University of Calgary

PRISM: University of Calgary's Digital Repository

Graduate Studies Legacy Theses

1998

Application of the exorphin hypothesis to attention

deficit hyperactivity disorder: a theoretical

framework

Hoggan, Ronald

Hoggan, R. (1998). Application of the exorphin hypothesis to attention deficit hyperactivity

disorder: a theoretical framework (Unpublished master's thesis). University of Calgary, Calgary,

AB. doi:10.11575/PRISM/17013

http://hdl.handle.net/1880/25999

master thesis

University of Calgary graduate students retain copyright ownership and moral rights for their

thesis. You may use this material in any way that is permitted by the Copyright Act or through

licensing that has been assigned to the document. For uses that are not allowable under

copyright legislation or licensing, you are required to seek permission.

Downloaded from PRISM: https://prism.ucalgary.ca

THE UNTVERSITY OF CALGARY

Application of the Exorphin Hypothesis to Attention Deficit Hyperactivity Disorder: A Theoreticai Fmework

Ronald Hoggan

A ITIESIS

SUBMflTED TO THE FACULTY OF GRADUATE STUDlES

IN PARTIAL FULriXIMXï OF THE REQUIREMENTS FOR THE

DEGREE OF MASER OF ARTS

GRADUATE DIVISION OF EDUCATIONAL RESEARCH

CALGARY, ALBERTA

APRIL, 1998

O Ronald Hoggan 1998

National Libraty Bibliotheque nationale du Canada

Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Street 395. nie Wellingtm OttawaON K1AON4 OttawaON K1A ON4 Canada Canaoa

The author has g-anted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distriibute or sell reproduire, prêter, disbri'buer ou copies of this thesis in microfonn, vendre des copies de cette thèse sous paper or electronic formats. la forme de rnicrofiche/film, de

reproduction sur papier ou sur format élecîrmique.

The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thèse ni des extraits substantiek may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation.

Abstract:

This document suggests that m e n t pradces which lead to the diagnosis and treatment of

attention deficit hyperadv i~ disorder (ADHD) may obscure underiying pathologies which

can have dangerous consequences when undiagnosed. Whiie nimulant therapies are

sometimes an effective tool for the short-tem management of ADHD symptoms, they offer

little long-temi hope to the afioicted child, peihaps placing that person's health in serious

jeopardy. Teacher involvernent in this diagnostic and treatment process may aid in

perpeniating this problem. An alternative understanding ofADHD, informeci by the exorphin

hypothesis, offers a d e , powemil tool for dealing with the underiying condition in many

cases of ADHD, and an effeaive treatment for ADHD. A large and growing body of evidence

supports the application o f the exorphin hypothesis to ADHD, and points to some specific

research needs in this area. Such research requires a shift away nom the pharmacological

paradigm, in recognition of distinctions between pharmaceutid and dietary intementions.

Pre face

The possibihty that exorphins may underiay many cases of ADHD is not a oew

perspective (Reicheh, Ekrem, Scott, 1990). What is offered here is an assembiy ofthe various

t h r d ftom peer reviewed, scieminc literaîure, dong with an integration of those threads

into a tape* which forms a compehg picaire of what may constitute much of the

condition we currently c d ADHD. This thesis is infomied and shaped by the growing body

of peer rwiewed herature which has increasingS. pointeci toward exorphins as a factor in

ADHD (Reichelt et al., 1990; Crawford, Kaplan, Kinsboume, 1994; Uhiig, Merkenschlager,

Baodmaier, Egger, 1997). A vaxiety of fimors have contributeci to the deiayed emergence of

this perspective regardhg ADHD, incfuding limited access to some of the literatwe in

question, the absence of work which inteptes the various elements of supporthg evidence,

and a language barrier which distances research findings fkom many of those who rnight

benefit fiom knowledge of that meciid and scimtific information. An issue of M e d

availability of research funding rnay also have contributed to obscuring the applicability of the

exorphin hypothesis to ADHD.

A variety of 6ictors linnt access to medical libraries, including their smaii numbers,

hours of operation, and isolation from the c o d t y . Teaching hospitals have such libraries,

but much of the public is unaware of their existence. Perhaps there is an intimidating air for

the few who do manage to h d such h'braries.

Once access is gained, a fiirther limiting fàctor is the scientific language in which

research reports are written This language obscures meanhg to aIi who are aot prepared or

able to invest the necessary time required to master that lmguage which is the medium of

published medical and scientific reports. Part of the offering of this doauneat is to provide

an interpretation and an imegration of- reports pertinent to the issue M hand.. . . . ADHD.

What foilows is offered in a fonn accessible to teachers and parents. The dtimate

iment of üUs document is to aid children with ADHD. dong with their parents, th& teadias.

and their medicd caregivers &OU@ providing an aitemative perspective of ADHD. Inberent

in this view is a d e and effective alternative treatment for many, perhaps most, y o u n g ~ s

dering from this condition.

The hypothesis embodied here is readily testable, and readers d judge for themselveç

whether the evidence presented w m t s the expendiîure of a very few dollars for s e m

antiibody testins or a few weeks of dietary investigation. The exorphin hypothesis suggests

a broadiy apphcabie set of principles which may also deviate some of the current stniggle

to undetstand the underiying dynamics in a v a r i e of psychiatric ilinesses, including ADHD.

It is also a postulation which offers an alternative, perhaps more appropriate path for teachen

and parents who are dishirbed by the behaviour of some of the children in their charge, but

who recognize the fdacy underiying the current practice of administering powerful

medications to children, thus redu- the unpleasaut symptoms of ADHD, in the absence

of a clear understanding of the condition behg treated, or the therapeutic action ofthe dnigs

administered. The practice is one of placing some very dangerous band aids on symptoms

without an understanding of the underlying cause of those symptoms.

Neither does this thesis or its author offer a claim of ceftainty in the representation of

ADHD that f'llows. This hypothesis does offer a d e , effective, and heaithy means of deaiing

with a majonty of cases of ADHD, but it is recognized that there wiU be other causes in some

cases of this condition. Aiso embodied here is an understanding which resolves rnany of the

apparent anomalies in the m d d and popuiar literature regarding this pervasive, debilitating

condition that carries Iife-long implications regardles of the therapeutic intervention chosen

This thesis refiects the love, support, and encouragement Ite gotien nom my d e ,

Betty, my rnother, Edm, and my children, Donovan, Darren, Kari and Kyra Their

contn'butions have helped me fmd my way. It also reflccts the mentoring, support,

kindness, and understanding of my advisor, Dr. Anthosy Marini. I am aiso gratefui to Dr.

Garth Benson for helping me see science through many windows, and see my ansst as an

impetus to explicate those windows. And fhaiiy, I am grarefui to Dr. Jim Paul for heiping

me to understaud understanding through the incoqment, dissonant, dichotomous

metaphor of moderdy, and through its counterpart.

Dedication

In memory of my brother, Jack Emest Hoggan, June 17, 1946 to November 18,

1996. His pain inspired the work that lies before you. ffis death inscribed its meaning on

my soul. May his passing light a betta path for others.

Table of Contents: T i t l e Page .................................................................... i

............................................................... Approval Page i i ... Abstract .......................................................................... r r r

................................................................... ........................... Pr&ce , ... ,. iv ............................................................ Acknowledgement s vii

Dedication ......................................................... viii Table of Contents ...................................................................... ix List o f Tables ................................................................ xi List of Figures ............................................................... xii

Chapter One .... Parents, Politicians. Physicians. Pedagogues. Pupils. and Peptides .. 1 DSMIV .............................................................................................................. 2

Blind Partnenhip ............................................................................................. 3 .......................................................................... The Diagnostic Process 6

Adjunctive/drugless therapies ................................................................................ 7 . . Intestinai permeabilrty ............................................................................................ I I Vîous atrophy ..................................................................................................... 12 MolecularMimiay .............................................................................................. 12 Cytot oxicity of Gliadin ....................................................................................... 14

.............................. ...........*................................................. UrUiary Peptides .. 14 Beyond the Blood Brah Bax~ier .......................................................................... 15 Some aws involve gluten der dm collsumpti011 ........................................ 16 Exorphins ........................................................................................................ 18 Backtotheteacher ......................... .., ................................................................. 19

..... Chapter Two How Exorphins May Comect with ADHD Diagnostic Criteria 2 1 Comparative evaiuations may be appropriate ................................................ 21 Differentiation ...................................................................................................... 22 Additional thaapy is needed ................................................................................ 23 When ADHD chiidren grow up ................... .... ...................................................... 26 Why do stimulams sedate? ................................................................................... 27 Some problems with urinary peptide filtrate patterns ............................................ 29 Age-of-onset Criterion ......................................................................................... 32 Merentiation fiom celiac disease ................... ,. .................. ,,. 33 ................

........................................................................... variety 0fADHD presentatolls 34 ........................ Some mecdotal evidence ..., ....................................................... 35

SummaIy ........................................................................................................... 39

Chapter Three ..... Converging Data: Exorphins; Food Intolerance; ADHD 41 Peptide Structure ..................................................................... 42

................................. ........................ Intestinal Penneabiiïty .... 44 Celiac, Schizo phrenia, and other food intolerances ....................... 50

............................................................................... Digestive Enzymes 54

Table of Contents continued: Neurological Manifestations ............................................................. 58 DepressiodSerotonin .............................................................................. 59 M o l d a r Mimicry .................................................................................. 60 BraUi Morphology & Perfusion .......................................................... 62

.............................................................................................. Neuotransmitters 70 Serot onin.. ............................................................................. .. ............ 71

.............................................................................................. Dopamine 73 Peptides ................................................................ .. .......................... 74

Mineral Deficiencies .............................................................................. 75 Iton ................................................................................................. 76 Trace and Other Miaerals ..................................................... 78 EEGs, ADHDs, and Exorphins ............................................................. 79

............................... ... Chapter Four A Modd for Exorphin-Induceci ADHD 84 Stage One ....................................................................................... 86

.......................................................................................... Stage Two 87 ......................................................................................... Stage Three 88

Chapter Five .... .Education, Research Recomxnendations, Limitations. Implications ..... 91 Applications t O fication- .......................................................................................... 92 Recommendations for Future Research ................................ ., ............................... 94

The Investigators ............................................... 95 The Group to be investigated .................... .. .................................. 95 Establishing a Baseline .................................................. Terminal Assessments ................... ... ........................... S e l e c t i o n Bias .............................................. Other Research Possibilities ......................................

Limitations ofthe Mode1 ........................................................................................ Implications of Ignoring the Mode1 ................ ... ............................................... Conclusion ..................................................................................................

References .................................................................................................

Appendices: ûne: Lewen tested negative for annidies but responded positively to the diet .. Two : Temper tantnims and overweight child fiom Carol l ............................... 133 Three: Giuten is the dubious luxruy of non.celiacs .................................................. 1 135 FOUT: Predictive Vahie of Serology Testing in Celiac Disease ..................... ... .... 141 Fie: Stimulant medication as a mask .................................................... 145 Six: Irnmunopathology Update .......................................................................... 154

List of Tables:

Table 4.1 Points of Convergence in the Iiterature .................................... .. .............. 85

List of Figures:

Figure 4.1 HLA-BS Dis tn ion in Europe ..................... .... ....................... 87

Figure 4.2 Web of hterconneztions between ADHD and Celiac Disease ........ 90

Chapter One Parents, Poiiticians, Physicians, Pedagopes, Pupils & Peptides

The proposition set fonh here is that current diagnostic procedures for attention

deficit hyperadvify disorder (ADHD), and the thenipeutic interventions currently used to

manage this condition, dong with teacher involvement in this process, d l need to be re-

thought. Recent medical research indicates that there are common environmental, dietary

substances which may be at the root of a majonty of cases of ADHD, and these shouid be

appropriately investigated. Continued teacher support for a process that l a d s to stimulant

therapy may therefore be problematic. It is m e that ongoing research continues to support

the short-term efficacy of nimulant medications in ADHD, but such therapies may be

inadquate, short-sighted responses to this pervasive problern that afliicts from 2% to 10V0

of schoul children (Rowe 1988; Bons & Mandel 1994; Castellanos 1997).

Whereas there are several foUow-up investigations of subjects who undment lengthy

courses of stimulant therapy, no signiticant long-term benefit f?om such therapies was

reported (Barkiey, 1977). This absence of long-terni benefit may also be seen through

comparing a 15 year foilow-up of 63 hyperactive children who were not treated with

stimulant therapy (Weiss, Hechtman, Milroy, Perîman, 1985). and a 12 year foüow-up of 60

childrea moa of whom had undergone nimdmt therapy (Claude, Firestone, 1995). Both

p p s had fard equaliy poorly when contacteci at foiiow-up.

Evidence of an associated delayed maturation of parts of the brain involved in

executive f'unction until the third decade of Me, has dso been reported (Castellanos 1997;

2

Ucles, Loreaîe, Rosa. 1996). One such report also asserts that 52% of adolescent ADHD

subjects display substance abuse and criminal behaviour (Castelianos 1997). This research

contniutes to a growing paradigm crisis (Kuhn 1970) in psychiatrie and educational

research. Xore and more children are being prescribed stimulant medications, yet only short-

term benefits can be claimeci for the majority sub-group of ADHD children who respoad to

SUCh therapy. Conversely, an examination of dietary e x o r p h offers the possibility of a

natud. long-tem means to control symptoms and address the underlyhg pathology for m a .

who s&er fkom ADHD. These exorphins are morphine-like peptides (Zioudrou, Streaty,

Klee, 1979) which have been shown to result 6om the partial digestion of foods which have

repeat edly been implicat ed in investigations of ADHD (Breakey, 1 997).

DSM IV

Acwrding to the fouth edition of the Diagnostic and Statistical Manual of Mental

Disorders (DSM IV) (American Psychologicai Association, 1994), ADHD is characterized

by four sets of features and one broad form of dinerentation including hyperactivity and

impulsivity, or inattentioq which interfere with social, academic or occupational fhction; and

which appear in two or more settings. Some of this impairment is required to have been

present prior to seven years of age.

In spite of some semantic difficdties, this delineation of features is identifying a very

reai and debilitating probiem which moa classroom teachers see daily. This latter assertion

is based upon the 2% to lû?h reporteci incidence of ADHD (Rowe 1988; Boris & Mandel

1994; Castellanos 1997). Our culture relies upon teachers and h d t h care professionais to

render appropriate instruction, accurate diagnoses, and eEeCtive treatment. This expectation

3

rnay aceed reality. The risk of misdiagnosis, dong with a singular reliace upon stimulant

therapy, =y simply cunstitute a short-tenn maskuig of the symptoms of physicai ailments,

and of the undedying causes of what may constitute most cases of ADHD.

The teacher's and perhaps the clinician's Eimiliarit-y with the diagnostic and differential

f a e s of ADHD may be hindefed by the succession of changes tr, the various editions and

revisions of the DSM. Whiie the pfactice of conducting periodic revisions rdects an attempt

to keep pace with a growing and changing understanding of the ADHD syndrome, the

situation seems problematic. Subjecting children to pharmacological interventions with He-

long implications and consequences should be based upon a much more solid fbundation than

the teacher's observations rendered in ignorance of the critical and Werentiat. features of

ADHD (Ho- and Duniop, 1996). Yet that may be the usual comext of such teacher

evahrations which ofien lead to the diagnosis of ADHD and subsequent initiation of stimulant

&~=PY.

Blind Partnenhip

Even if teachers were to be trained in such diagnostic procedures, ignoring any

paradigm dissonance between the two professionsT medicine and education, çome vexy clear

contingencies threat en to compromise the teac her ' s objectivity. Students, whether SUffering

&om ADHD or not, have been shown to have improved powers of concentration while

undergoing stimulant therapy (Mayor, 1996 ). Such dnigs offer to aid the teacher in

controllhg classes through improving the behaviour and pedorma~lce of most chiltiren, not

just those who suffer kom ADHD. In a political context whexe class sizes continue to grow,

and student manageabiiity is iikely to be aided by stimulant thaapy, it may be very tempting

4

for the teacher to simply nod assent in a cornplex diagnostic process, rather than oppose the

powerful popular following that supports such diagnostic and therapeutic practices.

Another facet of the current politicai climate is the threat that merit pay and teacher

evaluations may be comected to mident performance on standarcheci testing, while ignoring

or rninimïzing socio-economic factors which have long been recopized to impact on such

performance (Rower. 1998). A constituent perspective in this trend is the simplistic notion

bat tacher effectiveness is wholly or largely reflected in aandardwd testing. Such

connections deny the uniqueness of the personal, educational and social histones of the

children in question. The threat of legislative policies of this sort provide scapegoats; not

accountabifity. Regrettably, tirne and space do not aüow a broader discussion of these

political issues, yet they are an important force in the diagnosis and treatment of ADHD. The

subtie impact is to inappropriately increase pressures upon the classroorn teacher, which rnay

result in their embracing measures which wiU heip them avoid the professional humiliation of

being penaiized or censured with losses in pay.

In addition to the incentives for teachers to incline their evaluations toward a

diagnosis of ADHD, which are embodied in current public policies, dong with those which

may be in the offing, there are also disincentives which threaten to penahe teachers who do

not facilitate an ADHû diagnosis. Classroom teachers are well aware of the behavioural

benefits of stimulant treatment. Most may be Less aware of whether a given child fds within

the parameters prem'bed by the DSM IV. Teachers who fail to facilitate such diagnoses may

h d themselves deahtg with a number of behaviour problerns in th& classes which, in many

cases, could have been avoided through participation in a process aimed at an ADHD

5

diagosis regardIess of the red nature of the underiying pathology. The disxuptive behaviour

which is ofien associated with ADHD can sene as a powerfiil inducement to teachers and

parents to accept any m e r , whettier temporary or not. Neither are some parents likely to

be pleased by a teacher who resists participation in the process if the parents in question are

searching foi a easy means to manage their diflicult child. Regardes of the various

rationales offered in the medical literanire, teacher participation in this process is suspect due

to current incentives and disincentives previously outhed. Inadequate teacher training in the

cntical and differentiating features of ADHD also offers cause to be suspicious of this

process. The current status quo is that we are pressured into participating in a diagnostic

process about which we usuaiiy know very iittie.

I regret that pnor to my own explorations of the scientSc and teaching literature, 1

participateci in such student evaluations. Only recently have 1 begun to see the hazards to

children posed by this blind partnership with medicd chicians. It is a partnership which

obscures issues of accountabiiity. Each participant, whether teacher or physician, is placed

beyond reproach in the current situation. Where there is an underiying pathology, the child

conhues to suffer the short and long-terni consequences of that pathology, while the

symptoms have been msked, and the problematic systemic procedures for the diagnosis of

ADHD are perpeniated. This process places children at an unnecesaxy risk. It also provides

an easy escape &om responsibility to medical and teaching professionais hvolved in the

diagnostic process.

My explorations of the literature have also convinceci me that stimulant therapy

offers a very effective focussing and settling agent to aid in classroom management, thus

6

merhg the interests of the &cted child's classrnates, teachers, and the shareholders of

mdtinationai pharmaceutid manufactwers, while offerhg iittle beneM to the ADHD child.

The diagnostic process

It mut be admitted that several cornplex assessrnent processes have been deiineated,

and the diagosis of ADHD may be much more defensible where such exhaustive as~essmerit

procedures are followed.

Shelton & Barkiey (lg9O) have outlined the multi-methoh multi-informant diagnostic

process for ADHD children employed at the ADHD chic ofthe University ofMassachusett~

Medical Center. The fint stage is referral. Nat a diagnostic interview is conducteci with the

parents, which is followed by a briefinterview with the child. This is foiiowed by a medicai

interview with the chilci, a medical examination, and the compilation of a great deal of data,

taking into consideration the cbiid's social, schooi, and family situatioq developmental

status, and a host of other factors.

Of principle relevance to the current discussion is that the above collection of data

includes a telephone interview with the child's prinary tacher where a Viefand Adaptive

Behaviour Scale is sornetimes used. The teachers are, in addition to the interview, asked to

report on the child's behaviour using the foiiowing instnrments:

The CMd Behavior Checklist:

The Child Attention Problems Scale;

The ADHD Rating Scale;

The School Situations Questionnaire, and;

The Cornors Teacher Rating Scaie-Revised.

7

It may be of interest that in 10 yean of teaching, and having participated in several

evaluations of children toward the diagnosis of ADHD, and subsequent monitoring of their

behaviour to determine medication effectiveness, 1 have never been Qiven more than a single

form to complete. which was unially a page or two in Iength 1 have been given several copies

of the same form for seriai evaluations of a cfiild's behaviour, and on another occasion,

regardhg a different cMd, 1 was given a single, but lengthy form to complete. M y expexience

is very different fiom the process outlined by Shelton and Barkley (1990). Neither have I

ever spoken with any hedth care professioual prior to, durinq, or after their rendering of a

diagnosis of ADHD. It is Wrely that such thorough methods for the diagnosis of ADHD are

not as common as might be hoped. Perhaps economic considerations, in the currem c b t e

of cut-backs in education spending render such a meticdous process beyond the means of

parents and school boards.

It is also important to note that this cornplex diagnostic process, however defensible,

does not reduce the probability that an underiying food intolerance disease will go

undetected. For hance, neither the medical interview nor the physical examination would

be likely to identify celiac disease. It is rarely considered, and physicians are rarely

knowledgeabie beyond the classic symptoms which apply oniy to a relatively small minority

of untreated celiac patients beyond infancy (Fasano, 19%). Ceiiac disease is the moa

common food intolerance disease, suggesting that milk protein intolerance, and other such

diseases would be even less iikely to be identifieci by this process.

Adj unctive/drugless thenapies

Behaviour modification programs, the way they are too ofien implemented, while not

8

themselves pharmaceutical interventions, are recommended as an adjunct to stimulam therapy

(CPS, 1997). 1 also take philosophical issue with many behaviour rnodincation techniques.

Such interventions appear to innill an excessive concern for consequences, while teaching a

poi&ed, righdwrong syaem of seif-monito~g which is wholly deriveci f?om extemai

judgements about what behaviour is acceptable. lfeducation is a process which encourages

and facilitates increasingly independent thought, then rnany behaviour modification programs

are largely or wholly counter-educationd. If they teach dependence upon extemal codes of

appropriate behaviour coupled with a fear ofemefnal coasequences, nich programs offer Iittie

more than the training involved in dealing with a puppy. As an educator, 1 find this approach

to children offensive, although 1 do not deny its practical value in some very exceptional

Circwnstan~~.

For these and other reasons, 1 have pursueci a greater understanding of dietary

intervention therapies in ADHD. An area which holds particular promise is the exorphin

hypothesis, as applied to ADHD. There is a compehg body of direct and indirect &dace

in the peer reviewed scientific and medical literature, as well as in aaecdotal reports. which

supports the exorphin hypothesis and its appiication to ADHD, yet it remains a relatively

obscure perspective. Implicit in the theoretical fhmework ofFered here, is also a therapeutic

intervention which has had little prior application to ADHD, but which may partly or wholiy

alleviate this condition. This hypothesis and the attendant treatment protocol suggests the

specific nature of the underlying cause of many cases ofthe ADHD condition, thus providing

a treatment pian which offers rnuch more than simpiy masking symptoms.

First postulated by Curtis Dohan, the exorphin hypothesis led to improvements

9

among schizophreriic patients, in aclinicai trial of a gluten-nee, dairy-fiee di- intervention

(Dohan, Grasberger, Lowe4 Johnson, Arbegast, 1972). Subsequent double-blind trials

supported these hdings (Singh & Kay, 1976; Reichelt, Sageda Landmark, SaagVic. Eggen,

Helge, 1990; Reichelt, Ekrem, Ston, 1990). Successive investigations of the exorph

hypothesis by several groups workmg primdy with autistic patients have revealed

information which offers to explain many othenvise contradictory findings in the literature

(Hoggan 1997a). A congruent, broadIy applicable set of principles inherent in the exorphui

hypothesis offers to shed light on many features of a vax-iety of mental iIlnesses, including

ADHD. which remain obscure within the m e n t paradigm.

The exorphin hypothesis postdates an interaction between a genetic predisposition

and ingestion of two very cornmon foods, dairy products and some cemi grains (Dohan

1989). These same foods are also împiicated in the two moa common food intolerance

diseases. This is a point of convergence which is more than coincidental. The Twentieth

Cenhüy has wiaiessed repeated reports of clinical hdings which suggest the involvement of

these dietary proteins in a variety of illnesses.

During Wodd War II, Dicke observed that the cereal grains, wheat and rye, are the

primary pathogen in celiac disease @icke, 1950). Barley was subsequdy added to the lin.

Dicke's findings were fist ignored, then mocked, and then subjected to unreasoned resistance

(Hoggan 1997a). Over a period of two decades, and in the absence of any other effkctive

treatment for this disease, Dicke's findings fhaiiy began to gain acceptance, in the context

of the development of a technology which facilitated endoscopic, intestinal biopsies thus

providing ostensibly objective evidence of the intestinal damage due to dietary gluten

10

(Paulley, 1954), which supportecl Dicke's claims. Much greater resistance to dietary

imewentioas in conditions which have been shown to nspond to phamiaceutcai intervention

should therefore be anticipated, regardles of the stms of the intestinal mucosa. Dietary

interventions in psyciihc conditions are not airremly in vogue. Worse, proponents of nich

intenmtions are often mocked, just as Dicke was (Hoggan, 1997a).

Rwioval of the same cereals, which have k e n shown to be pathogenic in celiac

disease, have also been shown to resdt in remission of symptoms of some f o m of epilepsy

wbich appea. to be varianis of the Sturge-Webber Syndrome (Bye, Andermaoq Robitaille.

Bohane, Andemanu, 1993; Piatella, Zamponi, Carchdi, 1993; Tiacci, D'Alesandro.

Cantisani, Piccirfi, Signonni, Peili, Cavdetti, CasteHua& P w Battis& Federico, 1993)

some cases of a rather wide variety of neurological dysfhctions (Hadjivassiliou.

Chattopadhyay, Davies-Jones, Gibson, GNenwaM, Lobo, 1997; Kelkar, Ross, Murray, 1996;

Holmes, 1996; Sandyk, Brennan, 1983; Sm&, S a l e Brittoa Brown, 1997) and a number

of central nervous system (CNS) aiiments previousiy thought to be unrelateci to diet (Watson,

McMillaq Dickey, Biggart, Porter, 1992). These reports do not provide clear evidence that

these conditions resuit partly or whoiiy fkom one or more of the opioid acting peptides found

in the digests of wheat, rye, and barky, but the complete and partial remissions reported in

the üteratwe leave little doubt that cotlsumption of this comm011 food group can r d t in

finaional and morphological changes to the centrai and peripherd nenous systems. It

should therefore not be surprising if behavioural and attentional changes also occur in

response to these foods. In fkt , the oppositc would be surpriskg (Reicheh, 1996).

The exorphins denved fhm the aforementioned grain proteins and milk proteins are

I l

chaios of amino acids called peptides, and they have been demonstrated to bind to cellular

opioid receptors (Zioudrou et al. 1979). The similarity between these exogenous, opioid-

acting peptides and uarcotics derived fkom opium, such as morphine, is sugge~ed by

similarities in hction and attachent at identicai recepton as weil as by the blockage of such

binding by drus which also block the binding, at the sarne receptors, of opiates (Zioudrou

et ai., 1979).

Exorpbins act as neurotransmi~efs. It is possible that the comorbidity of alcoholinn

and ADHD (Wiiens, Prince, Biederman, Spencer, Frances, 1995; Schulz, McKay, Newcorn,

Vanshdeep, Gabriel Halperh, 1998) is reiated, in part, to an addicting action of exogenous

opioid peptides, which may lead to the reported predilection to substance abuse in ADHD

(Casteiianos, 1997; Schuiq et al 1998). The corticaf atrophy associatecl with both ADHD and

dcoholism (Hechtman 1993; Nasrailah et aL 1986) may ais0 suggest the possibility of some

commonalities. Work suggesting tetrahydroisoquinoline (TMQ) attachent at cNS

endorphin receptors, in alcoholism, may offer a mode1 for understanding one action of

exorphins. (Bedingfield, Hoiloway, 1998 ).

Intestinai permeabüity

On a less speculative note, it is possible to identify two types of pathological

conditions in which exorphins rnay enter the circulatory system. Both conditions are pady

or wholly constituted by increased intestinal pemeability. The first condition is simply the

redt of inflammation of the tissues which form the wd of the srnail intestine, leading to

incread permeability of that waii. The cause of the inflammation is often unclear. A variety

of causes have been reported in such permeability, fiom autohunity ( Geboes, 1994 ). to

12

yeast overgrowth (McKenzie, Main, Pennhgton, Parratt, 1990 ), to bacterial UIfeCtions

(Aiper, Lencer, 1997 ), to ingestion of non-steroidal ami-inflarnmatory dmgs ( Segawa, Ohya,

Abe, Ornata. Tniniike, Itokani, Yoshida, Tagashira, Ueda, 1992 ). Whatever the cause,

spectfic serum antibody production irnplies that macromoIecules of p d y digested dietary

protein are being absorbed through the intestinal wall and into the bloodsaeam.

Vious atrophy

The second goup of conditions is characterized by damage to the mucosal

architecture of the smali intestine- This viuous atrophy is the primary diagnostic feature of

food intolerance diseases such as celiac disease, milk protein intolerance, etc., when

improvement of the intestinal mucosa can be demonstrated after exclusion of the suspect

proteins (Cooke, Holmes, 1984). Although increased intestinal permeabiiity is also a weii

known feature of these diseases, the presence of this pemeability without villous atrophy,

or increased intraepithelial îymphocytes (Marsh, l992), is not currentiy cmsidaed a definhg

characteristic (Cooke & Holmes, 1984). Further, the variety of auto-Unmune diseases, in

association with food intolerance disease, may weli derive f b m the constituent intestinai

permeability, as is suggested in discussions of molenilai mimicry (Scott, 1996; Scott et al.

1997; Karlsen, Dyerberg, 1998), which rnay offer an explanation for much of the high

incidence of atopy found in ADHD ( Biederman J, Milberger S, Faraone SV, Guite J,

Warbunon R 1994; Boris & Mandei, 1994; Rapp, 1979).

Molecular Mimicry

Molecdar mimicry is a theoretical perspective suggesting that the absorption of

dietary proteks and peptides into the ciradation results in antiiody activation against amino

13

acid sequences found in these substances, or against complexes which are combinations of

these substances with self tissues ( Karlsen, Dyrberg, 1998; Scott 1996 ).

People with leaniing ditncuiûes, specificaily with r h g , have b e n reported to have

an increased individual and family incidence of immune problems and auto-immune

diso rders, particularly those involving the gastrointestinal tract and thyroid gland (C rawford.

Kaplan, Kinsbourne, 1994), which is relevant, given the very hi& cornorbi- of ADHD and

leaniing disabilities (Biedeman, Faraone, 1996). ADHD symptoms were also reported in

association with an increased familial incidence of Crohn's disease (Crawford et al., 1994)

which further supports the posnilated c o ~ e d o n . ïhe reported excess of gastrointesthd

malignancies, in the context of an overali reduced incidence of maiignancy arnong one group

with learning disabilities, also becomes relevant, in that light (Cooke, 1997), as does the

excess incidence of maligna.ncy, especially in the gastrointestinal tract, in untreated celiac

disease ( Hoggaq 199%).

As may be deduced Born the above, there are many possible and probable causes of

intestinal permeability. Undigesteci food particles are being absorbed into the blood of rnany

apparently hedthy people. Testing of a random population sample in Iceland reveaied that

15% of this group had elevated class G immunoglobulin (IgG) ant i ies against gliadin, a

group of proteins found in wheat (Aarnason, Gudjonsson, Freysdottk, Jonsdottir,

Valdimarsson, 1992). This is clear evidence of the inappropriate absorption under discussion,

which is m e r supportai by gluten-denved exorphins demonstrateci in pancreatic secretions

(Fukudome, hsmaa, Matsukawa, SitSaki, Yohsikawa, 1997). These hdings ais0 suggest that

many and perhaps ali of the same group would have exorphins in their circulatory systems,

although this does not estabiish their presence in the central nenrous system.

Cytotoxicity of GIiadin

Gliadins have also been demonnrated to destroy a varïety of tissue tek. This

cytotoxic activity is reported in a varieîy of tissues tiom people without ceiiac disease

(Doherty & Barry, 198 1; Hudsoq hirdhmn, Corne4 Rolles, 1976; Latine, Briggs, Harding,

Nolte, 1966). The entry of gliadins into the circulation can apparently lead to tissue damage

in mon, ifnot al1 people. The genetk difference between heaith and disease may therefore be

found in whether the mucosa can protect the individual f?om moderate quantities of gluten.

Of course, hormonal and extemai factors may aiso eEect intestinai pemeability, thus m e r

confounding an already cornplex issue.

The general cytotoxicity of giiadin, once it has gained entry into the blood, may be

the very vehicle by which the exorphins can bypass the blood brain bamer (BBB) in the

context of mental illness. If there are concomitant exorphins, and gliadins in the circulation

at the same time, which seems likely because they can be denved f?om the same foods, then

the gliadins may damage the tight epithelial junctions of the BBB, thus dowing passage of

the exorphins into the centrai nervous system. This postulation is, of course, speculative, but

as prevïously demonstrateci, the gluten-associated CNS and general tissue damage is well

established. The accuracy of this speculation rnay not reasonably be taken to besmirch the

larger thesis embodied here. The notion of cytotoxicity as a vehicle for the breach of the BBB

is ofEered as an interesting, reasonable, and plausible possibiliw nothing more.

