While Roche was relieved that few paid attention to the conclusions about Librium, internal memos reveal the company’s senior executives correctly predicted that it was only the first volley in what would become a war between pharma and federal regulatory and narcotics agencies. The Advisory Commission Report kicked off a multiyear battle during which the federal government tried to rein in illicit drug use and prescription drug abuse. The following year, 1964, Connecticut senator Thomas Dodd introduced the Psychotoxic Drug Control Act, a sweeping bill aimed at beefing up the antidrug laws, the first such effort since the 1914 Harrison Act had banned opium imports.1 To control the supply of barbiturates and amphetamines siphoned to the black market, Dodd’s bill made it a crime if pharma firms, drug wholesalers, and pharmacists failed to maintain meticulous records of manufacturing, distribution, and sales. That was no small task given that the FDA estimated that the drug industry had churned out eight billion pills the previous year.2 Dodd’s bill would add law enforcement to the FDA’s mission, with armed inspectors seizing illegal drugs and making arrests. (The Drug Enforcement Administration was created nine years later.)
Doctors and pharmacists opposed Dodd’s bill, citing the onerous paperwork and raising concerns about the privacy of patient records. When a last-minute addition broadened the definition of drugs, pharma unleashed its full lobby.3 Dodd’s bill stalled. Congress did, nevertheless, pass the Drug Abuse Control Amendments the following year, expanding government authority to regulate barbiturates and amphetamines.4 Although it gave the FDA the power to regulate any drug that had “a potential for abuse,” the intensive pharmaceutical arm-twisting had succeeded in omitting any express mention of benzodiazepines.5
Advocates for the new law were concerned whether the FDA, which was already operating at full capacity, was capable of enforcing its new powers. In many instances, the agency seemed mostly reactive. Morale was low. The HEW secretary appointed an advisory committee tasked to make recommendations to reenergize the FDA. Named as chairman was James Goddard, a forty-two-year-old doctor with a master’s in public health. Having joined the Public Health Service in 1951, Goddard had spearheaded federal research on the benefits of mandatory seat belts in autos. In 1962 he became the youngest chief ever of the Communicable Disease Center (the predecessor to the Centers for Disease Control and Prevention). He made no secret that he wanted to be surgeon general, so he accepted the role with the FDA advisory board on the understanding that it was temporary.6
Goddard thought that pharma had interpreted Commissioner Larrick’s low-key regulatory approach as a sign of weakness. Drug companies made everything a battle on the assumption that Larrick would rather compromise than get into a nasty fight. That had happened with Larrick’s much heralded August 1963 decertification of Achrocidin and other antibiotic combo cold remedy rivals. It faced vociferous opposition from pharma and the AMA’s Council on Drugs. Larrick decided the battle was not worth the effort and withdrew the order.7
Incredibly, the FDA had not even begun the review required by the Kefauver Amendments of the efficacy of the four thousand pre-1962 medications still on sale to the public. The law had created a two-year waiting period between its enactment and when the FDA could start the review. That waiting period was intended to give the pharma firms the opportunity to do some testing and gather the data to convince the FDA that their early drugs were effective. No one in Congress had thought that the FDA would be too overwhelmed to fulfill its mandate under the Kefauver Amendments. Goddard was not sure how it could ever be taken seriously by the industry it was supposed to watch over. Instead of focusing, as Larrick had, on cooperating with other agencies on matters of public education and science, Goddard thought the FDA’s top priority should be regulation.
As 1965 ended, Goddard’s commission had assembled a long list of recommended reforms. Lyndon Johnson and the HEW secretary decided the most important change was who ran the FDA. George Larrick was out after eleven years and James Goddard was in, the first doctor in a generation and the first commissioner selected from outside the FDA.
Goddard decided to send a strong signal to the pharmaceutical industry that the change at the top of the FDA was substantive. The day after he took office, the agency announced formal hearings into whether Miltown and Equanil as well as Librium and Valium had a “potential for abuse.” If they did, it would subject them to the strict controls in place on barbiturates and amphetamines.8 Soon after Goddard’s lightning directive, the contested administrative hearings got under way. Dozens of expert witnesses lined up by the government and the industry battled over what qualified as addiction. The lesson for Goddard was that few things were fast in the FDA bureaucracy. The hearings would drag on for years (Miltown and Equanil continued losing market share all that time to Roche’s Librium and Valium).9
As part of his overall plan to recast the FDA as a more robust guardian of public health, Goddard also focused during his first weeks on the industry’s runaway drug promotion. He was concerned that drug companies “trumpeted results of favorable research and have not mentioned unfavorable research; they have puffed up what was insignificant clinical evidence: they have substituted emotional appeals for scientific ones.”10 The FTC regulated medical ads before the Kefauver Amendments transferred this responsibility to the FDA. There were more than four million pages of ads annually just in medical journals.11 Goddard knew the FDA did not have the resources to keep abreast of all of them. Still, he wanted to take early actions to at least emphasize to pharma that it was one of his priorities.
