The effects of simultaneous alcohol and cannabis use on subjective drug effects: A narrative review across methodologies.

Over 75% of young adults who use cannabis also report drinking alcohol, leading to increased risks that include impaired cognition, substance use disorders, and more heavy and frequent substance use. Studies suggest that subjective responses to either alcohol or cannabis can serve as a valuable indicator for identifying individuals at risk of prolonged substance use and use disorder. While laboratory studies show additive effects when alcohol and cannabis are used together, the impact of co-using these substances, specifically with respect to cannabidiol, on an individual's subjective experience remains unclear. This narrative review explores the effects of simultaneous alcohol and cannabis (SAM) use on subjective drug effects, drawing from qualitative research, laboratory experiments, and naturalistic studies. Experimental findings are inconsistent regarding the combined effects of alcohol and cannabis, likely influenced by factors such as dosage, method of administration, and individual substance use histories. Similarly, findings from qualitative and naturalistic studies are mixed regarding subjective drug effects following SAM use. These discrepancies may be due to recall biases, variations in assessment methods, and the measurement in real-world contexts of patterns of SAM use and related experiences. Overall, this narrative review highlights the need for more comprehensive research to understand more fully subjective drug effects of SAM use in diverse populations and settings, emphasizing the importance of frequent and nuanced assessment of SAM use and subjective responses in naturalistic settings.

Substance use patterns, quantities, and associated risk factors in women with polysubstance misuse.

Polysubstance use (PSU), the use of two or more substances proximally, is highly prevalent and has amplified the risk for morbidity and mortality. However, PSU patterns and associated risk factors are not well characterized. This may be especially relevant to women who are known to be vulnerable to stress/trauma, craving, pain, and anxious and depressive symptoms as associated risk factors for PSU. A cross-sectional observational study was conducted to characterize substance use patterns in women who regularly used cocaine, opioids, marijuana, alcohol, benzodiazepines and/or nicotine and were being assessed for a placebo-controlled study of guanfacine treatment (n = 94; ages 19-65). Data on stress/traumatic life events, drug cravings for each substance, pain ratings, and anxiety and depressive symptoms were also obtained using standardized well-validated surveys. High use per day of two or more drugs was observed (72.7% ± 33.3%) and opioid amounts were high relative to other drug amounts (p's < 0.001). Notably, higher stress/trauma events and higher cravings are each associated with cumulative PSU days, amounts and probability of an individual PSU day (p's < 0.02). This remained when PSU versus single substance use was compared. Pain, anxiety and depressive symptoms were not associated with PSU metrics. These findings characterize specific patterns of PSU in women and show that average drug craving and stress/trauma events are associated with PSU. Interventions that focus on stress/trauma and craving management could be of benefit in reducing PSU risk in women.

Mindfulness-oriented recovery enhancement in opioid use disorder: Extended emotional regulation and neural effects and immediate effects of guided meditation in a pilot sample.

OBJECTIVE: Mindfulness-Oriented Recovery Enhancement (MORE) is an efficacious intervention to aid recovery from substance use disorder. This study in a pilot sample of individuals in treatment for opioid use disorder (OUD) characterizes longer-term changes after the MORE intervention and immediate effects of a brief MORE guided meditation session. DESIGN: Twelve female participants in residential treatment for OUD completed an 8-week MORE intervention. Participants completed two sessions: one before and one after the 8-week MORE intervention. Each session included an emotional regulation questionnaire outside an MRI scanner first and then a 10-minute guided MORE meditation inside the scanner during which functional magnetic resonance imaging (fMRI) data were collected. Emotional regulation was measured after 8-weeks of MORE intervention. In addition, functional connectivity (i.e. correlated fMRI signal) between regions in a hypothesized affect regulation network was measured during the meditation state to assess change in brain network function due to 8-weeks of MORE. For each 10-min guided meditation, we also assessed their mood and opioid craving. RESULTS: Nine participants completed all measurements. Participants' emotional regulation difficulty significantly decreased after 8-weeks of MORE intervention. Furthermore, after 8-weeks of MORE, there was significantly increased connectivity between left ventromedial prefrontal cortex and left amygdala and between left ventrolateral prefrontal cortex and left nucleus accumbens captured during a meditation state. In both sessions, positive mood significantly increased after 10-min of guided mediation, however opioid craving was not significantly influenced. CONCLUSIONS: This pilot study characterizes potential benefits of 8-week MORE intervention in improving emotional regulation difficulty and brain function. A 10-min guided MORE meditation may immediately improve mood, with potential to reduce acute stress- or cue-provoked craving. These results warrant future studies with larger sample size.

