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Speed, Ecstasy, RitalinThe Science of Amphetamines$

LESLIE IVERSEN

Print publication date: 2008

Print ISBN-13: 9780198530909

Published to Oxford Scholarship Online: March 2012

DOI: 10.1093/acprof:oso/9780198530909.001.0001

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Medical uses of amphetamines

Medical uses of amphetamines

Chapter:
(p.29) Chapter 3 Medical uses of amphetamines
Source:
Speed, Ecstasy, Ritalin
Author(s):

Leslie Iversen

Publisher:
Oxford University Press
DOI:10.1093/acprof:oso/9780198530909.003.0003

Abstract and Keywords

Amphetamine was first introduced into medicine as the ‘Benzedrine inhaler’ in 1932, followed soon after by pill forms of the drug. As with many new medicines, amphetamine was at first embraced enthusiastically by the medical profession as a valuable and completely safe treatment for many ailments and it rapidly became enormously popular. It was only later that the potential hazards associated with amphetamine use became apparent. In practice, the genuine medical uses of amphetamine proved to be far more limited and few of the original indications remain current today. This chapter reviews the medical uses which gained the most acceptance, even though most of these are no longer current, such as amphetamine's use as decongestant, and treatment for narcolepsy, depression, and ADHD.

Keywords:   Benzedrine, decongestants, narcolepsy, ADHD, medical uses, depression

Estimated legal production of amphetamine tablets in the United States in 1970 = 10 000 000 000

(Grinspoon and Hedblom 1975)

3.1. Introduction

Amphetamine was first introduced into medicine as the ‘Benzedrine inhaler’ in 1932, followed soon after by pill forms of the drug. As with many new medicines, amphetamine was at first embraced enthusiastically by the medical profession as a valuable and completely safe treatment for many ailments and it rapidly became enormously popular. It was only later that the potential hazards associated with amphetamine use became apparent. In a review of the literature, Reifenstein and Davidoff (1939) were able to quote 115 papers published between 1935 and 1938 on various potential therapeutic applications for Benzedrine. By 1946, the US physician W. R. Bett was able to describe 39 ‘clinical uses’ (Bett 1946). These included epilepsy, Parkinson's disease, schizophrenia, alcoholism, barbiturate intoxication, anaesthetic overdose, morphine and codeine addictions, tobacco smoking, behavioural problems in children, enuresis, migraine, heart block, multiple sclerosis, myasthenia gravis, myotonia (muscular rigidity), infantile cerebral palsy, urticaria, dysmenorrhoea, colic, irradiation sickness, and hypotension (low blood pressure). Bett was not alone among US physicians, who rated amphetamine almost as highly as aspirin. This may now seem naive, but it is worth remembering that the range of medicines available to doctors in the 1940s was very limited; effective treatments for most of the conditions listed were not available. However, in practice the genuine medical uses of amphetamine proved to be far more limited and few of the original indications remain current today. We have come to recognize that amphetamines are both potentially addictive and quite toxic. In this chapter we will review the medical uses which gained most acceptance, even though most of these are no longer current.

(p.30) 3.2. Amphetamine inhalers as decongestants

The first medical use of amphetamine made use of the fact that it acts as a ‘sympathomimetic’ amine, promoting the release of norepinephrine from sympathetic nerve terminals in the periphery (Chapter 2). Scientists at the drug company Smith Kline and French (SKF) found that inhaled amphetamine had a beneficial effect in constricting blood vessels in the nasal cavity and dilating the bronchial tubes in the lung, and thus could be used to treat the symptoms of the common cold, hay fever, or asthma. The company licensed the patents for amphetamine from the British chemist Gordon Alles and launched the Benzedrine inhaler in 1932. This was a simple device containing quite a large amount (about 350 mg) of Benzedrine (DL-amphetamine) as the free base in oil form impregnated in cotton strips inside a simple inhaler device (Fig. 3.1).

Because amphetamine oil is quite volatile, even at room temperature, sniffing the inhaler gave the patient a small dose of Benzedrine and some degree of relief from nasal congestion and/or wheeziness in the lungs. The device could continue to deliver Benzedrine for several weeks. There is no doubt that this was effective, and the Benzedrine inhaler was hugely successful; it remained on the market in one form or another for more than 25 years. Although SKF held the patents on the Benzedrine inhaler, it was widely copied by other companies using other compounds from the amphetamine family. Burroughs Wellcome marketed an inhaler containing methamphetamine, Wyeth Laboratories had the ‘Wyamine inhaler’ containing the amphetamine analogue mephentermine (N-methyl analogue of phentermine; see Fig. 2.2), and there were several others. However, it was soon discovered that the Benzedrine inhaler could be a source of amphetamine for those more attracted by the euphoriant effects than by treatment of the common cold (Grinspoon and Hedblom 1975). The 350 mg of Benzedrine free

                   Medical uses of                         amphetamines

Figure 3.1 Benzedrine inhaler.

(p.31) base that was present in each inhaler was equivalent to 560 mg of amphetamine sulphate, enough for many large doses when the inhaler was broken open and the contents ingested or injected (see Chapter 5). Increasing evidence of abuse led SKF to decide voluntarily to stop marketing the Benzedrine inhaler in 1949. They replaced it with the Benzedrex inhaler which contained proplyhexedrine, a sympathomimetic amine which, although still effective as a decongestant, is devoid of central stimulant properties and abuse potential. Other companies were less scrupulous, and amphetamine- and methamphetamine-containing inhalers continued to be freely available until they were finally banned by the Food and Drug Administration (FDA) in the USA in 1959. Even then several companies continued to market inhalers containing other amphetamine-like drugs. One mid-western company even continued to sell the ‘Valo inhaler’, containing 150 mg of methamphetamine after the 1959 ban, and the Wyamine inhaler containing the amphetamine analogue mephentermine continued to be sold over the counter until 1971 and was also misused (Angrist et al. 1970). Although effective in their medical uses, amphetamine inhalers introduced hundreds of thousands of people on both sides of the Atlantic to amphetamine abuse.

Even today, over-the-counter inhalers containing amphetamine-like drugs are still available as decongestants, although the compounds now used are ones that act solely on the norepinephrine system in the peripheral sympathetic nervous system and are devoid of psychostimulant properties or abuse potential. A little known fact is that the popular ‘Vick inhaler’ contains 50 mg of methamphetamine (described on the label by the synonym deoxyephedrine) in free base oil form; however, it is not the psychoactive D-isomer of the drug but L-methamphetamine, which has no psychostimulant properties but retains some sympathomimetic activity. Innocent users of the Vick inhaler to treat the symptoms of the common cold can get into trouble with the law if subjected to a drugs test, as this will indicate the presence of methamphetamine unless the test is sufficiently sophisticated to tell the difference between the L- and D-isomers of the drug!

3.3. Narcolepsy

Narcolepsy is a strange medical condition marked by an uncontrollable desire for sleep and sudden attacks of sleep during the waking day. Onset of the illness usually occurs between the ages of 10 and 20 and it remains as a lifetime disorder. It is estimated that 50 000–100 000 people suffer from this condition in the USA. Obviously the symptoms are not only inconvenient but can be dangerous to those whose jobs require them to stay awake and alert (e.g. drivers, miners, those in control of complex machinery). Narcolepsy was one of the first medical conditions to gain official approval for amphetamine use. The American Medical Association (1937) recommended this as one of the conditions for (p.32) which Benzedrine was effective, citing positive clinical trial data from Prinzmetal and Bloomberg (1935). This was followed by many other positive reports. D-Amphetamine or methylphenidate taken twice a day is usually very effective. Until recently these remained widely used treatments for narcolepsy, but a new medicine, modafanil (trade name Provigil), seems likely to replace the amphetamines. Modafinil is not an amphetamine, but it is able to prolong wakefulness in narcoleptics and even in normal people without an unpleasant hangover effect and with no abuse potential. The mechanism of action remains unknown, but the advantages of having a non-scheduled and apparently safe medicine are obvious (Ferraro et al. 1997; Banerjee et al. 2004).

3.4. Depression

The American Medical Association (1937) also recommended Benzedrine as ‘useful’ in the treatment of ‘certain depressive psychopathic conditions’ when used ‘under the strict supervision of a physician’. They spoke of the drug's ability to promote ‘a sense of increased energy or capacity for work, or a feeling of exhilaration’. However, the clinical data underlying this recommendation were far less convincing (Guttmann 1936; Myerson 1936). Guttmann (1936), rediscovering what Alles (1928) had discovered several years earlier in experiments on himself, commented on the mood-elevating effects of Benzedrine in a study of the relation between the effects of the drug on blood pressure and mental phenomena. Guttmann subsequently published reports on the beneficial euphoriant effects of Benzedrine in depressed patients, although in one study (Guttmann and Sargant 1937) he reported that while the drug was effective in mildly depressed patients, it could make those with severe depression worse by provoking or intensifying anxiety. This paper ended with the prophetic statement:

The possibility of addiction needs to be guarded against and the case of a person who has been purchasing Benzedrine at chemist's shops without medical supervision has already come to our notice, although none of our patients have so far shown a tendency to addiction…At present, however, Benzedrine may be purchased at any chemist's shop without prescription and this seems inadvisable with a drug all the properties of which have yet to be fully investigated…. It is hoped that this drug will not be discredited by misuse. (Guttmann and Sargant 1937)

Benzedrine was freely available as an over-the-counter medicine until 1939, when in the USA it became available on prescription only. Despite the weakness of the evidence, Benzedrine and other amphetamine products became widely used for a time in the treatment of depression (Fig. 3.2). In his enthusiastic review of the place of Benzedrine in medicine, Bett (1946) enthused that:

A large number of clinical observations both from general practitioners and from specialists testify to [amphetamine's] immediate, and often dramatic, value in (p.33)

                   Medical uses of                         amphetamines

Figure 3.2 Early advertisement for Dexedrine as an antidepressant (1940s). (www.amphetamines.com/dexedrine.jpg)

breaking the stranglehold of depression, restoring ‘energy feeling’, and renewing optimism, self-assurance, increased initiative, appetite for work and zest for living.

It must be remembered that during the 1940s there were none of the highly effective antidepressant drugs that are available today. Physicians of that era also had little concept of how to conduct controlled clinical trials. In particular, little or no allowance was made for the fact that depression often shows spontaneous improvements. Nowadays any clinical trial of a new antidepressant drug would automatically include a comparison of groups of depressed patients receiving the active drug with another group receiving only dummy (placebo) pills. Neither doctor nor patient must know whether an individual subject is receiving drug or placebo (double blind). Even so, clinical trials of antidepressants are notoriously difficult to conduct because there is nearly always a significant improvement in the placebo group as well as in the drug-treated group.

The clinical experience with amphetamines in the treatment of depression soon made it clear that many patients reacted unfavourably, and that there were (p.34) cardiovascular and abuse hazards. Drug companies attempted to counter the increasing awareness of the dangers of amphetamine by introducing new amphetamine-like drugs. One of these was methylphenidate (Ritalin), later to become famous in the treatment of behavioural disturbances in children (see section 3.5). It was claimed that methylphenidate elevated the mood of depressed patients without causing insomnia or anxiety (Nathensohn 1956; Landman et al. 1958). However, subsequent clinical trials failed to confirm this; most properly controlled trials found methylphenidate to be no more effective than placebo (Robin and Weisberg 1958; Thal 1969).

Another strategy used to counter the psychostimulant effects of amphetamine, particularly in causing insomnia and anxiety, was to combine amphetamine with a sedative barbiturate (Gottlieb 1949). These combinations began to be marketed under a variety of brand names (e.g. Dexamyl, Amber), but in reality the strategy was not effective. In a controlled clinical trial the British physician David Wheatley compared a combination of 5 mg D-amphetamine and 65 mg amobarbital with the individual components and placebo in groups of depressed patients (Wheatley 1969). There was no difference between D-amphetamine or the combination and placebo, and Wheatley concluded that amphetamines, whether alone or combined with barbiturates, had no place in the treatment of depression. Nevertheless, drug companies, seeing a large new market, continued to produce the combination products until they were eventually displaced by a new generation of safer and more effective antidepressants. For a while, particularly in the UK during the 1950s and 1960s, the combination drugs became very popular and were subject to abuse and black market dealing.

