Since our last report on it in February 2001 (WDDTY vol 11 no 11), the antihyperactivity drug Ritalin has chalked up a number of milestones. It is now one of the most prescribed children's drugs in the US, with more than six million prescriptions a year approaching $500 million in annual sales. That's good news for its manufacturer, drug giant Novartis.
Less rosy for the company is the fact that Ritalin has attracted more lawsuits than any other drug in the pharmacopoeia, and that the millions of children now taking Ritalin may be at risk of dying prematurely from cancer of the liver.
Although Ritalin has been sold for more than 40 years, it arrived on the market before drug companies were required to test for carcinogenicity. It was only as late as 1995 - after millions of children had already been 'medicated' with the drug - that toxicological tests were completed.
When mice were fed relatively high doses of Ritalin for two years, a significant number developed liver tumours. While some of the tumours were benign, others were a cancerous type known as hepatoblastomas (Toxicology, 1995; 103: 77-84).
These are animal studies, which don't necessarily apply to humans, but the results are compelling. Although rare in humans, hepatoblastomas are most commonly seen in children under the age of four. Knowing this, Novartis has responded to the toxicology study by emphasising that Ritalin is not supposed to be prescribed to anyone under the age of six.
Nevertheless, the fact remains that the drug is now increasingly being prescribed for children as young as two (J Pediatr, 2002; 141: 71-5).
The cancer-causing potential of methylphenidate hydrochloride (MPH, the active ingredient in Ritalin) has now been added to the official list of adverse effects of the drug (see box, p 2). However, despite this, no recommendations have been made to limit its use.
In fact, the opposite has happened. Prescriptions for MPH-based drugs have continued to soar, with sales tripling in the last five years alone. Doctors in the UK have traditionally been more cautious than in the US but, even here, prescription rates have risen by a staggering 100-fold over the last decade. According to the UK Department of Health, there are now over 200,000 prescriptions written for Ritalin each year.
A valid diagnosis?
In the US, the goal of many experts appears to be to have all children with attention-deficit hyperactivity disorder (ADHD) treated with MPH drugs; indeed, some doctors have gone on record bemoaning the fact that 'only 50 per cent' of hyperactive children are being medicated (Curr Psychiatr Rep, 2000; 2: 102-9).
At the same time, diagnoses of hyperactivity - first dubbed ADHD in 1987 - have been multiplying exponentially, boosted by the American Psychiatric Association's revised symptom checklist (see box, p 3). According to a US survey, doctors were three times more likely to diagnose ADHD in 1998 than only eight years earlier. There was a particularly sharp rise in girls, once considered at much lower risk than boys. By 1998, new cases of ADHD had risen to over three million, representing 5.9 per cent of the US child population (CNS Drugs, 2002; 16: 129-37).
All these children are candidates for Ritalin. In some American schools, the prescribing rate is even higher, with 10 per cent of all children, and an unprecedented 20 per cent of fifth-grade pupils, taking Ritalin (Am J Publ Health, 1999; 89: 1359-64). 'It's hard to believe this many children have the specific brain-related problem called ADHD,' said Dr Gretchen LeFever, one of the authors.
Small wonder that one of the recent lawsuits against Novartis has linked the rise of ADHD diagnosis to the rise of Ritalin, alleging a conspiracy between the drug makers and the American Psychiatric Association to create a false diagnosis of hyperactivity.
However, conspiracy is notoriously difficult to prove, so the lawsuit failed. Nevertheless, the basic issue of whether ADHD is a medical condition that needs drug treatment remains in question.
For years, the mainstay of the prescribing rationale has been that ADHD is caused by a chemical imbalance in the brain, a condition that MPH-based drugs can supposedly reverse. But obtaining actual evidence of a biochemical abnormality is difficult.
For a start, the way the drug is supposed to work is paradoxical. MPH is a drug closely related to amphetamine and cocaine - and, as such, it's a stimulant. Yet, its apparent action is as a suppressant.
This paradox is now claimed to be resolved by detailed brain scans from children taking MPH. These show that both MPH and cocaine stimulate the production of the brain chemical dopamine. ADHD children are believed to have low dopamine levels (J Neurosci, 2001; 21: RC121). But these new findings are reported to have 'shocked' the researchers involved. 'The data clearly show that the notion that Ritalin is a weak stimulant is completely incorrect,' says team leader Dr Nora Volkow. 'This is a cocaine-like drug.'
So, it should come as no surprise that MPH has serious effects on the brain. The most dramatic are epilepsy-like seizures. Reviewing their experience with 200 hyperactive children, US neurologists recently reported that MPH led to epileptic seizures in six of them - in most cases by triggering a preexisting dormant condition (Pediatr Neurol, 2001; 24: 99-102).
