Influence of alcohol and acetaldehyde on cognitive function: findings from an alcohol clamp study in healthy young adults
- Research achievement for promoting proper drinking -
While drinking alcohol beverages brings joy and enrichment to daily life, it can also cause various problems for individuals, families, and society, if not done properly. In response, initiatives have been taken in recent years to eradicate inappropriate drinking throughout society. The Asahi Group is working to raise awareness of proper drinking, such as the “Smart Drinking ※1” project, where we promote more diverse styles of drinking. We aim to realize a society with less incidents of alcohol-related problems where each person can freely choose a drinking style according to his or her health condition and the situation. As part of this initiative, Asahi Quality & Innovations, Ltd. studied effects of alcohol and acetaldehyde on cognitive function in healthy young adults using the alcohol clamp method ※2.
● We studied influences of alcohol and acetaldehyde on cognitive function in healthy young adults using the “alcohol clamp method,” which is less affected by individual differences in alcohol metabolism.
● We conducted an unprecedented large-scale study on approximately 300 healthy Japanese adults between the ages of 20 and 24.
● We studied and elucidated the correlation between blood alcohol concentration (BAC) and multiple areas of cognitive function, as well as blood acetaldehyde concentration (BAAC) and multiple areas of cognitive function, taking into consideration the genetic polymorphisms of acetaldehyde dehydrogenase 2 (ALDH2), an alcohol-metabolizing enzyme.
Realizing that drinking is becoming a major social problem, I thought we should somehow contribute to solving the problem. I started working on research to prevent alcohol-related problems in early 2000. It has been known that acetaldehyde produced in the metabolic process of alcohol has a negative effect on memory and other cognitive functions, but there have been no studies that clearly show it with data. Also, none of oral intake tests that have been conducted produced accurate data due to individual differences in absorption and metabolism. As such, we conducted an experiment with the National Hospital Organization Kurihama Medical and Addiction Center, which has a technology that enables tests while maintaining a certain level of alcohol concentration after intravenous injection of alcohol. It was quite challenging to gather about 300 test participants, but I was very happy when the research was successfully started. This study has since been followed up by questionnaires, which adds another feature to this experiment as a long-term study. Investigating the influence of alcohol on the human body may be controversial in various aspects, including from an ethical point of view, but that is why it is important to conduct research to yield solid data. As you know, alcohol enriches our time, but one wrong step can negatively impact on both society and our health. Therefore, I hope this kind of research can provide each consumer with an opportunity to give another thought to how to enjoy alcoholic beverages.
Since the establishment as Japan’s first specialized hospital for alcoholism in 1963, the National Hospital Organization Kurihama Medical and Addiction Center has provided a great number of pioneering alcoholism treatments and research. Especially, the technology to maintain a constant blood alcohol level using the alcohol clamp method developed by Vijay Ramchandani, Ph.D. at the US National Institute on Alcohol Abuse and Alcoholism, is one of the representative features of the Center. The major point of this study is that it scientifically showed the effects of acetaldehyde, a metabolite of alcohol, on cognitive function with numerical data. We are still conducting research to elucidate the mechanism. Studies, including this one, have examined the effects of alcohol in a short period of time, while others have investigated the effects of chronic alcohol in alcoholism. But there is no translational study linking these two statuses. To fully understand the pathogenesis of alcoholism, we believe that research that links the two conditions is also essential. While alcohol is considered to be an addictive substance that has been involved in humans since ancient times, its actions are still largely unknown. We hope that this study will help us better understand the nature of the substance.
