The scare campaign against Kefauver failed and he won in a landslide. It was bad news for pharma since he turned to preparing a final subcommittee report and also drafting legislation. While Kefauver had been fighting for his political survival, and the focus on pharma was on the fallout from the Welch/FDA scandal, a watershed moment had passed for the industry. The FDA approved Chicago’s G. D. Searle’s Enovid—put on sale three years earlier for “menstrual disorders”—to be dispensed as the first ever oral contraceptive.1 Women could now control when and if they got pregnant. Objections from social conservatives and religious groups had delayed the FDA’s decision for nearly two years. Some commissioners were uncomfortable with a medication for long-term daily use to otherwise healthy people. When the FDA finally said yes in 1960, they avoided any long-term safety questions by approving it for a maximum of twenty-four months. No one followed that directive once Enovid went on sale.2 It was wrapped in such controversy, that the lay public and much of the press referred to Enovid and later me-too competitors as the Pill. Doctors and patients thought it was simple, safe, and reliable (it was three years before a Senate investigation revealed that the FDA made its momentous decision based on clinical studies of only 132 women who had taken the Pill for a year, sometimes a little longer).3 I 4
It was impossible at the time to fully appreciate how great an impact the Pill would have. It debuted only a few years before the 1960s sexual revolution and women’s liberation movement (NOW, the National Organization for Women, was founded in 1966). Some saw in it a social tool to break the housewife-at-home-raising-a-family stereotype. As the first pharmaceutical reversible contraceptive, it introduced a newly minted term, “reproductive rights.”
Searle took advantage of the Pill’s sweeping promise in its advertising campaign. It featured Andromeda, a goddess of Greek mythology, breaking free of the chains around her wrists, symbolizing women breaking free of their worries of unwanted pregnancies.5
Many greeted the Pill enthusiastically. That was matched by the fervor of those opposing it on religious grounds. Sackler had intently followed the controversy. Bill Frohlich represented Ortho Pharmaceutical, one of the companies with its own oral contraceptive. Ortho was the first to offer the pills in a circular plastic container with a movable dial that made it much easier for women to remember when to take them (start on the fifth day of menstruation, then take one a day for twenty days, and then take a five-day break before restarting the cycle).6 Arthur’s idea about how to refine the promotion strategy seemed radical: do not directly mention the Pill or birth control. Frohlich thought at first it was counterintuitive to sell a product without talking about it, but Sackler won him over. Arthur thought that protestations about the Pill might taper off if the ads pitched the idea that it empowered families to choose how much time they wanted between children. Frohlich’s full-page color ads ran in Family Circle and True Story. They featured a young woman talking to an older woman over a picket fence. “Don’t plan your family over the back fence,” was the headline at the top. At the bottom, it suggested that women talk to their doctors about ways to space pregnancies. “He can recommend a method that is dependable, simple, inexpensive, and best suited to the needs of you and your husband.” The last line, in small print, read: “This message is sponsored by Ortho Pharmaceutical Corp., to whom medical methods of family planning are a particular concern.”7 The Sackler-inspired, Frohlich-designed campaign to soft-pedal the Pill as good family planning ran into fierce opposition from the Catholic Church, which called it “immorality in advertising.”8 Priests used their pulpits across the country to urge parishioners to inundate the magazines with protests. In under a month, Family Circle, with a circulation of seven million, issued a statement from its advertising director: “The objections from readers was ferocious. We no longer are carrying the ads.”9 The magazine returned the $120,000 Ortho had paid for what was scheduled as a series of six ads. Other women’s magazines followed.
Pharma companies and Medicine Avenue had underestimated the pent-up demand among women for something that at last gave them control over if and when to have children. They also misjudged the extent to which many social commentators and the mainstream press viewed the Pill as the progenitor of grand societal change. “If the Pill can defuse the population explosion,” wrote Time in an article titled “Freedom from Fear,” “it will go far for eliminating hunger, want and ignorance.”10 “It was the twentieth century’s greatest technological advance,” The Economist later concluded.11 The Pill was groundbreaking for the reason that it had first stumped the FDA: it established the precedent that a drug need not address an infection or chronic condition. It was enough to help fulfill a personal lifestyle choice. That concept had been the pharmaceutical industry’s Holy Grail, a medication separate from sickness.12
Even without ads in most major women’s publications, the Pill was instantly a top seller. Searle’s stock doubled in the year after it went on sale.13 Ortho, with its clever packaging, sold more pills by 1962 than any other company. Its profits surged.
Sackler thought that if the Pill succeeded despite the fierce resistance, another lifestyle medication free of any moral controversy could be an even bigger blockbuster. His psychiatric training led him to conclude the next great challenge was developing a lifestyle medication for so-called mind drugs. It was possible, he speculated, that a hybrid, some type of “be happy” pill, might one day replace antibiotics as the industry sales leader. He focused on two broad classes of mind drugs: stimulants (uppers) that enhanced a patient’s mood, and sedatives (downers) that targeted anxiety and mental illness.
