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Application of the Exorphin Hypothesis to Attention Deficit Hyperactivity

   A Theoretical Framework 


    Ronald  Hoggan            

              A THESIS                 



APRIL, 1998

© Ronald Hoggan 1998

University of Calgary          



The undersigned certify that they have read, and recommend to the Faculty
of Graduate Studies for acceptance, a thesis entitled , “Application of the
Exorphin Hypothesis to Attention Deficit Hyperactivity Disorder: A
Theoretical Framework” submitted by Ron Hoggan in partial fulfilment of the
requirements for the degree of Master of Arts..

Supervisor,  Anthony Marini, Ph.D.              
Graduate Division of Educational Research   

 Sal Mandaglio, Ph.D.                                  
Department of Educational  Psychology       

 Ashton Embry, Ph.D.                                 



This document suggests that current practices which lead to the diagnosis
and treatment of attention deficit hyperactivity disorder (ADHD)  may
obscure underlying pathologies which can have dangerous consequences when
undiagnosed. While stimulant therapies are sometimes an effective tool for
the short-term management of ADHD symptoms, they offer little long-term
hope to the afflicted child, perhaps placing that person’s health in
serious jeopardy. Teacher involvement in this diagnostic and treatment
process may aid in perpetuating this problem. An alternative understanding
of ADHD, informed by the exorphin hypothesis, offers a safe, powerful tool
for dealing with the underlying condition in many cases of ADHD, and an
effective treatment for ADHD. A large and growing body of evidence supports
the application of the exorphin hypothesis to ADHD, and points to some
specific research needs in this area. Such research requires a shift away
from the pharmacological paradigm, in recognition of distinctions between
pharmaceutical and dietary interventions. 

The possibility that exorphins may underlay many cases of ADHD is not a new
perspective (Reichelt, Ekrem, Scott, 1990). What is offered here is an
assembly of the various threads from peer reviewed, scientific literature,
along with an integration of those threads into a tapestry which forms a
compelling picture of what may constitute much of the condition  we
currently call  ADHD.  This thesis is informed and shaped by the growing
body of peer reviewed literature which has increasingly pointed toward
exorphins as a factor in ADHD (Reichelt et al., 1990; Crawford, Kaplan,
Kinsbourne, 1994; Uhlig, Merkenschlager, Bandmaier, Egger, 1997). A variety
of factors have contributed to the delayed emergence of this perspective
regarding ADHD, including limited access to some of the literature in
question, the absence of work which integrates the various elements of
supporting evidence, and a language barrier which distances research
findings from many of those who might benefit from knowledge of  that
medical and scientific information. An issue of limited  availability of
research funding may also have contributed to obscuring the applicability
of the exorphin hypothesis to ADHD.     
A variety of factors limit access to medical libraries, including their
small numbers, hours of operation, and isolation from the community.
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 find such libraries. 
Once access is gained, a further limiting factor is the scientific language
in which research reports are written. This language obscures meaning to
all who are not prepared or able to invest the necessary time required to
master that language which is the medium of published medical and
scientific reports. Part of the offering of this document is to provide an
interpretation and an integration of these reports pertinent to the issue
at hand..... ADHD.  
What follows is offered  in a form accessible to teachers and parents.  The
ultimate intent of this document is to aid children with ADHD, along with
their parents, their teachers, and their medical caregivers through
providing an alternative perspective of ADHD.  Inherent in this view is a
safe and effective alternative treatment for many, perhaps most, youngsters
suffering from this condition.  
The hypothesis embodied here is readily testable, and readers will judge
for themselves whether the evidence presented warrants the expenditure of a
very few dollars for serum antibody testing, or a few weeks of dietary
investigation.  The exorphin hypothesis suggests a broadly applicable set
of principles which may also alleviate some of the current struggle to
understand the underlying dynamics in a variety of psychiatric illnesses,
including ADHD. It is also a postulation which offers an alternative,
perhaps more appropriate path for teachers and parents who are disturbed by
the behaviour of some of the children in their charge, but who recognize
the fallacy underlying the current practice of administering powerful
medications to children, thus  reducing the unpleasant symptoms of  ADHD,
in the absence of a clear understanding of the condition being treated, or
the therapeutic action of the drugs 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 certainty in the
representation of ADHD that follows. This hypothesis does offer a safe,
effective, and healthy means of dealing with a majority of cases of ADHD,
but it is recognized that there will be other causes in some cases of this
condition.  Also embodied here is an understanding which resolves many of
the apparent anomalies in the medical and popular literature regarding
this pervasive, debilitating condition that carries life-long implications
regardless of the therapeutic intervention chosen.  


This thesis reflects the love, support, and encouragement I've gotten from
my wife, Betty, my mother, Edna, and my children, Donovan, Darren, Kari and
Kyra. Their contributions have helped me find my way. It also reflects the
mentoring,  support, kindness, and understanding of my advisor, Dr. Anthony
Marini.  I am also grateful to Dr. Garth Benson for helping me see science
through many windows, and see my angst as an impetus to explicate those
windows. And finally, I am grateful to Dr. Jim Paul for helping me to
understand understanding through the incongruent, dissonant, dichotomous
metaphor of modernity, and through its counterpart. 


In memory of my brother, Jack Ernest Hoggan, June 17, 1946 to November 18,
1996. His pain inspired the work that lies before you. His death inscribed
its meaning on my soul. May his passing light a better path for others.

Table of Contents: 

Chapter Two.....How Exorphins May Connect with ADHD Diagnostic Criteria....

Comparative evaluations may be appropriate........................  21
Differentiation...................................................  22
Additional therapy is needed......................................  23
When ADHD children grow up........................................  26
Why do stimulants sedate?.........................................  27
Some problems with urinary peptide filtrate patterns..............  29
Age-of-onset Criterion............................................  32
Differentiation from celiac disease...............................  33
Variety of ADHD presentations.....................................  34
Some anecdotal evidence...........................................  35
Summary............................................................ 39

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

Peptide Structure.................................................  42
Intestinal Permeability...........................................  44
Celiac, Schizophrenia, and other food intolerances................  50
Digestive Enzymes.................................................  54
Neurological Manifestations.......................................  58
Depression/Serotonin..............................................  59
Molecular Mimicry.................................................  60
Brain Morphology & Perfusion......................................  62
Essential Fatty Acids.............................................  64

Neurotransmitters  ...............................................  70
Serotonin.........................................................  71
Dopamine..........................................................  73
Peptides..........................................................  74

Mineral Deficiencies..............................................  75

Iron..............................................................  76
Trace and Other Minerals..........................................  78
EEGs, ADHDs, and Exorphins ....................................     79 

 Chapter Four ...A Model for Exorphin-Induced ADHD................  84

Stage One.......................................................... 86
Stage Two.......................................................... 87
Stage Three........................................................ 88

Chapter Five.....Education, Research Recommendations, Limitations,
Implications..... 91

Applications to Education.........................................  92
Recommendations for Future Research...........................      94

The Investigators ................................................. 95
The Group to be investigated....................................... 95
Establishing a Baseline ........................................... 96
Terminal Assessments .............................................. 96
Selection Bias .................................................... 98
Other Research Possibilities ...................................... 98

Limitations of the Model.......................................    100
Implications of Ignoring the Model...........................      100
Conclusion.................................................        101

References........................................................ 103


One: Lewen tested negative for antibodies but responded positively to the
diet..  130
Two:  Temper tantrums and overweight child from Carol............. 133
Three: Gluten is the dubious luxury of............................ 135
Four:  Predictive Value of Serology Testing in Celiac Disease..... 141
Five: Stimulant medication as a................................... 145
Six: Immunopathology Update ..................................     154

List of Tables:

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

List of Figures:

Figure 4.1     HLA-B8  Distribution in Europe.........              87

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

Chapter One
Parents, Politicians, Physicians, Pedagogues, Pupils & Peptides   

The proposition set forth here is that current diagnostic procedures for
attention deficit hyperactivity disorder (ADHD), and the therapeutic
interventions currently used to manage this condition, along with teacher
involvement in this process, all need to be re-thought.  Recent medical
research indicates that there are common environmental, dietary substances
which may be at the root of a majority of cases of  ADHD, and these should
be appropriately investigated. Continued teacher support for a process that
leads to stimulant therapy may therefore be problematic. It is true that
ongoing research continues to support the short-term efficacy of stimulant
medications in ADHD, but such therapies may be  inadequate, short-sighted
responses to this pervasive problem that afflicts from 2% to 10% of school
children (Rowe 1988; Boris & Mandel 1994; Castellanos 1997). 
Whereas there are several follow-up investigations of subjects who
underwent lengthy courses of stimulant therapy,  no significant long-term
benefit from such therapies was reported (Barkley, 1977). This absence of
long-term benefit may also be seen through comparing a 15 year follow-up of
63 hyperactive children who were not treated with stimulant therapy (Weiss,
Hechtman, Milroy, Perlman, 1985), and a 12 year follow-up of 60 children,
most of whom had undergone stimulant therapy (Claude, Firestone, 1995).
Both groups had fared equally poorly when contacted at follow-up.  
Evidence of an associated delayed maturation of parts of the brain involved
in executive function until the third decade of life, has also been
reported (Castellanos 1997; Ucles, Lorente, Rosa, 1996).  One such report
also asserts that 52% of adolescent ADHD subjects display substance abuse
and criminal behaviour (Castellanos 1997).   This  research contributes to
a growing paradigm crisis (Kuhn 1970)  in psychiatric and educational
research. More and  more children are being prescribed stimulant
medications, yet only short-term  benefits can be claimed for the majority
sub-group of ADHD children who respond to such therapy. Conversely, an
examination of dietary exorphins offers the possibility of a natural,
long-term means to control symptoms and address the underlying pathology
for many who suffer from ADHD.  These exorphins are morphine-like peptides
(Zioudrou, Streaty, Klee, 1979)  which have been shown to result from the
partial digestion of foods which have repeatedly been implicated in
investigations of ADHD (Breakey, 1997).  
According to the fourth edition of the  Diagnostic and Statistical Manual
of Mental Disorders (DSM IV) (American Psychological Association, 1994),
ADHD is characterized by four sets of features and one broad form of
differentiation  including hyperactivity and impulsivity, or inattention,
which interfere with social, academic or occupational function; 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 difficulties, this delineation of features is
identifying a very real and debilitating problem which most classroom
teachers see daily. This latter assertion is based upon the 2% to 10%
reported incidence of ADHD (Rowe 1988; Boris & Mandel 1994; Castellanos
1997).  Our culture relies upon teachers and health care professionals to
render appropriate instruction,  accurate diagnoses, and effective
treatment. This expectation may exceed  reality. The risk of misdiagnosis,
along with a singular reliance upon stimulant therapy, may simply
constitute a short-term masking of the symptoms of physical ailments, and
of the underlying causes of what may constitute most cases of ADHD. 
The teacher’s and perhaps the clinician’s familiarity with the diagnostic
and differential features of ADHD  may be hindered by the succession of
changes to the various editions and revisions of the DSM.  While the
practice of conducting periodic revisions reflects 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 life-long implications and consequences should be based
upon a much more solid foundation than the teacher’s observations rendered
in ignorance of the critical and differentiating features of ADHD  (Hoggan
and Dunlop, 1996). Yet that may be the usual context of such teacher
evaluations which often lead to the diagnosis of ADHD and subsequent
initiation of stimulant therapy. Blind Partnership
Even if teachers were to be trained in such diagnostic procedures, ignoring
any paradigm dissonance between the two professions, medicine and
education,  some very clear contingencies threaten to compromise the
teacher’s objectivity.  Students, whether suffering from ADHD or not, have
been shown to have improved powers of concentration while undergoing
stimulant therapy (Mayor, 1996 ). Such drugs offer to aid the teacher in
controlling classes through improving the behaviour and performance of most
children, not just those who suffer from ADHD. In a political context where
class sizes continue to grow, and student manageability is likely to be
aided by stimulant therapy, it may be very tempting for the teacher to
simply nod assent in a complex diagnostic process, rather than oppose the
powerful, popular following that supports such diagnostic and therapeutic
Another facet of  the current political climate is the threat that  merit
pay and teacher evaluations may  be connected to student performance on
standardized testing, while ignoring or minimizing socio-economic factors
which have long been recognized to impact on such performance (Flower,
1998).  A constituent perspective in this trend is the simplistic notion
that teacher effectiveness is wholly or largely reflected in standardized
testing. Such connections deny the uniqueness of the personal, educational
and social histories of the children in question.  The threat of
legislative policies of this sort provide scapegoats; not accountability.
Regrettably, time and space do not allow a broader discussion of these
political issues, yet they are an important force in the diagnosis and
treatment of ADHD. The subtle impact is to inappropriately increase
pressures upon the classroom teacher, which may result in their embracing
measures which will help them avoid the professional humiliation of being
penalized 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,
along with those which may be  in the offing, there are also disincentives
which threaten to penalize teachers who do not facilitate an ADHD
diagnosis. Classroom teachers are well aware of the behavioural benefits of
stimulant treatment. Most may be less aware of whether a given child falls
within the parameters prescribed by the DSM IV.  Teachers who fail to
facilitate such diagnoses may find themselves dealing with a number of
behaviour problems in their classes  which, in many cases, could have been
avoided through participation in a process aimed at an ADHD diagnosis,
regardless of the real nature of the underlying pathology. The disruptive
behaviour which is often associated with ADHD can serve as a powerful
inducement to teachers and parents to accept  any answer, whether 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 for a quick, easy means to manage their difficult child.
Regardless of the various rationales offered in the medical literature,
teacher participation in this process is suspect due to current incentives
and disincentives previously outlined. Inadequate teacher training in the
critical 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 usually know very
I regret that prior to my own explorations of the scientific and teaching
literature,  I participated in such student evaluations. Only recently have
I begun to see the hazards to children posed by this blind partnership with
medical clinicians.  It is a partnership which obscures issues of
accountability. Each participant, whether teacher or physician, is placed
beyond reproach in the current situation. Where there is an underlying
pathology, the child continues to suffer the short and long-term
consequences of that pathology,  while the symptoms have been masked, and
the problematic systemic procedures for the diagnosis of ADHD are
perpetuated.  This process places children at an unnecessary risk. It also
provides an easy escape from responsibility  to medical and teaching
professionals involved in the diagnostic process. 
My explorations of the literature have also  convinced me  that stimulant
therapy offers a very effective focussing and settling agent to aid in
classroom management, thus furthering the interests of the afflicted
child’s classmates, teachers, and the shareholders of  multinational
pharmaceutical manufacturers, while offering little benefit to the ADHD
The diagnostic process
It must be admitted that several complex assessment processes have been
delineated, and the  diagnosis of ADHD may be much more defensible where
such exhaustive assessment procedures are followed. 
Shelton & Barkley (1990) have outlined the multi-method, multi-informant
diagnostic process  for ADHD children employed at the ADHD clinic of the
University of Massachusetts Medical Center. The first stage is referral.
Next a diagnostic interview is conducted with the parents, which is
followed by a brief interview with the child. This is followed by a medical
interview with the child, a medical examination,  and the compilation of a
great deal of data, taking into consideration the child’s social, school,
and family situation, 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 primary
teacher  where a Vineland Adaptive Behaviour Scale is sometimes used.  The
teachers are, in addition to the interview,  asked to report on the child’s
behaviour using the following instruments:
The Child Behavior Checklist;
The Child Attention Problems Scale;
The ADHD Rating Scale;
The School Situations Questionnaire, and;
The Connors Teacher Rating Scale-Revised.
It may be of interest that in 10 years 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, I have never been given more than a single  form to
complete, which was usually a page or two in length. I have been given
several copies of the same form  for serial  evaluations of a child’s
behaviour, and on another occasion, regarding a different child, I was
given a single, but lengthy form to complete. My experience is very
different from the process outlined by Shelton and Barkley (1990).  Neither
have I ever spoken with any health care professional prior to, during, or
after their rendering of a diagnosis of ADHD.  It is likely that such
thorough methods for the diagnosis of ADHD  are not as common as might be
hoped. Perhaps economic considerations, in the current climate of cut-backs
