Rita was the wife of a chemist at the Swiss drug company CIBA who concocted a new stimulant by modifying amphetamine, and Rita enjoyed tennis. The chemist shared his invention with his wife, and—to their delight—the substance had a wonderful effect on her tennis game. He named the new drug in honor of his darling. He named the new drug Ritaline.
In 1956, CIBA began marketing this drug as Ritalin in the United States, for a wide range of adult psychiatric maladies. But soon, evidence emerged that it might benefit what were then called “disturbed children.” In a landmark randomized clinical trial conducted in Baltimore by the child psychiatrist Leon Eisenberg and the child psychologist Keith Conners (then at Johns Hopkins) that was published in 1963, the drug improved behavioral symptoms, from “demanding” and “disobedient” to “leads into trouble” and “lying.” The diagnostic label “attention deficit hyperactivity disorder” (ADHD) did not yet exist, but the pair had put the drug on the child psychiatry map.
This story of the origins of Ritalin is described in journalist Alan Schwarz’s hard-hitting new book, ADHD Nation: Children, Doctors, Big Pharma, and the Making of an American Epidemic But Schwarz proceeds to show another side of the story, describing an episode that occurred in the aftermath of the trial. Some weeks after the publication of Conners and Eisenberg’s paper, the pair received a curious visitor: A man in a suit showed up at Eisenberg’s office and, with his protégé Conners looking on, gratefully glided a slip of paper across his desk, for what he referred to as “further studies.” The man, Schwarz notes, was a representative from CIBA (later to become a part of today’s drug giant Novartis), and the slip of paper was a check for $5,000. Eisenberg, Schwarz continues, tucked the check into a desk drawer, warned Conners to “watch out for these guys,” and never spoke of the day thereafter.
And thus was the study of ADHD therapy linked to Big Pharma’s silver from almost its very first day.
The addictive potential of amphetamines was well known by the time Conners and Eisenberg carried out their trial in the 1950s. “America’s First Amphetamine Crisis,” as the historian Nicolas Rasmussen describes it in a paper the American Journal of Public Health, began soon after the drugs’ discovery in 1929. The drug firm Smith, Kline and French began marketing them first as a decongestant (in inhaler form), he notes, and later as a treatment for depression and weight loss. During World War II, the US military provided amphetamines as a stimulant for soldiers, some of whom—Rasmussen describes—became addicted. In the following decades, production skyrocketed and addiction became a major public health problem.
Rasmussen gives sense of the truly massive amphetamine use, addiction, and resultant suffering that followed. By 1962, he notes, 80,000 kg of amphetamine was being produced annually in the US, translating into some 8 billion typical 10mg doses, or approximately 43 doses for every single person in the country each year. “The original amphetamine epidemic,” he asserts “was generated by the pharmaceutical industry and medical profession as a byproduct of routine commercial drug development and competition.” In other words, Big Pharma followed its usual approach to the mass-commercialization of a new prescription drug, and in so doing produced an epidemic of abuse.
Of course, simply because a medication has significant addictive potential—and here there is a strong parallel with today’s opioid pain-killer crisis—doesn’t mean that it doesn’t also have important therapeutic uses. Yet, as Schwarz’s book makes distressingly clear, the pharmaceutical industry apparently learned nothing from the first amphetamine epidemic it helped cause, when it began setting the research agenda for what was once called “minimal brain dysfunction” and later became ADHD. His book—a dazzling piece of journalism, based on extensive research and an enormous number of interviews—sheds some much needed light on what he calls a new “American epidemic.”
The epidemic is twofold. First, there are adults or adolescents who become addicted to stimulants, whether they first acquire them in clinical or recreational settings. Second, there are the enormous number of children who—it seems difficult to dispute—are being overdiagnosed with ADHD. Diagnosis rates, as Schwarz describes, are skyrocketing: Whereas expert groups (i.e. the American Psychiatric Association) contend that ADHD is a mental illness affecting 5 per cent of children, numbers from the Centers for Disease Control indicate that today, some 15 per cent of children in the United States will ultimately be diagnosed with the disorder by the end of their childhood. Indeed, he states, the drugs are even being given to thousands of toddlers as young as 2 and 3 years of age—despite a lack of good evidence for their use in such neuro-developmentally immature individuals.
ADHD, it seems, has become something of a runaway train. But who is its conductor?