By the end of his first month he had gotten a “no contest” plea from Carter-Wallace in the FDA’s first prosecution under the Kefauver provisions. It had advertised a combination drug, Pree MT, a mixture of Miltown and hydrochlorothiazide, a strong diuretic. In JAMA advertisements, the ad copy read, “Contraindications: None Known.” In fact, the company knew its drug caused a sometimes fatal blood disease in addition to other side effects from gout to blood vessel constrictions. Carter-Wallace paid the maximum fine set by the new law, only $2,000.12
Encouraged by the Carter-Wallace plea, Goddard commenced other “false advertising” cases. Merck and Wyeth had failed to report adverse effects causing temporary blindness in its animal testing of an experimental drug, DMSO, used as a preservative for transplants. Ciba was accused of having kept secret reports that demonstrated Elipten, its epilepsy drug, was responsible for masculinization of young girls. Merck, which had merged with Philadelphia-based Sharp & Dohme, hid “alarming” findings of breast cancer in four of six dogs on which it had experimented with a combination oral contraceptive.13
Another priority Goddard wanted to address was restricting how pharma targeted women for drugs that they often did not need.14 It was an issue he became aware of a few years earlier when he ran the Communicable Disease Center. In 1963 he read Betty Friedan’s The Feminine Mystique, a book credited as launching the second-wave feminist movement.15 “Feminine mystique” was the notion—reinforced by everyone from Freudian psychoanalysts to Madison Avenue advertisers to women’s magazines where the top editors were men—that women were fulfilled only as loving mothers and loyal, supportive housewives.16 Friedan’s best-selling book—it sold over a million copies—made a powerful case against the ingrained stereotype that those who wanted careers were neurotic and unhappy. What caught Goddard’s attention was Friedan’s conclusion that tens of millions of women were the ideal pharmaceutical customers because of boredom and lack of personal fulfillment.
“You wake up in the morning,” Friedan wrote, “and feel as if there’s no point in going on another day like this. So you take a tranquilizer because it makes you not care so much.”17
Other feminist writers followed Friedan, furiously working to undo what they saw as centuries of societal distortion of female identity and diminution of self-worth.18 American psychiatry, then dominated by Freudian-based psychoanalysts, got much of the blame. The writers condemned Sigmund Freud’s theories as misogynistic, particularly his view that male was the norm and that fundamental differences with women were biological—“penis envy”—not the by-products of culture and environment.19
Goddard had studied the grim American medical history that had treated women differently than men when it came to ailments and care. Doctors in the eighteenth and nineteenth centuries believed women alone suffered from “treatable illnesses” of hysteria, nervousness, and excessive emotion.20I Physicians dispensed powerful sedatives. If those did not work, over twenty states allowed a husband to commit his wife to a mental asylum without a hearing.21 A step beyond institutionalization was lobotomy. Nearly two thirds of all lobotomies in the U.S. were performed on women.22 In the late 1940s and early 1950s, when lobotomies reached their zenith, the vast majority of patients were former housewives or living-at-home unmarried daughters.23
Goddard’s interest in whether modern pharma had targeted and typecast women was perfectly timed. His arrival at the FDA coincided with Valium becoming America’s top selling drug. Most of the customers for the hit tranquilizers were women.24 That was no mistake. In the case of Valium and Librium, it was the strategy and skilled handiwork of Arthur Sackler. Arthur, as were his two brothers, was a Freudian-based psychiatrist.25 Roche recognized that Sackler had an advantage over his lay Medicine Avenue competitors. As a doctor who had stayed active in laboratory trials and writing for scientific journals, he provided a unique perspective on how to best market drugs to other physicians.
How and why doctors should prescribe tranquilizers differently to men and women is laid out in an extraordinary eighty-page hardcover book, Aspects of Anxiety, that Roche sent to nearly ten thousand of the top prescribing physicians in the U.S. in 1965.26 Aspects of Anxiety was Arthur’s brainchild. No drug company had ever produced anything like it. There were twelve short chapters that laid out the different causes of anxiety and its physical and psychological toll. Produced on fine paper and with eye-catching charts and graphs, it was not only intended as a quick reference for doctors, but as a collectible to display in their offices.