People have long been interested in the effects of alcohol consumption on human cognitive function. Studies have reported that alcohol has a negative impact on cognitive function. However, as the prior studies were conducted on a small number of study participants (between 20 and 41), caution was needed to interpret their results. Furthermore, the effects of acetaldehyde have not been fully investigated because there was almost no previous studies investigating genetic variation in ALDH2 (either *1 or *2) (genetic mutations that determine the activity of the enzyme that decomposes aldehyde generated after alcohol breakdown and determine whether a person can or cannot hold much alcohol). As such, we conducted an unprecedentedly large-scale study of the effects of alcohol administration on cognitive function on about 300 healthy young adults. In order to understand the effects of alcohol and acetaldehyde separately, we examined the correlation between BAC and multiple aspects of cognitive function, as well as correlation between BAAC and multiple aspects of cognitive function, taking ALDH2 genetic polymorphisms into consideration, using the alcohol clamp method, which is less affected by individual differences in alcohol metabolism.
We conducted a study with 298 healthy Japanese participants (158 male and 140 female adults) aged between 20 and 24. Of these, 197 (66%) had normal homozygotes (ALDH2*1/*1) of aldehyde dehydrogenase, which is involved in acetaldehyde degradation, and 101 (34%) had normal heterozygotes (ALDH2*1/*2). All participants were infused intravenously with alcohol using the alcohol clamp method, maintaining a BAC at 0.50 mg/mL for 180 minutes. This level of BAC is generally said to be equivalent to drinking about one medium bottle of beer. BAC and BAAC were measured before intravenous injection (0 minute), and 60 minutes and 180 minutes after intravenous injection, and three kinds of tests were conducted to assess the participants' cognitive function.
Fig.1 BAC of all participants at each measurement time (based on the results in the original study paper)
We examined the shift of BAC by intravenous infusion using the alcohol clamp method. As a result, we confirmed that the BAC of all participants were maintained at around the target level of 0.50 mg/mL for 180 minutes (Figure 1). BAC quickly dropped after the intravenous injection was stopped at the 180-minute time point. This made it possible to investigate the effects of BAC at a certain concentration in all participants.
Fig.2 BAAC of male and female participants at each measurement time (based on the results in the original study paper)
Fig.3 BAAC of genotypes ALDH2*1/*1 and ALDH2*1/*2 at each measurement time (based on the results in the original study paper)
We measured BAAC over time by intravenous infusion using the alcohol clamp method. There was no significant difference in BAAC between male and female participants at each measurement time after intravenous drip injection (Figure 2). On the other hand, as shown in Fig. 3, a significant difference in BAAC was observed between the two genotypes of aldehyde dehydrogenase. Acetaldehyde was detected in the blood of people with ALDH2*1/*2, suggesting that the degradation of acetaldehyde is slower in people with ALDH2*1/*2 than in people with ALDH2*1/*1 (Fig. 3). In addition, the decrease in BAAC over time showed that acetaldehyde is continuously metabolized even in people with ALDH2*1/*2.
Fig.4 Results of CPT at each measurement time (based on the results in the original study paper)
In the continuous performance test (CPT), the scores decreased at the time points of 60 minutes and 180 minutes after intravenous alcohol infusion (Figure 4). Specifically, the decrease of scores in the first 60 minutes correlates with the shift of BAAC shown in 1-2), suggesting that the worsening of the scores would be due to the effect of blood acetaldehyde. Scores were significantly different between the ALDH2 genotypes and among the genotypes × time from intravenous alcohol infusion.
Fig.5 PASAT results at each measurement time (based on the results in the original study paper)
The results of the test on working memory (PASAT) did not show any decrease in the scores associated with intravenous alcohol infusion, but rather showed an improvement in the scores. This rise in the score seems to be due to the learning effect. On the other hand, there was a negative correlation between BAAC and the change in scores of PASAT performed prior to (0 minutes) and 60 minutes after intravenous infusion. These results suggest that acetaldehyde in the blood affects the decline of working memory.
Fig.6 Results of RTT at each measurement time (based on the results in the original study paper)
In the reaction time test (RTT) for speed and accuracy, we gave the participants three tasks: Task A, Task B, and Task C. In Tasks A and B, the reaction was worst 60 minutes after alcohol administration, but did not correlate with BAC or BAAC. Although some reported the speed and accuracy correlate with BAC, this study showed no significant difference, probably because the BAC was moderate.
