One in seven children in the US and a growing number of children in the UK are being given stimulants with a long list of side effects to treat a condition that may be due to a simple deficiency of certain vital nutrients.
Attention-deficit hyperactivity disorder (ADHD) in children is fast becoming one of the most overdiagnosed and many would argue overprescribed paediatric ‘diseases’ both in the US and now in Britain. It is certainly one of the most fiercely debated childhood disorders.
In the US, its incidence is estimated to be 3-5 per cent and as high as 10 per cent if less stringent criteria are used. In the UK, 2 per cent of children aged 6-16 years are diagnosed as hyperactive, with some 69,000 considered to be suffering from ‘severe ADHD’ (Crit Pub Health, 2000; 10: pp?).
While many argue over what exactly constitutes ADHD (see box, p 2), the medical profession especially in the US tends to speak with one voice as to the solution. Since the 1960s, the psychostimulant Ritalin, generically known as methylphenidate hydrochloride (MPH) an amphetamine like addictive drug that mimics the biochemical properties of cocaine has been administered to thousands of children. It is now estimated that up to one in seven American children is being given the substance daily.
A similar staggering increase in use has been recorded in the UK, where MPH is designated a class B controlled drug (class A if in solution). Professor Steve Baldwin of the University of Teeside states that the rate had risen 15 fold, from 6000 prescriptions a year in the UK in 1994 to 92,000 in 1997 (2000, op cit). By 1999, this had reached 131,000 (covering some 21,000 children), but this is likely to be a gross underestimation because official statistics (based on pharmacy returns) do not include prescriptions given out in private practices, young offender centres or social services residentials.
In France, MPH use is rare and, in the rest of Europe, its prescription for minors is either uncommon or unheard of. However, Baldwin and colleague Rebecca Anderson estimate that if MPH prescriptions were allowed to double year by year, by 2007, the UK would match the US in having one in seven schoolchildren taking the drug daily (Crit Pub Health, 2000; 10: 81-6).
All the indications suggest that drug companies have just this kind of scenario in mind. Since the end of 1999, the leading manufacturer of MPH Novartis (formerly Ciba Geigy and Sandoz)has lost its sole product license for the compound (as Ritalin), allowing other companies to launch their own brands (such as Equasym, by Medeva) while three others Mallinckrodt, Schein Pharmaceuticals and MD Pharmaare in the process of preparing products (2000, op cit).
The selling of Ritalin
In the US, where Ritalin was first used in 1955, Novartis and other drug companies producing similar drugs for use in children, such as dextroamphetamine and metamphetamine, have been very successful in persuading psychiatrists and health authorities of the alleged benefits of these drugs, despite the potential risks and contraindications.
MPH is not licensed for use in children under the age of six (although, in practice, it is given
to children as young as three) nor is it for those who suffer marked anxiety, agitation or tension, or those who have symptoms or a family history of tics or Tourette’s syndrome, hyperthyroidism, severe angina or cardiac arrhythmias, glaucoma or thyrotoxicosis (a condition caused by an excessive amount of thyroid hormones). Caution is required in the prescribing of MPH for children and young people with epilepsy or psychotic disorders, or a history of drug or alcohol dependence.
Proponents assert that MPH works by correcting a ‘brain disorder’, ‘biochemical imbalance’ or ‘biological dysfunction’, but no scientific rationale for MPH prescription has ever been made explicit by its adherents (Jensen PS et al. unpublished paper, Walter Reed Army Institute of Research, Washington, 1989; Pediatrics, 1989; 86: 184-92).
In November 1998, the US National Institute of Health held a consensus development conference on the diagnosis and treatment of ADHD. The 31 expert panel members (including psychiatrist Dr Peter Breggin, one of America’s fiercest critics of MPH, noted that there was no valid, reliable or independent test of ADHD, and that there were “no data to indicate that ADHD is due to a brain malfunction” or that it might be a disease state or brain pathology (NIH, Rockville, 1998; for the full report, see www.odp.od. nih.gov/consensus).