3.5. Amphetamines as anti-obesity agents

For more than 50 years, in the post-war period of prosperity, obesity has been seen as an increasingly important public health problem in many Western countries, none more so than the USA. People have been only too willing to believe that medicines could help them lose weight, and drug companies have been happy to oblige by providing diet pills. This became a major profitable market for the companies, and amphetamines and amphetamine-like drugs played a key role. There have been many unforeseen consequences, and some catastrophic tragedies, as this story developed.

Amphetamine has a well-recognized ability to suppress appetite, perhaps acting through its effect in increasing the synthesis of the CART peptide in the hypothalamic feeding centres of the brain (see Chapter 2). After the first clinical reports of the use of Benzedrine as an anti-obesity agent (Lesses and Myerson 1938), it was approved for this use by the FDA in 1939, followed a few years later by approval of methamphetamine also for this indication. The FDA stated: ‘The (p.35) sympathomimetic amines have been found of value, when administered under the supervision of a physician, as an adjunct to the dietary management of obesity’.

The amphetamines rapidly became extremely popular diet pills. By 1948 more than 90 per cent of US physicians were using them to treat obesity, and some two-thirds of patients seeking treatment for obesity were receiving them (Grinspoon and Hedblom 1975). The initial clinical studies were followed by a series of further trials and reports, many poorly designed and inadequately controlled. Physicians were slow to recognize the adverse side effects inherent in amphetamine use. For example, Finch (1947) advocated the use of D-amphetamine to control weight gain in pregnant women. He stated: ‘Dexedrine is a nontoxic safe drug which may safely be used in obstetric patients to aid them in preventing excessive gain of weight’.

The patients who lost most weight appeared to be those who ate least, and so the main effect of the amphetamines seemed to be to reduce appetite rather than to increase activity levels or basal metabolic rate. The rationale for using amphetamines was that it might make it easier to adhere to a dietary regime that demanded a lower food consumption than the dieter would normal desire. Amphetamines were generally combined with dietary restrictions and for the first few weeks of treatment they were often very effective. Adlersberg and Mayer (1949) studied a total of 299 obese patients and found that those following dietary restriction plus amphetamine (5 or 10 mg twice daily) lost more weight than those on diet alone. However, they also found that the most impressive weight losses for diet alone or diet plus amphetamine occurred in the first 1–2 months of the trial. After several months the effectiveness of amphetamine wore off and higher doses had to be given to maintain weight loss; eventually there was little difference between the diet alone and diet plus amphetamine groups. Similar findings were reported by Gelvin and McGavack (1949). They studied 27 obese patients who were permitted to eat as much as they wanted. They were treated with 15 mg D-amphetamine per day, increased to 30 mg per day. After 8 weeks 47 per cent maintained a weight loss of 1 lb per week, but after 12 weeks only 23 per cent continued to lose that much. Twenty weeks after the start of the trial only one patient was still losing weight. The development of tolerance to the appetite-suppressant effects of amphetamines and the need to increase the dose, thus risking the development of addiction, meant that in practice these drugs were of only limited usefulness.

In addition, although the psychostimulant properties of amphetamine were initially disregarded, some patients suffered severely from these effects. Grinspoon and Hedblom (1975) gave the following personal account of the experience of a 25-year-old obese woman treated with amphetamine.

I was convinced, because I was not told otherwise, that these magic little pills would solve my weight problem, which was substantial, amounting to an excess of 50 pounds. I would eventually be thin. I filled the prescription and the next morning took the first pill…. The day passed uneventfully and so did the evening (fat girls (p.36) don't go out), and then I got ready to go to bed. And couldn't. What's the sense in going to bed if you can't go to sleep, and this eluded me? I was so ‘high’ that my mind was running circles around itself. My thought patterns resembled Joyce's stream of consciousness technique; I could not concentrate on any thought for more than a matter of seconds and then my mind would dart to something else, seemingly unrelated. To say the least I was disconcerted because I had no control over my thoughts…. The next day was little better but eventually, as I recall, my tolerance built up quickly, and I did not have nighttime ‘highs’ after a couple of weeks. My weight problem was much more persistent. I found that Dexedrine did depress my appetite as long as my will power was in high gear; when I slipped I became a compulsive snacker, eating literally anything and everything I could get my hands on. When will power took the reins again, I would manage to drop a few pounds.

Weeks and months passed, and I remember thinking that the pills were no longer doing their job. I experienced a craving to take more than one pill a day, but never quite had the courage to do so. I also found myself becoming jittery and jumpy. Minor things would unnerve me and I tended to want to be alone more and more; I became progressively unhappy and would burst into tears over the most trivial things. I remember a period of strange, weird dreams, where I was thin, lovely, and the centre of attraction. Then I would wake up to fat reality.

After six months, I began to question the validity of continuing; I wasn't losing weight, and I was miserable in the bargain…I became alternatively moody, euphoric, depressed. I would snap at people for no reason at all, and was generally ‘bitchy’ to those around me.

In April I decided to stop taking ‘the magic diet pills’

(After recovering from amphetamine withdrawal symptoms, she later went on to join Weight Watchers and lost 51 lb.)

Of course, not all those treated with amphetamines had such harrowing experiences, and many patients found that the pills did help them to lose weight, although much of this would often be regained after treatment stopped.

The recognition that many patients could not tolerate the high doses of amphetamine needed for sustained weight loss because of their psychostimulant effects led to the development of new medicines in which amphetamine was combined with a sedative barbiturate to counteract the stimulant effects, although there was little evidence that these medicines were any more effective or safe (Shapiro and Michaile 1956; Necheles and Sorter 1957). Eventually, the FDA recognized the limited usefulness of the amphetamine barbiturate combinations, stating that they differed ‘…neither in efficacy or in the incidence of adverse side effects from anorectic drugs alone’ (FDA Bulletin 1972).

The pharmaceutical industry also introduced a range of new once-daily amphetamine formulations and a family of new amphetamine-like drugs, claiming each time that they had retained the desired effects on weight loss while removing any liability to over-stimulation or addiction. In the period (p.37)

Table 3.1 Affinities of some amphetamine-like appetite suppressant drugs for human brain monoamine transporters

Compound

Ki(nM)

Norepinephrine

Serotonin

Dopamine

Phentermine

244

13 900

1580

DL-Phenmetrazine

153

〉10 000

607

DL-Fenfluramine

1987

269

23 700

D-Fenfluramine

1290

150

22 000

DL-Norfenfluramine

242

480

4305

Chlorphentermine

451

338

3940

Aminorex

55

1244

216

Ki, nanomolar concentration needed to occupy half of the monoamine transporter sites.

Data from Rothman and Baumann 2003.

between 1956 and 1960 alone these included the novel drugs phendimetrazine, phentermine, benzphetamine, phenmetrazine and diethylpropion. These drugs all share the same basic amphetamine-like chemical skeleton (Fig. 2.2) and all act as monoamine-releasing agents in brain, with much the same effects and side effects as the parent amphetamines, although this conclusion was strenuously denied by the manufacturers. The affinities of some of these compounds for the monoamine transporters in brain are summarized in Table 3.1.

Modell (1960) reviewed the newer agents and concluded:

It seems unlikely that any minor structural change in this group which continues the same theme will separate the effect on appetite from the other effects of the central stimulant action that may be clinically undesirable. Yet it is precisely this which is inferred from many claims made for these drugs, namely the recurrent claims for reduced incidence of insomnia, anxiety and nervousness, with potent anorectic effect.

The quality of the scientific data supporting claims for these new drugs was often very poor, even though the results were published in reputable scientific and medical journals. The standards of rigour for clinical trials were not very high 50 years ago. The paper by Freed and Hays (1959) is an example of the genre. They reported on a new formulation of the dieting drug phentermine. In the preparation, which was called Ionamin, phentermine was linked to an ion exchange resin, giving a formulation that released the drug gradually in the gastrointestinal tract for absorption into blood. The paper does not indicate how the subjects were selected or how obese they were at the start of the trial. No control (placebo) or D-amphetamine comparator groups were included, and the data presented are sparse, although the conclusion was that subjects treated with 30 mg phentermine daily lost an average of 7 lb over the 1-month period (p.38) of the trial. The authors minimized the importance of adverse side effects, describing the insomnia that patients often experienced as ‘somewhat different from that occurring during amphetamine therapy’; their patients ‘reported a wakefulness which was not unpleasant, compared to the nervous overexhilaration which prevented sleep following amphetamine treatment’. The authors concluded that Ionamin was ‘…chemically and pharmacologically different from amphetamine’.

Modell and Reader (1970), in their review of anorectic agents, gave a more accurate verdict on phentermine: ‘All systemic effects, therefore, stem from an amphetamine-like action. There is no good evidence that this is in any way a superior member of the group’.

In Europe the amphetamines and amphetamine-like drugs also proved popular as anti-obesity agents. In addition to the amphetamine-like drugs introduced in the USA, there were some that were used in Europe but never registered in the USA. A combination of caffeine and ephedrine known as the ‘Elsinore pill’, which was invented in Denmark, was popular for a while (Malchow-Møller et al. 1981) and is still available.

Another tragic example was the compound aminorex (Fishman 1999). Aminorex had the traditional dopamine/norepinephrine-releasing properties of other amphetamines, but in addition it had other pharmacology. Notably, it impaired the normally rapid removal of serotonin from the blood as it passes through the lungs and it also acted to constrict the arteries carrying blood to the lungs (Weir et al. 1996). None of this was known when the drug was first marketed, but these features may explain why aminorex was associated with an outbreak of the serious lung disease primary pulmonary hypertension (PPH) in Europe during the 1960s. PPH is a distressing and often progressive condition in which the pulmonary blood vessels carrying blood to the lungs are constricted, leading to impaired oxygenation and fluid accumulation in the lungs. Patients literally drown in their own fluids, gasping for breath. In many cases PPH is irreversible and leads to death. Fortunately, PPH is a rare disease with an incidence of 1–2 per million in the normal population. Although manufactured by an American company, McNeil Laboratories, aminorex was never approved for use in the USA. However, it became a popular anti-obesity agent in some European countries, capturing 80 per cent of the market for such medicines in Switzerland and also selling well in Austria and Germany. In late 1967 an astute Swiss physician, Gurtner, noted a dramatic and unexplained 20-fold increase in the numbers of patients with PPH coming for treatment at the University Medical Clinic, Bern. He noted that most of the new patients were obese and most had been taking aminorex. Ingestion of more than eight packs of aminorex tablets over a period of months was associated with a 10 per cent risk of developing PPH. The patients with drug-induced PPH had the classical (p.39) pathology of spontaneous PPH cases, but their disease often progressed rapidly and although some showed reversal when the drug was stopped, many became progressively worse and died. Gurtner and his colleagues were cautious in interpreting their findings as proof that aminorex was the cause of the new spate of PPH cases, but nevertheless the Swiss authorities withdrew the drug from sale in 1968, and similar action followed later in Austria and Germany, the two other European countries in which the drug had found favour. In the USA, McNeil Laboratories withdrew their application for approval of the drug by the FDA and discontinued further development, but by then the damage had been done. In total, some 600 patients in Switzerland, Austria, and Germany may have developed PPH as a result of taking aminorex between 1967 and 1969. The numbers of new cases dropped dramatically after the withdrawal of the drug. The aminorex ‘epidemic’ should have acted as a warning for the future that the effects of new appetite suppressants on the lungs should be carefully monitored, but this did not happen, with further tragic consequences. This may in part be due to the fact that the Swiss findings were largely published in German-language journals and the data took some time to reach an English-speaking readership (Follath et al. 1971; Gurtner 1985). Even then a cause-and-effect relationship between aminorex and PPH was not always accepted; it was argued that less than 2 per cent of patients treated with the drug developed PPH, and animals treated with high doses of aminorex had not exhibited any signs of pulmonary changes (Lancet 1971). The aminorex episode was soon forgotten.