Amphetamines, the stimulant gold standard, had long been promoted as a cure for all types of depression. The surging demand for amphetamines doubled after World War II following the AMA’s approval to advertise them for weight loss.14 Burroughs Wellcome introduced Methedrine to shed extra pounds. Abbott targeted narcolepsy with Desoxyn, its methamphetamine tablet. Ciba’s entry was not an amphetamine, but a new drug that competed for the same market: Ritalin.15 In 1950 Ciba had released Dexamyl, a combination of Dexedrine and Lilly’s Amytal barbiturate that some doctors dubbed “among psychiatry’s greatest hits.”16 Ads featuring all-American housewives touting it for treating “nervous tension, anxiety and agitation” had helped make it one of the most widely dispensed by general practitioners.17 Rivals tried copying that success with their own amphetamine-sedative combinations, helping to expand the market throughout the 1950s.18
By the 1960s, the American amphetamine market hit a record eight billion pills annually. That output was constant for the rest of the decade. Authorities later discovered that about half that production was diverted illegally to street dealers or unscrupulous diet doctors. Some popular weight loss clinics were unmasked as virtual subsidiaries of generic amphetamine manufacturers. Their profits were enormous; 100,000 10 mg amphetamine pills cost the diet center $71 and were resold on average for $12,000. Its broad popularity had resulted in a spike in recreational abuse and adverse reactions.19 That finally caught the media’s attention. A series of national stories about former users recounting “amphetamine induced psychosis,” antisocial behavior, and crippling paranoia added to the drug’s darker narrative. The FDA had been slow to recognize the problems. It had such a benign view of stimulants that as late as 1963 it weighed approving Ciba’s Dexamyl for over-the-counter sales.20
Sackler knew there had been little innovation in amphetamines in the thirty years since their discovery. And he had never found it useful during his Creedmoor research. He admired amphetamine’s commercial success but he was skeptical about its long-term prospects and doubted it could be the basis for the hybrid mind/lifestyle drug he envisioned.
What about sedatives? The postwar barbiturate market was huge, second only to antibiotics.21 There were 1,500 competing brands in the U.S. An estimated third of those manufactured were resold on the street—with names such as goofies, yellow jackets, and pink ladies—for recreational highs. They delivered big profits, rivaling the gross margins of the industry-leading antibiotics.22 Barbiturates, as with amphetamines, had become a victim of their success. The federal Narcotics Bureau in 1947 listed them the most abused drug. Overdoses set a grim record in 1950 with one thousand dead.23 The following year, The New York Times concluded that barbiturates “are more a menace to society than heroin or morphine.”24
Congress responded with the Durham-Humphrey Amendment, meant to address the barbiturates problem by fixing vague language in the 1938 Food, Drug, and Cosmetic Act.25 Before the amendment, prescriptions were required only for narcotics and sulfa drugs.26 Thirty-six states had not waited for federal intervention, instead requiring prescriptions for barbiturates. The state rules were a confusing hodgepodge of regulations. More than half had no restrictions on the number of refills. The Durham-Humphrey Amendment invested the FDA with the power to deem any drug as dangerous “because of toxicity or other potentially harmful effect.” Once the FDA made that threshold decision, the drug would be by prescription only.27
One of the law’s omissions, however, was that it did not require drug companies to include side effect warnings to patients. Pharma firms only had to provide the drug data to pharmacists, who were then supposed to warn patients about potential abuse.
The Durham-Humphrey Amendment did not dent barbiturate sales. Because it did not have the resources, the FDA did not enforce its “prescription only” rule for six years, and then it went only after bromides, a cruder early-generation sedative.28 Even then, requiring a prescription for barbiturates only meant that millions of habitual users began shopping for doctors willing to write prescriptions without asking too many questions.29
Sackler saw a glimmer of promise in the hypnotic qualities of strong barbiturates such as Lilly’s Seconal. It could be useful in controlling seizures and constant agitation, two debilitating physical symptoms of mental illness. They were not optimized for serious mental disorders, however, and did not treat bipolar or schizophrenia. Smith Kline filled that market in 1954 in America when it rolled out Thorazine, a tranquilizer accidentally discovered in the late 1940s by a French surgeon who had been hunting for malaria cures. “Tranquilizer” was the new word in the pharma world, having appeared the first time the previous year in promotion for a hypertension drug from Ciba.II30
