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ASAM Weekly for June 27th, 2023

This Week in the ASAM Weekly

The field of addiction is dynamic. Epidemiological studies show that alcohol consumption is associated with multiple negative health outcomes, yet a cardioprotective effect continues to persist. A study using advanced brain imaging helps explain why. Light to moderate alcohol consumption can reduce the activity of stress-related brain regions (the amygdala) which subsequently reduces the risk for cardiovascular disease (Journal of the American College of Cardiology). The authors aren’t calling for more light-to-moderate drinking; rather, they recommend we further study therapeutics that could offer similar (but safer) benefits. 

The Fitbit has been re-imagined for adolescent rats, helping scientists demonstrate how alcohol can continue to disrupt a teenager’s circadian rhythm even weeks after last exposure (Alcohol Clinical and Experimental Research). Also important to teenagers and rats, dopamine is known to play a role in learning and motivation, and a new study shows that a dopamine ramp likely bridges the gap between Pavlovian (learning) and operant conditioning (motivation) (The Journal of Neuroscience).

Our approach to opioid use disorder is constantly in revision. A review on buprenorphine dosing presents a thorough history of the evidence while calling on the FDA to update their guidance for a modern-day crisis (Journal of Addiction Medicine). As the crisis widens, drug overdose data are showing that men are dying at significantly higher rates than women, raising concern about a male bio-psycho-social vulnerability gap (Neuropsychopharmacology).

Even the cultural experience of substance use is regularly revisited. Nostalgia for the uncanny synchronicities between the “The Wizard of Oz” and “The Dark Side of the Moon” begs us to consider how cannabis influenced the origins of a quasi-cultural phenomenon (NY Times). A white supremacist’s awakening through MDMA may have reinvigorated a discussion about the power of empathy and the potential for psychedelics to heal a divided society (BBC). But before the enthusiasts propose putting MDMA in the drinking water, the FDA has issued a draft guidance for developing clinical trials to study psychedelics (FDA).

Thanks for reading,

Nicholas Athanasiou, MD, MBA, DFASAM
Editor in Chief

with Co-Editors: Brandon Aden, MD, MPH, FASAM, Debra R. Newman, PA-C, MSPAS, MPH, Jack Woodside, MD, John A. Fromson, MD

Lead

Reduced Stress-Related Neural Network Activity Mediates the Effect of Alcohol on Cardiovascular Risk

Journal of the American College of Cardiology

Chronic stress is associated with major adverse cardiovascular events (MACE) via increased stress-related neural network activity (SNA). Light/moderate alcohol consumption (ACl/m) has been linked to lower MACE risk, but the mechanisms are unclear. This study evaluated whether the association between ACl/m and MACE is mediated by decreased SNA. Individuals enrolled in the Mass General Brigham Biobank who completed a health behavior survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography, enabling assessment of SNA. Alcohol consumption was classified as none/minimal, light/moderate, or high (<1, 1-14, or >14 drinks/week, respectively). ACl/m associates with reduced MACE risk, in part, by lowering the activity of a stress-related brain network known for its association with cardiovascular disease. Given alcohol’s potential health detriments, new interventions with similar effects on SNA are needed.

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Research and Science

Association of Mandatory Warning Signs for Cannabis Use During Pregnancy With Cannabis Use Beliefs and Behaviors ðŸ”“

JAMA Network Open

This cross-sectional study investigated whether exposure to warning signs about cannabis use during pregnancy (CUDP) impacted use and beliefs by pregnant women. The study included recreational cannabis states that did and did not include warning signs and a subset of those that do not allow recreational cannabis with obviously no warning sign policy. Items of interest included whether CUDP is not safe, should not be penalized, and is stigmatized. Living in a state that implements warning signs was associated with beliefs that CUDP is safe and should not be penalized. The opposite results were seen for pregnant women who did not use, hence believing that CUDP is unsafe and should be penalized. Interestingly, those who used cannabis during pregnancy reported message fatigue and mistrust of the warning signs.