Despite the doubtful efficacy and safety of amphetamines in the treatment of obesity their use grew to remarkable proportions as figures for the USA show (Colman 2004):

  • 1958: 3.5 billion tablets

  • 1967: 8 billion tablets

  • 1967: 23 million prescriptions (80 per cent female).

A large proportion of these prescription drugs were being diverted to other non-medical uses. However, important changes were on the way in USA. In 1962 the Kefauver–Harris amendments to US drug approval laws meant that in future the FDA would require that prescription drugs be shown to be clinically effective as well as safe to use in patients (previously only safety had to be demonstrated). The FDA established a number of panels of experts to undertake a retrospective review of the efficacy of amphetamines as anti-obesity agents. By 1970, their conclusion was that amphetamine-like drugs were at best ‘possibly effective’ and there were several criticisms of the data available in the literature. Studies were of short duration, there was no available evidence that the drugs altered the natural history of obesity, there was some evidence that the anorectic effects may have been strongly influenced by the suggestibility of the (p.40) patient, and there were concerns about the adequacy of the controls in some of the clinical studies (Colman 2004).

The FDA set up further advisory groups to formulate a formal policy on the approval of anorectic drugs. In 1971 guidelines were issued requiring that a statistically significant difference be demonstrated between drug-treated and placebo groups, and that clinical trials be at least of 12 weeks duration. European regulatory agencies soon followed suit with similar recommendations.

The FDA went on establish the Amphetamine–Anorectic Drug Project, which undertook a meta-analysis of clinical data submitted to FDA for all amphetamine and amphetamine-like compounds. There were 200 clinical studies involving 10 000 patients. The conclusions were that patients treated with active medication lost ‘some fraction of a pound a week more than those on placebo’. However, the data did not suggest that one drug was superior to another. The FDA stated:

…all anorectic drugs including amphetamines and methamphetamines have a limited usefulness in the treatment of obesity, and because of their significant potential for dependence and abuse should be used with extreme care. (Colman 2004)

Nevertheless, as a result of this analysis, in 1973 the FDA stopped short of an outright ban and declared that amphetamine and amphetamine-like drugs were to some extent effective for the treatment of obesity, although concerns about abuse led the FDA to impose a short-term (a few weeks) limit on all amphetamine and amphetamine-like drugs for this use. These warnings did have some effect. A review of 450 US physicians in 1973 (Lasagna 1973) showed that 73 per cent rated the abuse potential of amphetamines as ‘very high’. Nevertheless, about two-thirds continued to prescribe them for obesity.

The FDA continued to be concerned about the use of amphetamines as anti-obesity agents and in 1979 called for removal of the obesity indication for D-amphetamine and methamphetamine, arguing that there was no evidence that these drugs were more effective for treating obesity than the other supposedly safer amphetamine-like drugs. In reality none of the amphetamines or their congeners resulted in much more than a 3 kg loss of weight, and this was very likely to relapse once treatment was stopped.

FDA requirements for approval of new anorectic agents have become progressively more stringent. Guidelines issued in 1996 require that clinical trial data show that the mean weight loss in the drug group is at least 5 per cent greater than the mean weight loss in the placebo group; in addition, the proportion of patients who lose at least 5 per cent of baseline weight must be greater in the drug group than in the placebo group. Clinical trials should include at least 1500 patients studied for 1 year under placebo-controlled conditions and 200–500 patients for an additional year of open-label study.

(p.41) Despite these new hurdles, new drugs continued to be approved in Europe and the USA. The most notable additions were fenfluramine and its optical isomer D-fenfluramine (dexfenfluramine). If aminorex had proved to be a health hazard, fenfluramine was to become a disaster of epic proportions. Its use would result in serious heart or lung disease in nearly half a million people in the USA, and an untold number in Europe, and it would trigger the largest mass tort lawsuit ever seen in American legal history. The story is well told in the book Dispensing with the Truth (Mundy 2001).

Although fenfluramine shares some of the characteristic chemical features of other amphetamines it differs radically in its pharmacology from the compounds discussed previously. The drug appears to have its principal action on serotonin mechanisms in the brain, rather than dopamine. It is taken up by the serotonin transporter and can displace serotonin (see Chapter 2), and it was initially thought that increased drug-induced levels of serotonin in the hypothalamic appetite control centres in the brain might explain its anorectic action (Curzon and Gibson 1999). However, experiments in animals showed that blockade of the serotonin transporter by the selective inhibitor fluoxetine (Prozac®) blocked the ability of fenfluramine to release serotonin in rat brain but did not prevent its appetite-suppressant action. Similarly, treatment of animals with the serotonin synthesis inhibitor PCPA (p-chlorophenyl-amphetamine) blocked the serotonin-releasing action without preventing appetite suppression (Curzon and Gibson 1999). It seems likely that the ability of fenfluramine to act directly on some subtypes of serotonin receptor in brain may be the key to its anorectic actions (Curzon et al. 1997). Fenfluramine is recognized by a number of serotonin-receptor subtypes in brain (NIMH Psychoactive Drug Screening Program, http://kidb.cwru.edu); in addition, it can interact directly with norepinephrine receptors in the a-subtype family and has weak dopamine-blocking activity. The latter may explain why fenfluramine, unlike traditional amphetamines, is sedative rather than stimulant.

Fenfluramine was approved for use in Europe and the USA in the 1970s and was marketed as a mixture of D- and L-isomers under the trade name Pondimin in the USA. However, the unwanted sedative actions limited the popularity of fenfluramine as an anti-obesity medicine. People who had to work or look after children were reluctant to take it for more than few weeks because of the drug-induced drowsiness.

Sales of DL-fenfluramine (Pondimin) received an unexpected boost in the 1990s as a result of a momentous new discovery when Mike Weintraub, a research scientist at the University of Rochester with an interest in the pharmacological treatment of obesity, hit upon a novel idea. Since the problem with fenfluramine was too much sedation and the problem with old-fashioned amphetamine-like drugs was the opposite, why not combine the two of them? (p.42) Thus was born the famous, and later infamous, Fen–Phen cocktail in which fenfluramine was combined with the older amphetamine-like drug phentermine (Fig. 2.2). Weintraub did not undertake any animal experiments, but launched a lengthy clinical trial of this new drug combination in 121 obese people, charting their weight over a 4-year period. The studies were completed in the 1980s, but the results were not published in full until 1992 (Weintraub 1992). The findings were dramatic, with the subjects showing sustained weight loss over this period. Perhaps more importantly, the study appeared to show that it was possible to undertake long-term treatment with anti-obesity medicines safely and with minimal side effects.

A. H. Robins, the company that controlled sales of DL-fenfluramine (Pondimin) in the USA under license from Wyeth, was acquired by Wyeth, who saw a potential for boosting sales of the flagging fenfluramine product. Although the companies decided not to explore the difficult path of gaining FDA approval for a combination product, they helped to promote the ‘off-label’ use of the Fen–Phen combination (Mundy 2001). It is alleged that some of the financial support for Weintraub's research came from Wyeth–Robins, and after his results were published they helped to disseminate them. Reprints of his publication landed in doctors' offices around the country and on the desks of health writers at major newspapers and magazines. The story received prominent coverage in women's magazines, and in the Reader's Digest. The idea of a safe new medicine that caused substantial weight loss and could be used over long periods of time caught the public imagination and the Fen–Phen frenzy took off in the USA. Neither Wyeth nor the companies selling phentermine could undertake overt advertising for Fen–Phen as it was not an FDA approved medicine; nevertheless, their ‘soft’ promotion campaigns proved highly successful, as the sales figures showed (Table 3.2).

Weintraub's clinical data on the Fen–Phen combination were later given added support by results from animal studies showing that the two drugs had synergistic rather than merely additive interactions. The drug combination had a greater effect in suppressing appetite and boosting brain serotonin levels than either alone, suggesting that it was possible to use lower doses of each drug and yet maintain adequate appetite control with minimal side effects (Wellman and Maher 1999).

Table 3.2 Number of prescriptions for phentermine and fenfluramine in the USA

1992

1996

Phentermine

2 000 000

11 000 000

Fenfluramine

69 000

7 000 000

Data from Colman (2004).

(p.43) Another way of improving the profile of fenfluramine emerged from research in France and the USA which showed that in animals and humans the D-isomer of fenfluramine (dexfenfluramine) retained the appetite-suppressant properties but was much less sedative. In France, Jacques Servier, the founder of Servier Laboratories, saw dexfenfluramine as a way of expanding his company's sales of anti-obesity medicines after the original patents on DL-fenfluramine expired. He launched dexfenfluramine in Europe in 1987 under the trade name Isomeride, and initial sales were very successful. In the USA, Dick and Judith Wurtman, a husband-and-wife team of scientists at Massachusetts Institute of Technology, also showed the advantages of dexfenfluramine as a less sedative anorectic agent in animal experiments and filed a patent covering this use in the USA in 1980. In their research the Wurtmans had long promoted the notion that serotonin played a key role in the brain as a satiety signal controlling appetite for carbohydrates. Wurtman et al. (1987) claimed that dexfenfluramine had a selective effect in suppressing the intake of foods with high carbohydrate content rather than protein, and suggested that the drug would reduce the frequency of ‘snacking’ in obese patients prone to consuming high-carbohydrate foods. Clinical trials with dexfenfluramine showed long-term results (6–12 months) no better than those seen with traditional amphetamine-like drugs, with maximum weight losses of 2–3 kg more in the drug-treated groups than in those seen in placebo-treated groups, but the drug seemed to be well tolerated (Silverstone 1992). Dick Wurtman went on to found a commercial company, Interneuron, in 1988 to develop dexfenfluramine as an anti-obesity medicine for the US market. He formed an alliance with a large company, Wyeth, in order to develop and market the drug, a task far beyond the resources of Interneuron. At first things went well, but relations between Interneuron and Wyeth grew more complex as Wyeth saw the Fen–Phen combination emerge as a means of giving new life to the old product Pondimin, which they also owned. Nevertheless, Wyeth invested heavily in clinical trials and other development costs for dexfenfluramine, and prepared the extensive documentation needed for FDA approval.

However, the fairy story of a safe diet pill would eventually come to an abrupt end for both Fen–Phen and dexfenfluramine (Redux). While the USA was indulging in the Fen–Phen craze and the FDA was beginning to review dexfenfluramine for approval, serious worries were emerging in Europe about the safety of fenfluramine. It had long been known that some patients taking fenfluramine developed PPH as a rare adverse side effect, but on both sides of the Atlantic the risk had been considered so small that it was outweighed by the benefits of treating obesity. However, in the late 1980s hospitals in France began reporting many new cases of PPH in younger women taking the newly launched dexfenfluramine (the Fen–Phen combination was never used in (p.44) Europe). The French government commissioned Lucien Abenhaim, a prominent epidemiologist, to undertake a detailed review of the possible links between the diet drugs and PPH. The International Primary Pulmonary Hypertension Study (IPPHS) drew experts from across the world, including the USA, and after 2 years they produced their report, initially presented in draft form to the French government and to the companies involved (Servier, Interneuron, and Wyeth), and later published in final form in the New England Journal of Medicine (Abenhaim et al. 1996). The findings were damning. PPH affects only 1–2 people per million in the general population, but among patients taking fenfluramine or dexfenfluramine the risk was increased more than 10-fold. Furthermore, the risk increased with duration of drug treatment, rising much higher with longer use (3 months or more). French and European health officials were said to have wanted to withdraw the drugs from the market altogether, but apparently fearing the wrath of Jacques Servier, who had powerful political allies (Mundy 2001), they announced plans merely to place severe restrictions on the use of fenfluramine and dexfenfluramine, making them available only to morbidly obese patients, and then only for a limited time. Sales of both drugs dropped precipitately. This should have prevented dexfenfluramine (Redux) from ever being approved in the USA. As Abenhaim said: ‘We assumed that after the news about the European health authorities' decision, naturally the FDA would never approve Redux’. But he was wrong. In one of the most inexplicable episodes in its history the FDA, normally regarded as a hard-nosed evidence-based organization, did go on to approve Redux, despite warnings from many of the experts involved in an advisory capacity. However, the approval process was tortuous.