in education spending render such a meticulous process beyond the means of
parents and school boards. 
It is also important to note that this complex diagnostic process, however
defensible,  does not  reduce the probability that an underlying food
intolerance disease will go undetected. For instance, neither the medical
interview nor the physical examination would be likely to identify celiac
disease. It is rarely considered, and physicians are rarely knowledgeable
beyond the classic symptoms which apply only to a relatively small minority
of untreated celiac patients beyond infancy (Fasano, 1996).  Celiac disease
is the most common food intolerance disease, suggesting that milk protein
intolerance, and other such diseases would be even less likely to be
identified by this process.
Adjunctive/drugless  therapies  
Behaviour modification programs, the way they are too often implemented,
while not themselves  pharmaceutical interventions, are recommended as an
adjunct to stimulant therapy (CPS, 1997). I also take philosophical issue
with many behaviour modification techniques.  Such interventions appear to
instill an excessive concern for consequences, while teaching a polarized,
right/wrong system of self-monitoring which is wholly derived from external
judgements about what behaviour is acceptable. If education is a process
which encourages and facilitates increasingly independent thought, then
many  behaviour modification programs are largely or wholly
counter-educational. If they teach dependence upon external codes of
appropriate behaviour coupled with a fear of external consequences, such
programs offer little more than the training involved in dealing with a
puppy.   As an educator, I find this approach to children offensive,
although I do not deny its practical value in some very exceptional
For these and other reasons, I have pursued 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
compelling body of direct and indirect evidence in the peer reviewed
scientific and medical literature, as well as in anecdotal reports, which
supports the exorphin hypothesis and its application to ADHD, yet it
remains a relatively obscure perspective. Implicit in the theoretical
framework offered here,  is also a therapeutic intervention which has had
little prior application to ADHD, but which may partly or wholly  alleviate
this condition. This hypothesis and the attendant treatment protocol
suggests the specific nature of the underlying cause of many cases of the
ADHD condition, thus providing a treatment plan which offers much more than
simply masking symptoms. 
 First postulated by Curtis Dohan, the exorphin hypothesis led to
improvements among schizophrenic patients, in a clinical trial of a
gluten-free, dairy-free dietary intervention (Dohan, Grassberger, Lowell,
Johnson, Arbegast,  1972). Subsequent double-blind trials supported these
findings  (Singh & Kay, 1976; Reichelt, Sagedal, Landmark, Sangvic, Eggen,
Helge, 1990; Reichelt, Ekrem, Stott, 1990).  Successive investigations of
the exorphin hypothesis by several groups working primarily with autistic
patients have revealed information which offers to explain many otherwise
contradictory findings in the literature (Hoggan 1997a).  A congruent,
broadly applicable set of principles inherent in the exorphin hypothesis
offers to shed light on many features of a variety of mental illnesses,
including ADHD, which remain obscure within the current paradigm. 
The exorphin hypothesis postulates an interaction between a genetic
predisposition and ingestion of two very common foods, dairy products and
some cereal grains (Dohan 1989). These same foods are also implicated in
the two most common food intolerance diseases. This is a point of
convergence which is  more than coincidental. The Twentieth Century has
witnessed repeated reports of clinical findings which suggest the
involvement of these dietary proteins in a variety of illnesses. 
During World War II,  Dicke observed that the cereal grains, wheat and rye,
are the primary pathogen in celiac disease (Dicke, 1950). Barley was
subsequently added to the list.  Dicke’s findings were first ignored, then
mocked, and then subjected to unreasoned resistance (Hoggan 1997a).  Over a
period of two decades, and in the absence of any other effective treatment
for this disease, Dicke’s findings  finally 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 (Paulley, 1954),
which supported Dicke’s claims.  Much greater resistance to dietary
interventions in conditions which have been shown to respond to
pharmaceutical intervention should therefore be anticipated, regardless of
the status of the intestinal mucosa. Dietary interventions in psychiatric
conditions are not currently in vogue. Worse, proponents of such
interventions are often mocked,  just as Dicke  was (Hoggan, 1997a).  
Removal of the same cereals, which have been shown to be pathogenic in
celiac disease, have also been shown to result in remission of symptoms of
some forms of epilepsy which appear to be variants of the Sturge-Webber
Syndrome (Bye, Andermann, Robitaille, Bohane, Andermann, 1993; Piatella,
Zamponi, Cardinali, 1993; Tiacci, D’Alessandro, Cantisani, Piccirilli,
Signorini, Pelli, Cavalletti, Castellucci, Palmeri, Battisti, Federico,
1993) some cases of a rather wide variety of neurological dysfunctions
(Hadjivassiliou, Chattopadhyay, Davies-Jones, Gibson, Gruenwald, Lobo,
1997;  Kelkar, Ross, Murray, 1996; Holmes, 1996; Sandyk, Brennan, 1983;
Smith, Saldanha, Britton, Brown, 1997) and a number of central nervous
system (CNS) ailments previously thought to be unrelated to diet (Watson,
McMillan, Dickey, Biggart, Porter, 1992). These reports do not provide
clear evidence that these conditions result partly or wholly from one or
more of the opioid acting peptides found in the digests of wheat, rye, and
barley, but the complete and partial remissions reported in the literature
leave little doubt that consumption of this common food group can result in
functional and morphological changes to the central and peripheral  nervous
systems. It should therefore not be surprising if behavioural and
attentional changes also occur in response to these foods.  In fact, the
opposite would be surprising (Reichelt, 1996).
The exorphins derived from the aforementioned grain proteins and milk
proteins are chains 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
narcotics derived from opium, such as morphine, is suggested by
similarities in function and attachment at identical receptors as well as
by the blockage of such binding by drugs which also block the binding, at
the same receptors, of opiates (Zioudrou et al.,1979).			
Exorphins act as neurotransmitters.  It is possible that the comorbidity of
alcoholism and ADHD (Wilens, Prince, Biederman, Spencer, Frances, 1995;
Schulz, McKay, Newcorn, Vanshdeep, Gabriel, Halperin, 1998) is related, in
part, to an addicting action of exogenous opioid peptides, which may lead
to the reported predilection to substance abuse in ADHD (Castellanos, 1997;
Schulz, et al 1998).  The cortical atrophy associated with both ADHD and
alcoholism (Hechtman 1993; Nasrallah et al. 1986) may also suggest the
possibility of some commonalities. Work suggesting tetrahydroisoquinoline
(THIQ) attachment at CNS endorphin receptors, in alcoholism, may offer a
model for understanding one action of exorphins. (Bedingfield, Holloway,
1998 ).  
Intestinal permeability
On a less speculative note, it is possible to identify two types of
pathological conditions in which exorphins may enter the circulatory
system. Both conditions are partly or wholly constituted by increased
intestinal permeability.  The first condition is simply the result of
inflammation of the tissues which form the wall of the small intestine,
leading to increased permeability of that wall. The cause of the
inflammation is often unclear. A variety of causes have been reported in
such permeability, from autoimmunity ( Geboes, 1994 ), to yeast overgrowth
(McKenzie, Main, Pennington, Parratt, 1990 ), to bacterial infections
(Alper, Lencer, 1997 ), to ingestion of non-steroidal anti-inflammatory
drugs ( Segawa, Ohya, Abe, Omata, Tsuzuike, Itokazu, Yoshida, Tagashira,
Ueda, 1992 ).  Whatever the cause, specific serum antibody production
implies that macromolecules of partly digested dietary protein are being
absorbed through the intestinal wall and into the bloodstream. 
Villous atrophy
The second group of conditions is characterized by damage to the mucosal
architecture of the small intestine. This villous 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 permeability is also a well known
feature of these diseases, the presence of  this permeability without
villous atrophy, or increased intraepithelial lymphocytes (Marsh, 1992), is
not currently considered a defining characteristic (Cooke & Holmes, 1984).
Further, the variety of auto-immune diseases, in association with food
intolerance disease,  may well derive from the constituent intestinal
permeability, as is suggested in discussions of molecular mimicry (Scott,
1996; Scott et al. 1997; Karlsen, Dyerberg, 1998), which may offer an
explanation for much of the high incidence of atopy  found in ADHD (
Biederman J, Milberger S, Faraone SV, Guite J, Warburton R, 1994; Boris &
Mandel, 1994; Rapp, 1979).  
Molecular Mimicry
Molecular mimicry is a theoretical perspective suggesting that the
absorption of dietary proteins and peptides into the circulation results in
antibody activation against amino 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 learning difficulties, specifically  with reading, have been
reported to have an increased individual and family incidence  of  immune
problems and auto-immune disorders, particularly those involving the
gastrointestinal tract and thyroid gland (Crawford, Kaplan, Kinsbourne,
1994), which is relevant, given the very high comorbidity of ADHD and
learning disabilities (Biederman, 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 postulated
connection. The reported excess of gastrointestinal malignancies, in the
context of an overall reduced incidence of malignancy among one group with
learning disabilities, also becomes relevant, in that light (Cooke, 1997),
as does the excess incidence of malignancy, especially in the
gastrointestinal tract, in untreated celiac disease ( Hoggan, 1997b). 
As may be deduced from the above, there are many possible and probable
causes of intestinal permeability. Undigested food particles are being
absorbed into the blood of many apparently healthy people.  Testing of a
random population sample in Iceland revealed that 15% of this group had
elevated  class G immunoglobulin (IgG)  antibodies against gliadin, a group
of  proteins found in wheat (Aarnason, Gudjonsson, Freysdottir, Jonsdottir,
Valdimarsson, 1992). This is clear evidence of the inappropriate absorption