Urinary Peptides

Evidence of exogenous peptides is frequeutiy found, in a varïety of mental ilinesses

15

including ADHD. in the characteristic patterns of excreted urinary peptides in each of these

illness groups (Gilberg, Trygstad, Foss, 1982; Reichelt, Knivsberg, Lincl, Nodland, 1991;

Reichelt, Elcran, Scott, 1990b; Reichelt, Sagedal, L a n u Sangvic, Eggen, Helge, 1 WOa;

Saelid Haug, Heiberg, Reichelt, 1985). S p d c patterns of peptide fdtrates are associated

with specific sub-groups of mental ihess. A confoundhg factor is that the peptide filtration

patterns in asthma are sometimes very similar to those associated with ADHD, and the

ADHD patterns are sometimes not present in milder presentations of this latter condition.

thus reducing the value ofsuch testing as a diagnostic tooi (Hole, Lingjaerde, Morkrid, Boler,

Saelid, Diderichsen, Ruud, Reichelt, 1988) until the process is funher refined. Convenely,

these urinary n 1 M e s do facilitate ditferentiation between specific sub-groups of ADHD.

While not in themselves diagnostic, urinaq filtrates do offer corroboration of other diagnostic

masures, as weli as some important Uinghts into the presenting features of many instances

of ADHD. These urinary peptides also offer direct support for the application of the

exorphin hypothesis to this condition, in a large majority of cases, especially those of greater

severity .

Beyond the Blood Brain Bamer

The next question that may be of interest is whether exorphùis must bypass the blood

brain barrier (BBB), to dEêct the C N S fhction in an ADHD-specific mamer. The answer

is equivocai, and must be deduced fiom animai studies and disorders commonly associated

with ADHD, as weli as common responses of ADHD subjects to some medications. On one

hand. the increased presence of exogenous peptides in general circulation has a systemic

effkct of inhibithg breakdown of endogenous peptides. The argument has thus been made

16

that absorption of arogenous opioids into the cÏrculation, may result in incratsed conservation

of endogenous opioid peptides in CNS (Hole, et ai. 1988 ).

On the other hanci, in animal studies, exorphins have been demonstrated to bmd to

opioid receptors in the brain. It may be îhat either endogenous opioid peptide consemation

resutting nom exogenous opioik or a direct activity of exogenous opioids upon eiements

of the CNS is at work, or perbaps both dynemics contniute to the etiology ofglutenldajr

induced ADHD.

Some ases ci- invoive gluten and/or dijl

That a t m &or dairy products are dological fâctors in some cases of ADHD is

well established (Egger, Stolla, McEwen, 1992; Egger, Carter, Graham. Gdey, Sootha

1985; Boris, Mandel, 1994; Uhlig, Merkeaschlager, Brmdmaier, Egger, 1997; Breakey, 1997;

Carter, Urbanowicz, Hemsley, Mantilla, Strobel, Graham. Taylor, 1993). The only reai

question is to establish the relative fiequency of ADHD resuithg fiom these very common

foods. Although the incidence is thought, by =me, to be a s d percentage of aU cases.

there is rather a lot of evidence to suggest that extensive exploration of the exorphin

hypothesis may briag some dramatic changes to that perception Little dietasr research of

ADHD has specifically looked for the complex signs of exorphins, by simultaneously

exclucihg all foods which can produce exogenous peptides. The little work that has

examined this issue offers considerable evidence to support this perspective.

There is some evidence &om animal studies that such apparentIy d e foods cari result

in senous pathologies. One study of cats, a carnivorous species, reports that they develop

morphologid CNS changes, dong with behaviourai changes, d e r regular feedings of casein

17

and gluten (Thibault, Codon, Roberge, 1988 ). Another midy of a grwp ofIrish Setters fed

predominantly glutenous diets bas resulted in villous atrophy and increased intraepithelial

lymphocytes. whch resolved on a gluten-he diet (Pembertos Lobley, Holmes, Sorensen

Ban, 1997). There is also animal study evidence suggesting that these opioids may be at work

in a variety of neuropathies (Schick Schusdzîarra. 1985) and mental abnormaiities (Drysciale,

Deacon, Lewis, OUey, Electricwala, Sherewood, 1982). Yet another study reports gluten

induced autoimmunity in rats (Scott, 1996). Humans are more omnivorous than some of

these animais, but there is also some hurnan evidence suggesmig that gluten-derived exorphins

can and do directly impact on the human centrai and peripherai nervous synems

(Hadjivassilliou.et al. 1996, 1997; Bye et al., 1993). A detailed discussion of this point is

offered in Chapter 3. For the moment, it may be valuable to point out that there are at least

15 recurrences of one cpioid-acting amino acid sequence of GYYPT which can be isolated

ftom one m o l d e of giiadh, and there are a total of five amino acid sequences, with opioid

aaivity, that have been characterireci m Qliadins (Fdcudome & Yoshikawa, 1992).

Additiody, at least eight opioid acting peptides have been identifiai in milk proteins

(Teschernacher Koch G, Brant1 V, 1997; My& Wei, Bernardin, Kasarda, 1982 ). This

oners 13 distinct amino acid sequences, each with opioid advity, which can act singly or in

concert, a s s u h g that all can bypass the BBB, to produce a wide variety of presentations,

many of which may reflect various manifestations of ADHD, as weii as suggesting situational

variations in presenting symptoms of ADHD. When this number is added to the repetitions

of some of these sequences which occur as maay as 15 times in a single m o l d e (Fukudome

dé Yoshikawq 1993). and aii the possible u ~ q u e combinations of exogenous, psychoactive

18

peptides is added to the number of endogenous peptides which may be acting individually or

in concert upon opioid receptors there is a very large number of possible variations in

quantity, ratio, and identity of peptides and consequent alterations to behaviour.

Exorphins

Zioudrou et aL(1979) have also presented evidence to support their suggestion that

other, non-opioid, psychoactive materials cm be found in the pepsin digests of wheat, and

which constitute approximately 30% of the psychoactive peptides derived nom wheat. We

may thus reasonably anticipate a wide variety of individual responses to tiese various and

combined exorphins and endorphias. The variabiïty in presentation of ADHD, and other

mental illnesses that are impiicated by detection of nich urinary peptides. is consistent with

the variations made possible by exogenous psychoactive peptides, and tbeir impact upon the

preservation of, and interaction with, endogenous, psychoactive peptides.

Of course, the inaeased intestinal permeability herein ponulated as a feature of mon

cases of ADHD, dong with a pathway for exorphins to pass through or exert an innuence

beyond the BBB, might also facilitate a similar dynamic involving a variety of other partly

digested f d protans which may enter the circulation containhg amino acid sequences which

can exert a psychoactive ia8uence. Thus the exorphin hypothesis does not preclude, and may

offer an explanation for the reported impact of food additives and a variety of food proteins,

as weii as suggesthg a cause for the reported variety of atopic presentations and allergies

often associated with ADHD patients (Colquhouq Bunday, 198 1 ; Franklin 1 984; Breakey.

1997; Kinleq Baldwin, 1970; A ~ ~ I I , Mitcheii, Turbott, 1987; Stevens, De& Abate, Watkins,

Lipp. Burgess, 1995; Mitchell, Aman, Turbott, Manlai, 1987; Holman, Johnson, Hat& 1982;

Stevens, Zentaii, Abate, Kuczek,Burgess, 1996 ).

Back to the Teacher

Classroom teachen are burdened with the safety, weilness, aud learning of their

students. as weU as administrative chores associateci with aitendauce and formal progress

reporting. These duties have recently expandecf to include issues of school governance as a

part of the current potitical climate (personal experieace). Enlisting teacher involvement in

the evaluation of student behaviour, toward a diagnosis of ADHD may be h g h t with

problems, since a blind partnership, as described earlier, appears to be the current status quo.

h order to bring an end to this unsatisfbctory situation, it may be appropriate for teachers and

prospective teachers to undertake lemming about the diagnostic criteria and the appropriate

differentiation of this condition nom other ihesses with similar presentations. It may also

be useful for teachen to apply considerable critical thought to the popular advocacy of

stimulant therapy which appears to be gaining a great deal of momentum.

Further to that perspective, and assuming that the classroom tacher's primary

concems are the leaTning, hedth, and s a f i of students, in addition to concems about the

richness of students' fritures, the uncontested follow-up reports which deny long-term

benefits of stimulant therapy ( Barkley, 1977; Weiss et al., 1985; Claude et ai., 19%) should

herald ciramatic changes to classroom teachers' involvement in the diagnostic process.

Teacher resinance to blindly rendering evaluations may encourage appropriate investigation

and exclusion of a variety of pathologies, as well as leading to interventions which do not

involve drugging children into quiet submission Teachers need a clear understandimg of

alternative perspectives, as weU as the diagnostic critena for ADHD. Such an informeci

20

approach is one reasonable means by which teachers may extticate themselves from their

current and unfortunate involvement in this diagnostic process. Some consmictive

suggestions for altering teacher participation in this process will be postuiated later.

This integration of the various factors in the Literature which support the exorphin

hypothesis in ADHD offers teachers insight and understanding which has heretofore been

unavaiIable to them. obxured by the parlance of medicai research, and the relative

inaccessibility ofthe literanire which embodies that specidized and exclusive language. It also

odrs a safe and effective intervention for that part of the ADHD population afEiicted by one

or more of the several conditions by which exorphins alter their behaviour. Part of the

joumey to understanding ADHD behaviour in light of this perspective will first require that

we explore the DSM IV diagnostic criteria. in relation to the advity of exorphui$ which

wili foliow in the next chapter.

Cbapter Two

Eow Exorphins May Conneet With ADHD Diagnostic Criteria

The DSM IV is the most recent version of this highiy regarded publication which is

produced by the American Psychiatnc M a t i o n . It is a manuai that reflects both the

current understanding of various mental disorders and the standards of diagnosis in North

America and other parts of the world. Ongoing revisions to the DSM N ennire that it

reff ects contemporary concepts in the evolving understandins of ADHD.

According to the DSM IV, the fkst set of criteria for identifling ADHD are either

a combination of hyperaaive and impulsive behaviour, or inattention. The second criterion

is that these symptoms be present and problematic prior to age seven. Third, the problematic

symptoms mua be present in more than one setting, which seems a reasonable means of

avoiding an inaccurate diagnosis where there is a personaiity wnflict, or some sirnüar

problem. The fourth critenon requires that these symptoni. mua cause "significant

impairment of socid, academic, or occupational hctioning."

Comparative evaluations may be appropriate

These features are comparative, based on the usual behaviours of the subject7s peas.

Whereas such comparative evaluations may seem Uisupportably subjective, suggesting a

weakness in the underiying criteri% such criticism may not be warranteci. We judge body

temperature by similar cornparisons to the nom, yet body temperature measwement is

thought to be quite objective. Body temperature n o m are weU understood among

pracùtioners in appropriate professional venues. Dierentiation f?om other disorders, and

attendant ethical issues notwithstanding, teachers appear to command the greatest '

22

competence in identifying behaviour which is either consistent with, or divergent nom the

nom for student groups with whom these teachers work (Martin, Wdsh, McKay, Bareuther,

1984; Hasiam. a al- 1984; Taylor, et al. 199 1).

It follows that teachers are ofien best able to ident@ usual and unusual behaviour in

th& students, and that this is a judgement based on c o m p a r i s ~ which does not n e c e s d y

compromise that assessment. In the interest of clarity, I will repeat that it does not follow

that teachen have demonstrated competence to differentiate ADHD fiom other medical

disorders, thus they are not competent to diagnose ADHD simply be*uw they are arguably

best able to idenhfy chiidren who present with unusuai behaviour. Such unusual behaviour

might stem from a variety of medical problems ranghg corn ce& disease, to hypogiyceniia

to abnormal thyroid fbnction, su it is the Iegitimate province of the medical practitioner to

differentiate ADHD f?om medical conditions. According to Barkley (1990) extensive

difrentiation of ADHD tiom other, similar conditions has ofien not received appropriate

attention h m the medical practitioner:

"in the past such examinations have often been bnef. relatively s~peficiai, and as a

resdt ofien unreiiable and invaiid for achieving a dianosis of ADHD or identifying

comorbid bebavioral, psychiatnc and educational conditions. "

This problem may result tiom excessive reliance upon teachers' reports on student

behaviour.

Differentiation

Block (1997) provides an indepth discussion of the overlap in signs of both

hypoglycemia and hypenhyroidism with the signs of ADHD, yet how rnany diagnoses of

23

ADHD have involved thorough-t&g for, and exclusion of these other ailments? She

explains how the impulsive patient with hypoglycemia becornes very agitated as hermis blood

sugar levels &op. and how this is very easy to contiise with other types of impulsive

behaviour. She also reports that severai of her patients had previously been prescnied

stimulants when simple blood tests rwealed thyroid disorders.

Reduced attention to differentiation may be rooted in erroneous assumptions being

made by both professional groups. Physicians may give too much weight to the teacher's

assessment of the child's behaviour. which is arguably fostered by the medical and scientitic

Literature. Once the teacher has completed the questionaries, idemifyug abnomai behaviour.

the Mû's determination of dosage and subsequent prescription may be the ody actions taken.

The diagnostic criteria for ADHD are rarely discemable in the doctor's office (Rapp, 198 1).

The physician is ofken forced to rely upon school records as weil as teacher and parent

reporthg. The peer reviewed Iiterature is very clear in recommending that the physician give

much p a t e r weight to the teacher's assessment of the child's behaviour (Taylor et al. 1991;

Haslam et al. 1984). Barkley (1990). in addition to criticiting perfùnctoiy medical

examinations of the pan, harkens to the possibility of treatable underlying medical conditions.

Additional therapy is needed

The child who is judged hyperactive and impulsive or inattentive, by the teacher, ofien

goes directly to stimulant therapy. Yet, even the Compendium of Pharmaceutical Specialties

(CPS) carries a clear admonition £tom the producer of the most common therapeutic

h u l a r r t , Ritalin- This admonition is that the administration of this drug should comprise oniy

part of the patient's care. How often is this paid more than Iip service? What systemk

24

accommodations have been made for these children, either in the schools, or in the

pediatncian's ofnce? It is doubtfid that more than a handfbl of teachers are even aware of the

additional mdent needs outlined in the CPS. How cm teachers reasonably be srpected to

meet needs they are unaware of? Funher, in a culturai context where there is tittie b d i n g

avaiiable for emergency health-care ne&, it is doubttiil that we can expect medicai or

educational fundins to aid in dealing with the needs of these cMdren

The short-term efficacy of methylphenidate is consistent with the short-sightedness

of much current political thought. Reduction ofgovernmental deficits appears to enjoy greater

political popularity than the provision of adequate care to our children.

Given the economic and political chute, and in spite of the admonition in the CPS,

it is al1 too Eequentiy the case that teacher and medical practitioner aiilce facilitate stimuIant

therapy, without provision of additional aid for the ADHD chiid. Shaywitz (1988) has

expresseci the foliowing concem about stimulants:

The finding that an hcreasing number of children are receiving stimulant

medication to treat hyperactivity and inattention rnay reflect a regressive nep

in which di behavioral and leaming disorciers are lumped together and treated

in the same way.

A patch is thus placed upon the symptoms which trouble the teacher and the problem

chiid's classrnates, but no genuine aid to the child has been rendered. Labelhg a child with

ADHD is of littie value if ody dmg therapy is provideci. Such practices are contrary to the

recommendations in the CPS. contrary to the lirerature, and contrary to the best interests of

the child.

25

Diagnosis of ADHD is most frequently driva by teacher ratings ofcbildren (Taylor,

Sandberg, Thorley, Giles 199 1, p.) 7; Haslam, Dalby, R a d d e r , 1984) in the context of a

process which is often initiateci &er one or more teachers cornplain about the student's

behaviour (persona1 expenence). Many of the same teachers who have cornplained about the

child are then f?equemIy called upon to render f o n d evahations of mident behaviour.

These teachers are unlikely to be trained in procedures for psychiatrie diagnosû, including

the critical features of ADKD and the means of dserentiating ADHD &orn other medical

disorders. There is the additional risk that teachers will incorredy ideaàfy situation-spdc

abnomial behaviour as consistent with ADHD (Taylor et al. 199 1, p.3 7). Despite the DSM

IV diagnostic requirernent that syrnptoms be observed in two or more setthp. teacher

evaluations are given so much weight that a school-based bias may be a built-in feawe of the

current diagnostic process. Observations made at school alone shouid not, accord@ to the

DSM IV, result in a diagnosis. But the reaiity may be contrary to that DSM N provision-

This situation is firaught with hazards for children.

Yet the peer reviewed, medical and scientSc literature harkens to the reliability and

validity of assessments of -dents' behaviours by teachers ( DSM III; DuPa4 Rapport,

Pemello, 199 1 ; Haslam et al 1984; Martin, Welsh, Mc- Bareuther, 1984; Taylor et al.

199 1). Complex rationales in support of this pmtice are oEered in the same Literature (Martin

et al. 1984; DuPaul et al., 1991). One report asserts that because teacher judgements of

leamhg disabilities are more accurate than a combination of standardized tests, that teacher

evaluations are important with regard to both diaposis and "effkcts of trament on chiidren

with disruptive behaviour disorders" (hi Paul, et al., 199 1). One may speculate that the very

26

presence of nich arguments in the literahire is signailhg a problematic relationship which has

developed and which may aiso contriiuîe to some ofthe diagnostic and long-term treaunent

diiculties mentioned earlier.

When ADaD chiidren grow up

It is Linle wonder that foilow-up studies of adults who had undergone long-tenn

stimulant therapy as children show iittle merence fiom matched groups of ADHD patients

who did not undergo such interventions (Barkiey, 1977). Since no sigdicant, long-tem

benefit can be prediaed for the ADHD child on stimulant therapy, the primary benefactors

of such interventions are the ADHD child's teachers, parents, and classrnates, dong with

providing a sipficant income to the manufacturers of these medications The ADHD child's

needs are not being met, but the unpleasant manifestations of their problem are being masked.

This is the Iegacy of stimulant therapy, as reponed in the peer reviewed lïterature. The huge

incorne nom the sale of these dnigs provides an irnmensely powerfd voice ..... one that

ovenvhelms the sound of those who would speak for the best interests of ADHD chiidren.

One of the Ioudest supporters of stimulant therapy is an organizatioa laiown as

CHADD. They gave the appearance of being an independent, non-profit, charitable group of

parents with children suffering fkom ADHD, and adults with ADHD. An expose, last year,

on the popular television news show, 20/20, reveaied that much of this group's fimding cornes

direaly f?om Ciba Giegy, the manufacturer of the most commonly prescribed form of

methylphenidate, Ritah. Dietary interventions do not enjoy the profitability that dows for

the extensive fhding provided to CHADD and stimulant research. It wodd probably be in

the best interests of such dmg manufàcturers to fund work aimed at dimedithg dietary

ïntenemions, although 1 bave no.knowledge of nich practices.

Perhaps due to our society's predilection for pharmacology, there is comparatively

M e pubiished work on the exploration of dietary interventions. This may be due to the

absence of economic incentives for investment in such investigations. Of coune, it does not

appear to be in the best hteresu of pharmaceutical mi111Uracturers to invest in exploring the

efficacy of dietary interventions in association with any condition, and it seerns urneasonable

to expect them to fÙnd work Uiat would undennine their sales.

Why do stimulants sedate?

Aaother venue that warrants investigation, but is unlikely to be Nnded by those with

an eye to profits in the marketplace, is the apparently contradictory finding that stimulant

therapy has a calming effect on many hyperactive ADHD subjects while diminishing the

symptoms of many who present primarily with inattention It is a contradiction which may

reveal something of the underiying dynamics of ADHD. These stimulants have a calming

&ect on hyperactive children, while causing a mitigating eEect upon the apparently opposite

symptoms of the lethargic, inattentive audent. Some concern arising n o m this contradiction

may f d by the wayside, as we h d that stimdant therapy improves attentiveness even in

normal chiidren (Mayor, 1996). Apparently there is somethhg about these stimulants that

u s d y Wta te s increased intentional focus of attention, regadess of whether the pre-drug

status was lethargy, hyperactivity, or rewnably normal attentional capacities. Whether it

aids ~~~g is another question which will be disaisseci shortly, but the apparent

contradiction dso opens the possibility that the methylphenidate counteracts some of the

deleterious effects of exogenous opioids.

28

Many explanations may be offered to explain the second part of this puzzle, which is

that some ADHD children are calmed by stimulant therapy, while others are apparently

invigorated by the sarne intervention The challenge is to undentand how one therapy can

mitigate the symptoms of two apparently opposite presentations, hyperactivity and lethargy,

aitering each to a condition that appears more in keeping with the attentional capacities and

activity levels of the subject's peers. Among the possible explanations is that morphine-like

exorphins are playing a role which is sunilady darnpened or blocked by s ~ u l a n t therapy.

Some exorphins have been demonstrated to elicit hyperactivity (Zioudrou et al. 1979). So

the distinction between the hyperactive and the lethargic ADHD subject may be a fùnction

of individual differences and stimdant tfierapy, ifit interferes with the impact of exorphins,

may thus mitigate both hyperaaivity and hypoactivity in ADHD children.

Exorphins are opioid-acting peptides which denve f?om externaf sources. instead of

being synthesized within the body. These exogenous opioids have been shown to bind to the

sarne cellular receptors that endogenous opioids bind to, thus impacthg on the immune

system, nerve bction, myehation processes, vascular walli, neuromuscular hct ioq and

a variety of C N S fiinctions. As rnay be expeaed, such opioids can have an anaesthetizing,

analgesic. and addictive effect.

Opioids, in general. have been implicated in sleep onset (Wilson, Dorosz , 1984) and

hypothalmic-pituitary-adrend axis fiution ( H o m 1997b). Reduced attention rnay be the

result of the CNS atîachment of opioid-acting exorphias. Some investigation has shown that

many hyperactive children lapse quickly into sleep when they are inactive, and they oflen sleep

very soundly. Lf we see deficits in aîîention as a possible result of opioid advity in the CNS,

29

then the variations between urinary peptides, which have been reported to differentiate the

subgroups of ADHD, rnay support the postulation that some of the exorphins wül result in

hyperactivity, wwhile othen wili inaease hypoactivity. Perfiaps it is the variations in specific

. . circulaihg opioid peptides which determine whetûer will accompany inattention,

but most or aii may cause the characteristic inattention in both sub-groups.

The lethargïc, inattentive ADHD child, and the hyperactive ADHD child may have

much in commoq in that they are both under the idhemx of powerfti anaesthetics.. . . ones

which are similar to those used to aid people who are d i x h g great pain. And the positive

results of stimulant therapy, in that light, may be quite understandable. Perhaps they simply

h c t i o n to counteract some of the gross behaviourai manifestations of the exorpb. But

the elimination of the murce of these exorphins seems a much more sensible approach wIEch

may serve the ADHD d e r e r in two ways. It may d u c e the risk of the comorbidities of

ADHD. whiie it alleviates the debilitating, short-tem symptoms of this condition

Ttie use of chernicals to maçk the symptoms, d e r than getting at the cause of such

ihess seems to embody a less than prudent approach to our children's health. In fact, there

may be cause to see the administration of stimulant thexapy as self-indulgence on the part of

the adults in Our culture. Piiis are much easier and les costly than the initiation of indepth

medical investigations. perhaps foîlowed by a cornplex dieîary intervention, or some other

therapy appropriate to the fin- of these studies.

Some problems with u ~ a r y peptide filarte patterns

Of course, the exorphin hypothesis, as applied to ADHD is specuiative, but there is

some h a d objective evidence, as well as some mecdotai reports, which support this

30

perspecbire. As has aiready been mentioned, opioid peptides have been filtered from the urine

of ADHD Ctiirdren, and there is a Merentiating pattem of specific amiw acid sequences and

codtuents in the two sub-groups of ADHD.

The four prhmq problerns with measuement and characterization of urinaiy peptides

in ADHD are:

1. Some asthmatic patients dernonstrate similar peptide excretions, thus denying us

an objective cimgnostic tool for ADHD, and;

2. Some ADHD subjects do not demonstrate these peptide excrdons, and;

3. Increased peptide concentrations are associated with increased severity of ADHD,

and;

4. It is not clear if these opioid peptides have fùnctioned in the CNS prior to

subsequem excretion.

The first problem may just involve a clùncal Merentiation between asthmatics and

ADHD patients. I would not anticipate a great deal of diffidty there.

The second problem may reflect cases of ADHD which result nom some of the 0th

conditions such as those postulateci by Block (1997).

The third problem suggests that ADHD may be located on a continuum *ch wouid

include autism, schizophrenia, and some other meutd illnesses. Of course, this is a political

and a paradigm probiem. From a politicai perspective, recognition of such a continuum would

force increasing resources to be channefleci toward a better understanding of these conditions,

as there wouki be an increased recognition ofthe severity of ADHD when it is associated with

nich more Msibiy serious conditions. The paradigrn âifEcuity associated with this problem is

3 1

rooted in the arbitrary classification of illness which now dominates conventional medical

wisdom, and wodd be challengeci by recognition of nich a continuum. The additiody

arbitrary notion which aiso drives conventional medical wisdo14 that most people are healthy

most of the tirne, would f&ll imo serious question, in light of the broad hazards to humanity

posed by these two very common Western foods. Such paradigms do not change ea~iiy

(Kuhn, 1970).

The founh problem may be one of perception rather than reality. As Hole et al.

(1988) point out, increased circulating exogenous peptides will inhibit the breakdown of

endogenous peptides, thus reducing the overaii breakdown rate of opioid-acting peptides. The

exorphins may thereby have either a direct opioid-induced effect upon some parts of the CNS,

or an indirect e f k t through the preservation of endogenous peptides, or a combination of

both dynamics may contribute to the ADHD condition- Opioid-acting peptides, irrespective

of origin have been shown to induce naairal sleep and sleepiness. Perfiaps the folk-way use

of a warm giass of milk as an aid to sleep onset may have its root in the psychoactive potential

of the opioid peptides found in milk.

Of course, it is important to establish whaher, as the DSM IV requûes, this behaviour

occurs in more than one environment. Problematic behaviours in maay environments would

be consistent with the exorphin hypothesis, as weii as other postulations about the etiology

of this disorder, but would Wecentiate situational problems. Contra-indicating, situational

problems could arise out of personality contlias, Ieaming difnculties, or other issues which

may not be related to, or syrnptomatic of ADHD, but which wodd be likeIy to occur in a

single settuig. ï h e biologic effeas of exorphins are unlikely to be reStncted to one setting,

32

although regdar meals cootaining one or the other, or both d a j r and cereal, for only one

meai of the day could, conceivably, result in syrnptoms which are specific to suigle

environ ment^^ although such a practice seems unükely. Paul et al. ( 1985) have indicated that

exorphins can stay in the circulation of ceiiac children for as long as a year &er consumption

of gluten. Others. however, have suggested that behavioural improvements can be seen within

days of b-g a gluten-fkee diet (Colquhoun & Bunday, 198 1 ).

Agcof-onset criterion

The DSM IV also requires that some symptorns of ADHD mua be recalled as hakg

presented prior to age 7. Few people with problems associated with exorphins would be

missed, except where the initiating agent was exposure to a virus, or trauma, resdting in the

onset of intestinal permeability above that age.

It is clear that the DSM IV criteria would imply the analiment of 7 years of age as

a precondition of diagnosis of ADHD, yet diagnosis requires the preseace of some ADHD

symptoms prior to that age. There is a cognitive dissonance here (Barkley, 1997) as weii as

the possibility that in iight of the exorphin hypothesis this may be a mon unfomuuite feature

of these criteria.

if ADHD is ofien the result of dietary opioids, and since cell dierentiation is

completed prior to that age, there may be some permanent damage which rnight have been

reversible at an eariier age, through dietary changes. Paul, Henker. Todt, and Eyesold (1985)

offer a ciear argument, in this regard, for children with celiac disease. The same consideration

may dso apply to children with food-induced ADHD. The literature is clear that at least some

cases of ADHD are food induced. The ody r d issue under debate is the proportion of

ADHD children whose diet is partially or totally resulting in their problems.

The requirement that symptoms appear prior to age 7 has corne under anack nom

other directions. Barkley and Biederman ( 1 997) have stated:

No nippon exists for the selection of age 7 years for onset of a valid

disorder. either for syrnptom onset or for onset of impairment.

Another group indicated that many diagnoses of ADHD primariiy characterized by

inattention would be missecl if the age of onset was blindly accepted (Applegate, Lahey, Hart.

B i e d e m Hynd Barkley, Oiiendick, F& Greenhill. McBumett, Newcom, Kerdyk

Garhkie, Waldman, ShaEer, 1997). On one hami, I am asking that less attention be paid to

the age-of-onset aitenon, whiie 1 have previously argueci for increased attention to the

ditferentiation of ADHD corn other pathologies which can be identified via standard blood

tests.

Considerable overlap between ADHD children, and those with untreared d a c disease

aiso exists in the frequency with which their condition interferes with their social, academic,

or occupational firnction. Many celiac chilàren are withdrawu, emotionally volatile,

argumentative, and resistant to direction, as are many children &cted by ADHD. It must

be conceded that such unpleasant behaviours may also present in a va&y of other conditions,

and celiac disease is offered as a mode1 for behavioural impact of exogenous opioids. and

cenainly not as a blanket diagnosis of aii cases of ADHD.

Differentiation fmm celiac disease

The ha1 diagnostic criterion in the DSM IV is that the symptoms of ADHD shouid

be differentiated from other disorders. Few, if any, diagnoses of ADHD have been

34

differentiated nom celiac disease with an endoscopic biopsy, the curent gold standard for the

diagosis of the latta condition Given the wide spectnim of p r e ~ e ~ ~ g symptoms, beyond

infancy, it is probably not possible to accurately differentiate this disease in any mamer other

than serological testing or endoscopic biopsy. A majority ofchildren with untreated cehac

disease past the age of 7 do not present with classic symptoms of celiac dwase (Fasano

1997), yet celiac disease is uniike1y to be in the Merential for most, and perhaps aU

practitioners diagnosbg A D m . Again, 1 do not niggest that celiac dkease accounts for

more than a smaii minority of cases of ADHD. But it c m serve as a model where

behavioural features and exogenous opioids causing EEG theta production which is very

sunilar to that seen in ADHD, are weii documented (Kozlowska, 199 1; Paul et al.. 1985) .

It is dm an important dserential diagnosis to make, given the ciramatic increase in risk of

malignancy among those with untreated celiac disease (Hoggan 1997b).

Vanety of ADaD presentations

Further to the requirement that the symptoms of ADHD be Merentiated fkom other

disorders, it should be noted that this is not an easy task It sornetimes seems that

presentations of ADHD are almost as various as the number of ADHD diagnoses rendered.

This is also consistent with the exorphin hypothesis. Varieties of known e x o r p b interacting

or acting singly should predict a broad array of distinct pretamions of ADHD. The degrees

of severity may also be expected to Vary according to levels of deficiency of digestive

enzymes, quantity of daiy products and cereal grains consume& dong with a host of other

enwonmentai and interna1 factors.

Since there are Bve known types of opioids which have been isolated fkom proteins

35

in wheat, and eight which have been isolateci nom miik proteins the number of possibie

variations in presentations should amount to the square of the sum ofthese two numbers. This

computation ignores variations wbich may arise fiom variations in immune responses,

quantities consumed, as wel as other pady digested food particles and a variety of fod

additives which may be entering the blood via the route prepared by dmgs+ idkction, or food-

indu& intestinal permeability which will be discussed at 1engt.h in a subsequent chapter. It

is clear that the variety of possible presentations of ADHD, if exogenous peptides are an

etiologic fictor in this syndrome. is very large indeed. Differentiation of ADHD can be a

difficult t& a d the Exorphin hypothesis offers a very good explaaation for this difficuky,

as well as offering nrong inducement for including both milk protein intolerance and gluten

intolerance in the differential diagnosis of ADHD.

Failure to diffefentiate these conditions may lead, by default, to children being denied

treatment of another condition which may have some very serious, Iife-tbreatening and

debilitating sequelae. The administration of stimulants without tust excluding gluten

imolerance, cm lead to a very high nsk of a variety of rnalignancies (Hogga 199%) but it

can also lead to epilepsy, crippling nemoIogical disease, and serious skeletal and articular

maladies, al1 of which may have been averted by accurate diagnosis, and appropriate

t r m e a t .

%me anecdotal evidence

Dietary exclusion of giuten and davy may provide a r a i and lasting answer for rnany

who d e r fkom ADHD. Appendices one, two, and six provide examples of the realization

of just such a possibility.

36

The first is about b e n , a young f i o w who did not mwnt a disCernable IgA or IQG

immune response to gluten, but who bas experienced great bene* nom the gluten-Eee diet.

This is one problem with seeking evidence of immune responses against giiadins or casein-

Some people who have an imolerance to these proteins do not seem to mount an immune

response of the sort identified in gluten sensitivity by cu.rrent testing mahods. These f o k do

not have celiac disease, but they are cleariy intoierant, as is wimessed by cfiange~ in their

behaviour during âktary exciusion of gluten and dairy products. Most, including the patients

themseives, would agree that the changes are large improvements-

The reverse of lewen's situation was a h report@ in a magazine article which bas

been submitted for publication (Hoggan & Fasano, 1998). The principles have chosen to

remain anonymous to avoid further victimking a young man who has aiready paid too great

a pnce for the medical profission's Mure to diagnose his ceiiac disease at a much earlier

date. The article chronicles the various diagnoses and events whkh cventually led to bis

cormitment to a mena hospital. It does little to recount the emotional anguish he and his

parents suffered. Therapists joined with other hedth care professionals who attended their

son, and chastised the parents hr th& p r parentmg skills. It is quite conceivable that this

young man could have languished for most of his life in a senes of institutions untii he

evamially sucaimbed to one of the deadly sequehe of celiac disease. He was diagnoseci with

ADHD at an eariy point in his Me. Consistent with the dramatic rates of under-diagnosis of

celiac disease, he was labeiied as having this psychiatrie disocder without ever having been

tested for food intolerances.

