Alternative Medicine Review 2000 (Oct); 5 (5): 402–428 ~ FULL TEXT
Parris M. Kidd, PhD
Introduction
Attention Deficit/Hyperactivity Disorder (ADHD) is a loosely defined assemblage of neuropsychiatric symptom clusters that emerge in childhood and often persist into adulthood. [ 1 ] Though the means to its diagnosis is only empirical, ADHD increasingly is being employed as a diagnostic label for individuals who display a wide range of symptoms, such as restlessness, inability to stay focused, mood swings, temper tantrums, problems completing tasks, disorganization, inability to cope with stress, and impulsivity. [ 2 ] The etiology of ADHD is not understood, yet potent drugs are being employed for its medical management while safe and effective alternatives are being neglected. [ 2, 3 ] ADHD is the most prevalent behavioral disorder in children, [ 4 ] and frequently its symptoms are commingled with learning problems, oppositional conduct, and depression, which altogether compound the family's emotional burden. Particularly since the dominant mode of treatment to date has involved the drug methylphenidate (Ritalin®), which acts on the CNS much like cocaine and has marked potential for severe side-effects and addictive abuse, ADHD has become a lightning rod for controversy. The scientific literature on ADHD is voluminous, with more than 4,000 peer-reviewed articles published since 1966. [ 5 ]
An intense debate has developed around the diagnosis, etiology, and medical management of ADHD. Parent groups, consumer advocacy organizations, and progressive physicians are calling for alternatives to methylphenidate and the many other potent stimulants used to treat ADHD, while pharmaceutical interests and physicians particularly oriented to prescribing pharmaceuticals attempt to defend the status quo (currently in the United States, between 1.5 million and 3 million ADHD children are likely taking methylphenidate). This review is intended to bring the medical and scientific issues surrounding ADHD into sharper focus, to better define a wholistic/integrative strategy for its medical management.
Background and Scope of the ADHD Problem
A condition in children somewhat resembling ADHD was first described by Still in 1902. [ 6 ] He discussed 43 cases of children with aggression, defiance, emotionality, limited sustained attention, and deficient rule-governed behavior. Although his population possessed normal intellectual capacity, he commented, "...the control of activity in conformity with moral consciousness is markedly defective." He suggested, "inhibitory volition," that is, the capacity to exercise good judgment, might be imperfectly developed in these subjects. From 1940 through 1960, the condition was identified with "minimal brain damage or dysfunction," and its etiology was speculated to be insults to the brain such as head injury, infection, and toxic damage.6 In the 1960s it became "hyperactivity" or "poor impulse control," reflecting that no underlying organic damage had been identified.
By the 1970s-1980s, the "hyperactivity" symptomatology had taken on more diagnostic significance in comparison with the other symptoms. In 1980, the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) listed the term "hyperkinetic reaction of childhood," which then evolved through "hyperkinetic syndrome" and "hyperactive child syndrome," to "attention deficit disorder" (ADD), either "with hyperactivity" or "without hyperactivity." By 1987, in the revised DSM-III (DSM-III-R), the earlier focus on hyperactivity had shifted toward inattention and impulsivity. [ 7 ]
As the research on ADHD progressed, the balance between the three major diagnostic symptom clusters was subsequently further refined, so that in the 1994 DSM-IV the official term was Attention Deficit/Hyperactivity Disorder, or ADHD, with three subtypes. [ 1 ] Inattention and impulse control are now regarded more as the cardinal defects than is hyperactivity. [ 5 ] Some professionals continue to reserve the term ADD for children who are only inattentive and ADHD for children who are also hyperactive, but all official reports or other records are required to use ADHD.
ADHD is usually diagnosed in school-age children, and is conservatively estimated to occur in 3-6 percent of this population from diverse cultures and geographical regions. [ 5, 8-12 ] In some U.S. cities the percentage may reach 10-15 percent. [ 8 ] As of 1993, more than two million U.S. children were diagnosed ADHD, the number having increased steadily from 902,000 in 1990. Currently, as many as four million carry this diagnosis, which is responsible for 30-50 percent of the referrals to mental health services for children. [ 9, 10 ] Elsewhere, ADHD estimated prevalence ranges from 1.7-10.0 percent in Canada, Puerto Rico, the United Kingdom, Norway, the Netherlands, Germany, and New Zealand. [ 10-12 ] ADHD routinely continues into adolescence, and also can persist into adulthood in as many as half of those individuals who manifest the disorder in adolescence. [ 10 ]
The adverse social, familial, and personal consequences of ADHD cannot be overstated. Most ADHD subjects develop emotional, social, and family problems as a consequence of their primary difficulties. ADHD is a major problem both for society and for the child, as it causes friction in school or at the workplace, depresses the academic performance of the student's entire class, interferes with peer relationships, and increases intra-family stress. For the individual afflicted, until ADHD symptomatologies can be recognized and brought under medical management, daily existence is likely to be severely compromised along with the lives of those around him (or her, although ADHD is more prevalent in boys by a 3:1 margin). [ 5 ] Parents and children express desperation for interventions that will work, but without the adverse effects inflicted by the pharmaceutical management model.