under discussion, which is further supported by gluten-derived exorphins
demonstrated in pancreatic secretions (Fukudome, Jinsmaa, Matsukawa,
Sasaki, Yohsikawa, 1997). These findings also suggest that many and perhaps
all of the same group would have exorphins in their circulatory systems,
although this does not establish their presence in the central nervous
Cytotoxicity of Gliadin
Gliadins have also been demonstrated to destroy a variety of tissue cells.
This cytotoxic activity is reported in a variety of tissues from people
without celiac disease (Doherty & Barry, 1981; Hudson, Purdham, Cornell,
Rolles, 1976; Levine, Briggs, Harding, Nolte, 1966). The entry of gliadins
into the circulation can apparently lead to tissue damage in most, if not
all people. The genetic difference between health and disease may therefore
be found in whether the mucosa can protect the individual from moderate
quantities of gluten. Of course, hormonal and external factors may also
effect intestinal permeability, thus further confounding an already complex
The general cytotoxicity of gliadin, once it has gained entry into the
blood,  may be the very vehicle by which the exorphins can bypass the blood
brain barrier (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 derived from the same foods, then
the gliadins may damage the tight epithelial junctions of the BBB, thus
allowing passage of the exorphins into the central nervous system. This
postulation is, of course, speculative, but as previously demonstrated, the
gluten-associated CNS and general tissue damage is well established. The
accuracy of this speculation may 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 offered as an interesting, reasonable, and
plausible possibility; nothing more. 
Urinary Peptides
Evidence of exogenous peptides is frequently found, in a variety of mental
illnesses including ADHD, in the characteristic patterns of excreted
urinary peptides in each of these illness groups (Gilberg, Trygstad, Foss,
1982; Reichelt, Knivsberg, Lind, Nodland, 1991; Reichelt, Ekrem, Scott,
1990b; Reichelt, Sagedal, Landmark, Sangvic, Eggen, Helge, 1990a; Saelid,
Haug, Heiberg, Reichelt, 1985). Specific patterns of  peptide filtrates are
associated with specific sub-groups of mental illness.  A confounding
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 of such testing as a diagnostic tool (Hole, Lingjaerde,
Morkrid, Boler, Saelid, Diderichsen, Ruud, Reichelt, 1988) until the
process is further refined.  Conversely, these urinary filtrates do
facilitate differentiation between specific sub-groups of ADHD. While not
in themselves diagnostic, urinary filtrates do offer corroboration of other
diagnostic measures, as well as some important insights 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
Beyond the Blood Brain Barrier
The next question that may be of interest is whether  exorphins must bypass
the blood brain barrier (BBB), to affect the CNS function in an
ADHD-specific manner.  The answer is equivocal, and must be deduced from
animal studies and disorders commonly associated with ADHD, as well as
common responses of ADHD subjects to some medications.  On one hand, the
increased presence of exogenous peptides in general circulation has a
systemic effect of inhibiting  breakdown of endogenous peptides. The
argument has thus been made that absorption of exogenous opioids into the
circulation, may result in increased conservation of endogenous opioid
peptides in CNS  (Hole, et al. 1988 ). 
On the other hand, in animal studies, exorphins have been demonstrated to
bind to opioid receptors in the brain. It may be that either endogenous
opioid peptide conservation resulting from exogenous opioids, or a direct
activity of exogenous opioids upon elements of the CNS is at work, or
perhaps both dynamics contribute to the etiology of gluten/dairy induced
Some cases clearly involve gluten and/or dairy
That gluten and/or dairy products are etiological factors in some cases of
ADHD is well established (Egger, Stolla, McEwen, 1992; Egger, Carter,
Graham, Gumley, Soothill, 1985; Boris, Mandel, 1994; Uhlig, Merkenschlager,
Brandmaier, Egger, 1997; Breakey, 1997; Carter, Urbanowicz, Hemsley,
Mantilla, Strobel, Graham, Taylor, 1993). The only real question is to
establish the relative frequency of ADHD  resulting from these very common
foods.  Although the incidence is  thought, by some, to be a small
percentage of all cases, there is rather a lot of evidence to suggest that
extensive exploration of the exorphin hypothesis may bring some dramatic
changes to that perception. Little dietary  research of ADHD  has
specifically looked for the complex signs of exorphins, by simultaneously
excluding all  foods  which can produce exogenous peptides. The little work
that has examined this issue offers considerable evidence to support this
There is some evidence from animal studies that such apparently safe foods
can result in serious pathologies. One study of cats, a carnivorous
species, reports that they develop morphological CNS changes, along with
behavioural changes, after regular feedings of casein and gluten (Thibault,
Coulon, Roberge, 1988 ).  Another study of a group of Irish Setters  fed
predominantly glutenous diets has resulted in villous atrophy and increased
intraepithelial lymphocytes, which resolved on a gluten-free diet
(Pemberton, Lobley, Holmes, Sorensen, Batt, 1997). There is also animal
study evidence suggesting that these opioids may be at work in a variety of
neuropathies (Schick, Schusdziarra, 1985) and mental abnormalities
(Drysdale, Deacon, Lewis, Olley, Electricwala, Sherewood, 1982). Yet
another study reports gluten induced autoimmunity in rats (Scott, 1996).
Humans are more omnivorous than some of these animals, but there is also
some human evidence suggesting that gluten-derived exorphins can and do
directly  impact on the human central and peripheral nervous systems
( 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
opioid-acting amino acid sequence of GYYPT  which can be isolated from one
molecule of gliadin, and there are a total of five amino acid sequences,
with opioid activity, that have been characterized in gliadins (Fukudome &
Yoshikawa, 1992).  Additionally, at least eight  opioid acting peptides
have been identified in milk proteins (Teschemacher H, Koch G, Brantl V,
1997; Mycroft, Wei, Bernardin, Kasarda, 1982 ).  This offers 13 distinct
amino acid sequences, each with opioid activity, which can act singly or in
concert,  assuming that all can bypass the BBB, to produce a wide variety
of presentations, many of which may reflect various manifestations of ADHD,
as well 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 many as 15 times in a single molecule (Fukudome &
Yoshikawa, 1993), and all the possible unique combinations of exogenous,
psychoactive 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.  
Zioudrou et al.(1979) have also presented evidence to support their
suggestion that other, non-opioid, psychoactive materials can be found in
the pepsin digests of wheat, and which constitute approximately 30% of the
psychoactive peptides derived from wheat. We may thus reasonably anticipate
a wide variety of individual responses to these various and combined
exorphins and endorphins. The variability in presentation of ADHD, and
other mental illnesses that are implicated by detection of such urinary
peptides, is consistent with the variations made possible by exogenous
psychoactive peptides, and their impact upon the preservation of, and
interaction with, endogenous, psychoactive peptides. 
Of course, the increased intestinal permeability herein postulated as a
feature of most cases of ADHD, along with a pathway for exorphins to pass
through or exert an influence beyond the BBB, might also facilitate a
similar dynamic involving a variety of other partly digested food proteins
which may enter the circulation containing amino acid sequences which can
exert a psychoactive influence.  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 well as suggesting a cause
for the reported variety of atopic presentations and allergies often
associated with ADHD patients (Colquhoun, Bunday, 1981; Franklin1984;
Breakey, 1997; Kittler, Baldwin, 1970; Aman, Mitchell, Turbott, 1987;
Stevens, Deck, Abate, Watkins, Lipp, Burgess, 1995; Mitchell, Aman,
Turbott, Manku, 1987; Holman, Johnson, Hatch, 1982; Stevens, Zentall,
Abate, Kuczek, Burgess, 1996 ).
Back to the Teacher 
Classroom teachers are burdened with the safety, wellness, and learning of
their students,  as well as administrative chores associated with
attendance and formal progress reporting. These duties have recently
expanded to include issues of school governance as a part of the current
political climate (personal experience). Enlisting teacher involvement in
the evaluation of student behaviour, toward a diagnosis of ADHD may be
fraught with problems, since a blind partnership, as described earlier,
appears to be the current status quo.  In order to bring an end to this
unsatisfactory situation, it may be appropriate for teachers and
prospective teachers to undertake learning about the diagnostic criteria
and the appropriate differentiation of this condition from other  illnesses
with similar presentations. It may also be useful for teachers 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 teacher’s
primary concerns are the learning,  health, and safety of students, in
addition to concerns about the  richness of  students’ futures, the
uncontested follow-up reports which deny long-term benefits of stimulant
therapy ( Barkley, 1977; Weiss et al., 1985; Claude et al.,1995)  should
herald dramatic changes to classroom teachers’ involvement in the
diagnostic process.  Teacher resistance 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
understanding of alternative perspectives, as well as the diagnostic
criteria for ADHD. Such an informed approach is one reasonable means by
which teachers may extricate themselves from their current and unfortunate
involvement in this diagnostic process. Some constructive suggestions for
altering teacher participation in this process will be postulated 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 unavailable to them, obscured by the parlance of
medical research, and the relative inaccessibility of the literature which
embodies that specialized and exclusive language. It also offers a safe and
effective intervention for that part of the ADHD population afflicted by
one or more of  the several conditions by which exorphins alter their
behaviour.  Part of the journey to understanding  ADHD behaviour in light
of this perspective will first require that we  explore the DSM  IV
diagnostic criteria, in relation to the activity of exorphins, which will
follow in the next chapter.

