Chapter 2. Benzedrine: The Making of a Modern Medicine [excerpt]
To demonstrate that amphetamine was safe, Smith, Kline and French (SKF) commissioned a study by a University of Pennsylvania medical school professor of internal medicine named Wallace Dyer. Because amphetamine was thought of as an artificial adrenaline, one of the most obvious issues was the rise in blood pressure that it caused. This effect might be beneficial for those with low blood pressure, but it might be a dangerous side-effect for patients with high blood pressure. So, to establish whether such people would have to be ruled out for Benzedrine Sulfate prescriptions, whatever the drug's medical use might be, among his hospital patients Dyer recruited subjects with normal, low, and high blood pressures. At first he gave them all 10 mg to 20 mg of amphetamine a day, and then after a few months, on instructions from SKF, he raised their doses to 30 mg per day. It would be ethically unacceptable today to experiment like Dyer did with his high blood pressure patients, who stood a particularly good chance of being harmed and could not reasonably be expected to benefit. However in those days doctors had few doubts about their own beneficence, and there was nothing very unusual about such experimentation. Only after the Second World War's revelations of Nazi medical atrocities did American medical researchers begin to reconsider their own ethics around human experimentation. In any case, nothing bad seems to have happened to Dyer's patients, and his study was eventually published in the high-profile American Journal of Medical Science.3
------------- Drug Seeking Disease -------------
In the 1930s proof of safety was required only for AMA permission to advertise. Legally, a new drug could be used on people, and indeed sold at pharmacies, before even animal studies were done. So while the safety studies were underway in 1935 and 1936, SKF also worked on clinical testing to solve the harder problem: finding what Benzedrine Sulfate would be useful for, helping the drug find its place in medicine. Amphetamine was a "drug looking for a disease," in sociologist Rein Vos's memorable phrase. In 1936 almost any use was imaginable, since amphetamine had adrenaline-like effects on the circulation, respiration, and involuntary muscles, as well as the brain. So SKF took a two-pronged approach. The first prong consisted of providing a free drug supply to almost any interested doctor, in exchange asking only to be kept informed. By mid-1936 SKF already had a list of "sixty-odd men doing special work" on amphetamine, most of them free-lancers following their own scientific interests. Doctors both eminent and obscure were sent samples of the drug, for experiments on conditions ranging from colitis to multiple sclerosis.4 SKF even sent some in liquid form to a Buffalo, New York, endodontist who wanted to try it instead of adrenaline as an additive with local anesthetic injections-even though it had already been shown in laboratory tests that amphetamine is inferior to adrenaline for constricting capillaries, and therefore a poor choice for reducing surgical bleeding. SKF research managers greatly appreciated such "scientific hunches" coming from practitioners, who after all were the prescribers on whom sales ultimately depended. If these free-lance experimenters should turn up "something of interest or value" the firm wanted to know, whether or not they intended to publish, so the researchers were regularly "tickled" for updates (in the words of SKF's Assistant Director of Research, Ted Wallace).5
On the other hand, not everything could be left to the random hunches of the medical profession. Thus the second prong of the drug firm's approach consisted of commissioning targeted studies by relevant experts, to explore the most obvious and potentially lucrative possibilities for the new product. Apart from narcolepsy, already being pursued by Alles's old colleague Prinzmetal and several others, two of the most obvious potential uses of amphetamine were for asthma and allergies, and for dysmenorrhea (painful menstruation). The dysmenhorrea idea seemed plausible based on laboratory physiology, since the drug reduced contractions in uterus muscle. The market might be huge: since dysmenorrhea was extremely common and little could be done for it, the complaint was the "bete-noir of the gynecologist," as one of them, J. M. Hundley of the University of Maryland, put it. With Alles's acquaintance Leventhal, Hundley was one of several gynecologists trying out Benzedrine Sulfate with funding from SKF in 1936. The first results from a study on 40 women complaining of dysmenhorrea were very encouraging; many patients were coming back to the doctor, asking for more of the new pills. So Hundley and colleagues arranged a larger trial with women working in a General Electric factory. Although 114 of 186 women treated for dysmenhorrea over six months experienced 'good' results in that they reported that their menstrual pain subsided after one 10 mg tablet, SKF did not choose dysmenorrhea as its main path for bringing amphetamine to market. The reason may be that other experimenters were not finding any such benefits, or that the latest physiological research was suggesting that dysmenorrhea was not actually caused by abnormal contraction of the uterus. Or perhaps the firm realized that these 'good' results were due to the drug's mental 'side effects:' many women reported that the pills made work easier and that they left the factory feeling remarkably energetic.6 Neither did studies to test amphetamine for asthma find the drug particularly useful. Amphetamine would not find its place with the allergists or gynecologists.
Another possibility for amphetamine specially targeted by SKF was the use of the drug for mental performance enhancement. Higher intelligence test scores with the drug were reported by psychiatrist William Sargant from London's Maudsley clinic, in the prominent journal Lancet in late 1936. (Recall that Alles' old San Francisco friend Peoples had brought amphetamine along when he went for training there). To follow up, SKF funded psychologists William Turner and George Carl at University of Pennsylvania's hospital to conduct a very extensive battery of tests on normal volunteers, mostly nurses and other hospital staff. The tests were intended to show how the drug affected performance in a variety of mental and physical tasks, and also to assess effects on a wide range of other psychological characters such as imagination, optimism, and other aspects of personality. These researchers found that the drug did improve efficiency in simple mental tasks and tests of hand-eye ('psychomotor') problem-solving, especially where persistence and alertness were required. They concluded that the increased performance on such mental tasks did not come from any actual improvement in thinking ability, but from increased confidence and other mood effects of the drug. And while these researchers did not feel that the drug caused true personality change, their psychometric tests showed that amphetamine typically produces increased optimism, extroversion, initiative, and aggression even in smaller doses...