Despite this, the pro Ritalin lobby cites a large scale multiple treatment study of ADHD the MTA Study sponsored by the National Institute of Mental Health and carried out at six separate sites (Arch Gen Psychiatry, 1999; 56: 1073-86). The Ritalin lobby claims that the results showed the superiority of stimulant treatment over behavioural and other treatments (although no nutritional alternative was included in the trial).
However, Dr Breggin, of the Johns Hopkins University Education Faculty and author of Talking Back to Ritalin (Common Courage Press, 1998; see www. breggin.com) has produced a 16 point rebuttal of the MTA Study that severely undermines its credibility and findings. Chief among his criticisms is that it was not a placebo controlled, double blind trial.
Furthermore, the blind classroom raters found no differences between any of the four treatment groups; there was no control group of untreated children; the children themselves did not rate themselves as improved; and out of the 4541 children originally screened, only 2.7 per cent (123 children) completed the medication management trial.
This demolishing of the MTA Study is especially important because, in the UK, the National Institute for Clinical Excellence (NICE) issued its guidance on the use of MPH last October (NICE, Technology Guidance No 13; 2000; see www.nice.org.uk) based on the official MTA results with little critical analysis, even referring to the study as “well conducted”. The NICE report essentially endorses the use of MPH, although it does acknowledge that “if improvement of symptoms is not observed. . .over one month, the drug should be discontinued”.
However, it does not mention that about 30 per cent of children show no response or that up to 50 per cent develop side effects. Professor Baldwin states:
“Adverse drug reactions and side effects [more accurately described as ‘main effects’] from MPH include: CNS sequelae, gastrointestinal effects, cardiovascular effects, liver abnormalities, convulsions (including grand mal), drug dependency and addiction, drug withdrawal reaction, hair loss, low white blood cell count, agitation, hostility, depression, psychotic depression, abnormal thinking, hallucinations, psychoses, emotional lability, overdose and suicide (Ethical Hum Sci Serv, 1999; 1: 13-33).
“Paradoxically, the supposedly desirable bahavioural effects (including passivity, attention, reduced spontaneity) are the primary toxic effects of psychostimulants.’ [Baldwin’s italics] In effect, the ‘efficacy’ of MPH lies in producing serious adverse effects.
The NICE report only mentions nervousness and sleeplessness as common side effects, and claims that the other effects reported were “relatively minor”.
Despite the general acceptance by the US and UK psychiatric community to medicate this highly controversial disorder, there are now signs that the debate has reached a turning point. Recently, various legal actions have been launched in the US against not only Novartis, but also the American Psychiatric Association for alleged fraud and corruption (see box on p 3), with similar actions pending in the UK.
As the problems with MPH have surfaced, so have promising alternative treatments, specifically, growing evidence for nutritional and heavy metal detoxification treatments.
Twenty years ago, Sally Bunday and her mother, the late Irene Colquhoun, founders of the UK Hyperactive Children’s Support Group (HACSG; see box on p 4), were the first to propose that essential fatty acid (EFA) deficiency might be a factor in ADHD (Med Hypoth, 1981; 7: 673-9).
Surveying a group of hyperactive children, they found an excess of males, a link with asthma, eczema and other allergic conditions, and evidence from hair analysis of zinc deficiency. Clinical signs, such as excessive thirst, frequent urination, dry skin and dry hair, were observed, which are also consistent with EFA deficiency.
In the US, a diet developed by the late paediatrician Dr Benjamin Feingold (Am J Nurs, 1975; 75: 797-803; Why Your Child is Hyperactive, NY: Random House, 1975) was designed to eliminate certain synthetic additives and particular foods, especially fruits, containing natural salicylates, which inhibit the conversion of long chain polyunsaturated fatty acids to prostaglandins (see below). The diet was successful in reducing symptoms, and numerous groups sprang up across the US, and continue to be active in promoting and researching Dr Feingold’s treatment. Groups were also started in the UK, and the HACSG has adapted the diet for its own use.