Chapter Two
How Exorphins May Connect With ADHD Diagnostic Criteria  The DSM IV is the
most recent version of this highly regarded publication which is  produced
by the American Psychiatric Association.  It is a manual 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 IV ensure that it reflects contemporary
concepts in the evolving understanding of  ADHD.
According to the DSM IV, the first set of criteria for identifying  ADHD
are  either a combination of hyperactive and impulsive behaviour, or
inattention. The second criterion is that these symptoms be present and
problematic prior to age seven. Third, the problematic symptoms must be
present in more than one setting, which seems a reasonable means of
avoiding an inaccurate diagnosis where there is a personality conflict, or
some similar problem.  The fourth criterion requires that these symptoms
must cause “significant impairment of social, academic, or occupational
Comparative evaluations may be appropriate
These features are comparative, based on the usual behaviours of  the
subject’s peers. Whereas such comparative evaluations may seem
insupportably  subjective, suggesting a weakness in the underlying
criteria, such criticism may not be warranted.  We judge body temperature
by similar comparisons to the norm, yet body temperature  measurement is
thought to be quite objective.  Body temperature norms are well understood
among practitioners in appropriate professional venues. Differentiation
from other disorders, and attendant ethical issues notwithstanding,
teachers appear to command the greatest competence in identifying behaviour
which is either consistent with, or divergent from the norm for  student
groups with whom these teachers work (Martin, Welsh, McKay, Bareuther,
1984; Haslam, et al. 1984; Taylor, et al. 1991).
It follows that teachers are often best able to identify usual and unusual
behaviour in their students, and that this is a judgement based on
comparison, which does not necessarily compromise that assessment.  In the
interest of clarity, I will repeat that  it does not follow that teachers
have demonstrated competence to differentiate ADHD from other medical
disorders, thus they are not competent to diagnose ADHD simply because they
are arguably best able to identify children who present with unusual
behaviour. Such unusual behaviour might stem from a variety of medical
problems ranging from celiac disease, to  hypoglycemia to abnormal thyroid
function, so it is the legitimate province of the medical practitioner to
differentiate ADHD from medical conditions.  According to Barkley (1990)
extensive differentiation of ADHD from other, similar conditions has often
not received appropriate attention from the medical practitioner:
“in the past such examinations have often been brief, relatively
superficial, and as a
result often unreliable and invalid for achieving a dianosis of ADHD or
comorbid behavioral, psychiatric and educational conditions.”
 This problem may result from excessive reliance upon teachers’ reports on
student behaviour. 
Block (1997) provides an in-depth discussion of the overlap in signs of
both hypoglycemia and hyperthyroidism with the signs of ADHD, yet how many
diagnoses of ADHD have involved  thorough testing for, and exclusion of
these other ailments?  She explains how the impulsive patient with
hypoglycemia becomes very agitated as her/his blood sugar levels drop, and
how this is very easy to confuse with other types of impulsive behaviour.
She also reports that several of her patients had previously been
prescribed stimulants when simple blood tests revealed 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 scientific literature.  Once the teacher has
completed the questionaries, identifying abnormal behaviour,  the MD’s
determination of dosage and subsequent prescription may be the only actions
taken. The diagnostic criteria for ADHD are rarely discernable in the
doctor’s office (Rapp, 1981). The physician is often forced to rely upon
school records as well as teacher and parent reporting.  The peer reviewed
literature is very clear in recommending that the physician give much
greater weight to the teacher’s assessment of the child’s behaviour (Taylor
et  al. 1991; Haslam et  al. 1984).  Barkley (1990), in addition to
criticizing perfunctory medical examinations of the past, 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, often goes directly to stimulant therapy.  Yet, even the
Compendium of Pharmaceutical Specialties (CPS) carries a clear admonition
from the producer of the most common therapeutic stimulant, Ritalin. This
admonition is that the administration of this drug should comprise only
part of  the patient’s care. How often is this paid more than lip service?
What systemic accommodations have been made for these children, either in
the schools, or in the pediatrician’s office?  It is doubtful that more
than a handful of teachers are even aware of the additional student  needs
outlined in the CPS. How can teachers reasonably be expected to meet needs
they are unaware of?  Further, in a cultural context where there is little
funding available for emergency health-care needs, it is doubtful that we
can expect medical or educational funding to aid in dealing with the needs
of  these children. 
The short-term efficacy of methylphenidate is consistent with the
short-sightedness of much current political thought. Reduction of
governmental deficits appears to enjoy greater political popularity than
the provision of adequate care to our children.     
Given the economic and political climate, and in spite of the admonition in
the CPS, it is all too frequently the case that teacher and medical
practitioner alike facilitate stimulant therapy,  without provision of
additional aid for the ADHD child. Shaywitz (1988) has expressed the
following concern about stimulants:
     The finding that an increasing number of children are receiving
stimulant                       medication to treat hyperactivity and
inattention may reflect a regressive step                        in which
all behavioral and learning disorders are lumped together and treated
in the same way.
 A patch is thus placed upon the symptoms which trouble the teacher and the
problem child’s classmates, but no genuine aid to the child has been
rendered.  Labelling a child with ADHD is of little value if only drug
therapy is provided. Such practices are contrary to the recommendations in
the CPS, contrary to the literature, and contrary to the best interests of
the child.  
Diagnosis of ADHD is most frequently driven by teacher ratings of children
(Taylor, Sandberg, Thorley, Giles 1991, p.37; Haslam, Dalby, Rademaker,
1984) in the context of a process which is often initiated  after one or
more teachers complain about the student’s behaviour (personal experience).
Many of  the same teachers who have complained about the child are then
frequently called upon to  render formal evaluations of student behaviour.
These teachers are  unlikely to be trained in procedures for psychiatric
diagnosis, including the critical features of ADHD and the means of
differentiating ADHD from other medical disorders. There is the additional
risk that teachers will incorrectly identify situation-specific abnormal
behaviour as consistent with ADHD  (Taylor et al. 1991, p.37).  Despite the
DSM IV diagnostic requirement that symptoms be observed in two or more
settings, teacher evaluations are given so much weight that a school-based
bias may be a built-in feature of the current diagnostic process.
Observations made at school alone should not, according to the DSM IV,
result in a diagnosis. But the reality may be contrary to that DSM IV
provision. This situation is fraught with hazards for children.
Yet the peer reviewed, medical and scientific literature harkens to the
reliability and validity of assessments of students’ behaviours by teachers
( DSM III; DuPaul, Rapport, Perriello, 1991;  Haslam et al 1984; Martin,
Welsh, McKay, Bareuther, 1984; Taylor et al. 1991). Complex rationales in
support of this practice are offered in the same literature (Martin et al.
1984; DuPaul et al., 1991). One report asserts that because teacher
judgements of learning disabilities are more accurate than a combination of
standardized tests, that teacher evaluations are important with regard to
both diagnosis and “effects of treatment on children with disruptive
behaviour disorders” (Du Paul, et al., 1991). One may speculate that the
very presence of such arguments in the literature is signalling  a
problematic relationship which has developed and which may also contribute
to some of the diagnostic and  long-term treatment difficulties mentioned
When ADHD children grow up
It is  little wonder that follow-up studies of adults who had undergone
long-term stimulant therapy as children show little difference from matched
groups of ADHD patients who did not undergo such interventions (Barkley,
1977).  Since no significant, long-term benefit can be predicted for the
ADHD child on stimulant therapy, the primary benefactors of such
interventions are the ADHD child’s teachers, parents, and classmates, along
with providing a significant 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 legacy of
stimulant therapy, as reported in the peer reviewed literature.  The huge
income from the sale of these drugs provides an immensely powerful
voice..... one that overwhelms the sound of  those who would speak for the
best interests of ADHD children. 
One of the loudest supporters of stimulant therapy is an organization known
as  CHADD. They gave the appearance of being an independent, non-profit,
charitable group of  parents with children suffering from ADHD, and adults
with ADHD. An expose, last year, on the popular television news show,
20/20, revealed that much of this group’s funding comes directly from Ciba
Giegy, the manufacturer of the most commonly prescribed form of
methylphenidate, Ritalin. Dietary interventions do not enjoy the
profitability that allows for the extensive funding provided to CHADD and
stimulant research. It would probably be in the best interests of such drug
manufacturers to fund work aimed at discrediting dietary interventions,
although I have no knowledge of such practices.    
Perhaps due to our society’s predilection for pharmacology,  there is
comparatively little published work on the exploration of dietary
interventions. This may be due to the absence of economic incentives for
investment in such investigations. Of course, it does not appear to be in
the best interests of pharmaceutical manufacturers to invest in exploring
the efficacy of dietary interventions in association with any condition,
and it seems unreasonable to expect them to fund work that would undermine
their sales.
Why do stimulants sedate?
Another venue that warrants investigation, but is unlikely to be funded 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 underlying  dynamics of ADHD.  These stimulants have a
calming effect on hyperactive children, while causing a mitigating effect
upon the apparently opposite symptoms of  the lethargic, inattentive
student. Some concern arising from this contradiction may fall by the
wayside, as we find that stimulant therapy improves attentiveness even in
normal children (Mayor, 1996). Apparently there is something about these
stimulants that usually facilitates increased intentional focus of
attention, regardless of whether the  pre-drug status was lethargy,
hyperactivity, or reasonably normal attentional capacities.  Whether it
aids learning is another question which will be discussed shortly, but the
apparent contradiction also opens the possibility that the methylphenidate
counteracts some of the deleterious effects of exogenous opioids. 
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 same intervention. The challenge
is to understand how one therapy can mitigate the symptoms of  two
apparently opposite presentations, hyperactivity and lethargy, altering
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
similarly dampened or blocked by stimulant 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
function of individual differences, and  stimulant therapy, if it
interferes with the impact of exorphins, may thus mitigate both
hyperactivity and hypoactivity in ADHD children.
Exorphins are opioid-acting peptides which derive from external sources,
instead of being synthesized within the body. These exogenous opioids have
been shown to bind to the same cellular receptors that endogenous opioids
bind to, thus impacting on the immune system, nerve function, myelination
processes, vascular walls, neuromuscular function,  and a variety of CNS
functions. As may be expected, 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-adrenal axis function (Hoggan, 1997b).
Reduced attention may be the result of the CNS attachment of opioid-acting
exorphins. Some investigation has shown that many hyperactive children
lapse quickly into sleep when they are inactive, and they often sleep very
soundly. If we see deficits in attention as a possible result of opioid
activity in the CNS, then  the variations between urinary peptides, which
have been reported  to differentiate the subgroups of ADHD, may support the
postulation that some of the exorphins will result in hyperactivity, while
others will increase hypoactivity. Perhaps it is the variations in specific
circulating opioid peptides which determine whether hyperactivity will
accompany inattention, but most or all may  cause the characteristic
inattention in both sub-groups. 
The lethargic, inattentive ADHD child, and the hyperactive ADHD child may
have much in common, in that they are both under the influence of  powerful
anaesthetics.... ones which are similar to those used to aid people who are
suffering great pain.   And the positive results of stimulant therapy, in
that light, may be quite understandable. Perhaps they simply function to
counteract some of the gross behavioural manifestations of the exorphins.
But the elimination of the source of these exorphins seems a much more
sensible approach, which may serve the ADHD sufferer in two ways.  It may
reduce the risk of the comorbidities of ADHD, while it alleviates the
debilitating, short-term symptoms of this condition.	
 The use of chemicals to mask the symptoms, rather than getting at  the
cause of such illness 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 therapy as self-indulgence on the part of the adults in our
culture. Pills are much easier and less costly than the initiation of
in-depth medical investigations,  perhaps followed by a complex dietary
intervention, or some other therapy appropriate to the findings of these
Some problems with urinary peptide filtrate patterns
Of course, the exorphin hypothesis, as applied to ADHD is speculative, but
there is some hard, objective evidence, as well as some anecdotal reports,
which support this perspective. As has already been mentioned, opioid
peptides have been filtered from the urine of ADHD children, and there is a
differentiating pattern of specific amino acid sequences and constituents
in the two sub-groups of ADHD. 
The four primary problems with measurement and characterization of urinary
peptides in ADHD are:
 1. Some asthmatic patients demonstrate similar peptide excretions, thus
denying us               an objective diagnostic tool for ADHD, and; 
2. Some ADHD subjects do not demonstrate these peptide excretions, and;
3. Increased peptide concentrations are associated with increased severity
of ADHD,              and;
4. It is not clear if these opioid peptides have functioned in the CNS
prior to              subsequent  excretion.
The first problem may just involve a clinical differentiation between
asthmatics and ADHD patients. I would not anticipate a great deal of
difficulty there. 
The second problem may reflect cases of ADHD which result from some of the
other conditions such as those postulated by Block (1997). 
The third problem suggests that ADHD may be located on a continuum which
would include autism, schizophrenia, and some other mental illnesses. Of
course, this is a political and a paradigm problem. From a political
perspective, recognition of such a continuum would force increasing
resources to be channelled toward a better understanding of these
conditions, as there would be an increased recognition of the severity of
ADHD when it is associated with such more visibly serious conditions. The
paradigm difficulty associated with this problem is rooted in the arbitrary
classification of illness which now dominates conventional medical wisdom,
and  would be challenged  by recognition of such a continuum.  The
additionally arbitrary notion which also drives conventional medical
wisdom,  that most people are healthy most of the time, would fall into
serious question, in light of the broad hazards to humanity posed by these
two very common Western foods. Such paradigms do not change easily (Kuhn,
The fourth 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 overall
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 effect 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
natural sleep and sleepiness. Perhaps the folk-way use of a warm glass 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 whether, as the DSM IV requires,
this behaviour occurs in more than one environment. Problematic behaviours
in many environments would be consistent with the exorphin hypothesis, as
well as other postulations about the etiology of  this disorder, but would
differentiate situational problems. Contra-indicating, situational problems
could arise out of personality conflicts, learning difficulties, or other
issues which may not be related to, or symptomatic of ADHD, but which would
be likely to occur in a single setting. The biologic effects of exorphins
are unlikely to be restricted to one setting, although regular meals
containing one or the other, or both dairy and cereal, for only one meal of
the day could, conceivably,  result in symptoms which are specific to
single environments, although such a practice seems unlikely. Paul et al.
(1985) have indicated that exorphins can stay in the circulation of celiac
children for as long as a year after consumption of gluten. Others,
however, have suggested that behavioural improvements can be seen within
days of beginning a gluten-free diet (Colquhoun & Bunday, 1981). 
Age-of-onset criterion    
The DSM IV also requires that some symptoms of ADHD must be recalled as
having 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, resulting in the onset of  intestinal permeability
above that age. 
It is clear that the DSM IV criteria would imply the attainment of 7 years
of age as a precondition of diagnosis of ADHD, yet diagnosis requires the
presence of some ADHD symptoms prior to that age. There is a cognitive
dissonance here (Barkley, 1997) as well as the possibility that in light of
the exorphin hypothesis  this  may be a most unfortunate feature of these
If ADHD is often the result of dietary opioids, and since cell
differentiation is completed prior to that age, there may be some permanent
damage which might have been reversible at an earlier age, through dietary
changes.  Paul, Henker, Todt, and Eyesold (1985) offer a clear argument, in
this regard, for children with celiac disease. The same consideration may
also apply to children with food-induced ADHD. The literature is clear that
at least some cases of ADHD are food induced. The only real 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 come under attack
from other directions. Barkley and Biederman (1997) have stated:No support
exists for the selection of age 7 years for onset of a valid
disorder,  either for symptom  onset or for onset of impairment. 

