Monday, 10 May 2010

A speedy cure for depression

One of the charges frequently thrown in the face of the pharmaceutical industry these days is that they have run out of diseases to target, and have started inventing maladies in order to increase profits. Sometimes dubbed 'disease-mongering', this practice is hardly new. The story of the use of amphetamine to treat minor depression is a classic reminder of how little has changed in the way that drug companies interact with medical researchers and practitioners to peddle drugs.

Amphetamine was first developed by an American by the name of Gordon Alles. Between the wars there had been an interest in developing drugs that acted like adrenaline, but had a longer duration of action. Adrenaline had become a useful drug to clinicians because it could reverse the symptoms of asthma, as well as increase blood pressure in cases of shock. But adrenaline doesn’t have a very long half-life, and had been surpassed in the late 1920s by ephedrine (more on this another time). Alles was trying to make a drug to better the longer-lasting effects of ephedrine. Amphetamine was one of the compounds he came up with in 1929, although it wasn’t known by this name until sometime later (to organic chemists it is phenylisopropylamine). Alles tested it in animals and found that, much like ephedrine, it increased blood pressure and was active if swallowed. Before the close of 1929 he had tried it himself and had it tested on asthmatics. Both he and the asthmatics noted the marked stimulatory effect that amphetamine had on the central nervous system. Unfortunately, the asthmatics also noticed that it wasn't as good a remedy for their ailment as ephedrine. He and one of his clinician friends presented these findings at a meeting of the American Medical Association in the same year. Alles went on to pursue other projects in his bid to improve upon ephedrine, but dejected by the lack of efficacy of the compound in asthmatics, doled out amphetamine to clinical colleagues from time to time for them to test on their patients with various conditions.

Smith Kline and French, as they then were (now Glaxo Smith Kline) released Benzadrine onto the market in 1933. Benzadrine was amphetamine in all but name, and Alles had had the sense to patent his work. It’s not entirely clear to me what interaction Alles and SKF had, but by the end of 1933 Alles was working closely with the management of SKF and was receiving a 5% royalty on sales of benzadrine. Some sort of understanding had clearly been reached. Benzadrine was initially marketed as an inhaled decongestant. It would have worked, in the same way that cocaine would have worked before it was usurped by adrenaline and then ephedrine. As a company trying to embrace science and move beyond more cosmetic products, SKF had bigger hopes for amphetamine. Much like Alles (and with his guidance), but with a more brutal commercial attitude, SKF started sending samples of amphetamine to any clinician working with patients who might conceivably benefit from the drug’s actions. This included trials of amphetamine in abating chest colds, dysmenorrhea ("period pains") and heart conditions. What SKF wanted was evidence that the drug was more than a decongestant so that they could legitimately advertise it for other indications. There aren’t many published reports of just how useless amphetamine was in how ever many conditions SKF considered, since then, as now, drug companies were a bit too secretive about negative findings. It certainly didn’t work in dysmenorrhea, which must have been a blow for SKF as this was (and still is) considered a cash cow. But they struck gold in the end.

Alles already knew from his clinician colleagues that amphetamine was useful for narcoleptic patients – people who fall unpredictably asleep. SKF obtained more data from additional trials and advertised the drug for this condition as well in 1935, but it is not a common condition. In 1936 SKF finally heard the news they were waiting for. Abraham Meyeson, a psychiatrist reported that amphetamine appeared to be of benefit in some cases of depression. This is where the disease-mongering began. Meyeson had unusual ideas about the psychiatric disorders that were crudely recognised at the time, and they fitted perfectly with the central nervous system side effects of amphetamine (the very effects that Alles had tried to eliminate.) Meyerson had written two popular works, the titles of which suggest something about his views on the psychiatric problems of the day: When life loses its zest, and The nervous housewife. He coined the term "ahedonism" for the ailment that he thought was raging through society and causing people live in conflict with the world around them. In short, he thought they’d lost the "pep", "zest" or "energy feeling" that more adjusted people retained. Amphetamine, he reasoned, filled the hole. By 1937 SKF started pushing amphetamine to treat any mood disorder that psychiatrists could identify and the money started flowing in. Slowly a consistent picture emerged: amphetamine appeared to be useful in mild depression, but ineffective (or worse) in more severe cases, and other psychiatric conditions. Initial AMA regulations insisted that amphetamine should be used only in patients already institutionalised, but many general practitioners prescribed the drug in response to SKF's advertising campaign.

Without amphetamine, ahedonia was just one popular psychiatrist's concept, and without ahedonia, Benzadrine was just a decongestant. Conservative estimates put Benzadrine sales at about a million pills per day in the US by 1945.

Further reading:

There is a very good, if rather long account of the amphetamine story in:
Rasmusse, N (2006) Making the first anti-depressant: amphetamine in American medicine 1929-1950. J Hist Med Allied Sci 61(13) 288-323.


  1. My mum recalls her fellow students at King's College London in the late 50s buying Dexedrine / Benzedrine when they had to stay up all night finishing an essay. Buying over-the-counter in chemists' shops without a prescription, that is - was legal OTC at the time.

  2. SK&F relied on all the off-label uses for benzadrine. It's the best example of this that I've come across.