Therapeutics for Substance-Using Women: The Need to Elucidate Sex-Specific Targets for Better-Tailored Treatments.

In the last decade, alcohol consumption in the US has risen by 84% in women compared with 35% in men. Furthermore, research has shown that sex- and gender-related differences may disadvantage women in terms of developing a range of psychological, cognitive, and medical problems considerably earlier in their drinking history than men, and despite consuming a similar quantity of substances. While this "telescoping" process has been acknowledged in the literature, a concomitant understanding of the underlying biobehavioral mechanisms, and an increase in the development of specific treatments tailored to women, has not occurred. In the current chapter we focus on understanding why the need for personalized, sex-specific medications is imperative, and highlight some of the potential sex-specific gonadal and stress-related adaptations underpinning the accelerated progress from controlled to compulsive drug and alcohol seeking in women. We additionally discuss the efficacy of these mechanisms as novel targets for medications development, using exogenous progesterone and guanfacine as examples. Finally, we assess some of the challenges faced and progress made in terms of developing innovative medications in women. We suggest that agents such as exogenous progesterone and adrenergic medications, such as guanfacine, may provide some efficacy in terms of attenuating stress-induced craving for several substances, as well as improving the ability to emotionally regulate in the face of stress, preferentially in women. However, to fully leverage the potential of these therapeutics in substance-using women, greater focus needs to the placed on reducing barriers to treatment and research by encouraging women into clinical trials.

Hypothalamic-pituitary-adrenal and autonomic response to psychological stress in abstinent alcohol use disorder individuals with and without depressive symptomatology.

BACKGROUND: Stress and depression have each been associated with relapse risk. In clinical practice, chronic alcohol use is often accompanied by poor emotional and self-regulatory processes. Tonic and phasic changes in stress responsivity impact an individual's relapse risk to alcohol. A further complicating factor is the pervasive coexistence of depressive symptoms in those with Alcohol Use Disorder (AUD), where the contribution of depressive symptomatology to these processes is not well understood. Individuals with AUD (AD) (21 with and 12 without sub-clinical depressive symptoms) and 37 social drinking controls (16 with and 21 without sub-clinical depressive symptoms) as part of a more extensive study (Fox et al., 2019). All participants were exposed to two 5-min personalized guided imagery conditions (stress and neutral) in a randomized and counterbalanced order across consecutive days. Alcohol craving, negative mood, Stroop performance, and plasma measures (cortisol, adrenocorticotrophic hormone, and salivary alpha-amylase) were collected before and after imagery exposure. RESULTS: Elevations in autonomic response (heart rate) to imagery (stress and neutral) were observed as a function of drinking (in both depressed and non-depressed individuals with alcohol use disorder compared with depressed and non-depressed social drinkers). Conversely, suppressed cortisol following stress was observed as a function of depressive symptomatology across both drinking groups. Individuals with comorbid AD and depressive symptoms demonstrated attenuated Adrenocorticotropic Hormone and poor Stroop performance compared with the other groups, indicating an interactive effect between drinking and depression on pituitary and inhibitory systems. CONCLUSION: Sub-clinical depressive pathophysiology may be distinct from drinking severity and may alter relapse-related stress adaptations during protracted abstinence from alcohol.

Cognitive Test Scores and Progressive Cognitive Decline in the Aberdeen 1921 and 1936 Birth Cohorts.