In spite of many allergies, a slight build, cüfiïculty swallowing, and abdominal distress,

37

this young man was never investigated for celiac disease untii after he had very nearly

Mled by the combination of phannaceutids he was given to deal with bis allergies and bis

psychiatnc symptorns. It is amaMg that we continue to listen more caremy to apparently

objective claims, to the exclusion of simple symptom reports nom This young

fellow's dismissal was tantamount to d e n a his voice. He was silenced on the issue of hû

own health and almost died because of& proces. Perhaps the lesson it teaches is

that we need to genuinely listen to chikiren.

Appendix two is a summary of examples of gluten-induced anger in the children of

people with celiac disease. It is written by Carol. who has celiac disease herse& yet she

misseci the possibility in her own child. Responses fiom other parents have motivated her to

have the child tested for celiac disease. This mger and aggressive behaviour may well be

similar to that demonstrated in m q ADHD children, perhaps arising out of shilar causes.

Anyone who is knowiedgeable in the r e h ofceliac disease and giuten-induced behavioural

abnormalities d recognize the chara&&, violent, irratiod anger.

These accounts offer an intereshg perspective on ADHD and a compelling

comection with gluten. It wouid appear that the gluten, and perbaps the derivative exorphins

were at the root of the attentional and behaviod syrnptorns recounted in these anecdotes.

1 have seen accounts of s d a r reactions to dauy produas. There may be other foods

that warrant investigation as weU. Perhaps the most salient issue here is that humanity has

ody consumed these foods for a very short period, in evolutionary terms. Aithough gluten-

contaiaing grains have been cultivated for 10.000 years, and dajr products have been

consumed for 5,000 years, some cultures have been consuming them for ody a few decades,

38

while others for only a few centuries. That is a very short h e , and is probabb insufncia

for adaptation, especiaily &ce the maay of the more lethal sequefae may not devdop umil

weU after puberty, and heace reproductive capacity.

Appendix four is a discussion of some of the health problems associated with early

cultures adapting to cereals. aven the rates of both autoimmunity and ADHD m o n .

indigenous Amerindian populations, there may be more value to a more traditional diet for

ttLese foiks than the celebration of their traditional culture. There may be Mme genuine health

benefits. The incidence of type II diabetes in these hereditary groups as was discussed

earlier, wrtainly supports the notion thaî a more traditional diet may lead to improved

physicai and mental heaith, as weii as improving ademic prospects in this group.

Vijahur Stefmson (1960) has suggested a Link between health problems ammg

North American Natives, and the Western diet. He did not iden* gluten or dais, produas

as spe!cificdy problematic, but these may well be the elements of the European diet that

caused the pro blems Stefàosson observeci and reported.

Most of the industrial worid is now consuming large quantities of gluten-containhg

grains. These grains have k e n demonstrateci to compromise absorption of calcium and other

minerals in everyone consuming then For a Sgoificaat minority of the population, a host of

heatth problems accompany the comumption of these grains. Tlwe is a great deal of evidence

suggesting that gluten may also contribute to the rapidy increasing incidence of umhgrmcy.

Gluten has been implicated in the pathogenesis of schizophrenia, bi-polar disorder, obsessive-

compuisive disorder, and autism (Dohan et ai., 1969; Singh & Kay, 1976; Reichelt, et al,

1990a). It does seems very reasonable to suggest that it may aiso be involveci in ADHD.

39

in the absence of a positive response to the exclusion of h w n sources of acorphins,

there is some cause to Ezvour stimulant therapy. ADHD children ofien d e r socidy because

of their behaviod (imitations. Stimuiants may help a child to avert serious injury to both

seIfksteem and social d d o p m e m , through allowing the student to "fit in" with peas.

Interference with classrnates' leaming may also lead to social difiiculties for the child, and

wch interference is fess ükeiy during stimulant therapy, but this does not obviate the need to

differentiate ADHD fkom food intoierance disease prior to considerhg stimulants.

Appendix f i e offers a description of one person's experience with stimuiant thaapy,

when the underiyhg pathology was gluten intolenuice. The stimulant was a very effective tool

for calming this boy. What he redy needed, however, was a conscientious physician to

explore the other possible causes of his learning and behaviour problems, including the

possibility of food intolerance disease. An understanding of the identification and action of

exorpb could du, have contributeci to the child's wel being, but that research had not yet

been done when he was in school.

Summary

In spite of the benefits of stimulants, the curent &uat.ion may sometimes be seen as

tantamount to teachers prescnbing methylphenidate.. . . . . a responsibdity that certainly should

not lie with teachers. It m y also be seen as a cultural abandonment of these children, since

we are not pursuing an accurate diagnosis of the mddying pathology, whether thyroiditis,

hypoglycemia, food intolemnce diseases, sensitivities to food additives, or a combination

thereof; wbich require medical interventions, other than h u h t s , for the good heaith and

fbture pros* of the cMd. Cwent diagnostic practices often fail to differentiate these

40

other conditions fiom ADHD. Masking the pptoms of such conditions with stimulants may

deny these children appropriate medical and/or di- intervention.

The time has corne for extensive research of this question The next chaprer will

discuss a number of reported connections between exorphins, food intolerance, and ADHD.

These connections may sugges similar dietary m e r s for many children currendy conSigmi

to lives with poor long-tem prospects.

Chapter Three

Convergiog data: Exorpbins: Food Lntolerance; and ADHD

The exorphin hypothesis offers to aid our understanding of ADHD and this

postulation is supporteci in a variety of converging research reports in the bterature, as weU

as in anecdotal reports fiom parents which were discussed in the previous chapter. Whde no

singie body of evidence could reasonably be expected to move a disceming adherent of

another perspective to consider the exorphin hypotfiesis, it is hoped that the convergence of

multiple and diverse "proofs" wiii invite the thoughtful reader to weful consideration of this

possible explanation for many of the various presentations of ADHD.

The application of the exorphin hypothesis suggests what is probably the least

cornplicated explanation of the greatest number of features of ADHD. Hypoarousai, in

some regions of the brain, has long been recognized as a feawe of ADHD. The possi'bility

that there is a narcotic e e c t ffom opioid peptides is very consistent with such reduced

arousal, with comorbid learning disabilities, and with the DSM IV observation that ADHD

children " ofien appear as if'their mind is elsewhere or as if they are not iistening or did not

hear what has just been said (Cnterion Alc)." The elevated incidence of atopy in ADHD

(Boris & Mandel, 1994; Breakey, 1997) is both parallelied by a similar incidence in food

intolerance disease, and is quite possibly the result of immune system abnonnaiities in

response either to foreign peptides, or nutrient deficiencies, which are reported in association

with celiac disease, other enteropathies, and ADHD. Increased opioid activity in atopic skin

disorden may be implicated through autoimrnunity (Scott, 1996). Delayed myebation and

delayed CNS development, dong with a b n o d t i e s in myelin, CNS, and neurotransmitten

42

are dso reported in wmection with both A . and ce& disease. Opioids have been

implicated, in ammal studiesy in delaying neuron and giial development (Zagos

1990) dendrite development (Hauser, M c L a u w Zagon, MW), and brain developmen?

(Zagon, McLaughlus 1984). AdditionalJy, abnormalities in mood and behaviour, are also

rqorted in food intolerance disease and are a definhg characteristic of ADm, as was

rnentioned d e r .

Each of these points of convergence have been reported in the medical fiterature as

sisnifiady connectai with ADHD, food intolerance disease, and opioid or opiate activity.

The challenge is to bring together all the disparate evidence in a cohesive and cogent manner.

Examination of the cornplex web of evidence that exorphins are a large fâctor in a majority

of cases of ADHD, Eddy presented hae, seems iikeiy to sway even the most skeptical reader

to consider the exorphin hypothesis in ADHD.

This hypothesis provides possibie explmations for variations in severity, various

presentations, and many of the wide m y of comorbidities. To fùrther this discussion, it wiU

be necessary to engage in a more detailed exploration of peptide structureT intestinai

permeability, and food protein imolerance diseases. It wili also be valuable to explore the

double-bhd trials which first suggested the existence of exorphins, the fhctional smilarity

of exorphins to morphine, the role of opioids in essenbal fany acid metaboiism, opioid-

related alterations to the immune system, brain development and perfiision abnormalities

in the neurotransrnitters, serotonin and dopamine, mineml deficiencies, and finslllyy how these

làeton may undeday the various signs and symptoms of ADHD.

Peptide Structure

43

Since exorphins are the focal point of this discusnon. and suice they are peptides of

specific origin, it may be valuable to provide a brief explmation of peptides. While

exorphim. by definition., are derived fkom the breakdown of fooddaived proteins, and may

thus be understood as partial proteins, peptides are chahs of amino acids which may also be

synthesized in a dehydrathg, covalent bonding process (Tortora & Grabowski 1996). In

other words, peptides may be synthesized fiom individual amino acids, or they may be the

result of p a d d y degradins proteios.

WMe we are curtendy aware of about twenty amino acids there is a vast number of

proteins and peptides. Proteins are complex structures, the details of which are beyond the

scope of this discussion. It will be sdficient to recognize that proteins can and do CiifFer quite

dramaticaliy fiom each other. both on the basis of constituent amino atids, and the s p d c

sequence of these amino acids in the prUnary structure of the protein.

imagine a language where there are twenty letters in the alphabet, and word length

can Vary fiom two Ietters, as in a dipeptide (Tortora & Grabowski 1996), to 800 letters, as

in the primary structure of high molecular weiight glutenin 0:ukudome & Yoshikawa 1992)

and other proteins with even more complex structures can exceed 2,000 amino acids (Beaver,

1998). This suggests an almost f i t e number of possible combinations in peptides and

protehs of distinct structures. That is the language of peptides and proteins.

It is a langwge that speaks directiy to the human digestion process, which cleaves the

peptide bonds in dietary proteins, through a variety of mechanicd and chernicd processes,

dtimately depding these proteins to constituent amino acids which can then be absorbeci

the intestinal wail, and into the circulation as numents. In addition to the provision

44

of water, acids, and mechanical insult, to faciltate this liberation of amino acids fiom the

proteins of which they are constituents, the gastrointestmal tract mua provide catdysts to

speed the chernical cleavage of these peptide bonds, in the breakdown of dietary protein. In

the absence of such atalysts the process would be impossibly slow (Tortora & Grabowski,

1996).

Digestive enzymes serve as such catalysts. Beginning with salivary excretioas in the

mouth, Our food is exposed to a very wide variety of enzymes as it makes its passage thou&

us. These enzymes often target particdu covalent bonds. Thus the absence or reduced

quantity of s p d c enzymes may herald the s u ~ v a l of some of these peptide bonds, and

herein lies one of the preconditions for exorphins to act as etiologic factors in ADHD.

The exorphins are peptides which result nom incornplete digestion of prote* and

by themselves may lack significance. However, when such produas of enzymatic deficiency

are coupled with intestinal permeability, there is a host of problems which may be in the

o e s , whm consuming a modem Western diet. includïng ADHD. If these peptides are

dowed to enter the circulation, they can act upon the body in ways sùnilar to narcotics,

and/or endogenous opioid peptides.

Intestinal permeability

Intestinal pemeability is a condition where rnacrornolecules are aiiowed to pass

through the intestinal wall. and into the bloodstrearn. Such large m o l d e s may comprise in-

tact protek, or partial proteins, known as poly-peptides, with lengthy chahs of amino acids.

Since a h d t h y intestinal waU fiindons as a barrier against dangerous foreign

substances, such as viraI and bacterial agents, intestinal permeability in a heaithy organism

45

shodd bar passage of the vast majority of dietary proteins and large peptides. Coaversely.

there should be suffitient perrneability to allow for efficient transport of nutrients. The

intestinal barrïer should bar uifkctious agents and undegraded or p d y degraded dietary

protek whiie permitting passage of amino acid nutrients. If there is hcreased intestinal

permeability, this p ro tdve function of the intestinal wall is compromised.

Where there is enzymatic deficiency in combination with increased intestinal

permeability. the hdings of Zioudrou et al. ( 1979) take on a powerflll significance. There

cm be linle doubt that in such cases, exorphins would be entering the circulation. Those who

test positive for IgG anti-giiadin antibodies, approximately 15% of a randorn sample

(Amason, et al., 1992), may identify most of those who have intestinal permeability.

Even where there are adequate digestive enzymes, it seems reasonable to suggest that

increased intestinal penneability may result in the absorption of a d number of exorphins

which would otherwise have remained in the intestinal lumen for M e r digestion.

Passage of whole and partiy digesteci proteios has been estabiished evea in heaithy

subjects (Husby et al, 1985 ). Zioudrou et al. (1979) have identifieci some opioid peptides

in the digests of wheat prolamines and dairy proteins which have opioid activity. and

Fukudome and Yoshikawa (1992) have since ctiaracterired 1 5 separate amino acid sequences

of gluten-exorphin A-5 in a single rnolecuie of wheat. It wodd be surprishg if there were not

some quantity of these psychoactive peptides entering the blood of a sigdcant number of

people consurning a Western diet . It bears noting that four other opioid-acting amino acid

sequences have also been identified in wheat protein and may also occur in multiple regions

of the proteins in this very comrnon food ( Fukudome & Yoshikawa, 1992).

46

It is thus clear that the exorphins which are herein postdateci as undetfyhg ADHD

can be deriveci t?om the incomplete disests ofaiwhol soluble proteins found in the conmion

cereai grains: wheat; rye; bariey, and perhaps oats, as well as from the incornplete digests of

daky products. It is also likely that passage of at least some of these exorphins into the blwd,

as is witnessed by anti-ghadin antiiodies, is occmhg in at least 15% of the random

population mentioned earlier (Anuison, et al., 19%). There is dso a sisntficant population of

patients with autism, schizophrenia, and bi-polar disorder, many of whom do not mount a

discernabfe antibody response to these proteins, but whose symptoms improve on a diet which

excludes them (Reichelt, 1 9%).

One sequence of amho acids which has been i d d e c l in abundant quantity in both

wheat and cow's milk is similar to melanocyte-stimdahg-hormone-release-inhibitin8 fâctor

(ME) which has been shown to enhance CNS dopaminergic activity in aallnas (Mycroft et

ai. 1982). A condition of increased central dopamùiergic activity has long been associated

with ADHD and a Mnety of other psychiatric conditions (a Daly, Heron, Hawi, Fitzgerald.

1997; Ras& Shaywitz, ShaywÏtz, Anderson, Cohen, 1984).

The earliest report that opioid peptides could be denved fiom food proteins is

probably that of Zioudrou et a1.(1979). This group named exorphins and established their

functional sindarity to morphine. They reporteci that Naloxone. a morphine antagonist,

blocked 70% of gluten-derived exorphin activity, while blocking IOWA of milk-derived

exorphin activity. Ammal studies conduaed by the same group show that these exorphins will

bind to opiate receptors in the brain. Gluten-derived opioids are thought to have a much

greater potency than those derived fiom rn& and the fonner are claimed to have a potency

47

that is a d MOU of that of morphine (Huebner. Lieberman. Rubino, Wail, l984), so the

signs of behavioural impact would likely be much more subtle than is seen in morphine

addiction.

Recognition of Qluten and dairy products as the source of such daqerous peptides

is relatively new. There was evidence almost thirty years ago, fkom double blind trials that

some schizophrenics benefked fiom exclusion of gluten and dairy from theù diets (Dom et

al, 1969; Singh & Kay, 1976). Apparentiy no other information was then available to expiain

the postulated pathogenic nature of these foods.

The earliest report was fiom Dohan et al. (1969). A total of 102 patients, on a

locked ward, participateci and everyone in the experimental group showed improvement

which apparently resuited nom the dietary intervention. The patients in question were

released eariier than previous patients who had consumed a regdar diet These positive

results were replicated by all the researchers who worked within the clear and simple

parameters outluied by Dohan. It was a decade after publication of the first clinid trial of this

diet with sckophrenics, that Zioudrou et al. (1979) published their discovery of morphine-

like peptides in the digests of wheat and d a j r produas, thus providing subsequent support

for the application of the exorphin hypothesis to schizophrenia.

The identification and characterization ofthese exorphins foliowed some problematic

attempts to replicate the early trials which had implicated these foods in the pathogenesis of

schizophrenia Davis (1978) and Missides, Venulet, Jenner (1986) and others attempted to

test the thenpeutic value of gluten-fk diets in schizophrenics. Each M e d to cornply with

the original hvestigative methodology established by Dohan et al. (1 969) in several important

48

feahws of their work. Missides et al. (1986) chose to test chronic schizophrenics and other

chronic patients with distinct mental disorders, who had a mean duration ofhospitalization

of more than 4 years. This is a group which Dohan ( 1972) had expressly indicated that he had

littie hope wodd benefit fiom the dietary protocol he and his group had pioneered. Vlissides

et ai. ( 1986) also fded to exclude milk ftom the experimental diet and they allowed relatives

to bMg gats of food, after providing a lia of giuten-containin3 foods to avoid.

Anyone who mounts a f&ly si@cant and rapid response to gluten, and has therefore

foliowed a strict gluten-&ee diet can explain the weakness in this approach Dietary

cornpliance is an intense leaming experience. Erron are the d e , not the exception. as one

learns the pi t f ' s of such a diet in the context of a culture inundated with giuten. The

expatation that relatives could master nich a diet f5om a lia is, at best, foolish. This practice

may be very revealing of the care that was taken with the diet within the hospitaI. 1 find it

astounding that there were any irnprovements, but Viissides et aL(1986) reported some

marginal hprovements among their chronic patients, which did not reach aatisticai

sisnificance.

Similarly, Davis chose trial periods of wmparatively short duration, of s k weeks, and

indudeci milk. It wu, in fact, used as a medium for administerhg the placebo and/or the

gluten in the context of a double- b h d trial. It aiso appears that Davis expected the patients

to mûnage their own cornpliance with the diet, on the basis of a posted copy of "the Coeliac

Society's handbook of acceptable and non-acceptable food and drink". Wheat starch, which

was Iisted as acceptable by that society, has since been s h o w to cause symptoms in a large

majonty of celiac patients studied (Chattrand, Russo, Duhaime, Seidman, 1997). The net

49

resuit was tkî these flawed studies underminecl the solid results of much more defensible

methodologies ernployed by Dohan, et ai, (1969); Sin& & Kay (1974); Reich& (1997) and

others, who had achieved positive results. The casuai amtude toward diet, as refi ected in the

published reports of Vlissides et aL(1986) and Davis (1978) wodd predict their quivocal

and negative results, yet theirs was the work that held sway.

This scenario may lead us to question why scientists would have blithely accepted the

resuits of the weaker midies as legitimate refùtations of the earlier, more mehculous work.

Thomas Kuhn (1970) has addressed a similar question about scientists7 observations. by

c i h g two experhents which offer insight into the m e n t question. Both reports show that

human subjects sometimes see what they expect to see. The fim experiment he cited was

conducted by Bruner and Postman. They flashed playing car& to their subjects, a few of

which had been altered to either black or red, the opposite of the usual colour for that suit.

Subjects quickiy identined the usual playing cards comectly, but they identifieci anomalous

cards as either belonging to the correct suit, based upon the shape of the icons, or the suit

which would be correct for that colour. Hesitation and doubt ody arose when the subjects

were exposed to the anomalous cards for lengthier penods of the. In other words, d e s s

forced to study the issue, they saw what they expected to see, and neatiy fined it into their

current schema.

In another, siniilar experimeat cited by Kuhn, subjects were given eye glasses which

tumed their vision up-side-down. The subjects quickiy adapted to these lenses. Again, the

notion that we see what we expect to see was supporteci. 1 suggest that in the absence of

the later work dmonstrating opioid peptides in these comaion foods, members of the

50

scientific community saw what they expected to see when they read refitations of the

therapeutic ben& of the gluten-ftee, dauy-fiee diet in schizophrenia.

Consequentiy, the eariy work of Dohan et a1.(1969) Sina and Kay ( 1976), and

others had been dismissed as one of the many "blind deys" which are common to science.

and which are weii recogized as valuable because they exclude fiuitless avenues for scientists

who will follow. Thus, the subsequent evidence fiom Mycrofl et al. ( 1982), Fukudome &

Yoshikawa (1992), and Zioudrou et al (1979). about cereds and milk as sources of

psychoactive peptides, had Little impact upon the thinking of researchers investisating

schizophrenia and other mental ilinesses. To most, it was a closed issue. Perhaps the later

work reveaiing exorphins in these foods was imerpreted as an attempt to shore up a fàltering

hypothesis. Fomuiately, a few researchers have continued to recognize the importance of

those clinical trials and the subsequent findings about the constitution of these food-denved

exorphins. These latter few investigaton have pressed forward.

Connections to celiac, schizophrenia, and other intoferanca

Celiac disease, or more cor~ectly~ the dramatic over-representation of celiac di-

among schizophrenics, was the first due Dohan encountered, about 1960 @ohan, 1966).

which eventuaily led him to investigate the gluten-fieeV dairy-free diet in schizophrenia Since

the diet had helped aiieviate psychiatrie symptorns demonstrated by some celiac patients, and

since this food intolerance was over repremted mon3 schizophrenic~~ Dohan wnsidered

the possibility that such a diet might also help schizophrenics. Dohan dedicated much of his

professional life to the scient& investigation of this possibility (Hoggan, 1997a). He, and

a team of health-care professionals, were the nrst to implement a trial of gluten and daky free

diet as part of the treatrnent of schizophremic patients.

Dohan's predilection for rnystery stories may have serveci him weii. He lcnew he had

corne upon some very important dues to understanding schizophrenia. He continueci this

work to the end of bis Me.

'"The day before he died, we got a paper from a scientist in Nonvay, Evidence and

Armments for Schizo~hrenia a s a Dietarv Disease and i? was the last thing 1 read

to him' said his d e Marie. That night, she got as fâr as Page 5 . He died the

folowing moming." (Philadetphia Inquirer, Nov 14, 199 1) (Ronan, 1995).

Dohan had experienced considerable hstration as he aied to disseminate his findings.

His work challenged conventionai medical wisdom in an important way. He was suggesting

that a food which had been consumed by humankind for as long as 10,000 years, was

pathogenic to perhaps as much as 2% of the world's population. If Dohan's claims were

supported, many of the dietary recommendations offered by many physicians throughout

much of the Twentieth Century might be seen as ariskg out of consensus, rather than

scientific thought Dohan's ideas were not weU received. StiIl, there is a recent article

suggehg an immunologicd connedon between ADHD and schizophrenia (Holden, Pakula,

1995).

It is also interesthg that a report published in November of 1997 identifieci reduced

perfusion of the frontal cortex. measured by photon emission cornputeci tomography, in

comection with schizophrenia. It is even more interestins that the patient in question was

nibsequently diagnosed with celiac disease, and foilowing institution of a gluten-fiee diet,

the psychiaaic symptoms resolved and thae was a nomaikation ofblood flow to the &ontal

52

cortex (De Santis, Addolorato, Romito, Caputo, Giordano, Gambassi, Taranto, Manna

Gasbarrhï, 1997). Such techaologicai advances threaten to discredit the wren t medical

paradigm, but history continues to repeat itselfas resistance to new ideas continues to be very

strong, and succumbs only to very compelling evidence.

Institution of Dohan's dietary interventions was a clear outgrowth of Dicke's

discovery of the therapeutic value of a gluten-&ee diet in the treatment of celiac disease,

which was the fh t effective treatment to be found for an iilness that had been characterized

as much as 2,000 yean eariier (Cooke & Holmes. 1984). This disease had a childhood death

rate which was reporteci, more than a c e m q ago, in as much as 75% of one physician's

experience (Gibbons, 1889).

Celiac disease and other food intolerance diseases offer a window of insight into the

possibility that exorphins are pathogenic in ADHD as weiî as a variety of psychiatrie illnesses,

but such a hypothesis rnay be subjected to vigorous resistance, just as Dicke's and Dohan's

work was dismissed and mocked (Hoggan, 1997a). Celiac disease is grossly under-diagnosed,

and many people fd prey to malivcies that could have been prevented (Hoggan, 199%).

The gluten and dairy-fke diet has even been shom to have therapeutic value in the treatment

of rnalignancy (Donaidson, Jundt, Ricour, Sarrazh, Lemerle, Schweisgnith, 1 975; Reading

& Meiilon 1984; Donaidson, 1977).

Early descriptions of ceiiac children characterue them as whiny, impulsive, attention

seeking, sornetimes angry, and a behavioral challenge to their caretaken (Colquhoun &

Bunday, 198 1). Some of these children are hyperactive or given to violent temper tantrums

(appendix 2) others are lethargic. This description may also be applied to most of those

53

people who have been diagnosed with ADHD. Anger and defiance are feahires ofien

reported in untreated celiac patients. Additionally, celiac disease is a condition where there

is an overwhelming body of evidence supporting the involvement of exorphim. Increased

intestinal permeabiliq is a weii recognized feature ofthis disease, and Pmi et ai. (1985) have

stated that when celiac children ingest glutea there is a dose-dependent seventy of EEG

abnonnalities. Kozlowska (199 1) has asserted that these abnormalities are the sarne as those

found in ADHD.

Short sature is another point of convergence between ADHD (Spencer, Biedemian

Harding, O'Donnei!, Faraone, Wilens, 1996) and celiac disease (Amchio, et al., 1988).

Celiac disease is prùnarily seen as a bowel disease which is variously characterized by chronic

constipation N o r diarrhea (Fasano, 1996). ADHD has al- been associated with chronic

constipation (Snow, 1975) and with chronic diarrhea (Kahn 1983).

Although not uniaiiy seen as a cntical feanire of celiac disesse, increased intestinai

pemeability is a consistent feature of this condition (Amam, Bode, Kingstone, Fergusoh

1994; Hoh, Savilahti Koskimies, Lipsanen, Maki, 1994). The presence of IgG class

antibodies against gli- one of the alcohol soluble protein groups in wtieat, in virtuaiiy aii

untreated ceiiacs, is one more indication of increased intesthal perrneabiiity in this condition.

These antibodies may aiso be found in the circulation of many who s a e r with other

conditions, but they are found in the sera of most untreated ceiiac patients (appendix seven).

The association of increased intestinal permeability with untreated celiac disease is so weU

accepted that the more economic testing for such permeability has sometimes been used to

screen for celiac disease (Smecuol Vazquez, Kogan, Cabanne, NiveIoni, Pedreira, Boerr,

54

Maurino, Meddmgs, 1997; Vogehg, Gemer, Wyatt, Lochs, Ferenci, Granditsch, Pemer,

1995). although there Ge critics of such methods who assert that such screening misses the

milder cases of ceiiac disease (Catassi Fabiani, Ratsch, Bonucci, Dotti, Coppa, Giorgi, 1997).

This permeability may expiain the increased incidence of atopy commody reporteci in ceiiac

patients (Kitts, Yuan, Joneja, Scotî, Srilagyi, Amiot, Zarkadas, 1997; Stevens, Comolly.

Murray, McCarthy, 1990; Reading, Watson, Plan, Bir& 197 1; Sandyk Bre- 1983). It

may dso offer insight into similar comorbidmes amoag ADHû subjects (Biedermae

Milberger, Faraone, Guite, Warburtoa 1 994; Breakey, 1 997; Mitchell, et al. 1 987; Stevens,

et al. 1995; h a n , et al. 1987; Stevens, et al. 1996).

There is evidence independent of the ADHD iiterature that atopy such as recurrent

serous otitis media should be investigated for dietary allergens (Nsouli, et ai, 1994). Despire

a weaith of reports of increased Uiner ear infections in ADHD, the possibility of food

intolerance is ignored by many of these investigaton.

if one can accept the possibiiity of increased penneability which is similar although

usually not identical to that found in celiac disease and other food intolerance disease, as a

feature of many cases of ADEID, the next step is to estabiïsh the iikelibood that incompletely

digested peptides, exorphuis, may be over-represented in the ADHD subject's gut, leading

to transport of significant quantities of exorphins into the blood.

Digestive Enzymes

Susceptibiiity to celiac disease is a genetically transrnitted trait which has been

associateci with genetically coded immune system factors identified as human leukocyte

antigens @LA) (Auricchio, Greco, Troncone, 1988). There is a significant association with

55

HLA B8, which has a h been dernonstrateci in to 300/0 of European populatioos

(Ammerman, Cavalli-Svorsa, 1984). Other HLA fkctors have been demonstrated to have an

even stronger association with celiac disease, but the HLA B8 is found in more than 80% of

celiac patients (Cooke & Holmes, 1984). Deficiencies in digestive enzymes are ais0

associated with celiac disease (Dohan 1972; Horvarh, Hom, Bodanszky, Toth, Varadi, 1983;

Leung, Robson, 1996 ).

I f these enzymatic deficiencies are genehcally coded, and if they are si@cantly

associated with HLA B8, there may be cause to believe that a large percentage of our chiIdren

who are af£ücted with ADHD, which also appears to be influenceci by genetic factors, fidl

into the genetic category which codes for HLA B8. Ifthat is the case, then a fdure to cieave

the peptide bonds within some of the exorphins, in combination with increased intestinal

permeability, may lead to absorption o f these macromolecular exorphins into the blood of

ADHD sufferen. Although speculative, confirmation rnay result in changes to current

perspectives on many mental illnesses, incIuding ADHD. It is a scenario which is possible.

Questions of relative rkk are not answerable untii the connections are investigated but there

is some interesting data which support such a genetic possibiiity. Kacmiarski. Kurzatkowska

(1988) have reponed a very high familial incidence ofcow's d k intolerance in the families

(34%) of chiidren with cow's milk intolerance, and a 13.3% f a d y incidence of gluten

intolerance was reveaied in the families of children with celiac disease. There appears to be

a very mong familial pattern of food intolerance, which may also include pattern of

digestive enryme deficiencies. Similar famiiiai patterns have also been obsewed regarding

ADHD patients (Biedermaq Faraone, Keenan, 1992; Sandberg, 1996; Hechtrnan, 1996).

56

Investigation of ADHD subjects for deficiencies of digestive enzymes may thefeby be very

reveaijng.

Imrestigations of children of short stature has revealed that 5% to 200/o of these

childm have celiac disease ( A m d o , et ai, 1988). Growth defi* in ADHD subjects have

recently been reported to be independent of the stimulant therapy, dthough these dnigs had

previously been blamed for this problem, thus illuminating yet another conneetion bween

the two conditions.

The relative risk of malignancy is so drarnatidy greater among untreated d a c

patients, that regardas of whether the exorpbin hypothesis proves to be applicable to

ADHD, it is a matter of some urgency to accurately attirm or deny the possibility. Rapidly

increasing numbers of chiIdren who are diagnosed with ADHD may predict an explosion in

malignancy rates, especidy lymphomas and gastroimestina( adenocarcinornas. If action is

not soon taken and the possibiiity of fkquem, underiying dietary intolerance disease is éther

refbted or supporteci, our negtect of this issue may incur a huge hidden cost.

It is important to note that a deficiency state, not a total absence of such enzymes.

would be a suffiCient pre-condition of the postulation hypothesired above. Neither would the

genetic coding for enzymatic deficiencies consrihite a critical feature of the application of the

exorphin hypothesis to ADHD. The foregohg is purely speculative, but the evidence of atopy,

food allergies, food imolerances, and similar EEG a h o d t i e s in both celiac disease and

ADHD is compeuing. This evidence suggests both increased intestinai penneabiiity, and

pahap, enzymatic ddciency in both ADHD and celiac disease. The genetic, atopic, and

dietary fitcton which have been identifid in celiac disease and ADHD have offered the

57

opportunity for such speculation, but this shodd not be constnied as a critical fuihire of the

central argument of this discussion.

Neither should the above comments be taken to suggest that ADHD and celiac disease

are the same condition. Although there is strong evidence of considerable overlap of the

symptoms of both conditions, aml there may be many cases of untreated celiac disease among

those sufTering from ADHD (see appendix five), it is clear that the ADHD group constitutes

a much larger segment of the population.

It may once have been defensible to overlook celiac disease in the differentiai

diagnosis of ADHD. Celiac disease was previously thought to be rare. New research (Not et

al. 1997) however, has revealed an incidence of about 1 :250 among healthy Amencan blood

donors, and approximately the same incidence among Italian school cbiidren (Ca- et al.,

1996). Occult celiac disease may weU consthte a si@cant portion of ADHD. Undiagnosed

cases of milk protein intolerance, and other protein intolerance diseases may du, comprise

a signifiant percentage of ADHD cases. There is also some evidence suggesting that

intestinal permeability is a feature of most cases of ADHD which wiii be discussed shortly.

For now, it mi& be valuable to examine the rates of intestinal pemeability that have aiready

been reported in the fiterature.

The sarne population of hedthy blood doaors who showed a 1 :250 incidence of celiac

disease, demonstrateci an incidence of antiiodies against gliadin in 4.75% of the subjects

suggesting at least a seventeen fold increase of intestinal permeability compared to the

incidence of celiac disease, but this is in a select population of blood donon. Those witb

anaemia, and other such conditions which are rnuch more common in food intolerances,

58

wodd be excluded &om giving blood. Testing a random population would be much more

Uiformative. An examination of a random population in Iceland revealed that 15% of those

tested demonstrateci elevated antiidies against gliadh, suggesting that 15% of the general

population may have increased intestid permeability. A majonty ofthese folks are not likely

to have celiac disease, but the &bodies indicate that they are mounting an immune response

to the most cornmon food in our Western diet These antibodies imply that rnacromoleailes

of dietary proteins are entering the circulation of at least 15% of the general population, many

of whom are deemed to be healthy. While most of these foks probably do not have celiac

disease, some features of gluten intolerance may be present, and may offer important insights

into ADHD.

Neurologicai Manifestations

Another area of research., which converges with the exorphin hypothesis, but was not

shaped by it, is some work fiom the fields of neurology and gastroenterology, which bave

explored celiac-associated: epilepsy; psychiatrie disturbances; aphasia; depression; centrat and

peripheral newous system demyelination; cerebrovascular disorders; neurornusailar disorden;

and immune system down-regdation through penpheral and central action. Untreated celiac

disease has a reported association with some instances of aii of these conditions.

Additionally, each may be seen as suggestive of one or more of the elements of ADHD.