The first report of stimulant use to treat ADHD was in 1937. [ 13 ] The current overwhelming reliance on methylphenidate and other stimulants for ADHD treatment belies the ample evidence that ADHD symptomatologies can be ameliorated without the use of drugs. This degree of reliance on methylphenidate is unfortunate because its action is virtually identical with cocaine, to such an extent that in the United States it is a Schedule II controlled drug. [ 14-16 ] The frequent practice of maintaining ADHD subjects on methylphenidate over many years increases the potential for its abuse. In fact, it is fast becoming a "street drug" among teenagers. [ 17 ] The controversies over methylphenidate use and the ever-increasing frequency of ADHD diagnosis are now so politicized that they are interfering with society's urgent need to better serve the children (and adults) involved. Fortunately, a balanced examination of the available scientific and clinical evidence reveals an improved prognosis for ADHD.
ADHD Medical Management-Current Status
The conventional management of ADHD formally involves a multimodal approach. [ 18, 19, 23-25 ] Currently, this approach includes individual and family education, counseling, behavioral therapy, school remediation, and medication. [ 24 ] Close coordination between the subject, the family, the practitioner and the school system ought to be integral to this approach, but in mainstream pediatric practice medication with pharmaceuticals is practically the sole component of medical management. [ 25 ] Typically, it falls on the family of the afflicted child to implement additional modes of management that have proven effectiveness, such as clearing allergies, regulating the diet, and supplementing with nutrients.
Psychostimulant medications are generally the first choice in medication of ADHD. Approximately 70 percent of the children treated show improvement in the primary ADHD symptoms and in co-morbidity such as conduct disorder, [ 24, 25 ] although the benefits may not hold beyond two years. Currently, methylphenidate is the drug of choice; other first-line stimulants include dextroamphetamine (Dexedrine®) or a mixture of four salts of dextroamphetamine (Adderall®). [ 18,19 ] The second-line stimulants include methamphetamine (Desoxyn® or the longer-lasting Desoxyn Gradumet®), or pemoline (Cylert®), which causes hepatotoxicity in about three percent of subjects treated and can cause death, so must be closely monitored. In practice, the use of any of these stimulants is so fraught with uncertainties and potential complications that only the most intrepid practitioners prescribe them with comfort. [ 17, 24, 25, 27-29 ]
The psychostimulants ought to be severely limited in their applicability, due to their marked and sometimes severe adverse effects. [ 29 ] Decreased appetite secondary to anorexia or nausea may occur, leading to weight loss. Insomnia may also occur, as can headache. Lowering the dose and changing the timing may eliminate these side-effects. Rarely, psychostimulants may cause tics to develop, and cases of leukopenia and psychosis have been reported. [ 25 ] Methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and Adderall are all classified as Schedule II agents in the U.S., consonant with their significant abuse potential. [ 25, 29 ] As blood levels of the stimulant decrease over time, irritability may manifest as a "rebound" type of withdrawal symptom.
Some subjects are very prone to abusing stimulants and must be placed on non-stimulant, alternative medications. A subgroup with more depression and anxiety may respond better to tricyclic antidepressants (imipramine, desipramine) than to stimulants, [ 24 ] although both can have major adverse effects, with desipramine linked to sudden death. [ 25 ] The antidepressant bupropion (Wellbutrin") can, like the stimulants, exacerbate an underlying tic disorder. This drug is also contraindicated in children with anorexia nervosa, bulimia, or epilepsy. ADHD subjects have a higher risk of moving into drug abuse, [ 34 ] and there is now a trend toward placing ADHD children on Prozac®, withdrawal from which has been linked to violence and other possibly disastrous outcomes. [ 27, 28 ]
Certain non-stimulant medications can serve as allopathic alternatives in ADHD when stimulants have failed. Among these are the alpha-adrenergics clonidine (Catapres®) and guanfacine (Tenex®). Both are less well validated than the stimulants and not as efficacious. Clonidine can cause sedation and dysphoria, and both of these drugs require blood pressure monitoring because they are also antihypertensives. [ 24, 25 ]
The psychological disorders that often coexist with ADHD also require management. The more serious of these include tics or Tourette's syndrome; depression, including the bipolar type which is quite prevalent; anxiety; and obsessive-compulsive disorder. For children who have tic disorders, extreme overactivity, oppositional or conduct disorder, or hyperarousal, clonidine may prove useful. [ 24 ] ADHD also can be associated with impulse control problems more extreme than the usual ADHD spectrum; sometimes antipsychotics are prescribed, although their risks outweigh their advantages. [ 25 ] In summary, pharmacologic management of ADHD and the coexisting conditions can challenge even the most experienced practitioner, and safer modes of management are urgently indicated for this unfortunate patient population.