In addition to the risk of drug-induced PPH, Wyeth had to argue against strong opposition from some members of the neuroscience community in the USA, who worried about the possible neurotoxic actions of dexfenfluramine. It had been known for some time that fenfluramine caused a long-lasting depletion of serotonin from the brain in laboratory animals, including rats, mice, guinea pigs, and monkeys, and some studies had suggested that this was accompanied by actual damage to the distal terminals of serotonin-containing nerves (Molliver and Molliver 1990; Sotelo 1991). As in the similar case of ecstasy-induced damage to the serotonin system in brain (see Chapter 8) the husband-and-wife team of Una McCann and George Ricaurte in Baltimore contributed data and warned against the possible dangers of brain damage caused by Redux (McCann et al. 1997a). Dick Wurtman at Interneuron believed that the findings from the animal experiments had been over-dramatized, and accused Ricaurte of ‘running a cottage industry showing that everything under the sun is neurotoxic’.

The FDA Advisory Committee for Redux, a group of scientific and medical experts convened to advise the FDA, met in September 1995 to consider the (p.45) approval of the drug. Committee members heard directly from Lucien Abenhaim about the IPPHS findings. Wyeth downplayed his findings and argued that the risk of PPH, although real, was minor and likely to affect only small number of patients. They cited the statistic of 300 000 deaths from obesity annually in the USA as a counter-argument, claiming that obesity was a public health crisis in the USA that could be helped by Redux, although it was never clear what the origin of this statistic was. Warnings about possible human neurotoxicity were given to the Committee by two prominent US neuroscientists, Lewis Seiden and Mark Molliver. Wyeth again downplayed these findings, arguing that there was no evidence for human neurotoxicity. The Committee discussed the possibility of approving Redux under the condition that the risks of PPH and neurotoxicity would be rigorously monitored after marketing the drug had started, in a so-called ‘Phase 4’ study. Finally, the Advisory Committee voted against approval by 5–3. The meeting ended in some disarray and some members departed prematurely; almost incomprehensibly the Chairman said that he would have to reschedule another meeting to vote again. The second meeting was held in November 1995, and this time the neuroscientists Seiden and Molliver were not present as they were attending the annual meeting of the Society for Neuroscience in California. Despite continuing concerns about PPH and neurotoxicity, the vote this time went in favour of Redux, but by the smallest of margins (6–5).

In May 1996 Redux was launched on the US market with a $52 million public relations and advertising campaign from Wyeth. Media interest was high, and sales of both Redux and the older drug Pondimin took off. Wyeth stood to make a profit of $180 million on the two drugs that year, with some 6 million patients using the drugs in the USA. Redux had one of the fastest sales build-ups of any new prescription medicine ever, and was rapidly heading towards the magic $1 billion annual sales within the first 2 years. This was despite the fact that the final report of the IPPHS published only a few months after the Redux launch showed even higher risk figures than those estimated in the earlier draft report, suggesting that patients who took the drugs for more than 3 months ran a 23-fold increased risk of developing PPH. However, the impact of this publication was blunted by an accompanying Editorial in the New England Journal of Medicine (Manson and Faich 1996) which denigrated the IPPHS report and concluded:

Obesity is an escalating problem in the United States, and the condition is notoriously difficult to treat. Because the associated health hazards are considerable, medications are needed that produce and maintain weight loss safely and effectively. Dexfenfluramine is an important new drug in the clinician's arsenal, but it is not free of risk. Although physicians and patients need to be informed, the possible risk of pulmonary hypertension associated with (p.46) dexfenfluramine is small and appears to be outweighed by benefits when the drug is used appropriately.

It was only later that the journal learned that the authors of this Editorial were hardly unbiased commentators; both had acted as consultants to Wyeth and had given evidence in favour of Redux at the FDA hearings!

However, if the risks of drug-induced PPH and possible brain damage were bad, what was to come next was far worse. In the mid-West town of Fargo, North Dakota, an observant medical technician, Pam Ruff, who ran echocardiogram equipment (a technique which used ultrasound to image the beating human heart) at the local hospital, began to notice an unusual incidence of heart valve defects in young women, many of whom had been taking the Fen–Phen combination. She alerted the hospital cardiologists and one of these, Jack Cary, eventually became seriously concerned. He contacted colleagues at the Mayo Clinic, Rochester, Minnesota, who had also seen instances of similar heart valve defects in patients taking the diet drugs. They pooled their data on the first 24 cases and published a brief report in the New England Journal of Medicine in August 1997 (Connolly et al. 1997). In view of the serious implications of their findings, the journal allowed the authors to make the data public before publication and placed an advance copy of the paper on the journal website, both highly unusual moves. If the findings from North Dakota and the Mayo Clinic were extrapolated, they implied that as many as a quarter or a third of patients taking Fen–Phen for 3 months or more were at risk of heart valve damage—a potential public health disaster. The high incidence of heart valve defects implied by the initial data dwarfed the risk of drug-induced PPH which, although real, was far smaller. On 8 July 1997 the Mayo Clinic held a nationally televised press conference to publicize the findings, and the story led the network television news that night across the USA. Thousands of diet drug patients panicked and stopped taking their medicines immediately. Sales of Pondimin, Redux, and phentermine rapidly began to drop. Meanwhile the doctors from Fargo and the Mayo Clinic had provided their data to both Wyeth and the FDA as they were accumulated, although neither recipient appeared to have taken them very seriously to begin with. Later lawsuits would even accuse Wyeth of deliberately covering up the initial evidence of this serious drug-induced side effect. In Fargo the local hospital was sufficiently concerned that they issued a ban on any further use of the Fen–Phen combination or the new drug Redux. Another immediate consequence was the damage done to the alliance between Interneuron and Wyeth. Incredibly, Wyeth had not kept Interneuron informed of the developing heart valve problem, so that when executives from both companies were invited to attend an emergency meeting at the FDA to review the problem, Interneuron did not know what hit them. (p.47) As Mundy (2001) put it, two of the leading scientists in the Fen–Phen and Redux stories, Dick Wurtman and Mike Weintraub,

…found themselves sucked into the vortex of corporate pharmaceuticals, where academics were disposable accessories. Scholars who made cracks about barracuda fights in think tanks suddenly found themselves in real shark tanks when they got involved with drug companies.

The initial report of heart valve problems was rapidly followed by the description of 28 additional cases (Graham and Green 1997). Of the initial 52 patients, 11 were sufficiently ill to require heart surgery. Heart valve defects were seen in patients treated with fenfluramine (Pondimin) or dexfenfluramine (Redux) alone, but they were more common in people taking the Fen–Phen combination (Seghatol and Rigolin 2002). It appears that fenfluramine and dexfenfluramine or their metabolites acted directly on serotonin receptors of the 5-HT-2B subtype on the heart valves to cause cell proliferation and scar tissue formation (Fitzgerald et al. 2000), or they caused sufficient elevation of blood levels of serotonin to achieve the same result. In addition, fenfluramine and dexfenfluramine, like aminorex, contracted pulmonary arteries, increasing the risk of PPH (Weir et al. 1996; Fishman 1999). Furthermore, animal experiments indicated that the Fen–Phen combination acted synergistically to enhance neurotoxicity (McCann et al. 1997a, 1998a; MacLean 1999; Wellman and Maher 1999).

Wyeth fought a desperate rearguard action to keep Redux and Pondimin on the market, at first denying the validity of the heart valve findings and refusing to accept that any causal relationship had been established. In July 1997 they were forced by FDA to include a ‘black box’ in the label inserted into every package of drug, warning patients of valvular heart disease or PPH, but still denying any cause-and-effect relationship. However, by August 1997 the FDA had received reports on 58 cases of heart valve defects in patients taking Fen–Phen or Redux and it was clearly only a matter of time before the drugs would have to be voluntarily or forcibly withdrawn. Wyeth and Interneuron finally agreed to a ‘voluntary’ recall of both drugs in September 1997.

What followed was the largest civil legal action ever seen in the USA, as patients who had possibly experienced heart valve damage joined a mass legal action against Wyeth and Interneuron. More than 300 000 people, mostly women, were represented in this action which was eventually successful, largely because juries were convinced that Wyeth had deliberately withheld or delayed crucial early warning data on the heart valve problem from the FDA. By November 2004 the company had paid out or reserved $16 billion in damages for fenfluramine or dexfenfluramine claims. Another 62 000 patients decided not to join the mass settlement, but to sue Wyeth and its parent company (p.48) American Home Products directly. Some of these cases proved highly successful, and by 2005 the total cost of Fen–Phen litigation had risen to a staggering $22.1 billion.

The outcome of this dreadful episode in America was in sharp contrast to that in Europe where fenfluramine and dexfenfluramine were also withdrawn. Although European patients died as a result of drug-induced PPH and some also suffered heart valve problems, no-one sued and no payments were granted by juries. It is a sharp reflection of the cultural/medical differences that exist across the Atlantic that fenfluramine had been on the market in many European countries for some 20 years without reports of serious adverse effects, apart from rare instances of drug-induced PPH. Dexfenfluramine was approved in France in 1985 and subsequently in 65 other countries. By 1995 sales corresponded to 41 million patient-months (Curzon and Gibson 1999), but although reports of an increased incidence of drug-induced PPH led to the IPPHS study, there were few reports of heart valve defects. However, in the US experience such defects were often sufficiently minor as to be asymptomatic and only detectable by use of ultrasound heart scanning technology. A Belgian cardiologist, Mariane Ewalenko, had noticed six patients taking fenfluramine or dexfenfluramine who developed valvulopathies, and she reported this to the parent company Servier in 1992, but no further action was taken (Mundy 2001). After the initial furore had subsided, a more careful analysis of the US data suggested that the original estimates of as many as a third of patients developing heart valve defects may have been exaggerated; in some of the initial studies the investigators were not blinded to patient versus control groups and the estimates may have failed to take proper account of the fact that obese patients who are not treated with diet drugs have quite a high spontaneous incidence of heart valve abnormalities (up to 5 per cent) (Loke et al. 2002). The numerous US studies that sought to establish the true incidence of diet-drug-induced valvulopathies gave estimates as high as 31 per cent in some cases, but as low as 5 per cent in others (Seghatol and Rigolin 2002). The lawyers preferred to believe the higher figures, although the numbers of patients joining the lawsuits compared with the estimated six million US patients exposed to fenfluramine and dexfenfluramine suggest that an incidence of heart valve defect of 5–10 per cent may be the correct figure.

Given the appalling history of diet pills as relatively ineffective anti-obesity agents with a poor safety record, one might think that their day had come and gone. However, this is far from the case. A variety of amphetamine-like medicines are still available in the USA as prescription drugs. These include benzphetamine, diethylpropion, phentermine (including the sustained-release resin Ionamin), phendimetrazine, and phenylpropanolamine (nor-pseudoephedrine). All of these are nowadays more or less freely available at (p.49) various on-line pharmacies, not requiring a visit to the doctor's office. In 2000, the European Union Committee on Proprietary Medical Products recommended the withdrawal of all amphetamine-like appetite suppressants on the grounds of an ‘unacceptable risk/benefit ratio’. The drugs involved were phentermine, diethylpropion, amfepramone, clobenzorex, fenproporex, mefenorex, phenylpropanolamine (nor-pseudoephedrine), and phendimetrazine. However, this decision was challenged in the European courts by the manufacturers and by physicians (Kinnell 2003). The European Union eventually lost its case after an appeal to the European Court of Justice and the decision to withdraw the drugs had to be annulled (SCRIP, 30 July 2003).

The public appetite for a quick fix to obesity does not seem to have abated. Following the demise of fenfluramine, the new compound sibutramine, which acts as a mixed inhibitor of monoamine transporters for norepinephrine, dopamine, and serotonin, has been approved in the USA and Europe for weight loss (Arterburn et al. 2004). There have also been important advances in understanding the complex brain mechanisms involved in appetite control and regulation of body mass, with an increasing emphasis on neuropeptides and circulating hormones (Neary et al. 2004). Pharmaceutical companies continue to view obesity as an ever-increasing area of unmet medical need and a potentially lucrative market for new diet pill products. They are investing millions of dollars in research in this area in the hope of achieving the ultimate goal of a safe and effective means of controlling appetite and obesity.

