Sherry A. McKee’s research while affiliated with Yale-New Haven Hospital and other places

Importance Preclinical, observational, and pharmacoepidemiology evidence indicates that glucagon-like peptide 1 receptor agonists (GLP-1RAs) may reduce alcohol intake. Randomized trials are needed to determine the clinical significance of these findings. Objective To evaluate the effects of once-weekly subcutaneous semaglutide on alcohol consumption and craving in adults with alcohol use disorder (AUD). Design, Setting, and Participants This was a phase 2, double-blind, randomized, parallel-arm trial involving 9 weeks of outpatient treatment. Enrollment occurred at an academic medical center in the US from September 2022 to February 2024. Of 504 potential participants assessed, 48 non–treatment-seeking participants with AUD were randomized. Intervention Participants received semaglutide (0.25 mg/week for 4 weeks, 0.5 mg/week for 4 weeks, and 1.0 mg for 1 week) or placebo at weekly clinic visits. Main Outcomes and Measures The primary outcome was laboratory alcohol self-administration, measured at pretreatment and posttreatment (0.5 mg/week). Secondary and exploratory outcomes, including prospective changes in alcohol consumption and craving, were assessed at outpatient visits. Results Forty-eight participants (34 [71%] female; mean [SD] age, 39.9 [10.6] years) were randomized. Low-dose semaglutide reduced the amount of alcohol consumed during a posttreatment laboratory self-administration task, with evidence of medium to large effect sizes for grams of alcohol consumed (β, −0.48; 95% CI, −0.85 to −0.11; P = .01) and peak breath alcohol concentration (β, −0.46; 95% CI, −0.87 to −0.06; P = .03). Semaglutide treatment did not affect average drinks per calendar day or number of drinking days, but significantly reduced drinks per drinking day (β, −0.41; 95% CI, −0.73 to −0.09; P = .04) and weekly alcohol craving (β, −0.39; 95% CI, −0.73 to −0.06; P = .01), also predicting greater reductions in heavy drinking over time relative to placebo (β, 0.84; 95% CI, 0.71 to 0.99; P = .04). A significant treatment-by-time interaction indicated that semaglutide treatment predicted greater relative reductions in cigarettes per day in a subsample of individuals with current cigarette use (β, −0.10; 95% CI, −0.16 to −0.03; P = .005). Conclusions and Relevance These findings provide initial prospective evidence that low-dose semaglutide can reduce craving and some drinking outcomes, justifying larger clinical trials to evaluate GLP-1RAs for alcohol use disorder. Trial Registration ClinicalTrials.gov Identifier: NCT05520775

Importance: Despite increased initiatives and funding to improve access to evidence-based treatments for opioid use disorder (OUD), including medications for OUD (mOUD), pregnant/postpartum individuals have significant obstacles to accessing these life-saving medications. Observations: Current legislation, specifically the Comprehensive Addiction and Recovery Act (CARA), mandates that the Governor of each state has systems in place to identify and address the needs of substance-exposed infants. However, this legislation removed the word "illegal" when defining substance use and left other important words in the law up to each individual state to define. These changes resulted in pregnant/postpartum individuals with OUD who were receiving legally prescribed mOUD, being subject to legal actions. In many states, such notifications result in investigation and punitive actions, which may include the removal of children from the care of postpartum individuals. These state policies have created additional barriers to accessing mOUD for pregnant and/or postpartum individuals. Research has demonstrated that pregnant individuals delay and/or avoid recommended prenatal care or decide to stop taking mOUD altogether, to prevent potential legal and child welfare-related consequences. This situation is problematic as it places individuals at risk of overdose and death and infants at risk of health complications. Importantly, such policies are subject to bias and disproportionately impact individuals of color and those from lower socioeconomic backgrounds. Conclusions and Relevance: The need to address and change the criminalization of pregnant/postpartum substance use laws to not penalize individuals adhering to the recommended standard of evidence-based care is urgent. Specific recommendations include: not relying on toxicology testing, reinstating "illegal/non-prescribed" language in legislation, implementing Plans of Safe Care, use of a two "track" reporting system, and federal support for states complying with Child Abuse Prevention and Treatment Act Reauthorization of 2010 (CAPTA) laws, increasing resources to improve outcomes for infants/postpartum individuals with OUD, and additional mandated training to educate key individuals, such as hospital/outpatient clinic providers and child-welfare workers.

Background Alcohol‐associated hepatitis (AH) is a subtype of alcohol‐associated liver disease (ALD) resulting in severe acute liver inflammation. This study aims to examine longitudinal trends in mortality from AH in the United States (US) from 1999 to 2020, stratifying the data by sex, age, and racial/ethnic groups. Methods We performed a cross‐sectional study using data from the US Centers for Disease Control and Prevention Wide‐ranging Online Data for Epidemiologic Research (WONDER) to determine annual AH‐related mortality rates (MR) in adults ≥21 years between 1999 and 2020. Data were stratified by sex, race, and 10‐year age groups. Considering 1999 as baseline, mortality rate ratio (MRR) was calculated to characterize the MR in a particular year compared to baseline. Joinpoint regression analysis was conducted to characterize year‐wise log‐linear time calendar trends in MR. Results From 1999 through 2020, AH‐related deaths doubled from 0.5 per 100,000 (95% CI 0.5 to 0.6) to 1.1 per 100,000 (95% CI 1.1 to 1.2). While mortality rates for males doubled from 0.8 per 100,000 (95% CI 0.7 to 0.8) to 1.5 per 100,000 (95% CI 1.4 to 1.6), mortality rates for females almost tripled from 0.3 per 100,000 (9%% CI 0.3 to 0.4) to 0.8 per 100,000 (95% CI 0.7 to 0.8). The steepest increase in AH‐related deaths from 1999 to 2020 were among American Indians/Alaska Natives and young adults 25–34 years, and particularly young adult females. Conclusions Over the past two decades, overall AH‐related mortality in the US has doubled. The steepest increase in AH‐related mortality was noted among American Indians/Alaska Natives and young adults, particularly young adult females. Education and prevention efforts should target these high‐risk populations, and studies aimed at elucidating biological and sociodemographic factors resulting in the differential rise in mortality are warranted.

