and this effect was greater in women than men (gender by treatment interaction; p = 0.006). Yohimbine also increased salivary cortisol (p < 0.001) and dehydroepiandrosterone (p = 0.003) levels, regardless of diagnostic group. Women had a significantly greater heart rate response following yohimbine as compared with men (p < 0.001). Stress may increase the salience of cocaine cues for cocaine-dependent women as compared with men. This suggests gender differences in vulnerability to craving and relapse under stressful conditions.

Early life stress and tumor necrosis factor superfamily in crack cocaine withdrawal

BackgroundBoth early life stress (ELS) and substance abuse, especially cocaine, have robust effects on the inflammatory system. Considering the role of the tumor necrosis factor system in inflammatory signaling and its association with ELS, the aim of the study was to compare plasma levels of TNF-alpha, its soluble receptors and ligands during early abstinence of crack cocaine. MethodsThis study included 24 crack cocaine-dependent women with (CRACK-ELS) and 20 without (CRACK) a history of ELS. A healthy control group (HC), containing 25 participants, was included to provide reference values. The Childhood Trauma Questionnaire (CTQ) retrospectively assessed childhood maltreatment history of patients. Plasma levels of TNF-alpha, TNF-related weak inducer of apoptosis (TWEAK), TNF-related apoptosis-inducing ligand (TRAIL), soluble receptors TNFRI (sTNFRI) and TNFRII (sTNFRII) were assessed on the 18th day of treatment. ResultsThe CRACK-ELS group had higher TNF-alpha and lower TWEAK levels compared to the CRACK and HC groups. sTNFRII was increased, but only in comparison with the crack cocaine group and the controls. TRAIL levels were slightly higher in the CRACK-ELS group, while no differences were found for sTNFRI levels. Also, TNF-alpha plasma level was positively predicted by abstinence severity and childhood maltreatment severity, and TWEAK was negatively predicted by childhood maltreatment severity. ConclusionsThis is the first study to evaluate the newly secreted tumor necrosis factor superfamily ligands, TWEAK and TRAIL, during crack cocaine abstinence, supporting the association between early life stress and peripheral pro-inflammatory levels.

EPA-1366 – Gender differences in cocaine-dependent patients

Introduction Cocaine dependence disorder has been widely described. However, differences due to gender remain unknown. Aim To compare clinical gender differences in a large sample of cocaine-dependent patients. Methods We performed a cross-sectional, observational study in 902 patients (35.47 yo, 21.3% women) with a cocaine dependence according DSM-IV criteria, seeking treatment during 2005 to 2013. Sociodemographic and clinical variables were collected The SCID-I, SCID–II, BIS and a structured interview about cocaine-induced psychosis were performed. Simple descriptive statistics were carried out for demographic and clinical data. Bivariate analysis was made to compare the main variables by sex using SPSSvs18.0. Results No differences in age of dependence onset, other clinical variables or cocaine-induced psychosis were detected. However, less cocaine used in the last month (2.12 vs 3.37g) (p Conclusions Sedative dependence and anxiety disorders should be investigated in cocaine-dependent women in order to treat these conditions. Surprisingly high impulsivity level was detected and could moderate cocaine consumption. However, no difference have been found previously in studies about gender differences in cocaine-dependent patients, so this finding should be confirm in new studies.

Childhood neglect and increased withdrawal and depressive severity in crack cocaine users during early abstinence

Studies have shown that environmental factors, such as exposure to childhood maltreatment, might shift the course of addiction. Little is known, however, about whether childhood physical neglect (PN) influences the severity of withdrawal and depressive symptoms during the detoxification period. This is a 3 weeks follow-up study. The participants were divided into 2 groups: those with a history of PN (PN+) (n=32) and those without a history of PN (PN−) (n=48). Clinical variables were assessed with the SCID-I, BDI-II, Childhood Trauma Questionnaire, Addiction Severity Index and Cocaine Selective Severity Assessment. Depressive symptom assessments were repeated at three time points. Withdrawal symptom assessments were repeated at five different points following detoxification. A repeated measures analysis of covariance indicated that the PN+ group exhibited a significantly lower reduction in the severity of withdrawal symptoms compared to the PN− group (p<0.05). Post hoc analyses showed that after 12 days of treatment, the severity of withdrawal symptoms in the PN+ group did not decrease in the same level as was observed in the PN− group. Moreover, a strong correlation was found between the severity of depression and the intensity of the abstinence symptoms during treatment. Patients who reported more depressive symptoms also exhibited more severe withdrawal symptoms. The ASI-6 indicated higher severity problems related to alcohol and psychiatric disorders in the PN+ groups. Our data support the role of childhood PN in the contingencies of the detoxification process of crack cocaine-dependent women.