ADHD Etiology and Contributory Factors
ADHD is highly inhomogeneous in the biological sense, and although classed as a disorder it amounts to hardly more than an assemblage of symptom clusters. Its etiology also is far from homogeneous, with many likely contributory factors. Certainly some of these etiological factors generate symptomatologies that closely resemble ADHD. Among these are sensitivities to food additives, intolerances to foods, nutrient deficiencies and imbalances, heavy metal intoxication, and toxic pollutant burden. Also, evidence is mounting that abnormal thyroid responsiveness, perhaps engendered perinatally by environmental pollutants, is on the rise and predisposes to ADHD. [ 35 ]
ADHD has been linked to inherited susceptibilities; for a critical review refer to Tannock. [ 5 ] Findings from twin studies and adoption studies support some degree of heritability for the disorder, [ 32 ] though co-morbid conditions complicate the analyses. Numerous familial-genetic studies have documented a higher prevalence of psychopathology, particularly ADHD, in the parents and other relatives of children with ADHD, and there is a statistically and clinically significant risk for ADHD to occur in children where either biological parent had onset in childhood. [ 36-40 ] Sophisticated studies confirm a higher incidence of ADHD in the closest relative of ADHD males. [ 5 ]
The actual degree to which genetic heritability may predispose to childhood onset of ADHD is still an open question. Population studies indicate attentional problems, conduct problems, and emotional problems tend to cluster within families. [ 41 ] Genetics and environment are notoriously difficult to separate within the family unit, and Fisher suggested the genetic predisposition to ADHD might fuel a negative family atmosphere that exacerbates latent ADHD in the child. [ 19 ]
Twin and adoption studies are generally the most precise means for estimating relative heritability of a trait. Such studies in ADHD suggest a relatively high degree of heritability. [ 5 ] They also suggest that rather than being a discrete disorder, ADHD may be viewed as the extreme end of a behavior continuum that varies genetically throughout the population. [ 42 ] Both inattention and impulsivity/hyperactivity appear to be heritable and share a genetic component, [ 39, 43 ] but no one gene is likely to be the culprit.
Important advances have been made in the pursuit of genes for ADHD. [ 5 ] To date, the evidence for single-gene inheritance is unconvincing; rather, a polygenic mode of inheritance is more likely-either several strong genes or many genes with weak effect. Genes within the dopamine transmitter system are the most likely to be most involved, given: (1) the effective reduction of symptoms by dopamine agonists such as methylphenidate; (2) results from brain imaging studies that implicate brain structures with rich dopaminergic innervation, such as the frontostriatal circuitry; [ 44 ] and (3) early results from gene isolation studies. [ 5 ]
The heritability of the associations between ADHD and its various co-morbid conditions may span the entire spectrum of possibilities. Biederman and his colleagues suggest ADHD and major depressive disorders may have common familial vulnerabilities. [ 22, 23 ] ADHD with co-morbid conduct disorder also may be preferentially associated, whereas the anxiety and learning disorders may segregate separately. ADHD relatives of patients with ADHD do have markedly higher risk for major depressive disorder, antisocial disorders, and substance abuse. To date there is insufficient data to quantify any relative degree of co-heritability of ADHD with a trait for any of these co-morbid conditions.
Food Additives and Food Intolerances in ADHD
In the mid-1970s, Feingold broke new ground with his claim that up to 50 percent of all hyperactive children were sensitive to food additives (artificial food colors, flavorings, and preservatives) as well as to salicylates that occur naturally in some foods. [ 45, 46 ] Feingold's basic finding of the connection between food additives and ADHD symptomatology was not new. As early as 1922, Shannon had published on the successful treatment of children with hyperactivity and learning disorders using an elimination diet. [ 47 ] On this regimen 30-50 percent of children improved. Most recently, Schardt reviewed 23 double-blind studies that examined whether food dyes or ordinary foods worsened behavior in children with ADHD or other behavioral problems. [ 48 ] In eight of the nine studies conducted with ADHD children, the behavior of some children worsened after consumption of food dyes or improved on an additive-free diet. The symptomatology of these adverse responses mimicked ADHD.
The other 14 studies reviewed by Schardt looked at children with ADHD plus asthma, eczema, or food allergies, irritability or sleep disturbances, or more severe behavioral or neurological disorders. In 10 of the 14 studies, some children improved when they ate diets free of additives or certain foods. Some deteriorated when they ate food dyes or foods like corn, wheat, milk, soy, oranges, eggs, or chocolate. Schardt concluded his critique with suggestions from experts that dietary modification be systematically attempted before the decision is made to place an ADHD child on a pharmaceutical regimen.