3.6. Amphetamines for children: treatment of attention deficit hyperactivity disorder

While other medical uses of amphetamines have been in decline in recent years, one area has seen dramatic growth—the treatment of children with ADHD. The two principal products, Ritalin (methylphenidate) and Adderall (mixed amphetamine salts), have sales in excess of $2 billion annually, and the market is growing at an annual rate of around 20 per cent (www.shire.com). It may seem paradoxical that drugs considered at high risk of abuse by adults should prove acceptable as medicines for children aged as young as 3 years! However, ADHD and its treatment by psychostimulant drugs has generated great scientific and social interest in recent years. PubMed, the US National Library of Medicine database of publications in the scientific literature, lists nearly 10 000 published articles on this subject, and a search using Google yielded 447 000 items!

3.6.1. What is ADHD?

Attention deficit hyperactivity disorder (ADHD) is a condition that becomes apparent in some children in the preschool and early school years. It is hard for (p.50) these children to control their behaviour and/or pay attention. It is estimated that 3–5 per cent of children have ADHD, or approximately 2 million children in the USA. This means that in a classroom of 25–30 children, it is likely that at least one will have ADHD. The term ADHD supersedes terms such as ‘minimal mental dysfunction’, ‘minimal brain dysfunction’, or ‘hyperkinetic disorder’ used in the earlier literature. An adult form of ADHD is also increasingly recognized. The impact of ADHD on society is enormous in terms of the stress it causes to families, adverse academic and vocational outcomes, and negative effects on self-esteem.

This remarkable story started at the turn of the twentieth century when a behavioural syndrome that resembles what we now refer to as ADHD was first described in children. The British physician Sir George Still gave a series of lectures to the Royal College of Physicians in England in which he described a group of impulsive children with significant behavioural problems that he believed were caused by a genetic dysfunction and organic brain disorder, and not by poor child rearing—children who today would easily be recognized as having ADHD (Still 1902). In the language of the time, Still described these children as suffering from ‘an abnormal defect of moral control’, which he defined as ‘…the control of action in conformity with the idea of the good of all’. Still gave an example of a girl who was ‘wantonly mischievous’ and who would throw cups, saucers, and knives at her mother, or scream and kick if disciplined.

Many studies have compared normal children with those with ADHD in an attempt to define the precise nature of the neuropsychological differences that characterize this condition. Denney and Rapport (2001) reviewed 98 such studies published between 1980 and 1999. Among those differences that were ‘highly reliable’ between normal and ADHD groups were tests that involved sustained attention or the ability to inhibit behaviour (impulsivity). Sustained attention tests, for example, commonly involve identifying a letter or combination of letters from a continuous list presented over a period of several minutes. Impairments were also reliably seen in tests of memory for lists of digits or pairings of words and colours. Less reliable differences were seen in more complex cognitive tasks involving planning or visual/motor control, and in general there were few differences in tests of verbal fluency or motor performance.

Nowadays there is an international agreement on the diagnosis of ADHD (American Psychiatric Association 2000). A good description of the characteristic features of the disorder is given in the publication Attention Deficit Hyperactivity Disorder issued by the US National Institute of Mental Health in 2003 (available online at: nimh.nih.gov/publicat/adhd.cfm#adhd3)

According to the most recent version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (American Psychiatric Association 2000), there (p.51) are three patterns of behavior that indicate ADHD. Children with ADHD may show several signs of being consistently inattentive. They may have a pattern of being hyperactive and impulsive far more than others of their age. Or they may show all three types of behavior. This means that there are three subtypes of ADHD recognized by professionals. These are the predominantly

hyperactive-impulsive type (that does not show significant inattention); the predominantly inattentive type (that does not show significant hyperactive-impulsive behavior) sometimes called ADD—an outdated term for this entire disorder; and the combined type (that displays both inattentive and hyperactive-impulsive symptoms).

Hyperactivity-Impulsivity

Hyperactive children always seem to be ‘on the go’ or constantly in motion. They dash around touching or playing with whatever is in sight, or talk incessantly. Sitting still at dinner or during a school lesson or story can be a difficult task. They squirm and fidget in their seats or roam around the room. Or they may wiggle their feet, touch everything, or noisily tap their pencil. Hyperactive teenagers or adults may feel internally restless. They often report needing to stay busy and may try to do several things at once.

Impulsive children seem unable to curb their immediate reactions or think before they act. They will often blurt out inappropriate comments, display their emotions without restraint, and act without regard for the later consequences of their conduct. Their impulsivity may make it hard for them to wait for things they want or to take their turn in games. They may grab a toy from another child or hit when they're upset. Even as teenagers or adults, they may impulsively choose to do things that have an immediate but small payoff rather than engage in activities that may take more effort yet provide much greater but delayed rewards.

Some signs of hyperactivity-impulsivity are:

Feeling restless, often fidgeting with hands or feet, or squirming while seated

Running, climbing, or leaving a seat in situations where sitting or quiet behavior is expected

Blurting out answers before hearing the whole question

Having difficulty waiting in line or taking turns.

Inattention

Children who are inattentive have a hard time keeping their minds on any one thing and may get bored with a task after only a few minutes. If they are doing something they really enjoy, they have no trouble paying attention. But focusing deliberate, conscious attention to organizing and completing a task or learning something new is difficult.

Homework is particularly hard for these children. They will forget to write down an assignment, or leave it at school. They will forget to bring a book home, or bring the wrong one. The homework, if finally finished, is full of errors and erasures. Homework is often accompanied by frustration for both parent and child.

(p.52) The DSM-IV-TR gives these signs of inattention:

Often becoming easily distracted by irrelevant sights and sounds

Often failing to pay attention to details and making careless mistakes

Rarely following instructions carefully and completely losing or forgetting things like toys, or pencils, books, and tools needed for a task

Often skipping from one uncompleted activity to another.

Children diagnosed with the Predominantly Inattentive Type of ADHD are seldom impulsive or hyperactive, yet they have significant problems paying attention. They appear to be daydreaming, ‘spacey’, easily confused, slow moving, and lethargic. They may have difficulty processing information as quickly and accurately as other children. When the teacher gives oral or even written instructions, this child has a hard time understanding what he or she is supposed to do and makes frequent mistakes. Yet the child may sit quietly, unobtrusively, and even appear to be working but not fully attending to or understanding the task and the instructions.

These children don't show significant problems with impulsivity and overactivity in the classroom, on the school ground, or at home. They may get along better with other children than the more impulsive and hyperactive types of ADHD, and they may not have the same sorts of social problems so common with the combined type of ADHD. So often their problems with inattention are overlooked. But they need help just as much as children with other types of ADHD, who cause more obvious problems in the classroom.

Is It Really ADHD?

Not everyone who is overly hyperactive, inattentive, or impulsive has ADHD. Since most people sometimes blurt out things they didn't mean to say, or jump from one task to another, or become disorganized and forgetful, how can specialists tell if the problem is ADHD?

Because everyone shows some of these behaviors at times, the diagnosis requires that such behavior be demonstrated to a degree that is inappropriate for the person's age. The diagnostic guidelines also contain specific requirements for determining when the symptoms indicate ADHD. The behaviors must appear early in life, before age 7, and continue for at least 6 months. Above all, the behaviors must create a real handicap in at least two areas of a person's life such as in the schoolroom, on the playground, at home, in the community, or in social settings. So someone who shows some symptoms but whose schoolwork or friendships are not impaired by these behaviors would not be diagnosed with ADHD. Nor would a child who seems overly active on the playground but functions well elsewhere receive an ADHD diagnosis.

To assess whether a child has ADHD, specialists consider several critical questions: Are these behaviors excessive, long-term, and pervasive? That is, do they occur more often than in other children the same age? Are they a continuous problem, not just a response to a temporary situation? Do the (p.53) behaviors occur in several settings or only in one specific place like the playground or in the schoolroom? The person's pattern of behavior is compared against a set of criteria and characteristics of the disorder as listed in the DSM-IV-TR.

Despite these seemingly clear diagnostic criteria, the borderline between ADHD and what might be termed ‘boisterous mischief’ remains hard to define. There are transatlantic differences in rates of diagnosis; until recently European doctors seemed more reluctant that those in the USA to diagnose ADHD. As a consequence US children currently account for 85 per cent of the world sales of amphetamines and amphetamine-like drugs for the treatment of ADHD. However, the transatlantic differences may be diminishing. The UK Department of Health reported that, in 2004, 5 per cent of British schoolchildren met the diagnostic criteria for ADHD, and by 2006 prescriptions for Ritalin and other amphetamines had risen to near 500 000 up from 270 000 in 2003.

The reality of life with a child suffering from ADHD is vividly depicted in the following excerpt from an article in Time magazine:

Dusty Nash, an angelic-looking blond child of seven, awoke at 5 one recent morning in his Chicago home and proceeded to throw a fit. He wailed. He kicked. Every muscle in his 50-lb body flew in furious motion. Finally, after about 30 minutes, Dusty pulled himself together sufficiently to head downstairs for breakfast. While his mother bustled about the kitchen, the hyperkinetic child pulled a box of Kix cereal from the cupboard and sat on a chair.

But sitting still was not in the cards this morning. After grabbing some cereal with his hands, he began kicking the box, scattering little round corn puffs across the room. Next he turned his attention to the TV set, or rather, the table supporting it. The table was covered with a checkerboard Con-Tact paper, and Dusty began peeling it off. Then he became intrigued with the spilled cereal and started stomping it to bits. At this point his mother interceded. In a firm but calm voice she told her son to get the stand-up dust pan and broom and clean up the mess. Dusty got out the dust pan but forgot the rest of the order. Within seconds he was dismantling the plastic dust pan, piece by piece. His next project: grabbing three rolls of toilet paper from the bathroom and unraveling them around the house.

It was only 7:30, and his mother Kyle Nash, who teaches a medical-school course on death and dying, was already feeling half dead from exhaustion. Dusty was to see his doctors that day at 4, and they had asked her not to give the boy the drug he usually takes to control his hyperactivity and attention problems, a condition known as attention deficit hyperactivity disorder (ADHD). It was going to be a very long day without help from Ritalin. (Claudia Wallis, Time, 18 July 1994)

3.6.2. The neurobiology of ADHD

Numerous studies have sought to investigate the genetic and psychosocial factors that contribute to the disorder, and to understand what abnormalities exist in the (p.54) brains of patients with ADHD (Faraone and Biederman 1998). A number of family studies have shown that ADHD runs in families; parents exhibiting symptoms of adult ADHD have a 1 in 4 risk of having a child with ADHD. Studies of identical twins have shown a concordance rate of 0.8, i.e: if one twin develops ADHD the other has an 80 per cent chance of also developing the disorder. The fact that the concordance rate in identical twins is not 100 per cent suggests that although genetic factors are important, environment may also play a part. There is also some evidence that the genetic risk of ADHD is linked to familial vulnerability to depression and possibly to bipolar disorder (Faraone and Biederman 1998). More detailed genetic analysis has suggested that ADHD may be caused by several interacting genes rather than a single gene. Thus ADHD fits into the common genetic models of psychiatric illnesses, which have a complex multi-gene basis. Bobb et al. (2005) reviewed over 100 studies that have examined the genetics of ADHD by linkage or association, seeking to identify the genes responsible. These included three genome-wide linkage studies and association studies of 94 polymorphisms in 33 candidate genes. While no definite conclusions can yet be reached, consistent evidence for association exists for four genes in ADHD: the dopamine D4 and D5 receptors, and the dopamine and serotonin transporters. Others are promising but need further replication, including the dopamine D2 and serotonin 2A receptors. It is notable that three of the four genes for which evidence of association is strongest are associated with dopamine function in the brain, suggesting the possibility that ADHD is associated with abnormalities in dopamine systems.