The Aberdeen birth cohorts of 1921 and 1936 (ABC21 and ABC36) were subjected to IQ tests in 1932 or 1947 when they were aged about 11y. They were recruited between 1997-2001 among cognitively healthy community residents and comprehensively phenotyped in a long-term study of brain aging and health up to 2017. Here, we report associations between baseline cognitive test scores and long-term cognitive outcomes. On recruitment, significant sex differences within and between the ABC21 and ABC36 cohorts supported advantages in verbal ability and learning among the ABC36 women that were not significant in ABC21. Comorbid physical disorders were self-reported in both ABC21 and ABC36 but did not contribute to differences in terms of performance in cognitive tests. When used alone without other criteria, cognitive tests scores which fell below the -1.5 SD criterion for tests of progressive matrices, namely verbal learning, digit symbol and block design, did not support the concept that Mild Cognitive Impairment (MCI) is a stable class of acquired loss of function with significant links to the later emergence of a clinical dementia syndrome. This is consistent with many previous reports. Furthermore, because childhood IQ-type data were available, we showed that a lower cognitive performance at about 64 or 78 y than that predicted by IQ at 11 ± 0.5 y did not improve the prediction of progress to MCI or greater cognitive loss. We used binary logistic regression to explore how MCI might contribute to the prediction of later progress to a clinical dementia syndrome. In a fully adjusted model using ABC21 data, we found that non-amnestic MCI, along with factors such as female sex and depressive symptoms, contributed to the prediction of later dementia. A comparable model using ABC36 data did not do so. We propose that (1) MCI criteria restricted to cognitive test scores do not improve the temporal stability of MCI classifications; (2) pathways towards dementia may differ according to age at dementia onset and (3) the concept of MCI may require measures (not captured here) that underly self-reported subjective age-related cognitive decline.

Moderation of Prazosin's Efficacy by Alcohol Withdrawal Symptoms.

OBJECTIVE: Alcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated secondary outcomes of alcohol craving and mood, anxiety, and sleep disturbances, which are predictive of poor treatment outcomes. The authors examined whether alcohol withdrawal symptoms moderate the efficacy of prazosin in reducing alcohol intake and associated secondary outcomes. METHODS: A 12-week, double-blind, randomized, controlled proof-of-concept trial of prazosin (16 mg/day, with a 2-week titration) was conducted in community-recruited adults with current alcohol dependence (N=100) with varying levels of alcohol withdrawal symptoms assessed at treatment entry. Primary outcomes were daily self-reported drinking days and heavy drinking days, and secondary outcomes were average drinks/day and mood, anxiety, craving, and sleep quality ratings. RESULTS: Modified intent-to-treat analyses indicated a significant interaction of alcohol withdrawal symptom score by treatment by full-dose treatment period (weeks 3-12) for drinking days, heavy drinking days, and average drinks/day. By week 12, participants with high alcohol withdrawal symptoms on prazosin reported 7.07% heavy drinking days and 27.46% drinking days, while those on placebo had 35.58% heavy drinking days and 58.47% drinking days (heavy drinking days: odds ratio=0.14, 95% CI=0.058, 0.333; drinking days: odds ratio=0.265, 95% CI=0.146, 0.481). No such benefit of prazosin was observed in those reporting low or no alcohol withdrawal symptoms. Individuals with high alcohol withdrawal symptoms on prazosin compared with placebo also showed significantly improved anxiety, depression, and alcohol craving over the course of the trial. CONCLUSIONS: The findings indicate that alcohol withdrawal symptoms are a significant moderator of prazosin treatment response for alcohol use outcomes and for associated symptoms of alcohol craving, anxiety, and mood symptoms. These data support further evaluation of alcohol withdrawal symptoms as a prognostic indicator of prazosin's efficacy in the treatment of AUD.

Effects of Prazosin on Provoked Alcohol Craving and Autonomic and Neuroendocrine Response to Stress in Alcohol Use Disorder.

BACKGROUND: Chronic alcohol use results in changes to stress biology and autonomic arousal contributing to acute alcohol withdrawal symptoms, neuroendocrine tolerance of the hypothalamic-pituitary-adrenal axis responses, high stress-induced craving, and risk of alcohol relapse. Thus, stress coping and recovery from alcohol during early abstinence may be jeopardized by such stress system dysfunction. Significant preclinical evidence suggests that noradrenergic disruption may contribute to these alcohol-related stress arousal changes and that alpha-1 adrenergic antagonists, such as prazosin, may normalize these stress system adaptations and reduce alcohol intake. Thus, we hypothesized that prazosin would reduce stress-induced craving and improve neuroendocrine and autonomic response to stress and alcohol cue exposure during early abstinence. We secondarily also assessed the role of lifetime anxiety disorders on these prazosin effects. METHODS: Forty inpatient treatment-seeking alcohol-dependent individuals were randomly assigned to receive placebo (n = 18) or 16 mg/d, T.I.D., prazosin (n = 22) in a double-blind manner, titrated over 2 weeks. In weeks 3 to 4 after achieving full dose, patients were exposed to 3 5-minute personalized guided imagery conditions (stress cue, alcohol cue, neutral/relaxing cue), on 3 consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, heart rate, cortisol, and adrenocorticotropic hormone (ACTH) levels were assessed at baseline, following imagery and at repeated recovery timepoints. RESULTS: Prazosin reduced stress cue-induced alcohol craving (p < 0.05) and stress- and alcohol cue-induced anxiety (p < 0.05) and increased heart rate responses in all imagery conditions (p < 0.05). Prazosin lowered basal cortisol and ACTH (p's < 0.05) and attenuated stress cue-induced rises in cortisol (p < 0.05) versus placebo. Finally, in those without lifetime anxiety disorder, the placebo group showed stress- and alcohol cue-induced increases in cortisol (p's < 0.05), while the prazosin group did not. CONCLUSIONS: Prazosin may attenuate stress cue-induced alcohol craving and anxiety during early abstinence while improving adrenergic and stress system function, effects which are independent of a history of lifetime anxiety disorders.