Even more dramatic, the drug can cause inflammation of the arteries of the brain. In one eight-year-old boy taking MPH, such cerebral arteritis led to the child having a stroke. This 'should not be surprising,' said the hospital doctors charged with saving the boy's life, 'since stroke is a well-documented complication of amphetamine abuse, and methylphenidate is chemically and pharmacologically similar to amphetamines' (J Child Neurol, 2000; 15: 265-7).
Another side-effect of amphetamines and cocaine is psychosis, defined as 'a severe mental disorder in which the patient loses contact with reality.' As expected, Ritalin can produce the same effects. Canadian neurologists have found that more than 6 per cent of ADHD children treated with MPH became psychotic, with hallucinations and paranoia. No such symptoms were seen with any ADHD children not taking MPH (Can J Psychiatry, 1999; 44: 811-3).
Psychosis and depression can be seen as withdrawal symptoms following long-term MPH use (Am J Psychiatry, 1979; 136: 226-8). Withdrawal symptoms are a sign of addiction, yet the suggestion that MPH is addictive is hotly disputed by Novartis.
Another adverse mental effect is obsessive-compulsive disorder (anxiety leading to compulsive rituals), which doctors in France have found can result from using MPH for as little as 10 months. (Encephale, 2000; 26: 45-7). Most ADHD children in the US take the drug for considerably longer than that.
Tourette's syndrome (a syndrome of facial, vocal and bodily tics) is yet another adverse brain effect. Up to 10 per cent of children taking MPH develop these symptoms, which are chronic in some cases (Arch Pediatr Adolesc Med, 1994; 148: 859-61).
MPH also seems to adversely affect childhood growth. Doctors in the US followed up children taking MPH for an average of three years, and recorded their height and weight at around age 22. Sure enough, they found that the children given higher doses of MPH were significantly shorter as adults (J Am Acad Child Adolesc Psychiatry, 2000; 39: 517-24).
So how does the drug affect growth? Since appetite suppression and anorexia are common side-effects (see box, p 2), it may simply be malnutrition. However, German paediatricians have recently discovered that MPH has direct effects on the pituitary, the gland controlling growth hormone production (J Child Adolesc Psychopharmacol, 2002; 12: 55-61).
As the pituitary controls five other major hormones besides growth, MPH has a potential to cause long-term damage to the endocrine system.
These findings underline the paucity of research on the potential long-term hazards of MPH. They also provide ammunition for the critics who charge that MPH is being used as a short-term chemical 'fix' for behavioural problems that may require more fundamental - and certainly less toxic - solutions (see box, p 4).
Supporters point to the good results in the classroom, where MPH appears to reduce impulsive and disruptive behaviour. Critics, however, say the drug has not improved IQ tests, academic performance or learning disabilities.
Whatever the short-term benefits of the drug, it appears to have few long-term effects on ADHD symptoms (acting out, conduct and separation anxiety) as rated by parents on Stony Brook Checklist-3R subscales (Res Dev Disabil, 1996; 17: 417-32).
It's clear that many children with ADHD have food intolerances (see box, p 4). But if withdrawing the problem foods is impractical, there are two effective 'desensitising' treatments.
In the provocation/neutralisation technique, developed by American allergist Dr Joseph Miller about 25 years ago, minute amounts of the problem foods are either injected into the skin or placed under the tongue. Miller found that a certain concentration of extract will 'neutralise' the intolerance, switching off the adverse food reaction (Ann Allergy; 1997; 38: 85-190).
The second method, enzyme potentiated desensitisation, was developed in Britain by Dr Leonard McEwen in the early 1980s. In this case, food allergens are allowed to enter the body through a large patch on the skin, thus gently stimulating the immune system to combat the intolerance. A large clinical trial found it to be effective in 80 per cent of hyperactive children with food intolerance (Lancet, 1992; 339: 1150-3).
Sugar is a food that has been anecdotally linked to hyperactivity, but most studies have failed to make the connection. However, it has been shown that sugar can cause problems in a minority of children, suggesting that it too is an intolerance reaction (J Abnorm Child Psychol, 1989; 17: 127-32).
If hyperactivity is so closely related to food, can nutrition also help? Studies led by American criminologist Dr Stephen Schoenthaler have consistently shown that antisocial and violent behaviour is often related to poor nutrition, and that supplementation with multivitamins/minerals improves behaviour (J Alt Complement Med, 2000; 6: 31-5). UK scientists achieved similar results in young British prisoners, with a daily vitamin/mineral supplement improving behaviour by 26 per cent. As in the US studies, the crucial finding was that it was only the previously malnourished offenders who benefited (Br J Psychiatry, 2002; 181: 22-8).
