Articles of Public Interest

Abstract

Among young adults who frequently use cannabis, drinking alcohol is linked to intensified cannabis cravings in men and reduced cannabis cravings in women, a novel study suggests. The findings potentially illuminate mechanisms driving the combined use of the two substances and could inform sex-specific approaches to preventing or addressing the resulting harms. Young adults commonly use alcohol and cannabis together (i.e., co-use), and people who use both substances experience more negative consequences—including worse outcomes for alcohol use disorder treatment—than those who use one or the other. Co-use may be partially driven “cross-substance-induced” craving, in which the repeated co-use of two substances prompts one to become a trigger for the other. Research on this effect involving alcohol and cannabis—previously limited to laboratory testing and remote monitoring—has hinted at sex differences in these effects. For the study in Alcohol: Clinical Experimental Research, investigators explored cross-substance craving in daily life contexts, the first study of its kind.

Researchers worked with 63 young adults (aged 18–21, predominantly White) who used cannabis frequently. Across two weeks, participants reported their alcohol use and cannabis cravings multiple times each day, a method known as ecological momentary assessment, which yielded more than 3400 reports. Using statistical analysis, the researchers explored whether drinking was associated with stronger cannabis cravings. They also examined the influence of sex and the amount of drinks consumed on this effect.

Overall, participants used cannabis about 6 days a week and alcohol 2 days a week. Co-use occurred on 27% of days, with similar rates reported by men and women. Among men, drinking alcohol was linked to higher cannabis cravings, implying that the use of alcohol enhanced their desire for cannabis. When women drank, however, they reported somewhat reduced cannabis cravings (this effect was not significant). Levels of alcohol use did not affect men's cannabis cravings, although higher alcohol consumption was linked to more significant reductions in the desire for cannabis among women.

These findings may reflect differing motives for co-use based on sex. Young men often use substances for social reasons and to enhance positive feelings. In these cases, using one substance may amplify the desire for another to intensify the “high.” In contrast, young women are more likely than men to use substances to cope with negative emotions. For them, one substance may suffice to fulfill this function, reducing the need for additional substance use. Alternatively, young women may consciously seek to avoid the negative consequences of combining substances, which can include sexual assault.

Alcohol and cannabis co-use are likely to continue to increase as cannabis laws become more permissive, and young men may be especially vulnerable to negative outcomes due to heightened susceptibility to cross-substance craving. In contrast, young women may use substances more on a substitution, rather than complementary, basis. As such, restricting cannabis access might lead women to shift toward greater alcohol use instead. This highlights a challenge for policies: efforts to reduce risk for one group could inadvertently increase harm for another. These findings may not generalize to other demographics or to young people who use alcohol and cannabis less frequently. Further research is needed in diverse populations and communities with varying substance use policies.

Alcohol use and cannabis craving in daily life: Sex differences and associations among young adults. C. Davis, N.E. Ramer, L. Squeglia, K. Gex, A. McRae, S. McKee, W. Roberts, K.M. Gray, N.L. Baker, R. Tomko. (https://doi.org/10.1111/acer.15461)

Moderate alcohol use does not reduce cardiometabolic disease risk among veterans of European, African, or Hispanic ancestry, a new study suggests. The findings add to growing evidence that traditional research methods applied to drinking levels and certain disease outcomes have created illusory and misleading results. Heavy drinking is known to be linked to coronary heart disease (CHD) and type 2 diabetes (T2D). Traditional observational studies have, however, associated moderate drinking with the lowest risk and abstinence with a moderate risk (the U-curve or J-curve effect). In recent years, the U-curve has been increasingly attributed to confounding errors—when study results are distorted by other factors. In this case, the abstinence category is implicated since it establishes a false equivalence between study participants with widely differing risk factors (lifelong non-drinkers, those who stopped drinking for health or other alcohol-related problems, and those who falsely reported not drinking). Scientists have become able to control for these and other confounders using Mendelian randomization (MR), which draws on genetic data to explore disease risk. Most MR studies—largely limited to people of Asian and European origin—have found no link between moderate alcohol use and CHD or T2D, though some suggest a raised risk. For the study in Alcohol: Clinical & Experimental Research, investigators applied old and new analytical methods to a large, diverse data pool of US veterans.

Researchers worked with participants from the Million Veteran Program (MVP), which incorporates genetic information, alcohol exposure data, and electronic health records. The researchers identified more than 33,000 patients with CHD diagnoses, whom they matched to 165,000 controls without CHD, with a median age of 61% and 97% male. Seventy-four percent were European American, 18% African American, and 6% Hispanic American. There were more than 28,000 patients with T2D, matched to 141,000 controls without T2D, with a median age of 59, 93% male, and 65% European American, 25% African American, and 8% Hispanic American. They performed both observational and MR analyses exploring the relationship between alcohol consumption, CHD, and T2D. The models accounted for demographic factors, blood pressure, smoking, and other factors. For ancestry groups of sufficient size, genetic risk scores linked to alcohol use, blood pressure, and smoking were incorporated.

The observational analysis yielded the familiar U-shaped curve linking alcohol use with CHD and T2D among European and African Americans—but not among Hispanic Americans, a much smaller sample. The MR analysis of the full sample found no evidence of drinking level as a causal risk factor for CHD or T2D. This was the case when working with variants of ADH1B, a gene with well-established links to alcohol use, and when using genetic risk scores based on other relevant variants (for European Americans). Adjusting for the effects of blood pressure and smoking similarly showed no link between alcohol use and cardiometabolic disease risk.

This study provides persuasive additional evidence that moderate drinking is not protective against cardiometabolic disease and that the U-shaped curve is a product of confounding errors. It provides the most extensive exploration to date of the relationship between drinking level and CHD and T2D in African American and Hispanic American populations. Additional MR analysis is needed involving larger samples of non-European populations.

