Sex Differences in AUD-Related Sleep Health Outcomes

During “Effects of Sex on the Bi-directional Relationship Between Sleep and Substance Use” presented at SLEEP 2021, experts highlighted research on the role sex plays in different circadian disturbances and substance use disorders.

“While sleep loss and circadian misalignment affect the reward system and increase the risk of substance use, on the other hand, acute and chronic substance use differently affect sleep and circadian rhythms,” explained session chair Rui Zhang, PhD, of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

However, several challenges exist when it comes to understanding the effects of sex in this complicated relationship. For example, large sample sizes are often needed to study sex differences in these cohorts, and to overcome this barrier, multisite collaborations are common. In addition, previous research has found sleep and reward functions in females are affected by menstrual cycles, which means researchers must take into account other factors like hormonal birth control use.

When it comes to substance use differences, “We also need to consider sex differences in body and brain size,” Zhang said. “With the same amount of alcohol use, women tend to have more alcohol in their blood than men because of their low body water and higher body fat.”

Discrepancies between objective and subjective sleep measures are also reported among those with substance use disorder, Zhang added, potentially reflecting individuals’ dependance severity.

Studies on sleep problems and substance use disorder typically focus on men, making sex differences an understudied aspect in this field. However, during her talk, Zhang outlined data on sex differences and sleep problems during the withdrawal stage of addiction—defined as the first 30 days of abstinence.

Specifically, Zhang and colleagues assessed brain correlations of sleep problems in patients with alcohol use disorder (AUD). Because females are more sensitive to the adverse effects of alcohol and alcohol-related diseases, the researchers hypothesized females would show greater impairments in sleep and greater changes in sleep-related brain structure and brain function.

Thirty-six patients with AUD undergoing 3-week detoxification were included in the study, among whom 10 were female. The study also included 26 healthy controls. During the first week of assessment, data showed that female patients with AUD exhibited a significant reduction in slow-wave sleep compared with healthy controls, while no significant differences were observed for males with AUD and healthy males.

Patients with AUD also had less rapid eye movement sleep and exhibited overall gray matter reduction compared with healthy controls. Researchers found lower cortical thickness most prominently in the occipital cortex among those with AUD.

The investigators then compared patients’ sleep from week 3 to week 1. “We found that for slow-wave sleep, there's a significant recovery in AUD females after 3-week detoxification, at which time point, it did not differ from healthy controls,” Zhang said. “We did not find significant differences between AUD males and healthy males during week 1 and week 3.”

These esults need to be replicated in the future with a larger sample size, and the researchers were unable to determine directionality of the relationship between slow-wave sleep and brain changes. Future longitudinal research will also help determine sex-specific and stage-specific interventions for patients with AUD, Zhang concluded.

During an additional talk, Corinde E. Wiers, PhD, an assistant professor of psychiatry and radiology at the Perelman School of Medicine at the University of Pennsylvania, discussed sex effects on alcohol withdrawal, mood, and sleep quality in individuals with AUD.

“On average, women have been shown to be affected—or their brains have been affected—more by alcohol, but the sex difference literature in insomnia and AUD is not that clear,” Wiers said.

Using data from NIAAA, Wiers and colleagues examined a large sample of individuals with AUD (n > 600) and compared findings with over 500 healthy volunteers.

When adjusted for weight, no differences between sexes were found for drinks per day among those with AUD. However, despite equal drinking histories and based on responses to the alcohol dependence scale, women with AUD reported higher alcohol dependence scores compared with men.

Analyses revealed those with AUD had higher Pittsburgh Sleep Quality Index scores indicating worse sleep quality compared with controls. “But overall, there were no sex differences,” for this measure, Weirs said.

But among those with AUD who were inpatients (who sought out 3 to 4 weeks of treatment as opposed to a day of testing [outpatients]), “women had poorer sleep than men, but only in the AUD inpatients, not in the outpatients, and not in the healthy control group.”

This finding was consistent both at baseline and after 4 weeks of treatment. Females with AUD also recorded worse scores for depression compared with males with AUD, while no differences were reported in the control group. Being an inpatient was also a driving factor for this association, as no sex differences were reported in outpatients.

Results also showed females with AUD received more total milligrams of benzodiazepines prescribed compared with males with the disorder during detoxification.

When it came to withdrawal symptoms, “On day 1, females had stronger withdrawal scores than males. The overall maximum of the first week was higher for females than males, and also the average maximum was higher for females than males,” Weirs said, indicating women had stronger withdrawal symptoms than their male counterparts.

In both controls and patients with AUD, females exhibited larger gray matter volumes than males based on MRI findings. But for females with higher alcohol dependance scores and a larger lifetime drinking history, “their gray matter volumes were more rapidly declining than for males.”

“The conclusion of this study was that these findings suggest that alcohol has more severe effects on sleep, mood, and withdrawal in women than in men, but not on brain structural measures,” Weirs concluded.