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.

Cumulative adversity and emotion dysregulation effects on suicidal ideation and attempts in a community sample.

Adversity, trauma, and emotion dysregulation are commonly cited risk factors for suicidal thoughts and behaviors. Thus, the role of these factors in conferring risk for suicidal ideation (SI) and suicide attempts (SA) amongst community adults was assessed. A cross-sectional cohort-based study with community adults (n=757; female=55.0%) assessed emotion dysregulation, cumulative adversity including highly stressful and traumatic events, as well as other known risk factors for suicidality (e.g., self-reported depression and anxiety history) to predict a lifetime history of SI or SA, SI but no SA, or SI and SA. Higher cumulative stress and trauma scores conferred risk for SI, specifically on the subscales major life events, recent life events, and chronic stressors. Higher emotion dysregulation was associated with an increased risk for a SA relative to no SI or SA, particularly nonacceptance of emotional responses. Lifetime trauma was the only predictor of SA relative to SI. Nonacceptance of emotions significantly mediated the association between life traumas and suicidality. Cumulative adversity and emotion dysregulation confer risk for suicidal ideation and attempts, and higher lifetime trauma predicted attempts over ideation. These findings suggest that targeting emotion dysregulation, and specifically nonacceptance of difficult emotions, may be a useful strategy in reducing suicidal behaviors in individuals with trauma history and concurrent suicidal ideation.

Patients with AUD exhibit dampened heart rate variability during sleep as compared to social drinkers.

Chronic heavy alcohol use profoundly affects the cardiovascular system, contributing to several life-threatening cardiovascular diseases. Heart rate variability (HRV), or the fluctuations in heart rate, reflects dynamic autonomic nervous system processes that change to meet biological demands and environmental challenges. In the current study, we examined whether HRV metrics are altered in alcohol use disorder (AUD) during waking and sleeping with passive biomonitoring as participants went about their daily lives. Social drinkers (standard deviation: n = 10, 5 female) and treatment-seeking individuals with moderate to severe AUD (n = 16, 7 female) provided continuous, real-world heart rate monitoring for 5 days of monitoring on average (M = 5.27 ± 2.22). Five indices of respiration and HRV-respiratory sinus arrhythmia (RSA) amplitude, high frequency (HF), low frequency (LF), HF/LF ratio, root-mean-square standard deviation (RMSSD), and standard deviation of the N-N intervals (SDNN)-were analyzed separately for waking and sleeping hours. Both RMSSD and SDNN decreased the longer the participants were awake (Ps < .013). During sleeping hours, HF, RSA amplitude, RMSSD, and SDNN were significantly higher in light social drinkers as compared to patients with AUD (all Ps < .009), indicating higher parasympathetic activation during sleep in the SD versus AUD group. Sleep and waking HRV measures were significantly correlated with patient-reported symptoms of depression and sleep difficulties in the AUD group (Ps < .05). This natural observational study utilizing continuous autonomic biomonitoring in the real world indicates parasympathetic dysfunction that is clearly detectable during sleep in AUD and HRV measures, which are also related to clinical, patient-related symptoms of AUD.

Daily stress predicts later drinking initiation via craving in heavier social drinkers: A prospective in-field daily diary study.

Stress has been linked to increased alcohol use but how stress may increase drinking in social drinkers is not well understood. Negative reinforcement processes may explain this link but the role of specific motivational processes, such as craving, and how these motivational processes are altered by drinking have not been studied. The current study assessed social drinkers (n = 81) for recent quantity and frequency of alcohol intake (quantity and frequency index, QFI) upon study enrollment, who then completed 30 days of electronic daily records of stress, craving, and alcohol intake. Multilevel structural equation models tested if person-averaged (between-person) and daily (within-person) craving mediated the link between stress and later drinking each evening and if recent quantity-frequency of drinking (QFI) moderated these associations. At the between-person level, both greater subjective stress, Est = .38, 95% confidence interval (CI) [.19, .57], and higher QFI predicted higher levels of craving, Est = .34, 95% CI [.20, .49]. Higher craving predicted more frequent drinking throughout the study, Est = .34, 95% CI [.01, .29]. At the within-person level, higher subjective stress predicted higher within-person craving; and the link between craving and later drinking was significant among those who had a higher QFI, Est = .84, 95% CI [.58, 1.12]. The subjective stress-drinking relationship was mediated by a greater alcohol craving response in social drinkers, and higher the QFI, greater the alcohol craving response. These results indicate that both higher levels of stress and greater recent alcohol intake patterns sensitize the craving response that in turn facilitates later alcohol intake. The findings suggest that higher recent alcohol use predict greater stress-potentiated initiation of drinking via higher craving responses. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Alcohol craving and withdrawal at treatment entry prospectively predict alcohol use outcomes during outpatient treatment.