Background Alcohol and cannabis are commonly used together by young adults. With frequent pairings, use of one substance may become a conditioned cue for use of a second, commonly co‐used substance. Although this has been examined for alcohol and cannabis in laboratory conditions and with remote monitoring, no research has examined whether pharmacologically induced cross‐substance craving occurs in naturalistic conditions. Methods In a sample of 63 frequent cannabis‐using young adults (54% female) who completed 2 weeks of ecological momentary assessment, we tested whether alcohol use was associated with stronger in‐the‐moment cannabis craving. We also examined whether sex moderated this association and whether cannabis craving was stronger at higher levels of alcohol consumption. Results Although alcohol use and cannabis craving were not significantly associated at the momentary level, there was evidence that this relation significantly differed by sex. Among female participants, there was a negative association between alcohol use since the last prompt and momentary cannabis craving (b = −0.33, SE = 0.14, p = 0.02), while the association among male participants was positive (b = 0.32, SE = 0.13, p = 0.01). Similarly, alcohol quantity was negatively associated with cannabis craving at the momentary level for female participants (b = −0.10, SE = 0.04, p = 0.009) but was not significantly associated for male participants (b = 0.05, SE = 0.04, p = 0.18). Conclusions Alcohol may enhance cannabis craving among male individuals but reduce desire for cannabis among female individuals. This may point to differing functions of co‐use by sex, highlighting a need for research to elucidate the mechanisms underlying this increasingly common pattern of substance use.

Background Stress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [¹⁸F]AS2471907 to measure 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls. Methods We imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11β-HSD1 inhibitor radiotracer [¹⁸F]AS2471907 as a bolus injection and were imaged for 150–180 min on the High-Resolution Research Tomograph. 11β-HSD1 availability was quantified by [¹⁸F]AS2471907 volume of distribution (VT; mL/cm³). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate. Results Individuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [¹⁸F]AS2471907 VT was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [¹⁸F]AS2471907 VT was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02). Conclusions This is the first in vivo examination of 11β-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11β-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11β-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.

Background Alcohol use and the criminal justice (CJ) system have long been integrally connected in the United States and have both disproportionally impacted Communities of Color. Despite this connection, scholarly literature has largely focused on substance use as a whole, and little literature has examined the influence of race on CJ referral to alcohol treatment and treatment outcomes. Methods A total of 749,349 cases from the treatment episodes dataset discharge were used in the current study. A series of ANOVA and logistic regression analyses were conducted to examine the impact of race on (i) likelihood of referral to alcohol treatment by the CJ system and (ii) the association between CJ referral and treatment completion. Results Results revealed significant disparities in both who is referred to alcohol treatment by the CJ system and the association of that referral to treatment completion. Notably, American Indian/Alaska Native people were significantly more likely than people of all other races to be referred by the CJ system. However, American Indian/Alaska Native people showed the smallest association between CJ referral and treatment completion. Conclusions Contrary to previous literature, findings showed that referral of and positive association between CJ referral and treatment completion are not equal across people of different races. Taken together, these results highlight continued racial inequities in the role of the CJ system in alcohol treatment and the unique potential for non-CJ-related treatment to best serve people combatting alcohol use disorder.

Digital and remote technologies (DRT) are increasingly being used in scientific investigations to objectively measure human behavior during day-to-day activities. Using these devices, psychologists and other behavioral scientists can investigate health risk behaviors, such as drug and alcohol use, by closely examining the causes and consequences of monitored behaviors as they occur naturalistically. There are, however, complex ethical issues that emerge when using DRT methodologies in research with people who use substances. These issues must be identified and addressed so DRT devices can be incorporated into psychological research with this population in a manner that comports the ethical standards of the American Psychological Association. In this article, we discuss the ethical ramifications of using DRT in behavioral studies with people who use substances. Drawing on allied fields with similar ethical issues, we make recommendations to researchers who wish to incorporate DRT into their own research. Major topics include (a) threats to and methods for protecting participant and nonparticipant privacy, (b) shortcomings of traditional informed consent in DRT research, (c) researcher liabilities introduced by real-time continuous data collection, (d) threats to distributive justice arising from computational tools often used to manage and analyze DRT data, and (e) ethical implications of the “digital divide.” We conclude with a more optimistic discussion of how DRT may provide safer alternatives to gold standard paradigms in substance use research, allowing researchers to test hypotheses that were previously prohibited on ethical grounds.