Sackler had the idea when Librium was the only Roche benzo on the market. Roche had released Valium by the time it was published. It was too late to change the thrust of its focus on Librium, but Sackler thought it still a valuable doctor’s guide for understanding anxiety and especially for directing them to Roche’s benzodiazepines as the best treatment for most patients. A clever marketing ploy disguised as an “informational tool,” it sidestepped all FDA and FTC regulations.27 Sackler convinced Professor Charles Henry Hardin Branch, the president of the American Psychiatric Association, to write the preface (they had met in 1953 while separately researching endocrine psychiatry and possible treatments for depression; both published medical journal articles about their parallel research the following year).28
Roche did not identify the author of Aspects of Anxiety but Sackler’s handiwork is evident throughout.29 The book was a combination of detailed medical and psychological jargon mixed with breezy passages that today seem a rudimentary Men Are from Mars, Women Are from Venus worldview.
Both sexes shared plenty of common worries and stress from major life events. However, the pressure on men—dubbed “executive neurosis”—was caused by the expectation that they had to be breadwinners for their families without showing any of the stress that led to ulcers and high blood pressure. Similar intense pressure on women did not morph into any organic illness but instead produced behavioral disorders such as neurosis, hysteria, anxiety, and depression.30 II 31
In a chapter titled “Anxiety and the Female Psyche,” Aspects of Anxiety presented why women are prone to an “unstable emotional equilibrium” uniquely female. “In its most severe form, premenstrual tension may be characterized by panic states, suicidal tendencies and psychotic decisional episodes.” Those who suffered from menstrual cramps often had “a low pain threshold… [and] this hypersensitivity increases their anxious anticipation.” As women age, “menopause does represent deep psychological trauma, for the badge of femininity—menstruation—is now irretrievably lost.” The feminist encouragement for women to get jobs outside their homes would “bring about an even greater denial of her biologic female role (childbearing and child-care contributions to society).” In fact, “numerous studies discuss the higher incidence of disorders in women who repudiate their roles as wives [and] mothers.”32
Sackler and Roche cited eighty controlled studies and 162 clinical trials to encourage physicians to dispense Librium liberally for their patients reporting “anxiety and tension” as well as those complaining of everything from tension headaches, acne (evidence, said Roche, of a hormonal response to stress), gastrointestinal and cardiac problems, “behavior disorders in children,” and “gynecologic, including premenstrual disorders.”33 Aspects of Anxiety made a shameless pitch toward male doctors—who then composed 95 percent of all American physicians—when it addressed premenstrual tension. “It has been said it is a condition known to many women but perhaps even better known to their husbands and children—victims of monthly personality change.”34
Sackler and Roche were not the first pharma/advertiser combination to play on female typecasting in marketing a drug. Ads for phenobarbital, the 1960s best-selling generic barbiturate, featured always some slight variation of a harried housewife. One featured a woman screaming at her daughter, another was exhausted from mopping the floor, and still another at her breaking point toiling over a stove.35 Amphetamine ads, meanwhile, emphasized that since women had to raise the couple’s children, keep the house tidy, and cook dinner for their hardworking spouse, they might need a pharmaceutical jolt of energy to do all that and still be attentive to their husband’s needs (sex was always implied, never directly addressed). Moreover, pharma added an inducement: speed might help keep them thin.
