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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disorder: a theoretical framework (Unpublished master's thesis).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
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THE UNTVERSITY OF CALGARY
Application of the Exorphin Hypothesis to Attention Deficit Hyperactivity Disorder: A Theoreticai Fmework
Ronald Hoggan
A ITIESIS
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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
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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
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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 [email protected]> > Poster: Carol Leather <[email protected]> > 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: [email protected] .corneU.edu
To: Ron Hoggan <hoggm@cadvision. corn> From: George & GyIe Kennedy <[email protected]>
Subject: Thesis- appendix?
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
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