Acetaminophen is helping you deal with your headache but making you more willing to take risks

While acetaminophen is helping you deal with your headache, it may also be making you more willing to take risks, a new study suggests.

People who took acetaminophen rated activities like “bungee jumping off a tall bridge” and “speaking your mind about an unpopular issue in a meeting at work” as less risky than people who took a placebo, researchers found.

Use of the drug also led people to take more risks in an experiment where they could earn rewards by inflating a virtual balloon on a computer: Sometimes they went too far and the balloon popped.

“Acetaminophen seems to make people feel less negative emotion when they consider risky activities—they just don’t feel as scared,” said Baldwin Way, co-author of the study and associate professor of psychology at The Ohio State University.

“With nearly 25 percent of the population in the U.S. taking acetaminophen each week, reduced risk perceptions and increased risk-taking could have important effects on society.”

The study extends a series of studies led by Way that have shown acetaminophen – the main ingredient in the pain-reliever Tylenol and nearly 600 other medicines—has psychological effects that most people don’t consider when they take it.

Previous research by Way and his colleagues has shown that acetaminophen reduces positive and negative emotions, including hurt feelings, distress over another’s suffering and even your own joy.

Way conducted the current study with Alexis Keaveney, a former doctoral student at Ohio State, and Ellen Peters, a former professor at Ohio State who is now at the University of Oregon. The study was published online in the journal Social Cognitive and Affective Neuroscience.

In one study, 189 college students came to a lab and took either 1,000 mg of acetaminophen (the recommended dosage for a headache) or a placebo that looked the same. After waiting for the drug to take effect, the participants rated on a scale of 1 to 7 how risky they thought various activities would be.

Results showed that those under the influence of acetaminophen rated activities like bungee jumping, walking home alone at night in an unsafe area of town, starting a new career in your mid-30s, and taking a skydiving class as less risky than those who took the placebo.

The effects of acetaminophen on risk-taking were also tested in three separate experimental studies.

Across these studies, 545 undergraduate students took part in a task developed in 2002 that is often used by researchers to measure risk-taking behavior.

Other researchers have shown that taking more risk on this task predicted risky behaviors outside the laboratory, including alcohol and drug use, driving without a seatbelt and stealing.

In the task, participants click a button on the computer to inflate a balloon on their computer screen.

Each time they inflate it they receive virtual money. They can stop at any time and add the money to their “bank,” and move on to the next balloon. But there is risk involved.

“As you’re pumping the balloon, it is getting bigger and bigger on your computer screen, and you’re earning more money with each pump,” Way said.

“But as it gets bigger you have this decision to make: Should I keep pumping and see if I can make more money, knowing that if it bursts I lose the money I had made with that balloon?”

For those who took the acetaminophen, the answer was: Keep on pumping. Results showed that those on the drug pumped more times than those on the placebo and had more burst balloons.

“If you’re risk-averse, you may pump a few times and then decide to cash out because you don’t want the balloon to burst and lose your money,” he said.

“But for those who are on acetaminophen, as the balloon gets bigger, we believe they have less anxiety and less negative emotion about how big the balloon is getting and the possibility of it bursting.”

The results have a variety of real-life implications, Way said.

For example, acetaminophen is the recommended treatment by the CDC for initial COVID-19 symptoms.

“Perhaps someone with mild COVID-19 symptoms may not think it is as risky to leave their house and meet with people if they’re taking acetaminophen,” Way said.

Even everyday activities like driving presents people with constant decisions involving risk perception and assessment that could be altered by use of the painkiller.

“We really need more research on the effects of acetaminophen and other over-the-counter drugs on the choices and risks we take,” he said.

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Acetaminophen (i.e., paracetamol; the active ingredient in Tylenol) has long been known to be an analgesic and antipyretic. However, a growing body of work is finding that the effects of acetaminophen extend beyond physical pain and fevers to psychological processes.

It is therefore natural to ask whether acetaminophen might affect people’s social behavior. This is important because acetaminophen is the most commonly used pain medication in the United States with 23% of the population taking it each week1. If acetaminophen impacts social behavior, there could be broad implications from the personal to the societal level.

Trust is commonly studied in behavioral economics because it is a critical component of social relationships2, and is vital for the functioning of the institutions that form the backbone of large-scale integrated societies such as governments, businesses, and religions3,4.

Acetaminophen is of interest because it has recently been found to influence social and affective processes, on which these behaviors are thought to rely. For example, acetaminophen reduced self-reported hurt feelings and neural responses associated with experiences of social pain5,6.

It also reduced distress about another person’s physical and social misfortunes7. Recently, acetaminophen was shown to reduce affective responses to both negative and positive emotional images8. Based on these findings, we sought to examine whether acetaminophen would have effects on trust.