Stress-related suppression of peripheral cytokines predicts future relapse in alcohol-dependent individuals with and without subclinical depression.

Chronic alcohol abuse and depressive symptoms are both associated with peripheral cytokine changes. Despite this, cytokine adaptations have not been assessed in co-morbid populations or prospectively as predictors of relapse. We examine cytokine responses to stress in alcohol-dependent individuals and social drinkers, both with and without subclinical depression. We also examine the potential link between cytokine adaptations in response to stress and prospective alcohol relapse risk. Thirty-three, alcohol-dependent individuals (21 with and 12 without high depressive symptoms) and 37 controls (16 with and 21 without high depressive symptoms) were exposed to two 5-minute personalized guided imagery conditions (stress and neutral) across consecutive days in a randomized and counterbalanced order. Alcohol craving and serum measures of tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1ra) were collected prior to and following imagery exposure. Following treatment discharge, follow-up interviews were conducted over 90 days to assess relapse. Dampened IL-1ra and IL-6 in response to stress was observed as a function of alcohol dependence and not moderated by depressive symptoms. Lower levels of IL-6 following stress also predicted greater drinking days following treatment. Conversely, high depressive symptomatology was associated solely with pro-inflammatory adaptations. Stress-related suppression of TNFα predicted drinking severity only in alcohol-dependent individuals with subclinical depression, and suppressed TNFR1 following stress was only seen in individuals with subclinical depression. Stress-induced suppression of pro-inflammatory TNF markers may indicate a risk factor for alcohol-dependent individuals with co-occurring depressive symptoms.

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

AIMS: Chronic 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. METHOD: Forty 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. RESULTS: Guanfacine 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. CONCLUSIONS: Enhancing 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.

Peripheral immune system suppression in early abstinent alcohol-dependent individuals: Links to stress and cue-related craving.

BACKGROUND: Peripheral immune system cytokines may play an integral role in the underlying sensitized stress response and alcohol craving during early alcohol withdrawal. To date, the nature of these immune changes during early abstinence have not been examined. METHODS: A total of 39 early abstinent, treatment-seeking, alcohol-dependent individuals and 46 socially drinking controls were exposed to three guided imageries: stress, alcohol cue and neutral. These were presented randomly across consecutive days. Plasma measures of tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-10 (IL-10), were collected at baseline, immediately after imagery and at various recovery time-points. Ratings of alcohol craving, negative mood and anxiety were also obtained at the same time-points. RESULTS: The alcohol group demonstrated decreased basal IL-10 compared with controls particularly following exposure to alcohol cue. They also showed a dampened TNFα and TNFR1 response to stress and cue, respectively, and a generalized suppression of IL-6. In the alcohol group, these immune system adaptations occurred alongside significant elevations in anxiety, negative mood and alcohol craving. CONCLUSIONS: Findings demonstrate that broad immunosuppression is still observed in alcohol-dependent individuals after 3 weeks of abstinence and may be linked to motivation for alcohol.

Recreational 3,4-methylenedioxymethamphetamine or 'ecstasy': Current perspective and future research prospects.

AIMS: The purpose of this article is to debate current understandings about the psychobiological effects of recreational 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'), and recommend theoretically-driven topics for future research. METHODS: Recent empirical findings, especially those from novel topic areas were reviewed. Potential causes for the high variance often found in group findings were also examined. RESULTS AND CONCLUSIONS: The first empirical reports into psychobiological and psychiatric aspects from the early 1990s concluded that regular users demonstrated some selective psychobiological deficits, for instance worse declarative memory, or heightened depression. More recent research has covered a far wider range of psychobiological functions, and deficits have emerged in aspects of vision, higher cognitive skill, neurohormonal functioning, and foetal developmental outcomes. However, variance levels are often high, indicating that while some recreational users develop problems, others are less affected. Potential reasons for this high variance are debated. An explanatory model based on multi-factorial causation is then proposed. FUTURE DIRECTIONS: A number of theoretically driven research topics are suggested, in order to empirically investigate the potential causes for these diverse psychobiological deficits. Future neuroimaging studies should study the practical implications of any serotonergic and/or neurohormonal changes, using a wide range of functional measures.