Many aspects of the biological and psychosocial environment have also been examined as potential risk factors for ADHD (Faraone and Biederman 1998). A number of speculative hypotheses have attempted to link dietary lead poisoning, excess sugar intake, or synthetic food additives with ADHD, but systematic studies failed to support these ideas. However, psychosocial risk factors appear to play a real and important role. Rutter's now classic studies of psychosocial risk factors for childhood mental disorders, including ADHD, led the way (Rutter et al. 1975). He studied the prevalence of mental disorders among children living in very different environments in the UK: the middle-class affluence of the Isle of Wight, and a deprived area of inner London. This research revealed six risk factors that correlated with childhood mental disturbances: severe marital discord, low social class, large family size, paternal criminality, maternal mental disorder, and foster placement. The aggregate of these rather than any individual factor seemed to be critical. Rutter's ‘index of adversity’ was later found to be positively associated with ADHD (Faraone and Biederman 1998).

Attempts to pin down specific abnormalities in brain function in ADHD have been less successful (Faraone and Biederman 1998; Solanto et al. 2001). There have been many studies using the most modern brain imaging techniques. Some studies using magnetic resonance imaging (MRI) have found that certain brain areas are consistently smaller in the ADHD brain; these include the right (p.55) prefrontal cortex, the caudate nucleus, the globus pallidus, and a subregion of the cerebellar vermis. Imaging studies that aimed to detect functional changes in brain blood flow or glucose metabolism have yielded inconsistent results; with some showing increased activation of frontal cortex and others reduced activation in subjects undertaking a variety of mental tasks (Solanto et al. 2001). Again, it is interesting to note that, with the exception of the cerebellum, the brain regions implicated all receive a dopaminergic input. However, ADHD remains a poorly understood disorder in terms of the nature of the brain malfunction underlying it, or the molecular genetic basis.

3.6.3. Chemistry and pharmacology of methylphenidate (Ritalin) and Adderall

Methylphenidate

Methylphenidate (MP) (trade name Ritalin) was first synthesized in 1944 and was marketed by the Ciba-Geigy pharmaceutical company, which later became Novartis (Fig. 3.3). The compound exists in several isomeric forms; the racemic

                   Medical uses of                         amphetamines

Figure 3.3 Early example of an advertisement for Ritalin for ADHD, which was formerly known as minimal brain dysfunction (MBD). (www.amphetamines.com/methylphenidate/ritalinkid.html)

(p.56)
                   Medical uses of                         amphetamines

Figure 3.4 Structures of methylphenidate (Ritalin) and amphetamine. Some chemical bonds are highlighted in bold to illustrate the chemical similarities between the compounds.

mixture of the D- and L-isomers of threo-methylphenidate which is used medically. The erythro forms of MP were removed in the 1950s because they caused elevated blood pressure (Swanson and Volkow 2001). MP was introduced as a medicine because, like D-amphetamine, it alleviated fatigue and stimulated mental and physical performance. It was initially recommended for the treatment of chronic fatigue, lethargy, disturbed senile behaviour, depression, and narcolepsy. Virtually all these uses have been abandoned and the use of MP is now largely confined to the treatment of ADHD, where it is the most widely used pharmaceutical (Leonard et al. 2004).

MP bears an obvious structural resemblance to D-amphetamine (Fig. 3.4) and it is also closely similar in its pharmacology. MP is a potent inhibitor of dopamine and norepinephrine uptake in monoamine neurons by virtue of its affinity for the catecholamine transporters (Ferris et al. 1972; Gatley et al. 1996). However, unlike D-amphetamine, MP has little affinity for the serotonin transporter, and it is less effective than D-amphetamine in displacing catecholamines from their vesicular storage sites (Kuczenski and Segal 1997). The affinities for monoamine transporters are as follows: norepinephrine transporter, 37 nM; serotonin transporter, 〉 10 000 nM; dopamine transporter, 345 nM (NIMH Psychoactive Drug Screening Program; available online at http://kidb.cwru.edu/). When given to rats by intravenous injection it causes a rapid and substantial increase in the rate of release of both dopamine and norepinephrine in brain, comparable to the effects of D-amphetamine (Hurd and Ungerstedt 1989; Kuczenski and Segal 1997). However, unlike D-amphetamine, MP does not cause any increase in serotonin release in rat brain (Kuczenski and Segal 1997). In rats, MP elicits behavioural changes similar to those seen after D-amphetamine, with increased locomotor activity followed by repetitive stereotyped behaviour after large doses. The behaviourally active doses corresponded to those which caused significant increases in catecholamine release in rat brain (Kuczenski and Segal 1997). In terms of both behavioural stimulation and its ability to promote catecholamine release in the brain, MP is approximately 10 times less potent than D-amphetamine.

(p.57) Using brain imaging techniques, Volkow and colleagues at the Brookhaven National Laboratory (Volkow et al. 1999; Swanson and Volkow 2003) showed that clinical doses of orally administered MP caused more than 50 per cent blockade of the dopamine transporter sites in brain, comparable to the effect of the powerful psychostimulant drug cocaine which also acts as an inhibitor of dopamine uptake in brain. However, unlike cocaine, orally administered MP does not cause marked euphoria and is unlikely to lead to dependence. Swanson and Volkow (2003) argued that this is because the onset of the effect of MP on the dopamine transporter is slow, whereas that of cocaine is very rapid. This seems to be an example of the phenomenon discussed previously, i.e. the rate at which drugs enter the brain and bind to their targets plays a crucial part in their reinforcing and addictive properties. Grace (2001) has argued that slowly absorbed psychostimulants, such as MP, can only mimic the ‘tonic’ function of dopamine in the brain, which is normally activated by a constant low level of dopamine release. When dopamine neurons are activated to fire in bursts, a surge of dopamine is available at the synapse to mediate ‘phasic’ functions (Grace 2000). This can only be mimicked by drugs that are delivered rapidly to the brain, allowing sufficient build-up of dopamine to simulate that achieved by rapid neuronal discharge. It is argued that it is the ‘phasic’ mode of dopamine release that is associated with euphoria and reward. A subsequent imaging study from the same laboratory (Volkow et al. 2004) showed that clinical doses of MP were able to cause increased release of dopamine in human brain, but the effect was most marked when subjects were asked to undertake a challenging mental arithmetic task as opposed to passively viewing cards. This illustrates an important difference between MP and D-amphetamine. As an inhibitor of dopamine reuptake with little ability to displace the vesicle stores of dopamine, MP will enhance dopamine levels in brain most effectively only in those brain regions where dopamine is being released, such as during a difficult mental task. In this respect MP may differ qualitatively from D-amphetamine which causes dopamine release irrespective of the underlying activity state of the dopamine neurons.

MP is rapidly absorbed after oral administration, with peak drug levels in plasma within 1–3 hours. However, there is considerable degradation of the drug by liver metabolism before it enters the bloodstream, and the extent of this varies markedly between individuals (Swanson and Volkow 2001; Leonard et al. 2004). Consequently there is a wide range of individual variability in plasma drug concentrations for a given dose of MP. The proportion of MP actually entering the bloodstream unchanged (oral bioavailability) ranges from 11 to 53 per cent in children (Chan et al. 1983). The drug also has a relatively short duration of action because it is rapidly metabolized and eliminated, giving an effective duration of only about 3–4 hours. These factors mean that the (p.58) optimum dose of MP varies among individuals, and when treatment is started the dose has to be gradually increased to determine this (Wolraich and Doffing 2004). The short duration of action also means that the drug needs to be taken more than once a day, creating difficulties for schools in managing drug dosing and offering opportunities for inappropriate use of drug supplies. This problem has been partly overcome by the development of slow-release formulations of MP (trade names: Concerta and Metadate) which extend the duration of action to 7–8 hours, making drug administration during the school day unnecessary (Swanson and Volkow 2001; Leonard et al. 2004). A further development has been the marketing of D-MP as a separate single-isomer form of the drug (trade names Focalin and Attenade) (Keating and Figgit 2002). The D-isomer appears to account for essentially all of the activity of DL-MP. Human brain imaging studies showed that L-MP penetrates the brain together with D-MP, but in animal behavioural experiments it was devoid of stimulant actions (Ding et al. 2004). The use of D-MP allows the dose of MP to be halved and there is a small increase in duration of action, but apart from this there seems to be no real scientific advantage in using the single isomer. Another pharmaceutical advance is the development of a skin-patch formulation for delivering MP (Methypatch) (in advanced stages of development by Shire Pharmaceuticals); this should permit an even greater extension of the duration of action of MP, with attendant advantages of convenience and minimization of risk of abuse. Another approach is the development of a prodrug form of MP chemically linked to an amino acid. The conjugate is pharmacologically inert and can only release MP when digested in the gut, thus precluding administration by any other route (www.shire.com/shirepharma).

Adderall

MP is by far the most widely used compound for the treatment of ADHD, but a second medicine Adderall®, has become popular in recent years and in 2004 accounted for nearly a quarter of the US sales of prescription medicines for ADHD. Adderall was first developed more than 20 years ago by Rexar Pharmaceuticals in the USA as Obetrol, and was marketed as an appetite suppressant. It is a complex mixture of different salt forms of amphetamine, containing D- and L-amphetamine sulphate, D- and L-amphetamine aspartate, and D-amphetamine saccharate, with a ratio of D- to L-amphetamine of 3:1. There seems little rationale for this mixture, except perhaps to distinguish Obetrol from other amphetamine products marketed at the time. Clinical trials comparing D- and L-amphetamine in treating hyperactive children have shown that L-amphetamine is effective although, as expected, less so than the pharmacologically more potent D-isomer (Arnold et al. 1972; Gross 1976). Adderall has a duration of action of 6–7 hours, and this has been extended further by the (p.59) preparation of a slow-release formulation (Adderall-XR®) (McGough et al. 2003). Comparisons of Adderall with MP have shown the two drugs to be of similar efficacy, although the longer duration of action of Adderall compared with standard-release MP gives it some advantages (Arnold 2000; Faraone et al. 2002).

3.6.4. What are the effects of amphetamines in children and adults with ADHD?

                   Medical uses of                         amphetamines
The first evidence for beneficial effects of amphetamine in children was reported by Bradley (1937). He studied 30 children (aged 5–14years) of normal intelligence suffering from a variety of behavioural disturbances sufficiently severe to be admitted to hospital. They were treated with a daily dose of Benzedrine (DL-amphetamine) for 1 week. Several obvious changes in behaviour were observed, including subdued emotional responses and less aggressive, noisy, or domineering behaviour. However, most remarkable were changes in school behaviour.

Possibly the most remarkable change in behaviour during the week of Benzedrine therapy occurred in the school activities of many of these patients. Fourteen children responded in a spectacular fashion. Different teachers, reporting on these patients, who varied in age and school accomplishment, agreed that a great (p.60) increase of interest in school material was noted immediately. There appeared a definite ‘drive’ to accomplish as much as possible during the school period, and often to spend extra time completing additional work. Speed of comprehension and accuracy of performance were increased in most cases. Insight into school improvement was generally present, though few of the children attributed it to the medication they had received earlier in the day. The improvement was noted in all school subjects. It appeared promptly the first day Benzedrine was given and disappeared on the first day it was discontinued. (Bradley 1937)

Is it any wonder that many parents with behaviourally disturbed children have given Ritalin and Adderall a warm welcome?

Bradley and Bowen (1941) published further positive findings from clinical studies in 100 children with hyperactivity and other behavioural disorders undergoing treatment with Benzedrine. Most subsequent work was done with MP rather than amphetamine. Denney and Rapport (2001) reviewed 50 different studies published between 1961 and 1991 that compared the effect of MP with placebo in children with ADHD, using a variety of neuropsychological tests. Not surprisingly, the most significant and consistent drug-induced benefits were seen in tests of attention and vigilance, impulsivity (matching to sample, reaction time), and learning/memory (paired associations, spelling). MP had little or no effect on tests involving visual/perceptual skills or perceptual/motor tasks. Some experiments have involved treating children with drugs that blocked dopamine or norepinephrine receptor function in the brain before receiving MP. The results indicated that the ability of MP to stimulate both dopamine and norepinephrine function are important, but that dopaminergic stimulation may be particularly important for improvements in attention/ vigilance and decreased hyperactivity, while stimulation of norepinephrine function may be critical for improvements in learning/memory and planning functions (Rapport et al. 1993; Solanto 1998; Denney and Rapport 2001; Mehta et al. 2001). A review of the cognitive-enhancing effects of amphetamine and MP in normal volunteers also concluded that both the dopamine and the norepinephrine systems were involved (Mehta et al. 2001).