Another group indicated  that many diagnoses of ADHD primarily
characterized by inattention would be  missed if the age of onset was
blindly accepted (Applegate, Lahey, Hart, Biederman, Hynd, Barkley,
Ollendick, Frik, Greenhill, McBurnett, Newcorn, Kerdyk, Garfinkle, Waldman,
Shaffer, 1997). On one hand, I am asking that less attention be paid to the
age-of-onset criterion, while I have previously argued for increased
attention to the  differentiation of ADHD from other pathologies which can
be identified via standard blood tests. 
Considerable overlap between ADHD children, and those with untreated celiac
disease also exists in the frequency with which their condition interferes
with their social, academic, or occupational function. Many celiac children
are withdrawn, emotionally volatile, argumentative,  and resistant to
direction, as are many children afflicted by ADHD. It must be conceded that
such unpleasant behaviours may also present in a variety of other
conditions, and celiac disease is offered as a model for behavioural impact
of exogenous opioids, and certainly not as a blanket diagnosis of all cases
of ADHD.  
Differentiation from celiac disease
The final diagnostic criterion in the  DSM IV is that the symptoms of ADHD
should be differentiated from other disorders.  Few, if any, diagnoses of
ADHD have been differentiated from celiac disease with an endoscopic
biopsy, the current gold standard for the diagnosis of  the  latter
condition. Given the wide spectrum of presenting symptoms, beyond infancy,
it is probably not possible to accurately differentiate this disease in any
manner other than serological testing or endoscopic biopsy. A  majority of
children with untreated celiac disease past the age of  7 do not present
with classic symptoms of celiac disease (Fasano 1997), yet celiac disease
is unlikely to be in the differential for most, and perhaps all
practitioners diagnosing ADHD.  Again, I do not suggest that celiac disease
accounts for more than a small minority of cases of  ADHD. But it can serve
as a model, where  behavioural features and exogenous opioids causing EEG
theta production which is very similar to that seen in ADHD,  are well
documented (Kozlowska, 1991; Paul et al., 1985) . It is also an important
differential diagnosis to make, given the dramatic increase in  risk of
malignancy among those with untreated celiac disease (Hoggan 1997b).  
Variety of ADHD presentations
Further to the requirement that the symptoms of  ADHD be differentiated
from other disorders, it should be noted that this is not an easy task. It
sometimes 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 exorphins interacting or acting
singly should predict a broad array of distinct presentations of ADHD. The
degrees of severity may also be expected to vary according to levels of
deficiency of digestive enzymes, quantity of dairy products and cereal
grains consumed, along with a host of other environmental and internal
Since there are five known types of opioids which have been isolated from
proteins in wheat, and eight which have been isolated from milk proteins
the number of possible variations in presentations should amount to the
square of the sum of these two numbers. This computation ignores variations
which may arise from variations in immune responses, quantities consumed,
as well as other partly digested  food particles and a variety of food
additives which may be entering the blood via the route prepared by drugs,
infection, or food-induced intestinal permeability which will be discussed
at length in a subsequent chapter.  It is clear that the variety of
possible presentations of ADHD, if exogenous peptides are an etiologic
factor in this syndrome, is very large indeed. Differentiation of ADHD can
be  a difficult task, and the Exorphin hypothesis offers a very good
explanation for this difficulty, as well as offering strong inducement for
including both milk protein intolerance and gluten intolerance in the
differential diagnosis of ADHD.
Failure to differentiate these  conditions may lead, by default,  to
children being denied treatment of another condition which may have some
very serious, life-threatening and debilitating sequelae. The
administration of stimulants without first excluding gluten intolerance,
can lead to a very high risk of a variety of malignancies (Hoggan, 1997b)
but it can also lead to epilepsy, crippling neurological disease, and
serious skeletal and articular maladies, all of which may have been averted
by accurate diagnosis, and appropriate treatment.
Some anecdotal evidence  
Dietary exclusion of gluten and dairy may provide a real and lasting answer
for many who suffer from ADHD. Appendices one, two, and six provide
examples of the realization  of just such a possibility. 
The first is about Lewen,  a young fellow who did not mount a discernable
IgA or IgG immune response to gluten, but who has experienced great
benefits from the gluten-free diet. This is one problem with seeking
evidence of immune responses against gliadins or casein. Some people who
have an intolerance to these proteins do not seem to mount an immune
response of the sort identified in gluten sensitivity by current testing
methods. These folks do not have celiac disease, but they are clearly
intolerant, as is witnessed by changes in their behaviour during dietary
exclusion of gluten and dairy products. Most, including the patients
themselves,  would agree that the changes are large improvements.

