attention deficit/hyperactivity disorder (adhd) in …attention deficit/hyperactivity disorder...

Alternative Medicine Review ◆ Volume 5 Number 5 ◆ 2000

Copyright©2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

Parris Kidd, PhD (Cell biology, University of California at Berkeley) – Contributing Editor, Alternative Medicine Review;Health educator and biomedical consultant to the supplement industry. Correspondence address: 847 Elm St, El Cerrito,CA 94530

Attention Deficit/Hyperactivity Disorder(ADHD) in Children: Rationale for Its

Integrative Management

IntroductionAttention 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 asa 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 notunderstood, yet potent drugs are being employed for its medical management while safe and

Parr is M. Kidd, PhD

AbstractAttention Deficit/Hyperactivity Disorder (ADHD) is the most common behavioral disorderin children. ADHD is characterized by attention deficit, impulsivity, and sometimesoveractivity (“hyperactivity”). The diagnosis is empirical, with no objective confirmationavailable to date from laboratory measures. ADHD begins in childhood and often persistsinto adulthood. The exact etiology is unknown; genetics plays a role, but major etiologiccontributors also include adverse responses to food additives, intolerances to foods,sensitivities to environmental chemicals, molds, and fungi, and exposures toneurodevelopmental toxins such as heavy metals and organohalide pollutants. Thyroidhypofunction may be a common denominator linking toxic insults with ADHDsymptomatologies. Abnormalities in the frontostriatal brain circuitry and possiblehypofunctioning of dopaminergic pathways are apparent in ADHD, and are consistentwith the benefits obtained in some instances by the use of methylphenidate (Ritalin®)and other potent psychostimulants. Mounting controversy over the widespread use ofmethylphenidate and possible life-threatening effects from its long-term use make itimperative that alternative modalities be implemented for ADHD management. Nutrientdeficiencies are common in ADHD; supplementation with minerals, the B vitamins (addedin singly), omega-3 and omega-6 essential fatty acids, flavonoids, and the essentialphospholipid phosphatidylserine (PS) can ameliorate ADHD symptoms. Whenindividually managed with supplementation, dietary modification, detoxification,correction of intestinal dysbiosis, and other features of a wholistic/integrative programof management, the ADHD subject can lead a normal and productive life.(Altern Med Rev 2000;5(5):402-428)


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effective alternatives are being neglected.2,3

ADHD is the most prevalent behavioraldisorder in children,4 and frequently itssymptoms are commingled with learningproblems, oppositional conduct, anddepression, which altogether compound thefamily’s emotional burden. Particularly sincethe dominant mode of treatment to date hasinvolved the drug methylphenidate (Ritalin®),which acts on the CNS much like cocaine andhas marked potential for severe side-effectsand addictive abuse, ADHD has become alightning rod for controversy. The scientificliterature on ADHD is voluminous, with morethan 4,000 peer-reviewed articles publishedsince 1966.5

An intense debate has developedaround the diagnosis, etiology, and medicalmanagement of ADHD. Parent groups, con-sumer advocacy organizations, and progres-sive physicians are calling for alternatives tomethylphenidate and the many other potentstimulants used to treat ADHD, while phar-maceutical interests and physicians particu-larly oriented to prescribing pharmaceuticalsattempt to defend the status quo (currently inthe United States, between 1.5 million and 3million ADHD children are likely taking me-thylphenidate). This review is intended to bringthe medical and scientific issues surroundingADHD into sharper focus, to better define awholistic/integrative strategy for its medicalmanagement.

Background and Scope of theADHD Problem

A condition in children somewhat re-sembling ADHD was first described by Stillin 1902.6 He discussed 43 cases of childrenwith aggression, defiance, emotionality, lim-ited sustained attention, and deficient rule-gov-erned behavior. Although his population pos-sessed normal intellectual capacity, he com-mented, “...the control of activity in confor-mity with moral consciousness is markedly

defective.” He suggested, “inhibitory volition,”that is, the capacity to exercise good judgment,might be imperfectly developed in these sub-jects. From 1940 through 1960, the conditionwas identified with “minimal brain damage ordysfunction,” and its etiology was speculatedto be insults to the brain such as head injury,infection, and toxic damage.6 In the 1960s itbecame “hyperactivity” or “poor impulse con-trol,” reflecting that no underlying organicdamage had been identified.

By the 1970s-1980s, the “hyperactiv-ity” symptomatology had taken on more di-agnostic significance in comparison with theother symptoms. In 1980, the American Psy-chiatric Association’s Diagnostic and Statisti-cal Manual of Mental Disorders, Third Edi-tion (DSM-III) listed the term “hyperkineticreaction of childhood,” which then evolvedthrough “hyperkinetic syndrome” and “hyper-active child syndrome,” to “attention deficitdisorder” (ADD), either “with hyperactivity”or “without hyperactivity.” By 1987, in therevised DSM-III (DSM-III-R), the earlier fo-cus on hyperactivity had shifted toward inat-tention and impulsivity.7

As the research on ADHD progressed,the balance between the three major diagnos-tic symptom clusters was subsequently furtherrefined, so that in the 1994 DSM-IV the offi-cial term was Attention Deficit/HyperactivityDisorder, or ADHD, with three subtypes.1 In-attention and impulse control are now regardedmore as the cardinal defects than is hyperac-tivity.5 Some professionals continue to reservethe term ADD for children who are only inat-tentive and ADHD for children who are alsohyperactive, but all official reports or otherrecords are required to use ADHD.

ADHD is usually diagnosed in school-age children, and is conservatively estimatedto occur in 3-6 percent of this population fromdiverse cultures and geographical regions.5,8-

12 In some U.S. cities the percentage may reach10-15 percent.8 As of 1993, more than twomillion U.S. children were diagnosed ADHD,

Alternative Medicine Review ◆ Volume 5, Number 5 ◆ 2000


the number having increased steadily from902,000 in 1990. Currently, as many as fourmillion carry this diagnosis, which is respon-sible for 30-50 percent of the referrals to men-tal health services for children.9,10 Elsewhere,ADHD estimated prevalence ranges from 1.7-10.0 percent in Canada, Puerto Rico, theUnited Kingdom, Norway, the Netherlands,Germany, and New Zealand.10-12 ADHD rou-tinely continues into adolescence, and also canpersist into adulthood in as many as half ofthose individuals who manifest the disorderin adolescence.10

The adverse social, familial, and per-sonal consequences of ADHD cannot be over-stated. Most ADHD subjects develop emo-tional, social, and family problems as a con-sequence of their primary difficulties. ADHDis a major problem both for society and forthe child, as it causes friction in school or atthe workplace, depresses the academic perfor-mance of the student’s entire class, interfereswith peer relationships, and increases intra-family stress. For the individual afflicted, un-til ADHD symptomatologies can be recog-nized and brought under medical management,daily existence is likely to be severely com-promised along with the lives of those aroundhim (or her, although ADHD is more preva-lent in boys by a 3:1 margin).5 Parents andchildren express desperation for interventionsthat will work, but without the adverse effectsinflicted by the pharmaceutical managementmodel.

The first report of stimulant use to treatADHD was in 1937.13 The current overwhelm-ing reliance on methylphenidate and otherstimulants for ADHD treatment belies theample evidence that ADHD symptomatologiescan be ameliorated without the use of drugs.This degree of reliance on methylphenidate isunfortunate because its action is virtually iden-tical with cocaine, to such an extent that in theUnited States it is a Schedule II controlleddrug.14-16 The frequent practice of maintainingADHD 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 overmethylphenidate use and the ever-increasingfrequency of ADHD diagnosis are now so po-liticized that they are interfering with society’surgent need to better serve the children (andadults) involved. Fortunately, a balanced ex-amination of the available scientific and clini-cal evidence reveals an improved prognosis forADHD.