Smith Kline marketed Thorazine as an antipsychotic.31 It was so potent that in Europe it was informally dubbed “a medicinal lobotomy” and dispensed only to patients suffering severe psychosis.32 Smith Kline’s first ad featured a close-up of a man’s head, electrodes attached to his forehead, and a large rubber stopper jammed into his mouth. It announced “Thorazine: Reduces Need for Electroshock Therapy.” Psychiatrists, particularly those who worked in public asylums, wrote nearly 80 percent of the three million Thorazine prescriptions in its first year.33 The drug arrived at a time when psychiatric institutions were increasingly vilified in scandalous public reports about cruelty and violence toward patients.34 Thorazine marked the start of a pharmaceutical revolution in the treatment of those with disabling mental illness, moving away from the custodial-institutionalized care that had been the standard since the early nineteenth century. Thorazine’s widespread use spurred a decline in the number of patients committed to New York’s mental institutions—the largest state population—by 19 percent, the first reduction since records were kept.35 Fewer patients meant lower costs, saving state governments $1.5 billion in the decade after Thorazine’s introduction. The director of Washington, D.C.’s, eight-thousand-bed St. Elizabeth’s Hospital heralded Thorazine as marking the end of “bedlamism,” the word used by asylum workers to describe the chaos and disorder that was the hallmark of many insanity wards.36
Smith Kline trumpeted its success at the nation’s mental hospitals, although no one seemed to have figured out the early taxpayer savings might be canceled out later by increased medical costs for the outpatient care of those who relapsed or whose illness worsened.37 III 38
Despite the big sales numbers, Smith Kline worried there was a limit to the size of Thorazine’s market. The better the drug worked, the greater the falloff in sales as patients were discharged from mental institutions. Smith Kline tried expanding the market by targeting doctors who cared for those patients who returned to society. Ads in JAMA featured a man fishing in a stream, personifying the mental calmness that was touted as the drug’s hallmark. “Continuing therapy is almost always well tolerated, and is central to most patients’ continued well-being,” read the copy.39 Smith Kline next tried adding “senile agitation” as a treatable condition. Ads, illustrated with an elderly man wielding his cane in a threatening manner, promised Thorazine would “control the agitated, belligerent senile” and “help the patient to live a composed and useful life.”40 It even tried marketing it for chronic nausea. But that was like using a sledgehammer to put a thumbtack on a corkboard. Few patients were so distressed by even the worst nausea to put up with side effects that could include difficulty breathing, severe fever and muscle pain, trembling, seizures, and even rarely, suicidal depression.41
Sackler was waiting for something more like a Thorazine-lite, a mood-altering medication that could offset anxiety while not being too sedating. He told his pharma clients about the great profit potential in a discovery of “emotional aspirin,” a medication that treated a person’s psychological well-being as well as antibiotics cured serious infections. Sackler knew from his tenure at Creedmoor that any drug that addressed anxiety or depression would have a greater side effect profile than aspirin. He hoped that by putting the concept of “emotional aspirin” into the research and development milieu, it might spark pharma firms to make it a laboratory priority.
Drug companies undoubtedly had the incentive for such a project. There was an enormous market for relieving the stress and anxiety that many Americans perceived as an unfortunate but integral part of twentieth-century life.42 Magazines and newspapers ran stories about stress from the Cold War and how the fast pace of technology added to daily pressure. Composer Leonard Bernstein had in 1950 named his Second Symphony “The Age of Anxiety,” after W. H. Auden’s Pulitzer Prize–winning poem of the same title. The government provided significant financial incentive for discovering a drug as Sackler envisioned. When the Mental Health Study Act was passed in 1955, it established a Psychopharmacology Research Center at the NIH. That new government division focused on biological psychiatry and had a multimillion-dollar research budget, which it shared with interested pharma firms.43 Some drugs under review were still experimental although they showed promise in the lab. Lithium had been discovered in the early nineteenth century but clinical studies for treating mania had only begun in Denmark in the mid-1950s (the FDA did not approve it until 1970). The same was true for LSD-25, a synthetic compound discovered by a Swiss scientist in 1951, but only subjected to therapeutic testing for mental illnesses in the mid-1950s at the Rockefeller Institute for Medical Research.IV44
The most advanced new class of drugs were the so-called minor tranquilizers. As had happened with Thorazine, it was another accidental discovery. Frank Berger, a Jewish Czech scientist who had emigrated to England when Hitler annexed Czechoslovakia, had chemically modified a disinfectant in the hope of finding a better preservative for penicillin. When he injected his altered compound into mice he noticed they remained awake and responsive at the same time that their muscles relaxed and they became passive.45 When Berger moved to America in 1947, he took a job as a research professor at the University of Rochester Medical School. Two years later the patent drug and toiletries company Carter Products—whose most famous product was Carter’s Little Liver Pills, a laxative with annual sales topping $450 million—hired him. They upped his university salary from $5,400 to $12,000 and gave him a 1 percent royalty on meds he discovered, up to a maximum of $75,000.46 Carter’s prescription drug sales were only $500,000 and it had only twenty employees in that department. Berger knew that two of Carter’s other consumer products, Nair hair removal and Arrid deodorant, sold more in a week than the drug division did in a year.47 After hiring Berger, Carter formed an alliance with Wallace Laboratories, a New Jersey–based medical research company. It also hired Bernie Ludwig, a respected organic chemist, as its medical director.