Psychotic incidents have been reported in ADHD (Pine et al. 1993), which are

responsive to stimulant therapy. These incidents include hallucination and delusions,

symptoms which are cousistent with, but not exclusive to schizophrenia, bi-polar disorder.

and autism. Many of the symptoms describeci by Shannon (1922) in what was, perhaps, the

59

eariiest report of the treatment of ADHD symptoms with di- excIusion, are symptoms

found in ADHD patients, ceiiac patients, and in a variety of mental disordm which may be

implicated in the Exorphin hypothesis. Shannon d e s c n i these children as neurotic. S i e

psychiatrie symptoms are reported in more than 7094 of cehc chilcirem (Kotlowska, 1991).

Comorbidities in ADHD iaciude ianguage and leamhg probiems reported at 32% and

74% respectively (Mitchell, et al. 1986) . It is of more than p a s h g interest that progressive

aphasia and dysarthria have been reported in some cases of untreated ce& âisease (Skully,

Maark, McNeely, McNeely, 1988). In such cases, kingpage cornpetence d y improves

fonowing iostitution of a gluten-fiee diet In ceiiac disease, we may deduce the possibility tbat

e x o r p h were somehow involved m the intaference with language cornpetence. Of course,

other factors in celiac disease may, partly or whoiiy, be the cause of such Imguage and

leamhg problems. Nonetheless, the possibility of exorphin involvement seems quite

arguable. ï h e same also seems possible in the large number of aises of ADHD7 where there

are cornorbid language leaming problems ( Mitchell et al., 1986; Biederman et al. 1996).

Depreuionlscrotonin

Depression has recentîy becorne a concem in ADHD. A number of reports suggest

an important association (Biedeman, Mi& Faraone, 1998; Faraone, B i e d m Weber,

Russell 1998; Katz, Wood, G01âstek4 Auchenbach. GeckIe, 1998; Faraone* Biederman,

Mennin. W o m i a Spencer, 1997). Selective serotoinin re-uptake inhibitor, anti-depressant

medications are reporteci to be effective when used in the treatment of some cases of

depression in ADHD (Fidling, 1996). Depression has also been asserted to be the most

prevalem symptom of celiac disease (Cooke & Holmes 1984) and reported as very mmmon

60

by others ( Addolorato, Stefiinllii, Capristo, Caputo, Gasbamini, 1996; Holmes 1996;

Pellegrino. D'Altiiia, Germano, 1995; HaUert, Astrom, W a i a 1983) which is thought to be

a function of cenaal monoamine metabolkm dydimction (Halert, Martenssoq Allgen, 1982)

or due to reduced serotonin binding sites on the plateiets of celiac patients (Chiaravaloti

Marazziti, Batistini FaviUï Ughi Ceccarelli, Cassano, 1997). Coleman (1 971) has reponed

low platelet serotonin in 88% of the hyperactive children tested. The irnplicit co~ection is

cornpehg.

Molecular Mimierg

Neuropathic presentations of celiac disease aiso include central and peripheral nervous

system demyelination. A variety of explanations have been postulateci for these presentations.

The suggestion which may prove to be of greatest sisnificiince is the notion that molecular

mimicry could underlay an autoimmune attack upon myeh basic protein.

The concept of molecular mimicry arises out of a theoreticai perspective which has

been supported in several important research venues. This concept is currently enjoying

increasing attention, if the volume of publications on this subject can be taken as refleaing

such an increase ( Medline search, March, 1998). The molecdar mjmicry perspective argues

that the incursion of polypeptides hto the circulation lads to selective amibody production.

These antibodies are sensitized to specific amino acid sequences present in the invading

peptide or in a combination o f the invadimg peptide and tissues to which they have bound. I f

similar amino acid sequences are present in protein sauctures within body tissues, the same

amibodies may attack these self ceus, resulting in autoimmune damage to the tissues in

question (Tuckova, Tlaskalova-Hogenova. Farre, Karska, Rossmann, Kolinska, Kocna, 1995;

Oldstone, 1987).

The invading peptides, ifderived fiom a common fmd which is usudy consumed on

a daily basis, such as dairy products or @uten, may thereby incite autoimmunity and

perpeniate it as long as such dietary psactices continue. This, of course, would apply to many

of the autoimmune conditions which have been associated with cetiac disease, iocluduig

neuropathies. It may also apply to neuropathic and other autoimmune conditions which are

often found in ADHD. some of which may have suggested the eariier name for this condition:

4mhima.l brain damagen (Mitchell et al., 1987).

Delayed myeiination and delayed development of CNS morphology have also been

suggested as features of ADHD (Castelianos, 1997; Casteilanos, Giedd Rappoport, 1994;

Hynd, Semrud-Clilceman, Lorys. Novey, Eliopulos, 1990; Semnid-CIikeman, et ai. 1994;

Ucles. Lorente. Rosa, 1996). These are also consistent with the concept of moiecuiar

rnimicry resulting fiom increaseci intestid penneability, combinecl with consumption of

cereals andor dairy products. Delays in neuron, gha, dendrite, and brain development have

also been associated with opioid peptides (Hauser, et al, 1989; Zagon, et al., 1991; Z ~ ~ O R

et al.. 1984).

Another autoimmune condition, thyroiditis is an ailment which is commonly associated

with bath ADHD and food intoierance disease. Bmcker-Davis, Skanilis, Grace,, Benichou,

Hauser, wggs, Weintraub. (1 995) report a 60% incidence of ADHD arnong persons with

res iwce to thyroid hormone. Another group reports a 5.4 % incidence of thyroid

abnonnalities in ADHD, as compared to an incidence of less than 1% in the general

population (Weiss, Stein, Trommer, Fefét04 1993). Freeman (1995). Coullse4 Taha,

62

Ruddell, (1994) and Collin. Sahi , Wstrom, Reunala, Pasternack (1994) al1 report an

hcreased coincidence of autoimmune thyroiditis in association with celiac disease.

Brain morphology and perfusion

The generai size and conformation of the brain, as weli as the supply of nutrients to

the brain also provide important areas of interest. Longer chain fatty acids p a s through the

blood brain banier (BBB) by simple diEusion, and Iipids provide much o f the basic structure

of the membranes and myelin of the brain (Zeisel 1986), which can indiredy alter

neurotransmission. The electroencephalogmn (EEG) is used to measrire some of the braùi's

elearical activity in ADHD (Sattedeld, Scheli, Nicolas. Backs, 1988) dong with other

instruments sucb as magnetic resonance imaging (MRI), (Castellanos, et al. 1994; Hynd

Semrud-Clilceman, Lorys, Novey, Eliopulos, 1990) which can be used to determine quantities

of blood supply to various parts of the brain, and topographie EEG mapping, which can be

used to suggest the extent of myelination, and relative shape and size of various regions of

the b r a as weiî as identifjing characteristic patterns of pathological electrical activity ( Uhiig

et al., 1997).

HypopeIfusion, of some parts of the brah, has been reported in ADHD (Casteflanos,

et al.. 1994) and celiac disease (De Santis, et al. 1997). Cerebrovascuiar disorders have long

been identifid in celiac disease ( Rush, hmaq Bernstein, Carien, Resch, 1977). The

possibility of a conneaion seems worthy of investigation. The cortical atrophy reported in

long terni foiiow up nüdia of subjects who expenenced lengthy periods of stimulant therapy

as youngaers may be the result of reductions in blood nipply as a f'unction of their ADHD

condition, rather than a deleterious result o f eidier stimulant therapy, or substance abuse.

63

Alterations to vasnilar heaith and dilafion may r e d t fiom the same undatying cause in bath

celiac disease and ADHD. In keeping with the exorphin hypothesis, an increased risk of

cerebral vasctllitis has also been reported in legai and Uqal uses of opiate drup (Bnist,

1997).

Metabolicaiiy active areas of the brain command a greater portion of available

circulation (Zeisel, 1986) which would suggest reduced nutritive supply to those areas which

are less active, as may be inferreci in regional hypoarousal. Ceiiac disease has also been

demonstrated to exert an important effect upon vascdar dilation (Rush, et al. 1977; Bye.

Andennam, RobitailIe, Bohane, Andermaun, 1993; Tiaccï, D'Aiessandro, Cantisani, PicciriIli,

Signorini, Peili, Cavdetti, Casteilucci. P a i m e Battis& Federico, 1993; Rush , Inman ,

Bemstein, Carlen , Re& 1986) ) so it may be reasonable to suspect that the reduced blood

supply may result fkom the action of exorphins upon vascular waiis in some regions of the

brain.

This may also support the perspective niggesting a reduced state of arousai in some

regions of the brain, as lowered glucose metabolism has been reported in "medial fiontal,

parietal, and occipital areas"(Semrud-CIikeman M. Filipek P, Biedennan J, Steingard R

Kemedy D. Renshaw P. Bekken K, 1994). Additiondy, according to Castellanos et

d.(1994): "Functional imaging techniques used to pinpoint the specific anatomic substrates

of ADHD have implicated striatiai hypoperfusion and low global Qlucose metabolism.

particularly in fiontai regions" (Castellanos et al., 1994).

Altered brain morphology in ADHD supports the perspective that the problem is

"rooted in the processes ofthe cerebral cortex and some subcortical suuauresn (Levy, Ward,

64

1995). This information may prove duable to future diagonicians. Thaapeutic

intenientions in nutrient delivery to negiected parts of the bain in ADHD may already be a

feature of one type of intervention. Levy reports that " hypopemision of the caudate and

central fiontal lobes, accompanied by relatively hyper-pefised occipital lobes tended to be

reversed by m&.ylphenidaten (Levy, Ward, 1995).

Neuromuscular disorden have recently been reported as the presenting feature of

some cases of celiac disease (Hadjivassiliou et al., 1996, 1997; Cooke & Holmes 1984).

Perhaps sirnilar problems may a h have significance in the increased awkwardness reported

in ADHD (Kinsboume, 1975). In both celiac disease and ADHD, there are reports of many

disorden involving morphoiogical and bctional changes to the centrai and peripheral

nervous systems. In celiac disease, dietaqr intervention has been demonstrated to result in

improvement or remlution, in most cases of these symptoms. In a few mecdotal reports ( s e

appendices one and five, Calquhoun & Bunday, 198 1 ), similarly positive results have been

accomplished through dietary exclusion of gluten or gluten and dairy in ADHD. When two

groups of pathogens, as with gluten and dae, can be demonstrated as the cause of

attentional problems and abnormalities in C N S morphology and perfusion in celiac disease,

the assertion of similar possibilities in the context of ADHD does not seem unreasonable.

Essential Fatty Acids

hother factor which has an impact on brain morphology, and thus, presumably, brain

ninction, is essential fany acids. They are "either of 2 f a q acids that the body requires,

cannot make fiom other substances and Mua therefore get f?om foods" ( Erasmus 1996).

The names of these two EFAs are holeic acid (LA, 18:2w6) and alpha iinolenic acid (LN&

65

l8:3w3). The fonner is commody identined as omega 6, while the latter is commody

referred to as omega 3.

Reduced essential fatty acid (EFA) levels have long been recogized as over-

represented among ADHD patients (Aman, Mitchell. Turbotf 1987; Colquhoun & Bunday

1981; Mitchell, et al. 1987; Stevens, Zentaii, De& Abate, Watkins, Lipp, 1995; Wainwri@

1992 ). Accordmg to Colquhoun and Bunday (1 98 1). "A 1932 description of behaviour in

children with coeliac dwase who have a fat malabsorption problem could be one of the eariier

descriptions of hyperactivity". There is thus cause to suspect that many of the sofi

neurological signs associated with ADKD (Martin. Welsh, McKay, Bareuther, 1984) may be

associated with EFA deficiency (Mitchell et al. 1987). as has been suggested to apply to

ceiiac patients with neuropathic symptoms (Cooke & Hohes, 1984). It is these neurologid

signs which led to the early charactehtions of ADHD as "minimal brain damage" (MitcheU

et al.. 1987) although it was many decades before definitive evidence of altered rnorphology

of the brain, other than repms on pathological electrical activity, would emerge in

connection with what is now called ADHD. With the use of contemporary diagnostic

technology, we are now aware that oniy about 5% of ADHD children show solid evidence

of brain damage (Mitchell et al. 1987). There are developmental and morphologicai

abnormalities, but the terni 'damage' seems to imply mechanical damage, which does not

appear to apply to a large majority of ADHD subjects.

Moreover, in spite of the EFA deficiencies noted earlier, several controlled studies

indicate that EFA supplementation has only minimal, ifany, remedid value in the treatment

of ADHD patients (Aman et al. 1 987; Wainwnght 1 992). The explanation for this situation

66

renains unclear (Mitchell et al. 1987; Stevens et al. 1995). but speculation of maiabsorptioa

or reduced ability to conven fatty acids to loqer chab usatmteci fany acids. and i n a d

metabolism of. or impaired systemic or ceMar transport of EFAs, have di been included

in some of these discoura@g reports (Mitchell et ai. 1987; Stevens et al. 1995; Aman et d.

1987; Colquhoun & Bunday 198 1; Homan, Johnson, Hiitch, 1982; Stevens Zentall, Abate

Kuczec, Burgess, 1996; Wainwnght 1992; Ziesel 1986). The possibility of microvillous

damage, perhaps resulting nom dietary/autoimrnune dynamics, seems to have been *en

Iittle. if any. attention The microdi are the site of absorption of fats, for lymphatic

cransportation to the liver. As fats are not water soluble, they can not be absorbeci directly

into the circulation (Iro~gan 1997~). The unique nature of fat absorption, in combination with

common EFA deficiencies among people with ADHD, provides what may be an important

window through which to view this condition.

A revealing note in al1 of this is that the d l i s h e d comection between S A

deficiency and ADHD (Mitchell et ai. 1987; Stevens et ai. 1995; Aman et al. 1987;

Colquhoun & Bunday 198 1 ; Homan, Johnson, Hatch, 1982; Stevens Zentali, Abate K u c z ~ ,

Burgess, 1996; Wainwright 1992; Ziesel 1986) may suggest an answer to one previously

unexplained anomdy in ADHD. The high male to female ratio in ADHD has been suggested

to be a fiuiction of sender differences in EFA requirements (Colquhoun & Bunday 1981).

As one group put it: "Male anbals require approximateiy three times as much EFAs as

females for normal development" (Mitchell et al. 1987).

An ddit.ional factor related to essential fany acids is that exorphins (opioid peptides)

f?om and wheat cari block PGE formation fiom dihomogamma-linolenic acid (DGLA)

67

(Mitchell et al., 1987). PGE is a series 1 prostaglandin imrotved in a variety of immune ancl

circulatory hctioos (Erasmus, 1996). This may provide another due to the etiology of some

of the reported increases in immune syaem anomalies (Warren, Ode& Warren, Burger.

Maciuiis, Torres, 1995; Mitchell, et al, 1987; Stevens et al. 1995) and abnomaihies in

neuronannnission in many cases of ADHD (Hoshino, Ohno. Yamamoto. Kaneko.

Kumashiro. 1985; Greensberg, Cole- 1976; Haiperh, Newcom, Kopstein, McKay,

Schwartz Siever. Sharma, 1997; Coleman. 1971 )and celiac disease(Chiravdoti et al. 1997;

Hallert, et ai. 1982).

EFAs have a significant impact on phospholipids in the brain Ziesel(1986) telis us

that: "Essentiai fatty acids needed by the brain are obtained fkom the diet They traverse the

blood-brain barrier by translocation throu* endothelid c d membranes. Phospholipids are

synthesited within the brain from these fatty acids and glycerol. Fatty acids are also

precurson for the synthesis of prostaglandh, which are impartant neuromodulatonf'. Thus.

EFA deficiencies, as found in ADHD, are UeIy to impact upon brain structure,

neurotransmission, as weii as immune system fiindon. Such deficiencies of essential fatty

acids are also widely recognked as a common feature of celiac disease.

Others have shown that long chah, omega 3 fatty acids are very concentrated in nerve

tissues, and some omega 6 fatty acids are present in large quantity as functional and

structural components in cerebrai gray matter, and the retina (Wiens, Prince, Frances, 1995).

The ingestion and metabolism of these fats is critical to brain and nerve fiinction, hence the

term 'essential'. The variety of neuropathic syrnptoms often reporteci in ADHD may tuid at

least some explmation in the EFA deficiencies which are now known to be common in

ADHD.

Differentiation between ADHD subjects with omega 6 deficiency and those with

omega 3 EFA deficiency may aiso provide a greater understandin3 of etiological tàcto~s in

the identified sub-categories ofADHD. While omga 3 deficiencies predominate among those

presenting with hyperactivity (Mitchell et al. 1987). behaviour problems. temper tanu~u~is.

sleep, learning, and health problems, are parailelied by findllrgs in animal midies (Stevens et

al.. 1996) further re-reinforcing the suggestion of a relatiooship. Additionally, anunal studies

imply that the increased thirst often found in ADHD subjects may also be attributable to

deficiencies in omega 3 fatty acids (Wainwright, 1992). It is of interest to note that the

effects of DHA deficiency, a derivative of omega 3 fatty acids which may also be found in

fis& marine animais, and some orgaas, require long term deficiency before the composition

of the brain is altered (Wainwright. 1992). If the posnilated comection exïas. it is chronic.

and is thus unlikely to be remedied by interventions of short duration, as are ofien employed

in dietary investigations, ifit can be remedied at ail.

Conversely, "A high rate of speech diïculties was found among the children with low

arachidonic acid levels" (Mitchell et ai., 1987). These latter are synthesized fkom the omega

6 EFA linoleic acid, and they are found in meat, eggs, and milk (Erasmus 1996). Perhaps

the case of aphasia in celiac disease, mentioned earlier (Sculîy, et al., 1988) which slowly

resdved after several months of excluding gluten from the diet, refiects a deficiency in omega

6. The description is very consistent with the e x p l d o n provided by Mitchell et al. (1987)

If so. perhaps the cause of language leaming problems in some cases of ADHD is associateci

with a simiiar problem with absorption of EFA~.

69

ïhere is also evidence that "....cognitive and linguistic problems appear to precede

hyperactivity" (Sandberg 1996). Perhaps, with a greater understanding of EFA defitiencies,

the specific presentatiow of individual ADHD patients' EFA leveis may provide a means of

differentiating sub-groups, ultirnately revealing a food intolerance disease, or losses in

absorptive capacity.

An interesthg contradiction cornes to us nom Aman et ai. (1987) who report: "The

subgroup analyses.. . failed to indicate a diffeCentia.1 response for individuais who were i a i t d y

low or high on these substances," thus undenninuig the therapeutic use of EFAs in ADHD-

But this result may be interpreted in another mamer. Ifmalabsorption is oc&g in varying

degrees, due prirnarily to variations in microvillous morphology, or reduced bile delivery to

the duodenum. or both, then a more EFA deficient child would be less Wcely to ben& nom

supplementation. This wodd be true because the more deficient individual would iikely be

experiencing a more pervasive malabsorption pathology, rather than a dietary insufficiency

of EFAs. On the surfàce then, it is probably quite correct to say that EFA supplememahon

is not an effective therapeutic answer. but this does not obviate EFA deficiency as a very

important factor in ADHD signs and symptoms, and it does reinfiorce the notion of a

p2thoIogical connedon. Colquhoun and Bunday( 198 1) state: "Since an EFA deficiency itself

lads to a defa in fat absorption which will exaggerate the deficiency, a vicious circle codd

resdt" .

There is also the possibifity of reduced cholecystokinin ( C a ) production in the

duodenum (Tortora & Anagnostakos, 1989, p.751), due to damage caused by food

intolerance (Domschke, Bloom, Adrian, L m Bryant, Domschke. 1989). Absence of this

"NOTE TO USERS

Page(s) not included in the original manuscript and are unavailable from the author or university. The manuscript

was microfilmed as received.

This reproduction is the best copy available.

UMI

1986).

Serotonin

An important shared characteristic of neurotra-tters is that they are a h o s

exclusively derived fkom dietary protein or amino acids (Lovenberg, 1986). Serotonin is a

monoamine neurotransmitter which is widely distn'buted through the brah, as well as the rest

of the body (T~nora &Anagnoaakos, 1989). For some researchers, the question is not

whether neurotransmitter dyhct ion is a facet of ADHD. but which neurotraasmitters are

pathologically involved. Dopamine, noradrenaline, and serotonin appear to be the primary

suspects (Sandberg, 1996).

Interestingly, refined wgar may also influence central serotonin levels. It is a

substance which has long been suspecteci to be an Uiitiator of hyperactivity symptoms. This

has been repeatedly refuted in controlled midies. Although more refhed sugar consumption

has been reporteci among ADHD subjects, it appears to reduce d v i t y levels among both

normal controls ami experimental nibjects (Rapoport, 1986) and it has been demonsuateci to

reduce performance on school achievement tests (Egger, Stoila, McEwen, 1992). Perhaps

sugar is at work in attentional deficits, rather thao in hyperactivity. The hyperacivïty might

follow, as something akin to a rebound reaction.

It seems that "dietary dterations in precursor adabdity can mod* neuronal activity"

(Young, 1986). The availability of tryptophan through increased insulio productioq in

response to sugar ingestion, increases uptake of cornpethg large neutrai amino acids into

muscle cells. This inmeases the relative senun concentration of ayptophan, which is resistant

to insulin. ïhe relative increase in senun tryptopb foiiowing a rise in insulin, leads to a

cornpetitive advantage to tryptophan, for transport across the BBB. hcreased tryptophan

has been asserted to lead to increased levels of serotonin in the brain (Krasmer, 1986;

Femsvorn 1986; Wur- 1986; Ziesel 1986). Increased tryptophan can also lead to

drowsiness. and induction of endorp hin analgesia ( Ziesel, 1 986). Poor attentional

performance would seem consistent with this scenario.

Although a bit of a digression, the importance of which will become apparent shody.

it has also been shown that "oral or intravenous administration of gluten exorphins A5 and

B5 can duence the regdation of postprandiai insuiin release"(Fukudome, Shimatsu.

Suganuma Yoshikawa, 1995; S c a Cloutier, Kleemann, Woerz-Pagenstert, Rowseii. Modler.

KoIb, 1997; Scott, 1996).

Thus consumption of sugar or gluten should, other conditions being equai. predict

reduced activity levels. It is of interest to note that hyperactive chiidren appear more likely

to consume greater quantitia of sugar, while the same group also appears to have a superior

appreciation of the stimulant effects of caffeine (Rapoport, 1986) which offers some

interesting vantage points for considerin8 some of the symptomoIogy of ADHD.

There is dso familial evidence to suaest that serotonin deficiency may be involved

in aggressive behaviour, and a poor long-term prognosis for that behaviour (Young, 1986;

Haiperin, Newcom, Kopstein, McKay, Schwarn, Siever, Sharrna, 1997). There appean to

be something of a contradiction here. Hypoarousal is not easily associateci with aggressive

behaviour. To add to the confusion, sugar bas recentiy been demonstrated to alter EEG

patterns among subjects with food-induced ADHD fvhiig, Hoshino, Haskimoto, Okano,

Kumashiro, 1993). These are the contradictory findings reported in the titerature. If the in-

73

vivo action of exorphiru is factored into this array of wofliaing repons, perhaps some of that

contradictory cornplexity WU be reduced.

Dopamine

Dopamine, another monoamine neurotranstnitter. has repeatedly beeu implicated in

ADHD (Raskin et al. 1984; Hanna, Orniy b d m a n , 19961, and is thou@ to be involved

in ~aintaining normal dertness (Raskin et al. 1984) and executive control (Castellanos,

1997). Krassner provides us with a more complete explmation: 'Dopamine is thought to be

involved with emotions through the limbic system motor hct ion through the basai gangha,

some pihsitary hormones through the hypothalamus, and inhibition of the vegetaîive nervous

system through the autonornic gan@ïan0i(nissner, 1986).

As was mentioned earlier, dietary precursor availability can neuronal activity

m e r , 1986). Variations can occur in neurotransmitter release, as a function of variations

in diet " thereby dowing one's nutritionai state to affect one's behaviour"(Wwtman, 1986)

and specific neuronal cells can synthesize neurotransmitten ifthe precursor is avdable in the

diet" (Lovenberg, 1986). Tyrosine is the amino acid precunor of dopamine and epinephrine.

"Brain tyrosine levels are most convenientiy increased by ingesting pure tyrosine done or with

a carbohydrate (to Iower plasma levels of cornpethg LNAA)" (Lovenberg, 1986). Meals

hi@ in protein and carbohydrates also tend to raise tyrosine levels in the brain (Ziesel, 1986).

Thus. the reponed inverse relationship between urinary epinephrine levels and both fidgeting

and aggression among normal children (Hanna et ai., 1996) offen some interesthg hsight

when we look at reports that ADHD subj- show significantiy lower urinary levels of

epinephrine than in controis (Hanna et ai., 1996). Abnormalities in iron absorption may

74

suggest an explmation for this dynamic.

Sandaead (1986) haç suggested, on the basis of animal hdings, that iron may be

required for dopamine receptor fùnction in the caudate nucleus. Monoamine

neurotransmitters, principally dopamine, appear to affect neuronal communication in regions

of the brain invoived in executive hctions (Castellanos, 1997) which, by definition, is a

problem for ADHD patients @SM IV). Given the issues mounding problematic uptake in

iron supplementation associated with ADHD ( O u ho& Helu. Howanitz, 1983; Lozoff.

Viten Urmtia, 1982). in conjunction with evidence of iron requirement for receptor hct ion

(Smdstead, l986), this may be a very important interface of two dietary issues in ADHD and

celiac disease, as will be discussed shortly.

Peptides

Although peptides are not monoamines they do b c t i o n as neurotransmitters.

"Dietary protein serves as the ultirnate precursor for these neuropeptides"(Lovenberg, 1986).

Animal studies suggest, as one possibility, that dopamine release in the brain regions thought

to be most involved in ADHD, may be inhi'bited by peptidergic moduiation (Russeil, De

Vien, Taljaard, 1995). The peptides derived f5om gluten and dairy may or rnay not be

involved in such modulation. We may hope for fùrthw research in this regard. Stein and

S a d t a n o (1 984) offer the possibility that " some hyperkinetic children dBer fiom normal

children in their amino acid and protein metabotism".

Kapuna et al. (1989) have identifieci exogenous and endogenous peptides as

regulaton of kidney bction. Urinary dysfùnction is reported as very common in ADHD

(Maizels, Gandhi Keating, Rosenbaum, 1 993 ).

75

The data on monoamines- provide quite convincing evidence for the beiief that there

may be an interplay between diet and behaviour which is mediated by alterations in

neurotransmission. This can be important at ali levels of under-nutrition (Zeisel 1986 ).

Malabsorption is one means by which under-nutrition may occur in a clinically obscure

fashion ( Hoggq 1997a; 1997b).

Minerai deficiencies

ADHD s i p and symptoms in mineral dediciencies are well describeci (Krassner, 1986;

Sandaead, 1986; Lovenberg, 1986). At the level of neurotransrnission. "Neurons are unique

biochemicai units that have the ability to produce an el- cunent by causing intrace1lula.r

and extracellular exchange of sodium and potassium ions" (Krassner, 1986). Thus.

"macroelements (those present in the body in large amounts). sodium, potassium, calcium and

magnesium are essential for electrophysiologic fûnctionW(Sandstead, 1 986).

Since the parathyroid @and is involved in regdation of calcium and rnagnesium

metabolism, there is another connection with food intolerance provided by the report that IgA

class endomysiurn a n r i e s , which are a very s p d c indicator of celiac disease, can cross-

reaa with parathyroid tissue (Kumar, Valeski, Wortsman. 1996), and low magnesiun levels

have also been associated with fimctionai hypoparathyroid (Bertelloni, 1992). Recent

investigations reveal that the incidence of rnagnesiurn deficiency was found in 95% of ADHD

patients studied, and that remediating that deficiency can result in significant irnprovements

in ADHD symptoms (Starobrat-Hermelin, Kozielec, 1997; Kozielec. Starobrat-Hermelin,

1997). Similady, aii adult-diagnosed ceiiac patients demonstrate some level of bone

deminerakation, compared to the general population, regardless of dietary cornpliance

76

(Green, 1997). Many ceiiac subjects who demonstrate diminished calcium levels show

irnprovements to s e m calcium after magnesiun supplementation alone (Cooke & Holmes.

1984), and magnesium supplementation has been shown to aid bone remineralization, to a

greater degree than calcium and vitamin D supplementation, among treated celiacs (Cooke

& Holrnes, 1984). One report asserts that ai i of a group of celiac patients who underwent

magnesium supplementation dernonstrated si@cant bone remheralizahon (Rude & OIerich

1996).

Some dietary deficiencies of trace minerats may also affect neurotransmitter

hction (Lovenberg, 1986). For instance, iodine deficiency can have a devastating impact

on brain maturation and hction (Saodstead, 1986).

Iron

The proximal duodenum is the site ofmost iron absorption (Cooke & Holmes. 1984;

Barton, 1997). Coincidentaüy, it is usuaiiy the site of eariiest damage induced by protein

intolerance disease (Barton, 1997). It is weil established that iron deficiency, dwing &cal

stages of development, can i d to permanent or iong-stand@ inteliemal and behavioural

deficits (Bushneii, 1992). Iron defkiency syrnptoms have been reported as including

hyperactivity and attention deficits (Anderson, Hrboticky, 1 986; Sandstead, 1 986). Some

treatment interventions such as imramuscular iron therapy, produced signifiant improvement

in behaviour. .. . "(OW Honig, Hely Howani~ 1983). Yet there is a dissonance in reponed

findings. One group States: "We are unable to explain the discrepancy in the ueatment results

between our observation of a response with intrarnuscular iron and the lack of respome with

orai iron"(0lki et al., 1983).

77

The rationale presented for oral iron supplerndon is: "Oral iron was used because

t is the treatment of choice, with a therapeutic response paralel to that of intramudar iron,

and because of the slight risk associated with parenteral administration of uon" (LozoE

Viteri, Urrutia, 1982). In spite of the rhetoric, oral iron did not help. We are le& to wonder

why. Lozoff et al. (1982) su- the possibility of malabsorption, but found no other

evidence to support such a possibility and therefore dismissed it. Many cases of ceiiac

disease are identifid through investigation of the singular presentation of iron deficiency

anemia which is resistant to oral supplementation (Volpe, F e M Torre, Lucchesi, 1997;

Barton, 1997). We must wonder why malabsorption would be dismissed in ADHD with

associated iron deficiency that is resistant to oral supplementation (Lozoff et al.. 1982). Celiac

disease cm cause selective malabsorption of iron (Volpe et al., 1997). The asserted

association, in some cases of iron deficiency, of deficiency of vitamin B 12 and folic acid

(BushneU, 1992) should also increase suspicion of malabsorption, but iron deficiency alone

should significamly elevate suspicion of malabsorptioo disease (Carroccio, Iannino, Cavataio,

Montalto, Turnminello, Campagna, Lipari Notarbartolo, Iacono. 1998).

Another problem can iurk in Our desire to provide children with a healthy diet We

may err in what we feed them: " too much fibre in the diet wiii render available iron

unabsorbable" (Bushneii, 1992). This is arguably the result of phytic acid entering into

combination with the iron, thus forming a bond which m o t be broken by the enzymes in the

sut (Lindeberg, 1997). In support of this suggestion. iron deficiency is also reporred as overly

common where "cereds and legumes are the primary source of energy and protein"

(Sandstead, 1986).

78

Furthet to the rdationship between iron deficiency and ADHD, CantweU is reponed

to have " detected 'sofk' neurological s ips as long as six months der treatment for iron

deficiency anaemia at 6 to 18 months"(lozofF, et al., 1982). Also, leaming disabilities and

attention deficits are sometimes attniutable to iron deficiency anaemia (Bushneîi, 1992).

Other trace minerals

Copper deficiency may also be impticated in some brain damage (Sandstead, 1986).

Whiie such deficiency states are thought to be rare among humans, there is some recent

evidence suggesting that the Western diet may supply only marginal quantities of copper

(Sandstead, 1986). Given marginal dietary sources, any degree of maiabsorption may

compromise adequate copper levels. Hence, copper deficiency rnay underlay some facets of

ADHD related to delayed myelination. Copper deficiency is also reported in celiac disease

(Cooke & Hohes, 1984).

Zinc deficiency has aiso been reported in ADHD. Zinc deficiency indirectiy inhibits

some normal essential fany acid processes through inhibition of specific entymatic acrivity

(Mitchell, et al., 1987; Colquhoun & Bunday, 198 1). Zinc deficiency, as with iron defiuency,

can also result fiom elevated Ievels of fibre with phytic acid in the diet, as with cereals and

legumes (Sandaead. 1986). Animal midies in M C deficiency have revealed developrnental

delays as weU as alterations in neurotransmitter concentrations (Sandstead, 1986). Zinc

deficiency may also be involved in inhibition of growth and is aiso reported in celiac disease

(Cooke & Hohes, 1984).

In total then, mineral deficienci- individdy, or in combination, may result in some

ADHD spptoms, and rnany of these are suggestive of dietary deficiency, or metabolic

79

abnormaiities. Patients with celiac disease appear to SUffer similar denciencies in mon or d

cases.

Electroencephalograms, ADBD, and Exorphins

Perhaps some of the moa cornpeliiq evidence supporthg the pomilated corneaion

between giuteddairy pathoiogy and ADHD may be found in the study of patterns of

electrical activity in the braUi (Kittler, Baldwin, 1970; Ucles. Lorente, Rosa, 1996; Zamerk

Liebenauer, Fitzgerald, King, Mïnkunas, Herscovitch Yamada, Cohea 1993). This is

important evidence which nippons a connection between ADHD and &en holerance, and

which may signal the action of exorphins in the CNS. Exorphins have been shown to bhd to

CNS opiate receptors in rats.

Perhaps the earliest work which showed improvement in ADHD subjects' EEG

patterns, in response to diet, was conducteci by Kinler et aL(1970 ). W e they recognize

that EEG patterns have long been known to be abnormal in some dergic children, they aiso

believe that improvements of such EEG a b n o d t i e s had not previousiy been connected to

dietary changes in those with leaniing problems.