A Mendelian randomization study of alcohol use and cardiometabolic disease risk in a multi-ancestry population from the VA Million Veteran Program. R. Kember, C. Rentsch, J. Lynch, M. Vujkovic, B. Voight, A. Justice, T. L. Assimes, H. Kranzler. (https://doi.org/10.1111/acer.15445)

An early-stage study has found that a drug commonly prescribed for diabetes may prove to help treat people with alcohol use disorder. The study, published in Alcohol: Clinical and Experimental Research, found that the diabetes drug metformin reduced alcohol intake in mice. While more research is needed to determine whether metformin can be effective in treating humans with alcohol use disorder, the findings suggest a potential for improved options for affordable, effective treatment through the repurposing of currently available medications.

Using mice selectively bred for reaching high blood alcohol levels, researchers conducted a number of experiments to examine the effects of metformin on acute and chronic binge-like levels of alcohol consumption.

Metformin was found to reduce both acute and chronic binge-like consumption of alcohol in the mice. In one experiment, the mice were given access to alcohol, water, and saccharin. The mice that received metformin prior to having access to the alcohol consumed less alcohol than those that did not receive the metformin. The metformin did not affect the mice's intake of the other fluids. Another experiment showed that reductions in alcohol intake were not due to increased clearance of ethanol from the bloodstream; metformin had no effect on how the body breaks down alcohol in the body.

Based on prior studies, the researchers had hypothesized that a particular enzyme was influenced by ethanol and metformin and responsible for the reductions in alcohol consumption. They examined the levels and activity of adenosine monophosphate-activated protein kinase, or AMPK, an enzyme that is sensitive to alcohol and is considered to be involved in neural processes, including learning, memory, and motivation. However, metformin and ethanol appeared to have no effect on AMPK in this study.

The experiments showed no differences in effects between male and female mice, but prior studies have shown sex differences in effects, and human females have higher rates of adverse reactions to metformin. Given the small samples in this study, more rigorous research is needed to evaluate the effects and side effects on different populations. The study authors recommend additional research on dosing and the effects of metformin on the consequences of harmful drinking, such as cognitive impairments.

Alcohol use disorder costs the United States $250 billion and more than 175,000 lives each year. Metformin is an already FDA-approved drug that is shown to be safe, well-tolerated, and effective in Type 2 diabetes. It has also been shown to be protective against several neurological disorders. The researchers recommend further study on metformin as a treatment for alcohol use disorder, which could improve accessible, effective, and equitable treatment for people with alcohol use disorders. While they examined metformin as a standalone treatment, they also point to the potential to combine metformin with existing medications for alcohol use disorder to boost their effectiveness.

Effects of metformin on binge-like ethanol drinking and adenosine monophosphate kinase signaling in inbred High Drinking in the Dark - Line 1 mice. K. Grigsby, J. Palacios Aragon, A.E. Chan, S. Spencer, A. Ozburn. (https://doi.org/10.1111/acer.15460)

Half of 18- to 25-year-olds believe that the average young adult drives or rides in a car at least once a month while the driver is under the influence of alcohol and cannabis. Yet, seventy percent believe that both driving and riding in a car while the driver is under the influence of both alcohol and cannabis is totally unacceptable, and three percent of young adults report driving under the simultaneous influence of alcohol and cannabis, according to a study just published in Alcohol: Clinical and Experimental Research. The findings indicate that perceptions of social norms may sway young adults’ behavior related to driving under the influence of alcohol and cannabis differently than they do for alcohol alone and may inform strategies to reduce driving under the influence of alcohol and cannabis.

The study analyzed data from a cohort of two thousand 18- to 25-year-olds in Washington State to understand the associations between perceived social norms and self-reported behaviors related to driving or riding in a car while the driver is under the influence of alcohol and cannabis.

The findings showed a statistically significant positive association between the perceived social acceptability of driving under the influence of both alcohol and cannabis, as well as of riding with a driver who is under the influence of both substances and the likelihood of engaging in that behavior oneself. Perceptions of how common it is for other people to ride in a car while the driver is under the influence of both cannabis and alcohol were positively associated with the likelihood of doing so oneself.

The researchers did not find a significant association between perceptions of how common it was for other young adults to drive under the influence of both cannabis and alcohol and the individual's likelihood to do so. This finding was unexpected, as prior studies on alcohol have found perceptions of alcohol use by peers to be linked to one's own alcohol use.

For the study, participants were asked whether, in the prior 30 days, they had driven within three hours of using alcohol or cannabis or ridden in a car with someone who had. Twelve percent said they drove after using cannabis, and 20 percent said they rode with someone who had used cannabis. With regard to alcohol, 12 percent said they drove under the influence, and 11 percent were passengers in a car with an alcohol-impaired driver.

The rates of driving after using both alcohol and cannabis were lower–three percent for driving while impaired and five percent for riding with an impaired driver. However, simultaneous use of cannabis and alcohol seems to create greater impairment than either substance individually, with an estimated ten percent higher risk of accidents compared to driving under the influence of alcohol alone. Previous studies have found that many people perceive driving after cannabis use to be safer than driving after alcohol use.

The study highlights the discrepancy between perceived social norms and behavior and supports the need for efforts to reduce driving while impaired by the simultaneous use of alcohol and cannabis.

Young adult DUI behavior and perceived norms of driving under the influence of simultaneous alcohol and cannabis use. B. Hultgren, M. Delawalla, V. Szydlowski, K. Guttmannova, J. Cadigan, J. Kilmer, C. Lee, M. Larimer. (https://doi.org/10.1111/acer.15459)