Side Effects: The Truth Behind the Fiction
From the director of Oceans Eleven comes a new thriller, Side Effects, about the potentially dangerous consequences of psychoactive drugs. But how much of the film is fantasy?
By Jim Thornton
The Informant was the first screenplay that Scott Z. Burns sold to Hollywood. When renowned director Steven Soderbergh summoned him to Manhattan for a script consult, Burns immediately booked a flight from L.A. and packed up the essentials. These included two popular Rx drugs: Ambien to help him sleep and a beta blocker called Inderal, usually prescribed for hypertension. Burns' blood pressure was fine—his doctor had prescribed Inderal "off-label" as a never let them see you sweat psychological cosmetic. As a potent blocker of adrenaline, Burns knew from experience that a single tablet would steady everything from trembling hands to a quavering voice—allowing him to look, if not feel, cool and collected.
Thanks to the Ambien, Burns slept soundly the night before the big meeting, and the next morning, he popped what he believed was an Inderal. He'd arranged to eat breakfast with some friends in Brooklyn before the afternoon confab with Soderbergh. But by the time he reached the diner, he'd started feeling exceedingly strange.
"I think I may have taken an Ambien by mistake," he confessed to the doctor/husband of one of his friends, adding that both meds were blue pills of roughly the same size and shape.
"If so," the doctor replied, "you're going to have a very hard time remembering anything that happens today."
This prediction proved to be an understatement. "I remember going into the restaurant that morning," says Burns, "but I still have no idea how I got from Brooklyn to Soderbergh's office in Manhattan. I don't remember anything from our meeting. I have zero memory of how I got from his office to my plane at JFK, where I finally fell asleep. The whole experience, in retrospect, was actually quite terrifying."
FLASH FORWARD SEVERAL YEARS, and the latest Burns-Soderbergh cinematic collaboration, Side Effects, opens in theaters nationwide February 8. A contemporary noir set against the backdrop of America's pharmaceutical-marinated culture, the thriller stars Rooney Mara as a deeply troubled young woman and Jude Law as a psychiatrist trying to alleviate her suicidal depression via a combination of talk therapy and medication. When standard antidepressants fail to lift her mood, he prescribes a brand new antidepressant, Ablixa, whose name and side effect profile Burns fabricated for the movie with the help of a real-life forensic psychiatrist, Sasha Bardey, M.D. Under Ablixa's apparent influence, her mood and sex drive soar even as her behavior sinks quickly in the opposite direction.
"I asked Sasha one day," Burns recalls, "if someone were to feign mental illness and use that as a cover up for a crime, would it work?" Bardey replied that such attempted scams were, in fact, dispiritingly common. But so, too, were cases where real mental illness truly does rob patients of criminal responsibility for their actions. When you also factor in medications with potent and often unpredictable psychoactive side effects, Bardey added, questions of criminal intent have become increasingly complex and difficult for courts to untangle.
"A lot of what I did at Bellevue and what I now do in private practice," explains Bardey, "is try to figure out what's really going on in these situations. You get people hoping to beat the system by claiming voices commanded them to kill, say, a business partner because he was the Antichrist. Or they say that they couldn't help themselves, that Prozac made them do it."
SELF-SERVING AS SUCH EXCUSES OFTEN PROVE, sometimes a patient really is telling the truth. "In our criminal justice system, you need two basic components for a criminal conviction," explains Michel Cramer Bornemann, M.D., a sleep medicine expert and lead investigator for Minneapolis-based Sleep Forensics Associates, a company specializing in evaluating the impact of sleep-walking behaviors and drugs like Ambien on criminal culpability. "The first component is actus rea—you need to show, in other words, that the person has committed the physical act of the crime. The second is mens rea, or a guilty mind, which means the person has committed the act intentionally and voluntarily."
The first is usually easy to prove, the second more problematic. Many dog owners have no doubt witnessed the absence of mens rea firsthand. Under normal circumstances, your best friend shows you nothing but unconditional love. But try to move him when he's fast asleep and chances are good he'll reflexively snap at you, maybe even draw blood. Hence the maxim: Let sleeping dogs lie.