The EEG abwnnalities in food-induced autoimrnUMty such as celiac di- also has

a surprishgly long history in Europe, although I can h d no reports of such work published

in English. In a translation fiom German, Paul et al. (1985) teil us that Sidor & Mitarb and

Karczewska & Mitah suspect this mechanisrn to be the direct effect of the gluten upon the

central nervous system and hence on the brah wave awes, while Paul et al. have reported

their own investigations using EEG, in addition to other techniques. Their EEG

investigations revealed that 38 of 58 (66%) of the celiac chiidren studied showed pathoIogical

80

EEG changes which increased with increased duration of gluten c o ~ p t i o ~ aad that the

long-tenn cornpliance with a gluten-âee diet decreased the probability of pathoiogicd

readings. They go on to provide evidence for a correlation between the extent of mucosal

damage, and the duration of pathological EEG patterns and contend that the psychologicd

s i g s in celiac children reflect a direct or indirect influence of gluten ingestion, and that

damage to the intestinal mucosa is always accompaaied by pathologicd brain waves in the

celiac children studied. Several interpretations for this are: 1. People with damaged srnail

intestines absorb more toxic substance, resultiag in the pathological changes, or; 2. Toxic.

gluten-denved proteins and peptides may cause the pathological changes; 3. Both of the

above dynamics contribute to the pathologicd changes.

KoAowska (1 99 1) has reported a very sirdar incidence of EEG abnormalities in 7 1 %

of the celiac children studied. She has identifieci these abnofmaiities as the same as those

found in ADHD.

The importance of the startling report nom Uhlig et al. ( 1997) is difncult to over-

emphasize. It provides objective evidence for a comection between food intoierance and

ADHD. This group has reporteci their recent hding that topographic mapping patterns fan

be manipulateci by changes to the diet among ADHD subjects. Refined sugar, mük, and

gluten proteins were moa fiequentiy implicated in the ADHD-specific a b n o d t i e s identifieci

in topographic EEG mapping.

Of course, there is aiways the semantic difEicuity that if nmilarïy pathological EEG

patterns are presem in two conditions, then the pattern are sometimes discredited as

characteristic of one condition. For hance, one report indicates that some EEG patterns

81

under specinc conditions may be characteristic of ADHD, but under other circumstances

codd include some other categorks of mental illness (Levy, Ward, 1995). The converse

argument, that there is overlap between these conditions, also seems supporteci by the same

evidence. But perhaps the work of Ulig et al. (1997) in demonstra~g EEG changes

associated with dietary factors among ADHD nibjects wiU W y W t a t e an end to such

debates. Published replications of this group's findings may findy induce pediatricians,

teachers, and parents to engage in a carefid semch for dîetary pathogens prior to leaping for

easy pharrnacologicai answers.

Schmidt et al. (1997) claim that a "biochemical rationale for the dergy hypothesis

is stiIi lacking". This may not be accurate. Ifwe harken to Paul et aL(1985) again, they have

asserted that in celiac chiidren, the pathological brain wave patterns are the direct or indirect

result of gluten ingestion, and that damage to the intestinal mucosa is a necessary

precondition to the EEG abnormalities they studied. But this damage might not aeed to

include villous atrophy among non-celiacs who are suffering from similar symptoms. If we

are looking for a condition in which either dietary antigens or toxic substances cm enter the

blood, then a condition of permeable intestine may sutnce. Aaimal and humm studies

demonstrate that a variety of fomis of gluten-induced damage can occur in the absence of

celiac disease (Hadjivassiliou, Giôson, Davis-Jones, Lobo. Stephenson, Millord-Ward, 1996;

Thibault, Couio~, Roberge. 1988; Levine, Briggs, Harding, Nolte, 1966; Hudson, Purdham,

Corne4 Rolles, 1 976; Doherty, Barry, 198 1 ). This principle may also apply to a variety of

mental illaesses.

As mentioned earlier. Husby et a1.(1985) have dernomatai that many apparently

82

heaithy adults are aiiowing the- passage of gliadin proteins hto the blood. Antighdin

amibodies found in the sera of 15% of a random sample in Iceland (Amasson, et al 1992),

and 4.75% of heaithy blood donors in the USA (Not, et al. 1996) suggest that many of us

absorb partfy digested proteins into our blood. Fulcudome and Yoshikawa have characterized

5 distinct opioid-actins sequences of amino acids in the pepsh digests of wheat gluten. which

are repeated, sometimes as many as 15 times in a single gliadin molecule (Fukudome,

Yoshikawa, 1993), dubbed 'exorphins' (Zioudrou, et al., 1979). Mers have also isolated

such peptides in casein, one of the proteins in m i k (Mycfoft, Wei. Bernardin, Kasarda,

1982).

Perhaps originating with Dohan et al. (1966). and bellig continuai by Reichelt et al.

(1 997) the investigation of dietary proteins in gluten-containhg cereals and m& as regards

a variety of mental ilinesses, has led toward a perspective that an interaction between the

opioid peptides in these foods, and a genetic predisposition, may combine to result in a variety

of des ta t ions . Chical trials have shown that some schizophrenics benefït fkom the di-

exclusion of gluten and daky (Dohan, et al., 1969; Sin@ & Kay, 1976; Reichelt, Sagedal.

Landmark, Sangvic, Eggen. Helge, 1990a; Reichelt, Ekrem Scott, 1990b ). Other work

shows that many autists benefit fkom the same diet (Reichelt, Knivsberg, Linci, Nodland,

1991).

Lovenberg (1986) has indicated that diet could influence behaviour through " the

presence of psychoactive substances in food. Such compounds may bypass neuroaansmitter

synthesis to direaly advate or inhibit specific cell types in the brain". And this is the

perspective herein postulated to be at work in many cases of ADHD. The exorphins are

83

thought to either be transporteci- to the brain, and bction in a maMer sidar to opiates

(Zioudroy et al., 1979) resultiq in reduced alertness of soine parts of the brain, or to inhibit

the breakcîown of other peptides, thus resulting in elevated levels of endogenous opioid

peptides within the brain (Hole, Lingjearde, Morknd, Boler, Diderichsen, Saelid, Ruddd,

R e i c w 1988).

In support of this hypothesis, it has been demonstratecf that "children diagnosed as

having ADD of some severity excrete peptideîontaining complexes in the urine" (Hole, et

al.. 1988). As was previousiy discussed, there is considerable overlap between these groups,

and there also seems to be some relationship between the pattern of urinary complexes and

the presence or absence of hyperactivity (Hole, et al. 1988).

Although the exorphin hypothesis does not require breach of the BBB, it may be

possible that the cytotoxicity of giiacün peptides (Atkins, 1986) provides such a breach.

Cbapter 4

A Mode1 for Esorphin-Lnduccd ADaD

Understandhg ADHD &orn the penpective of the exorphin hypothesis may be aided

by a concrete representation. Whenever such models are proposeci, however. there are

necessary distortions due, in part, to gaps in pertinent data. Nonetheless, provision of such

a mode1 offers to enhance understanding of the concept underlying this document, and is

included despite the inherent risk.

Testing for anti-&adin anhibodies has rendered a range of positive resuits. The lowest

incidence reponed in a random population is 2.3% (Catassi, Ratsch, Fabiani, Rossini,

Bordicchia, Candela, Coppa, GiorW 1994). while the highea reported incidence is 15%

(Amason., et al., 1992). When coupled with the reported incidence range of ADHD, there is

an interesting, dthough not completely congruent picture, as the most common figures

suggest ADHD in 2% to 10% of school aged chiidren (Rowe, 1988, Boris & Mandei,

Casteilanos. 1997). The cornparison becomes ariking when we revisit the proportion of

celiac children who demonstrate ADHD-appearins EEG patterns (Paul et ai.. (1985);

Kozlowska, (1991) which suggest that about two-thirds of celiac children exhibit such

abnomalities. If we can assume that the 70°/0 proportional incidence of ADHD syrnptoms

found in celiac disease could also occur in a population dernonstrating anti-Qliadin antibodies,

then the reponed incidence of such antibodies in random populations. 2.3% to 15% would

suggest an incidence of ADHD at 2% to LI%, which is surprisingly close to what has been

n2poIteded It is such points of convergence that fonn the central th- of this thesis. Of itself,

one such point may aot be interesting. Severai such points of convergence must begin to

85

pique our interest, and a si@cant number of nich points rnay demand consideration. Table

1 offers an outline of twenty sisnificant points of convergence which may be found between

. t K D and food intolerance disease- It dso offers seven significant points of convergence

between elewated anti-giiadin antibodies and ADHD.

Table 4.1 Points of Convergence

Points of Convergence in the Literature

1 Abbreviations: u/k = unloiown; abn. = abnormal; def = deficiency, morph.= rnorphology; diso. = disorder

The above table demonstrates that ADHD and ceiiac disease have much Li cornmon.

It also shows a number of conditions associated with giiadïn antibodies, despite the faa that

these antibodies are non-specific and have therefore not inspirecl much investigation outside

the realm of celiac disease.

86

The process bolved in the exorphin hypothesis, a s it relates to ADHD is show on

the following pages. There are some cases, perhaps many, of ADHD that probably do not

derive from these dietary factors Many such cases wouid iikely f2.l outside the genetic coding

for the HLA factors most suspect in the case of food intolerance disease and thus, food-

Uiduced ADHD.

O* M e r research will plot the precise boundaries of food-induced ADHD. That

some cases of ADHD are caused or exacerbateci by di- Won is undisputeci. Some may

believe that those numbers are very smaii, as is suggested by the research conducted within

a pharmacological paradip. Work cited eariier, which has moved to the periphery of that

paradi= has demonstrateci an increased incidence of food-induced/exacerbated ADHD to

a slight majority of the subjects studied.

Other than examinations of urinary peptide excretion in ADHD, there has been little

work directiy investigating exorphins. As one may unwittingiy substitute one source of

exorphlis for another, triais involving single substance and single fwd-group exclusion, are

unlikely to iden* at least some of the cases of ADHD resuiting fÎom exorphs. In the

inte* as we await more research which directly investigates the exorphin hypothesis. it

seems useful to offer the foiiowing outline of the postulateci process of the action of exorphins

in A D m :

Stage One

Figure 1 HLA-B8 distribution in Europe (Ammeman & Cadi-Sfona, 1984) io

relation to the aarting point of cereal Qraio cultivation (lutz, 1995).

Figure 4.1 HLA-BII Distribution ia Europe

This is the fkst element of the model. While the HLA-BS group does not include al1

of those who have celiac disease, it is a genetic marker which is highly associateci with @en

intolerance. As such, the European distribution of this senetidy determined element of the

immune system indicates that members of this group are either reduced in the gene pool, in

direct proportion to the period ofexposure to cereal grains. While the focus of this document

would suggest that childhood disease and pre-reproduction deaths would account for some

of this distribution of HLA 88, population displacement is also a probable contributor.

Stage Two

Ody a small fiaction of the 10% to 30% ofEuropeans who have HLA-BI wouid have

cefiac disease, so that is probably not the cause of this genetic trimming. The increased

intesnaal permeability associated with the genetic group demonstrating HLA-BI, in

88

conjunction with giuten consumption, is probabiy at the rwt of some alteratiûns to the

intestinal wall which do not indude villous atrophy- With increased pameabitity, the &estinal

waIi d o w s absorption of undigested and pady digesteci proteins and peptides h o the blood-

Stage Three

There is a lot of evidence suggesthg that these peptides can also lead to psychiatrie

cktuhmces. Some of the peptides in question are weil estziblished as exogewus opioids,

or exorphins, which have a fiinction similar to morphine and rnay thus be expected to cause

altered behaviour, just as we would expect nich alterations in those who are under the

influence of morphine most of the thne.

The exorphins may effect the brai. by causing inappropriate waservation of

endogenous opioids. since increases Ui opioids can inhibit opioid breakdom. exorphias may

thus impact upon behaviour without breeching the BBB (Reicheit et al, 1988).

It rnay therefore be postuiated that the morphine-Like properties of exorphins, or

inappropnately conserveci endogenous opioids, impact upon behaviour. When binding occurs

within the brain many problems may arise, as has been suggested in discussions of points of

convergence betweem food intolerance and ADHD. As ~ s o a a i v e peptides, they rnay play

a roie in reduced blood supply to parts of the brain. They may anaesthetize parts of the cortex

invoived in speech production andor language leaming andlor mathematicai leaming. And

they may M e r e with some exeaitive fimctions through reducing activation and perfiision

of those parts of the brah

Ocr limited grasp of neurotransmittm makes it difEcuit to imagine exactiy how

changes f b m anachment of endorphins and other endogenous peptides, to cornpetition with

89

these latter, and attachment of exorphius rnay explain the behavioural and attitudinal chanses

witnessed in ADHD. yet we do recognize such changes, and accept them as normal, when

children and adults are diagnosed with food intolerances. We also recognize such changes in

those who are addicted to opiates.

Envisioning the mode1 in such a simplistic, three stage form may suggest a

superficiality which is inappropriate. The process outhed is a highly complex one, and the

f i t e representation herein may incorporate some mors, and lead to misunderstanding. This

shouid impugn the author, not the hypothesis.

The web on the foilowing page offers yet anotiier visual perspective which rnay better

represent the complexity of the postulation embodied here. It is an attempt to depict some of

the interconnections between the signs and symptoms of ADHD and ceiiac disease. Figure

4.2 is thus offered as an i m p e r f i representation of these associations of symptoms and signs

of celiac disease and AD)fD.

Eire 4.2 A Web of interconnections between ADHD and Cdiac Disease as mported in the peer reviewed medicai fiterature

Celiac Disease

Our next step will be to discuss both the limitations aud fiiture directions suggested by the application of the exorphin hypothesis to ADHD.

Cbapter Five

Applications, Reeommendatioos, Limitations, and Implications

That exorphins hction simiiarly to morphine, and can be derived &om daiiy and

gain products is weli established. That the removal of these substances fkom the diets of

patients with some forms of mental illness has produced significant improvements is aiso

reponed That food imolerance disease offen leads to similar mentai dimirbances is also

reporteci. There are many points of convergence between reponed features of ADHD and

similady recognized aspects of food intolerance disease. There are also points of convergence

between ADHD and the mental illnesses impiicated in food imolerances. Finally, there is a nch

literature which variously connects dietary interventions with improvements in small

minonties to large majorities of ADHD patients. Despite the fact that little work has been

done to directly explore exorphin activity in ADHD, there is a compelhg body of evidence . .

suggesting that exorphins may be at the root of much of this widespread mental illness which

mets fiom 2 % to 10% of school children, and has We-long implications for their fuhires.

If one accepts the notion that ADHD may often be the result of opioid peptides

derived from gluten, dairy, and perhaps, other diaary proteins passing through a penneable

intestinal wd into the circulation and then directly or indiredy irnpaaing on the brain, hence

influenchg behaviour, then it is important to understand what may be done to help deviate

this problem.

There is some suggestion of a detoxificatioo dynamic at work in some successfiil

dietary interventions in ADHD. "In several children the initial improvemem produced by the

92

diet was preceded by a deterioration in behaviour" (Egger, Carger, Gumley, Soothill.

1985). Such initial detenoration mi@ represent withbwal fiom dieüuy exorphins. and it

is important to anticipate such a response. Withdrawai from an addiaive substance mitb

analgesic fiindon might erroneously be characterized as a negative response to a short-term

dietary intervention and shouid suggest patience, rather than a rush to judgement and

abandonment of the diet Some of the delay in responding to re-introduction of a suspect

food is the result of healing and r e ~ o ~ c t i o n of the intestinal mucosa. The long period of

gluten challenge, of up to two years, required in some cases of celiac disease (Chanrand,

Seidman, 1996) rnay well be the result of a healed mucosa fûnctioning in a protective fishion

preventing harmfbl proteins, peptides, and t o h from entering the blood. The expectatioo

of a rapid response to dietary interventio~ although it sometimes happens in ADHD and

ceiiac disease, is misplaced. There is also the leamhg phase, in such interventions, which

many food intolerance patients can attest to. In the eariy stages of wmpliance with such a diet

there are many painful "leamhg experiences" resulting fiom mistakes.

Appiications to Education

The postdatai process involved in the wsation ofADHD, however hteresting, may

be less important to parents and teachers than the resdt of the dietary exclusions it suggests.

The most valuable test of such ideas must take place in reai people who suffer h m the

debilitating effects of th condition. Foxtumtely, the dietary exclusion of gluten and dairy is

perfectly safie. Additiondy, the exclusion of these foods rnay lead to more than

improvements in psychologicai health. For many, it may also lead to a vastly irnproved

quaiity of He thrwgh increased vigor.

93

Trials of fad dies, however, may not be the m e r . AU too often, cornphce is

difncult, and may wane over the, ifthere are only subjective, arguaMe rresults reponed- This

problem can be addressed by severai means. Assuming that thyroiditis and hypoglycemia

have been d e d out, serurn testuig for gliadin antibodies is an inexpensive, non-invasive test.

For less than the cost of a month's supply of Stimdmt medication, such testing wodd cleariy

iden* intestinal pemeability, suggesting both the need for dietaxy intervention, and the

sp&c nature of one of the appropriate dusions.

Serum antibody testhg for celiac disease, in the fom ofIgA anti-endomysium as weU

as IgG and IgA aatigliadin antibodies ( see appendices four and six, regarding serological

testing), in combination with testing for LgA deficiency, although more expensive than the first

option suggested, offers a vaiuable tool both for excluding celiac disease, and for identifjmg

intestinal permeability in ADHD. The range of possible interventions is broadened by this

more extensive testing.

The presence of IgA antibodies are more suggestive of celiac disease and hence, an

increased risk of malignancy, pulmonary abnormalities, and assotiated autoimmune diseases

which should lead to M e r testkg to de£initely ruie it out. The presence of IgG antibodies,

ifthere is no I g A deficiency, suggest a permeable intestine. As has previously been discussed,

such intestinal permeabiIity may point to the possibility of a dietary resolution to ADHD

symptoms.

As teachers, we need to protect the children in Our charge, not aid in a process that

silences their cries for help. Whether those cries are in the form of misbehaviour in Our

classes, or an apparent inability to focus their attention on the task at han& they are qmking

94

to us in the ody language they have, about an illness which thqr do not understand. It is up

to us to corne to understand it.

Teacher preparation programs should include discussion and opportunities for

contemplation of some of the ethical issues associateci with teacher participation in

evaluations of students toward ADKû diagnoses. These programs should ais0 provide

inmuctîon retated to the diagnostic and treatment processes currently employed wah cases

of suspected ADHD. E n t e ~ g employment as knowledgeable teachers, they will thus have

a choice about whether to participate in the process in a knowfedgeable mamer, or to exclude

themselves on the basis of their own ethicai determinations on the topic.

As knowledgeable participants in the process, they will be in a position to ask if

testing for thyroidais and hypoglycemia has been conducted. Such prior testins could even

be made a condition of their participation in the process, should the teacher feel strongly

enough about this issue. Teachers might also ask the student and parents to consider antibody

testing, prior to initiatuig an evaluation process which is aimed at possible stimulant or other

chemical therapies.

Recommendations for Future Research

While several options are available, 1 wiil tentatively outhe one co~l~truct which

would provide the opportunity to c o b or deny the application of the exorphin hypothesis

to ADHD. Of course, part of my personai journey toward the implementation of a test of this

hypothesis would be to ieam more about the design of such investigations. In the interim the

fouowing outhe suggests, in broad strokes, a process that might produce a meanin@,

objective test of the application of the exorphin hypothesis to ADHD:

The Investigaton

Such an undenaking wodd necessitate a group of professionais who would bring their

expertise to bear upon the investigation and would, without doubt, enhance the proposed

investigation. These investigators would include a medical practitioner, a clinical psychologia

who has expertise in the area of ADHD, a dietician knowledgeable in the realm of ghen-fke

and dairy-fkee diets, and a tacher who is weii versed in these diets, and able to communicate

on related issues with parents and children. m e r personnel wodd be necessary to draw,

cenuifuge, and ship s e m to a laboratory for testins, and to conduct administrative tasks.

ûther help might well be valuable, but such details are beyond the scope of the current

discussion.

The Group

A group of volunteer subjects would be invited to participate in a dietary exploration

of ADHD. The subjects would need to have previously been diagnoseci with ADHD by an

appropriate health care professional. Both child and parents would need to be willing

participants prepared to comply with a strict diet. The cooperation of parents and teachers

would also be required, to complete appropnate assessrnent instruments, and appropriate

interviews with the psychologist. School records would likely be helpfùi, and would also be

request ed.

Those volunteers with Reye's syndrome, a bistory of a hypoxic anoxic event, heavy

metal toxicity, signifiant head trauma, or central newous system infection, as outlined by

Barkley (1990) would be excluded. While Barkley includes cerebral-vascular disease as a

condition which should be included in the differential diagnosis of ADHD, such disease has

96

repeady been reported in the context ofoccult celiac di- and wodd therefore not be

an appropriate element of the differential diagnosis for the purpose of the proposcd

investigation.

Establishment of a BaseIine

Each student would need a badine assessment, which would kclude testing for

hypogiycemia and thyroiditis as recomnended by Block (1997), as weU as IgG and IgA

gliadin antibodies. A b n o d t i e s in giucose tolerance or thyroid function would result in the

exclusion of such subjects with recomrnendation that they seelc medical foilow-up. The results

of antibody testing would be withheld until the end of the investigation.

Current use of stimuiant or other medications would be noted, and any dietary or

other treatrnents currently employed would require investigation, and possible exclusion of

the subject, where appropriate. Current practices of dietary supplementation such as the use

of multivitamim would also require attention, especially regarding the nature ofbinders used.

It mi@ also be useful to standardize supplernents for ail participants duriag the course of the

study. A uniform starhg date for the trial would be u& especiaiiy if it codd be

coordinated with school reporthg periods, and end pnor to, or begin after occasions where

there is greater temptation to "break" the diet, such as during the Chrimas holiday.

Extensive instruction, regarding the diet and its many piâals, would be necessary,

and should be conducted by the tacher and a quatified dietician.

Terminai assessments

At the end of the 60 days of cornpliance with a gluten-fie, Qiry-fke diet, another 10

ml of blood would be drawn for IgG and IgA senim annibody testing. Reports nom parents

97

and teachers would aiso be gathered, to see what, ifany, hprovements had beai observed

in the children. 1 would anticipate that the basehe aotibody test d t s wodd Vary in

generd ways, and the termina! tests wodd vary in four ways.

Baseline tests:

1. Some of the subjects would demonstrate no abnormal presence of Gadin

antibodies.

2. Some nibjects wouid demonstrate elevated IgG antiiodies

3. Some subjects would demonsrrate elevated IgA antibodies, dong with elevated IgG

antibodies.

Terminai tests:

1. Those with no abnomal antibody levels at baseiine would likely show simiiar

terminal test results, although some members of this group may show improvernents in their

ADHD symptoms.

2. Many of those with elevated IgG antibodies, at this stage, might show some

reduction of anti'body levels, although 1 6 levels are very slow to respond to exclunon of

gluten nom the diet. A significam number wouid Iikdy present with a positive response to

the diet. as giiadin W o r dairy proteins would offer an explmation for many cases of

increaseci intestinal penneability in this group.

3. Those with reductions in their levels of 1gA gliadin antiiodies would kely

represent the group who showed the greatest nurnber of subjects with the most improvement

of their ADHD symptoms as a result of the diet.

4. Those who showed terminai elevations of IgA gliadin antibodies might reasonably

98

be suspected of dietary indiscretions (perhaps unintentiod) during the 60 &y diet period,

although some of these mi@ show improvement in their ADHD symptoms, as a result of

reductions in gluten and dairy proteins in their dim.

Seiection bias:

It is important to recognke that the test group for such a triai would not be

representative of the ADHD population. A number of selection biases wouid, of necessity,

shape this group. Such a trial would attract both parents and children who are quite

motivateci, as the diet requires quite an adjustment. Once one is accustomeci to the diet, t is

relatively easy, but the initiai adaptation is dif6cult because it is a chdense to be constantly

wary of hidden sources of both types of proteins which are rife in processed foods.

Such an investigation would kely be attractive, primarily, to parents and children

where the symproms were quite severe. Those whose personal perspectives opposed the use

of stimulant medications would also be likely to be over-represented among these volunteers.

Those best suited to meet the ecmomic, social, and time-use challenges ofa gluten-k, d@

-free diet would also be Iikeiy to be over-represented in rhis group. Such an initiai foray into

this research would probably not be inviting to a representative sample of ADHD subjeas,

and the results, regardless of how positive, could ody be taken as a herald for m e r research

in this area. Sti4 such a clinical trial could offer great insight into the murky world of ADHD.

Other Raearch possibiiities

As was mentioned earlier, there are many other possible avenues to investi~ate this

question. Naioxone has been demonstntted to block exorphim. It blocks 70% of psychoactive

peptides derived f?om gluten. and 1 O@% of those f?om dahy products. This offers an excitins

99

research opportunity. Ifthis or a similar opioid-blocking dmg can be demonstrateci to be safé

for aich usage, and it induces improvements in symptoms of a sisnificant number of ADHD

abjects, the central notion of this thesis wilI be supporteci. Such results can provide a rnuch

clearer pictue of both the etiology of many cases of ADHD, as weil as offering rasonable

treatments for this condition, which win not engender the nsk inherent in Stimulant and other

chernical therapies.

FoUowing Naloxone screening, and ana'body testing, clinicai trials ofgluten-fkeeddairy-

fiee interventions in ADHD would offer support for the use of serological testing of ADHD

children as an objective diagnostic tool and as an indicator of appropriate therapeutic

intervention.

Young offenders who are incarcerateci mi@ well benefit fkom such dietary

restrictions, and their periods of incarceration mi@ provide a very important service to

society and to these youngners.

Epiderniological work, perhaps in the form of anitbody testing in large groups of

ADHD children, would also be revenling. Perhaps this is the tool that may ident@ many of

those ADHD patients who wiii benefit &orn dietary interventions.

Funher refinement of urinary peptide filtration and characterization may also provide

a diagnostic tool for some nib-types of mm, as weii as providing a clear indication of who

may benefit nom dietary interventions. Investigations of the application of the exorphin

hypothesis to ADHD might also be conducted in a variety of rnanners and methods which the

author bas not considered.

Limitations of the Mode1

Far too littie is known about several stages of the process pomilated here; the

application of the exorphin hypothesis to A . . It is a theoretical constma which requires

a great deal of M e r research Not pubfished reports on the topic of ADHD were

investigated. It was just too large a task The process of selecting the iiterature that would

be exarnined was conducteci by a penon with a bias. .. . . the author.

A fwther limitation lies in the ciiffidty in implementing such dietary interventions.

Giuten and dairy proteins pervade the food supply in industrialized nations, and often do so

in occuit forms.

It is aiso a challenge to investigate or implement wch dietary interventions in the

context of an under-informeci medical comrnunity. Nutritional issues are given little or no

attention in moa of our medical aaining programs, and dietary issws are ofken dismisseci as

a result of such deprecation by some adherents to conventional medical wisdom.

Despite these Iunitations, the impressive body of evidence which suggests and

supports this perspective imparts an urgency to the call for m e r research in this venue.

Implications of Ignoring the Mode1

This section presupposes that chical trias will support this mode1 for understanding

ADHD. The need to investigate this possiiility with appropriate cluiical trials has some very

senous implications for ADHD patients, their fimilies, and their communities. Increased

mortality among ADHD patients has been reponed (Boyle, Decoufie, Holmgreen, 1994). but

this may reveal only the tip of the iceberg, as the maximum age Uicluded in tbis report was 19

years old at the time of death. If exorphins are the underlying pathogen in many or most cases

101

of A D m , then risks of malignancies (Hoggan, 19976) and the host of wurologic and other

debilita~g sequelae associated with celiac disease (Holmes, 1996) and elevated gkdh

antiaodies associated with a great varïety of neurof o g i d disease (Hadjivassiliou et al., 1996,

1997) may include aduits who have previously or who currently &er fiom ADHD. It is

not just a case of these dietary pathogens having a stratifjhng socio-economic impact. In

addition to social losses in productivity, increased coas of medical care and education, there

is the spectre of substance abuse, and the social costs of treating aii these ailments. This

g o u p who &ers eom ADHD may, through the search for aoswers to their iUs, light the

path to improved mental and phyncal health for every industriaiized nation in the world.

through identification with antibody testing and dietary intervention It is an issue with huge

social implications, and for that reason alone, warrants thorough investigation.

Conclusion

Exploration of the exorphin hypothesis, as applied to ADHD, offers a d e , non-

invasive, non-chernical approach to this penrasive problem. What rernains to be done to

investigate this application of the exorphin hypothesis is carefiilly constnicted c h c d trials.

It rnay offer an improved life-expectaacy, quality of Me. and understanding, which may

accrue to ADHD subjects, their teachers, familes, peddiatricians, and their cultures. It is a

window of opportunity for ail participants. Failure to explore this hypothesis may result in

continued social. f d a l , and individuai costs of this condiaon, and the associated ilinesses

mentioned eariier.

We are not just discussing 2% to 10% of the school cbiidren who have difficdty

settlllig to their work, or focussing their attention. We are tatking about a large segment of

102

the population, perhaps as much as 30%, which is increasingly inundateci with gluten and

dairy proteins in almost aü or our processeci food. Their immune systems are compromûed.

They are more likely to suffér nom maiignancy, autoimmunity. neuroses, or psychoses, or

perhaps di of these.

Teachers can participate in fostering social weiiness, or continue to aid in the process

that masks symptoms of treatable aihents so the ilinesses wiil C O ~ M U ~ to go untreated and,

ui some cases, result in deadiy and debilitating sequelae.

Sources:

Adesman, AR, Altshuler, L.A, Lipkh, P.H., Wafco, GA. (1990). Otitis media in chitdren with leaming disabilities and in childrai with attention deficit disorder with hyperactivity. Pediatrics (3 Pt 2):442-446.

.4ddoiorato. G., Stefanini G., Caprino, E.. ûasbarrhi, A, Gasbar- G. (1996). . - e t y and depression in adult untreated celiac subjects and in patients affécted by inflamrnatory bowel disease: a personality "trait" or a reactive ihess? HeDato~astroenteroiogy. 43( 12), 15 13- 15 17.

Ali, O. (1996). Childhood hyperactiMty. The Lancet 348: 895-896.

Am= M., Mitchell, E., Turbott. (1987). The EEects of Essential Fatty Acid Supplementation by Efamol in Hyperaaive Chiidren. Journal of Abnomal Child P~cholopv 15(1), 75-90.

American Psychiatric Association. (1994). Diaenostic and Statisticai Manual of Mentai Disorders - Fourth Edition @SM IV). Washington., D.C.: American Psychiatnc Association.

Amencan Psychiatric Association (1987). Diagnostic and Statistid Manual of Mental Disorders - Third Edition (DSM III). Washington, D.C.: Amencan Psychiatric Association

Ammerman, A & Cavalli-Sforza, L. (1984). The neolithic Transition and the Genetics of Pooulations in Eurom Princeton University press, Princetoa N.J., p. 99.

Anderson, G. & Hrboticky, N. (1986). Approaches to Assessing the Dietary Component of the Diet-Behaviour Co~ection. Nutrition Reviews. May Supplement, 42-5 1.

Anderson, I., Anderson, K, Anderwartha, J., et al. (1990). The Bantam Medical Dictionary . John Wiey , New York.

Applegate, B., Lahey, B., Hart, E., Biederman, J., Hynd G., Barkley R, OLlendic4 T.. Frick, P., Greenha L., McBurnett, K, Newcorn, J.. Kerdyk, L., Garnnkle, B ., Waldrnan, I., Shaffer, D. (1 997). Validity of the Age-of-ûnset Criterion for ADHD: A Repon f?om the DSM-TV Field Trials. Jounial of the Arnerican Academv of CMd and Adolescent Psychiatm 3 6(9), 12 1 1 - 122 1.

Amason, J., Gudjonsson, H, Freysdonir, J., Jonsdottir, I., Valdimarssoû, H. (1992).

Do Addts with hi& gliadin antibody concenaations have subclinid gluten intoleran~e? @S. 33(2), 194-197.

Arraaz. E., Bode, J., Kingstone, K., Ferguson, A (1994). Intestinal autibody pattern of coeiiac disease: association with y18 T ceil receptor expression by intraepithelial lymphocytes, and other indices of potentiai coeiiac disease. m. 3 5.476482.

Atkins, F., (1986). Food AUergy and Behaviour: Defitions, Mechanisms and a Review of the Evidence. Nutrition Reviews. May Supplemem, 104- 1 12.

Auricchio. S., Greco, L., Troncone, R (1988). Gluten-Sensitive Enteropathy in Childhood. Pediatric Gastroenteroloq. 35(1). 157-187.

Backon, J., (1989). Inbibiting Noradrenergic Overactivity by Inhibition of ïhrornboxaue and Concomitant Activation of Opiate Receptors via Dietary Means. Medical Hmtheses. 26,65-74.

Barkley, R, Biedemxm, J., (1997) Toward a Broader Definitionof the Age-of-Onset Cnt&on for Attention-Deficit Hyperactivity Disorder. Journal of the Amencan Academy of Child and Adolescent Psvcfiiatq. 36(9), 1204- 12 1 O.

Barkley, R ( 1990) Attention-Deficit Hweractivitv Disorder. Guilford Press, New York. pp. 254; 255; 28 1; 29 1.

Barton, R, (1997). Iron deficiency anaemia Patients must be screened for coeiiac disease British Medical Journal. 3 14(7096), 1759-1 760.

Beaver, J., (1 998). Lecture Notes. Human Biochemistrv: Teaching Resources. http ://science. canbema- eduUSUl/hbIIIS/humanbioA~&~oa~ddmonoa cids. htm

BerteHoni, S. ( 1992). The pafathyroid hormone- 1 -25-dihydroxyvitamin D endoche system and magneniim status in iasulin-dependent diabetes rneliitus: ment concepts. Mapnesium Research. 5(1), 45-5 1.