The reverse of Lewen’s situation was also reported in a magazine article
which has been submitted for publication (Hoggan & Fasano, 1998). The
principles have chosen to remain anonymous to avoid further victimizing a
young man who has already paid too great a price for the medical
profession’s failure to diagnose his celiac disease at a much earlier date.
The article chronicles the various diagnoses and events which eventually
led to his commitment to a mental hospital. It does little to recount the
emotional anguish he and his parents suffered.  Therapists joined with
other health care professionals who attended their son, and chastised the
parents  for their poor parenting skills. It is quite conceivable that this
young man could have languished for most of his life in a series of
institutions until he eventually succumbed to one of the deadly sequelae of
celiac disease. He was diagnosed with ADHD at an early point in his life.
Consistent with the dramatic rates of under-diagnosis of celiac disease, he
was labelled as having this psychiatric disorder without ever having been
tested for food intolerances. 
In spite of many allergies, a slight build, difficulty swallowing, and
abdominal distress, this young man was never investigated for celiac
disease until after he had very nearly been killed by the combination of
pharmaceuticals he was given to deal with his allergies and his psychiatric
symptoms. It is amazing that we continue to listen more carefully to
apparently objective claims, to the exclusion of simple symptom reports
from children. This young fellow’s dismissal was tantamount to denying his
voice. He was silenced on the issue of his own health, and almost died
because of that muting process. Perhaps the lesson it teaches is that we
need to genuinely listen to children.             
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 herself, yet she missed the possibility in her own child.
Responses from other parents have motivated her to have the child tested
for celiac disease. This anger and aggressive behaviour may well be similar
to that demonstrated in many ADHD children, perhaps arising out of similar
causes.  Anyone who is knowledgeable in the realm of celiac disease and
gluten-induced behavioural abnormalities will recognize the characteristic,
violent,  irrational anger.
These accounts offer an interesting perspective on ADHD and a compelling
connection with gluten. It would appear that the gluten, and perhaps the
derivative exorphins were at the root of the attentional and behavioural
symptoms recounted in these anecdotes. 
I have seen accounts of similar reactions to dairy products. There may be
other foods that warrant investigation as well. Perhaps the most salient
issue here is that humanity has only consumed these foods for a very short
period, in evolutionary terms.  Although gluten-containing grains have been
cultivated for 10,000 years, and dairy products have been consumed for
5,000 years, some cultures have been consuming them for only a few decades,
while others for only a few centuries. That is a very short time, and is
probably insufficient for adaptation, especially since the many of  the
more lethal sequelae may not develop until well after puberty, and hence
reproductive capacity.
Appendix four is a discussion of some of the health problems associated
with early cultures adapting to cereals. Given the rates of both
autoimmunity and ADHD among indigenous Amerindian populations, there may be
more value to a more traditional diet for these folks than the celebration
of their traditional culture. There may be some genuine health benefits.
The incidence of type II diabetes in these hereditary groups, as was
discussed earlier, certainly supports  the notion that a more traditional
diet may lead to improved physical and mental health, as well as improving
academic prospects in this group.
Vilhjalmur Stefansson (1960) has suggested a link between health problems
among North American Natives, and the Western diet.  He did not identify
gluten or dairy products as specifically problematic, but these may well be
the elements of the European diet that caused the problems Stefansson
observed and reported. 
 Most of the industrial world is now consuming large quantities of
gluten-containing grains. These grains have been demonstrated to compromise
absorption of calcium and other minerals in everyone consuming them. For a
significant minority of the population, a host of health problems accompany
the consumption of these grains. There is a great deal of evidence
suggesting that gluten may also contribute to the rapidly increasing
incidence of malignancy. Gluten has been implicated in the pathogenesis of
schizophrenia, bi-polar disorder, obsessive-compulsive disorder, and autism
(Dohan et al., 1969; Singh & Kay, 1976; Reichelt, et al, 1990a). It does
seems very reasonable to suggest that it may also be involved in ADHD.
In the absence of a positive response to the exclusion of known sources of
exorphins, there is some cause to favour stimulant therapy. ADHD children
often suffer socially because of their behavioural limitations. Stimulants
may help a child to avert serious injury to both self-esteem and social
development, through allowing the student to “fit in” with peers.
Interference with classmates’  learning may also lead to social
difficulties for the child, and such interference is less likely during
stimulant therapy, but this does not obviate the need to differentiate ADHD
from food intolerance disease prior to considering stimulants. 
Appendix five offers a description of one person’s experience with
stimulant therapy, when the underlying pathology was gluten intolerance.
The stimulant was a very effective tool for calming this boy. What he
really 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 exorphins could also have contributed to the
child’s well being, but that research had not yet been done when he was in
In spite of the benefits of stimulants, the current situation may sometimes
be seen as tantamount to teachers prescribing methylphenidate...... a
responsibility that certainly  should not lie with teachers. It may also be
seen as a cultural abandonment of these children, since we are not pursuing
an accurate diagnosis of the underlying pathology, whether thyroiditis,
hypoglycemia, food intolerance diseases, sensitivities to food additives,
or a combination thereof, which require medical interventions, other than
stimulants, for the good health and future prospects of the child.  Current
diagnostic practices often fail to differentiate these other conditions
from ADHD. Masking the symptoms of such conditions with stimulants may deny
these children appropriate medical and/or dietary intervention.
The time has come for extensive research of this question. The next chapter
will discuss a number of reported connections between exorphins, food
intolerance, and ADHD.  These connections may suggest similar dietary
answers for many children currently consigned to lives with poor long-term