The Diagnosis and Progression ofADHD

No matter how well trained the physi-cian may be in this area, making the diagnosisof ADHD is anything but straightforward. No“hard” clinical tests—physical, laboratory, orneurological—are available with which tounequivocally correlate the symptoms. Rather,the definitive diagnosis must be deduced froma highly detailed clinical history, as synthe-sized from information provided by parents,teachers, and (last but hopefully not least), theafflicted individual.18,19 The conscientious cli-nician will do an in-depth parent and patientinterview along with a physical examination,solicit corroborative information from adultsin other settings (especially teachers), and ob-tain an assessment of academic functioning.Many clinicians use standardized rating scalesin order to assess the age- and sex-matchedrelative symptom severity.18,20

For U.S. practitioners official ADHDdiagnostic guidelines are found in the DSM-IV, which is related to the World HealthOrganization ICD-9 and ICD-10 categories.1,21

In North America, ADHD is viewed as acommon but heterogeneous developmentaldisorder linked with diverse co-morbidities. Bycontrast, in Europe the diagnosis (i.e., ofhyperkinetic syndrome) is reserved for ADHDuncomplicated by co-morbidpsychopathology. With this relatively narrowdefinition the condition becomes relativelyrare, but the European perspective appears to

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be gradually shifting toward that of NorthAmerica.5

The symptoms of ADHD are most of-ten first recognized by the child’s teacher.ADHD children have difficulty sitting still,maintaining their attention on the task at hand,and thinking through their answers before theyrespond to questions. Although ADHD is dis-tinctly different from learning disability perse, the behavioral features that define this dis-order—short attention span, distractibility,impulsivity, overactivity—occur on a con-tinuum across the population, thus the ADHDdiagnosis requires thorough consideration ofthe severity of the symptoms and the relativedegree of functional impairment.

ADHD per DSM-IV is diagnosed infive major steps, each with specific criteria.1

The symptoms must appear before age seven,persist for at least six months, and appear inthe school environment as well as the home.The first step is to establish EITHER (a) ab-normal and persistent inattention, from at leastsix symptoms continuing over a minimum sixmonths, OR (b) abnormal and persistent hy-peractivity-impulsivity, also from at least sixsymptoms over six months. The second stepis to establish that these symptoms werepresent before seven years of age. Third, thesesymptoms must be present in two settings,usually at school (or work, if an adult) and athome. Fourth, there must be clear evidence of“clinically significant impairment in social,academic, or occupational functioning.” Thefifth criterion is exclusionary—that the symp-toms not be secondary to some other disorder.Whereas some of the ADHD symptomatolo-gies can be linked to family changes (e.g., di-vorce) or other life events (e.g., head trauma),ADHD typically begins early in life, is chronic,and is pervasive.

Once the basic ADHD diagnosis is es-tablished per the above-described criteria,three subtypes can be differentiated.1 These are(1) ADHD, combined type, applied where bothinattention and hyperactivity-impulsivity—(a)

and (b) above—are extant for at least 6 months;(2) ADHD, predominantly inattentive type, ifonly the inattention criteria are met; and (3)ADHD, predominantly hyperactive-impulsivetype, if only the hyperactivity-impulsivity cri-teria are met. There is also a DSM-IV crite-rion of ADHD In Partial Remission, for indi-viduals (usually adolescents or adults) whoexhibit only some of the required symptomsbut are otherwise experiencing significantfunctional impairment. Then come the assess-ments for the learning disabilities and otherneurologically based disorders with whichADHD is often associated.

Between 30-40 percent of ADHD sub-jects have learning disabilities,18,19 but theADHD child is not mentally retarded and canbe realigned toward a productive life path. Tohelp make this possible the physician and theother professionals involved must work closelywith parents and teachers to assess the childas a total individual. They must objectivelydiscern the entire range of difficulties the childis experiencing, and make the degree of com-mitment necessary to treat the childwholistically with all the resources available.Unfortunately, the current norm for ADHDmanagement is to do a minimal psychologicalassessment, then prescribe methylpheni-date.2,3,19

Other neurobiological difficulties en-countered in the ADHD population are motortic disorder or Tourette’s disorder, anxiety dis-order, anger control problems, and depres-sion.22,23 Some children will have two, three,or more of these difficulties without havingADHD, but Biederman studied a large popu-lation of ADHD children and found that morethan half also had depression, anxiety, andconduct disorder.23 The clinician must there-fore verify, document, and prioritize these vari-ous symptom clusters, both to assess their rela-tive contributions to the child’s apparentADHD patterns and to develop means for theirmedical management concurrently withADHD.



ADHD Medical Management—Current Status

The conventional management ofADHD formally involves a multimodal ap-proach.18,19,23-25 Currently, this approach in-cludes individual and family education, coun-seling, behavioral therapy, school remediation,and medication.24 Close coordination betweenthe subject, the family, the practitioner and theschool system ought to be integral to this ap-proach, but in mainstream pediatric practicemedication with pharmaceuticals is practicallythe sole component of medical management.25

Typically, it falls on the family of the afflictedchild to implement additional modes of man-agement that have proven effectiveness, suchas clearing allergies, regulating the diet, andsupplementing with nutrients.

Psychostimulant medications are gen-erally the first choice in medication of ADHD.Approximately 70 percent of the childrentreated show improvement in the primaryADHD symptoms and in co-morbidity suchas conduct disorder,24,25 although the benefitsmay not hold beyond two years. Currently,methylphenidate is the drug of choice; otherfirst-line stimulants include dextroamphet-amine (Dexedrine®) or a mixture of four saltsof dextroamphetamine (Adderall®).18,19 Thesecond-line stimulants include methamphet-amine (Desoxyn® or the longer-lastingDesoxyn Gradumet®), or pemoline (Cylert®),which causes hepatotoxicity in about threepercent of subjects treated and can cause death,so must be closely monitored. In practice, theuse of any of these stimulants is so fraughtwith uncertainties and potential complicationsthat only the most intrepid practitioners pre-scribe them with comfort.17,24,25,27-29

The psychostimulants ought to be se-verely limited in their applicability, due to theirmarked and sometimes severe adverse ef-fects.29 Decreased appetite secondary to anor-exia or nausea may occur, leading to weightloss. Insomnia may also occur, as can head-ache. Lowering the dose and changing the tim-

ing may eliminate these side-effects. Rarely,psychostimulants may cause tics to develop,and cases of leukopenia and psychosis havebeen reported.25 Methylphenidate (Ritalin),dextroamphetamine (Dexedrine), and Adderallare all classified as Schedule II agents in theU.S., consonant with their significant abusepotential.25,29 As blood levels of the stimulantdecrease over time, irritability may manifestas a “rebound” type of withdrawal symptom.

Some subjects are very prone to abus-ing stimulants and must be placed on non-stimulant, alternative medications. A subgroupwith more depression and anxiety may respondbetter to tricyclic antidepressants (imipramine,desipramine) than to stimulants,24 althoughboth can have major adverse effects, with de-sipramine linked to sudden death.25 The anti-depressant bupropion (Wellbutrin“) can, likethe stimulants, exacerbate an underlying ticdisorder. This drug is also contraindicated inchildren with anorexia nervosa, bulimia, orepilepsy. ADHD subjects have a higher riskof moving into drug abuse,34 and there is nowa trend toward placing ADHD children onProzac®, withdrawal from which has beenlinked to violence and other possibly disas-trous outcomes.27,28

Certain non-stimulant medications canserve as allopathic alternatives in ADHD whenstimulants have failed. Among these are thealpha-adrenergics clonidine (Catapres®) andguanfacine (Tenex®). Both are less well vali-dated than the stimulants and not as effica-cious. Clonidine can cause sedation and dys-phoria, and both of these drugs require bloodpressure monitoring because they are alsoantihypertensives.24,25

The psychological disorders that oftencoexist with ADHD also require management.The more serious of these include tics orTourette’s syndrome; depression, including thebipolar type which is quite prevalent; anxiety;and obsessive-compulsive disorder. For chil-dren who have tic disorders, extremeoveractivity, oppositional or conduct disorder,

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or hyperarousal, clonidine may prove useful.24

ADHD also can be associated with impulsecontrol problems more extreme than the usualADHD spectrum; sometimes antipsychoticsare prescribed, although their risks outweightheir advantages.25 In summary, pharmacologicmanagement of ADHD and the coexisting con-ditions can challenge even the most experi-enced practitioner, and safer modes of man-agement are urgently indicated for this unfor-tunate patient population.