Essential fatty acids
Following on from Bunday’s groundbreaking work, considerable evidence is accumulating that deficiencies in the body’s reserve or production of EFAs is a major contributory factor in a range of interrelated childhood disorders, including ADHD, dyslexia, asthma, allergies and even autism, and that EFA supplementation is of value in a significant number of cases (Prost Leukotr Essent Fatty Acids, 2000; 63: 1-9). The overlap of clinical features between ADHD and, for example, dyslexia is around 30-50 per cent.
Fatty acids play an essential role in brain structure and function. Two of themarachidonic acid (AA) and docosahexanoic acid (DHA)play a major role in the brain and eye, constituting 20 per cent of the dry weight of the brain and over 30 per cent of the retina. Two thers eicosapentaenoic acid (EPA) and dihomogamma linolenic acid (DGLA)are crucial for normal brain development, but play a more minor structural role.
The absolutely essential EFAs that cannot be synthesised by the body, and therefore must be supplied in the diet, are linoleic acid (omega-6 series, to which DGLA and AA belong) and alpha linolenic acid (omega-3 series, to which EPA and DHA belong). Both AA and DHA are termed longer chain poly unsaturated fatty acids (LC-PUFAs) and can usually be synthesised from their EFA precursors. The latter are critically important as they are precursors of a complex group of highly biologically active compounds, including prostanoids (prostaglandins, thromboxanes and prostacyclins, among others) and leukotrienes. These compounds perform numerous regulatory functions in the brain and the rest of the body.
Dr A.J. Richardson (Physiology Laboratory, Oxford) and B.K. Puri (MRI Unit, Imperial College) in a summary of the evidence (Prost Leukotr Essent Fatty Acids, 2000; 63: 79-87) state:
“EFA metabolism can influence many aspects of brain development, including neuronal migration, axonal and dendritic growth, and the creation, remodelling and pruning of synaptic connections (Crawford MA, in Bazan NG, ed, Neurobiology of Essential Fatty Acids, NY: Plenum, 1992: 307-14). Animal studies have shown that both neural integrity and function can be permanently disrupted by deficits of omega-6 and omega-3 fatty acids during fetal and neonatal development (J Lipid Res, 1987; 28: 144-51; Ann Rev Nutr, 1988; 8: 517-41;
J Nutr, 1989; 119: 1880-91). While both omega-6 and omega-3 fatty acids are required, the omega-3 fatty acids such as DHA appear to play a special role in highly active sites such as synapses and photoreceptors, and deficiencies have particularly been linked to visual and cognitive deficits (J Pediatr, 1994; 125: S39-47; Proc Natl Acad Sci USA, 1986; 83: 4021-5).”
Research by M. Makrides and coworkers has shown that infants may benefit considerably from the LC-PUFAs naturally present in breast milk, but absent from many formula feeds (Lancet, 1995; 345: 1463-8).
Although supplies of EFAs are necessary throughout development and adult life to maintain normal function and may be adequate it is the conversion of linoleic acid and alphalinolenic acid into their LC-PUFA derivatives that is crucial for proper brain function.
Unfortunately, there are a number of factors which can interfere with this conversion, including:
Saturated or hydrogenated fats
Deficiency of vitamin and/or mineral cofactors (especially zinc deficiency)
Diabetes, eczema, asthma or other allergic conditions.
Thus, even if the diet contains sufficient EFAs, LC-PUFAs may be inadequate due to deficiencies in conversion. In addition, individuals differ in their genetic constitutional ability to facilitate this conversion.
All the above factors, as well as disease factors, suggest the potential benefit of dietary supplementation with preformed LC-PUFAs.