Feingold's original case histories covered 1,200 pediatric cases in which food additives were linked to behavioral and learning disorders, and pointed the finger at some 3,000 different additives, yet subsequent research to "verify" his work focused on less than a dozen additives. The majority of the double-blind studies designed to test Feingold's hypothesis reported their outcomes as negative, yet a careful review of the data from these studies by Murray and Pizzorno concluded that a full half of the children placed on the Feingold diet in these studies actually showed a decrease in hyperactivity. [ 49 ] A pattern is evident, as discerned by Boris: single-agent elimination studies tended to show limited improvement or no improvement at all, while multi-agent elimination studies were almost universally successful. [ 50, 51 ]
Rippere has criticized in depth [ 52, 53 ] the methodologies of the "double-blind" studies conducted by Conners and other critics of Feingold. [ 54, 55 ] She points out: (a) the conscious design of active, potentially allergenic placebos (such as chocolate cookies); (b) the decisions to use dosages of test additives lower than known to be consumed in foods; (c) the use of highly unreliable laboratory tests for allergy determination; and (d) formulation of imprecise rating scales as outcome measures. Perhaps the most serious criticism by Rippere is that of investigator bias; i.e., the researchers ignored study outcome data that supported the Feingold interpretation while overemphasizing contrary data. Boris, [ 50, 51 ] Weiss, [ 56, 57 ] Crook, [ 58-61 ] Egger, [ 62,63 ] and others have conducted their own studies and trials, reviewed the cumulative data, and come out in support of the Feingold hypothesis. It is interesting to note that studies conducted in non-U.S. countries produced results markedly more favorable to the Feingold interpretation, [ 49 ] and that most of the U.S. investigations were sponsored by a corporate food lobby group, the Nutrition Foundation.
Food additives are big business, especially in the United States (see Murray and Pizzorno for an overview). [ 49 ] There are some 5,000 additives in widespread use, including but not limited to: anticaking agents such as aluminosilicates; synthetic antioxidants such as BHA and BHT; bleaching agents such as hydrogen peroxide; colorants such as artificial azo dye derivatives; preservatives such as benzoates, nitrates, and sulfites; and many others. Per capita daily consumption of food additives in the U.S. is 13-15 grams, and the population's total annual consumption of food colors alone is approximately 100 million pounds. Other countries have significantly restricted artificial food additives whereas the United States has never done so.
The removal of artificial food colorings and preservatives from the diet is an indispensable and practicable clinical intervention in ADHD, but rarely is sufficient to eliminate symptomatology. Up to 88 percent of ADHD children react to these substances in sublingual challenge testing, [ 49 ] but in blinded studies no child reacted to these alone. Allergies to the foods themselves must also be identified and eliminated. Doris Rapp, MD, a pediatrician with considerable experience in this area, has claimed that two-thirds of children diagnosed ADHD have unrecognized food allergies that generate most, if not all, of their symptoms (see Fig. 2). These can usually be detected and the symptoms cleared using a simple one-week elimination diet. She has thoroughly documented her findings in books, professional articles, and videotapes. [ 64-66 ]
Data from two double-blind studies indicated 73-76 percent of ADHD children responded favorably to food elimination diets. [ 61, 67 ] Maintenance on even more-restricted, low-antigen (oligoantigenic) diets raised the success rate to as high as 82 percent. [ 62, 63, 68 ] Invariably in these studies, reintroduction of the offending foods led to reappearance of symptoms.
Sugar intake makes a marked contribution to hyperactive, aggressive, and destructive behavior. [ 49, 61, 69 ] A large study by Langseth and Dowd found 74 percent of 261 hyperactive children manifested abnormal glucose tolerance in response to a sucrose meal. [ 70 ] Other studies have been conducted, but industry interests may have influenced their outcomes in a manner inconsistent with good scientific research.
Wolraich and collaborators conducted a trial on sugar and hyperactivity that was published in the New England Journal of Medicine in 1994. [ 55 ] The findings were portrayed by the study investigators and the media as proving that sugar did not significantly contribute to hyperactivity. Yet the control, "low-sugar" diet averaged 5.3 teaspoons of refined sugar per day, fed to children aged 6-10 years. This "baseline" level of sugar intake is arguably so high that the investigators should not have been surprised the "test" group on a higher sugar diet did not show significantly more symptoms than the "controls." No attempt was made to eliminate dietary allergens such as milk, wheat, and egg, which trigger behavioral problems in some hyperactive children, and all the children were allowed to consume soda drinks during the study. At the end of their report, the authors acknowledged their gratitude to General Mills, Coca-Cola, PepsiCo, and Royal Crown.