Though documented cases of reflexive, involuntary violence towards oneself or others are uncommon, a wide number of heavily prescribed prescription drugs have been linked in recent years to the potential, at least, for aggressive outbursts in certain susceptible individuals. The list includes drugs like Chantix, a smoking cessation drug that targets brain chemicals involved in drive, reward, and pleasure; Tamiflu and Singulair, prescribed for influenza and asthma, respectively, and which both act on inflammatory pathways to increase suicidal thinking in some patients; and even those ubiquitous cholesterol-lowering statin drugs, like Zocor and Lipitor, which researchers have known for decades correlate with a slightly elevated risk of dying violently (suicide, homicide, car crashes, and the like).
Even widely available OTC supplements, like popular muscle-building "fat-burner" concoctions, can reportedly tip vulnerable individuals over the edge. Bardey, for his part, testified successfully on behalf of a young man who, under the influence of such a mix of stimulants, became "hypersexual" at work. "He went after one of his female coworkers," says Bardey, "and when she rebuffed him, he disrobed and began masturbating in front of the whole office. This was a guy with no underlying psychopathic or sexual deviancy. It was a purely a side effect of the 'ripped fuel' mixture he was taking."
IN SIDE EFFECTS, the allegedly demon drug Ablixa is based on two different classes of pharmaceuticals that, in real life, have earned the most notorious reputations of any for inducing destructive behavior: SSRI antidepressants (like Prozac, Celexa, Zoloft, and Paxil), and so-called "novel hypnotic" sleep drugs (like Ambien, Sonata, and Lunesta). Burns and Bardey acknowledge that no actual drug on the market combines these two properties in a single pill. But if Ablixa remains a fully fictional chimera, plenty of real-life patients may be simulating something quite like it by combining both an SSRI for mood and a hypnotic to counter the insomnia antidepressants can cause.
Burns, for his part, says he has no personal experience with SSRIs, but he did know that the FDA has for years mandated a "Black Box" warning on the label alerting doctors and patients about the risk of increased suicidal events in children, adolescents, and young adults prescribed these medications.
"I also knew from my own bad Ambien trip," he adds, "that when the more primitive parts of your brain grab the controls, how easy it can become for a person to act really inappropriately. When I began writing Side Effects, the question for me was essentially this: if a drug company is suddenly in charge of your behavior, how exculpatory is it?"
Big Pharma, to be sure, is guilty of many well-documented sins, including the willful suppression of negative research data in order to exaggerate a drug's benefits while hiding rare but potentially lethal side effects. (See Merck's arthritis drug, Vioxx, pulled from the market in 2004.) As ethically challenged as such practices have been, would drug companies truly risk marketing a medication like the fictional Ablixa with its potential to unleash a murderer from within? Are they, in fact, already doing so via the one-two punch of SSRIs and novelty hypnotics?
SSRIs and "Suicidal Events"
CONSIDER FIRST THE EVIDENCE about SSRIs link to mayhem. The first case studies correlating these drugs with increases in suicidal thinking in young patients were published in 1990, says David Brent, M.D., a professor of psychiatry who holds the Endowed Chair for Suicide Studies at the University of Pittsburgh School of Medicine. Not long afterward, the British equivalent of our FDA decided to undertake a more comprehensive review of all the published and unpublished data on one particular SSRI, paroxetine, and its effects on adolescent depression. Their conclusion was that paroxetine did, indeed, result in a slight increase in "suicidal events" compared to patients on placebo.
The FDA soon followed up with its own extensive review, and after agreeing that the effect was real, issued its Black Box warning. Since then, other researchers have shown that this side effect seems limited to patients under 24. From 25 to 39, suicidal events are the same in patients on the active drug and placebo. And by age 40, SSRIs actually reduce suicidal events.
"Of course," says Brent, "no one wants their patients at any age to have new or worsening suicidal events, but it's important to put this in clinical perspective." For one thing, he explains, the term "suicidal event" can include everything from a fleeting thought of self-harm to an actual completed suicide. "In the 4000 adolescent patients studied by the FDA who were treated by antidepressants," says Brent, "there were no completed suicides. The majority of 'events' were new or increased suicidal thoughts, mostly passive death wishes."
Moreover, the differences between the active drug and placebo groups, though statistically significant, were tiny—0.9 percent. This did not, however, stop the mass media from focusing on the relative, as opposed to absolute risk, that these drugs pose for young patients. "Headlines proclaimed that Drugs Double the Risk of Suicide," recalls Brent. "This is a lot more dramatic, and misleading, then saying that there is less than a 1 percent difference in the rate of nonlethal events between drug and placebo."