Berger and Ludwig tested hundreds of synthetic compounds before they found a promising one, meprobamate, in May 1950. In subsequent animal testing it was tranquilizing without being too much of a sedative. The two scientists thought they had found the right balance between the therapeutic qualities of Thorazine and its oppressive side effect profile. Two months later they submitted their drug for a patent. Carter’s management was far less enthusiastic than its researchers since it was uncertain if there was sufficient demand for such a drug.Wallace Labs had conducted a study with two hundred doctors that showed most thought there was no use for such a medication. Three quarters said they could not think of any reason to prescribe it.48
Carter put the project on hold and delayed going to the FDA for approval. It took four years before Berger, armed with a battery of new clinical tests, convinced management that the drug was ready. It went to the FDA in December 1954. Faced with what category to apply for in its application, Carter feared “sedatives,” which included barbiturates, carried too many negative connotations. “Tranquilizers” was also troublesome, especially as that category included Thorazine and other powerful hypnotics. Carter proposed a clever solution: the FDA would list the drug under tranquilizers, but Carter would market it as a “minor tranquilizer.” While waiting for approval, Carter rejected a dozen brand names before settling on Miltown, the town where Wallace Labs performed the final testing on the product.V49
Even before the FDA approved Miltown, American Home Products bought a license from Carter to sell Miltown through Wyeth, its pharma subsidiary. Wyeth would sell the drug under the brand name Equanil. In May 1955, Miltown went on sale. Carter touted it as a less dangerous and toxic alternative to barbiturates and major tranquilizers, and emphasized it was effective for everyday “anxiety, tension and mental stress.”50
The first edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM) had been published only a few years earlier. It provided diagnostic criteria for identifying and treating many psychiatric illnesses. Instantly the bible for American psychiatrists, DSM had not listed anxiety as a stand-alone disorder (that would not happen until DSM-III in 1980).51 Carter worried that psychiatrists might not think Miltown was necessary and general practitioners might think it addressed a condition too far removed from their own practice.
Carter had underestimated the pent-up demand among millions of Americans looking for a quick fix to anxiety and stress. Few thought of it as an illness but rather shrugged off anxiety as an inevitable by-product of a busy and productive life. Some boasted of it as evidence of hard work, ambition, and achievement.52 The country was filled, concluded some psychiatrists, with “ambulatory psychoneurotics.”53 Miltown seemed ideally timed as an antidote to alleviate the occasional edginess and irritation caused by anxiety. A psychoanalyst welcomed it as the “penicillin of psychiatry.”54
Miltown’s sales took off. Three months after its release, Time noted that it “has become the fastest-selling pacifier for the frustrated and frenetic.” Hollywood was the leading market for “Miltown mania.” Celebrities from Tennessee Williams to Norman Mailer to Tallulah Bankhead created waiting lists at pharmacies for the “don’t-give-a-damn” pills.55 Sunset Boulevard’s famed Schwab’s Pharmacy sold 250,000 pills in four months before running out of stock. The frenzy in Hollywood spread to New York, Washington, and Boston. “It worked wonders for me,” said comedian Milton Berle. “In fact, I’m thinking of changing my name to Miltown Berle.”56
How successful was Miltown? In 1954 and 1955, Thorazine accounted for 99.6 percent of all tranquilizers sold in America. A year later, Miltown and its chemical twin, Equanil, went from less than 1 percent to 70 percent of sales.57 In 1956, Carter and Wallace Labs sponsored a New York City conference on the drug.58 Carter sent bound copies of those proceedings to 153,000 doctors.59 Two years after it went on sale, one in twenty Americans had tried the pill. Doctors had dispensed 36 million prescriptions, a staggering one third of all prescriptions written.60 The drug tripled Carter’s gross revenue. The company felt flush enough to commission the surrealist Salvador Dalí to design its exhibit at the AMA’s annual meeting in San Francisco in 1958. Dalí’s wife and collaborator, Gala, was a Miltown patient. When she earlier had met Frank Berger, she suggested her husband could capture in art how the drug helped transform her anxiety to tranquility. The exhibit cost $100,000, of which $35,000 was Dalí’s fee. Carter got its money’s worth.61 People marveled as they walked through Dalí’s sixty-foot-long, wriggling white caterpillar made of parachute silk. Time concluded that “the monster stole the show” and it “was worth its weight in gold to Miltown.”62
By the time Dalí created his Miltown exhibit, the surging demand for so-called peace of mind or happy pills resulted in a thriving black market for both the Carter and Wyeth brands as well as for counterfeits. In the absence of federal legislation, states began tightening rules for dispensing the drugs.63 In early 1960, the Justice Department filed an antitrust action against Carter and American Home Products for price-fixing and conspiracy to exclude other firms from the market.64 The CEOs of both firms denied gouging the public in testimony before Kefauver’s Senate investigation. It was a mere coincidence, they claimed, that they had submitted identical bids for every government contract, and they protested that higher advertising costs in the U.S. were the reason their drugs cost six times more in America than Europe.65
What Arthur Sackler and other pharma insiders knew was that no matter how much the companies complained about their costs, the minor tranquilizers were profitable. Extremely so. Most prescription drugs in the late 1950s and early 1960s returned on average a very healthy 20 percent net profit. The tranquilizers and barbiturates did better, boasting returns of 35 percent to 55 percent, second only to antibiotics.66 And most important in Sackler’s view was that by 1960 about 75 percent of American physicians had written at least one Miltown prescription. Thorazine, in contrast, was still mostly the province of psychiatrists.67
As Miltown’s success grew it attracted more scrutiny.68 Some doctors questioned its efficacy, contending it was little better than a sugar pill. Other physicians warned it created tolerance since ever-larger doses were required to maintain any benefits. A few thought it might be addictive.69 Previously unreported side effects flooded the FDA, everything from increased anxiety, impaired coordination, and confusion to tremors, muscle spasms, and vertigo.