Roles of Nutrient Deficiencies and Imbalances
Nutrients are required by the brain, as they are by every other organ, so virtually any nutrient deficiency can impair brain function. [ 49 ] Assessment of ADHD children often reveals nutrient deficiencies or imbalances which, when corrected, result in considerable behavioral and academic improvement. Little controlled research has been conducted into dietary supplementation effects on ADHD, but the sparse data available do indicate significant potential for benefit in this realm. This subject recently was reviewed by Galland. [ 106 ]
Multiple vitamin-mineral supplements
Dietary supplementation can improve academic performance in healthy school-aged children. In a series of studies that spanned 18 years and culminated in a double-blind trial, Schoenthaler et al found that a vitamin-mineral supplement produced significantly less antisocial behavior than did placebos in healthy elementary school children and teenage delinquents. [ 107 ] Cognitive performance also was significantly improved, but the researchers found no clinical improvement could be expected unless at least one nutrient was abnormally low by blood test. Pyridoxine, folic acid, thiamin, niacin, and vitamin C were the nutrients most commonly found to be low in children who responded to supplementation with measurable improvement. Deficiencies of vitamins A, E, B12, pantothenic acid, riboflavin, and of minerals also were linked to bad behavior. Improvement could not be expected unless all deficiencies were corrected.
B Vitamins in Combination
Two early controlled trials utilized combinations of B vitamins against ADHD and reported no benefit. [ 108,109 ] Later, Brenner successfully used B vitamin combinations to treat hyperkinetic children who had not responded favorably to Feingold's diet. [ 110 ] They also found that ADHD children responded variably to different B vitamins, with pyridoxine and thiamine antagonizing each other's benefits. Treatment with single B vitamins rather than combinations may sometimes be necessary in order to normalize lowered blood levels and selectively increase transmitters in ADHD; for example, pyridoxine can be used to normalize lowered blood serotonin. [ 106 ]
Vitamin B6 (pyridoxine)
This vitamin might help ameliorate hyperactivity, as indicated from widespread physician experience and one small double-blind trial conducted to date. Vitamin B6 is an essential cofactor for a majority of the metabolic pathways of amino acids, including decarboxylation pathways for dopamine, adrenaline, and serotonin. In 1979, Coleman et al reported that B vitamins improved the behavior of some children with ADHD in a double-blind crossover comparison with methylphenidate. [ 111 ] Coleman's group took note of physician observations that in some hyperactive children blood serotonin levels are low, and that high-dose B6 often benefited the symptoms while boosting serotonin into the normal range. They investigated six children ages 8-13, diagnosed with Hyperkinetic Reaction of Childhood (DS-II) and known to be responsive to methylphenidate. In a double-blinded, multiple crossover trial, each child received placebo, low and high doses of methylphenidate (averaging 10.8 mg/day and 20 mg/day, respectively), and low and high doses of B6 as pyridoxine (averaging 12.5 mg/kg/day and 22.5 mg/kg/day) over 21 weeks. Blood serotonin levels increased dramatically on B6, and teacher ratings showed a 90 percent level of statistical trend in favor of B6 being slightly more effective than methylphenidate.
Iron
This is the most common of all nutrient deficiencies in U.S. school-age children.49 Iron deficiency is associated with markedly decreased attentiveness, narrower attention span, decreased persistence, and lowered activity levels, which respond positively to supplementation. An uncontrolled Israeli study of boys with ADHD found a 30 percent improvement in Conners Rating Scale scores following iron supplementation. [ 112 ]
Magnesium
According to Galland,106 the magnesium deficiency status often observed in ADHD is reminiscent of Latent Tetany Syndrome, which features lowered red cell levels of the mineral. This disorder is believed related to three factors: inadequate dietary magnesium (Mg) intake, genetic susceptibility, and the Mg-depleting effects of catecholamines and related stress hormones which are elevated in the blood and urine of ADHD children. A Polish team reported reduced Mg levels in 95 percent of a group of 116 children with ADHD; [ 113 ] dietary supplementation with Mg significantly decreased their hyperactivity. [ 114 ]
Zinc
Several studies conducted in different countries have found this mineral to be low in ADHD (for references see Galland).106 Serum zinc can be markedly below normal, [ 115 ] and also urinary zinc clearance can be lower; both findings suggestive of poor zinc intake and/or absorption. Findings from one placebo-controlled trial suggest poor zinc status also may predict poor response to amphetamine treatment of the disorder. [ 116 ]
Essential fatty acids (EFA)
These oily, vitamin-like nutrients have shown promise in the non-pharmaceutical management of ADHD. The two main classes-omega-3 and omega-6-have a complementary, "yin-yang" relationship, functioning as pro-homeostatic constituents of cell membranes and as precursors to smaller molecules (eicosanoids) that transduce information inward to the cell interior, and outward from each cell to influence other cells. The longer-chain, 20- and 22-carbon species are both crucial for prenatal and postnatal early brain development. Some adult humans can generate the longer-chain molecular species from the shorter-chain, but infants are less competent in this regard. [ 117 ] The C22:6 omega-3 (docosahexaenoic acid, DHA) and the C20:4 omega-6 (arachidonic acid, AA) are homeostatically balanced in human mother's milk, and both are now added to infant feeding formulas.