If SSRIs don't increase rates of completed suicides, the evidence is even less compelling that they can turn otherwise nonaggressive patients into involuntary murderers—much to the chagrin of criminal defense attorneys who are always on the outlook for new sources of reasonable doubt.
There is, however, one notable if still putative exception here, says Bardey. When SSRIs are inappropriately prescribed to people with bipolar illness, as opposed to regular depression, they can sometimes "flip" a patient from melancholia to mania. "And mania," says Bardey, "has definitely been linked to increased aggression in some people."
Novel Hypnotics and Bizarre Sleep Behavior
THE RESEARCH LITERATURE AND INTERNET ALIKE ABOUND with sordid tales of bizarre behavior—from so-called sexsomnia to midnight food orgies—triggered in some sleeping patients UIA (under the influence of Ambien.) In Australia, where Ambien is marketed under the brand name Stilnoct, patients in the throes of such odd involuntary behaviors are known as Stilnoct zombies—and for good reason. ()
Dr. Bornemann says that most of us assume that when we fall asleep, our whole brains follow us into the Land of Nod. But to those prone to sleep walking and other peculiar sleep behaviors known as parasomnias, this isn't always the case. Ditto for more than a few patients on sleep drugs like Ambien.
"Sleeping pills," Bornemann explains, "can put the brain's prefrontal cortex asleep while leaving the more primal parts of the brain still awake." The former "intelligent brain" is what we use to form conscious intent. The latter, sometimes referred to as our primitive "reptilian" brain, drives basic hungers for food, sex, and other basic urges. Without our awake intelligence to override or moderate such drives, behavior can become reflexive and bizarre. Case-in-point, says Bornemann, are the spectacularly revolting midnight snacks he's seen some sleep eaters consume while on Ambien, from frozen meat and salt sandwiches, to buttered cigarettes and swigs of bleach.
As bizarre as involuntary sleep behavior can be, there are nevertheless limits to what sleeping pills can "make" a person do. Sexual assault, for example, has landed more than a few Ambien patients in legal limbo. But when is the drug really the culprit—and when is it just an excuse?
"Sexual activity when a person is truly asleep has a couple hallmark features that helps us determine the answer," explains Bornemann. For one thing, it almost always happens when people are in close proximity in the same bedroom. Your sleeping dog won't get up and rummage the house to find and bite you. Rather, he reacts reflexively only when disturbed. It's the same way with involuntary sexual behavior: It's a primal, reflexive behavior triggered by somebody sleeping nearby. If a perpetrator stalks his victim, drugs like Ambien are not to blame.
Drug-induced behavior also takes place within a predictable timeframe—usually 1 to 3 hours after a person has taken the sleeping pill. If criminal acts occur much outside this window, the drug usually bears little responsibility.
Further complicating matters, says Bornemann, is the distinction that our legal system makes between voluntary and involuntary intoxication. He's testified in trials where he was certain that hypnotics had robbed a defendant of his capacity for a guilty mind. But to win an acquittal, the defendant had to have taken Ambien exactly as prescribed—the right dose, taken at home right before bedtime, and with no alcohol or street drugs to alter or boost its effects. Any wavering from doctor's orders, in other words, invalidates the defense because of an assumption that the patient should have foreseen the potential for danger.
ALL OF WHICH CIRCLES US BACK TO ABLIXA, the fictitious movie drug that may or may not set loose Rooney's inner reptile upon an unsuspecting world. Did the drug make her do it? You'll have to watch this stylish thriller to find out.
In the meantime, consider a word of counsel from scriptwriter Burns. If you happen to find yourself on a red-eye flight, and the passenger beside you wakes up glassy-eyed and starts walking around the cabin, consider alerting the flight attendant.
"After my own Ambien adventure," he says, "I'm always afraid someone like me might go for a wander and involuntarily throw open the airplane door. Maybe that's just my deeply paranoid writer side coming out."
Maybe yes, maybe no. But if nothing else, it does sound like a great premise for a sequel—Side Effects 2: Unleashed Snakes on a Plane starring Samuel L. Jackson.
Jim Thornton Jim Thornton is a National Magazine Award–winning health writer and champion masters swimmer.
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