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Tomorrow's Anti-Anxiety Drug Is... Tylenol?

[caption id="attachment_165" align="alignleft" width="336" caption="Acetaminophen, the active ingredient in the brand-name drug Tylenol, likely helps buffer feelings of social pain in addition to relieving muscle and joint aches."]Acetaminophen, the active ingredient in the brand-name drug Tylenol, likely helps buffer feelings of social pain in addition to relieving muscle and joint aches.[/caption] Horror isn't the only film genre that specializes in dread. War movies like Apocalypse Now, sci-fi mysteries like Brazil and Blade Runner, and dramas like Melancholia and Requiem for a Dream all masterfully evoke a less violent, more subtle and pervasive sense that something is unwell with the world - that somewhere along the line, something went deeply wrong and now normality itself is unraveling before our eyes. The director David Lynch has arguably built his entire career on directing these kinds of films. In Lynch's universe, even the most banal moments are still somehow suffused with unnerving suspense. In films like Blue Velvet and Mulholland Drive, disturbing surprises erupt into scene after scene of buried tension, until every ordinary conversation feels like a trap waiting to spring. And then there's the infamous Eraserhead, where family life itself is transformed into an onslaught of surreal and nauseating images. It's hard to come away from these movies without feeling that a little of Lynch's unease has rubbed off on you. So when a team of researchers at the University of British Columbia set out to describe and treat an ancient biological alarm system buried deep within the human brain, they turned to Lynch's films as an analogy for - and a set of examples of - the feeling of omnipresent yet maddeningly vague "wrongness" that seems to underlie many anxiety disorders. "It's tough to articulate this feeling of ominous uncertainty; this general sense that you can't predict your environment," says Dan Randles, a PhD student at UBC's psychology department who led a recent study that examined an unusual type of intervention for anxiety disorders. "We don't have an exact scientific description for this quality yet, but we feel that Lynch is a good example of an artist who conveys it throughout his work." Randles, along with UBC professor Steve Heine, set out to test a new approach to issues that lie at the heart of anxiety, whether it takes the form of social nervousness or existential dread. What if, they wondered, instead of drugging patients out of feeling anxious, we could target and disarm the neural alarm system that raises those feelings in the first place? What if, in other words, we could trick a habitually anxious brain into seeing unpredictable circumstances as relatively harmless? Randles and Heine think that one way to achieve this may be with a new take on an old drug: Acetaminophen, better known by its brand name, Tylenol. Pharmaceutical tradeoffs Today, most people who suffer from chronic anxiety have to choose between a fairly limiting set of treatment options. Some psychiatrists prescribe antidepressants - such as Zoloft and Paxil - that target the brain's serotonin receptors, but these drugs can decrease a person's sex drive and invoke a sense of emotional numbness. Other doctors recommend benzodiazepines like Xanax and Klonopin, which enhance the effect of the inhibitory neurotransmitter chemical gamma-aminobutyric acid (GABA) - but these drugs often cause drowsiness and impair memory. While opioids like codeine and oxycontin - distant descendants of morphine - aren't widely prescribed for anxiety, patients still manage to obtain these drugs through illegal channels and use them to self-medicate. Herbalists, meanwhile, recommend infusions of passionflower and valerian, though the jury's still out on whether these herbs have any concrete clinical benefits. And then, of course, there's marijuana - a substance that calms some minds while promoting paranoia in others - and alcohol; far and away the most popular anti-anxiety drug in the world. One problem with many of these drugs - aside from their myriad side effects - is that patients tend to grow dependent on them. What's more, many lend themselves to off-label recreational use, while even those that are illegal in the U.S. have continued pouring into the country in record numbers over the past few years. In short, patients are left with very few anti-anxiety options that won't get them hooked, dull their intellect or mute their passions. This has led some researchers to to wonder if it might be possible to tackle our reactions to unexpected events on a deeper level - to simply mute certain types of error messages as they arise deep in the brain. Varieties of pain In principle, the idea behind this new approach to anxiety treatment isn't all that different from the goals of yoga and other forms of meditation: Both seek, in their own ways, to reconcile an individual's inner thoughts with the surrounding world. But