What differentiated Sackler’s promotion of Librium, and especially of Valium, was it repackaged the same sexual stereotypes but in a sleeker and ostensibly smarter pitch. Flipping through medical journals in the 1960s, it seemed that for any man who was a driven overachiever, an ulcer was a casualty of success. Roche’s benzos could tame the stress that was the culprit. Valium ads featured men from the worlds of business, sports, and entertainment, all telling their success stories. A typical one: “Have you heard the one about the traveling salesman? The strain of tracking down customers and living out of a suitcase—the family matters left unsolved at home—no joking matter to a man emotionally overreactive to stress and vulnerable to duodenitis [ulcers].” In this way Sackler pitched Valium as simply another indispensable tool for savvy businessmen on the way up.36
As for women, they were cast as responding to stress with emotional outbursts that took a gloomy toll on their own mental health as well as that of their husbands and children. Sackler therefore promoted Valium as pretty much an all-around female “fix.” Roche ads encouraged doctors to prescribe Valium for exhausted moms, bored housewives, still-hoping-to-be-married single women over thirty, those moody and irritable during their menstrual cycle, and any depressed or anxious during menopause. Valium could tame the “unpredictable grouch,” said one Sackler ad. For a “35, single and psychoneurotic” fictional spinster Sackler created, Valium alleviated her “alienation and hostility” and “neurotic sense of failure.” It would also treat the depair of a “childless widow.”37
Sackler’s Valium campaign worked at every level. Through the 1960s, as sales boomed annually and set industry records, the drug was twice as likely to be dispensed to women than men.38 Women got 63 percent of barbiturates, 68 percent of all antianxiety meds, 71 percent of the first generation of antidepressants, and 80 percent of all amphetamines.39
At that same time Roche and other pharma companies targeted women with psychotropics, Robert Wilson, a gynecologist colleague of the three Sackler brothers, was about to help make a hormone drug a blockbuster. Instead of playing to the subconscious biases of male physicians by emphasizing the emotional and fragile psyche of women, Wilson exploited their fears about losing their femininity and sexuality as they aged. Like the Sacklers, Wilson was born in Brooklyn and later moved his family and practice to Manhattan. The product he was tapped to sell was Premarin, made from the estrogen-loaded urine of pregnant horses (the brand name, approved by the FDA in 1942 to treat menopausal symptoms, is short for PREgnant MARes’ urINe). Premarin was developed by a Canadian pharmaceutical firm, Ayerst, McKenna & Harrison. American Home Products (AHP) bought the company in 1943 and changed its name to Ayerst Laboratories.40 In addition to his gynecological practice, Wilson got $1.3 million in the 1960s from Ayerst and other drug companies to conduct clinical studies on hormones and contraceptives.41
Bill Frohlich, Sackler’s Medicine Avenue colleague and sometimes silent business partner, promoted many of the drugs for AHP’s two drug subsidiaries, Ayerst and Wyeth. The company had much bigger plans for Wilson than having him offer a rave testimonial about Premarin in one of Frohlich’s ads. Ayerst and Wilson had concocted a secret plan that Arthur Sackler would later acknowledge was an inspired way of circumventing the FDA’s prohibition on direct-to-consumer advertising. Wilson had written several articles for medical journals extolling estrogen to offset bone loss and protect the heart during menopause.42 In an expansive piece in 1962 in the Journal of the American Medical Association, his opening line read, “There is no convincing proof that estrogen has ever induced cancer in the human being.” In that same article he became the first doctor to contend that estrogen actually reduced the incidence of cervical and breast cancers.43
In 1966, the same year that Goddard became FDA commissioner, Wilson published a book, Feminine Forever. Its cover proclaimed it as “one of medicine’s most revolutionary breakthroughs”: that “menopause is a hormone deficiency disease, curable and totally preventable.… And every woman, no matter what her age, can safely live a fully-sexed life for her entire life.”44
No one knew that Ayerst had subsidized Feminine Forever, paid all Wilson’s expenses, and even underwrote his national publicity tour.45 It was decades before one of Wilson’s sons disclosed the full extent to which pharma firms bought his father’s endorsement. They paid for his Park Avenue office and eponymously named research foundation, as well as subsidizing his lectures to doctors’ and women’s groups.46 Searle and Upjohn, both of which had their own hormone brands, paid him “consultation fees” so he would plug their products.
Sackler had already medicalized the best-known symptoms of menopause. Millions of women popped lots of Librium and Valium to keep hot flashes at bay, combat the blues, and fix disturbed sleep patterns. Roche’s book, Aspects of Anxiety, sent the previous year to ten thousand doctors, had become the bible for physicians looking for any of a dozen reasons to dispense benzos. Those drugs, however, could not address some of the purely physical changes that many women experienced during menopause, including vaginal dryness, thinning hair, decreased muscle tone, dry skin, and loss of sexual desire.
Wilson zeroed in on a passage in every woman’s life that he warned would turn them into nothing more than “the equivalent of a eunuch.” He eschewed subtlety for dramatic overstatement. Menopause was a “living decay,” he wrote, in which women were “desexed” and “dull-minded.”47 It was “a galloping catastrophe” for women fifty and older. Not only were women the “only mammal who cannot reproduce after middle age,” Wilson ticked off a depressing list of twenty-six “debilitating symptoms” that left unmedicated menopausal women as “docile creatures missing life’s values,” allowing them only to “exist rather than live.”