Features of EFA deficiency
The higher ratio of boys to girls with ADHD is well accepted and varies from 2:1 to 10:1 (J Child Psychol Psychiatry, 1989; 30: 219-30). This makes sense if ADHD is primarily a deficiency disease of EFAs since males are more vulnerable than females to LC-PUFA deficiency (Biochem Arch, 1990; 6: 47-54). The same excess male numbers are also found in other developmental disorders clinically associated with ADHD, including dyslexia and dyspraxia (Am J Clin Nutr, 2000; 71 [Suppl 1]: 3235-65; Prost Leukotr Essent Fatty Acids, 2000; 63: 1-9).
An excess of minor physical abnormalities, such as abnormal palm creases, is associated with ADHD (Pediatrics, 1974; 53: 742-7), and EFAs, phospholipids and their metabolites play important roles in the cell abnormalities likely to underlie them (J Nutr, 1996; 126: 603- 10). Hyperactive children have also been found to have more chronic health problems, such as asthma or allergies, than non ADHD children (Am J Orthopsy-chiatry, 1985; 55: 190-210).
Children with ADHD have been found to have a higher incidence of sleeping problems than normal children, such as difficulty settling, waking in the night and overtiredness in the morning (Ann Neurol, 1988; 24: 325). PUFAs play a major role in the control of sleep mechanisms, and directly affect the structure of neuronal membranes and indirectly affect the dynamics of complex lipids, prostaglandins, neurotransmitters, ami no acids and interleukins required for the initiation and maintenance of normal sleep (Med Hypoth, 1998; 50: 139-45).
ADHD children exhibit more physical complaints than do normal children, and these include stomach aches, headaches, proneness to infections and general malaise with no obvious cause. In one study, 24 per cent of ADHD boys and 35 per cent of girls between 12 and 16 years of age fulfilled the criteria for somatisation disorder (Child Psychol Psychiatry, 1989; 30: 219-30).
Because EFAs and their derivatives play a critical role in regulating immune and digestive functions (Nutrition, 1998; 14: 627-33), EFA deficiency is known to contribute to general health problems such as susceptibility to infections, and digestive and related disorders.
Symptoms of depression, anxiety and low self esteem are typical of ADHD, which is commonly associated with other behavioural and emotional disorders. Up to 44 per cent of sufferers have at least one other psychiatric disorder (Child Psychol Psychiatry, 1989; 30: 219-30).
There is increasing evidence that omega-3 fatty acid deficiency may be important in depression (Lancet, 1998; 351: 1213; Biol Psychiatry, 1998; 43: 315-9). A recent double blind, placebo controlled, study has shown the benefits of omega-3 fatty acids on the short term course of illness in bipolar disorder (Arch Gen Psychiatry, 1999; 56: 407-12).
Poor motor coordination is a frequent observation in those with ADHD, as are ‘soft’ neurological signs, such as motor overflow movements (Arch Neurol, 1978; 42: 228-31). In the general population, movement disorders are associated with deficiencies in LC-PUFAs (Prost Leukotr Essent Fatty Acids, 1996; 55: 83-7). Poor motor coordination is consistent with a lack of fatty acids.
The observed overlap of ADHD with dyslexia appears to be stronger for attentional disorder without overt hyperactivity than for the mainly hyperkinetic form (J Learn Disabil, 1991; 24: 96-103). The shared features include particular problems with specific aspects of visual and cognitive function (Conners CK, in Ravlidis G, ed, Perspectives on Dyslexia, vol 1, Chichester: John Wiley & Sons, 1990; 163-95). Deficiency in fatty acids has been proposed as contributing to dyslexia, and there is growing evidence that supplementation can help alleviate aspects of the disorder (Am J Clin Nutr, 2000; 71 [Suppl 1]: 3235-65).
Evidence of low fatty acids
In an early study, Michell and colleagues found lower plasma levels of DGLA, AA and DHA in 44 ADHD children compared with 45 matched controls (Clin Pediatr, 1987; 26: 406-11). He also found that significantly more of 48 ADHD children compared with 49 age and sex matched controls suffered polydipsia (chronic excessive intake of water) and polyuria (passage of very large volumes of urine over a given period) as well as health problems, and language, learning and reading difficulties.