Biedexman, J., Santangeio, S., Faraone, S., Kiely, K., Guite, J., Mi& E., Reed, E., b u s , L, Jehek, M., Perrin, J., ( 1995). Clinical correlates of enuresis in D H D and non-ADHD chiidren. Journal of Child Pmcholow and Psvchiatq. 36(5), 865-877.

Biede- J., Faraone, S., Keenan, K (1992). Further evidence for My-genetic factors in attention deficit hyperactivity disorder. patterns of comorbidity in

probands and relatves in psychiatndy and pediatricaily refmed samples. Archives of General Psvchiatq . 49(9), 728-738

Biedeman, J., Milberger, S., Faraone, S., Guitge, J., Warburton, R (1994). Associations between childhood asthma and ADHD: issues of psychiauic comorbidity and farni1i;ility. Journal of Amencan Child and Adolescent Psvchiatrv . 33(6), 842-848

Biedeman, J., Mi& E., Fanione, S. (1998). Depression in attention deficit hyperactivity disorder (ADHD) children: "true* depression or demoralizaron? J o d of Affective Disorden. 47(1-3), 1 13-122.

Biedennaq J., & Faraone, S. ( 1 996). Attention Deficit Hyperactivity Disorder. The Brain. 5( 1), 1-2.

Block. M. (1997). No More Ritalin . Kensington Books, New York

Bogden, J., Oleske, I., Louria, D. (1997) Lead Poisoning-One Approach to a Problern That Won't GoAway. Environmental Health Pers~ectives. 105(12), 1284-1287.

Boris, M. & Mandel F. (1994). Foods and additives are common causes of the attention deficit hyperactive disorder. h n a i s of AUerqy. 72,462468.

Boyle, C., Decode, P., Hohgreen, P. (1 994). Contniution of developmentad disabilities to childhood rnortaiity in the United States: a multiple-cause-of- death analysis. Paediatnc P e ~ a t a l E~idemiolow. 8(4), 41 1-422.

Brasic, J. & Barnett, J. (1997). Hyperkinesias in a prepubertal boy with autistic

disorder treated with haioperidol and valproic acid. Psvcholoev Rqort. 80(1),163-170.

Breakey, J. (1997). The role of diet and behaviour in chiidhood. Journal of Paediatrics and C hild Heaith. 3 3. 190- 1 94.

Breakey, I. & Breakey, C. (1997). Diet Therapy. Journal ofthe American Academv of Child and Adolescent Psvchiatrv. 36(8), s 10 14- 10 1 5.

Brenner, A(1982). The Effects of Megadoses of Selected B Compla Vïtamins on Children with Hyperkinesis: Controned Studies with Long-Tem Foilow-up. Journd of Leamhg Disabfities. 15(5), 286-289.

Brucker-Davis, F., Skariliis, M., Grace, M., Benichou, J., Hauser, P., Wiggs, E.. Weimraub, B. (1995). Genetic and Clinicai Features of 42 Kindreds with

Resistance to Thyroid Hormone. Annals of Internai Medicine. 123.572-583.

Bnist, J. (1997). Vasculitis owing to substance abuse. Neurolooic Clinics. 15(4), 945- 957.

Buriton-Bennet, I. & Robinson, V. (1987). A Single Subject Evaluation of the K-P Diet for Hyperkinesis. Journal of L e a r a Disabilities . 20(7), 3 3 1 -3 3 5.

Bushneli, F. (1992). A Guide to Primary Care of Iron Deficiency Anemia Nurse Practitioner 1 7( 1 1 ), 68-74.

Bye, A, Andemianq F., Robitaiiie, Y.. Oher, M, Bohane, T., Anderrnann, E. (1993). Cortical vascular abnormalities in the syndrome of celiac disease, epiiepsy, bilateral occipital calcifications, and folate deficiency. Annais of Neuroiow .34,39943.

Canadian Ceiiac Association (1 993). Canadian Ceiiac Association Handbook, Mississauga. Ontario.

Canadian Pharmaceutid Association (1997). Com~endium of Pharmaceuticals and Specidties. tbirty-second ediaon, Canadian Pharmaceutid Association, Ottawa, Ontario.

Carter, C., Urbanowicz, M., Hemsley, R, Mantilla, L., Strobel, S., Graham, P., Taylor, E. (1993). Effects of a Few Food Diet in Aîtention Deficit Disorda. Arcfiives o f Disease in Childhood. 69, 564-568.

Carroccio, A, ~annittq E., Cavataio, P., Montaito, G-, Tumminello, M., Campagna, P., Lipari, M., Norarbartolo, A., Iacono, G. (1998). Sideropenic anemia and celiac disease: one study, two points ofview. Digestive Diseases and Science. 43(3), 673-678.

Catassi C., Fabiani, E., Ratsch, L, Bonucci, A., Dotti, M., Coppa, G., Giorgi. P. (1997). 1s the sugar intestinal permeability test a reliable investigation for coeiiac disease screening? Gut. 40(2), 2 15-2 17.

Catassi, C., Ratsch, L, Fabiani, E., Rossini, M., Bordicchia, F., Candelq F., Coppa, G.. Giorgi P. 9 9 4 Coeiiac disease in the year 2000: e x p l o ~ s the iceberg. Lancez

343(8891). 200-203.

Casteilanos. X. ( 1 997). Toward aPathophysiology of Attention-DefiCitlHyperaetiVity

Disorder. Chical Pediatrics . 36(7), 3 8 1-393.

Casteilanos, F., Giedd, J,, Exkburg, P.. Ma&, W., Vaituzis, A., Kaysen, D., Hamburger, S., Rapoporf J. (1994). Quaiitative Morpholosg of the Caudate Nucieus in

Attention Deficit Hyperactivity Disorder. American Journal of Psvchiatrv. 151, 1791-1796.

Chartrand L., & Sei- E. ( 1996). Ceiiac disease is a lifeiong disorder. Ciinical investipative Medicine. 19(5), 35 7-36 1.

Chartrand, L.. Russo, P., hihaime, A, Seidman, E. (1 997). Journal of the American Diet etic Association. 97(6), 6 1 2-6 1 8.

Chiaravalloti G., Marazziti, D., Batistki, A, F a a T., Ugh, C., Ceccarelii, M.. Cassano, G- ( 1997). Acta Paediarrica 86(7), 696-699.

Claude. D., & Fiestone. P. (1995). The Development of ADHD Boys: A 12-Year Foilow-Up. Canadian Journal of Behaviod Science 27(2), 226-249

Coleman, M. (1971). Serotonin concentrations in whole blood of hyperactive children The J o d of Pediatrics. 78(6), 985-990.

Colquhoun, L, & Bunday, S., (198 1) A Lack of Essentid Fatty Acids as a Possible Cause ofHyperactiw i0 Children. Medicai Hv~otheses. 7,673479

Coghlan, J., & O'Morain, C. ( 1988)- Aduit lead toxicity and untreated coeliac dwase. Journai of the Roval Societv of Medicine. 8 l(IO),612

Cooke, W., & Hoimes, G. (1 984). Coeliac Disease. Churchill Livingstone. New York N.Y. pp. 95-97, 1 19, 132.206.

Cooke, L. (1997). Cancer and learning disabiity. Journal of Intellectual Disability Research. 4 I(pt.4). 3 12-3 16.

Collin, P., Sa& J., EIaUstrom, O., Reunaia, T., Pasternack, A ( 1 994). Autoimmune thyroid disordm and coeliac disease. European J o d of Endoc~oiocg'. 130, 137-140.

Coumeil, C., Taha, A. Ruddeü, W. (1994). Coeliac disease and autoimmune thyroid disease. Gut. 35,844-846.

Cr&, A (1986). Acute EEects of Meals on Perceptual and Cognitive Efficiency. Nutrition Reviews. May Supplement, 163- 1 7 1 .

Cradord S., Kaplan, B., KUisboume, M-, (1 994). Cortex. 30 (2). 28 1-292.

Davis. C. (1978). Dietary pathogenesis of schizophrenia. NursU1g Times. 74,2020- 202 1.

De Santis, A.. Mama, R, Gasbarrhi, G. (1997). Schizophrenic symptoms and SPECT abnodt ies in a coeliac patient: regression &er a @uten-fiee diet Journal of Intemal Medicine. 242(5), 42 1 -423.

Dews, P. ( 1986). Dietary Pharmaculogy. Nutrition Reviews . Supplement, 246-25 1 .

Dicke, W., Weijers, K. van der Kamer, J. (1952). Coeliac disease- II- The preseace in wheat of a factor having a deleterious effect in cases of coeliac disease. Acta Paediatrica. 42,34-42.

Dicke, W. (1950). COELIAC DISEASE Investigation of the harrnful effects of certain mes of cereal on ~atients with coeliac disease. Ph. D. thesis.

Doherty, M., Br Barry, R(1981). Gluten-induced mucosal changes in subjects without overt small-bowel disease. The Lancet March 7 ,5 1 7-520

Dohan, F., Grassberger, J., Loweil, F., Johnson, H., Arbegast, A (1969). Relapsed schizophrenics: more rapid improvement on a mille- and cerd-fke diet British journalof Psychiatrv . 1 15,595-596.

Dohan, F. (1989). Genetics and Idiopathic Schizophrenia American Journal of Psychiatry . 146(11), 1522-1523.

Dohan. F. (1 983). More on Celiac Disease as a Mode1 for Schizophrenia. Bioloaical P-hiatrv. l8(5), 56 1-564

Dohan, F. (1 972). An Internist Looks at Schizophrenia Medical Gffairs. University of Pennsyivania, 1 63, 7- 1 1 .

Dohan, F. (1988). Genetic Hypothesis of fdiopathic Schizophrenia: Its Exorphin C O M ~ ~ O ~ Schuo~hrenia Bulletin. 14(4), 489-494.

&han, F., m e r , E., Clark, M., Rodrigue, R, Zigas, V. (1984). 1s Schirophrenia Rare if Grain is Rare? Biolooicai Psvchiatrv. 19(3), 3 85-399.

Dohan, P., (1%6). Cereals and schizophrenia: data and hypothesis. Acta Pmchiatria

D o h a ~ F., (1 983). More on Celiac Disease as a Modd forSchizophrenia. Biolooical Psychiatry. 18(S), 56 1-564.

Donaidson S., Jundt, S., Ricour, C., Sarrarin, D., Lemerle, J., Schwekgutb O. (1975). 35, 1 167-1 178.

Domschke, S., Bloom, S., Adrian, T., Lux, G-, Bryant, M-, Domschke, W. (1989). Coeiiac sprue: abnorrnalities of the hormone pronle of gastroduodenal mucosa. ScandanaVian J o u d of Gasuoenterolosty. Supplement 167.86-89.

Drysdale, A, Deacon, R, Lewis, P., OUey, J., Eldcwala, A, Sherewood, R (1982) . A peptide containhg fraction of plasma fkum schizophrenic patients which binds to opiate receptors and induces hyper-reactivity in rats. Nwroscience. 7(6), 1567-1 573.

Duggan, J., (1997). Recent Developments in o u understanding of adult coeiiac disease. Medicai l o u d of Australia- 166, 3 12-3 1 5.

Du Paui, G., Rapport, M., Pemieiio, L. (199 1). Teacher Ratings of Academic SkiUs: The Development of the Academic Performance Rating Scale. Schoul Psvcholoa~ Review. 20(2), 284-300

Eaton, S., & Konner, M.. (1985). Paleohhic Nutrition. New Enpland I o u d of Medicine 3 12(5), 283-289.

Eatoq S., Konner, M., Shost& M. (1 988). Stone Agen in the Fast Lane: Chronic Degenerative Diseases in Evolutionary Perspective. The Amencan Journal of Medicine 84, 739-749.

Eaton. S. ( 1992). Humans, Lipids and Evolution LIPIDS .27(l O), 8 14-8 19.

Egger, I., Stolla, A, McEwen, L. (1992). Controiied trial of hyopsensitisation in children with food-induced hyperkinetic syndrome. The Lancet May 9, 339, 1150-1153.

Egger, J., Carter, C., Graham, P., Gumley, D., Soothill, J- (1985). Controfled Trial of Oligoantigenic Treatment in the Hyperkinetic Syndrome. The Lancet March 9, 1985, 540- 545 -

Erasmus. U. (1996). Fats -niat Heal Fats That W. Alive Books, Burnaby B.C.

Faraone, S., I3iedemn.n. J., Mennin. D., Womiak, J., Spencer, T. (1997). Attention-deficit hyperactivity disorder with bipolar disorder: a f U subtype? Joumd of the Amerïcan Academv of Child and Adolescent Psvchiatw. 36(10), 1378-1387.

Faraone, S., BiedeIman, J., Weber, W., Russeil, R (1998). Psychiatrie, neuropsychoi~gicaI, and psychosocial féatures of DSM-N subtypes of attention-deficitmyperadvity disorder: r d t s forrn a clinicaly refemd sampte. Journal of the Academv of Child and Adolescent P w c h . . 37(2), 185-193.

Fasano, A, (1996). Where have ail the American celiacs gone? Acta Paediatrica Supplement, 4 12, 20-24.

Feingolâ, B. (1 974). W ~ Y Your Child is Hweractive. Randorn House, New York.

Fernstrom, 1. ( 1 986). Acute and Chronic Effects of Protein and Carbohydrate Ingestion on Brain Tryptophan Levels and Serotonin Synthesis. Nutrition Reviews. Supplement May, 25-36.

Ferguson, A., Arritll~, E., OTMahony, S. (1993). Spectm of expression of intestinal cellular i d t y : proposal for a chanfe in diagnostic criteria of celiac disease. Aruials of Allerw. 7 1,29-32.

Findhg, R (1996). Open-label treatment of cornohid depression and attentional disorders with co-administration of serotonin reuptake inhibitors and psychostimulants in children, adolescents, and adults: a case senes. J o u d of Child and Adolescent Psvcho~harmacoloey. 6(3), 165- 1 75.

Fine& P., McEntee, W., Ambler, M., Kestenbaum. D. (1980). Adult celiac disease presenting as cerebeîiar syndrome. Neuroloq . 30, 245-249.

Flower. D., (1 998). 1s there merit in merit pay? ATA News 32 (1 7), 1-2.

Franklin, A, ( 1984). Diet and behaviour. Archives of Diseases in Childhood. 59(8), 799-800.

Frazer, A. (1952). Disordered gastrointestinal hc t ion and its relationship to tropical sprue, coeliac disease and idiopathic steatorrhoea. Transactions of the Rovd Societv of Tro~ical Medicine and Hvstiene -46, 576-585.

Freemaa H- (1995). Cefiac-associateci autoimrmuie thyroid disease: A study of 16 patients with oven hypothyroidism. Chical Gastroenterolozy. 9(5), 242- 246.

Fukudome, S., Shimatsu, A. Sugrnuma, H, Yoshikawa, M (1995). Effkct of Gluten Exorphias AS and B5 on the Postpmdiai Plasma Insuiin Lwel in Conscious Rats. Life Sciences. 5 7(7), 729-734.

Fukudome, S., & Yoshikawa, M. (1993). Gluten exorphin C. Febs Letters. 3 l6(l), 17-19.

Fulaidome. S., & Yoshikawa, M. (1992). Opioid peptides derived nom wheat @uten: their isolation and characterization FEBS Letters. 296(1), 107- 1 1 1 .

Fukudome. S., Limmaa, Y., Matsukawa, T., Sasaki R, Yoshikawa, M-. (1997). Release of opioid peptides, gluten exorphins by the action of pancreatic elastase. FEBS Letten. 4 l2(3), 475-479.

Gaiiand Leo (1995). Leaky Gut Syndromes: Breaking the V~cious Cycle. http://www. healthy.net/li%rary/articles/gdandneaky~ut~ htm

Geboes. K (1994). From inflammation to lesion. Acta Gastroenterolica BelPica. 57(5-6), 273-284.

Gibbons, R (1889). The Coeliac Mixtion in Chilciren Edinbur* Medical Journal. xxxv(iv), 3 2 1-3 3 0.

a, M., Daly, G., Heron, S., Hawi, Z., Fitzgerald, M. (1997). Codïmmtion of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism. Molecdar Psvchiatq. 2(4), 3 1 1-3 13.

Gittleman, R, ( 1 986). Assessrnent of the Classroom Behaviour of Hyperactive Chiidren. Nutrition Reviews. May Supplement, 13 5- 144.

Gillberg, C., Melander, H, von Knoming, A, Janols, L., Thenilund, G., Haggloc B., Eidevall-Wallin, L., GuStafsson, P., Kopp, S. (1 997). Long-term Samulant treatment of children with attention-deficit hyperactivity disorder synptorns. A randomized, double-blind, placebo-controiied trial. Archives of Cenerai Psvchiatn, 54(9), 857-864.

Gobbi .Ga, Banquet, F., Greco, L. (1992). Coeiiac disease, epilepsy, and cerebral dcifications. b c e t 340(88 1 7). 43 9-443.

Gosgins, M & KelIeher, D. (1994). Cetiac Disease and Other Nutrient Rehted Injuries to the Gastrointesîinal T m . Arnerican Journal of Gastroenterolo-m. 89, S2-S 13.

Golden, G. (1984). Controversiai Therapies. Pediavic Cluiics of North America 3 1 (2), 459-469.

G r a R, & Haadfor& A (1 96 1). Coeiiac syndrome in the case histories of five schizophrenics. Psvchiatric Ouarterhr. 3 5,306-3 1 3.

Green, P. ( 1997). The Adult Celiac. Unmaskinsz Celiac Disease Conference American Celiac Society, New ûrieacl~, November 1.

Greenberg, A, & Coleman, M (1976). Depressed 5-Hydroxyindole Levels Associated With Hyperactive and Aggressive Behavior. Archives of General Psvchiatrv. 3 3, 3 3 1-3 36.

Hadjivassiliou, M., Gibson., A, Davis-Jones, G., Lobo, A, Stephenson, T.. Milford-Ward, k (1996). Does cryptic gluten sensitivity play a part in neurologid h e s s ? Lancet 347, 369-3 7 1.

Hadjivassiliou, M, Chattopadhyay, A, Davies-Jones, G., Gibson, A, Gmenwald, R., Lobo, A. (1997). Neuromuscular disorder as a presenting feature of coeliac disease. J o d of Neurolow. Neurosur~erv. and Psychiaur~. 63, 770-775.

Hageman, R, & Faikensteia, A. (1987). An association between recurrent otitis media in infancy and later hypetactivity. Clinical Pediatrics ff hiladei~hia) 26(5), 253-257.

Hallen. C., Martensson, J., Mgen, L. (1 982). Brain avdability of monoamine precursors in adult coeliac disease. Scandanavian Journal of Gastroenteroloa. 17(1), 87-89.

Hdert, C., Asuom, J., Wdan, A (1983). Reversal of psychopathoiogy in adult coeliac disease with the aid of pyridoxine (vitamin B6). Scandanavian Journal of Gastroenteroloav. 1 8(2), 299-304.

Halperin, J., Newcoin, J., Kopstein, 1.. McKay, K, Schwartz, S., Siever, L., Sharxna, V. (1997).Serotonin, Agression, and Parental Psychopathology in Children with Attention-

Defitit Hyperactivity Disorder. Journal of American Academv of Child and Adolescent Psvchiatry. 36(10), 139 1 - 1398.

Haslam, R, Daiby, J., Rademaker, A (1984). ESects of Megavitamui Therapy on children with Attention Deficit Disorders. Pediatrics. 74( 1 ), 1 O3 - 1 1 1.

Harma, G., Ornitz, E., Hariharan. M. (1996). Urinary Epinephrine Excretion During Intelligence Testing in Attention-Deficit Hyperactivity Disorder and N o d Boys. Biolooicai Psvchiatry. 40, 553-555.

Hauser, K., McLaughh, P., Zagon, 1. (1989). Endogenous ûpioid Systems and the Regdation of Dendritic Growth and Spine ~okat ion . The Journal of Corn~arative NeuroIow. 28 1, 13-22.

Hechcmaq L. (1996). Families of Children with Attention Deficit Hyperactiviity Disorder: A Review. Canadian J o u d of Psvchiatrv. 4 1,3 50-360.

Hech- L. (1994). Genetic and Neurobiological Aspects of Attention Deficit Hyperactive Disorder: A Review. Journal of Pmchiatrv and Neuroscience. 19(3), 193-20 1 .

Hekkens, W. (1978). Antibodies to Qliadin in s e m of norrnalq coeliac patients and schizophrenics. The Biolopical Basis of Schizo~hrenia. eds. Hemmings & Hemmings, MTP Press, Lancaster 1978.

Hersker, L. (1978). Minimal brain dyshction and otitis media. Perce~nial and Motor Skifis December, 47(3 Pt 1 ),723-726.

Hoggan, R ( 1997a). Absolutism's Hidden Message for Medicd Scientism. Intercharme. 28(2/3), 183- 1 89.

Hoggat~, R (199%). C o n s i d e ~ g wheat, rye, and barley proteins as ai& to wcinogens. Medical Hpotheses. 49.285-288.

Hoggan, R, & Dunlop, T. (1 996) unpubiished data

Hoggan, R, (1996) Predictive Value of Serological Testing in Celiac Disease. http :///www. panix. corn/-donwisss/hoggad

Hoggaq R, (1997~). Blood and Guts. Newsweek. CX3D[(23), 27.

Hoggan, R, (1 998) Stay Healthy, Stay Gluten-fkee. S ~ Y ' S Living Without Premiere Issue, Libertyville, Il.

Hoggan, R, & Fasano, A, (1998). North Amena's Silent Stalker. Unpublished

Holden, R. & Pakuia, S. (1995). Tmmunological Muences in Attention-Deficit Disorder and Scbizophrenia: 1s there a Link Bemeen These Two Conditions? MedicaI Hvwtheses. 45, 575-587.

Hole, K., Lingjaerde, O., Morlaid, L.. Boler. J.. Diderichsen, J., Saelid, G.. Rudd, E.. Reichelt, K (1 988). Attention Deficit Disorders: A Study of Peptide- Containkg Complexes. Journal of Developmental and Behavioral Pediatncs. 9(4), 205-2 12.

Holm K., Savdahti, E., Koskimies, S., Lipsanen, V., Maki, M. (1994). Immunohistochemid changes in the jejunum in fht degree relatives of patients with coeliac disease and hte coeiiac disease marker DQ genes. HLA class II antigen expression, interleukin-2 receptor positive ceiîs and dividing crypt cells. Gut- 35,5560.

Hohes, G. (1996). Non-rnalignant complications o f coeliac disease. Acta Paediatrica Supplement. 412.68-75

Homan, R, Johnson, S., Hatch, T. (1 982). A case of human Linolenic acid deficiency involving neurological abnorrnalities. Amencan Journal of Clhicai Nutrition 3 5.6 1 7-623.

Horvath, K., Hom, G., Bodan*, H., Toth, K., Varadi, S. (1983). Disaccharidases in coeliac disease. Acta Paediatncia Hun~aria . 24(2), i 3 1 - 136.

Hoshino, Y.. Ohno, Y., Yamamoto, T ., Kaneko, M., Kumashuo, H. (1985). Plauna Free Tryptophan Concentration in Children with Attention Deficit Disorder. Folia Psychiatrica et Neuroloaca 3 9(4), 53 1-53 6.

Hudson, D., Purdham, D., Corne& H., Rolles, C. (1976). Non-speci£ic cytotoxicity of wheat gliadin towards dtwed human ceiis. The Lancet Febmary 14,339-341.

Huebner, F., Lieberman, K, Rubino, R, Wall, J., (1984). Demonstntion of high opioid-like activity in isolated peptides fiom wheat hydrolysates. Pe~tides. 5(6), 1139-1147.

Husby, V., Jensenius, C., Svehag, S.(1985). Passage of Undegraded Dietary Antigen into the BIood ofHealthy Aduits. ScandanaVian Journal of Irnmunoloqy. 22, 83-92.

Hynd, G., Semnid-CUeman, M., Lorys, A, Novey, E., Eliopulos, D.(1990). Brain

Morphology in Developrnental Dyslexia and Attention Deficit DisorderHyperaaMty. Archives of Neurolo~v. 47.9 19-926.

Jackson. N., & Murray, J. ( 1998). Celiac Disese. A practitioner's handbook of health-related disorders in children. Phelps L. (ed.) American Psychological Association, (in press)

Jeasen 1. ( 1988). Depression and Symptoms of Attention Deficit Disorder W~th Hyperactivity. JoumaU of the Amencan Academv oof Child and Adolescent Psvchiatw. 27(6), 742-747.

Kaczmarski, M., & Kurzatkowska, B. (1988). The contribution of some constitutional factors to the development of cow's milk and gluten intolerance in children. Roa. Akad. Med. Bialymst. 33-34, 167- 176.

Kaneko, M.., Eloshino, Y., Hashimoto, S., Okano, T., Kurnashiro, H (1993). Hypothalmic-pituitary-adrenal axis hc t ion in children with attention- deficit hyperactivity disorder. Journal of Autism and Deveio~mentd Disorders. 23(1), 59-65.

Kaplan, B., McNicol J., Conte, R, Moghadam, H (1989). Dietary Replacement in Preschool-Aged Hyperactive Boys. Pediatrics. 83 ( l), 7-1 7.

Kapuaa, D., Jones, S., Kopp, U., Diboaa, G. (1989). Role of Rend Nerves in Excretory Responses to Exogenous and Endogenous Opioid Peptides. The Journal of Phannacolosy and Exwrimental Threapeut ics. 248(3), 10391047

Karlsen. A, & Dyrberg, T. ( 1998). Molecdar mimicry between non-self; modifieci self and self in autoimmunity.Imrnunolow Feb; 1 O(l):25-34

L., Wood, D., Goldstein,G., Auchenbach, R, Gecide, M (1 998). The utility of neuropsychological tests in evaluation of attention-deficitmyperactivity disorder (ADHD) versus depression in addts. Assesment. 5(1), 45-52.

Kavale, K., & Fomess, S. (1983). Hyperactivity and Diet Treatment: A Meta- Anaiysis of the Feingold Hypothesis. J o u d of Leamhg Disabilities. 16(6), 324-330.

Kekar, P., Ross, M, Murray, 1. (1 996). Mononeuropathy multiplex associateci with ceiiac sprue. Muscle & Nerve. 19, 234-236.

Kinsbourne, M. (1975). MBD- A Fuzq Concept Misciirects Therapeutic Effon.

Postgaduate Medicine- 58(3), 2 1 1 -2 12.

Kinler, F., & Baldwin, D. (1970). The Role of Mergic Factors in the Chdd With Minimal Brain Dydhdon. Annals of M m . May, 28.203-206.

Kitts. D., Y u a Y., loneja, J., Scott, F., Szilagyi A, Amiot, J., Zarkadas, M ( 1 997). Adverse reactions to food constituents: aiiergy, intolerance, and autoimmunity. C a d i a n Journal of Phvsiolopv and Pbarmacoi~~w. 75(4), 34 1-254.

Kong, D. ( 1995). Psychiamc disorden in pre-schoolen. Shgamre Medical J o ~ . J u ~ 1,36(3), 3 18-32 1.

Koman, S. ( 1990). Pica as a presenting symptom in childhood ceiiac disease. American Journal of Clinical Nutrition 5 1(2), 1 3 9-1 4 1.

Korlowska, 2: ( 199 1). Results of investigation on children with coeliakia treated rnany y e a n with glutethen fiee diet Psvchiatria Polska .25(2). 130-134.

Krassner. M. ( 1986). Diet and Brain Function Nutrition Reviews. May Supplement. 12- 1 5

Krummel, D., Seligson. F., Guthrie. H. (1996). Hyperactivity: 1s Candy Causai? Ciinical Reviews in Food Science and Nutrition. 36( l m ) , 3 147.

Kuhn, T. (1970). The Structure of Scientific Revolutions. international Encvclopedia of Unitied Science. 1 1(2). 1-2 10.

Kumar, V., Valeski J., Wartsman, J. (1996). Celiac Disease and Hypoparathyroidism: Cross-Reaction of Endomysial Antibodies with Parathyroid Tissue. Clinical and Diamostic Laboratorv Immunolog. 3(2), 143-146.

LaPachia, P., (1987) Behavioural Disorders, L-3 Disabilities and Mesavitamin Therapy. Molescence. x~cÜ(87), 730-73 8

Larson, J. ( 1992). Alcohoiism: The Biochemical Connection Random House, Toronto.

Lemg, A. & Robson, W. (1 996). Evaluating the child with chronic diarrfiea. American Familv Phsician. 53(2), 63 5-64;.

Levine, R, Briggs, G., Harding, R, Nolte. L. (1966). Prolonged gluten . . admuiisaation in normal subjects. New Endand Journal of Medicine. 274(20), 1 109- 1 1 14.

Lew, F., & Ward, P. (1995). Neurornetrics, dynamic brain imagllig and attention deficit hyperactivty disorder. Joumai of Paediaaics and Child Hedth 3 1,

279-283.

Lewin R (1988). A Revolution of Ideas in Agridturd Origins. Science. 240, 984986.

Lindeberg, S. (1 997). http://www . pank com/-donwiss/lindet>er~

Lindstrom L., Nyberg, F., Terenius, L., Bauer, K.. Besev, G., Gunne, L., Lyrenas. S., Wddeck-Lund, G., Lindberg, B. (1984). CSF and Plasma B- Casomorp hin-Like Opioid Peptides in Postpamim Psychosis. Amaican Journal of Pmchiatrv. 14 1(9), 1 OSlO66.

Lou, H., Henriksen, L., Bruhn, P. (1984). Focal cerebrd hypopehsion in children with dy s phasia and/or attention deficit disorder. Archives of Neuroloav. 4 1 (8), 825-829.

Lovenberg, W. (1986). Biochemicai Regulation of Brain Function. Nutrition Reviews. May Supplement, 6- 1 1 .

Lozo$ B., Viteri, F., Umtia, J. (1982). The effects of short-temi oral iron thenipy on developmentd deficits in irondeficient anemic Xants. Journal of Pediatrics. 100(3), 35 1-357.

Lubar, J. ( 199 1). Discoune on the Development of EEG Diagnostics and Biofeedback for Attention-Deficit/Hyperactivity Disorders. Biofeedback and SeLE-Rewbion. 16(3), 20 1-225.

Lutz, W. (1995). The Coloniration of Europe and Our Western Diseases. Medical Hypotheses. 45, 1 15-120.

Mackamess, R (1994). Not AU In The Mind Thorson's, San Francisco, California.

W d d a , A, Bernardin, B., Kasarda, D. (1 993). Bilateral occipital calcification, epilepsy and coeliac disease: ciinical and neuroimagùig features of a new syndrome. Joumai of Neurolow. Neurosurmy & Psvchiatrv.56(8), 885- 889.

Maizels. M., Gandhi, K, Kea* B., Rosenbaum, D. (1993). Diagnosis and Treatment for Chiidren Who Cannot Control Urination. Current Roblerns in Pediatrics. 23, 402-450.

Manh M. (1992). Gluten, Major Histocompat%ility Cornplex and the Sm& Intestine. Gastroenteroloqy. 102, 330-3 54.

M- C., Welsh, R, McKay, S., Bareuther, C. (1 984). Hyperactivity (Attention-Deficit Disorder). The Journal of Family Practice. 19(3), 367- 380.

Mattes, J. (1983). The Feingold Diet: A Curent Reappraisai. J o u d of Le-% Disabilities. 16(6), 3 19-323.

Mayor, S. (1996). Warning against overuse of dmgs for inattentive children, British Medical Journal. 3 1 3, 770.

Mclver, C., & Camb, M.. (1 952). Gluten-6ree diet in idiopathic steatorrhoea. Lancet Dec- 6, 11 12-11 14. -

M c K e ~ e , 8, Main, J., Pennington, C., Parratt, D. (1990). Antibody to selected stmbs of Saccharomyces cerevisiae (baker' s and brewer's yeast) and Candida albicans in Crohn's disease. W. 3 1(5), 536-538.

McNichoL J. (1990). ïhe Great Big Food ExDeriment Stoddart Publishhg, Toronto.

Minich, D., Vodc, R, Verkade, H. (1997). Intestinal absorption of essentiai htty acids uader physiological and essentiai fatty aciddeficient conditions. J o u d of Lkid Research. 3 8(9): 1 709- 1 72 1.

Mitcheli, E., Aman, M., Turbott, S., Manku, M.. (1987). Clin id Characteristics and S e m Essential Fatty Acid Levels in Hyperactive Children. Clinical Pediatrics. 26(8). 406-4 1 1.

Murphy, K., & Barkiey, R (1996). Attention Deficit Hyperactivity Disorder Addts: Comorbidities and Adaptive impairments. Comvrehensive Psvchiatrv 3 7(6), 393 -40 1 .

MycroR F., Wei, E., Bernardin, J., Kasarda, D. (1982). ME-iîke squences in miik and wheat proteins. New Endand i o u d of Medicine. 307,895.

Nelsos R, Knowler, W., Pettitf D., Saad, M-, Bmett, P., (1993) Diabetes Care. 16(1), 335-341.

Nordin. J., Rolnick, S., Ehlinger, E., Nelson, A, Ameson, T., Cherney-Stafford, L., Grifnh 1. (1998). Lead Levels in High-risk and Low-risk Young Children in the Minneapolis-St Paul Menopolitan Area. Pediamcs. 1 O 1 (1),72-76.

Not, T., Citta, A, Lucchesi, A, Torre, G., Martelossi, S., Ventura, A (1997). h t i - e n d o m y s h antibody on human umbilical cord veh tissue: an inexpensive and sensitive diagnostic tool for the screenlig of coeliac disease. Eur J Pediatr. 1 56(8), 6 16-6 1 8.