OBJECTIVE: Chronic alcohol use increases risk of alcohol craving and withdrawal symptoms (AW) as well as abstinence-related distress symptoms, in those entering alcohol use disorder (AUD) treatment. Here, we examined whether AW and alcohol craving in AUD patients entering outpatient treatment prospectively predicts future heavy drinking days/week (HDD) and additional alcohol use outcomes during 8-weeks of outpatient treatment, and their relationship to abstinence symptoms of depression, anxiety and sleep difficulties. METHODS: Participants were 80 treatment-seeking adults with current DSM-5 AUD (39% female; 43% White; 20-60 years) who completed assessments of AW and alcohol craving and also alcohol abstinence symptoms of depression, anxiety, and sleep quality at treatment intake. Participants were prospectively followed using daily diaries for alcohol intake during 8-week of standardized weekly relapse prevention counseling to support recovery. RESULTS: After accounting for demographic and pre-treatment alcohol use, greater alcohol craving at treatment entry predicted higher HDD (p < .013) as well as greater drinking days (DD: p < .004), average drinks per drinking day/week (AvgD: p < .001) and relapse to heavy drinking (p < .05), while higher levels of pretreatment AW symptoms interacted with treatment week to predict greater HDD (p < .018). Abstinence symptoms of depression, anxiety, and sleep difficulties were associated with craving and AW but did not predict any drinking-related outcomes. CONCLUSIONS: These results provide evidence that increased alcohol craving and AW may serve as prognostic indicators of greater risk of heavy drinking in outpatient treatment. Findings suggest the need to evaluate craving and AW at outpatient treatment entry and develop targeted treatments to specifically address the effects of craving and AW on drinking outcomes in outpatient AUD treatment.

Subjective stress and alcohol use among young adult and adult drinkers: Systematic review of studies using Intensive Longitudinal Designs.

Background: Understanding how stress dynamically associates with alcohol use could provide a finer-grain resolution of drinking behavior, facilitating development of more effective and personalized interventions. The primary aim of this systematic review was to examine research using Intensive Longitudinal Designs (ILDs) to determine if greater naturalistic reports of subjective stress (e.g., those assessed moment-to-moment, day-to-day) in alcohol-drinkers associated with a) greater frequency of subsequent drinking, b) greater quantity of subsequent drinking, and c) whether between-/within-person variables moderate or mediate any relationships between stress and alcohol use. Methods: Using PRISMA guidelines, we searched EMBASE, PubMed, PsycINFO, and Web of Science databases in December 2020, ultimately identifying 18 eligible articles, representing 14 distinct studies, from a potential pool of 2,065 studies. Results: Results suggested subjective stress equivocally predicted subsequent alcohol use; in contrast, alcohol use consistently demonstrated an inverse relationship with subsequent subjective stress. These findings remained across ILD sampling strategy and most study characteristics, except for sample type (treatment-seeking vs. community/collegiate). Conclusions: Results appear to emphasize the stress-dampening effects of alcohol on subsequent stress levels and reactivity. Classic tension-reduction models may instead be most applicable to heavier-drinking samples and appear nuanced in lighter-drinking populations, and may depend on specific moderators/mediators (e.g., race/ethnicity, sex, relative coping-strategy use). Notably, a preponderance of studies utilized once-daily, concurrent assessments of subjective stress and alcohol use. Future studies may find greater consistency by implementing ILDs that integrate multiple within-day signal-based assessments, theoretically-relevant event-contingent prompts (e.g., stressor-occurrence, consumption initiation/cessation), and ecological context (e.g., weekday, alcohol availability).

Alcohol withdrawal symptoms predict corticostriatal dysfunction that is reversed by prazosin treatment in alcohol use disorder.