Miltown was repeating a common pattern for blockbuster drugs, particularly those that created dependency and could be abused recreationally. Doctors and patients enthusiastically welcomed those medications when they first went on sale. Over time their popularity led to abuse, thriving black markets, counterfeits, and a steady upswing in reported side effects, sometimes even overdoses (toxicology reports on drug deaths showed that when Miltown was present, it was usually in tandem with copious amounts of alcohol, amphetamines, and barbiturates).
The FDA considered recalling Miltown. The drug’s emerging darker narrative prompted a couple of dozen states to list Miltown on the same “no-refillable prescriptions” list that covered barbiturates.70
Sackler knew any headwinds Miltown faced opened the door to a competitor drug. In the mid-1950s neurophysiologist Ralph Gerard coined “psychotropic drugs” to refer to medicines developed for mental illness. Many pharma labs were working hard to find one that delivered enhanced therapeutic benefits with fewer side effects.
Swiss-based Hoffmann-La Roche had a secret research project under way at its New Jersey lab hunting for the next enhanced generation of Miltown.71 Martí-Ibáñez had learned about it because he was friends with Leo Sternbach, a pharmacist who led the Roche team. Roche had transferred Sternbach, a Polish Jew, to the U.S. in 1941. (Roche was the only Swiss pharma firm that sent its Jewish researchers and German dissidents—what Sternbach called “all the endangered species”—to safety in jobs in America.)72
Even by Sackler’s standards, Sternbach’s research was ambitious. In the mid-1940s he had synthesized biotin, a water-soluble B vitamin that had resisted all earlier efforts for a commercially viable man-made version. Roche was then the world’s top manufacturer of synthetic vitamins, so the discovery impressed even his more senior science colleagues. Beginning in the mid-1950s, he led a small team tasked with finding a drug that would win “the Great Tranquilizer War.”73 Roche made no pretense it was searching for a medication to eliminate deadly diseases or cure infections. It simply wanted to boost its bottom line by developing a better Miltown.74
The fastest route was to make a near therapeutic clone that had enough molecular changes so it did not violate Miltown’s patent. That is what Roche’s marketing department wanted. Sternbach, however, thought that a me-too drug was “boring.”75
In Roche’s Lab 303, Sternbach performed hundreds of modifications to dye chemicals, searching in vain for any sign of psychopharmacological activity. Biological chemists like Sternbach were called “backbench scientists” because they spent much of their time at benches and tables manipulating molecules (by the mid-1990s, computers generated the molecular changes in a fraction of the time and robots analyzed them for medicinal uses). For over two years Sternbach came up empty while half a dozen rival companies released me-too Miltown knock-offs.
Roche pharmacology chief Lowell Randall ordered Sternbach to end the project and shift to antibiotics.76 Sternbach did start working on antibiotics, but in his off hours he continued researching tranquilizers. Near the end of 1956, Sternbach isolated a chemical compound that “crystallized nicely” and had the biological activity for which he had been searching.77 The problem was how to tell Randall that he had not followed his order and stopped his tranquilizer research. Sternbach concocted a plan that would allow him to present his discovery as serendipity. On his birthday, May 7, 1957, he and his assistant, Earl Reeder, an organic chemist, announced they were setting aside the day for “a major spring cleaning” of their cluttered lab. It was, Sternbach later recalled, “covered with dishes, flasks, and beakers, all containing various samples and the working area had shrunk to almost zero.”78 During their cleanout, Reeder “found” two “discarded beakers” that bore the label “Ro5-0690.” A hardened crystalline powder was on the bottom of each. Sternbach had it planted there. According to the lab notes he made, those beakers were leftovers of the tranquilizer work and had never been tested. That afternoon Sternbach sent them to his boss with his notes and said they had “just been found under all the mess.”79
When Sternbach subsequently administered the compound to mice and cats, they relaxed as they did when fed other tranquilizers. The difference was the animals stayed active and alert. Every other tranquilizer, even Miltown, left them groggy and uncoordinated. Further testing demonstrated that Ro5-0690 “was vastly more potent [and] less toxic and sedating than any on the market.”80 A couple of months later, Sternbach again ignored company policy and tried the compound himself. That was not an unusual practice, many ambitious research scientists called themselves “two-legged rats.”81 His lab notes reveal that a couple of hours after ingesting it, he felt “slightly soft in the knees,” was “cheerful,” and also “pretty sleepy” all afternoon. He felt normal after ten hours.