More recently, studies at Purdue University have provided further confirmation of abnormal fatty acid metabolism in ADHD. A team led by L.J. Stevens (Am J Clin Nutr, 1995; 62: 761-8) found that, compared with 43 normal controls, 53 ADHD boys:
were less likely to have been breastfed (breast milk contains preformed LC-PUFAs, such as AA and DHA, whereas most formula does not);
were more likely to suffer from allergies and other health problems (already known to be linked with EFA deficiency);
showed clinical signs of EFA deficiency (excessive thirst, frequent urination, dry skin and hair, and soft or brittle nails);
had reduced blood levels of certain LC-PUFAs (especially AA, EPA and DHA), but not their EFA precursors;
had an adequate dietary intake of the EFA precursors.
The results support the proposal that EFA abnormalities are related to ADHD and that the problem lies in the conversion of EFAs to LC-PUFAs. Some 40 per cent of ADHD children had a raised frequency of clinical fatty acid deficiency signs versus only 9 per cent of controls.
Stevens and his team also showed that both clinical signs and blood biochemical indices of EFA deficiency were significantly associated with the severity of behavioural problems, and the incidence of learning and health problems (Physiol Behav, 1996; 59: 915-20).
Another team (J Child Psychol Psychiatry, 1996; 37: 225-7) found that the mean serum free fatty acid level in 48 ADHD children was significantly lower than in 45 matched controls. A further, significant correlation was found between zinc and free fatty acid levels in ADHD children.
Early studies of GLA supplementation showed only equivocal or modest benefits (Biol Psychiatry, 1989; 25: 222-8). This was probably because, as Richardson and Puri suggest (Prost Leukotr Essent Fatty Acids, 2000; 63: 1-9), omega-3 rather than omega-6 deficiency is more relevant in ADHD, and the studies did not last long enough to show any effects. Recent research indicates that LC-PUFA levels in the brain may take up to three months to recover from a chronic deficiency state (Prost Leukotr Essent Fatty Acids, 1993; 4: 171-80), and this must be taken into account in future studies.
At a National Institutes of Health workshop on omega-3, EFAs and psychiatric disorders, held in Bethesda, Maryland, in 1998, J.R. Burgess, of the Purdue team, presented the preliminary results of a double blind trial with ADHD children who had clinical signs of fatty acid deficiency. They found that supplementation with a combination of DHA, EPA, AA and DGLA (weighted in favour of omega-3 fatty acids) successfully changed blood fatty acid profiles and reduced ADHD symptoms.
However, another double blind trial, presented by R. Voight at the same NIH workshop, showed no benefits with DHA supplementation. Richardson and Puri suggest that one reason for this may be that DHA alone is ineffective and that other fatty acids, especially EPA, may account for the Purdue study’s positive findings. They also point to differences in subject selection: the Purdue study included children with prior indications of fatty acid deficiency whereas no such indices were used in the Voight study, which excluded children with any other disorders to ensure that the sample comprised only ‘pure’ ADHD diagnoses.
To investigate the importance of EPA, Dr Richardson is currently involved in a study of the effects of supplementing ADHD children with Eye Q (www.equazen.com), a product that contains a 4:1 ratio of EPA to DGLA.
The work of researchers like Dr Richardson and Dr Neil Ward point irrefutably to two prime causes of the symptoms associated with ADHD. There is no question that there is a paucity of evidence for long term benefit with MPH; serious side effects are common, and its use in minors correlates with later stimulant abuse in adulthood (J Learn Disabil, 1998; 31: 533-44).
It seems only common sense to assess the nutritional status and heavy metal burden of any child suspected of ADHD, to correct it and to observe any improvement in behaviour before considering any highly potent drug therapy. Let MPH advocates remember Hippocrates’ primary command: “First, do no harm”. He might also have added: “especially to children”.