Wilson wrote that he had witnessed his own mother change through menopause from “a vital, wonderful woman who had been the focal point of our family into a pain-racked petulant invalid.” He was not, however, all doom and gloom. He reported that one of his patients, a fifty-two-year-old unnamed woman, had started taking a “precious gift,” Premarin. When he examined her two months later, she appeared much younger and more vibrant.
As presented in Feminine Forever, Wilson medicalized not only menopause but female aging as well. Premarin was a fountain of youth in a one-a-day pill. “Breasts and genital organs will not shrivel. Such women will be much more pleasant to live with and will not become dull and unattractive.… What is really at stake is a subtle and almost metaphysical factor—a woman’s total femininity.” As Wilson repeatedly emphasized, women were not introducing a new medication to their body but rather replacing a hormone that evolution had somehow forgotten to make last longer.48 Wilson’s pitch, as The New York Times described it, was that “women would be replacing a hormone they had lost at menopause just as diabetics replace the insulin their pancreas fails to make.”49
Look and Vogue serialized Feminine Forever. It sold 100,000 copies in the first three months.50 Other women’s lifestyle magazines, some of which now dubbed estrogen the “Youth Pill,” wrote glowingly about it.51 Feminine Forever went from simply another “medical book about menopause” to a runaway best-seller in seventeen countries.52
Wilson’s Feminine Forever created a huge demand for Premarin because women asked their doctors for it. That demand was fed by subsequent publications. One, After Forty, was an ode to estrogen written by Sondra Gorney, an actress and public relations executive. As it did for Wilson, Ayerst paid for her services, employing Gorney through a New York City front organization, the Information Center on the Mature Woman.53
The same year Feminine Forever was published, Goddard labeled Wilson an “unacceptable investigator” and took the rare step of barring him from undertaking any subsequent hormonal research.54 That prompted his New York publisher to get in touch with the FDA to determine if Feminine Forever violated any federal regulations. Since the book recommended specific drugs for conditions for which they were not approved, the FDA said, the only limitation was that if the book was sold in drugstores, it could not be tied in to a promotion or made part of a sale of any prescription medication.55 Goddard’s frustration was that the FDA did not have any other way to curtail how Wilson marketed his book.
The problem with the entire estrogen revolution kicked off by Feminine Forever was that Wilson was wrong. Few suspected it, however. A New York cancer researcher, Saul Gusberg, sounded an early warning: “A human experiment has been set up in recent years by the widespread administration of estrogens to postmenopausal women.”56 When he was at Columbia in the late 1940s, Gusberg was alarmed to discover twenty-nine women taking estrogen pills had uterine cellular overgrowth and nine subsequently developed cancer. He suspected that estrogen might have been the culprit.
Gusberg’s warnings were never covered in the mainstream press. In the meantime, Wyeth and Robert Wilson helped the market for menopausal hormones take off. In the decade after the publication of Feminine Forever, estrogen prescriptions tripled to over 30 million annually and the average brand name price doubled.57 Premarin set company sales records. It accounted for 75–80 percent of the prescription estrogen market.58 It was by far the firm’s biggest profit maker. As Ayerst celebrated, Gusberg warned colleagues all the dosing could cause an explosive growth in cancer. Premarin and other estrogen drugs were a ticking time bomb, he predicted.59 Few were listening.
I. The word “hysteria” is from hysterika, Greek for “uterus.” Ancient Greeks believed that an unhappy and “wandering uterus” led to uniquely female afflictions, and that concept persisted through the centuries and had become an accepted tenet of Western medicine.
II. Sackler thought a series of Army experiments provided evidence to not only back his theory that untreated stress and anxiety caused organic diseases, but the resulting illnesses were different for each sex. The Walter Reed Army Institute of Research had conducted two years of experiments in the mid-1950s with hundreds of monkeys. In one series dubbed the “executive monkey trial,” two monkeys were strapped into adjacent “restraining chairs,” metal and glass contraptions that allowed limited movement only of their heads and arms. Electrodes attached to their feet delivered sharp electric jolts every twenty seconds. A lever situated next to one of the monkeys shielded both from the shocks when pressed. The “executive monkey” was the one with the responsibility to operate the lever in order to forestall the electric shocks. Every time the experiment was run, autopsies later revealed the executive monkeys developed acute intestinal and stomach ulcers while the control monkeys did not. The executive monkeys demonstrated what stress could do to men, Sackler and his colleagues concluded.