where meditation aims to produce a sense of calm by focusing attention on the body and breath instead of on external pressures, acetaminophen seems to disarm some of the brain's initial emotional reactions to unexpected events - almost as if it's downplaying those events' significance right from the start. The question of just how acetaminophen achieves this - especially while leaving other intellectual and emotional reactions intact - remains something of a mystery to psychiatrists and neuroscientists alike. In fact, to this day, no one's entirely sure how acetaminophen produces many of its more famous effects, either. We've known for decades that the drug relieves muscle and joint pain, eases fever, and reduces inflammation; probably by inhibiting the activity of a chemical known as cyclooxygenase (COX), which in turn contributes to the formation of other molecules that affect blood clotting, muscle relaxation and nerve sensitivity - along with a dizzying variety of related biological processes. The net result seems to be that feelings of pain and tension ease up a bit throughout the body. The plot thickens, though, when we raise the question of what exactly we mean by "pain." Researchers are becoming increasingly convinced that physical pain and social pain depend on many of the same chemicals and neural processes - and that, much like in cases of synesthesia, where musical notes or days of the week are perceived as having specific colors or tastes, physical and mental anguish often overlap and contribute to one another. Thus, psychologists have taken to describing what they call "pain-related affect" (pronounced "aff-fect") - subjective feelings or impressions of anguish that accompany almost any harmful stimulus, whether it's a stubbed toe or a drawn-out divorce - or even a disturbing movie scene. Though no one's quite sure what this affect is in neurological terms, it does seem to be one of the unpleasant sensations acetaminophen relieves. It takes a lot more digging, though, to uncover the process by which this plays out in our brains. Humor and horror One major player in pain-related affect - and, in fact, in all sorts of situations where our bodies and minds realize something's gone wrong - is a brain area known as the cingulate cortex. Buried deep in the interior of the cerebrum - that cauliflowery mass that comprises most of a human brain - the cingulate cortex is divided into anterior (front) and posterior (rear) sections, both of which appear to play vital supporting roles in the process of consciousness. [caption id="attachment_167" align="alignright" width="441" caption="The anterior cingulate cortex (highlighted in yellow here) plays central roles in error detection, anticipation of reward and punishment, and certain types of anxiety."]The anterior cingulate cortex (highlighted in yellow here) plays central roles in error detection, anticipation of reward and punishment, and certain types of anxiety.[/caption] The posterior cingulate cortex (PCC)'s role is the more elusive of the two. Studies of comatose and anesthetized patients have found that it's likely necessary for consciousness and working memory; but beyond that, no one's really sure what it actually does. The anterior cingulate cortex (ACC), on the other hand, is relatively easy to study, because it lights up with activity in almost any situation involving conflict - especially if that conflict involves the potential of making a mistake or getting hurt. The ACC gets highly active when people perform the Stroop task (that game where you try to read off the names of colors that are printed in other colors), and in lots of other games where winning and losing are at stake. It also goes nuts when we're socially anxious, and when we're held in suspense. "All these situations have to do with 'errors' in the behavior of one's environment," Randles says. "The ACC seems to be involved in trying to evaluate what it is that's gone awry with the nervous system's prediction process - and that activation seems to be triggered when negative affect arises." If it wasn't for that negative affect, our brains might react very differently to suspense and surprises, since many of the same factors that make us most tense and anxious - unpredictability, defiance of expectations, disjointedness - are also those that can make us laugh the hardest. Many comedians would even say that suspense is a central component of humor. So what makes the difference between humor and horror? "It seems to be whether or not people expect that something's going to be a little 'off,'" Randles says. In an earlier study, another team of UBC psychologists demonstrated that if people are shown a disjointed narrative and told in advance that it's going to be a joke, they won't be upset by the story, even if they don't find it particularly funny. But people who didn't receive that advance assurance react to the same story with nervousness, confusion and anxiety. "It's an interesting difference between the 'expected unexpected' and the 'unexpected