This study demonstrated the following three points. We presented clear numerical data showing the effects of alcohol on the cognitive function of healthy young adults under the condition of persistent presence of a certain concentration of alcohol in the body. This is a great achievement from the perspective of understanding proper drinking.
(1) The higher the BAAC after alcohol consumption, the lower the sustained attention.
(2) Working memory improves after alcohol consumption, although the higher the BAAC, the smaller the improvement.
(3) Even in people with ALDH2*1/*2, acetaldehyde is constantly metabolized during alcohol administration.
In addition to the effects on cognitive function shown in this study, we will further continue to evaluate alcohol’s various influences on physical and mental health and longer-term effects on a yearly basis to accumulate valuable data on alcohol consumption and increase our knowledge on its influences and effects on humans.
This study was conducted by the Core Technology Laboratories of Asahi Quality & Innovations, Ltd. (head office: Ibaraki; president: Manabu Sami), which is affiliated with Asahi Group Holdings, Ltd. (head office: Tokyo; president: Atsushi Katsuki) and responsible for the advanced research functions of the Asahi Group, in collaboration with Fumihiko Ueno, M.D., of the National Hospital Organization Kurihama Medical and Addiction Center. The results of this research were published in an international scientific journal Addiction on November 4, 2021. Asahi Quality & Innovations, Ltd. will continue to contribute to the health maintenance of our customers through the “Smart Drinking” campaign, which promotes various drinking styles, while working to prevent inappropriate drinking and raising awareness of proper drinking to realize a society with less alcohol-related problems.
※1. Smart Drinking
Asahi Breweries’ proposal of a variety of drinking styles that allow all people—both drinkers and nondrinkers—to smartly selects the appropriate alcoholic or non-alcoholic drinks according to their health conditions, moods and the situations—when they want to drink, when they cannot drink, or when they choose not to drink.
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Related Websites:https://www.asahibeer.co.jp/smartdrinking/
※2. Alcohol clamp method
A method of administering alcohol intravenously so that the target breath alcohol concentration can be maintained for an extended period of time. It was developed and first published in the late 1990s by Vijay Ramchandani, Ph.D., (then at Indiana University in the United States) and others. Since alcohol can be administered at a volume and rate calculated for each individual, variation in the levels of breath alcohol after drinking can be minimized. It is used for evaluating effects of several factors on alcohol excretion, such as sex, ethnicity, genetic variation in alcohol metabolizing enzymes, and food intake.
・S. O'Connor, S. Morzorati, J. Christian and T. K. Li 1998 Clamping breath alcohol concentration reduces experimental variance: application to the study of acute tolerance to alcohol and alcohol elimination rate Alcohol Clin Exp Res 22 1 202-10
・V. A. Ramchandani, J. Bolane, T. K. Li and S. O'Connor 1999 A physiologically-based pharmacokinetic (PBPK) model for alcohol facilitates rapid BrAC clamping Alcohol Clin Exp Res 23 4 617-23
※3. Continuous performance test (CPT)
One of the test methods (Clinical Assessment for Attention (CAT) tests) performed to assess the presence, degree, and quality of attention impairment for people with suspected attention disorders. In each of the three tasks (SRT task, X task, and AX task. AX task is used in this study), numbers are shown on the computer screen one by one and the test taker presses a key under specified conditions. CPT is used to evaluate persistent attention and selective attention.
※4. Paced auditory serial addition test (PASAT) for working memory
One of the test methods (Clinical Assessment for Attention (CAT) tests) performed to assess the presence, degree, and quality of attention impairment for people with suspected attention disorders. Test takers listen to the single-digit number read out from a CD player and add the numbers before and after the number heard. PASAT is used to evaluate working memory.
※5. Reaction time test (RTT) for speed and accuracy
Speed and accuracy of reactions are evaluated by determining how fast test takers press a key when an object appears on the computer screen.