Other research has looked at individual nutrients. In one small study, vitamin B6 reduced hyperactivity more effectively than Ritalin (Biol Psychiatry, 1979; 14: 741-51). Magnesium deficiency may also be a factor in ADHD as it can lead to excessive fidgeting, restlessness and learning difficulties. Polish doctors report dramatic improvements in behaviour with magnesium supplementation (Ann Acad Med Stet, 1998; 44: 297-314). Zinc deficiency has also been found in hyperactive children, but there have been few trials of supplementation (Ann NY Acad Sci, 2001; 931: 310-41).
In an unpublished clinical study in 1991, a nutrient cocktail of vitamin B6, magnesium, calcium, L-tryptophan and folic acid reportedly cured hyperactivity in 60 per cent of children after three months.
Other nutrients of interest are essential fatty acids (EFAs). First suggested by the British Hyperactive Children's Support Group 25 years ago, strong links between EFA deficiency and ADHD are now being confirmed in trials. Scientists at Purdue University in Indiana have found that a high proportion of hyperactive children have classic symptoms of low EFAs - excessive thirst, frequent urination, dry skin/hair, and soft/brittle nails (Physiol Behav, 1996; 59: 915-20).
Early studies giving EFA supplements to ADHD children were disappointing (Biol Psychiatry, 1989; 25: 222-8), but it was soon revealed that the helpful fatty acids were the omega-3s. Hyperactive behaviour was significantly improved in children who took highly unsaturated fatty acids for three months (Prog Neuropsychopharmacol Biol Psychiatry, 2002; 6: 233-9).
Few herbal remedies have been tested for ADHD. The most promising is Pycnogenol, an extract of French maritime pine bark. Extensive German research - in animals and thus not necessarily applicable to humans - has shown improvements in mental functioning (Int J Clin Pharmacol Ther, 2002; 40: 158-68). Another that may help as a general calmative in ADHD is the patent German remedy Melissengeist. Mainly of balm oil, it can reduce restlessness, excitability and headaches (Med Klin, 1974; 69: 1032-6).
Homoeopathy has also been tried. In one trial, Swiss doctors gave 'constitutional remedies' (those tailored to the individual) to over a hundred ADHD children. Three-quarters were better by more than 70 per cent within four months (Br Hom J, 2001; 90: 183-8).
Simple modifications to the environment may also help. Colouring classroom walls soft pink, painting murals on corridors and carpeting hard floors halved the incidence of aggressive behaviour (J Am Acad Child Adolesc Psychiatry, 1994; 33: 558-66).
Similar results were obtained by changing the lighting. In one Florida school, when the usual fluorescent lighting was replaced with daylight ('full spectrum') fluorescents, there was a marked decrease in nervous fatigue, irritability, lapses in attention and hyperactive behaviour (South J Optom, 1979; 21: 8-14).
'Bodywork' techniques are also promising. Cranial osteopathy can reduce hyperactive behaviour as structural problems in the neck (often caused by a difficult birth) can predispose to ADHD - though this has yet to be proven in trials.
A more unusual approach involves stroking the child's body, face and hands with a fine paintbrush. This is claimed to eradicate retained immature reflexes, which are believed to result in an excess of adrenaline. Again, however, there have been no clinical trials.
The drugged generation
Whatever the usefulness of alternative treatments for ADHD, in the US, parents are increasingly being pressurised to accept the 'chemical cosh' of Ritalin. Some American schools now insist that all disruptive pupils are given anti-ADHD drugs. Often, when the parents refuse, the schools have taken them to court - and won.
US drug companies have been quick to exploit this national climate of opinion - much of it, of course, fostered by their own skilful PR. Year by year, manufacturers have been adding to the armoury of anti-ADHD drugs. In addition to Ritalin, teachers and doctors can now call upon Strattera, Adderall, Concerta, Cylert, Focalin, Metadate CD, Ritalin SR, Ritalin LA and even a Ritalin patch. Some of these are being directly advertised to parents.
Most of the new drugs are still MPH-based, but they've been reformulated to make the drug more long-acting to avoid the 'problem' of ADHD children forgetting to take their tablets. All have similar side-effects to Ritalin's, though Cylert is even more dangerous. This product has caused severe liver toxicity, leading in some cases to death.
Besides these new drugs, waiting in the wings are two new official disorders of childhood behaviour: conduct disorder (CD; also called antisocial personality disorder of childhood or APDC) and oppositional defiant disorder (ODD).
The drug companies are no doubt already working on new chemicals to deal with these new behavioural disorders. And as they get nearer to the marketplace, it's likely we'll be hearing a lot more about CD, APDC and ODD.