Nsouli T., Nwdi S., Linde, R, O'Mara, F., Scadon. R, Bellad, J. (1994). Role of food dergy in serous otitis media. -of ?3 ,2 l5-2N.

O'Brien, G-, & Whitehouse, A (1990). Apsychiatric study of deviant e a ~ g behaviour among mentdy handicapped adults. British Journal of Psvchiatry. 157,281-284

Oldstone, M. ( 1 987). Molecular Municry and Autoinimune D i m . Cefl. 50-8 19- 820.

Olki F., Honig, A, Helu, B., Howanitz, P. (1983). Effect of Iron Therapy on Behavior Performance in Nooanemic, Tron-Deficient Infànts. Pediatrics. 71(6), 877-880.

O d z , E., Hanna, G., T4aversay, J. (1992). RaMnilation-induced startie modulation in attention-deficit hyperactivity disorder and nocnirnal enuresis. Psychophvsiolow. 29(4), 43 7-45 1.

Partridge, W. ( I 986). Blood-Brain Bitnier Traospon of Nutrients. Nutrition Reviews. May Supplemem, 1 5-23.

Paul, K., Todt, J., Eysold, R (1985) [EEG Research F'mdings in Chiidren with Celiac Disease Accordhg to Dietary Variations]. Zeitschrifk der Klinische M*. 40, 707-709.

Paui, K., Henker, J., Todt, A, Eysold, R (1985) Zoeliaki- Kranken Kindern in Abhaengigkeit von der Ernaehrung Seitschrifk der Kllliische Median 40; 707-709. as cited in Reicheit K (1990). The E f f i o f Gluten-Free Diet on Urinary Peptide Exmetion and CliMcal State in Schizophrenia Joumai of Orthomolecular Medicine . 5(4): 223-239.

Peiiegino, M.., D'Altilia, M., Gemiano, M (1995). Untreated coeliac disease and attempted suicide. Lancet 346(8979), 9 15.

Pemberton, P., Lobley, R, Holmes, R, Sorensen, S., Batî, R (1 997). Gluten- sensitive enteropathy in Irish setter dogs: characterizlation of jejunal microviUar membrane proteins by two-dimensional electrophoresis. Researc h in Veterinarv Science. 62(2), 19 1 - 1 93.

Piatelia, L., Zamponi, N., Cardin& C. (1993). Endocranid calcincations, bfhti le ceiiac disease, and epilepsy. Childs Nemous Svstem. 9(3), 172- 175.

Rapoport, 1. (1986). Diet and HyperaCmmyacmmy Nutrition Reviews. May Supplement, 158- 162.

Rapp, D. (1 98 1). Diet and Hyperactivity. Pediatncs. 67(6), 93 7-938.

Rapp, D. (1979). Meroies and the Hweractive Chiid. Sovereign Books, New York.

Raskin, L., Shaywitiq S., Shaywitq B., Anderson, G., Cohen, D., (1984). Neurochernical Corelsltes of Attention Deficit Disorder. Pediatric Ctinics of North Amena. 3 1 (2), 3 87-396.

Readins R, Watson, J., Platt, I., BK4 k (1987). Pulmonaxy haemosiderosis and gluten Archives of Disease in Childhood. 62, 5 13-5 15.

Reichelt, K. ( 1 996). http://www.p~.com/-donWiss/reichelt/

Reichelt, IC, Sagedai, E., Landmark, J., Sangvic, B., Eggen, O., Helge, S. (1 99Oa). The Effect of Gluten-Free Diet on Urinaiy peptide Excretion and Clinical State in Schizophrenia. Journal of Orthornolecular Medicine. 5(4), 169- 18 1.

Reichelt, K., Ekrem, J., Scott, H. (1990b). G l u t a Milk Proteins and Autism: DIETARY INTERVENTION EFFECTS ON BEHAVIOR AND PEPTIDE SECRETION. Journal of A~oi'ied Nutrition. 42(1), 1-1 1.

Reichelt, K., Knivsberg, A., Lincl, G., Nociland, M ( 199 1). Probable etioiogy and Poasiile Treatment of Childhood Autism. Brain Dvsfirnction. 4,308-3 19.

Riley, D. (1968). Changing paediatncs. 18 years admissions to a medical unit. ScottishMedicai J o d . 13(5), 159-161.

R i m l d , B. (1983). The Feingold Diet: An Assessrnent of the Reviews By Mattes, By Kavaie and Fomess and Others. Journal of Leamhg Disabilities. 1 6(6), 3 3 1-3 33.

Rimland, B., (1 986). Mesavitamins and Hyperactivity. Pediaaics 78(2), 3 74-375.

Rippere, V. ( 1 983). Food additives and Hyperactive children: A critique of Connors. British Journal of Ciinical Psvcholo~. 22, 19-32.

Robson, W., Jackson, K, Blockhurst, D., Leung, A (1997). Enuresis in children with attention-deficit hyperactivity disorder. Southern Medical Journal. 90(5), 503-505.

Rowe, K., & Rowe, K. (1994). Synthetic food coloring and behavior: A dose respome efféct in a double-bhd, placebwontroUed, repeated-mea~ufes study. The Jownaiof Pediarrics. 125,69 1-698.

Rowe, K. ( 1 988). Synthetic food colorings and 'hyperactivity': A double-bhd crossover study . Australian Paediatric Journal. 24, 143- 147.

Rude, R, Olench, M.(1996) Magnesiun deficiency: possible role in osteoporosis associated with giuten-sensitive enteropathy. Oneo~orosis International 6(6), 45346 1.

Ru&, I., Kurtz, S., Borland, J., Bain, C., Roufail, W. (1 954). Wheat-free diet in the treatment of sprue. New Endand Journal of Medicine. 250(7), 28 1 - 282.

Rufnn, I-, Carter, D., Johnston, D., Bay& G. (1964). Gluten-Free Diet for Nontropical Sprue. JAMA. April6, 162- 1 64.

Rufo. P., Meriin, D., Reigler, M., Ferguson-Maitzman, M., Dickinson, B., Bnignam, C., Alper, S., Lenceq W. (1997). The antif'irngai antibiotic, clotrimazole, inhibits chioride secrdon by human intestinal T M cens via lockade of distinct basdaterai K+ conductances. Demonstration of efficacy in intact rabbit colon and an in vivo mouse mode1 of cholera J o u d of Clinical Investigation. 100(12), 3 1 1 1-3 120.

Rush P., Inman. R, Bernstein, M., Carien, P., Resch, L. (1986). Isolated vSLSCULitis of the central nervous system in a patient with celiac disease. American J o d of Medicine. 8 1(6), 1092-1094.

Rus& V., De V i e r s , A, Taljaard, J. (1995). Altered dopaminer& h c t i o n of the prefkontai cortex, nucleus accumbens and mdate-putament of an animal mode1 of Attention-Deficit Hyperadvky Disorder - the spontaneously hypertensive rat Brain Research. 676, 343-35 1.

Saelid, G., Haug, J., Heilberg, T., Reichelt, K. ( 1985). Peptide-Containin3 Fractions in Depression. Bioloeical Psvchiam. 20,245-256.

Sandberg. S. (1996). Hyperkinetic or Aîtention Deficit Disorder. British J o d of Psvchia~v. 169, 10-1 7.

Sandstead, H. (1986). Nutrition and Brain Fundon: Trace Elements. Nutrition Reviews. May, 3741 .

Sandyk, R, & Brennan, M. (1983). IsoIated oc& myopathy and celiac disease in childhood NEUROLOGY.3 3, 792.

Santos, J., & Weriin, S. (1996). Ceiiac disease in childhood presenting with pi=: case report. Medical Iournai.95(8),58 1-582.

Satterfield, J., Schell, A, Nicholas, T., Backs, R (1988). Topographie Study of Auditory Event-Related Potentials in Normal Boys and Boys with Attention Deficit Disorder with Hyperactivity. Pwchophysiolopv. 25(5), 59 1-606.

Sattdeld, J., Schell, A, Nicholas, T. (1994). Preferenhai neurai processing of attendeci stimuli in attention-deficit hyperactivity disorder in normal boys. Psvchophvsiolopv. 31, 1-10.

Savidge, T., Shrnakov, A, Walker-Smith, J., PhiUips, A (1996). Epitheiial cell proliferation in childhood enteropathies. Gut - 3 9(2), 185- 193.

Schachar, R, & Tannoclq R (1995). Test of Four Hypotheses for the Comorbidity of Attention-Deficit Hyperactivity Disorder and Condua Disorder. Journal of American Academy of CMd and Adolescent

Schick R, & Schusdaarra, V. (1985). PsysiologÏd, pathophysiological and pharmacologicai aspects of exogenous and endogenous opiates. Clinicai Phvsiolow and Biochemistq. 3(1), 43-60.

Schmidt, M., Mocks, P., Lay, B., Eisert, H., Fojkar, R, Fritz-Si~mmd, D., Marcus, A, Musaeus, B. (1997). Does oligoantigenic diet influence hyperactive/wnduct&rdered children - a controlled trial. Eurowan Child and Adolescent Psychiatnr. 6. 88-95.

Sch& K, McKay, K., newcorn, I., Sharma, V., Gabriel, S., Halperin, J. (1998). Serotonin Fundon and Risk for Aicoholûm in Boys with Attention-Deficit Hyperactivity Disorder. Neur0p~~~ho~harma~01ooy~ 1 8(1), 10- 17.

S d y , R, Mark, E., McNeely, W., McNeely, B. (1 988). Case Records of the Massachuse!tts General Hospital. New Endand J o u d of Medicine . 319(17), 1139-1148.

Scott. F., Cloutier, H., Kleemann, R, Woen-Pagenstert, U., RowseU, P., Modler, K. Kolb, H (1997). Potentiai Mechanisms by Which Certain Foods Promote or Inhi'bit the Development of Spontaneous Diabetes in BB W. Diabetes. 46, 589-598.

Scott. F. (1996). Food-induced Type 1 Diabetes in the BB Rat. DiabetedMetabolisrn Reviews. l2(4), 34 1-3 59.

Segawa, Y., Ohya, O., Abe, T., Ornata, T., Tsuniike, N., Itokani, Y., Yoshida, K., TagashUa, E., Ueda. 1. (1992). Anti-inflammatory, analgesic, and anti pyretic effects and gastrointestina toxicity ofthe new anti-inamtory dnig N-(3-[3-@iperidinyhethyi)pheno~]propyl~~moyh&yl~o Iethyl 1-(p-chlorobenzoyl) 5-methoxy-2-methyl-3-indolylacetate. ArmeimitteKorschunq. 42(7), 954-958.

Semnid-CIikeman, M-, Filipew., Biedexman, J., Stehgard, R, Kennedy, D.

Renshaw, P., Bekken, K. ( 1994). Attention-Defkit Hyperactivity Disorder: Magnetic Resomce Imaging M o r p h o d c Analysis of the Corpus

Callosum Journal of the American Academv of Child and Adolescent Pmchiatry. 33(6), 875-88 1.

Shannon, W. (1922). Neuropathic Manifestations in Intàms and Children as a R d t of Anaphylactic Reaction to Foods Containecl in thier Dietary. Arnerican J o d of Diseases in Children. 24, 89-94.

Shelley-Tremblay, J., & Rosen, L. (1996). Attention Defich Hyperactivitv Disorder : An Evolutionary Perspective. l o d of Genetic Psvcholoq

157(4), 443-453.

Shelton . T . &Barkiey. R (1990) Clinicai, Developmentai, and Biophysical Considerations Attention-Defich Hweractivitv Disorder. W o r d Press, New York pp. 209; 2 19.

Sher, L. ( 1997). Autistic dwrder and the endogenous opioid system. Medicai &wotheses. 48,413414.

Sin& M., & Kay, S. (1976). Wheat gluten as a Pathogenic factor in Schizophrenia. Science. 19 1.40 1-402.

SmecuoL E.. Bai J., Vaquez, H., Kogaq Z., Cabanne, A, Nivelori, S.. Pedreira, S.. Bo- L., Maurino, E., Meddings, J. (1997). Gasaointestinal permeability in celiac disease. Gastroemterolo.qy. 1 l2(4), 1 12% 1 13 6.

Smith, G., Saldanha, G., Bntton, T., Brown, P. (1997). Neurological Manifestations of coeliac disease. Journal of Nenirolosw Neurosurgerv and Psvchiatw. 63(4), 550.

Smith, R, & Maes, M. (1995). The Macrophage-T-lymphocyte Theory of Schizopbrenia: Additional Evidence. Medicai Hymtheses. 45, 13 5- 14 1 .

Snow. P. (1975). Hyperkinesis and Chronic Constipation. New Zeland Medicai Journal. June 11, 515-517.

Spencer, T., Biederman, J., Harding, M., O'Domea D., Faraone, S., Wilens, T. (1996). Growth deficits in ADHD cbiidrm revisited: evidence for disorder- associated growth delays? Jounial of the Amencan Academv of Child and

Adofescent Psvchiatrv. 35(11), 1460-1469.

Spring, B., Liebennan, H, Swope, G., GArfield, G. (1986). Effects of Carbohydrates on Mood and Behavior. Nutrition Reviews. May Supplement, 5 1-60

Starobrat-Hemelin, B., Kozieiec, T. ( 1 997). The effects of magnesim physiologicai supplementation on hyperactim in cMdren with attention deficit hyperactivity disorder (ADHD). Positive response to magnesium oral loading. MaPnesium Research. 1 O(2): 14% 1 56.

Starobrat-Hermelin, B., Kozielec, T. ( 1997). Assessrnent of mangesïum levels in children with attention deficit hyperadvity disorder. M&gesium Re~ear~h. 10(2), 143- 148.

Stein, T., & Sammaritano, k (1984). Nïtrogen metabolism in normal and hyperkinetic boys. The American Journal of Chka1 Nutrition. April, 520- 524.

Stevens, L., ZentaJI, S., Deck, J., Abate, M., Watkuis, B.. Lipp, S. (1995). Essential fàtty atid metabolism in boys with attention-deficit hyperactivity disorder. American Joumal of Clinical Nutrition. 62(4), 76 1-768.

Stevens, L., Zentall, S., Abate, M., Ku& T., Burgess, J. (1996). Omega-3 Fatty Acids in Boys With Behavior, Learning, and Health Problems. Physioloav & Behavior. 59(4/5), 9 15-920.

Stevens, F., Comoliy, C., Murray, J., McCarthy, C. (1990). Lung Cavities in Patients with Coeliac Disease. Digestion. 46, 72-80.

Sugawara, M., Sadeghpour, M., De Traversay, J., Oniitz, E. (1994). Prestimdation-induced modulation of the P300 component of event related potentials accompanying stade in children Electroence~haiocna~hy

Taylor. E., Sandberg, S., Thoriey, G., Giies, S. (1991). The E~idemiolow of Childhood Hmeractivity. M o r d University Press, Toronto.

Teschexnacher. K, Koch, G., Brant, V. (1 997). MW protein-derived opioid receptor ligands. Biooolvrners. 43(2), 99- 1 17.

Thibaul& L., Codon, J., Roberge, C. (1988). Changes in semm amino acid content and dopamine-B-hydroxylase activity and brain neurotransmitter interaction in cats fed wein with or without gluten or gliadin. Journal of Clinical Biochemistrv and Nutrition. 4, 209-22 1.

Thorley, G. (1984). Review of Foiiow-Up and Foiiow-Back Studies of Chifdhood Hyperactivity. Psvcholo~ical Bulletin. 96(1). 1 16-1 32.

T M C., D'Alessandro, P., Carnisani, T., Piccirilli, M, Signorini, E., Pelli, M., Cavalletti, M., CasteUucci, G., Palmexi S., Battisti, C., Federico, A. ( 1993). Epilepsy with Bilaterai Occipital Calcificiations: Sturge-Weber Variant or a Dinerent Encepbalopathy?. Epilevsia 34(3 ), 528-539.

Tortora, G., & Anagnostakos N. (1989). Princi~les of Anatomv and Phvsiolow . Harper&Row NewYorlq p.751.

Tuckova, L., Tiaskalova-Hogenova, K. Fame, M. Karsh K., Rossmann, P., Koliaska, S., Kocna, P. (1995). Molecuiar Mimicry as a Possible Cause of Autoimmune Reactions in Celiac Disease? Aatibodies to Gliadin Cross- React with Epitopes on Enterocytes. Clinicai Irnrnunolo~v and Irnmunopatholow. 74(2), 170- 1 76.

Ucles, P., Lorente, S., Rosa, F. (1996). Neurophysiological methods testhg the

psychoneural basis of attention deficit hyperactivity disorder. Chiid's Nervous System. 12.2 1 5-2 1 7.

Uhlig, T., Merkeaxhlager. A-, Bandmaier, R. Egger, J. (1997). Topographic rnapping of brain electricai activity in children with food-induced attention deficit hyperkùietic disorder. Eurooean Journal of Pediatncs. 1 56(7), 55 7- 56 1.

Voipe. C., Festini, G., Torre, G-, Lucchesi, k (1 997). Occuit coeluic disease and iron-deficiency anaemia. Minerva Media. 88(I O),4O 1-403

Volsegan~ H., Genser, D, Wyatt, J., Lochs, H., Ferenci, P., Granditsch, G., Penner. E. ( 1995). Screening for celiac disease: a prospective study on the vahe of noniavasive tests. American Journal of Gastroenterolow. 90(3), 3 94-398.

Viissides, D., Venulet, A, Jenner, F. (1986). A Double-Blind Gluten-FrdGluten- Load ComoUed Trial in a Secure Ward Population British l o u d of Psvchiatw. 148,44742.

Wainwright, P. ( 1992). Do Essential Fatty Acids Play a Role in Brain and Behavioral Development? Neuroscience and Biobehavioral Reviews. 16, 193-205.

Ward W., Murphy, J., Greenburg, G. (1 985). Celiac disease and spinocerebellar degeneration with nomial vitamin E status. Neurolopy. 3 5, 1 199- 120 1.

Warren, R, Odet D., Warren, W., Burger, R, Maciulis, A, Torres, A. (1995). 1s Decreased Blood Plasma Concentration of the Complement C4B Protein Associateci with Attention-Deficit Hyperactivity Disorder? Joumal of Amencan Acadernv of Child and Adolescent Psychiatrv. 34(8), 1009-10 14.

Watson, R, McMiuan, S., Dickey, W., Biggart, J., Porter, K (1 992). Detedon of Undiaposeci Coeliac Disease with Atypicai Features Using Antiretiailin and Antigiiadin Antibodies. Ouarterlv Journal of Medicine. 84(305), 7 13- 7 18.

Weijers, H, Br van der Kamer, J. (1957). Celiac disease. Advances in Paediatrics. 9, 277-3 18.

Weiss. R, Stein, M., Trammer, B., Refetog S. (1993). Attention-deficit hyperactivity disorder and thyroid hction. The Journal of Pediatrics . 123(4), 539-545.

Weiss. G., Hechtman, L., Milroy, T., Perlman, T. (1985). Psychiatrie Stahis of Hyperactives as Adults: A Controiied Prospective 15-Year Foîiowvp of 63 Hyperactive Children. J o u d of the American Academy of Child Psychiatry. 24(2), 2 1 1-220.

Weader. P., & Kalm, M. (1983). Prdence of Attention Deficit Disorder, Residual Type, and ûther Psychiatrie Disorders in Patients With Irritable Colon Syndrome. American J o u d of Psvchiam. l4O( 12), 1 5 79- 1 582.

Wdens, T., Prince, J., Frances, R (1995). Alcohol & Dnig Abuse: Attention- Deficit Hyperactinty Disorder and Comorbid Substance Use Disorders in Aduits. P~chiaaic Services. 46(8), 76 1-765.

Wdson, L. & Doroq L. (1984). Possible Role of the Opioid Peptides in Sleep. Medical Hpotheses 1 4 269-280.

Wright, D. ( 1995). The major complications of coeliac disease. Baillierets ClimcaI Gastroenterolopy. 9(2), 3 5 1-369.

Wurtmaq R. (1986). Ways That Foods Can Affect the Brain Nutrition Reviews May Sdpplement, 2 6 .

Yamada, E., & Coheu, R (1993). Brain Metabolism in Teenagers With Aîtention- Deficit Hyperactiv* Disorder. Archives of General Psvchiatrv. 50, 3 3 3-

340.

Young, S. (1986). The E f f i on Aggression and Mood of Alterhg Tryptophan Levels. Nutrition Reviews. May Supplement, 1 12-122

Zagon, L, & McLaughh, P. ( 199 1). Identification of opioid peptides regulawig proiiferation of murons and glia in the developing nervous system. Br& Research. 542,3 18-323,

Zagon, L, & McLauQhlin. P. (1984). NaItrexone Modulates Body and Brain Development in Rats: A Role for Endogenous Opioid Systems in Growth. Life Sciences. 35,2057-2064.

Zametkin, A, Liebemuer, L., Fitzgerdd, G., King, A. Mhkms, D., Hencovitch, P.* Yamada, E., Cohen, R (1993). Brain metaboiisrn in teenagers with attention-deficit hyperactivity disorder. Archives of General Psvchiatry. 50(5),333-340

Zeisel S. (1 986). Dietary Influences on Neurotransmission. Advances in Pediatrics. 33, 23-48

Zioudrou, C., Streaty, R, Klee, W. (1979). Opioid Peptides Denved fkom Food Proteins. The Journal of Biolo~cal Chanistrv 254(7), 2446- 2449.

Appendk One: Kate and Frank Vicent

15 May 1997

55 R i v e ~ e w Street

Muwillumbah 2484

Australia

Dear Rog

A moment's peace ! Lewen is at school! ïhank you for your letter, 1 wiii endeavour to give you as much info as you want. You may do with it whatever you want; there is so much to remember. Perhaps express* some of these last five years with- Lewen wiil be a relief of sons - 1 know you WU understand the deep meaning of that.

We have di been ernotionaliy and physically drained as weU as socially depnved . Funny really, ail 1 had to do was skip the bread ide of the supermarket! But no bread and jam or toast or cake with my tea is just not cricket - 1 mean Pm English for Christ's sake! Change is always confionthg but the benefits speak for themselves. Thank you once again for your interest in Lewen.

PRE-LEWEN: Two children, Sarah 1 O, Nicholas 9. Civilkd, balanced, sociaiiy active. OK So we sat around our table and discussed hawig another addition to the f d y . . . everyone in hvor, we'd share evaything.. . waited. nine months passes.. .a very anxious expeztant family.

LEWEN: Born 18/lU9 1, three weeks late, dry birth due to ruptured membrane four days eariier. Consequence - Lewen is boni with HIB meningitis. Life-threatening situation, antibiotics, oxygen, humidicrib. First feed eight hours later is disastrous as is every other feed for next nhe months. Child would suckle one mouthfbl, arch his litde back into a ba& then pull away; then ay to suckle agaio; hated feeding generally. It looked Iike feeding was somehow very painful for hin Help h m chemists doctors, speciatists, clinics, etc. led us to try everythllig on the market At six weeks, paediatrician's synopsis, "moa extraordinary!", can offer no advice. Constandy on the move, loud, a rdess sleeper waking every couple of houn tili age the and burning mbber the moment his feet touch the floor.

At eleven month an evening meal abandoned as we rush screnming chad

to hospitai, suspecthg food poisoning; tums out to be a stool which had blistered his bottom in a cup-s~ed ring, quickiy relieved with paw paw ointment. Wakbg by nhe months, he rnanaged to climb to top sheifand dnnk bleach at age one. Trees around house ait down to keep him offthe root (two storey at fionî), s a f i hamess attached to 20 metre lead, a beU aitacheci to his clothes, neighbours on the lookout, Lewen's fit fht year of Iife was intense, ours desperate.

On the positive side, Lewie has a Fantastic memory; even though he d o a ' t reem to dweii on anything and it is ourprising the detail he can communicate when it aiits him He is very dexterous and loves building things. Kathe, our good neighbour, said he seemed to be drives as though uying to take his mind off whatever is u p s e t h ~ him He was like a buttedy on speed! More in-depth medical meny-30-round and dergy testing with no more help. He was totdy over the top, codd not still or concentrate for more than a minute on anyihuig, showed linle affection even though there were four of us craving it; we were begùining to suspect autisrn One paediatrician's advice at eighteen rnomhs. "This is a behavioural probiem, perhaps we should consider foster care!"

New GP in town (20 others), who listens, obsewes, understands Places Lewen on Serfontah Clinic waiting List for assessment. At age two, Lewen is diagosed as chronicaiiy hyperactive (ADHD). Gov't. regulations are four years minimum before he can be given medication for the condition! With a suick of documentation nipporting Lewen's condition, we appeai to the Health Dept. and wait. He began medication (dscamphetamine) at three years of age. Yesssssssssssss!

LEWEN MEDICATED: What an immediate change! He codd aaually watch a £ive minute TV program and tunieci the pages of a book as though re-discoverhg them Mead of speed reading. A much happier kid, more affeccionate, and although there was an initial weight loss, he regained it and actudly put on weight. He was still a cornado but at les t his concenaarion improved immensely. It was great but no panacea.

Christmas 1995 we miss script renewal by four days, we spend five days over Chrismias widi Lewen unmedicated. Disasrer! Day five, mother hospitaiised for ten days wirh nervous exhausion. Camping holiday postponed, reenagers devastated, Lewen rampant.

Now seeks adult supervision, clingy when dropped off at school. This year he started kindergarten and we decided not to say anything to the school about his condition and instead medicated hirn pnor to him going; we weren't sure if we had a bored genius or smggling child! If there was a problem, they would let us know. (Medication was given at 6am, 8:SSam, 3 pm.) It is now May and Lewie is doing well at school and loving it. Wants to learn, becoming more sociai, the dass clown and popular.

GLUTEN-FREE: Katheonce more to the rescue with wads of info on ADHD and in link with gluten teso. In the meantirne we decided to go aiead anyway, pamculady as there appeared to be suspect farnily background; (Lewie and Kate are from a long line of Berserks!), (in-house joke, both have the same birthday ) .

Within one week we couldn't believe the change coming over Lewen. H e began to laugh a lot more, appetite improved, overt affection to d l family members. Were we just imagining it? We detided to withhold medication ro see what would happen. Nothing! No ourrageous behaviour, just a reaily pleasant kid albeit still a live wire. M e r than let him feel different, it was one in al1 in; a gluten-free family.

Six weeks have passed with inaresting resuls. Relenting afrer consrant harassrnent from Nick we smuggle him in some bread buns and hide them in the freezer. Somewhere dong the way, Lewie discovered them and we immediately noaced a change in his behaviour. Three-year-old Brent asked, "Is Lewie medicated, Mum?" Serves us right, but it did demonstrate to especidly Nick, now founeen, the importance of staying gluten-free and that in all probability, he was also affected.

We were lucky enough to see the dramaric results on a five year whose system is more sensitive to change. We know we are al1 going to benefit because we have wimessed it in Lewen. It is now six since we fim went gluten- free and we have just got the first blood test result Negative! Thank Christ we didn't wait to look for some reason to ar least rry i t Ir really does work. S harne abour dl those foods denied but a new adventure shopping and surprisingly berner value for money and heaithier. Kate considers herself a fantastic cook, but to be suddenly told that she couldn't use the BROW (barley, rye, oats, wheat) produas to cook with, she was devastateci! Six weeks later however, she can now make absolutely anything she made before - but now al1 gluten-free! She finds k ing gluten-free no problem at all!

Cheers, Ron - and thanks!

Kate and Frank

Appendix Two:

At 08: 15 AM 1/17/98 +OOOO, you wrote: > --------- -------- Information from the mail header -------O---

> Sender: CeliadCoeliàc WheaGluten-Free List > c CELIAC@MAEWTROUSTJOHNS.EDU> > Poster: Carol Leather <carol@X-CALIBRE.DEMON.CO.UK> > Subject: Overweight and temper tantrums surnmary

> < < Disclaimer: Verify this information before applying it to your situation. > >

> Hi everyone,

>

>Sorry I've taken a while to summarise all the replies to my Iast posting

>regarding my son's behaviour problerns but I've been feeling pretry lousy

> this last week.

>

> We have been having trouble with his volatile temper for a number of

>years but (how stupid can you get?) had never connected it with CD

>althou& 1 have i t Many of you wrote wirh sirnilar expenences and

Sadvised me to get him checked out 1 took him to the doctor's yesterday

>and she has agreed i t may be a possibility (but coeliacs only get

>diarrhoea, was her fiat comment!) and will now organise blood tests. >

S o m e stones sounded so familiar and everyone was so helpful. I was

>unsure wether to change his diet to see what happened but Chris wrote

>"DO NOT cut back on your son's gluten intake prior totesting .. as the

>antibody tests and intestinal biopsy can show very normal IF therets

> been substantial heling from tack of gluten intake." Thanks Chris for

>your reassurance that I was not the only overweight coeliac. >

>My thanks aiso to D-Lynne your story sounded so much like ours. Ben has

> had sirnilar violent outbursts at school and once picked up a chair and

>threatened the teacher with it! >

> jill mentioned that her child also seemed mer hungry but did nor gain

>weight as did Kadiy in her reply. >

>If I mention everyone who responded rhis post will be too long to redd,

>so can 1 say thanks to you dl. >

>Irll be away from the cornputer next week when i go in for rny gallstone

>operation but will eagerly await the time when 1 can catch up on dl >your posa. Speak to you soon. > > -- >Carol Leather

>An English Coeliac

- Appendix Three: A speech 1 gave at the 1997 Annual General Meeting of the Calgary

Chapter of the Canadian Celiac Association:

Gluten is a Dubious Lwcury of Non-Celiacs

Ron Hoggan

(Note: In this paper 1 use the term "gluten" generically, as we celiacs use it, to refer to a l 1 toxic proteins in cereal grains. )

One must wonder why, in spite of increasing life-spans in the advanced industrialized nations, modern medicine has failed to clearly identify the cause of many neurological, autoimmune and malignant disease. The gluten-free diet is only recommended where there is a clear indication of advanced, gluten-induced disease, but is this the best advice?

We often feel disadvantaged by the strict gluten-free diet we have to follow. But perhaps it is those who continue to consume glutinous foods who should be feeling badly about their diets. Gluten, while dangerous to celiacs, has never been investigated for deleterious effects on the general population. Yet we have studies that show that hunter-gatherers following traditional life-ways do not develop the neurological,' auto-immune and malignant diseases that people living in the industrialized world experience, and these people rarely eat gluten-rich foods (1,2 . There is already cornpelling evidence connecting the advent of agriculture to bone and joint disease ( 3 ) , and humankind has only been cultivating cereal grains for approximately 10,000 years ( 2 , 4 ) , which Ls but a brief moment in

evolutionary terms. Remember too, it is only a small population located in the Near East, that bas had that length of exposure to cereal grains (4); most of the world has had agriculture for an even shorter period of time.

Neurological and auto-immune diseases, as well as malignancies, are over-represented among celiacs (51, suggesting that glutens/gliadins may be a major environmental contributor to such diseases. Yet this area

of investigation appears to have been avoided in research on these health problems. One must wonder at the cause of this neglect of such an important possibility.

We know, from the studies by palenotologists of human remains from the ancient past, that when a culture begins to cultivate cereal grains there is an overall reduction in height, which is variously reported as 5" and 6' (2,4) . Clearly, the reduction is substantial and significant. We know, too, that these remains demonstrate weaker bone structure (through reductions in peak bone-mass) and evidence of articula damage(3).

Additionally, ancient Egyptians, who consumed a d i e t that would be considered very "heart-healthy" in our culture, have left behind mummies which clearly demonstrate atherosclerosis (7). While the evidence from the ancients is compelling, there can always be counter-arguments and debates when we are reaching back as far as 10,000 years into the past. Yet a few marginal pockets of scientific enquiry have explored a f e w elements of modern implications of this issue.

W.J.Lutz (4) has offered an alternative perspective on the "French Paradox." (The "French Paradoxn is the unusually low rate of death by myocardial infarction among the French despite quite high per-capita rates of fat consumption.) Dr. Lutz has studied the spread of agriculture through Europe. He presents a picture whereby the spread of agriculture, and thus the period of time a culture has been exposed to cereal grains, is inversely related to the incidence of cardiovascular disease. The underlying assumption, of course, is that the longer the exposure, the greater the likelihood that those who were intolerant to these grains were trimmed from the gene pool of such cultures; it seems that the less time a culture has been exposed to gluten, the greater the portion of the population that continues to develop cancers and cardiovascular disease. (Lutz also provides sirnilarly compelling data on the rates of breast cancer mortality.)

A study done in China produced what the investiqators found to be rather surprising results(8). In this investigation, the researchers plotted the diets of more than 3500 rural Chinese women, and measured their levels of SHBG (sex-hormone binding globulins) which are quite rel iable predictors of cardiovascular disease, They were

very surprised to find-that wheat consumption, and perhaps, reduced f i s h consumption, were the strongest predictors of levels of SHBG which would Fndicate an increased risk of cardiovascular disease,

Another study has connected gluten with neurological illness (9). This group of researchers tested 53 patients with neurological illness of unknown origin for antibodies against gliadin. More than half of them (30 people) demonstrated these antibodies. Nine of those folks proved to have celiac disease, but the other 21 only demonstrated an immune response to gluten. This study has some far-reaching implications for neurological research.

Yet another indication that celiacs are not the only segment of the population to suffer from the adverse effects of gluten is a study that was carried out on a very small group of siblings of celiacs(l0). When subjected to rectal gluten challenge, half of the siblings showed an immune response to gluten, but these results did not correlate with the hereditary predictors of celiac disease.

As for the connection between autoimmunity and cereal grains, it is clear and compelling. The theoretical perspective of rnolecular mimicry suggests that gliadin- derived peptides, due to their structural similarity to to the Epstein-Barr virus, may activate the immune system. Since the invading gliadin peptides lodge in collagenous tissues, and since only intestinal permeability (not celiac disease) is al1 that is requried to allow the passage of these peptides into the bloodstream, a significant number of many types of autoimmune diseases seem likely to benefit from a gluten-free diet (11 ) ,

In total, then, there are several studies which demonstrate (often coincidentally) that a much larger group than those with celiac disease are mounting an immune response against gluten, and that this response i s causing or contributing to serious illness. Phytic acid in whole cereal grains binds to minerals, including calcium, and may be implicated in osteoporosis (12). Molecular mimicry may, as a result of gliadin peptides having similar molecular structures to the Epstein-Barr virus, provide a starting point for autimmunity, especially since gliadin peptides have demonstrated an affinity for collagenous tissue.