Ritalin—Its Benefits and RisksThe continuing status of methylpheni-

date, or Ritalin, as the single-most commonintervention for the symptomatic managementof ADHD is the basis for considerable,oftentimes bitter disagreement and contro-versy. The author considers methylphenidateto be a highly cerebroactive pharmaceuticalthat offers symptomatic benefit in ADHD butcarries high potential for abuse and possiblelife-threatening effects over the long term.30

Ritalin and Ritalin-SR® arepreparations of methyl-alpha-phenyl-2-

piperidineacetate hydrochloride.Methylphenidate acts on the central nervoussystem with a dopamine-agonistic effect thatis slower in onset but mechanistically almostidentical to cocaine and amphetamines.14-16

Advocates of methylphenidate attest that itworks more effectively than any other singleintervention to enhance attention span andimpulse control.31 Yet methylphenidate doesnot consistently benefit academicperformance. Opponents of the drug (alongwith some of its advocates) point to its manyserious adverse effects,26 and many criticsargue that children should not be put at riskfor the known major adverse effects of adrug that is virtually banned for use byadults. Methylphenidate also has potentialfor abuse, and the abuse pattern is verysimilar to cocaine and amphetamines.17

A majority of ADHD children—upto 70 percent of those treated—do seem to de-rive a degree of benefit from methylpheni-date,24,31 but its benefits have been overstatedand there are compelling reasons to believethis drug is being overprescribed. Citing cred-ible survey data, Swanson and collaborators9

documented a dramatic increase in outpatientvisits for ADHD in the early 1990s, accompa-nied by a near-tripling in Ritalin production—in 1993, more than 2.5 million Ritalin prescrip-tions were written for ADHD. They attributedthe markedly increased frequency of ADHDdiagnosis to heightened public awareness andto policy changes that have forced publicschools to identify students with ADHD. Butas so many of the “mainstream” practitionerstend to do, they dismissed the increase in me-thylphenidate prescribing as merely “requiredto meet the demand for stimulant medication.”

This intensifying confrontation is fu-eled by the realization that methylphenidatecan (and does) exert serious adverse effects.29,30

Scarnati29 listed the most severe effects re-ported in the professional literature: psychic(hypomania, mania, delusions, paranoid delu-sions, paranoid psychosis, toxic psychosis);

Figure 1: Methylphenidate hydrochloride (Ritalin®)

NH

C

O

OCH3

•HCL



hallucinations, auditory and visual; exacerba-tion of schizophrenia and autism; muteness,extreme withdrawal, partial dissociation;boundary loss, disorganization; nervousness,agitation, terrifying affect, aggressiveness,assaultiveness, anxiety, panic; drug abuse—rebound depression, psychic dependence, in-creased euphoria, and cocaine-like activity.The Indiana Prevention Resource Center30 cir-culated information on the major street abuseof methylphenidate currently occurring in In-diana and the potential for life-threateningdamage.

When methylphenidate is used withantidepressants (such as the tricyclics andProzac), seizures, hypertension, hypothermia,and convulsions can ensue.29 Over the longterm, weight loss can occur, as can scalp hairloss, vasculitis, leukopenia, visual distur-bances, and anemia. A no less recognized au-thority than the Physicians’ Desk Reference32

carries a long list of potential adverse reac-tions in children and also has this to say aboutmethylphenidate:

“In children, loss of appetite, abdomi-nal pain, weight loss during prolonged therapy,insomnia and tachycardia, mayoccur...Periodic CBC, differential, and plate-let counts are advised during prolongedtherapy...Ritalin should be periodically discon-tinued to assess the child’s condition...Drugtreatment should not and need not beindefinite...Patients with an element of agita-tion may react adversely; discontinue therapyif necessary.”—Physicians’ Desk Reference,53rd Edition, 1999, pgs. 2078-9.

The PDR section on methylphenidatealso starkly states, “Sufficient data on safetyand efficacy of long-term use of methylpheni-date in children are not yet available...”

In 1994, U.S. Government researchersreported that Ritalin caused liver cancer inmale mice.32 The carcinogenic doses wereequivalent to just 2.5 times higher than thehighest human prescribed dose. The U.S. Na-tional Toxicology Program has concluded that

methylphenidate is a “possible human carcino-gen.” This revelation about methylphenidate,taken together with the major adverse effectsof the other psychostimulants, makes it im-perative that alternative modalities be imple-mented for the management of ADHD.

ADHD Etiology and ContributoryFactors

ADHD is highly inhomogeneous in thebiological sense, and although classed as adisorder it amounts to hardly more than anassemblage of symptom clusters. Its etiologyalso is far from homogeneous, with manylikely contributory factors. Certainly some ofthese etiological factors generate symptoma-tologies that closely resemble ADHD. Amongthese are sensitivities to food additives, intol-erances to foods, nutrient deficiencies andimbalances, heavy metal intoxication, andtoxic pollutant burden. Also, evidence ismounting that abnormal thyroid responsive-ness, perhaps engendered perinatally by envi-ronmental pollutants, is on the rise and pre-disposes to ADHD.35

ADHD has been linked to inheritedsusceptibilities; for a critical review refer toTannock.5 Findings from twin studies andadoption studies support some degree of heri-tability for the disorder,32 though co-morbidconditions complicate the analyses. Numerousfamilial-genetic studies have documented ahigher prevalence of psychopathology, particu-larly ADHD, in the parents and other relativesof children with ADHD, and there is a statisti-cally and clinically significant risk for ADHDto occur in children where either biologicalparent had onset in childhood.36-40 Sophisti-cated studies confirm a higher incidence ofADHD in the closest relative of ADHD males.5

The actual degree to which geneticheritability may predispose to childhood on-set of ADHD is still an open question. Popu-lation studies indicate attentional problems,conduct problems, and emotional problems

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tend to cluster within families.41 Genetics andenvironment are notoriously difficult to sepa-rate within the family unit, and Fisher sug-gested the genetic predisposition to ADHDmight fuel a negative family atmosphere thatexacerbates latent ADHD in the child.19

Twin and adoption studies are gener-ally the most precise means for estimating rela-tive heritability of a trait. Such studies inADHD suggest a relatively high degree of heri-tability.5 They also suggest that rather thanbeing a discrete disorder, ADHD may beviewed as the extreme end of a behavior con-tinuum that varies genetically throughout thepopulation.42 Both inattention and impulsiv-ity/hyperactivity appear to be heritable andshare a genetic component,39,43 but no one geneis likely to be the culprit.

Important advances have been made inthe pursuit of genes for ADHD.5 To date, theevidence for single-gene inheritance is uncon-vincing; rather, a polygenic mode of inherit-ance is more likely—either several stronggenes or many genes with weak effect. Geneswithin the dopamine transmitter system are themost likely to be most involved, given: (1) theeffective reduction of symptoms by dopam-ine agonists such as methylphenidate; (2) re-sults from brain imaging studies that impli-cate brain structures with rich dopaminergicinnervation, such as the frontostriatal cir-cuitry;44 and (3) early results from gene isola-tion studies.5

The heritability of the associationsbetween ADHD and its various co-morbidconditions may span the entire spectrum ofpossibilities. Biederman and his colleaguessuggest ADHD and major depressive disordersmay have common familial vulnerabilities.22,23

ADHD with co-morbid conduct disorder alsomay be preferentially associated, whereas theanxiety and learning disorders may segregateseparately. ADHD relatives of patients withADHD do have markedly higher risk for majordepressive disorder, antisocial disorders, andsubstance abuse. To date there is insufficient

data to quantify any relative degree of co-heritability of ADHD with a trait for any ofthese co-morbid conditions.

Food Additives and FoodIntolerances in ADHD

In the mid-1970s, Feingold broke newground with his claim that up to 50 percent ofall hyperactive children were sensitive to foodadditives (artificial food colors, flavorings, andpreservatives) as well as to salicylates thatoccur naturally in some foods.45,46 Feingold’sbasic finding of the connection between foodadditives and ADHD symptomatology was notnew. As early as 1922, Shannon had publishedon the successful treatment of children withhyperactivity and learning disorders using anelimination diet.47 On this regimen 30-50 per-cent of children improved. Most recently,Schardt reviewed 23 double-blind studies thatexamined whether food dyes or ordinary foodsworsened behavior in children with ADHD orother behavioral problems.48 In eight of thenine studies conducted with ADHD children,the behavior of some children worsened afterconsumption of food dyes or improved on anadditive-free diet. The symptomatology ofthese adverse responses mimicked ADHD.