Sternbach had discovered benzodiazepines, “benzos” for short, a new class of synthetic tranquilizers (it had an extra carbon atom in the inner ring structure as compared to Miltown).82 Benzos would upend the market for happy pills. As another Roche researcher noted at the time, Sternbach’s discovery had made him a “grand master of modern medicinal chemistry.”83 Roche named it Librium, from the last syllables of “equilibrium.”
Roche undertook one of the largest and most diverse human clinical trials ever. Starting in 1958, it had more than two thousand doctors test Librium on some twenty thousand patients, from healthy undergraduate students to infirm elderly, psychiatric patients, premenopausal women, alcoholics, even drug addicts.84 There was no risk in conducting too much testing. The FDA permitted pharma firms to choose which of their trials to submit in support of a drug’s approval. If a study had a poor outcome, the company could withhold the results.85 The onus fell on the FDA; it could order additional testing if it had reason to believe the firm was hiding bad news.86
The following year Roche presented Librium to the FDA. Under the rules then in place, Roche did not have to prove efficacy, only that Librium was safe. It had selected the result of 1,163 of the 20,000 patients to make its case. The handpicked test subjects showed no signs of drug tolerance. Nor were there signs of dependence. High doses caused some motor coordination loss and higher doses induced drowsiness. Still, it was one of the cleanest side effect profiles submitted in a new application. (Although doctors later split about whether benzodiazepines caused tolerance and addiction, there was no doubt they were much safer than barbiturates.)87
Roche went a step further, however. Although it was under no requirement to do so, the company wanted to brag about what the clinical trials demonstrated about efficacy. Librium effectively treated all types of anxiety, from mild and moderate to severe and acute. It also was a good muscle relaxant, anticonvulsive, sedative, and helped alleviate mild depression and eased alcoholism withdrawal.
Roche insisted Librium should be classified as a new class of “antianxiety medication.” No one then understood why the drug had a more potent therapeutic profile (it took until 1977 before a Danish researcher discovered that benzodiazepines bind to brain receptors responsible for sending chemical messages related to anxiety and fear).88
The FDA gave Roche the approval to sell Librium in 1960, the same year that the Pill had become the industry’s first lifestyle drug. That timing was fortuitous since it was when a German-born psychiatrist based in London developed the eponymously named Hamilton Rating Scale for Depression (it remains one of the most widely used reference guides). As part of his work he developed an “Anxiety Rating Scale,” a simple fourteen-question survey intended as the first ever medical tool by which to measure a patient’s anxiety.89
Hamilton’s rating scale meant that anxiety was no longer something doctors had to diagnose subjectively as a mere feeling or state of mind described by a patient. Although Hamilton’s test was somewhat rudimentary, it was a major step toward medicalizing anxiety as an accepted psychiatric disorder.90 Roche later distributed the Hamilton tests to tens of thousands of doctors, calculating that physicians would prescribe more Librium if they felt they had a scientific basis for doing so. (Thirty-four years later, the Sackler family’s launch of their timed release opioid product, OxyContin, would similarly benefit from a reanalysis of pain and addiction that included a ten-point system by which doctors could supposedly better measure patient pain.)
For Arthur Sackler, the benzodiazepines were it, the class of medications he thought might one day replace antibiotics as the drug industry’s biggest seller. Roche picked him and his William Douglas McAdams agency to handle Librium’s rollout. Sackler assigned his top account executives to monitor his other big clients—Pfizer, Glaxo, and Hoechst-Roussel—while he turned his full attention to Librium. He hired Irwin “Win” Gerson, a twenty-eight-year-old pharmacist with an MBA, to help with the market research. Gerson, who moved up fast through the executive ranks at McAdams, had been a detail man selling Wyeth’s minor tranquilizer, Equanil.91
The $2 million campaign Sackler developed for Librium was a masterpiece, even by his exacting standards. Arthur kicked off the promotion with free coverage in the national press. He had figured out how to bypass the FDA’s prohibition on advertising to consumers. His workaround was a so-called mat (master of aligned type), a press release disguised as legitimate journalism. It allowed newspaper and magazine editors to run stories about advances in health while the sponsoring pharma firm benefited from the coverage of its drug as “news,” without being handcuffed by the disclaimers and warnings of traditional ads. Those companies distributed copies of the clinical trials to Arthur’s favorite science and medicine writers. Freelancers got detailed story outlines that only needed light editing before publication.