Chronic alcohol use increases risk of alcohol withdrawal symptoms (AW) and disrupts stress biology and resilient coping, thereby promoting excessive alcohol intake. Chronic alcohol intake and multiple alcohol detoxifications are known to impair brain medial prefrontal cortex (mPFC) and striatal functioning, regions involved in regulating stress, craving and alcohol intake. In two related studies, we examined whether AW predicts this functional brain pathology and whether Prazosin versus Placebo treatment may reverse these effects. In Study 1, patients with Alcohol Use Disorder (AUD) (N = 45) with varying AW levels at treatment entry were assessed to examine AW effects on corticostriatal responses to stress, alcohol cue and neutral visual images with functional magnetic resonance imaging (fMRI). In Study 2, 23 AUD patients entering a 12-week randomised controlled trial (RCT) of Prazosin, an alpha1 adrenergic antagonist that decreased withdrawal-related alcohol intake in laboratory animals, participated in two fMRI sessions at pretreatment and also at week 9-10 of chronic treatment (Placebo: N = 13; Prazosin: N = 10) to assess Prazosin treatment effects on alcohol-related cortico-striatal dysfunction. Study 1 results indicated that higher AW predicted greater disruption in brain mPFC and striatal response to stress and alcohol cues (p < 0.001, family-wise error [FWE] correction) and also subsequently greater heavy drinking days (HDD) in early treatment (p < 0.01). In Study 2, Prazosin versus Placebo treatment reversed mPFC-striatal dysfunction (p < 0.001, FWE), which in turn predicted fewer drinking days (p < 0.01) during the 12-week treatment period. These results indicate that AW is a significant predictor of alcohol-related prefrontal-striatal dysfunction, and Prazosin treatment reversed these effects that in turn contributed to improved alcohol treatment outcomes.

Noninvasive detection of human dehydroepiandrosterone, progesterone and testosterone using LC-MS/MS revealed effects of birth control pills/devices and body weight on ovulatory prediction.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been increasingly used to measure steroids in human saliva. We studied the performance of a conventional LC-MS/MS for measuring dehydroepiandrosterone (DHEA), testosterone and progesterone in human saliva. These three steroids were co-extracted by liquid-liquid extraction and derivatized. Derivatives were resolved on a C18 column and quantified using an LC-MS/MS (AB Sciex API 2000) instrument. The assay's limits of quantification were 0.03 ng/mL for all three steroids. Inter-assay coefficients of variation were 16.6-18.8% (DHEA), 12.0-15.8% (testosterone), and 12.7-19.3% (progesterone). Assay linearity analysis showed R2 of 0.9926, 0.9750 and 0.9949 for DHEA, testosterone and progesterone, respectively. No carry-over between samplings was observed. An ion-enhancement effect of 11.6% for DHEA determination and ion-suppression effects of 13.9% and 20.7% for analysis of progesterone and testosterone, respectively, were determined. No interferences by 9 steroid analogs were detected. Spiked recoveries were 85.5% (DHEA), 86.5% (testosterone), and 92.6% (progesterone). Comparison with laboratory developed test (LDT)-LC-MS/MS methods by other New York State Department of Health certified laboratories revealed R2 = 0.9425 (DHEA, LC-MS/MS = 1.0267 LDT + 21.989), R2 = 0.9849 (testosterone, LC-MS/MS = 0.9447 LDT + 9.8037), and R2 = 0.9736 (progesterone, LC-MS/MS = 1.1196 LDT + 0.0985). Reference intervals for the 3 steroids in saliva for young males and females were estimated. Results of intra-individual salivary progesterone analysis indicated that caution should be exercised when using progesterone concentrations in predicting ovulation for females who are under treatment with birth control pills/devices or has body a weight of > 90 kg.

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.

Association of Prefrontal-Striatal Functional Pathology With Alcohol Abstinence Days at Treatment Initiation and Heavy Drinking After Treatment Initiation.

OBJECTIVE: Alcohol use disorder (AUD) is associated with neuroadaptations in brain stress and reward circuits. It is not known whether such neuroadaptations are affected by number of days of alcohol abstinence and whether they influence heavy drinking during the early treatment phase. The authors used a novel functional MRI (fMRI) approach to assess brain responses during sustained exposure to standardized visual stimuli of stressful, alcohol cue, and neutral control images combined with prospective assessment of drinking outcomes during early outpatient treatment, in two related studies. METHODS: In study 1, 44 treatment-entering patients with AUD and 43 demographically matched healthy control subjects participated in the fMRI experiment to identify dysfunctional responses associated with chronic alcohol abuse. In study 2, 69 treatment-entering patients with AUD were assessed for whether fMRI responses at treatment initiation were influenced by alcohol abstinence and were prospectively predictive of early heavy drinking outcomes. RESULTS: Relative to control subjects, patients with AUD showed significant hyperreactivity in the ventromedial prefrontal cortex (vmPFC) in response to neutral images, but significant hypoactivation in the vmPFC and ventral striatum in response to stress images and to alcohol cues relative to response to neutral images. In study 2, this specific prefrontal-ventral striatal dysfunction was associated with fewer days of alcohol abstinence and also predicted greater number heavy drinking days during the subsequent 2 weeks of treatment engagement. CONCLUSIONS: Number of days of alcohol abstinence at treatment initiation significantly affected functional disruption of the prefrontal-striatal responses to stress images and to alcohol cues in patients with AUD, and the severity of this disruption in turn predicted greater heavy drinking during early treatment. Treatments that target this functional prefrontal-striatal pathology could improve early treatment outcomes in AUD.