The other 14 studies reviewed bySchardt looked at children with ADHD plusasthma, eczema, or food allergies, irritabilityor sleep disturbances, or more severe behav-ioral or neurological disorders. In 10 of the 14studies, some children improved when they atediets free of additives or certain foods. Somedeteriorated when they ate food dyes or foodslike corn, wheat, milk, soy, oranges, eggs, orchocolate. Schardt concluded his critique withsuggestions from experts that dietary modifi-cation be systematically attempted before thedecision is made to place an ADHD child on apharmaceutical regimen.

Feingold’s original case historiescovered 1,200 pediatric cases in which food



additives were linked to behavioral andlearning disorders, and pointed the finger atsome 3,000 different additives, yet subsequentresearch to “verify” his work focused on lessthan a dozen additives. The majority of thedouble-blind studies designed to testFeingold’s hypothesis reported their outcomesas negative, yet a careful review of the datafrom these studies by Murray and Pizzornoconcluded that a full half of the children placedon the Feingold diet in these studies actuallyshowed a decrease in hyperactivity.49 A pattern

is evident, as discerned byBoris: single-agentelimination studies tendedto show limitedimprovement or noimprovement at all, whilemulti-agent eliminationstudies were almostuniversally successful.50,51

Rippere has criti-cized in depth52,53 the meth-odologies of the “double-blind” studies conductedby Conners and other crit-ics of Feingold.54,55 Shepoints out: (a) the con-scious design of active,potentially allergenic pla-cebos (such as chocolatecookies); (b) the decisionsto use dosages of test ad-ditives lower than knownto be consumed in foods;(c) the use of highly unre-liable laboratory tests forallergy determination; and(d) formulation of impre-cise rating scales as out-come measures. Perhapsthe most serious criticismby Rippere is that of inves-tigator bias; i.e., the re-searchers ignored studyoutcome data that sup-

ported the Feingold interpretation while over-emphasizing contrary data. Boris,50,51 Weiss,56,57

Crook,58-61 Egger,62,63 and others have con-ducted their own studies and trials, reviewedthe cumulative data, and come out in supportof the Feingold hypothesis. It is interesting tonote that studies conducted in non-U.S. coun-tries produced results markedly more favor-able to the Feingold interpretation,49 and thatmost of the U.S. investigations were sponsoredby a corporate food lobby group, the Nutri-tion Foundation.

Figure 2: Changes in a child’s drawing and handwritingduring the four phases of acute reaction to offendingfood. Note the hostility expressed in the drawing.From Rapp, 1996.66

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Food additives are big business, espe-cially in the United States (see Murray andPizzorno for an overview).49 There are some5,000 additives in widespread use, includingbut not limited to: anticaking agents such asaluminosilicates; synthetic antioxidants suchas BHA and BHT; bleaching agents such ashydrogen peroxide; colorants such as artificialazo dye derivatives; preservatives such as ben-zoates, nitrates, and sulfites; and many others.Per capita daily consumption of food additivesin the U.S. is 13-15 grams, and the population’stotal annual consumption of food colors aloneis approximately 100 million pounds. Othercountries have significantly restricted artificialfood additives whereas the United States hasnever done so.

The removal of artificial food color-ings and preservatives from the diet is an in-dispensable and practicable clinical interven-tion in ADHD, but rarely is sufficient to elimi-nate symptomatology. Up to 88 percent ofADHD children react to these substances insublingual challenge testing,49 but in blindedstudies no child reacted to these alone. Aller-gies to the foods themselves must also be iden-tified and eliminated. Doris Rapp, MD, a pe-diatrician with considerable experience in thisarea, has claimed that two-thirds of childrendiagnosed ADHD have unrecognized food al-lergies that generate most, if not all, of theirsymptoms (see Fig. 2). These can usually bedetected and the symptoms cleared using asimple one-week elimination diet. She hasthoroughly documented her findings in books,professional articles, and videotapes.64-66

Data from two double-blind studiesindicated 73-76 percent of ADHD childrenresponded favorably to food eliminationdiets.61,67 Maintenance on even more-restricted,low-antigen (oligoantigenic) diets raised thesuccess rate to as high as 82 percent.62,63,68

Invariably in these studies, reintroduction ofthe offending foods led to reappearance ofsymptoms.

Sugar intake makes a marked contri-bution to hyperactive, aggressive, and destruc-tive behavior.49,61,69 A large study by Langsethand Dowd found 74 percent of 261 hyperac-tive children manifested abnormal glucose tol-erance in response to a sucrose meal.70 Otherstudies have been conducted, but industry in-terests may have influenced their outcomes ina manner inconsistent with good scientific re-search.

Wolraich and collaborators conducteda trial on sugar and hyperactivity that was pub-lished in the New England Journal of Medi-cine in 1994.55 The findings were portrayed bythe study investigators and the media as prov-ing that sugar did not significantly contributeto hyperactivity. Yet the control, “low-sugar”diet averaged 5.3 teaspoons of refined sugarper day, fed to children aged 6-10 years. This“baseline” level of sugar intake is arguably sohigh that the investigators should not have beensurprised the “test” group on a higher sugardiet did not show significantly more symptomsthan the “controls.” No attempt was made toeliminate dietary allergens such as milk, wheat,and egg, which trigger behavioral problemsin some hyperactive children, and all the chil-dren were allowed to consume soda drinksduring the study. At the end of their report, theauthors acknowledged their gratitude to Gen-eral Mills, Coca-Cola, PepsiCo, and RoyalCrown.

Metal Pollutants in ADHDAn amazing variety of toxins extant in

the modern environment have deleterious ef-fects on the central nervous system that rangefrom severe organic destruction to subtle braindysfunction.71,72 Toxic metals are ubiquitousin the modern environment, as areorganohalide pesticides, herbicides, and fumi-gants, and a wide range of aromatic and ali-phatic solvents.35 All these categories of envi-ronmental pollutants have been linked to ab-normalities in behavior, perception, cognition,



and motor ability that can be subtle duringearly childhood but disabling over the longterm.

Children exposed acutely or chroni-cally to lead, arsenic, aluminum, mercury, orcadmium are often left with permanent neu-rological sequelae that include attentional defi-cits, emotional lability, and behavioral reac-tivity.72 Lead is damaging to cognition andbehavior in children, and can cause develop-mental delay and mental retardation as well.The many studies conducted on the neurotox-icity of lead serve rather as a model for stud-ies with the other toxic metals. Perhaps theirmost significant consensus finding is that leadtoxicity observes no threshold for causingdamage.73

A meta-analysis of cognitive damagefrom lead exposure concluded there was nothreshold for damage down to blood lead lev-els of 7µg/dl,73 and levels as low as 10µg/dlhave been linked to psychobehavioral deficits.In the U.S., more than three million childrenare estimated to have blood lead levels of 10µg/dl or higher.73 In addition, increased tooth den-tine-lead and hair-lead levels have been linkedto increased distractibility and attentional defi-cit. Tuthill’s group sampled hair lead levelsfrom 277 first-grade children in Massachusettswho were diagnosed ADHD.73 Hair levelsranged from 1µg/g to 11.3µg/g, and a strikingdose-response relationship was found betweenhair lead level and the likelihood of being di-agnosed ADHD by a physician and the ratedseverity of attention deficit.

Some deleterious effects ascribed tolead may include contributions from othermetals. In ADHD subjects found to be loadedwith more than one toxic metal, whether athigh or threshold levels, the metals may beacting in combination to increase the totalityof the toxic effect.72 Thus, combinations of leadwith aluminum, lead with arsenic, lead withcadmium, and aluminum with arsenic all havethe potential for synergistic toxicity.75-77 Asdocumented by Marlowe and collaborators,

learning disabilities follow a pattern similarto ADHD, with lead, cadmium, and aluminumbeing the main culprits.76 Lead and aluminumseem especially synergistic, and mercury hasgreat potential for synergy with lead.

This growing body of pessimistic datastrongly indicate that children with ADHDshould be screened for heavy metal load, ei-ther where prior exposure is established and/or where other ADHD risk factors have beenruled out. Moon and collaborators72 called forteachers to have parents complete a MetalExposure Questionnaire in order to assist withthis process. Where levels are found to be high,children can be detoxified via lead chelationtherapy. David et al reported that chelationtherapy significantly improved hyperactivity,impulsivity, conduct problems, and learningproblems in children diagnosed ADHD withno apparent risk factors.71

Environmental Illness AffectsBehavior

Doris Rapp, MD, is a foremost author-ity on environmental illness (EI) and ADHD.For over a quarter of a century in her pediatricpractice she has documented the myriad re-sponse patterns children can display in re-sponse to dust, mold, or chemicals present intheir environment. Symptomatologies of hy-peractivity and impulsivity/loss of self-controlare common. Rapp, together with a growingnumber of physicians and environmentalistscientists, believes that more and more indi-viduals are falling prey to EI because of thecontinued widespread pollution of food, wa-ter, air, homes, workplaces, and schools.