unexpected,'" Randles says. "The latter seems to bother us a lot more." And since the ACC seems to be one of the main brain areas that responds to differences between the two, it's been drawing an increasing amount of attention in psychological and neuroscientific research. Negative negativity Although no researcher has yet put forth a specific theory of how acetaminophen modifies the ACC's activity on a neurochemical level, a 2010 study did demonstrate a clear relationship between acetaminophen and that brain area. In the study, investigators split volunteers into two groups - one group that took acetaminophen every day for three weeks and a second group that took a placebo for the same length of time - then put the volunteers into a functional MRI scanner and asked them to imagine situations involving social rejection. The brain scans were clear: The ACCs of people who'd been taking acetaminophen didn't respond nearly as strongly to feelings of social rejection as the ACCs of people who'd been on a placebo. The drug was buffering feelings of social pain - not by muting people's emotions or fears, but by somehow toning down the brain's central sense that anything was wrong or at risk in those particular scenarios. Thus, Randles felt the psychiatric field was ripe for a different type of examination of acetaminophen's impact on ACC-related phenomena - one that would focus not on brain scans, but on how the volunteers themselves subjectively perceived and described the drug's effect on their reactions to surreal or uncertain events. To start, Randles and Heine gathered 121 volunteers and split them into two subgroups - an acetaminophen subgroup and a placebo subgroup, like in the 2010 study. This time, though, instead of giving the volunteers a daily dose of the drug, the researchers gave them a single 1000-milligram dose, waited about 50 minutes, then asked them to think about their death and how it made them feel. Then the participants were given an opportunity to affirm a belief that was important to them, as past research has shown that when people feel uneasy, one common way for them to address that anxiety is to focus on things that still make sense, and things they feel strongly about. As Randles expected, the volunteers who'd taken acetaminophen expressed much less negativity in regard to the idea of their own deaths than the placebo group did. For act two of their study, Randles and Heine gathered a group of 207 volunteers, split them again into acetaminophen and placebo subgroups, and sat all the volunteers down to watch - of course - a creepy short film by David Lynch, called Rabbits. Then - as if this experiment wasn't already surreal enough - the researchers followed up by asking both subgroups of volunteers how they'd punish someone who participated in the Vancouver Stanley Cup riots of 2011. Again, as expected, people who'd taken acetaminophen chose more lenient punishments than those who'd been given a placebo. The big surprise, though, came when Randles and Heine asked their volunteers to describe how acetaminophen made them feel. As it turned out, the volunteers didn't think the drug made them feel any different at all - in fact, some people who took acetaminophen were sure they'd been given a placebo instead. "So far, we can't get anyone who's taken acetaminophen to self-report or consciously identify a change in mental state," Randles says - despite the fact that their responses to the study's questions were markedly, measurably different from those of people who'd taken a placebo. As far as the volunteers could tell, they just felt normal - except that the new normal didn't include the same old emotions, which makes for an altered state that's pretty unusual, to say the least. The only detectable psychological effects of acetaminophen, then, appear to fall into the "negative" category - not negative in the sense of "unpleasant," but in the sense that none of the volunteers who took the drug noticed anything unusual or "extra" in their feelings or perceptions. And if it hadn't been for the tests administered by Randles and Heine, they might never have noticed anything was missing, either. In spite of all this, acetaminophen is far from a miracle drug. Randles emphasizes that his study wasn't intended to assess any therapeutic use of acetaminophen. In fact, clinical studies have linked the drug with liver failure - especially when taken in high doses over long periods of time (Randles' 1000-mg dose is a safe median; the maximum recommended dose is 3000 mg per day) - and its effectiveness as a remedy for general anxiety remains largely unstudied. Though the drug - or perhaps more useful chemical analogues of it - may have psychiatric applications in the near future, today's patients may just have to remain in suspense a little longer. Images: Tylenol by Ragesoss; MRI anterior cingulate by Geoff B Hall

The views expressed are those of the author and are not necessarily those of Scientific American.

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