One reliable symptom of EFA deficiency in both animals and humans is excessive thirst (polydypsia), without matching polyuria. Colquhoun and Bunday, [ 118 ] working with the Hyperactive Children's Support Group of the United Kingdom, were the first to report that children with hyperactivity were significantly more thirsty (and without comparable polyuria) than children who were not hyperactive. Mitchell et al [ 119 ] measured plasma fatty acids in 44 hyperactive children and 45 matched control subjects, and found the hyperactive children had significantly lower concentrations of DHA, AA, and the AA precursor DGLA (dihomo-gamma linolenic acid, C20:3 omega 6). Stevens et al [ 120 ] extended these promising results, and Stordy correlated the symptoms with omega-3 deficiencies and learning disabilities. [ 132 ]
Stevens and her collaborators at Indiana University measured plasma and red cell fatty acid levels in 53 boys with ADHD and 43 controls, aged 6-12 years. [ 120 ] They also took detailed histories, compared clinical symptom patterns, and tracked daily dietary EFA intakes. They confirmed Mitchell's earlier report [ 119 ] of lowered plasma concentrations of DHA and AA (but not of DGLA); and found plasma eicosapentaenoic acid (EPA, C20:5 omega 3) was decreased, as was red cell arachidonic acid. As tracked by the parents, the ADHD group had significantly greater thirst, frequency of urination, and dry skin-all indicators of EFA deficiency-than did the control subjects. [ 121 ] Within the ADHD group, a subgroup with higher scores for EFA deficiency also had the lowest levels of plasma EFA. [ 124 ]
The omega-6 fatty acid GLA (gamma-linolenic acid) is a metabolic precursor to AA. [ 141 ] GLA was administered to ADHD children in two placebo-controlled studies. In the first, parents' ratings suggested benefit from GLA but teachers' ratings did not. [ 122 ] In the second, parents' ratings did not suggest benefit but one teachers' rating of benefit-the Conners Hyperactivity Factor-did achieve statistical significance. [ 123 ] Future studies might be more definitive if objective measures are taken to establish EFA status and if mixed omega-3 and omega-6 long-chain fatty acid preparations are administered.
The polyunsaturated, long-chain DHA and AA affect the biological and physical properties of cell membranes, as well as the functionality of numerous important membrane proteins. The biochemical fates of DHA and AA are structurally and functionally intertwined with the phospholipid substances that make up the bulk of the cell's membrane systems.
Phosphatidylserine (PS) and Other Phospholipids [ 105 ]
Most of the reactions that collectively amount to life occur on or in cell membranes. These are the physical-chemical entities on which the vast majority of the cell's enzyme assemblies are mounted. The phospholipids (PL) are the main foundational molecules for all cell membranes, serving much as building blocks for the membrane matrix into which the proteins are inserted. Within the membrane, the phospholipid (PL) molecules act as "parent" molecules for the long-chain, essential fatty acid molecules. They hold the EFA in position within the membrane, enabling enzymes of the membrane to metabolize the EFA to eicosanoids and other regulatory messenger molecules as appropriate.
Of the phospholipids, phosphatidylcholine (PC) is quantitatively the most common in all membranes. PC is also the body's main reservoir for choline, a small amine that is a component of the neurotransmitter acetylcholine. The PC precursor dimethylaminethanol (DMAE) is a major substrate for making PC in the body; it can have a stimulant-type action in the ADHD brain, and has been used with moderate success in the treatment of children with ADHD and developmental disorders. [ 125 ] DMAE does have adverse side-effects at high doses,126 but was effective against "hyperkinesis" in one double-blind trial and against learning disorders in another. [ 125 ]
Phosphatidylserine (PS) is clinically proven to benefit a wide range of brain functions. [ 105 ] This phospholipid occurs in the brain at far higher concentrations than it does in the other organs. It is a key constituent of nerve cell synaptic membranes, which are deeply involved in the production of neurotransmitters, their packaging for subsequent release, and their action via receptors located at the synaptic junctions. Ingested as a dietary supplement, PS energizes the human brain, facilitating synaptic connectivity and specifically boosting dopamine transmitter functions, i.e., its production, release, and postsynaptic receptor actions. In a physician in-office study of 21 consecutive ADHD cases aged 4-19, dietary supplementation with PS benefited greater than 90 percent of the cases. [ 127 ] At intakes of 200-300 mg/day of PS for up to four months, attention and learning were most consistently improved. Oppositional conduct proved most resistant to PS treatment.