In the promotional packet Sackler had assembled, he highlighted two of Librium’s most extreme clinical tests. The first involved violent prisoners in a Texas state prison. The “patients” in the second were wild animals at the Boston and San Diego zoos. The week Librium went on sale, the lead article in Time focused on those tests. The chief psychiatrist for Texas’s Mental Health Board told Time that Librium had been dispensed to inmates at Huntsville Prison who were “classical psychopathic personalities with lifelong histories of antisocial behavior.” They were regularly “mutilating themselves, setting fires, and starting fights.” What happened after they took Librium? According to the prison psychiatrist, they became “placid and alert, despite their tension-provoking environment.”92 As for the zoo animals, Time reported a “lynx that had bloodied its nose in a savage dash against the side of its cage… was soon gamboling like an alley cat” after it was given Librium. Baboons, macaques, monkeys, a lion and a tiger, and Australian dingoes “calmed down the same way [but] most important, they were not knocked out to the point of being dopey, but remained active, with full muscular coordination, and apparently retained possession of whatever faculties nature gave them.”93
Having established that Librium tamed wild animals and violent convicts, Time repeated much of Sackler’s press release. There was “encouraging evidence that it will have the same effect on 70 percent or more of anxious, tense and hostile humans as it had on dingoes.” Since the drug was new, finding the right dose for patients might be “admittedly tricky,” but once established, “Librium comes close to producing pure relief from strain without drowsiness or dulling of mental processes.” At high doses, while there might be some “impaired coordination,” Librium otherwise demonstrated “unusual freedom from harmful side effects.”94
Many national magazines had just begun regular columns devoted to medicine and health. Pharma companies correctly viewed those as additional outlets to sway public opinion, not just about specific drugs, but also about industry trends. (In 1983, Lilly became the first company to apply Sackler’s prepackaged story concept to television for its new arthritis drug; the elaborate media kit included video interviews with clinical trial patients, scientists in the lab, and rheumatology experts, all ready to be edited and used in a “what’s new in medicine” segment.)95
Sackler had tweaked and refined his promo tactics that he used for antibiotics. A month after Librium went on sale, he ran an eye-catching three-page ad in Life. It featured full-page pictures of the San Diego Zoo lynx before and after receiving Librium. “New Way to Calm a Cat” was the provocative headline.96 After Newsweek, National Geographic, and Esquire lavished praise on the “breakthrough drug,” Sackler sent tens of thousands of those magazines to doctors. He figured most would end up in patient waiting rooms. It was Sackler’s way of circumventing the strict FDA ban on advertising directly to consumers. In another issue of Time, he ran a splashy special advertising insert, implying that Librium could prevent “nervous breakdowns” and “cure peptic ulcers.” (When a Senate investigation later looked into that practice, Sackler and Roche defended the ad by noting the magazine insert had perforated edges so doctors could easily rip it out before placing it in their waiting rooms.)97
Sackler assumed that women would outnumber men as Librium patients, as they had with Miltown. He targeted Cosmopolitan and Family Circle for packaged stories.98 The McAdams agency also offered newspapers Librium-positive short-shorts, small boxes of text that filled the empty space between main stories. Radio and television stations got featurettes, short broadcast segments that filled dead air. Advertising Age heralded the Librium campaign—which touted the drug as “the successor to the tranquilizers”—as “innovative” and “dazzling.”99
Sackler also focused on the Roche detail team. Miltown had unwittingly provided the industry a cautionary tale about the importance of that personalized selling unit. Carter and Wallace Labs did not have a detail team. They relied on direct mailers to physicians, the ad campaign from their agency, Madison Avenue’s Ted Bates, and word of mouth. In contrast, American Brands/Wyeth had 1,500 detail men and they blanketed the country, visiting doctors and pushing their chemically identical brand, Equanil. Despite the tremendous publicity for Miltown, Wyeth’s Equanil surpassed Miltown in sales in 1956, only a year after they went on sale. Some pharma insiders thought that all the celebrity and Hollywood connections for Miltown made the drug less appealing to prescribing physicians. When many doctors went to dispense the latest minor tranquilizer, they increasingly wrote the Equanil prescription. Many traditional practitioners also considered Carter a patent drugmaker and not part of the pharma club. By 1960, Equanil had pulled away, outselling Miltown three to one.100
Sackler coached Roche’s detail team as if he were preparing them for a military operation. They should emphasize Librium’s wide therapeutic benefits, especially its “muscle relaxant” and “anti-anxiety effect,” which had gotten extensive coverage in the normally conservative JAMA.101 What if a doctor was prescribing Miltown or Equanil, what was the best way to distinguish Librium? Sackler had already written the ad copy that proclaimed Librium was “completely unrelated chemically, pharmacologically, and clinically to any other tranquilizer.… [It was] as different from the tranquilizers as they were from the barbiturates.”102 That was similar to how he had distinguished Pfizer’s Terramycin eight years earlier from a rival Lederle medication.103