Fluctuations in progesterone moderate the relationship between daily mood and alcohol use in young adult women.

BACKGROUND: Research has demonstrated associations between hormonal fluctuations during the menstrual cycle and women's alcohol use. This association has been explained by mood changes that, for some women, accompany decreasing levels of progesterone during the menstrual cycle, particularly during the late luteal/premenstrual phase. The current study examined whether participants' daily ratings of mood interact with changing levels of progesterone to predict alcohol use. METHOD: Young adult women attended two sessions scheduled two weeks apart, during which they completed questionnaires and provided salivary samples for the assay of progesterone levels. In the intervening two weeks, participants completed daily logs of their mood, alcohol use, and menses. Ordered Generalized Linear Mixed Models assessed the effects of daily mood (examined as both a within- and between-subject variable) on the likelihood of drinking, as a function of menstrual cycle phase and changes in progesterone across the two weeks. RESULTS: One standard deviation increase in progesterone corresponded to a 1.61 decrease in the odds of drinking. This main effect was moderated by daily mood. Women were more likely to drink during a decrease in progesterone on days they rated their mood as negative, whereas during an increase in progesterone they were more likely to drink on days they reported a positive mood. Between-subject analyses showed that women who reported lower overall mood during the two-week period were more likely to drink with an increase in progesterone and less likely with a decrease. CONCLUSIONS: Women's likelihood to drink increased when they experienced negative mood in the context of decreasing levels of progesterone, whereas the negative-mood/drinking association was mitigated among those with increasing levels of progesterone. However, compared to women who on average had an overall more positive mood, women with an overall lower mood (and corresponding higher levels of depression and anxiety at baseline) did not experience the protective effects of rising progesterone levels on drinking.

Stress responding and stress-related changes in cue reactivity in heavy smokers, problem gamblers, and healthy controls.

Addictions, both substance and behavioral, have been conceptualized as involving similar biopsychosocial processes with different opportunistic expressions. A maladaptive stress response in combination with craving or urges to engage in the addictive behavior may be among the underlying factors common to behavioral and substance addictions. The current study compared the neuroendocrine (cortisol) and subjective responses to stress of gamblers and smokers to healthy controls. We assessed if participants responded differently to smoking or gambling cues before and after a psychosocial stressor. To this end, the subjective urges/cravings of all participants were measured in response to smoking or gambling cues versus neutral cues, once under normal conditions and again after exposure to a stressor. Salivary cortisol was measured prior to, immediately following, and 10 minutes after conclusion of the stressor. Smokers and gamblers showed a similar blunted cortisol response to the acute stressor that differed from the control group's response. Following a stressor, subjective craving in smokers increased whereas gamblers' urges decreased. In smokers, a blunted cortisol and subjective stress response were related to increased urges. In contrast, for gamblers, changes in cortisol levels were unrelated to urges, and higher subjective stress was associated with decreased urges. In conclusion, individuals with a substance and a behavioral addiction share common patterns of reactivity to stress. However, while the stressor enhanced cue-related craving in smokers, it generally had the opposite effect on gamblers. Further research is necessary to elucidate the complicated patterns of similarities and differences that underlie substance and behavioral addictions.

Weaker Memory Performance Exacerbates Stress-Induced Cannabis Craving in Youths' Daily Lives.