Other Nutrients
Many of the neurotransmitters are metabolically derived from amino acids. Analyses of plasma amino acid levels determined that phenylalanine, tyrosine, tryptophan, and isoleucine were lower in ADHD patients than in controls. [ 128 ] In adults with ADHD, L-tyrosine treatment produced transient improvement. [ 128, 130 ] Also in ADHD adults, S-adenosyl methionine seemed beneficial in one small, short-term, uncontrolled study. [ 131 ]
A complex mixture of bioflavonoids (oligomeric proanthocyanidins or OPCs), which have potent antioxidant activity, were reported to benefit ADHD in an undisclosed proportion of children seen in a pediatric practice. [ 133 ] The symptom clusters related to attention and distractibility seemingly responded more significantly than hyperactivity and impulsivity. Side-effects were said to be minor.
Many among the wholistic/integrative practitioners who have substantial experience with ADHD believe intestinal dysfunction and dysbioses are important contributors to ADHD symptomatology. A proprietary mixture of oligosaccharides, which sometimes serve as substrates for probiotic intestinal bacteria, was reported to decrease the severity of ADHD in children during a six-week observation period. [ 134 ]
With the numerous nutrient deficiencies documented in ADHD, and the promise offered by a range of nutrients in controlled and non-controlled clinical trials, Galland's approach is a proven blueprint for success. [ 79, 106 ] He tests for signs and symptoms of EFA deficiencies, and corrects these through supplementation. Using a similar approach, he selects candidates for magnesium therapy. With the B vitamins, to avoid the potential for paradoxical responses he suggests careful titration using individual vitamins rather than beginning with mixtures; e.g., pyridoxine first, followed by thiamine, then by the others one by one. Serum ferritin and hair zinc levels can be useful as rough guides for supplementation with these minerals. In his view the nutrients PS and DMAE are particularly deserving of further study, especially for those ADHD children with learning disabilities. [ 106 ]
Developing an Integrative Treatment Model
Modalities for medical management of ADHD, other than the use of psychostimulants, have historically been minimized by the medical mainstream. Even so, ADHD has become a testing ground for modern wholistic/integrative medical management, at least as an alternative to the current "mainstream" predilection for carte blanche prescription of methylphenidate.
Safer and more effective treatment options are readily available to the interested practitioner; when combined and individualized to the ADHD child the success rate approaches 100 percent. First in order is dietary revision: removal of food additives, sensitizing foods, and sugar (sucrose) from the diet invariably results in some degree of improvement.[ 135-137 ] Then the child should be thoroughly assessed for allergies, nutrient deficiencies, and intolerances to foods and chemicals. The toxic burden should be assessed and corrected, including lowering the body burden of organics[ 78 ] and potentially toxic metals.[ 71 ] Lead contamination is an obvious culprit in some cases of hyperactivity; aluminum cookware and silver-mercury dental fillings should be avoided.
In ADHD every effort should be exerted to pursue the benefits from dietary modification and nutrient supplementation prior to resorting to psychostimulant pharmaceuticals. One clear benefit is that nutrients predictably have broader effect spectra and superior benefit-to-risk profiles. The foundational, pro-homeostatic benefits afforded by vitamins, minerals, essential fatty acids, phospholipids, and other nutrients to brain function would seem more compatible with the wide range of behavioral and cognitive symptom overlap seen in the ADHD population. Pharmaceuticals, by contrast, are mechanistically much more exclusive and therefore demanding of more precise symptom differentiation and diagnosis. Up to this point, nutrients and nutrient combinations have not been given a fair evaluation against ADHD and its constellation of co-morbid conditions.
For the practitioner managing ADHD, making a commitment to explore dietary supplementation as a treatment modality does not mean abandoning the use of stimulants and other pharmaceutical medications. The use of nutrients for symptom control in ADHD is not incompatible with the use of drugs; nutrients are compatible with drugs to a degree far superior to the compatibility of drugs with other drugs.
Charles Gant, MD, PhD, is one practitioner who has evolved from an allopathic philosophy of medical practice to a fully integrative practice for managing ADHD. He has advocated striking a balance between the conventional approaches to treating ADHD, with the strikingly bad drug side-effects involved, and the safer though less formally established, "alternative" or "complementary" approaches. Gant continues the tradition of other wholistic/integrative physicians who employ a wide spectrum of modalities to successfully treat ADHD.[ 49,58-61,64-66,79,106,136,137 ]Gant's idealized "nine-point" program is summarized in Fig. 4.