Peripheral Immune System Adaptations and Motivation for Alcohol in Non-Dependent Problem Drinkers.

BACKGROUND: Increasing evidence suggests that levels of pro-inflammatory and anti-inflammatory cytokines are dysfunctional in alcohol dependence. Moreover, some initial findings demonstrate that these adaptations in peripheral inflammation may contribute to motivation for alcohol and problem drinking via possible direct effects or the indirect effects of stress responsivity. Importantly, the role of pro-inflammatory and anti-inflammatory cytokines in the progression from healthy to problem drinking is not well understood. The aim of this study was to assess whether alcohol-related peripheral immune system changes affect stress and alcohol cue-induced craving and anxiety and behavioral alcohol motivation and intake in the laboratory among problem drinkers compared with socially drinking controls. METHODS: Twenty-six problem drinkers and 38 moderate, social drinkers participated in a laboratory challenge procedure during which they were exposed to 3 personalized 5-minute imagery conditions (stress [S], relaxing [R], and alcohol cue [C]), followed by the "alcohol taste test" (ATT) as a measure of implicit alcohol motivation and intake, presented across 3 consecutive days, 1 per day in a randomized and counterbalanced order. Measures of tumor necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), alcohol craving, and anxiety were assessed at baseline, immediately following imagery exposure and at discreet beer cue presentation in the ATT. RESULTS: Compared with moderate drinkers, problem drinkers demonstrated tonic attenuation of IL-6 and IL-1ra. In problem drinkers, these changes also accompanied elevated levels of stress- and cue-induced alcohol craving and anxiety and were predictive of provoked alcohol craving, behavioral alcohol motivation and intake, and severity of problem drinking. CONCLUSIONS: Current findings indicate that selective immunosuppression in problem drinkers may play a key role in motivation for alcohol intake.

Cerebral correlates of cognitive reserve.

Cognitive reserve is a hypothetical concept introduced to explain discrepancies between severity of clinical dementia syndromes and the extent of dementia pathology. We examined cognitive reserve in a research programme that followed up a non-clinical sample born in 1921 or 1936 and IQ-tested age 11 years in 1932 or 1947. Structural MRI exams were acquired in about 50% of the sample from whom a subsample were recruited into an additional fMRI study. Here, we summarise findings from seven inter-related studies. These support an understanding of cognitive reserve as a balance between positive life course activity-driven experiences and the negative effects of brain pathologies including cerebrovascular disease and total and regional brain volume loss. Hypothesised structural equation models illustrate the relative causal effects of these positive and negative contributions. Cognitive reserve is considered in the context of choice of interventions to prevent dementia and the opposing effects of cerebrovascular disease and Alzheimer like brain appearances.

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

OBJECTIVES: Fluctuations 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. METHODS: Plasma 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. RESULTS: Progesterone 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. CONCLUSIONS: As 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.

Effects of endogenous and exogenous progesterone on emotional intelligence in cocaine-dependent men and women who also abuse alcohol.

OBJECTIVE: As sex differences in substance dependence may impinge upon the perception and regulation of emotion, we assess emotional intelligence (EI) as a function of gender, menstrual cycle (MC) phase and hormonal changes in early abstinent cocaine-dependent individuals who abuse alcohol (CDA). METHODS: Study 1: The Mayer, Salovey, and Caruso Emotional Intelligence Test (MSCEIT) was administered to 98 CDA (55 M/43 F) and 56 healthy (28 M/28 F) individuals. Performance in women was also assessed by MC phase. Study 2: The MSCEIT was administered to 28 CDA (19 M/9 F) who received exogenous progesterone (400 mg/day) versus placebo for 7 days (study 2). RESULTS: Study 1: Healthy females were better than healthy males at facilitating thought and managing emotions. This gender discrepancy was not observed in the CDA group. Additionally, all women in the high compared with the low progesterone phase of their MC were better at managing their emotions. Study 2: Exogenous progesterone improved ability to facilitate thought in both males and females. CONCLUSIONS: CDA women may be vulnerable to difficulties managing and regulating emotions. Gonadal hormones may contribute to this gender effect, as increases in both endogenous and exogenous progesterone improved selective aspects of EI.