It is not a judgment on the legitimacy of stimulant therapy for ADHD—much less on the diagnosis itself—to assert that the research agenda on ADHD has been appallingly contaminated from its very genesis. Since that $5,000 check from CIBA, Schwarz makes clear, pharmaceutical money has irrigated the channels running through every corner of the ADHD ecosystem, feeding researchers, patient advocacy groups, celebrity spokespeople, and advertisers. In particular, Schwarz paints many industry-funded ADHD “opinion leaders” in the academy in an unflattering light, and sees their influence as pernicious:
Psychiatry journals teemed with more than a thousand studies on ADHD conducted by … pharma-sponsored scientists. The Food and Drug Administration relied upon them when green-lighting medications as safe and effective. Their findings served as the backbone for the lectures that drug companies’ key opinion leaders delivered on world tours. The whirlwind created a self-affirming circle of science, one that quashed all dissent.
Money also flowed to one of the book’s central figures, Keith Conners: Over the years, he received high six-figure annual royalties for his diagnostic ADHD questionnaire, research support, and speaking fees from all the big companies. Schwarz traces Conners’s career from his early days running trials with Eisenberg in Baltimore, to the heights of his academic prominence, to his present-day misgivings about the direction his field has taken.
His story ultimately intersects with that of two other individuals Schwarz follows; both were misdiagnosed with ADHD as children and subsequently began to abuse stimulants and other substances. One of the pair faked the answers on an ADHD questionnaire when he was a child in the hope that stimulants would improve his sagging grades. He was prescribed not Ritalin, but what is perhaps the second most well-known ADHD drug, Adderall.
Why had this “new” drug—in reality, an old amphetamine—emerged? Essentially, CIBA’s patent on Ritalin had run out, and, as Schwarz notes, “fortune beckoned the company that could invent a new drug to treat ADHD, get it approved and patented, then unleash it on the awaiting market.” This is par for the course for Big Pharma: When a patent dies, a new brand drug must rise—even if the new one is not one iota better.
The curious story of Adderall starts with a decades-old weight-loss amphetamine called Obetrol, which was being produced by a small company called Rexar. Bizarrely, it turns out that Rexar shouldn’t have been producing the drug at all: Approval of Obetrol had been “withdrawn by the [FDA] Commissioner’s order effective on October 5, 1973,” as the minutes of a January 1995 meeting with the FDA would describe. (The FDA documents regarding the affair are available online here) About a decade later, the minutes note, there had been a single communication within the FDA that “the product was unapproved,” though “no further action was taken.” So Rexar kept on selling the amphetamine for weight loss into the 1990s.
Along comes Roger Griggs, a former high school football coach, who started a small pharmaceutical company named Richwood Pharmaceutical and became interested in scooping up Rexar. (Schwarz’s story of Adderall is in part based on interviews with Griggs). Rexar wasn’t selling much Obetrol at that point, but—interestingly—an oddly high number of prescriptions for Obetrol were being penned by a Utah pediatrician who was using it for ADHD, as Schwarz describes. Learning this, Griggs, asked himself: “Could the United States, with its notoriously short memory, be ready to try amphetamine again? Of course it would—with the right marketing.”
Thus Griggs bought Rexar, and in the summer of 1994 began advertising and selling Obetrol as Adderall (a name derived from “ADD for All”) even though it was unapproved, and indeed hadn’t even been tested for ADHD. The FDA quickly put a halt to the baldly outrageous undertaking, and Richmond responded by starting a trial and submitting a new drug application. But at least according to Schwarz, Griggs wasn’t sure whether the application would actually be approved or not until he received a call from a “well-connected Washington lobbyist,” who told him that a US Senator was furious with the fact that his son could no longer obtain Adderall. “You’re golden,” the lobbyist assured Griggs. And sure enough, the application was approved, ADHD became a blockbuster, and Griggs sold Richwood to Shire Pharmaceuticals for a cool $186 million.
“Regardless of the moral issue, dishonesty in advertising,” the
advertising legend Leo Burnett is purported
to have said, “has proven very unprofitable.” The quote, which could very well
be apocryphal, happens to also be patently
Dishonest advertising with medical messaging has always made plenty of money, ranging
from outrageous ads featuring physicians
touting the health benefits of smoking to misleading ADHD drug advertisements
in the twenty-first century. “The Food and Drug Administration,” Schwarz noted
in an article
in the New York Times in 2013, “has
cited every major A.D.H.D. drug … for false and misleading advertising since
2000, some multiple times.” And this ongoing and often misleading advertisement
blitz has, no doubt, played at least some role in soaring diagnostic rates, as
Schwarz’s book makes clear.