The school environment is a major of-fending source of EI, for adults as well as chil-dren. Rapp66 cited data that indicate 25,000,or one-third of all U.S. schools, need exten-sive repair or replacement due to significantcontamination with lead, asbestos, radon, orsewage; leaking underground storage tanks;poor plumbing or ventilation; termites; or

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structural inadequacies. There are also the ad-ditional, and at times more significant, rolesof dust, molds, indoor chemicals, foods, andmicroorganisms. Placed in a contaminatedclassroom environment, a child can quicklybecome tired and irritable and suddenly seemincapable of learning. According to Rapp, thechild (as well as the teacher) “can feel con-fused, perplexed, bewildered, and depressed,when for no apparent reason they become ir-ritable, moody, angry, sad, aggressive, vulgar,or can’t think clearly.”66 Ironically, the adverseeffects of daytime exposure to a contaminatedschool environment may not manifest fullyuntil the end of the day, after the child is home.This can foster confusion between teachers andparents about the source(s) of the offendingexposures.

Nor is the home a necessarily safe,clean, and protected environment.66,78 Chemi-cals in carpets and wall materials, dust, molds,microorganisms, lead in paint, radon contami-nation, and pollutants in air, water, and foodcan be as offensive and toxic in some homeenvironments as in the worst schools. Themodern parent must be vigilant for environ-mental insults and observant of their child,never abdicating this responsibility to theteacher or pediatrician, especially since mostphysicians are not skilled at diagnosis of EI.Rapp has a “Big Five” list of symptoms that,when used before and after an adverse expo-sure, are surprisingly effective at pinpointingan EI response.66 These are:1. How does the child feel, behave, and remember?2. How does the child’s appearance change?3. Is there any handwriting or drawing change? (for a typical example, refer to Fig.2)4. Does asthma or other breathing problem appear?5. Is there a change in the pulse rate or rhythm? (especially a sudden 20-point increase in the rate)

Rapp maintains that in many childrenthe signs of EI can be traced all the way backto infancy, even as far back as in utero, wherethey are hyperactive and hiccup frequently inresponse to foods their mothers ate, beveragesshe drank, or odors she smelled. As a childgrows the symptoms of EI may change (e.g.,the responses to milk and other dairy productsdiffer between fetus, infant, toddler, child, ado-lescent, and adult).66,79 But these are merelydifferent manifestations of adverse responsesto the same food or other offending agent.

The environment surrounding thehome, school, or community may not be anyfriendlier to the susceptible child. Indeed, theentire planetary environment is now suffusedwith organochlorines and other persistent or-ganic pollutants.35,80,81 Children are especiallyvulnerable to these substances, as they havehigher cell-level turnover and relatively im-mature detoxification capacities.82 Children aremore susceptible to loss of brain function ifexposed to neurotoxins during critical devel-opment periods, however low the exposurelevel, as is evident from studies on irradiation,drug, alcohol, and lead toxicities.35,80,83

Pesticides capable of injuring the cen-tral nervous system include metals, chlorinatedhydrocarbons, organophosphates, and carbam-ates.35,78,80,81 The so-called “inert” pesticide in-gredients include benzene, formaldehyde, andpetroleum distillates, but all these are far frombeing inert to children. Crinnion recently re-viewed the extent to which these toxic pollut-ants are ubiquitous in the air, water, soil, foods,and human indoor and outdoor environments.78

Children may be exposed prior to birth, and/or after birth by ingestion, inhalation, transferthrough mother’s milk or baby food, andthrough skin contact.

Literally all residents of the industri-alized countries can be shown to carry “back-ground” levels—parts per billion to parts pertrillion—of organochlorine pollutants in theirtissues.78,80 Several studies of infants prenatallyexposed to background environmental levels



of organochlorine compounds demonstratedsubtle damage to the thyroid system, associ-ated with measurable changes inneurodevelopmental parameters.35,80

Thyrotoxins andNeurodevelopmental Damage

Thyroid hormones help regulate neuro-transmitter systems—dopaminergic, noradren-ergic, serotonergic—in the brain, and are piv-otal to the very process of fetal matura-tion.35,84,85 Regarding the possible contributoryfactors in ADHD, suspicion is growing arounda possible role for thyroid hypofunction dur-ing early childhood development. A link be-tween hypothyroidism during pregnancy anddiminished mental function in the offspring hasbeen recognized for more than 100 years,85 andin 1969 came the first solid indication that mildmaternal hypothyroidism could lower IQ val-ues in the offspring.

The condition of generalized resistanceto thyroid hormone, or GRTH, features re-duced tissue responsiveness to thyroid hor-mone.85 In children with GRTH attentionalfunction is abnormal,88 and among this popu-lation ADHD is very common, occurring in46-61 percent.87 Studies with animals estab-lished that adequate thyroid system integra-tion is required for the development of thesame brain zones found to have subtle anoma-lies in ADHD, such as the caudate, cerebel-lum, corpus callosum, cortex, and hippocam-pus.5 Children with ADHD have a higher fre-quency of occurrence of GRTH (estimated at5.4%, versus <1% for non-ADHD chil-dren).87,89

In 1999, Haddow and a large collabo-rative group reported in the New England Jour-nal of Medicine on a multi-center study thatfirst screened blood samples from 25,216mothers to assess thyroid adequacy, then testedtheir seven- to nine-year-old children for IQ,attention, language, reading ability, schoolperformance, and visual-motor performance.85

When the children from hypothyroid mothers(untreated during pregnancy) were comparedwith those of euthyroid (control) mothers, sta-tistically significant impairments were docu-mented for attention (WISC-III freedom fromdistractibility score, Continuous PerformanceTest of Conners) and school difficulties andlearning problems, along with several mea-sures of IQ and visual-motor performance.

The emerging evidence for involve-ment of thyroid damage in ADHD begs thequestion of what factors might be responsiblefor thyroid damage. Synthetic chemicals re-leased into the environment (pesticides andherbicides) are the main suspects, along withindustrial chemicals.35,84,90-93 In a major reviewof thyrotoxicity from chemicals, Brucker-Davis35 listed 77 chemicals proven to damagethe mammalian thyroid. Her list includes themost ubiquitous and persistent environmentalpollutants, among them PCBs (polychlorinatedbiphenyls), dioxins, furans, chlorophenols,chlorobenzenes, phenols, and related sub-stances, which are widespread in human tis-sues and routinely detectable in mother’smilk.78,92,93 The degrees of thyroid toxicity fromthese various chemical categories can be se-vere to mild, depending on the specifics ofexposure. Severe thyroid damage does notappear necessary to effect developmental braindamage; in the landmark Haddow study, mildand asymptomatic thyroid hypofunction sig-nificantly correlated with attentional and othercognitive impairment in children in the U.S.Northeast.85

PCBs remain ubiquitous in the envi-ronment. In 1996, Jacobson and Jacobson re-ported in the New England Journal of Medi-cine on their study of 212 children born towomen who had eaten Lake Michigan (USA)fish contaminated with PCBs.91 The childrenwere tested at 11 years of age. Prenatal PCBexposure was significantly associated withlower cognitive performance scores; the stron-gest deficits were related to attention andmemory. Incidentally, this same pediatric

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population evidenced reduced weight and headcircumference at the time of birth.90,94

The Neurobiology of ADHDModern brain monitoring techniques

have established that ADHD can be organi-cally expressed in the brain. Neuropsychologi-cal assessments were the first techniques tosuccessfully measure alterations in frontal cor-tical and frontal-basal ganglia information pro-cessing in the disorder.5,40 Ever more preciseneurochemistry, neuroimaging, and functionalneuroimaging techniques implicate these brainregions as well.