Theories of addiction posit that stimuli associated with drug use, including both exteroceptive (e.g., paraphernalia) and interoceptive (e.g., feeling tense or "stressed"), evoke craving and contribute to the pathogenesis of substance misuse. Control over drug cue response and stress is essential for moderating use. Building from laboratory data supporting associations between cue exposure, stress, and craving, this study tested whether these associations generalize to real-world settings and examined whether a well-vetted neurocognitive control capacity, i.e., working memory (WM), moderated associations. Youth (N = 85; 15-24 years) completed baseline and ecological momentary assessments. Cue exposure and participants' average stress predicted higher craving. Youth with weaker WM experienced stronger craving at higher-stress moments but not when faced with cues. Interactions were present for both previous-moment and same-moment stress. Craving among adolescents with stronger WM was not swayed by momentary stress. Findings suggest stronger WM protects against craving at more stressful moments.

A day-by-day prospective analysis of stress, craving and risk of next day alcohol intake during alcohol use disorder treatment.

BACKGROUND: Stress has been known to increase craving in individuals with Alcohol Use Disorders (AUD) and predict future alcohol relapse risk, but whether stress on a particular day affects craving on that day to impact prospective alcohol intake in the real world, particularly during early treatment and recovery, has not been studied thus far. METHOD: The first study included 85 AUD individuals who reported their daily stress, craving, and alcohol intake in the first two weeks of early treatment. A second validation study included 28 AUD patients monitored daily during eight weeks of outpatient 12-Step based behavioral counseling treatment for AUD. Data were collected from telephone-based daily diaries for 903 days in Study 1 and 1488 in Study 2. Multilevel latent models tested if daily and person-averaged craving mediated the link between stressful events and next day drinking during treatment. RESULTS: In both Study 1 and 2, exposure to a stressful event on a particular day predicted increased craving on that day (p's≤.002); and such increases in craving predicted the likelihood of drinking the next day (p's≤.014) and the drinking amount (p's< = 008). Individuals who experienced more stressful events reported higher craving (p's≤.012), and higher cravers reported greater next day drinking (p's<.001). CONCLUSIONS: The results across two studies with separate samples are the first to establish that craving directly mediates the association between stress and next day alcohol intake in individuals with AUD. Findings suggest a need for novel treatment approaches to address stress-induced craving to improve alcohol use outcomes.

Drug-induced stress responses and addiction risk and relapse.

A number of studies have assessed the effects of psychoactive drugs on stress biology, the neuroadaptations resulting from chronic drug use on stress biology, and their effects on addiction risk and relapse. This review mainly covers human research on the acute effects of different drugs of abuse (i.e., nicotine, cannabis, psychostimulants, alcohol, and opioids) on the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) responses. We review the literature on acute peripheral stress responses in naïve or light recreational users and binge/heavy or chronic drug users. We also discuss evidence of alterations in tonic levels, or tolerance, in the latter relative to the former and associated changes in the phasic stress responses. We discuss the impact of the stress system tolerance in heavy users on their response to drug- and stress-related cue responses and craving as compared to control subjects. A summary is provided of the effects of glucocorticoid responses and their adaptations on brain striatal and prefrontal cortices involved in the regulation of drug seeking and relapse risk. Finally, we summarize important considerations, including individual difference factors such as gender, co-occurring drug use, early trauma and adversity and drug use history and variation in methodologies, that may further influence the effects of these drugs on stress biology.

Noninvasive determination of human cortisol and dehydroepiandrosterone sulfate using liquid chromatography-tandem mass spectrometry.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) for measurements of steroids in human saliva has garnered increased interest in the area of clinical psychoneuroendocrinological research. However, performance characteristics of LC-MS/MS methods for the analysis of steroids in saliva are limited. Human saliva samples were collected via passive drool. Cortisol and dehydroepiandrosterone sulfate (DHEA-S) in the samples were extracted together, resolved on a C18-A column, and analyzed using tandem mass spectrometry. The LC-MS/MS method had limits of quantitation of 0.03 and 0.06 ng/mL for DHEA-S and cortisol, respectively. Method evaluations showed coefficient variation (%CV) of inter-assay ranging 4.6-17.9% for DHEA-S and cortisol, recoveries of 102.4-109.5% for DHEA-S and 94.6-98.3% for cortisol, and assay linearity with R2 = 0.9964 for DHEA-S (1.0-25.0 ng/mL) and R2 = 0.997 (1.0-25.0 ng/mL) for cortisol. No cross contamination among samples was observed. Human saliva showed 20% and 18% ion enhancement effect for DHEA-S and cortisol assay, respectively. No interference by ten common steroids was detected. Regression analysis of method comparisons with laboratory-developed test (LDT) method revealed R2 = 0.9688 (LC-MS/MS = 0.9665 LDT-LC-MS/MS - 0.7355) for cortisol, and R2 = 0.9039 (LC-MS/MS = 1.0173 LDT-LC-MS/MS + 3.6797) for DHEA-S. Reference ranges for young adults were determined to be 0.3-5.9 ng/mL for females and 0.1-5.6 ng/mL for males for salivary cortisol, and 0.6-7.4 ng/mL for females and 0.6-10.1 ng/mL for males for salivary DHEA-S. An LC-MS/MS method for quantifying cortisol and DHEA-S in human saliva was developed and validated for clinical and psychoneuroendocrinological research that require noninvasive means of measuring these hormones.