The history of direct-to-consumer (DTC) drug advertising is rather fascinating. As Schwarz describes, the US was actually a signatory to the 1972 United Nations’ Convention on Psychotropic Substances, which proscribed advertising for psychiatric drugs. Although this did not actually make the practice illegal, pharmaceutical companies avoided it in the subsequent decades. ADHD drug-makers, however, helped sweep this tradition into the dustbin of history. In 2001, USA Today noted that the appearance of “brand-name ads for ADHD drugs…women’s magazines and on cable TV” was “the first break from a 30-year-old agreement between nations and the pharmaceutical industry not to market controlled drugs to consumers.”
The advertising quickly went beyond the pale, a decline Schwarz traces. Celltech pharmaceuticals (which made a patented extended-release version of Ritalin) created a new “cartoon superhero,” Metaman, who would presumably rescue children from their ADHD symptoms. The company then produced plastic action figures to distribute to doctors offices, where children could play with them “while parents discussed treatment options.” Ads also made various outrageous, scare-mongering claims not backed by the evidence. Schwarz distills the message of one campaigns: “Give your child Adderall or else he could become a car-crashing, felonious psychopath.”
As profitable as the children’s market for ADHD drugs might prove, it was also inherently limited. On the horizon, however, a much larger market for adults glimmered like gold. “But how should a doctor diagnose adult ADHD,” Schwarz notes, “when a few of DSM’s official criteria, like ‘runs about or climbs excessively’ and ‘has difficulty waiting turn,’ sounded so childish?” Schwarz describes how Eli Lilly sponsored the efforts of some academic ADHD specialists at Harvard and New York University to create a diagnostic ADHD questionnaire that could be used in adults. The team subsequently slimmed it down, and the World Health Organization endorsed it, “an imprimatur that forever obscured its Big Pharma roots,” Schwarz says.
Big Pharma then spent considerable resources promoting public awareness of the illness. Shire Pharmaceuticals partnered with TV personality Ty Pennington and later Maroon Five star Adam Levine to spread awareness of adult ADHD. Shire’s “stable of key opinion leaders” also helped to get a new diagnosis—“binge eating disorder”—into the latest Diagnostic and Statistical Manual of Mental Disorders (DSM), while paying “university-affiliated doctors to conduct studies to prove the obvious, that amphetamine would in fact make people eat less.” (Not just any amphetamine, of course, but Vyvanse.) Shwartz relates all this in a chapter titled “This is your brain on capitalism.” In truth, “this is your brain on capitalism” could’ve been the title of Schwarz’s book.
Yet none of this delegitimizes the diagnosis of ADHD and none of this precludes the fact that stimulants are useful for those with the illness. Indeed, the weight of the medical advance shows that stimulants do indeed reduce ADHD symptoms.
Nonetheless, the benefits of stimulants are probably often oversold. While many may be content with the fact that the drugs have a beneficial effect on ongoing symptoms, others have no doubt been led to believe that they can have a permanently life-altering effect, steering a child (or adult) off a ruinous path and onto a successful and happier life course. While this is conceivably possible, there is simply insufficient evidence to say so.
Consider, for instance, the Cochrane Collaboration’s 2015 synthesis of the existing body of evidence for Ritalin treatment for children diagnosed with ADHD. (This is not ground covered in Schwarz’s book). Many consider the scrupulous reviews and meta-analyses that the Collaboration carries out to be a gold-standard of bias-free evidence synthesis in clinical medicine. Ole Jakob Storebø and colleagues—the investigators behind this Cochrane review—used a highly systematic protocol to find, assess and combine the results of all relevant existing studies on Ritalin therapy in children with ADHD. They ultimately identified some 185 relevant randomized trials, and in their combined analysis, indeed found evidence that the drugs resulted in a “modest improvement in ADHD symptoms,” as reported by teachers and parents. The drugs, that is to say, worked.
However, the investigators made several other important observations. First, the studies all had issues that increased their individual risk of bias; indeed, for the main study outcome, the “quality of the evidence was judged to be ‘very low’.” For instance, as they described, the side effects of the drugs could practically result in study participants—and their parents and teachers—being effectively unblinded (that is to say, side effects of the drug would make them aware that they were not in the placebo group). As I described in a recent review of Peter Kramer’s new book on antidepressants, such “unblinding” can function to effectively enhance a placebo effect—this is what investigators call an “active placebo” effect—and give the false appearance of efficacy. Storebø and colleagues thus recommend future trials (beginning with adults) that compare the drug against an active placebo (a “nocebo,” or a drug with no therapeutic action but noticeable side effects) so as to better understand its real efficacy.