Neurochemical studies suggest alter-ations in catecholaminergic—mainly dopam-inergic and noradrenergic—transmitter func-tions markedly contribute to the symptoms ofADHD (see Tannock5 and Glanzmann40 forreviews). The symptoms of ADHD are signifi-cantly ameliorated by agents that specificallyinfluence these neurotransmitter systems, andanimal studies implicate areas of the brain inwhich these neurotransmitters are most domi-nant.96 Studies of these catecholamines and

their metabolites in the blood, urine, and spi-nal fluid did not initially provide definitiveresults,95 but with better study design there ispromise for positive results in this area.40

Magnetic Resonance Imaging (MRI)scanning can be used to reliably measure thesize of a specific brain region. Fourteen stud-ies using volumetric analysis by MRI wereconducted on ADHD subjects and controls;they suggest localized abnormalities in theprefrontal cortex, basal ganglia, and corpuscallosum of children with ADHD.5,40,140

Smaller frontal lobe or right prefrontal cortexwas found for the ADHD groups in all studiesthat examined this measure. Five of six stud-ies found a smaller anterior or posterior cor-pus callosum. Four of six found loss of thenormal caudate asymmetry (left side greaterthan right, see Fig. 3), and these four also founda smaller left or right globus pallidus.5 In twomore recent studies, smaller volumes of rightprefrontal cortex and of other structures in-volved in impulse control—the caudate andglobus pallidus—correlated with deficient per-formance on response inhibition tasks in boyswith ADHD.97,98

Figure 3: Possible subtle brain differences in ADHD.Asymmetry (left minus right) of glucose metabolic rate, measured using PET. Theanterior putamen (subcortical, involved with motor activity) and sylvian region (parietal,involved with visual attention) differed significantly between girls with ADHD andnormal girls. From Ernst et al, 1997.99

ANTERIOR PUTAMEN SYLVIAN REGION

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Functional/dynamic neuroimaging is afield undergoing particularly rapid develop-ment. The techniques include positron emis-sion tomography (PET), single-photon PET(SPECT), quantitative electroencephalography(QEEG), and functional MRI (fMRI). Thesehelp quantify brain metabolic activity and cor-relate it with anatomical differences in thebrain, on a real-time basis. Certain QEEGmeasures do consistently differ betweenADHD and normals, but their functional mean-ing is not yet evident. Measures of event-re-lated potentials document P300 wave differ-ences consistent with ADHD children beingdeficient in response selection and organiza-tion.5 With PET, abnormal regional blood per-fusion is evident in the striatal region of ADHDchildren.100 Zametkin obtained similar findingsin adults101 but fell short of statistical replica-tion in children.102 Meanwhile, the first SPECTstudy in children revealed the ADHD grouphad greater overall metabolic asymmetry, withless activity in the left frontal and left parietalregions.103

From the neurobiological studies aconsensus is emerging that motor andattentional functions associated with the fron-tal cortex are adversely affected inADHD.2,40,104 Taken altogether, the volumet-ric and correlational functional analysesroughly point to the frontostriatal circuitry, andpossibly intracortical connections via the cor-pus callosum, in the neuropsychological defi-cits associated with ADHD. These zones arepredominantly dopaminergic, and hypofunc-tion of dopamine pathways is a consistent fea-ture of the disorder. The diagnostic potentialof this information is becoming evident. Thecerebellum is functionally linked with the pre-frontal cortex, and three anatomical measures,namely the right globus pallidus volume, cau-date asymmetry, and left cerebellum volume,correlate highly with ADHD in children.5 Butoverall, with the differences running as small asfive percent less than normal,98 definitive con-clusions on brain region differences in ADHD

must await further quantitative and qualitativeanalyses. The rapidly increasing understandingof the normal growth cycles of the brain shouldenable better design of controlled normal vsADHD comparisons in this area.

Roles of Nutrient Deficiencies andImbalances

Nutrients are required by the brain, asthey are by every other organ, so virtually anynutrient deficiency can impair brain function.49

Assessment of ADHD children often revealsnutrient deficiencies or imbalances which,when corrected, result in considerable behav-ioral and academic improvement. Little con-trolled research has been conducted into di-etary supplementation effects on ADHD, butthe sparse data available do indicate signifi-cant potential for benefit in this realm. Thissubject recently was reviewed by Galland.106

Multiple vitamin-mineralsupplements

Dietary supplementation can improveacademic performance in healthy school-agedchildren. In a series of studies that spanned 18years and culminated in a double-blind trial,Schoenthaler et al found that a vitamin-min-eral supplement produced significantly lessantisocial behavior than did placebos inhealthy elementary school children and teen-age delinquents.107 Cognitive performance alsowas significantly improved, but the research-ers found no clinical improvement could beexpected unless at least one nutrient was ab-normally low by blood test. Pyridoxine, folicacid, thiamin, niacin, and vitamin C were thenutrients most commonly found to be low inchildren who responded to supplementationwith measurable improvement. Deficiencies ofvitamins A, E, B12, pantothenic acid, ribofla-vin, and of minerals also were linked to badbehavior. Improvement could not be expectedunless all deficiencies were corrected.

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B Vitamins in CombinationTwo early controlled trials utilized

combinations of B vitamins against ADHD andreported no benefit.108,109 Later, Brenner suc-cessfully used B vitamin combinations to treathyperkinetic children who had not respondedfavorably to Feingold’s diet.110 They also foundthat ADHD children responded variably to dif-ferent B vitamins, with pyridoxine and thia-mine antagonizing each other’s benefits. Treat-ment with single B vitamins rather than com-binations may sometimes be necessary in or-der to normalize lowered blood levels and se-lectively increase transmitters in ADHD; forexample, pyridoxine can be used to normalizelowered blood serotonin.106

Vitamin B6 (pyridoxine)This vitamin might help ameliorate

hyperactivity, as indicated from widespreadphysician experience and one small double-blind trial conducted to date. Vitamin B6 is anessential cofactor for a majority of the meta-bolic pathways of amino acids, including de-carboxylation pathways for dopamine, adrena-line, and serotonin. In 1979, Coleman et alreported that B vitamins improved the behav-ior of some children with ADHD in a double-blind crossover comparison with methylpheni-date.111 Coleman’s group took note of physi-cian observations that in some hyperactivechildren blood serotonin levels are low, andthat high-dose B6 often benefited the symp-toms while boosting serotonin into the normalrange. They investigated six children ages 8-13, diagnosed with Hyperkinetic Reaction ofChildhood (DS-II) and known to be respon-sive to methylphenidate. In a double-blinded,multiple crossover trial, each child receivedplacebo, low and high doses of methylpheni-date (averaging 10.8 mg/day and 20 mg/day,respectively), and low and high doses of B6as pyridoxine (averaging 12.5 mg/kg/day and22.5 mg/kg/day) over 21 weeks. Blood sero-tonin levels increased dramatically on B6, and

teacher ratings showed a 90 percent level ofstatistical trend in favor of B6 being slightlymore effective than methylphenidate.

IronThis is the most common of all nutri-

ent deficiencies in U.S. school-age children.49

Iron deficiency is associated with markedlydecreased attentiveness, narrower attentionspan, decreased persistence, and lowered ac-tivity levels, which respond positively tosupplementation. An uncontrolled Israeli studyof boys with ADHD found a 30 percent im-provement in Conners Rating Scale scores fol-lowing iron supplementation.112

MagnesiumAccording to Galland,106 the magne-

sium deficiency status often observed inADHD is reminiscent of Latent Tetany Syn-drome, which features lowered red cell levelsof the mineral. This disorder is believed re-lated to three factors: inadequate dietary mag-nesium (Mg) intake, genetic susceptibility, andthe Mg-depleting effects of catecholaminesand related stress hormones which are elevatedin the blood and urine of ADHD children. APolish team reported reduced Mg levels in 95percent of a group of 116 children withADHD;113 dietary supplementation with Mgsignificantly decreased their hyperactivity.114

ZincSeveral studies conducted in different

countries have found this mineral to be low inADHD (for references see Galland).106 Serumzinc can be markedly below normal,115 and alsourinary zinc clearance can be lower; both find-ings suggestive of poor zinc intake and/or ab-sorption. Findings from one placebo-con-trolled trial suggest poor zinc status also maypredict poor response to amphetamine treat-ment of the disorder.116



Essential fatty acids (EFA)These oily, vitamin-like nutrients have

shown promise in the non-pharmaceuticalmanagement of ADHD. The two mainclasses—omega-3 and omega-6—have acomplementary, “yin-yang” relationship, func-tioning as pro-homeostatic constituents of cellmembranes and as precursors to smaller mol-ecules (eicosanoids) that transduce informa-tion inward to the cell interior, and outwardfrom each cell to influence other cells. Thelonger-chain, 20- and 22-carbon species areboth crucial for prenatal and postnatal earlybrain development. Some adult humans cangenerate the longer-chain molecular speciesfrom the shorter-chain, but infants are lesscompetent in this regard.117 The C22:6 omega-3 (docosahexaenoic acid, DHA) and the C20:4omega-6 (arachidonic acid, AA) arehomeostatically balanced in human mother’smilk, and both are now added to infant feed-ing formulas.