1 would now like to draw your attention back to the issue of malignancy. Medical Hypotheses , a peer reviewed - journal, has been kind enough to accept, for publication, a paper 1 have written which suggests (among other things) that gluten rnay be implicated in a great many cases of lymphoma(l4). Gluten has been demonstrated to interfere with the celiac patient's ability to mount an immune response to malignancies ( l 5 , 1 6 , l i ) . In my paper, 1 have postulated a dynamic whereby gluten may have a similar effect in others who are simply sensitive to gluten.

We hear al1 the time about pollution in the industrial world being the source for modern man's high incidence of cancer. It is the chemical additives, w e are told, in the food we eat, that causes much of the problem. Dietary fats have also corne under attack. 1 would like to suggest that the evidence from antiquicy, the pattern of the spread of agriculture in Europe coinciding with the patterns of civilizatory illnesses, the levels of SBHG associated with wheat consumption, the high incidence of gliadin antibodies among those with neurological illnesses of unknown origin, the sensitivity to gluten among siblings of celiacs in spite of the absence of genetic indicators associated with celiac disease, and my own investigation of the literature regarding lymphoma, al1 point to the strong possibility that gluten is a dangerous substance to many more people than just celiacs,

Sources : 1. Eaton B, Komer M, Shostak M, " Stone Agers in

the Fast Lane: Chronic Degenerative Diseases in Evolutionary Perspectiven The American Journal of Medicine - 1988; 84:739-749-

2. Eaton S, Konner M, Valeolithic Nutritionff - NEJM - 1985; 312 (5) : 283-289

3. Eaton S, Nelson D, "Calcium in evolutionary perspectiven - Am. J, Clin.Nutr. 1991; 54: 2815 - 287s -

4 . Lutz W J, "The Colonisation of Europe and Our Western Diseases" Medical Hypotheses 1995; 45: 115- 120

- d

5. Lindeberg, S, et al. Tardiovascular ris k factors in a Melanesian population apparently free from stroke and ischaemic heart disease: the Kitava studyn - J I n t e r n Med - 1994 Sep.

6. Lewin R, ''A Revolution of Ideas in Agricultural Originsn - Science - 1988; 240: 984-986

7 . Zimmerman M, "The paleopathology of the cardiovascular system" - Tex Heart Inst J - 1993; 20 (4) : 252-257

8. Gates et. al. "Association of dietary factors and selected plasma variables with sex hormone-binding g lobu l in in rural Chinese women" Am J Clin Nutr 1996; 63: 22-31.

9. Hadjivassiliou M, Gibson A, Davies-Jones G, Lobo A, Stephenson T, Milford-Ward A, "Does cryptic gluten sensitivity play a part in neurological illness?" -Lancet - 1996; 347: 369-371

10. Troncone R, Greco L, Mayer M, Mazzarella G, Maiuri L, Congia M, Frau F, devirgilis S, Auricchio S, "In Siblings of Celiac Children, Rectal Gluten Challenge Reveals Gluten Sensitization Not Restricted to C e l i a c HLA" - Gastroenterology 1996; 111: 318-324 -

11. Ostenstad B, Dybwad A, Lea T, Forre O, Vinje O, Sioud M, "Evidence for monocional expansion of synovial T cells bearing V Aipha 2.1/V beta 5.5 gene segments and recognizing a syntehtic peptide that shares homology with a number of putative autoantigensn

12. Lindeberg, S t a f fan, personal correspondence Feb, 1997

14. Hoggan R, "Considering Wheat, Rye, and Barley Proteins as Aids to Carcinogens" Medical Hypotheses - - In Press 1997.

15. Maclauria B, Cooke W, Ling N, "Impaired lymphocyte reactivity against tumor cells in patients with coeliac disease" Gut 1971; 12: 794-800 - -

16. Egan L, Walsh S, Stevens F, Connolly C, Egan E, McCarthy C, "Celiac-Associated Lymphomaw Journal of Clinical Gastroenterology 1995;21(2): 123-129 -

17. Swinson C, Slavin G, Coles E, Booth C, ''Coeliac Disease and Malignancy" Lancet 1983; Jan 15: - - 111-115

Appendix Four:

Predidve Value of Serology Testing in Celiac Dkease

Presented by Dr. Vijay Kumar at Mt. Sinai Medical Centre,

Nov. 9. 1996

Ainerican Ceiiac Society/Dietq Support Coalition

Mystery Golden Key Conference

Ron Ho-

Dr. Kumar has been working on serological testing for celiac Ciwe over the last 15 years, and was presenting &er having beai up all night ûyhg to catch a flight frorn B a o after a severe snow storm. We were all pleased by his dedication, as his presmtation was both informative and cornpelling. He began by asking some fimiamentai questions, which challenged several common beliefi about the diagnosis of celiac disease, k g h h g with: Tan we effectively diagnose celiac disease by its clinid p r d o n s ? " The answer came in the data he cited fkom Campbell & Davidson in their survey of 1 3 W ceiiac patients. The £ira item indicated that celiac disease may present with a broad variety of symptoms, and are easy for dinicians to miss- The second item indicated that the majority had visited 5 or more doaors prior to diagnosis. The third item indicated that it had taken an average of 5 to 10 yearq d e r initial presentation, for ceiiac disease to be diagnosed. ClearIy, the m e r to Dr. Kumar's question was that celiac disease can wt be diagnosed by its clinical ptesentations. What would be the value of histologicai, or any other evidence, if it couid be diagnosed on the basis of chkal presentation done? He mentioned the consideiable risk of misdiagnosis as weli. Whiie cLinical presentation rnay help in identifying the possibiliîy ofceiiac disesse, it can not, reasonably, be the sole aiteria for an accurate diagnosis. "Why do we need an eady diagnosis of celiac disease?" was his next question The m e r was twofoid. First, young children may not g o w and develop properly if they have unidentifid ceiiac disease. Normal development, for many ofthese childres requïres that they be on a gluten-@ee diet, thus recieving adequate nutrition. Second, untreated celiac ciisease is associateci with a very high risk of lymphoma, and the gluten fiee diet plays a protective role against lymphoma. It reduces the nsk to almost the same as the general population, after 5 years on a strict diet He cautioned that less than 5 years may not yeiid statistidy sismficant reductions in risk. Similar risk têctors for malignancy are at work in dermatitis herpetiforrnis. Histopathology gained acceptance in the mid-sioaies, to aid in the diagnosis of celiac disease, because of the problems with diagnosis on the bais ofchical presentation. This is where a biopsy is taken firom the srnail intestine, and the morphoiogy is examineci to determine the stahis of

in the patient. Siides were shown, fim demonstrating normal morphology of healthy then demonstrating total d o u s atrophy, dong with cxypt hyperp1asia, and increased

deasity of intraepitheiial lymphocytes. These were the critena proposed in the mid-shdes,

but such morphology aione is not diagnostic of cehc disease. Many other diseases like parasaic iaféctïom, h u n e deficiency disorders, and numtionai deficiency disorders, atl look quite similar. At that ùme, ESPGAN (European Society of Gastroenterology and Nutrition) proposeci a strict set of diagnostic criteria for cetiac disease. Fust, characteristic 0at or damaged villi were to be dernonstrateci. Second, after a Qluten-fke diet for an eaended period of tirne, when the patient was feeling nomai, a second biopsy should be taken, showing vdii of normal appearance. Finally, a gluten-contalliing diet would be re- institut& and if d e r a penod of about 6 months, ifvülous atrophy was demonstrated at biopsy, then the diagnosis of c e k disease was conhed. In many of the patients he has

there are poblerns gettiq them to eat enough @uten to codim rhe diagnvsis for the third biopsy. Then there is the Limitation that initidy, patients need to be identifieci as needing the biopg.. Yet another limitation of this approach is that when a biopsy is taken, it is removed from a srnail, localized area It may miss a region of typical celiac intestinal lesion and take the sample fiom a region showing very mild symptoms which are difficuit to identifjc These histological criteria are on a continuum, showhg Bat villi at one end, and nomial villi at the other. Yet auother limitation anses in the three recent reports which iden* ceiiac disease in patients with normal histopathology. Patho10gists apparently r a d them as normal biopsies. He cited papers f?om 1982, 1993 and 1996. Dr. Kumar used the iceburg metaphor to describe the m e n t mais of recognition of celiac disease, where the vast majority of celiac disease rernains undiagnosed. We are seeing ody typical ceiiac disease. This is where weight los, diarrhea, short stature, very typical &&stations, lead to the biopsy, where the histology revds characteristic damaged villi. What remains unda the d a c e is two large groups: 1) silent celiac disease where the the patient presents with mil& atypical manifestations like low levels of iron and low haemoglobin leveis. Some patients only present with aphthous ulcerations in their mouths but ifthey are tested, many of them demonstrate characteristic histopathology; 2) Then you have situations where patients who really have celiac disease, but ifyou test them, they show normal histopathology . What can be done, then? When it was fht identifie& in the 1960's that the &adin proteins in wheat were the toxic emities in celiac disease, many investigators in Europe began looking for anti-gliadin antibodies. For serology to be effective, the techniques have to be very refined and well standardized. Otherwise, one lab reporthg r d t s may not be as good as another lab reporthg results. Dr. Kumar reported on his own lab resuits in anti-ghadin antiibody tests. He indicated that 5% to 1û% of those demonstrating IgG anti-@adin antiibodies do not have celiac disease. Rarely, on the other hmd are IgA anti-giiadin antibodies d e m o n ~ t e d in non-celiacs. These antibodies are detected by very simple methods. The consensus in the field is that IgG antibodies are more sensitive, but uot specinc, and IgA antibodies are mon specific but less sensitive. The next antiidy identified in the fiterahire was the antireticulin antibody. We don? r d y know what protein antigen this antibody is developed in response to. The mune is a serologid tem, but it reacts to substances calleci reticulin which is in the tissues surrouncüng the tubules in the kidney. There are five types of reticulin antiiodies. Only one of these is associated with celiac disease, and this is not a very sensitive marker* but it is very specific for celiac disease. When a patient goes on a g-f diet, th& antibody leveis

wil l eventually disappear and become negative. The third type of antibody, reponed in 1984. was the endomysial antibody. It is nameci in referace to the endomysium which is the lining of the muscle fiben. These, and the atltildculin antlbdies are primarily of IgA class. In situations whae patients are IgA deficient, they will d e IgG autibodies. Patients with cetiac disease demonstrate this aatïibody with Wnially lûû% &equency. On a gluten-fiee diet, these antiibody levels become nonnal, or negative. They are a very sensitive. very specinc marker of celiac disease. It takes varying periods for these levels to become normal. They reappear very quickly on a gluten challenge. He then reponed on 133 celiac patients, 132 of whom showed IgA aatiendomysium antibodies when eating gluten. The one who did not was IgA defici= and was positive for IgG endoqsiai antibody. IgA is the more sensitive d e r . AU of the 133 patients eventuaily dernonstrateci negative levels of antiendomysial amibodies. When rechallenged with giuten 130 once again became positive for antiendomysial antîibodies. ûther studies indicate that ifthe other 3 were chaiienged with a high gluten-containing diet, they wodd have dernonstrateci amibodies too. Another group of 3 1 showed abnormal biopsies, but endomysial antibodies were not dernonstrateci. On a gluten-fkee diet, the the viIlous morphology retumed to normal, but could not be induced again on gluten challenge. Neither were antiendomysial antibodies detected. It appears that these were not cases of cetiac disease. A single biopsy can be misleading without additiooal evidence. Yet another goup of patients in Italy, reported in 1996, dernomteci symptorns suggestive of ceiiac disease. They tested positive for antiendomysid amibodies, but did not display abnofmalities in villous morphology. The question is, are these patients celiac or not? They demonstrated typical symptoms, which resolved on the gluten-fke diet, and the endomysium antibodies also disappeared on the diet Upon gluten chaiienge, these syrnptoms retumed, and the high a n t i i y levels retunied also. The chical ~ e s t a t i o n s , including diarrhea, steathoma, and abdominal cramping, are convincing evidence that these are cases of celiac disease in the early stages of immune response whicb, with tirne. wdi develop typical histology of cefiac disease. Foilow-up studies have demonstrateci just this. There are certain HLA markets which are associated with celiac disease. Nme of ten celiac patients in another shidy did not have these markers. That means that the genetic markers we cunentiy associate with celiac disease are also problematic. Lymphocyte density was also within the normal range. This indicates that these individuais are very early in their immune response. He used demonstrations of increased ICAM presentation in the same tissue, to indicate that an immune response was being mounted, but it was at a very early stage. Ifailowed to continue, Dr. Kumar was confident that the typicai histopathology of celiac disease would eventuaiîy be demonstrateci. He went on to show a snidy reported in -Acta Paediatri- where patients who demonstrated antiendomysial antibodies and normal muwsa, were re-biopsied three years later, and dernonstrateci dous atrophy. Quantity of gluten intake seems to be the prhary variable, and where increased intake occun d o u s atrophy follows. Ewmples reported as recently as 1994 indicate that diagnosis may di be slow among elderly patients, even where there is a tbreat to Me. This demonstrates that diagnosis of ceiiac disease continues to be a very slow process in many cases. A simple serological test could help immenseiy. Among

Eimily members of those with celiac disease, symptornatic or asyrnptomatic celiac disease is present in LW!% to 15% of fint degree relatives. This is cd aSSOciated with short stature, autoimmune disorders and cardiac abnormalities. A simple serological test should be considered for family mabers. Dr. Kumar presented a compelling case for the value of serological screening for ce& disease. He indicated that the biopsy remains the gold standard for diagosis, but 1 wdked away fkom his presedon convincd that the serologid testing offers earlier diagnosis, and thus improved health for celiac patients. We may be seeing the emergence of a new gold standard in the diagnosis of celiac disease; one which may reduce Nk, be more reliaMe thaa the biopsy, and it is les invasive.

Date: Sun. 26 Apr 1998 16: 1653 -0400 (EDT) X-Sender: gmk3@postoffice4.mail .corneU.edu

To: Ron Hoggan <hoggm@cadvision. corn> From: George & GyIe Kennedy <gmk.@corneU.edu>

Subject: Thesis- appendix?

Cc: crk7@uno.com

You asked for it, so, as you have deaches for your theaq FU take half an hour (How about an hour and a haif? ! !) and teii you a W e bit about

Clinî, our older son, and the saga of his gluten seasitivity and the s d

part that ritalin plays in the story.

It aU begins More he was boni. As o u fïrst c W , I didn't h o w what

n o d a b n o d in utero babies were like, so 1 assumeci ail the activity in my abdomen was normai. People thougbt 1 was exaggeraring and making a fuss when 1 w d d jump and bend over backwards sometimes when he would kick and stretch before he was born. 1 had no choice - be needed more room and was hyper-active even then, and was very saong. With a second pregnancy7

second son, I found how easy it is to cany a normal child. No extra

bending backwards- no jumping around because 1 was so severely kicked.

After he was bom, Clint was a difnnilt baby. At five days he oMe homc

fkom the hospital, fUy able to support his own weigbt on his legs - to

stand - as long as I kept him fkom fallinn over. Our best fiend and aeighbor was a doctor whose son was bom three days later. He simply codd not believe that Cl& couid stand at that age. But when the doctor held

bim, he found that it really was me.

He was dways hungry, and never satisfÏed, and cried constantly- George

and 1 waked the flwr for hours, holding and patting and soothuig and

uying to be good parents. There were no pediatncians anywhere around,

and as he appeared to be a 7 112 pound healthy baby, we thou* WE must be dohg somethiag wrong. He was not nuned, and for yean 1 Mt guilty

about thaf but now that 1 know that he and 1 are both sensitive to giuten,

I know that even if he had been nursed he wouid have been fussy. nie OB had susgesteci putthg him on food early, as he seerned fwy, so we starteci

with rice cereai, then added probably oatmeai, (my memory is hazy on this

sequence) and evennially pabulum, which, 1 befieve, contains wheat. No

partidar additional problem with rice cereal, but no solution either.

Some time &er htroducing pabuhun he had a t h e with severe diarrha I

thllik he had had that problem earlier, but I did not reaike that it was

a b n o r d . Then he developed thrush on his tongue and I got out Dr. Spock

and a couple of other books. They both said to only feed rice cered for a

month or so - so 1 did just that, and the thmsh went away. 1 believe we

dso eIiminated formula (cow's miUc based) for a few days. Then 1 put him back on regular baby pabuium, etc. The t h h did not renini. I do not

recall any virulent diarrhea nom that t h e on, but it has been 44 years,

and it's hard to r e c o m c t .

At three months he learned to suck his thumb - pa&ers did not work witb him - and he fhaiiy was quiet George and 1 were so @ad he wasn't aying

we didn't care about the thumb. AU dong, he gained weight and lwked

hedthy .

He never crawleci, but slid around on his stomach iike a sabander, and

got where he wanted to go. He sat at the usuai age. 1 know now tbat

crawiing is good for motor development, but I didn't know it then At 14

months he walked, and staned tallcllig. By the age of 18 months he had an

astonishingiy large vocabulary - weii over 250 words. 1 loa count after that, but he has always been eager to inaease his vocabuiq - even to

this &y.

At 14 months we moved. and sublet an apartment h Evamton, IL. Clun was

so active we diddt dare spend m c h time in the apartment. He was x,

active NOTHING was d i e - nor was he. He and I must have walked 10 d e s a

day - Clint being in and out of his stroiier - just to keep hirn busy and

out of harm's way.

Once he was walking 1 couici not take him anywhere because he was so very

active. Going to anyone else's home was a nightmsre, I never couid fobw

a conversation, nor would he play alone or with another child without

grabbing, pushing, shoving, generally making everyone miserable. Yet he

did not seem malicious - just seemed to have no control over what he did. As a result of this 1 had very few sociai contacts during his waking hous, and was too tired when he went to bed to have many fiends or much social

We.

When he entered kindergarten he was &en an IQ test - I have only limited

faith in those tests - and was found to be at the top end of the scale.

Great - or at least encouraging. He did aot, however, Iearn to read - in spite of having parents who read to him constantiy. By the end of firn

gade we knew we were in trouble. His thee 1/2 years younger brother was

already reading more words than he could handle.

1 have not taUced about the nightmares. From probably age 2 on Clint had

severe nightmares. He would awaken screamhg and rd go in to bis room,

pick him up, rock him and hold him until he wouid M y wake up, have a

drink of water. slowly realite that he was d e and atl was normai, then he

wouid go back to sleep. That eventuaiiy became sleep wallcmg andor screaming nightmares. Those continueci weii into adult-hood. In addition he

ground his teeth at night and by the t h e he was 10 or so the dentist had put him in a plastic retainer type tooth guard, which he still wears. I

honestly think he could throw the thing away, but he is so used to it he

wiU not even try to sleep without it.

He did not learn to read in first, second, third, and fourih grades, altho

he and I worked at home and he w e d y had a basic reading vocabulary. It was agony for both of us, and sounding out a new word was painful and

extremely hstrating for him. Fifth grade he was blessed with a newly

graduateci tacher who took a liking to him and tried to be of help. She

would send home assigmneats for us to do together, and kept me idormeci

about bis work and what areas needed help. That began to build some badly

needed self confidence. Recess and gym class were never codonable, probably bearuse he had nwer reaiiy learned how to play quietiy with other

boys without being too aggressive or too active.

A couple of things that have been left out. In fkst grade Clht became

tascinated with math. He would put himself to sleep at night reciting

addition tables, then subtraction, and d l in first grade was teaching himself to muitiply. By second grade he was dMduig. p e t s redy good

with cornputers!]

AU this time we were moving from one town to another, one school system to

another. one group of fiends to another. Lerting him go to pre-school or

early grade birthday parties was a nightmare, as he might accidentally

break a birthday toy before the birthday chiid had a chance to play with

t. Things were spilled, fiirnture tipped over. He just did not know how to piay with other chüdren-

I kept taking hùn to pediatricians and asking for help. "He would outgrow

it." "He needed more sleep." " He needed more exercise." The crowning

medical diagnosis was that "If his father is an engheer, that's probably

the r-n. They are much too aloof to be good parents." That was a

corker! When you meet George you will meet a kind, gentle, and loving

parent who vent as much time as he codd, playing with bis He did

not participate in the readïng classesT but I can't faut hùn for that, as

he had other things on his mind.

After tirst grade he was dropped into a slower class, and after second grade he was dropped into the slowest of the three third grade classes. This did not make a happy camper. SeIf-esteem plummeted.

1 had read about dyslexia in an article in the Saturday Review of

Literature, and decided that that was the problem. 1 also read about autism in Life Magazine and wondered if Clint was autistic, as he was so

distant and difiicult to reach at times. The dyslexia article gave

suggestions about how to help those children learn, and 1 did everything

they suggested, plus add'ig my own exercises and aids. The improvement was

painfully slow.

F i i y I read about ritaiin and taiked about that with the MD, who decided we could try it. That made a difference. 1 was, however, redy very

uncornfortable with using a strong h g that seemed to affect the brah, and in spite of a calming &ect in the classioom, 1 decided not to continue

with that. 1 dont know how I had the nerve to discontinue the medication. except that it seemed to tum him imo a robot instead of my brilliant, if non-reading., son

By seventh p i d e I W y had enough money to make an appoimment at the

University of Minak ta Child Development cerner. They spent a whole day

g b h g Clint tests. He thought it was a ba& and at the end of the

aftemoon, when the professors were telling us what they had lemed, he was busy showing me di the various block patterns he had put together for their tests, etc. The decision was that he was dyslexic and bfiant. [I could have told them that!] It was wonderfid to have my positive

feelings confbed. They said that 1 shodd c o n t . with what 1 had bem

doing, as it was obviously working, and that perhaps adolescence wodd make a change.

[It is interesthg that young cekcs fie~uently have a remission during

adolescence]

By the end of 7th grade he was reading a bit better. I would read

mysteries to him and leave off the endhg - some excuse about hawig to go

iron or wash dishes. The book would stay next to the bed, and he wodd

struggie thru the last two paragraphs. Then it was the last two pages, an

eventually the last chapter. By the middle of 8th grade he was reading.

By the beginnhg of 9th grade he was reading Shakespeare and loving it.

>From then on he became a top student. One with absolutely awful hand writing. which persists to this &y. And spebg is a mystery even now.

1 assume that visual memory and small muscle coordination are problem areas.

He was accepteci by Comell University and managed to graduate fiom the

Coilege of Liberal Arts in three years plus huo summer sessions at the

University of Minnesota. He knew we were really metchkg to pay for Ivy

Leque coîiege education, and theref'ore took too ma.ny classes at once. But

we promised the M o n money fiom the 4th undergraduate year for graduate

school so he then went to Northwestern University for and MBA

As each college year began he would retum to campus in good health, eating good rneals with very h i e bread - we ciidnt go in for sandwiches,

d o u ~ u t s , spaghetti, hamburgers, and pizza at my house. By the end of the

school year he would retum looking haggared and exhausteci, a littie slow

of speech and definitely not relating well to others. In addition he had

very Me stamina for sports.

not get a job - did not intentiew weii - much too intense and driven, I'm

sure. He went into the Peace Corps, h e d in hot climates ate bread and

strong tea with lots of sugar, and came home after 2 yean lookùig like death wamed over. He got and Ioa two jobs.

By then 1 was becornino aware that my Metirne of feeling a M e different

£kom others had tumed into steatonhea and constant irrational anger - another of C W s syrnptorns. Fortunately one of the many docton that 1

saw over a ten year period finally said that maybe it wasn't in my mind.

Maybe 1 had Whipple's disease. 1 went to the iiirary. Ah, blessed

library! There, after reading about Whipple's and thinking the profile

didn't a 1 con6nued reading in the area of gastro-erterologicai

illnesses and carne to celiac. The lights wem 0% the belis rang! 1 took

myself off gluten and within three days 1 felt as though 1 had just been

bom. I had dways rnanaged to ccpe with people and jobs and school so my

problems had never been as severe as CM'S, but I was not an easy person

to be around. like to think that I am a Linle bit Wre hun in

intelligence, but that's never been testeci.. . ]

So then 1 learned about a nutritionkt in Washington, DC, where my mother

was living, and made an appointment with her. She recommended the ELISA test -and Dr. JafFe, who developed that test, actually administered the test himseK A charming man With those test resdts 1 was told to

remove miik protein and milk sugar [butter is ok] and remove a few other

foods Eom my diet - many of which have now been added back. 1 was also given a large List of vitamin and minera1 supplements to take to make up for a leaky et.

Next step was to convince Cl& to try my new found solution. Mer

returning fkom South Amenca, he had seen many doctors at the Peace Corps'

expense, and then at our expense, and they all said he was healthy- He even

passed a hypogiycemia test, when 1 knew that he was about to explode with

anger at me, and the doctor and the aurse, and -one else in the waiting

room. and ody years worth of extreme seK-controI kept the professionaIs

ftom seeing what was happening.

So then we drove across the USA together and as he &ove 1 read the book

Brain AUergies by Philpott, and another book about Psycho-Nktion by

Carlton Fredenchs aloud to him. Each time we came across any symptom that

seemed related to b, we wrote d o m the offending food or the helpful

vitamin or mineral supplement. When we amved home, 1 went to the drug

store and bought the lot, and that day we took him off gluten and added all

those things at once. The next morning, for the fkst tirne in my He, 1

woke up to the sound of Clint sioging dowosrairs. I simply couldn't believe my eyes when 1 saw him. The almost gray pailor that had always

been his c o l o ~ g was gone and he was rosy cheeked and sniiling. The

mindomation was nothhg short of miraculous. Of course we continu& the

@uten-âee, vitamin-heavy process for a second day.

The next &y was Sunday, and I announced that 1 was going to attend church

as a kind of public ackwwledgement of my fkelings - we were not a c b c h

s o i . family. Clint said he would go with me. George said he'd corne, too.

Mer the s e ~ c e 1 went to talk with a fiend, George went to talk with

another fiend, and Clint went to congatulate the soloist. He &ed her

to go the theatre the foilowing weekend, but she said she was going home to

the tami for the summer Corn and Clover Festival (Hinckiey, M N - population

about 1000. ma..). Somehow Clim managed to be inviteci to go along for the

weekend. A year later they were married and now I have two loveiy

grandsons She cooks gluten-fkee most of the time for the whole family,

tho she spoils herseif and the boys once in a wMee

Mer Clint's transformatioo. 1 rdked that for yean I had manageci our

whole f d y in a way that aied to keep him c a h and non-belligerent. By

the time he was himseIf; or cwed, or whatever the term is that applies,

our younger son had grown up and left home, and many problems that were

caused in his life were out of our hands. There are many regrets, but we

are ail just glad that the disease had been w e d and Clint had become the

person that had been biding ioside the diflicult sheli aii those years.

Ifyou are interested in d d s , it is extremely important for C h to

avoid gluten aad also to remember to take B-Cornplex and extra niacin in

order to stay hedthy.

There, tbat's the long story of Clint K e d y . He's a delightful44 year

old man who nins the Boy Scouts and the Rotary Club and the Church and is a candidate for political office or manages campaigns for other candidates,

and was elected to the school board, ..... You would Wre him. He accepts

that he is gluten-sensitive and is very carefuI about bis diet, but he will

not go to doctors, as he feels they missed his diagnosis for so many years

they are not worth the effort. Eventualiy that wili probably catch up with

him, and it concerns me. He also will not get involveci with this LIST, but

now does keep a file of information that 1 forward to him f?om the LIST. And 1 send recipes to his wife, Karen.

Anything eise you need to know? 1 hope this has been helpful.

Pli be home until tomorrow around noon Q suppose that's 8 AM your time)

and woutd be interested in your response. Think 111 send a copy of this

to Clint.

Best of luck with the thesis. I think it would be a lot shorter with

footno tes ! ! !

Gay le

Patients wirh gluten sensitive enteropathv tceliac disease and dematitis herpetitormisi are reported to have antibodies to endomysium IEMA). reticulin r ARA) and gliadin {AGAP-13. These serological rnarken have recentlv b e n incomorated into the revised crirena ior the diaqnosis or celiac disease (CD) by the European Society or Pediatric Castroenrerology and Nutr i t ion iESPCANi8.r. This inchdes villous atrophy and at least two or the three serological antibodv markers to be positive for making the ciiagnosis or CD.

The levels or these antibodies iluctuate with disease activitv and hence can be useci as a eutde towards the management or the parient. A rmid decrease in EMA. ARA and AGA ensues rollowing a gluten iree diet anci this response 1s useruf in monirorrnc patients ror cornpliance wtrh a gluten-rree cfier. .A qluten challenge in turn leacis to CI reappearance or an increase or anriboclv levels.

From rhe above and other data it is obvious that endomvsial and reticulin .intiboches are sensirive and speciiic markers or $luten sensitive enteropathv. For AGA. IcC class antibodies seern robe *;ensirive hiit less specitic whereas IgA class ,mihodies are less sensitive but more sueciric ror cluten censitive enteroc~thv.

The ciraunostic erricacv rit the vwous immunolacrcsi markets ror CD 1s inci~c.ired in the enclosea rables.

Incidence of Endomysiai, Reticulin and GIiadin Antibodies

EMA Confsnned CD on giuten 5 t152-98Ye~ on CFD i 7/58-290%

Suspectcd CD on qluten 68/82-83% on CF0 5/30-16%

'cont~(>Is tnciuaed v~tients wah ma~absomtive rvmpomr, uicerative corlits. cmhn,s .lm ltrer tiiramcrs.

ARA 65 100 100 72

AGA 88 92 88 92

IkA 52 94 87 74

CD - certain

CD - certain

CD-highly probable

CD- possible

CD - unlikaly but may not b. prsdudeâ

CD - exduded

For more inrormation on rhis and other autoimmune disorders contact:

Y IMMCO Diagnostics. Inc.

Td. No. (716) 876-5612 TO" F m (800) 537-Mi Fax No. (7'1 6) 876-3869 ,,ii IMMEST~AOLCOM -

Midhagen C. lamerot C. hu W k a n d I Camenaml 23:loOO-1004. 1988. Pare P. Owvilie P. C m O. and LcgKt R La in C m r n o l 1 OJ95-U)O. 1988. Hall MI. Cooper 81. Rooricy i l and Read A€ a b c di- and rruiignancy of the duodenm diagnats by -. lucoariul mtmnt ot malignancv and mpamsc to gluîai frce diet Gui 32.-90-92. 1991. C h d s k i W. &mer EH. Kumu V. And Zalewrki TK (eds) Seroloq~ d i a m Ccli disease CRC Pms. 80CJ Raton. FI. 1990- Leveclian 5 0 . Austin RK. Di* MO. Kasafda 00. Kaqnorf M F Spccifiatv or amdiadin dntibodv in celiac disease Gastrocnlcrology 891 -S. 1985. Tu* NT. Baqhuthy FS. Rihoda TI. Kumar V. Lemu A. Lebenthal E. AntiglLdin antrbodies decicd by «uymdinked i m m u m t assay as a marker or cfiildhood ceiiac disease I Pediatnc 1 1 3286-289. 1988. H a l l s m O Cornpan~cr & IgA-class miculin and endomwium anttbdia in cotliac disease and d-itts herpatifomiis Gut 3&Y 22!5-1232.1989. Khoshoo V. Bhan MK. U n d 01. Kumar R. Walker-Smith A Anii-reIiculin antrbodm usaul adiund to histopathalogy in diagno~mg celiac disease. ~pec ia l l y in a devctoping country. I Pediamc tauromteml Nu& 7: 864-866. 1988. Kapuximùa A. kkvnki T. Chcmdski.fP. Suiez 1, Beum EH. Kumar V. Roui T. DiscaK spectficity and dynamics of changes in IgA cfass anti- endomysiaf ant~bodies in d iac di- LPediamc d t ~ l Nutt, 6: 529-534. 1987.

IO. R c w TM. Kwnar V. Lcmci A. Hciilingcr LA. Tu& N, Fischer 1. Rdatiomhip oiedanysial amibodies ro iqu~tal mucosdl patholw specificity towards holh sympromatic and alymptornatic celiao. 1 Pdiatrtc Casuwntml NUU. 7: 85-63. 1988.

I l . Kumar V. Lerner A. Valesici le. Beutner EH. Chorzdski TP. Rosa T. Endomysial antibodies in the diawmts or cefiac dise- and the &ms di glutm on antibodv liters. immun IML 18533- 544. 1989.

i 2. Calahuiq M. forregosa R. Polo P. Tusa L a el S«oloocal markers and celiac disease: A new

irom childrcn wiih coeliac disease. Lancet 336:1335-38. 1990.

14. Walkef-Smith IA. Quandalini S. Schmirz 1. S&neding DH. Visalcorpi IL R ~ t s d aiteria ror dia~noitr oi ctliac disease. Rcpwi ot workinq grouo rit European Soctetv of Paediatric Gasiroeniemlogy and Nutrition. Arch Dis Chiid 65:9(19-9 1 1. 1990.

15. Lerner. A. Kurnar. V. lanrv TC. Immunolog~cal D~agnosis ni Childhood Coeiidc ûise~se: Cornpancon between anrtqiiadin. antirmicuim tnd .iniimdmvuai antibodies. Clin. h p Immunor 95: 78-82: 1994

EXCELLENCf IN UBORATORY SERVICE SINCE 1977

IMAGE EVALUATION TEST TARGET (QA-3)

APPLlED IMAGE. lnc - = 1653 East Main Street - -- - - Rochester. NY 14609 USA -- ,== Phorte: 716/482-0300 -- --= Fax: 71 6Rûû-5989