How can one explain the apparently paradoxical effects of psychostimulants in calming children with ADHD and improving their cognitive function? One hypothesis invokes the theory of rate dependency for CNS drug actions. Rate dependency refers to the observation that low baseline rates of response are increased by a drug, whereas higher rates are found to increase to a lesser extent or to decrease as a result of drug treatment. Thus response rate is an inverse function of baseline rate, as described in the model

                   Medical uses of                         amphetamines
where D is the response rate on the drug, C is the baseline response rate, and a and b are constants (Dews and Winger 1977).

(p.61) Many studies in a wide range of species, reviewed by Dews and Winger (1977), have documented rate-dependent effects of amphetamine on fixed-interval and fixed-ratio schedules of reinforcement. Such effects have been shown for amphetamine doses as low as 0.1 mg/kg, with doses between 0.3 and 1.0 mg/kg found to produce decreases in high base rate responding. Thus it appears that decreases in motor activity can be produced by amphetamines at doses lower than those which generate stereotypy and associated reduction in locomotor activity.

Robbins and Sahakian (1979) postulated that the decrease in spontaneous motor activity seen in children with ADHD after treatment with stimulant drugs is attributable to rate-dependent effects. Their re-analysis of raw data from several drug studies of ADHD children yielded a good fit to the rate-dependency equation. In particular, re-analysis of data from the NIMH study of drug effects on normal children, normal adults, and children with ADHD (Rapoport et al. 1980) yielded a slope of – 0.65 for the plot of drug response rate as a function of base rate. Whereas both groups of children showed a decrease in activity on 0.5 mg/kg D-amphetamine, normal men, who had as a group much lower activity counts at baseline, showed a very small (but statistically significant) decrease only on the lower of the two D-amphetamine doses (0.25 and 0.5 mg/kg) they received. Furthermore, the greatest reductions in activity were found for the most active ADHD children, whereas increases in activity were found for some normal adults within the group. A subsequent study of children with ADHD by Solanto (1986) also reported a highly significant correlation of – 0.94 between baseline spontaneous locomotor activity and the change in activity level following MP administration.

While these scientific insights are valuable, the approval of psychostimulant drugs as prescription medicines for the treatment of children with ADHD depended on more concrete evidence that they were effective and safe. A variety of different rating scales have been devised to assess the effects of these drugs on ADHD symptoms. Commonly used rating scales include the Conners Teachers' Scale and the Conners Parents' Scale (Conners 1969, 1998) and their revised forms (Conners et al. 1998), now backed up by large databases of information derived by applying these scales to large populations of normal and ADHD children of various ages. These and other similar rating scales use the diagnostic criteria for ADHD and ADD defined by DSM-IV (see above) to provide numerical scores. Converting the complex cluster of symptoms characteristic of ADHD, with the variations in symptoms between individuals, into numbers is of course an oversimplification, but in order to conduct clinical trials of drugs for treating ADHD it is a convenience as it permits statistical analysis of the resulting data. However, the results are always subject to the individual bias of teachers and parents. Nowadays, approval of a new medicine for ADHD will (p.62) rely on positive data from a variety of outcome measures involving teachers, parents, and physicians, including some form of global clinical assessment measure of improvement. An example of an ADHD rating scale for teachers is shown in Table 3.3.

A recent development has been the increasing recognition that the symptoms of childhood ADHD often persist into adolescence and quite frequently into

Table 3.3 Teachers' ADHD rating scale

El Camino Pediatrics: ADHD Rating Scale-IV School Version

Child's Name____________

Child's Age_____Sex: M F Grade_____Child's Race_____

Circle the number that best describes this student's school behavior over the past 6 months (or since the beginning of the school year).

Never or rarely

Sometimes

Often

Very often

1. Fails to give close attention to details or makes careless mistakes in schoolwork

0

1

2

3

2. Fidgets with hands or feet or squirms in seat

0

1

2

3

3. Has difficulty sustaining attention in tasks or play activities

0

1

2

3

4. Leaves seat in classroom or in other situations in which remaining seated is expected

0

1

2

3

5. Does not seem to listen when spoken to directly

0

1

2

3

6. Runs about or climbs excessively in situations in which it is inappropriate

0

1

2

3

7. Does not follow through on instructions and fails to finish work

0

1

2

3

8. Has difficulty playing or engaging in leisure activities quietly

0

1

2

3

9. Has difficulty organizing tasks and activities

0

1

2

3

10. Is ‘on the go’ or acts as if ‘driven by a motor’

0

1

2

3

11. Avoids tasks (e.g. schoolwork, homework) that require sustained mental effort

0

1

2

3

12. Talks excessively

0

1

2

3

13. Loses things necessary for tasks or activities

0

1

2

3

14. Blurts out answers before questions have been completed

0

1

2

3

15. Is easily distracted

0

1

2

3

16. Has difficulty awaiting turn

0

1

2

3

17. Is forgetful in daily activities

0

1

2

3

18. Interrupts or intrudes on others

0

1

2

3

(p.63) adulthood (Wender 2001; Wilens et al. 2002; Newton-Howes 2004). As many as a third of children with ADHD will continue to manifest similar symptoms in adulthood. However, the diagnosis of adult ADHD remains controversial, with no firmly agreed diagnostic criteria (McGough and Barkley 2004). A widely used self-diagnostic test is the Wender Utah Rating Scale (Ward et al. 1993; Wender 2001) which uses a retrospective diagnostic assessment by means of self-report on a 61-item checklist of childhood behaviour. There seems little doubt that adult ADHD is real, although the symptoms are not identical to those seen in children. Adult ADHD is often accompanied by poor academic achievement or work performance and may be associated with antisocial behaviour, depression, and anxiety disorders. Nevertheless, the same psychostimulant drugs used to treat ADHD in children are also effective in adults (Faraone et al. 2004; Spencer et al. 2004). Rating scales have been adapted for use in adult ADHD, including a version of Conners Adult Rating Scale, the Brown ADHD Scale, and ADHD Rating Scale IV. Adults and adolescents, unlike children, can also be asked to complete self-report assessment scales, for example the Adult ADHD Self Report Scale (Murphy and Adler 2004). MP and Adderall have been shown to be effective in treating the symptoms of adult ADHD (Faraone et al. 2004; Spencer et al. 2004) and are available as prescription medicines for this indication. No doubt pharmaceutical companies see adult ADHD as a new area of unmet medical need that will allow further expansion of the market for amphetamine-like psychostimulants. One company (Eli Lilly) posts a six-item self-report checklist on its website so that adults can diagnose themselves (http://www.adhd.com/adult/index.jsp)!

3.6.5. How safe are Ritalin and Adderall?

Both Ritalin and Adderall are remarkably safe drugs when used in the correct oral dosage regimes as recommended. However, as with any medicines there are adverse side effects, some of which are serious and others less so. Behavioural side effects sometimes occur that are reminiscent of the stereotyped repetitive patterns of behaviour seen in laboratory animals after high doses of amphetamine. These include abnormal movements, perseverative/compulsive behaviours, lip smacking, lip licking, and stereotyped behaviour (e.g. picking at fingernails/fingertips, rubbing eyes or face, head jerking, eye blinking, etc) (Leonard et al. 2004). Children treated with Ritalin or Adderall may suffer loss of appetite and sleep disturbances. Loss of appetite may be so severe that growth is significantly impeded, but both these side effects are usually controllable by adjusting the dose and ensuring that the first dose of the day is given after rather than before breakfast. There is no evidence for long-term growth impairment (Hechtman and Greenfield 2003).

The most serious adverse side effects are associated with sympathomimetic actions. As explained in Chapter 2, amphetamines and amphetamine-like drugs (p.64) act on the peripheral sympathetic nervous system to promote norepinephrine release. This can cause an increase in heart rate and blood pressure, which in most healthy young people is of little consequence. However, there have been reports of serious adverse events associated with the cardiovascular system and even some deaths. This led to the temporary suspension of Adderall XR in Canada in 2005, and as a result the FDA carried out a review and in February 2007 directed the manufacturers of all ADHD medicines to add a ‘black box’ warning to their products, pointing to the potential cardiovascular and psychiatric risks. These risks are heightened when children being treated with psychostimulants indulge in strenuous exercise or sports activities, which themselves activate the cardiovascular system.

Instances of abuse and dependence liability with Ritalin or Adderall are rare, but this is largely because they are administered orally and build up slowly in the brain, triggering ‘tonic’ rather than ‘phasic’ dopamine mechanisms (see above). There is little doubt that both methylphenidate and amphetamine can cause euphoria and have abuse potential if administered intravenously or by other fast-absorption routes (see below).

3.6.6. Social impact: the Ritalin Age

In the past 20 years the recognition of ADHD as one of the most common childhood psychiatric disorders and the dramatic increase in the use of psychostimulant drugs to treat it has had an enormous social impact. This is particularly notable in the USA where the use of drugs to treat ADHD has grown most rapidly, but it is also increasingly so in Europe. In the UK, the annual number of prescriptions for Ritalin was only 2000 in 1990, but rose to 92 000 by 1997 and to 500 000 by 2006. The UK National Institute for Clinical Excellence (NICE) issued guidelines for the use of Ritalin in ADHD in 2000 and recommended that Ritalin be used. In 2000 and 2001 NICE recommended that Ritalin be used only for the most severe cases of ADHD, sometimes termed hyperkinetic disorder. These children display all three of the key symptoms of inattentiveness, hyperactivity, and impulsiveness. It was estimated that this might include about 1 per cent of all schoolchildren, far less than the 5–10 per cent routinely treated with Ritalin or Adderall in the USA. But in updated guidance issued in 2006 NICE recommended the possible use of medications in all children or adolescents diagnosed with ADHD, estimated at 5% of all school children (http://guidance.nice.org.uk/TA98). Is the cautious UK approach the right one? Or does it deprive many children and families of an effective medicine? Has the prescribing of psychostimulants to both children and adults gone too far in the USA, creating problems of control and diversion of supplies to non-medical uses? The answer probably lies somewhere in mid-Atlantic between these two extremes.

In the USA, the first decade of widespread Ritalin use in the 1980s and 1990s was largely a period of optimism. As the numbers of children using the drug (p.65) grew, ADHD awareness became an industry, a passion, and an almost messianic movement. In the USA an advocacy and support group called CHADD (Children and Adults with Attention Deficit Disorders) exploded from its foundation in 1987 to 28 000 members in 48 states by the mid-1990s Information bulletin boards and support groups for adults sprang up on CompuServe, Prodigy, and America Online. Numerous popular books were published on the subject, advocating increased awareness of ADHD and explaining its treatment with Ritalin. Notable among these were Barbara Ingersoll's now classic Your Hyperactive Child, published in 1988, and the best seller Driven to Distraction: Recognizing and Coping with Attention Deficit Disorder from Childhood to Adulthood by psychiatrists Edward Hallowell and John Ratey, published in 1994. The first sentence of their book was to become an accurate prophesy: ‘Once you catch on to what this syndrome is all about, you'll see it everywhere’.

Summer camps designed to help children with ADHD were organized, videos and children's books appeared, and therapists, tutors, and workshops offered their services to the increasingly self-aware ADHD community. It is a community that continues to view itself with some pride. Popular books and lectures about ADHD often pointed out positive aspects of the condition. Adults with ADHD see themselves as creative; their impulsiveness can be viewed as spontaneity; hyperactivity gives them enormous energy and drive; even their distractibility has the virtue of making them alert to changes in the environment. Many ADHD adults gravitate into creative fields or work that provides an outlet for emotions.