One reliable symptom of EFA defi-ciency in both animals and humans is exces-sive thirst (polydypsia), without matchingpolyuria. Colquhoun and Bunday,118 workingwith the Hyperactive Children’s SupportGroup of the United Kingdom, were the firstto report that children with hyperactivity weresignificantly more thirsty (and without com-parable polyuria) than children who were nothyperactive. Mitchell et al119 measured plasmafatty acids in 44 hyperactive children and 45matched control subjects, and found the hy-peractive children had significantly lower con-centrations of DHA, AA, and the AA precur-sor DGLA (dihomo-gamma linolenic acid,C20:3 omega 6). Stevens et al120 extended thesepromising results, and Stordy correlated thesymptoms with omega-3 deficiencies andlearning disabilities.132

Stevens and her collaborators at Indi-ana University measured plasma and red cellfatty acid levels in 53 boys with ADHD and43 controls, aged 6-12 years.120 They also tookdetailed histories, compared clinical symptom

patterns, and tracked daily dietary EFA intakes.They confirmed Mitchell’s earlier report119 oflowered plasma concentrations of DHA andAA (but not of DGLA); and found plasmaeicosapentaenoic acid (EPA, C20:5 omega 3)was decreased, as was red cell arachidonicacid. As tracked by the parents, the ADHDgroup had significantly greater thirst, fre-quency of urination, and dry skin—all indica-tors of EFA deficiency—than did the controlsubjects.121 Within the ADHD group, a sub-group with higher scores for EFA deficiencyalso had the lowest levels of plasma EFA.124

The omega-6 fatty acid GLA (gamma-linolenic acid) is a metabolic precursor toAA.141 GLA was administered to ADHD chil-dren in two placebo-controlled studies. In thefirst, parents’ ratings suggested benefit fromGLA but teachers’ ratings did not.122 In thesecond, parents’ ratings did not suggest ben-efit but one teachers’ rating of benefit—theConners Hyperactivity Factor—did achievestatistical significance.123 Future studies mightbe more definitive if objective measures aretaken to establish EFA status and if mixedomega-3 and omega-6 long-chain fatty acidpreparations are administered.

The polyunsaturated, long-chain DHAand AA affect the biological and physical prop-erties of cell membranes, as well as the func-tionality of numerous important membraneproteins. The biochemical fates of DHA andAA are structurally and functionally inter-twined with the phospholipid substances thatmake up the bulk of the cell’s membrane sys-tems.

Phosphatidylserine (PS) and OtherPhospholipids105

Most of the reactions that collectivelyamount to life occur on or in cell membranes.These are the physical-chemical entities onwhich the vast majority of the cell’s enzymeassemblies are mounted. The phospholipids(PL) are the main foundational molecules for

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all cell membranes, serving much as buildingblocks for the membrane matrix into whichthe proteins are inserted. Within the membrane,the phospholipid (PL) molecules act as “par-ent” molecules for the long-chain, essentialfatty acid molecules. They hold the EFA inposition within the membrane, enabling en-zymes of the membrane to metabolize the EFAto eicosanoids and other regulatory messen-ger molecules as appropriate.

Of the phospholipids, phosphatidyl-choline (PC) is quantitatively the most com-mon in all membranes. PC is also the body’smain reservoir for choline, a small amine thatis a component of the neurotransmitter ace-tylcholine. The PC precursordimethylaminethanol (DMAE) is a major sub-strate for making PC in the body; it can have astimulant-type action in the ADHD brain, andhas been used with moderate success in thetreatment of children with ADHD and devel-opmental disorders.125 DMAE does have ad-verse side-effects at high doses,126 but was ef-fective against “hyperkinesis” in one double-blind trial and against learning disorders inanother.125

Phosphatidylserine (PS) is clinicallyproven to benefit a wide range of brain func-tions.105 This phospholipid occurs in the brainat far higher concentrations than it does in theother organs. It is a key constituent of nervecell synaptic membranes, which are deeplyinvolved in the production of neurotransmit-ters, their packaging for subsequent release,and their action via receptors located at thesynaptic junctions. Ingested as a dietarysupplement, PS energizes the human brain,facilitating synaptic connectivity and specifi-cally boosting dopamine transmitter functions,i.e., its production, release, and postsynapticreceptor actions. In a physician in-office studyof 21 consecutive ADHD cases aged 4-19, di-etary supplementation with PS benefitedgreater than 90 percent of the cases.127 At in-takes of 200-300 mg/day of PS for up to four

months, attention and learning were most con-sistently improved. Oppositional conductproved most resistant to PS treatment.

Other NutrientsMany of the neurotransmitters are

metabolically derived from amino acids.Analyses of plasma amino acid levels deter-mined that phenylalanine, tyrosine, tryp-tophan, and isoleucine were lower in ADHDpatients than in controls.128 In adults withADHD, L-tyrosine treatment produced tran-sient improvement.129,130 Also in ADHD adults,S-adenosyl methionine seemed beneficial inone small, short-term, uncontrolled study.131

A complex mixture of bioflavonoids(oligomeric proanthocyanidins or OPCs),which have potent antioxidant activity, werereported to benefit ADHD in an undisclosedproportion of children seen in a pediatric prac-tice.133 The symptom clusters related to atten-tion and distractibility seemingly respondedmore significantly than hyperactivity and im-pulsivity. Side-effects were said to be minor.

Many among the wholistic/integrativepractitioners who have substantial experiencewith ADHD believe intestinal dysfunction anddysbioses are important contributors to ADHDsymptomatology. A proprietary mixture of oli-gosaccharides, which sometimes serve as sub-strates for probiotic intestinal bacteria, wasreported to decrease the severity of ADHD inchildren during a six-week observation pe-riod.134

With the numerous nutrient deficien-cies documented in ADHD, and the promiseoffered by a range of nutrients in controlledand non-controlled clinical trials, Galland’sapproach is a proven blueprint for success.79,106

He tests for signs and symptoms of EFA defi-ciencies, and corrects these through supple-mentation. Using a similar approach, he se-lects candidates for magnesium therapy. Withthe B vitamins, to avoid the potential for para-doxical responses he suggests careful titration



using individual vitamins rather than begin-ning with mixtures; e.g., pyridoxine first, fol-lowed by thiamine, then by the others one byone. Serum ferritin and hair zinc levels can beuseful as rough guides for supplementationwith these minerals. In his view the nutrientsPS and DMAE are particularly deserving offurther study, especially for those ADHD chil-dren with learning disabilities.106

Developing an IntegrativeTreatment Model

Modalities for medical management ofADHD, other than the use ofpsychostimulants, have historically beenminimized by the medical mainstream. Evenso, ADHD has become a testing ground formodern wholistic/integrative medicalmanagement, at least as an alternative to thecurrent “mainstream” predilection for carte

blanche prescription ofmethylphenidate.

Safer and moreeffective treatment optionsare readily available to theinterested practitioner;when combined andindividualized to the ADHDchild the success rateapproaches 100 percent.First in order is dietaryrevision: removal of foodadditives, sensitizing foods,and sugar (sucrose) fromthe diet invariably results insome degree ofimprovement.135-137 Then thechild should be thoroughlyassessed for allergies,nutrient deficiencies, andintolerances to foods andchemicals. The toxic burdenshould be assessed andcorrected, includinglowering the body burden oforganics78 and potentially

toxic metals.71 Lead contamination is anobvious culprit in some cases of hyperactivity;aluminum cookware and silver-mercury dentalfillings should be avoided.