Sex differences in guanfacine effects on drug craving and stress arousal in cocaine-dependent individuals.

Currently, no FDA-approved medication exists for the treatment of cocaine use disorder. Furthermore, as women become increasingly more at risk for the consequences of cocaine addiction, the need to establish better-tailored treatment medications is paramount. We examine the effects of the alpha2 adrenergic agonist, guanfacine HCl, on responses to stress and drug cue in a group of cocaine-dependent men and women who also abuse alcohol and nicotine. Forty early abstinent treatment-seeking cocaine-dependent males and females were randomly assigned to receive either daily placebo (12 M/7 F) or guanfacine (2 or 3 mg) (15 M/6 F) for 3 weeks. In week 4, they participated in a laboratory experiment and were exposed to three 10-min guided imagery conditions (stress/stress, cue/cue, and stress/cue), one per day, consecutively in a random, counterbalanced order. Craving, negative emotion, anxiety, and cardiovascular function were assessed at baseline, immediately following imagery exposure, and at various recovery time points. Guanfacine significantly attenuated cocaine craving, alcohol craving, anxiety, and negative emotion following exposure to all three imagery conditions in females, but not males. Guanfacine did, however, reduce sympathetic tone as well as stress and cue-induced nicotine craving and systolic blood pressure (SBP) in both males and females. These findings highlight sex-specific effects of guanfacine on drug craving, anxiety, and negative mood with significant effects in women and not men. The findings suggest further evaluation of guanfacine in the treatment of cocaine use disorder with a specific focus on sex differences in treatment response.

Polygenic risk for Alzheimer's disease is not associated with cognitive ability or cognitive aging in non-demented older people.

Alzheimer's disease (AD) and non-pathological cognitive aging have phenotypic similarities which may be influenced by an overlapping set of genetic variants. Genome-wide complex trait analysis estimates that common genetic variants account for about 24% of the variation contributing to liability for AD. It is also estimated that 24% of the variance of non-pathological cognitive aging is accounted for by common single nucleotide polymorphisms. However, although the APOE locus is associated with both AD and cognitive aging, it is not known to what extent other common genetic variants, with smaller effect sizes that influence both, overlap. We test the hypothesis that polygenic risk for AD is associated with cognitive ability and cognitive change in about 3,000 non-demented older people (Cognitive Ageing Genetics England and Scotland-CAGES-consortium). We found no significant association of polygenic risk for AD with cognitive ability or cognitive change in CAGES, indicating that the genetic etiologies of AD and non-pathological cognitive decline differ.

The effects of exogenous progesterone on drug craving and stress arousal in cocaine dependence: impact of gender and cue type.

AIMS: Exogenous progesterone has been shown to attenuate the rewarding effects of cocaine. However, its effects on provoked drug craving, stress arousal and cognitive performance has not been systematically investigated in cocaine dependent men and women. Thus, we conducted a double-blind placebo-controlled study assessing the efficacy of progesterone in reducing provoked drug craving, stress system arousal and improving cognitive performance in cocaine dependent men and women. METHODS: Forty-two early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily doses of placebo (12M/9F) or micronized progesterone (12M/9F) (400 mg/day), for 7 days. Under experimental conditions, all subjects were exposed to three 5-min personalized guided imagery conditions (stress, cocaine cue, relaxing), one per day, consecutively in a random, counterbalanced order. Subjective craving, mood, hypothalamic-pituitary-adrenal (HPA) and cardiovascular output, and a cognitive measure of inhibitory control (Stroop Color Word Task) were assessed pre- and post imagery. RESULTS: Progesterone relative to placebo significantly decreased cue-induced craving and cortisol responses and increased cue-induced ACTH. In addition, women but not men receiving progesterone reported lower ratings of negative emotion and higher ratings of relaxed mood following stress exposure. Improved Stroop performance was observed in all participants receiving progesterone, across all conditions. CONCLUSIONS: Progesterone was selectively effective in reducing cocaine cue-induced but not stress-related cocaine craving as well as specific measures of the provoked arousal state. Findings suggest that progesterone's effects on drug craving and arousal are moderated by both the type of environmental cue exposure and gender.