However, CHADD overreached itself in 1995 when it petitioned the US Drug Enforcement Agency (DEA) to reclassify Ritalin from the tough Schedule II category (used for dangerous narcotics) to Schedule III, which would have made Ritalin more easily available. The DEA refused this request, and during the course of the hearings it emerged that CHADD had received substantial funding ($900 000) from the drug company Ciba-Geigy, which was then the sole supplier of Ritalin.

A variety of groups in North America opposed the use of Ritalin and denied the validity of the diagnosis of ADHD from the beginning. The Church of Scientology is traditionally opposed to modern psychiatry and to all psychotropic drugs. It has waged a persistent campaign, claiming that Ritalin represented a ‘chemical straitjacket’ and that children with ADHD were merely ‘energetic and bored’. Scientologists waged their war against Ritalin and psychiatry through the Citizens Commission on Human Rights, a non-profit organization based in Los Angeles which was formed by the Church in 1969 to investigate mental health abuses. The Commission helped to promote a major legal action in which five separate class action suits were filed against Novartis (the manufacturer of Ritalin), the American Psychiatric Association (APA) and CHADD. All five of the suits alleged that APA and Novartis engaged in an illegal (p.66) conspiracy to boost the sales of Ritalin and thus improve the company's bottom line. The suits charged that to achieve these increased profits for Novartis, APA and the drug company conspired to widen the diagnostic criteria of ADD and ADHD, which have appeared in the last several editions of DSM-IV, in an unnecessarily broad manner. The suits then alleged that APA and Novartis touted the efficacy of Ritalin as a treatment for the disorder. If successful, these lawsuits could have resulted in huge payments to the families of the children involved. However, in October 2001 the judge in the New Jersey suit, Charles Walsh of the Superior Court of New Jersey in Bergen County, ruled that the plaintiffs' claim was insufficiently specific. He gave them 90 days to provide additional material to bolster their charges. The plaintiffs did not follow through on the judge's order, and once the deadline had passed decided to withdraw their complaint.

Opposition to Ritalin and Adderall and the widespread diagnosis of ADHD in American children has grown more vociferous in recent years, and has been taken up as a campaign among the Conservative Right. A considerable negative impact followed the discovery that MP was as effective as cocaine in blocking the dopamine transporter in human brain (Volkow et al. 1999). These findings received much media attention, and MP was portrayed as being as hazardous as cocaine. However, as explained earlier, there is in fact a great difference between the subjective euphoriant effects of injected or smoked cocaine, which enters the brain rapidly and activates ‘phasic’ dopamine mechanisms, and the slow build-up of MP in the brain after oral administration, which triggers ‘tonic’ dopamine actions. If cocaine is taken in tablet form orally, it is absorbed slowly and is no longer a powerful euphoriant. However, such pharmaceutical nuances were not what those opposed Ritalin wanted to hear, and the analogy between MP and cocaine continues to be used repeatedly. Some of the phrases used by critics to describe Ritalin included ‘kiddie cocaine’, ‘more potent than cocaine’, ‘cheap fix’, ‘discipline in pill form’, ‘legalized drug pushing to children’, ‘making drug addicts out of America's children’, and, at the wilder fringes, ‘ban Ritalin not guns’ or the concept that this was all a feminist conspiracy to make boys more like girls! ADHD has been described as ‘a creation of the psychiatric-pharmaceutical cartel’, ‘a hoax’, or ‘the perfect way to explain the inattention, incompetence, and inability of adults to control their kids’. Parents were accused of masking their own failings by ‘doping up their children to calm them down’. Another concern that has often been voiced by critics of Ritalin is that exposing children to powerful psychotropic drugs will make them more likely to abuse drugs later in life. Along with the comparison of Ritalin to cocaine, this concept has become embedded in the popular media as proved. If true, it would indeed represent a serious social problem and provide a strong reason for limiting the use of Ritalin and related drugs. However, the evidence from longitudinal (p.67) studies of the subsequent drug history of children treated with Ritalin has actually led to precisely the opposite conclusion. Although some earlier studies gave conflicting results, a meta-analysis of all the available data concluded that childhood use of Ritalin was protective against adult alcohol or drug misuse (Wilens et al. 2003). Use of a meta-analysis is an approach often used to reconcile conflicting findings. The method evaluates whether the aggregate evidence across all available studies provides evidence for statistically valid conclusions to be made. Wilens et al. (2003) analysed data from six published studies, involving a total of 674 children treated with Ritalin or related drugs and 360 unmedicated subjects. Overall, there was a statistically significant protective effect of medication. Children treated with psychostimulants were nearly six times less likely to use alcohol or illegal drugs in adolescence, and the protective effect persisted into adulthood, although reduced to an odds ratio of 1.5. A possible explanation for these findings could be that unmedicated children or adolescents with ADHD may be more likely to ‘self-medicate’ by seeking out alcohol or illegal psychotropic agents. Hechtman and Greenfield (2003), reviewing the long-term safety of psychostimulant use in children, also concluded that the evidence did not suggest an increased risk of substance abuse.

Some US politicians have been caught up in the campaign to restrict the use of psychostimulants in children. Several states have passed laws forbidding school staff other than those who are medically qualified to recommend the use of Ritalin or Adderall to parents or their pupils. At the other extreme, some schools have insisted that unruly children be treated with medicines. In the UK some schools threatened to expel badly behaved pupils unless they were treated with Ritalin (BBC News, 24 July 2003). In the USA, a couple in New York State faced child abuse charges when they tried to take their 7-year-old son off Ritalin. They feared that the drug was harming their son's appetite and sleep. However, after complaints from the school district social service a family court judge ruled that they must continue giving him the drug (Albany Times Union, 19 July 2000).

The widespread use of psychostimulants in schools and colleges is not without its problems. In the USA, with more than 2.5 million children being treated with these drugs, it is inevitable that there is some diversion of supplies and abuse. Some schoolchildren sell their prescription drug supply to others, and Ritalin tablets have become known as ‘Vitamin R’, ‘R-ball’, or ‘Smart Drug’; at a price of $1.00–$5.00 per pill most can afford to try it. Some estimates suggest that as many as a quarter to a third of all schoolchildren will have tried illicit Ritalin at some time or another during their school careers. There are indications that organized drug dealers are also becoming involved in the marketing of illicit supplies of Ritalin. Although orally administered Ritalin is not strongly euphoriant, abusers have found other ways of administering the drug. The most (p.68) common is to crush the Ritalin tablets and snort the powdered drug into the nose. The nasal cavity is richly endowed with blood vessels and, as with cocaine, the intranasal route provides a means of rapidly delivering drug to the bloodstream and brain. However, repeated use of this route leads to damage to the delicate intranasal membranes and inflammation as the tablet contains various other inert fillers that are not absorbed. This also makes intravenous injection hazardous, although some have used this route after dissolving the crushed tablets in water. There is little doubt that MP can be highly rewarding when administered by these routes—it is after all a member of the amphetamine family—and it is correctly classified as a Schedule II narcotic (Sannerud and Feussner 2000). In the USA, the DEA continues to issue warnings about the abuse potential of MP, but it is difficult to estimate how serious a problem this has become. More than 1000 emergency room visits for young people with MP intoxication are reported in the USA annually. One questionnaire among 6000 US high school students indicated that 13 per cent were taking illicit Ritalin, in many cases as a study aid. In normal people MP does have definite alerting and anti-fatigue effects. The children treated with psychostimulants may tend to want to continue using them when they become adolescents or college undergraduates and they no longer have a legitimate doctor's prescription. As one anonymous Harvard student put it:

In all honesty, I haven't written a paper without Ritalin since my junior year in high school. I even wrote my Harvard essay on it. It keeps you up when you're tired, and makes you much more aware of what you're doing. Although there are certain risks involved, I think it's worth it.

Adderall is not immune from problems of abuse. According to a report from Texas, college students like Adderall because it allows them to stay awake all night for their studies:

Adderall is going to react the same way with every person whether an individual needs it or not. It makes students stay awake and study because they take it at night—if you are prescribed Adderall, you are supposed to take it in the morning—so ultimately Adderall is supposed to last a patient all day, but when students abuse it and take it at night, it makes them have the effects it would have had if they took it in the morning.

Judging by the number of US campus websites currently reporting Adderall abuse, this may be a growing trend among college students. They like Adderall because of its relatively long duration of action and the drug-induced heightening of concentration and alertness that it provides.

It is difficult to predict how this problem will grow. The situation in schools should become less acute with the increasing adoption of sustained-release formulations of Ritalin and Adderall. These allow once-daily dosing to be done (p.69) at home, making it unnecessary for the school nurse to undertake the distribution of supplies of the drugs during the school day, and this should eventually make the school premises essentially drug free. The sustained-release preparations are also impossible to abuse by snorting or injection as the active drug is trapped in an insoluble wax or resin matrix. However, currently the sustained-release drugs are very much more expensive and this may limit their adoption. The skin-patch formulation version of MP will make diversion to illicit use even more difficult or impossible. On the other hand, Ritalin and Adderall appear to be readily available ‘with no hassle’ from a variety of online pharmacies, making them easily obtainable. It is likely that among a generation of schoolchildren who have become accustomed to treatment with psychostimulants there will be many who will wish to continue such use into adolescence and adulthood. Others may find these drugs an easy way into the ‘performance-enhancing’ properties of the amphetamine class, and there will be yet others who abuse the drugs for their rewarding properties and become dependent upon them.

Society has learned to adjust to ADHD and the widespread use of psychostimulant drugs in many different ways. For example, it took some time and argument, but concessions were eventually won by advocates in the area of college athletics in the USA. The National College Athletic Association (NCAA) once prohibited Ritalin usage (as do the US and International Olympic Committees today) because of its ‘possible acute performance-enhancing benefits’. In 1993, citing legal jeopardy as a reason for changing course, the NCAA capitulated. A letter from the team physician will suffice to allow an athlete to ingest Ritalin, even though that same athlete would be disqualified from participating in the Olympics if he were to test positive for stimulants.

In the field of higher education, where the first wave of Ritalin-taking children has now arrived, a diagnosis of ADHD can give entitlement to various types of special treatment. Students with ADHD can successfully demand extra time for various tests and examinations, or even for routine assignments. To refuse ‘accommodation’ is to risk a hornet's nest of liabilities, as a growing caseload shows. An article in Forbes Magazine in 1996 cited the example of Whittier Law School, which was sued by an ADHD-diagnosed student for giving only 20 extra minutes per hour-long examination instead of a full hour. The school, fearing an expensive legal battle, settled the suit.

A pharmacological advance has been the introduction of a new drug, atomoxetine (trade name Strattera), to treat the symptoms of ADHD. Atomoxetine does not belong to the amphetamine class and is not a scheduled narcotic. It acts as a selective inhibitor of the norepinephrine transporter in brain. It is too early to know whether atomoxetine will take over a large share of the ADHD market. It requires only once-daily dosing and it is not a stimulant drug; therefore it has little or no abuse potential. There have been few rigorous (p.70) comparisons of atomoxetine with Ritalin or Adderall, but NICE (2006) reviewed the three medicines and concluded that they were all of comparable efficacy (http://guidance.nice.org.uk/TA98).

The story of ADHD and its treatment with psychotropic drugs has been a remarkable one, awash with myths, critics, sceptics, pariahs, personal agendas, messiahs, enthusiasts, real science, and pseudoscience. I personally believe that Ritalin and Adderall have helped hundreds of thousands of children live more positive lives; it has saved them from educational under-achievement and lowered self-esteem and has relieved much family stress. To dismiss the potentially dramatic benefits of pharmacological treatment for ADHD risks withholding an effective treatment for a serious heritable behavioural disorder. In Europe, ADHD is still underdiagnosed and undertreated; we have much to learn from both the positive and the negative aspects of the Ritalin Age in the USA. On the other hand, the Ritalin Age has probably gone too far in the USA with overprescription of psychostimulants and some parents encouraging the use of such medicines for any badly behaved or academically underperforming child.