In ADHD every effort should be ex-erted to pursue the benefits from dietary modi-fication and nutrient supplementation prior toresorting to psychostimulant pharmaceuticals.One clear benefit is that nutrients predictablyhave broader effect spectra and superior ben-efit-to-risk profiles. The foundational, pro-ho-meostatic benefits afforded by vitamins, min-erals, essential fatty acids, phospholipids, andother nutrients to brain function would seemmore compatible with the wide range of be-havioral and cognitive symptom overlap seenin the ADHD population. Pharmaceuticals, bycontrast, are mechanistically much more ex-clusive and therefore demanding of more pre-cise symptom differentiation and diagnosis. Up

Figure 4: Integrative protocol for ADHD treatment(adapted from Charles Gant, MD, PhD)2,135

1. Establish subjective diagnosis (DSM-IV) and objective behavioral (macroscopic) diagnosis using newer-generation neuropsychological testing instruments such as the IVA/CPT of Sanford.2. Move to the biochemical-physiologic (microscopic) level, using laboratory tests such as hair, blood, stool, saliva, urine, or other, based on risk factors reported in each case.3. Prescribe nutritional supplements and other non-toxic biochemical interventions that uniquely fit the lab results for each person. Use anti-yeast medications and probiotics as necessary for intestinal rebalancing.4. Attend to family/environmental risk factor(s) and/or recommend family therapy as needed. Detoxify metals and organics as necessary.5. Allow a minimum period (weeks to months) for these measures to have an effect.6. Retest using laboratory indicators, to assess progress at the biochemical-physiologic level.7. Retest at the behavioral level to determine if functional improvement has occurred. This also allows publishing measurable outcomes and comparing the data to other methodologies.8. Retest or expand the range of testing at the behavioral and/or biochemical levels at the first sign of relapse or if symptoms persist past a reasonable period.9. Retest/reassess several months or years later to ascertain long-term results.

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to this point, nutrients and nutrient combina-tions have not been given a fair evaluationagainst ADHD and its constellation of co-morbid conditions.

For the practitioner managing ADHD,making a commitment to explore dietarysupplementation as a treatment modality doesnot mean abandoning the use of stimulants andother pharmaceutical medications. The use ofnutrients for symptom control in ADHD is notincompatible with the use of drugs; nutrientsare compatible with drugs to a degree far su-perior to the compatibility of drugs with otherdrugs.

Charles Gant, MD, PhD, is one practi-tioner who has evolved from an allopathicphilosophy of medical practice to a fully inte-grative practice for managing ADHD. He hasadvocated striking a balance between the con-ventional approaches to treating ADHD, withthe 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 widespectrum of modalities to successfully treatADHD.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 thepatient suspected of having ADHD andsearches for seven target symptoms—hyper-activity, impulsivity, inattention, mood labil-ity, temper outbursts, disorganization, andstress sensitivity. He then applies the moreextensive DSM-IV diagnostic criteria,1 andwith the diagnosis established he proceedswith his “Ideal Protocol” as summarized inFigure 4. He treats approximately 50 percentof his ADHD patients with antibiotics andother medications, mostly to remove gas-trointestinal dysbiotic organisms and to che-late heavy metals.

Many children presenting with mentaland behavioral abnormalities have intestinalbacterial imbalances from antibiotic overuse,as from treatment for ear infections, which are

a proven risk factor for ADHD.61 These chil-dren tend to have impaired speech and lan-guage development, and may have a two-foldhigher risk of becoming learning disabled.49

Gut dysbiosis—imbalances of the symbioticbacteria, presence of nematode or protozoanparasites, yeast (Candida) overgrowth causedby antibiotic overuse—once corrected canmanifest as multisystem improvement, includ-ing sometimes marked clearing of the mental-behavioral symptoms.61 Fungi and their me-tabolites also play a role, and can be detectedand treated.138

To most effectively treat ADHD, theintegrative medical practitioner must also workclosely with the subject and/or the parents tofurther eliminate toxic metals (e.g., lead, mer-cury) and chemicals (including cigarettesmoke, home building materials, pesticide-contaminated foods, lawn and garden chemi-cals, etc.) from the child’s environment—thiscan have the added benefit of improving theparents’ health. Allergies must be tested forand eliminated, whether of the food-related orthe inhalant type (pollen, mold, dust, volatilechemical).

The next phase in the integrative medi-cal management of ADHD is to identify andcorrect nutrient deficiencies, especially of min-erals (iron, magnesium, zinc, selenium, oth-ers); essential fatty acids; B vitamins; and othernutrients on a case-by-case basis. By this pointthe vast majority of hyperactive ADHD chil-dren are likely to be noticeably improved.

Objective testing of patients undergo-ing treatment for ADHD is important. Con-tinuous performance tests (CPT) measure re-sponse preparation, planning and inhibition,and neuropsychological performance via thefrontal lobes. CPT involve a period of testingduring which numbers or letters are presentedin rapid sequence on a computer screen andthe subject is asked to respond selectively tothem. Errors of omission are felt to representinattention, while errors of commission (pre-mature responses) may represent impulsivity;



the total number of correct responses is thoughtto represent capacity for sustained attention.The IVA (Intermediate Visual and Auditory)CPT is probably the best of these. In two pilotprojects, Harding, Judah and Gant used theIVA CPT to objectively assess improvementsin ADHD children not sorted for co-morbid-ity.135 They treated with methylphenidate or vianutraceutical interventions, and with or with-out their usual full workups for metal toxicity,gut dysbiosis, allergies and intolerances, andnutritional deficiencies prior to intervention.They found nutraceutical management wasstatistically superior over pharmaceutical man-agement for improving response control andattention, including cases where the in-depthworkups were NOT carried out.

After 3-6 months of testing-retestingand calibrating nutritional corrections, the useof medication may be considered if the childhas not significantly improved or continues tobe particularly impaired or oppositional. In anycase, lower doses of medication can be used,and titrated upward only as necessary to meldwith the benefits evident from the other inter-ventions. The responsible integrative physicianwill use medication only when the non-phar-macologic protocols have been exhausted;Crook suggests that the non-allergic, non-hy-peractive ADHD children are the subpopula-tion most likely to benefit from stimulant medi-cation.

ADHD in the FutureThe current extreme diversity of pro-

fessional opinion about ADHD—whether de-bating the many possible contributory factors,speculating on its neuropsychology and neu-robiology, dogmatically supporting or oppos-ing the use of stimulant medications, spawn-ing honest disagreement as to whether the dis-order truly exists—promises to continue intothe future. Some of the areas of controversyshould soon take on new clarity, most notablythe neurobiology of ADHD.

As the 1990s progressed, emphasisbegan to shift away from a purely “attentionaldeficit” as underlying ADHD, to a perhaps“intentional” deficit involving inappropriateresponse to an incoming stimulus, or a moredelocalized deficit in the development of theinhibition of behavior.5,40 Increasingly it is be-coming evident that ADHD subjects do payattention, and do receive stimuli, but may havetrouble processing the information and formu-lating an appropriate response.

With more research into the neurobi-ology of ADHD, more focused wholistic/in-tegrative treatment regimens might be forth-coming. Increasing controversy over the wide-spread use of methylphenidate and possiblelife-threatening effects from its long-term usemake it essential that complementary/alterna-tive treatment regimens be implemented forADHD management. Correction of nutrientdeficiencies commonly found in these patients,along with dietary modification, allergy treat-ment, detoxification, correction of intestinaldysbiosis, family counseling, and behaviortherapy can ameliorate symptomatology andallow the child diagnosed with ADHD to leada normal and productive life.

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c. Total paid and/or requested circulation (sum of 15b (1),(2),(3), and (4): 2753 / 2898d. Free distribution by mail (samples, complimentary, other free):

(1) outside-county as stated on Form 3541: 1667 / 2119(2) in-county as stated on Form 3541: 0 / 0(3) other classes mailed through the USPS: 38 / 38

e. Free distribution outside the mail (carriers or other means): 0 / 0f. Total free distribution (sum of 15d and 15e): 1705 / 2157g. Total distribution (sum of 15c and 15f): 4458 / 5055h. Copies not distributed: 4702 / 1195i. Total (sum of 15g and h): 9160 / 6250j. Percent paid and/or requested circulation (15c/l5g x 100): 61% / 57%

16. Publication of Statement of Ownership: printed in October 2000 issue17. Signature and title of publisher: Albert F. Czap, publisherDate: September 26, 2000

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