Here we investigate the effects of acetaminophen on trusting behavior using a combination of survey data on interpersonal trust and social integration, and laboratory experiments using a social preference game from experimental economics, the trust game. We find that acetaminophen use is associated with reduced neighborhood trust and feelings of social integration.

In a series of laboratory experiments, we find that an acute dose of acetaminophen reduces the correlation between expectations about trustee repayment and investments in the trust game. Based on this result of acetaminophen reducing the correspondence between expectations and behavior, we ran larger experiments with a trust game in which we manipulated expectations about the trustees.

In this context, we found that acetaminophen increased behavioral trust, regardless of expectations. Our results point to possible effects of acetaminophen on trust-related behavior and underscore the likely important influence of various contextual and environmental factors on the effects of this drug.

Discussion
Across an analysis of data from a national survey and five laboratory experiments, we found suggestive evidence that acetaminophen may influence interpersonal trust perceptions and behavior.

In a national sample, greater acetaminophen usage was associated with reduced perceptions of trust in one’s neighborhood and reduced feelings of social integration. Additionally, in a series of experimental studies, we found evidence that acetaminophen reduced the influence of self-generated expectations about trustee behavior on investor trusting behavior in a trust game.

In large follow-up experiments using a trust game where we manipulated expectations about trustee behavior, investors on acetaminophen entrusted more to their anonymous partners, regardless of expectations.

Our work is the first demonstration that the widely-used, over-the-counter drug acetaminophen may affect the fundamental social process of trust.

Thus, the results of our study add to the emerging body of work showing that acetaminophen has psychological and behavioral effects. Though a couple of prior studies have found effects of acetaminophen on decisions, our results go beyond what has been shown before. DeWall and colleagues19 suggested that acetaminophen may reduce the endowment effect, but the endowment effect is not typically attributed to social factors to the degree that the trust game is.

Instead, it is generally attributed to a differing focus on positive versus negative attributes20. Another set of studies found effects of acetaminophen on the severity of hypothetical punishments in response to norm violations21. Our findings are largely consistent with this work, but we use real decisions in well-established economic tasks.

Overall, our results suggest possible effects of acetaminophen on trust-related behavior. However, the complexity of our findings suggest that if acetaminophen does indeed influence trust behavior, its effects are unlikely to be straightforward, and critically influenced by situational factors. In what follows, we discuss several of these potential moderating factors.

Acetaminophen’s Psychological Effects
Although the investigation of acetaminophen’s psychological effects is in its infancy, one mechanism that may account for many of the prior findings is that acetaminophen reduces the extremity of affect and its effects on behavior5,6,7,8,21.

For example, a recent study found that acetaminophen reduced the extremity of participants’ evaluations of both positive and negative emotional images8. That study also found that acetaminophen had no effect on the extremity of a non-evaluative judgment (i.e., the amount of blueness in the images)—indicating that acetaminophen’s dampening effect may be selective for affect.

Our experiments found mixed support for affective dampening. While acetaminophen reduced the relationship between expectations and anticipated affective responses in Experiment 2, it did the opposite in Experiment 3, which resulted in a null result in the combined analysis.

Taken together, these mixed findings suggest that acetaminophen may exert these effects by an affective process not captured by self-report or some non-affective process. Some of our other results are in line with an affective dampening mechanism. Acetaminophen reduced the relationship between counterfactual returns and guilt in trust game trustees16.

Furthermore, acetaminophen reduced the influence of trial-to-trial fluctuations in fairness on proposal acceptance among ultimatum game responders15. Future work should seek alternative mechanisms or draw on the rapidly growing literature on affect and decision-making to clarify when, if, and how acetaminophen’s blunting of affect is likely to influence interpersonal economic decision processes. Consulting these lines of work will be particularly important given the complex nature of affect’s effects on decisions22,23,24.

One psychological mechanism by which acetaminophen could influence trust behavior is by reducing feelings of betrayal aversion11,25. Dampened betrayal aversion would produce an overall increase in the amounts invested and thus could account for the effect of acetaminophen in Experiments 4 and 5.

Neuroimaging work has also associated anterior insula activity with betrayal aversion26 and acetaminophen has been shown to dampen anterior insula responses related to social pain5, which lends further support to reduced betrayal aversion as a possible mechanism. However, reduced betrayal aversion cannot account for all of our results. In particular, it does not provide a compelling explanation for the reduced correspondence between expectations and investments observed in Experiments 1–3 because betrayal aversion has generally been observed when controlling for expectations in past studies27.

A better understanding of acetaminophen’s psychological effects would also help to improve understanding of the survey data results. One issue is that the survey data is correlational and so it could be that low levels of neighborhood trust lead to greater pain or illness, which brings greater acetaminophen consumption.