Gant does an intake screening on the patient suspected of having ADHD and searches for seven target symptoms-hyperactivity, impulsivity, inattention, mood lability, temper outbursts, disorganization, and stress sensitivity. He then applies the more extensive DSM-IV diagnostic criteria,1 and with the diagnosis established he proceeds with his "Ideal Protocol" as summarized in Figure 4. He treats approximately 50 percent of his ADHD patients with antibiotics and other medications, mostly to remove gastrointestinal dysbiotic organisms and to chelate heavy metals.
Many children presenting with mental and behavioral abnormalities have intestinal bacterial imbalances from antibiotic overuse, as from treatment for ear infections, which are a proven risk factor for ADHD.[ 61 ] These children tend to have impaired speech and language development, and may have a two-fold higher risk of becoming learning disabled.[ 49 ] Gut dysbiosis-imbalances of the symbiotic bacteria, presence of nematode or protozoan parasites, yeast (Candida) overgrowth caused by antibiotic overuse-once corrected can manifest as multisystem improvement, including sometimes marked clearing of the mental-behavioral symptoms.[ 61 ] Fungi and their metabolites also play a role, and can be detected and treated.[ 138 ]
To most effectively treat ADHD, the integrative medical practitioner must also work closely with the subject and/or the parents to further eliminate toxic metals (e.g., lead, mercury) and chemicals (including cigarette smoke, home building materials, pesticide-contaminated foods, lawn and garden chemicals, etc.) from the child's environment-this can have the added benefit of improving the parents' health. Allergies must be tested for and eliminated, whether of the food-related or the inhalant type (pollen, mold, dust, volatile chemical).
The next phase in the integrative medical management of ADHD is to identify and correct nutrient deficiencies, especially of minerals (iron, magnesium, zinc, selenium, others); essential fatty acids; B vitamins; and other nutrients on a case-by-case basis. By this point the vast majority of hyperactive ADHD children are likely to be noticeably improved.
Objective testing of patients undergoing treatment for ADHD is important. Continuous performance tests (CPT) measure response preparation, planning and inhibition, and neuropsychological performance via the frontal lobes. CPT involve a period of testing during which numbers or letters are presented in rapid sequence on a computer screen and the subject is asked to respond selectively to them. Errors of omission are felt to represent inattention, while errors of commission (premature responses) may represent impulsivity; the total number of correct responses is thought to represent capacity for sustained attention. The IVA (Intermediate Visual and Auditory) CPT is probably the best of these. In two pilot projects, Harding, Judah and Gant used the IVA CPT to objectively assess improvements in ADHD children not sorted for co-morbidity.[ 135 ] They treated with methylphenidate or via nutraceutical interventions, and with or without their usual full workups for metal toxicity, gut dysbiosis, allergies and intolerances, and nutritional deficiencies prior to intervention. They found nutraceutical management was statistically superior over pharmaceutical management for improving response control and attention, including cases where the in-depth workups were NOT carried out.
After 3-6 months of testing-retesting and calibrating nutritional corrections, the use of medication may be considered if the child has not significantly improved or continues to be particularly impaired or oppositional. In any case, lower doses of medication can be used, and titrated upward only as necessary to meld with the benefits evident from the other interventions. The responsible integrative physician will use medication only when the non-pharmacologic protocols have been exhausted; Crook suggests that the non-allergic, non-hyperactive ADHD children are the subpopulation most likely to benefit from stimulant medication.
ADHD in the Future
The current extreme diversity of professional opinion about ADHD-whether debating the many possible contributory factors, speculating on its neuropsychology and neurobiology, dogmatically supporting or opposing the use of stimulant medications, spawning honest disagreement as to whether the disorder truly exists-promises to continue into the future. Some of the areas of controversy should soon take on new clarity, most notably the neurobiology of ADHD.
As the 1990s progressed, emphasis began to shift away from a purely "attentional deficit" as underlying ADHD, to a perhaps "intentional" deficit involving inappropriate response to an incoming stimulus, or a more delocalized deficit in the development of the inhibition of behavior.[ 5,40 ] Increasingly it is becoming evident that ADHD subjects do pay attention, and do receive stimuli, but may have trouble processing the information and formulating an appropriate response.
With more research into the neurobiology of ADHD, more focused wholistic/integrative treatment regimens might be forthcoming. Increasing controversy over the widespread use of methylphenidate and possible life-threatening effects from its long-term use make it essential that complementary/alternative treatment regimens be implemented for ADHD management. Correction of nutrient deficiencies commonly found in these patients, along with dietary modification, allergy treatment, detoxification, correction of intestinal dysbiosis, family counseling, and behavior therapy can ameliorate symptomatology and allow the child diagnosed with ADHD to lead a normal and productive life.
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