Correction to: Appetitive startle modulation in the human laboratory predicts Cannabis craving in the natural environment.

The name of Hayley Treloar Padovano was incorrectly tagged in the original version of this article. Instead of Padovano as family name and Hayley Treloar as given name, it should be Hayley as given name and Treloar Padovano as family name. Correct presentation of author name when online should be Treloar Padovano H.

Appetitive startle modulation in the human laboratory predicts Cannabis craving in the natural environment.

RATIONALE: Drug-related cues evoke craving and stimulate motivational systems in the brain. The acoustic startle reflex captures activation of these motivational processes and affords a unique measure of reactivity to drug cues. OBJECTIVES: This study examined the effects of cannabis-related cues on subjective and eye blink startle reactivity in the human laboratory and tested whether these effects predicted youth's cue-elicited cannabis craving in the natural environment. METHODS: Participants were 55 frequent cannabis users, ages 16 to 24 years (M = 19.9, SD = 1.9; 55% male; 56% met criteria for cannabis dependence), who were recruited from a clinical trial to reduce cannabis use. Eye blink electromyographic activity was recorded in response to acoustic probes that elicited startle reactivity while participants viewed pleasant, unpleasant, neutral, and cannabis picture cues. Following the startle assessment, participants completed an ecological momentary assessment protocol that involved repeated assessments of cue-elicited craving in real time in their real-world environments. RESULTS: Multilevel models included the presence or absence of visible cannabis cues in the natural environment, startle magnitude, and the cross-level interaction of cues by startle to test whether cue-modulated startle reactivity in the laboratory was associated with cue-elicited craving in the natural environment. Analyses showed that cannabis-related stimuli evoked an appetitive startle response pattern in the laboratory, and this effect was associated with increased cue-elicited craving in the natural environment, b = - 0.15, p = .022, 95% CI [- 0.28, - 0.02]. Pleasant stimuli also evoked an appetitive response pattern, but in this case, blunted response was associated with increased cue-elicited craving in the natural environment, b = 0.27, p < .001, 95% CI [0.12, 0.43]. CONCLUSIONS: Our findings support cue-modulated startle reactivity as an index of the phenotypic expression of cue-elicited cannabis craving.

Real-time assessment of alcohol craving and naltrexone treatment responsiveness in a randomized clinical trial.

INTRODUCTION: This secondary data analysis examined whether and how the dopamine receptor D4 gene (DRD4) influenced naltrexone treatment responsiveness in a randomized clinical trial. We leveraged intensive experience sampling methods to test the hypothesis that craving recorded at drinking and non-drinking moments would mediate naltrexone effects on the likelihood of heavy drinking, but only among carriers of the DRD4 long (DRD4-L) allele. METHODS: Participants (Mage=29.8years, SD=12.1) were non-treatment seeking heavy drinkers (n=104, 54.8% female, 61.5% alcohol dependent) randomized to 3weeks of daily naltrexone (50mg) or placebo. During these 3weeks, participants used handheld electronic devices to complete real-time reports of alcohol use and craving multiple times per day in their natural environments. This approach afforded intensive repeated assessment of focal variables and provided in-the-moment data to test whether craving when not drinking or early in drinking episodes explained naltrexone effects on drinking. RESULTS: Moderated-mediation multilevel structural equation models showed that craving during non-drinking moments mediated the treatment effect of naltrexone on heavy drinking but only among carriers of the DRD4-L allele. The same pattern of associations was not shown when evaluating craving while participants were consuming alcoholic beverages. CONCLUSIONS: Findings provide the first in vivo evidence that, among carriers of the DRD4-L allele, naltrexone blunts craving in real-world settings, and this effect in turn reduces the likelihood of heavy drinking. This work highlights the utility of EMA methods for elucidating how treatments work and further demonstrates the importance of genetic factors for understanding individual differences in pharmacotherapy responsiveness.