Cross-phenotype relationship between opioid use disorder and suicide attempts: new evidence from polygenic association and Mendelian randomization analyses

Molecular Psychiatry

This study investigated the cross-phenotype relationship of the high co-occurrence between suicide attempts (SA) and opioid use disorder (OUD). It utilized raw phenotypes and genotypes from >150,000 UK Biobank samples and genome-wide association summary statistics from >600,000 individuals with European ancestry. Strong associations between OUD and SA were observed at both the phenotypic level; non-psychiatric subgroup and the genetic level. Consistently, increasing polygenic susceptibility to SA is associated with increasing risk of OUD, and similarly, increasing polygenic susceptibility to OUD is associated with increasing risk of SA. However, these polygenic associations were much attenuated after controlling for comorbid psychiatric diseases. A combination of MR analyses suggested a possible causal association from genetic liability for SA to OUD risk. This study provided new genetic evidence to explain the observed OUD-SA comorbidity.

DEA

Overdose mortality rates for opioids and stimulant drugs are substantially higher in men than in women: state-level analysis ðŸ”“

Neuropsychopharmacology

Using 2020-2021 CDC WONDER data, this study is a state- and age-specific examination of differences between males and females in overdose mortality due to opioid and stimulant drugs. Outcome measures included rate of overdose death for synthetic opioids such as fentanyl, heroin, and stimulants such as methamphetamine and cocaine. Across these drug categories, males died from overdoses at rates 2–3 times greater than females. Across state-level jurisdictions, males were found at greater risk of overdose death than females. More research is needed to investigate the factors impacting sex differences and vulnerability to overdose.

 

Learn More

Evidence on Buprenorphine Dose Limits: A Review ðŸ”“

Journal of Addiction Medicine

This study discusses the evidence regarding buprenorphine dosing, noting the Food and Drug Administration’s (FDA) product label target dose of 16 mg/d. Early dose recommendations were based on mu receptor occupancy, and FDA buprenorphine literature states occupancy implies little difference between 16 and 24 mg. However, clinical studies demonstrate effectiveness at higher doses, including effects such as blocking the rewarding effects of opiate agonists, complete suppression of apnea from fentanyl, and improved treatment retention. These effects all require doses greater than 16 mg/day and upwards of 32 mg/day, thus urging the FDA to reconsider buprenorphine dosing guidance. 

Treatments Used Among Adolescent Residential Addiction Treatment Facilities in the US, 2022 

JAMA

While buprenorphine (BUP) is recommended for treatment of adolescents with opioid use disorder (OUD), it is unclear how often it is available to adolescents in residential treatment facilities. The authors conducted a "secret shopper" approach to survey 160 residential treatment facilities and found 39 (24.4%) offered BUP either at the program or through outside clinicians. Among those facilities, 17 initiate and provide ongoing BUP, 12 initiate BUP but discontinue before discharge, and 3 continue BUP if the patient is already prescribed. Of the facilities, 27 (22.3%) required adolescents to not be receiving BUP. Given these findings, adolescents with OUD face significant barriers in accessing BUP, the recommended standard of care, in residential treatment settings.

Use of a Fitbit-like device in rats: Sex differences, relation to EEG sleep, and use to measure the long-term effects of adolescent ethanol exposure ðŸ”“

Alcohol Clinical and Experimental Research

There is evidence that alcohol use in adolescents is associated with disturbances in circadian rhythms, but it can be difficult to untangle the effects of alcohol and other lifestyle factors. To better assess the impact of alcohol, animal models can be utilized. In this study, researchers utilize a "Fitbit-like" device ("FitBite") to track adolescent rat activity patterns during 4 weeks of alcohol exposure, "acute" withdrawal (24 hours), and protracted withdrawal (4 week). There was a decrease in overall activity during the intoxication phase and more episodes of activity of shorter duration in light (day) during "acute" and protracted withdrawal. These findings support evidence of sleep disturbance that can persist after alcohol withdrawal. 

Anticipation of Appetitive Operant Action Induces Sustained Dopamine Release in the Nucleus Accumbens ðŸ”“

The Journal of Neuroscience

This study investigated the details of dopamine release in the nucleus accumbens in response to a cue followed by a food reward. To measure dopamine release, electrodes were placed in the nucleus accumbens of male rats, who were then divided into 2 groups: Pavlovian conditioning and operant conditioning. In both groups, dopamine increased when the light appeared but only in the operant conditioning group was the dopamine level sustained during the cue. The authors conclude that sustained dopamine release served to motivate the rat to execute the lever press. This evidence ties the mesolimbic dopamine system to motivation in addition to reinforcement learning.