Additionally, there were non-serious but real side effects: They found that those on Ritalin were about 60 per cent more likely to have problems sleeping, and 266 per cent more likely to have a reduced appetite.
But most importantly of all, as they describe, the vast majority of these studies were short-term trials, with an average length of only two months. Thus, as they write, “little can be concluded about the benefits and harms of methylphenidate used for longer than six months”—nor for years on end (as they are sometimes used), much less a lifetime.
Compare these relatively modest conclusions with the enthusiasm frequently exuded by the ADHD commentariat. At an important and highly-publicized conference, convened by the National Institutes of Health in 1998, one of the participants, quoted by Schwarz, told the Philadelphia Inquirer: “Parents have to weigh the risk of not treating with stimulants,” and that “children with ADHD not treated go on to have serious consequences the rest of their lives.” It’s not clear that this is true: the clinical trial evidence we have is almost entirely for short-term symptomatic benefits, as noted above.
Or consider what ADHD guru and child psychiatrist Ned Hallowell stated to Ty Pennington on an episode of ABC’s The Revolution in 2012, an episode narrated in Schwarz’s book. (Pennington was a paid spokesperson for Shire, though didn’t bother to disclose this on the show). After Hallowell performs a breezy ADHD exam on an adult member of the audience, he concludes:
So you passed the test. Welcome to the illustrious club [of ADHD]! It’s a good-news diagnosis…there’s medication, which people are so afraid of, but they shouldn’t be. Medication works about 80 percent of the time. And when it works it works like eyeglasses! … You can suddenly see!
Such enthusiasm again goes well beyond the evidence. Again, here’s Hallowell in a recent interview with Gwyneth Paltrow’s lifestyle website GOOP:
If you are an adult reading this, and you feel you are underachieving, learn more about ADHD. It could be the answer you’ve been looking for—for years. Diagnosis and treatment could replace frustration and underachievement with success … The diagnosis of ADHD and the treatment that follows, if done properly, truly can change a life, at any age, from one of frustration and underachievement (if not worse), to one of triumph, fulfillment, and joy.
You do not speak about the diagnosis and treatment of a serious mental illness by promising a solution to all of life’s problems. That is of course how you effectively sell a product.
So where to from here? While Schwarz’s book is an outstanding exposé, he has only seven pages on solutions, which feels tacked on to the end of the book. It contains a handful of milquetoast if not unreasonable solutions, for instance that physicians should seek out more ADHD-specific education. Yet there is a nary a word about perhaps the most important issue, namely, pharmaceutical reform.
That said, I’ll admit that real “solutions” will not come easy, and they will not come cheap. It seems clear that new postmarket clinical trials (with no industry involvement) are needed to better understand the potential benefits of ADHD drugs, and to address the issues identified by the Cochrane investigators in their Ritalin study. This is to say, trials that perhaps compare drugs to “nocebos,” and even more importantly truly long-term randomized trials lasting many years in duration that examine not just how the drugs change ADHD scores on a questionnaire, but their effect on more meaningful and sustained life outcomes.
Additionally, as is the case with other mental illnesses, more emphasis should be placed on modifying the social factors contributing to the disease. Indeed, with all the media emphasis on stimulant use (or misuse) on college campuses, it could be forgotten that ADHD is associated not with wealth, but with deprivation. In a study published last year in the journal PLOS One, for instance, Abigail Russell and colleagues examined the socioeconomic predictors of ADHD in a cohort of more than 8,000 children who were followed from birth in the United Kingdom. Among a multitude of socioeconomic factors, the one that most potently predicted the development of ADHD at age 7 was the presence of family financial strain—essentially, when parents couldn’t afford basic necessities. In the US, such findings are especially important to consider in the context of the dismantling of the nation’s system of cash assistance for the poor by the administration of Bill Clinton, a “reform” that left in its place “a diminishing pool of money that guaranteed the poor precisely nothing,” as Slate’s Jordan Weissmann put it. Addressing such putative economic determinants of ADHD seems critical, even when we have enough reasons to eliminate poverty already.
Finally, if there is one overarching lesson here, it is that we need a sweeping reform of the way drugs are developed, studied, marketed, priced, and sold. Big Pharma has deeply corrupted the mission—and the methods—of medical research. It has squeezed families by pricing drugs at the maximum the market will tolerate (and then some). And it has been reckless and dishonest in its promotion of addictive drugs, with grave consequences for the public’s health. Those with ADHD deserve much better—indeed, as we all do. For we are all patients, now or later, with lives more valuable than Big Pharma’s silver.