Although Arthur was confident Librium was an antianxiety drug superior to anything that had preceded it, he recognized that some doctors would feel more comfortable sticking with Miltown since they were familiar with its benefits and risks after its five years on the market. Roche had to overcome that hesitation. In instances in which doctors were reluctant to switch to Librium, Sackler prepared a backup plan for the detail team: disparage Miltown and its me-too rivals. The salesmen were armed with reports of surging Miltown addiction, impairment that included considerable confusion and drowsiness, and even a spike in suicides among daily users.104 They handed out reprints of a harsh review about Miltown that had run in the much respected Medical Letter on Drugs and Therapeutics, a nonprofit, peer-reviewed, bimonthly journal. It reinforced the core message that was part of every Roche product brochure, “benzodiazepines are unlike any other drug.”105
Sackler designed the detail team guidelines with general practitioners in mind. He knew that psychiatrists would be acquainted with tranquilizers. Only a small fraction, however, of the consumers who Sackler and Roche hoped would become Librium patients had ever gone to a psychiatrist. Nathan Kline, who had replaced Sackler at Creedmoor, understood why Arthur saw so much potential in a small pill: “A lot of people shy away from the stigma of going to a psychiatrist. Their friends will say, ‘He—or she—must be crazy.’ But these same people are willing to take their problems to the family doctor. That is socially acceptable.” Sackler was right. Psychiatrists ultimately wrote only 10 percent of Librium’s prescriptions.106
Physicians wrote 1.5 million Librium prescriptions in its first month of sales. It was dispensed for alleviating anxieties and phobias, as well as illnesses then thought to have a link to stress, including high blood pressure, ulcers, acne, muscle pain, and headaches.107 It was not public knowledge then, but even John Kennedy—wracked by lower back pain from his wartime injury—took Librium.108 VI 109 Miltown’s maker, Carter-Wallace, saw its profits tumble nearly 20 percent.110
Roche gave Sternbach the $10,000 prize it offered for the discovery of a successful and profitable drug. The sum didn’t change just because he produced the company’s biggest ever blockbuster. But Sternbach was not disappointed. “I was a very happy scientist [since] I made the compound [but] it also made me.”111
Before Librium, five medications, dominated by Miltown and Thorazine, accounted for 70 percent of the tranquilizer market.112 In just three months, Librium was the best-selling tranquilizer in America. Sternbach’s son, Michael, later recalled that his father was unusually emotional when he learned that his laboratory discovery had “buried Equanil [and] Miltown.”113 It was a spot Librium would not relinquish for eight years—to another Roche drug discovered by Sternbach and promoted by Arthur Sackler.114
I. Margaret Sanger, a nurse who coined the term “birth control,” had opened America’s first birth control clinic in 1916. She later battled religious and socially conservative opposition to the development of a female drug contraceptive. The organizations Sanger founded ultimately morphed into one as Planned Parenthood. Much of the money for the Pill’s research came from Katharine McCormick, an heir to the International Harvester fortune. Sanger and McCormick were convinced that readily accessible and easy-to-use birth control was key to women’s emancipation as housebound spouses. When journalist Clare Boothe Luce learned about the FDA’s approval of Enovid, she summed up the sentiment behind the movement: “Modern woman is at last free as a man is free to dispose of her own body.”
II. In the nineteenth century, “tranquilizer” referred to the invention by a Philadelphia psychiatrist of a restraining chair into which agitated mental asylum patients were strapped.
III. Thorazine and a succession of other tranquilizers were one reason that JFK had the confidence to announce the Mental Retardation Facilities and Community Mental Health Centers Act in 1963, an ambitious plan to release half of the 500,000 committed to state asylums. The savings were supposed to fund 1,500 community health centers to provide ongoing outpatient care to those released. States instead used most of the savings on matters unrelated to mental health. Fewer than half were built, and not one was fully funded. Between 1955 and 1980, “deinstitutionalization” reduced the population of American asylums from 558,922 to 130,000. The New York Times later reported the entire program to be “a vast failure.” That was partly because federal and state governments had subsequently shifted the responsibility for serious mental illness to the prison system or to nursing homes. Medicaid allowed states to move the poor elderly to nursing facilities; by the mid-1980s, more than 600,000 of those two million nationwide residents had been diagnosed with mental illness. Ten times as many people suffering from severe psychotic disorders were in prison by 2018, rather than in psychiatric clinics.
IV. Swiss-based Sandoz had the LSD patent and produced small batches for researchers. It asked the FDA for an “investigational exemption” in 1963. What the FDA should do with LSD was a heated topic, eventually coming under scrutiny by three different congressional committees. The issue was moot after the 1965 Drug Abuse Control Amendments; LSD was outlawed for any use.
V. It took until the mid-1960s before psychotropic drugs were marketed with more specificity as antianxiety agents, antidepressants, or antipsychotics. “Antidepressant” was used in a 1947 ad for Edrisal, a Smith Kline combo drug of amphetamines and painkillers. By 1952, it referred only to tranquilizing drugs, but it did not become widely used by pharma companies until the mid-1960s. “Antipsychotic” was not even used to describe a drug until 1961. Sometimes the pharma marketing departments had more say than the scientists and medical directors.
VI. Kennedy, who also had colitis and Addison’s disease, an adrenal gland insufficiency, was on eight daily medications and hormones. Max Jacobson, JFK’s German-trained physician—nicknamed later by the press as “Dr. Feelgood”—also was the personal doctor of, among others, Tennessee Williams, Truman Capote, the Rolling Stones, and a who’s who of Hollywood. In addition to Librium, JFK took barbiturates for sleep, and both codeine and Demerol for pain relief. Jacobson countered the sedative effects of those drugs by regularly administering 15 mg of methamphetamine to the president.