Though the time period between when the participant took the drug and completed the survey is unclear, the fact that acetaminophen influenced behavioral trust in our placebo-controlled experiments makes it plausible that acetaminophen use could affect perceptions of neighborhood trust. Still, if acetaminophen is indeed influencing perceptions of neighborhood trust, the mechanism remains unclear.

Furthermore, it is unclear why there was a negative correlation between acetaminophen usage and neighborhood trust while an acute dose of acetaminophen increased behavioral trust in Experiments 4 and 5. One relevant factor might be age differences between the sample used in the national survey (middle aged and older adults) and the experimental data (young adults). Inflammation increases with age28 and because acetaminophen inhibits the brain effects of inflammation29 it may have age-dependent effects on trust.

Another possibility is that while our laboratory experiments used an acute dose of acetaminophen, the survey measured chronic usage. Chronic acetaminophen use may produce neural adaptations such as alterations in receptor density. It is then these receptor changes that could be responsible for the reduced neighborhood trust.

A third possible explanation stems from the fact that our experimental results found that acutely administered acetaminophen increased trust behavior towards partners who were explicitly expected to betray that trust.

Regular acetaminophen consumption may therefore increase the frequency with which people misplace trust in others whom they would otherwise avoid.

Increased rates of misplaced trust would thus also increase their experiences of betrayal, which may ultimately lead to the development of more distrustful perceptions of the world.

A longitudinal experiment examining effects of chronic acetaminophen consumption on social behavior and social perceptions would shed light on these and other possible explanations.

Reputational Knowledge about Partner and Differential Effects of Acetaminophen
An intriguing result of these studies is that acetaminophen had different effects depending on the implementation of the TG-I. While acetaminophen increased trusting behavior overall when participants were provided with expectations for trustee behavior, it did not have this effect when participants were required to make their decisions without any information about their partner.

Consistent with the different pharmacological effects in these different versions of the TG-I, prior neuroimaging results suggest that the neural processes involved in making trust decisions vary across instantiations of the TG-I. For example, an fMRI study found that the anterior insula showed greater involvement during trust decisions when lacking prior information about the reputation of a trustee than when information was not provided30.

This is in line with a recent meta-analysis that found greater anterior insula involvement during one-shot TG-I games, where there is a lack of knowledge about the partner, relative to multiround trust games, where the trustor plays with the same partner over multiple trials31.

Experiments 1–3 of the present study were one-shot decisions without any information about past behavior. In contrast, because the investors in Experiments 4 and 5 formed expectations about each trustee’s reciprocity based on information about past behavior, these experiments bear some similarity to multiround trust games.

The same meta-analysis did not find any overlap in neural activations between one-shot and multiround trust games, indicating that it is feasible for a drug such as acetaminophen to have differential effects in separate instantiations of the TG-I due to the different neural circuits involved.

These neural differences across instantiations of the TG-I suggest that trust decisions made in different contexts may rely on different psychological processes that could be differentially impacted by acetaminophen31.

Although a few studies have examined differences in trusting behavior across repeated interactions when investors were either given prior expectations or not30,32, more research is needed to understand how trust decisions differ psychologically when information predicting reciprocity is or is not available.

One possible difference is that when participants are not provided with any expectations, they must generate them on their own, presumably by drawing on past experiences with other people in similar situations. This process is likely not required when participants are provided with expectations.

In this way, our two trust games parallel the distinction between decision-making under risk versus ambiguity, which have also been shown to rely on different neural processes33,34. That is, Experiments 1–3 reflect decisions made under social ambiguity while Experiments 4 and 5 entail decisions made under social risk. In this way, acetaminophen might be expected to interact with expectations to impact trust in socially ambiguous situations but to affect trust behavior directly when the social risk is known. Future work should examine trust decisions made in different contexts and consider the processes involved in order to make predictions about what sorts of effects acetaminophen might have.

Broader Implications
Though the effects found in our lab experiments were small, a relatively minor change in a person’s behavior can have an amplified impact in the context of more dynamic and repeated social interactions (e.g., see ref.35). This is especially likely to be the case with alterations to a fundamental social process such as trust, which is important across a wide-range of social contexts36 and is critical to the development and maintenance of relationships37,38.

However, these pharmacological effects could also have implications that extend beyond interpersonal relationships. For example, less trust is associated with myopic economic choices and boosting community-level trust can reduce the discounting of future economic outcomes observed among people with low incomes39.

At a societal level, the amount of interpersonal trust among a country’s population is predictive of future economic growth3 and is associated with increased participation in civic activities and decreased government corruption4. Thus, pharmacological alterations to trust may trigger reverberations that are felt throughout a social system.

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More information: Alexis Keaveney et al. Effects of acetaminophen on risk taking, Social Cognitive and Affective Neuroscience (2020). DOI: 10.1093/scan/nsaa108