Chapter Three
Converging data: Exorphins; Food Intolerance; and ADHD
The exorphin hypothesis offers to aid our understanding of ADHD  and this
postulation is supported in a variety of converging research reports in the
literature, as well as in anecdotal reports from parents which were
discussed in the previous chapter. While no single body of evidence could
reasonably be expected to move a discerning adherent of another perspective
to consider the exorphin hypothesis, it is hoped that the convergence of
multiple and diverse “proofs” will invite the thoughtful reader to careful
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 complicated explanation of  the greatest number of features of ADHD.
Hypoarousal, in some regions of the brain,  has long been recognized as a
feature of ADHD. The possibility that there is a narcotic effect from
opioid peptides is very consistent with such reduced arousal, with comorbid
learning disabilities,  and with the DSM IV observation that ADHD children
“ often appear as if their mind is elsewhere or as if they are not
listening or did not hear what has just been said (Criterion A1c).”  The
elevated incidence of atopy in ADHD (Boris & Mandel, 1994; Breakey, 1997)
is both parallelled by a similar incidence in food intolerance disease, and
is quite possibly the result of immune system abnormalities 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 disorders may be implicated
through autoimmunity  (Scott, 1996).  Delayed myelination and delayed CNS
development, along with abnormalities in myelin, CNS, and neurotransmitters
are also reported in connection with both ADHD and celiac disease.  Opioids
have been implicated, in animal studies, in delaying neuron and glial
development  (Zagon, McLaughlin, 1990) dendrite development (Hauser,
McLaughlin, Zagon, 1989), and brain development (Zagon, McLaughlin, 1984).
Additionally, abnormalities in mood and behaviour, are also reported in
food intolerance disease and are a defining characteristic of ADHD, as was
mentioned earlier.
Each of these points of convergence have been reported in the medical
literature as significantly connected 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
complex web of evidence that exorphins are a large factor in a majority of
cases of ADHD, if duly presented here, seems likely to sway even the most
skeptical reader to consider the exorphin hypothesis in ADHD.   
This hypothesis provides possible explanations for  variations in severity,
various presentations, and many of the wide array of comorbidities.  To
further this discussion, it will be necessary to engage in a more detailed
exploration of  peptide structure,  intestinal permeability, and food
protein intolerance diseases.  It will also be valuable to explore the
double-blind trials which first suggested the existence of exorphins, the
functional similarity of exorphins  to morphine, the role of opioids in
essential fatty acid metabolism, opioid-related alterations to the immune
system, brain development and  perfusion,  abnormalities in the
neurotransmitters, serotonin and dopamine, mineral deficiencies, and
finally, how these factors may underlay the various signs and symptoms of
Peptide Structure
Since exorphins are the focal point of this discussion, and since they are
peptides of specific origin,  it may be valuable to provide a brief
explanation of  peptides. While exorphins, by definition, are derived from
the breakdown of food-derived proteins, and may thus be understood as
partial proteins, peptides are chains of amino acids which may also be
synthesized in a dehydrating, covalent bonding process (Tortora &
Grabowski, 1996). In other words, peptides may be synthesized from
individual amino acids, or they may be the result of partially degrading
While we are currently 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
sufficient to recognize that proteins can and do differ quite dramatically
from each other, both on the basis of constituent amino acids, and the
specific sequence of these amino acids in the primary structure of  the
Imagine a language where there are twenty letters in the alphabet, and word
length can vary from two letters, as in a dipeptide (Tortora & Grabowski
1996),  to 800 letters, as in the primary structure of high molecular
weight glutenin (Fukudome & Yoshikawa 1992) and other proteins with even
more complex structures can exceed 2,000 amino acids (Beaver, 1998). This
suggests an almost infinite number of possible combinations in peptides and
proteins of distinct structures.  That is the language of peptides and
It is a language that speaks directly to the human digestion process, which
cleaves the peptide bonds in dietary proteins, through a variety of
mechanical and chemical processes, ultimately degrading these proteins to
constituent amino acids which can then be absorbed through the intestinal
wall, and into the circulation as nutrients. In addition to the provision
of water, acids, and mechanical insult,  to facilitate this liberation of
amino acids from the proteins of which they are constituents, the
gastrointestinal tract must provide catalysts to speed the chemical
cleavage of these peptide bonds, in the breakdown of dietary protein. In
the absence of such catalysts, the process would be impossibly slow
(Tortora & Grabowski, 1996).
Digestive enzymes serve as such catalysts. Beginning with salivary
excretions in the mouth, our food is exposed to a very wide variety of
enzymes as it makes its passage through us. These enzymes  often target
particular covalent bonds. Thus, the absence or reduced quantity of
specific enzymes may herald the survival 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 from incomplete digestion of
proteins, and by themselves may lack significance. However, when such
products of enzymatic deficiency are coupled with intestinal permeability,
there is a host of problems which may be in the offing, when consuming a
modern, Western diet,  including ADHD. If  these peptides are allowed to
enter the circulation, they can act upon the body in ways similar to
narcotics, and/or endogenous opioid peptides. 
  Intestinal permeability 
Intestinal permeability is a condition where macromolecules are allowed to
pass through the intestinal wall, and into the bloodstream. Such large
molecules may comprise in-tact proteins, or partial proteins, known as
poly-peptides, with lengthy chains of amino acids. 
Since a healthy intestinal wall functions as a barrier against dangerous
foreign substances, such as viral and bacterial agents, intestinal
permeability in a healthy organism should bar passage of the vast majority
of dietary proteins and large peptides. Conversely, there should be
sufficient permeability to allow for efficient transport of nutrients.  The
intestinal barrier should bar infectious agents and undegraded or partly
degraded dietary protein, while permitting passage of  amino acid
nutrients. If  there is increased intestinal permeability, this protective
function of the intestinal wall is compromised.    
Where there is enzymatic deficiency in combination with increased
intestinal permeability,  the findings of Zioudrou et  al. (1979)  take on
a powerful significance. There can be little doubt that in such cases,
exorphins would be entering the circulation. Those who test positive for
IgG anti-gliadin antibodies, approximately 15% of a random sample (Arnason,
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 permeability may result in the absorption
of a small number of exorphins which would  otherwise have remained in the
intestinal lumen for further digestion. 
Passage of whole and partly digested proteins has been established even in
healthy subjects (Husby et  al., 1985 ). Zioudrou et  al. (1979)  have
identified some opioid peptides in the digests of wheat prolamines and
dairy proteins which have opioid activity, and Fukudome and Yoshikawa
(1992) have since characterized 15 separate amino acid sequences of
gluten-exorphin A-5 in a single molecule of wheat.  It would be surprising
if there were not some quantity of these psychoactive peptides entering the
blood of a significant number of people consuming 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 common food ( Fukudome & Yoshikawa, 1992).   
It is thus clear that the exorphins which are herein postulated as
underlying ADHD can be derived from the incomplete digests of alcohol
soluble proteins found in the common cereal grains: wheat; rye; barley; and
perhaps oats,  as well as from the incomplete digests of dairy products. It
is also likely that passage of at least some of these exorphins into the
blood, as is witnessed by anti-gliadin antibodies, is occurring in at least
15% of the random population mentioned earlier (Arnason, et al., 1992).
There is also a significant population of patients with autism,
schizophrenia, and bi-polar disorder, many of whom do not mount a
discernable antibody response to these proteins, but whose symptoms improve
on a diet which excludes them (Reichelt, 1996).  
One sequence  of amino acids which has been identified in abundant quantity
in both wheat and cow’s milk is similar to
melanocyte-stimulating-hormone-release-inhibiting factor (MIF) which has
been shown to enhance CNS dopaminergic activity in animals (Mycroft et
al,1982).  A condition of increased central dopaminergic activity  has long
been associated with ADHD and a variety of other psychiatric conditions
(Gill, Daly, Heron, Hawi, Fitzgerald, 1997; Raskin, Shaywitz, Shaywitz,
Anderson, Cohen, 1984). 
The earliest report that opioid peptides could be derived from food
proteins is probably that of  Zioudrou et  al.(1979).  This group named
exorphins and established their functional similarity to morphine. They
reported that Naloxone, a morphine antagonist, blocked 70% of
gluten-derived exorphin activity, while blocking 100% of milk-derived
exorphin activity. Animal studies conducted 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 from
milk, and the former are claimed to have a potency that is a small fraction
of that of morphine (Huebner, Lieberman, Rubino, Wall, 1984), so the signs
of behavioural impact would likely be much more subtle than is seen in
morphine addiction.  
Recognition of gluten and dairy products as the source of such dangerous
peptides is relatively new. There was evidence almost thirty years ago,
from double blind trials that some schizophrenics benefited from exclusion
of gluten and dairy from their diets (Dohan, et al, 1969; Singh & Kay,
1976).  Apparently no other  information was then available to explain the
postulated pathogenic nature of  these foods.   
The earliest report was from Dohan et  al. (1969).  A total of 102
patients, on a locked ward, participated and everyone in the experimental
group showed improvement which apparently resulted from the dietary
intervention. The patients in question were released earlier than previous
patients who had consumed a regular diet  These positive results were
replicated by all the researchers  who worked within the clear and simple
parameters outlined by Dohan. It was a decade after publication of the
first clinical trial of this diet with schizophrenics, that  Zioudrou et
al. (1979) published their discovery of morphine-like  peptides in the
digests of wheat and dairy products, thus providing  subsequent support for
the application of the exorphin hypothesis to schizophrenia. 
The identification and characterization of these exorphins followed some
problematic  attempts to replicate the early  trials which had implicated
these foods in the pathogenesis of schizophrenia.  Davis (1978) and
Vlissides, Venulet, Jenner (1986) and others attempted to test the
therapeutic value of gluten-free diets in schizophrenics. Each failed to
comply with the original investigative methodology established by Dohan et
al. (1969) in several important features of their work. Vlissides et  al.
(1986) chose to test chronic schizophrenics and other chronic patients with
distinct mental disorders,  who had a mean duration of hospitalization of
more than 4 years. This is a group which Dohan (1972) had expressly
indicated that he had little hope would benefit from the dietary protocol
he and his group had pioneered. Vlissides et al. (1986) also failed to
exclude milk from the experimental diet and they allowed relatives to bring
gifts of food, after providing a list of gluten-containing foods to avoid.
Anyone who mounts a fairly significant and rapid response to gluten, and
has therefore  followed a strict gluten-free diet can explain the weakness
in this approach. Dietary compliance is an intense learning experience.
Errors are the rule, not the exception, as one learns the pitfalls of such
a diet in the context of a culture inundated with gluten. The expectation
that relatives could master such a diet from a list is, at best,  foolish.
This practice may be very revealing of the care that was taken with the
diet within the hospital. I find it astounding that there were any
improvements, but Vlissides et  al.(1986)  reported some marginal
improvements among their chronic patients, which did not reach statistical
Similarly, Davis chose trial periods of comparatively short duration, of
six weeks, and included milk. It was, in fact, used as a medium for
administering the placebo and/or the gluten in the context of a
double-blind trial. It also appears that Davis expected the patients to
manage their own compliance 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 listed as acceptable by that society, has
since been shown to cause symptoms in a large majority of celiac patients
studied (Chartrand, Russo, Duhaime, Seidman, 1997). The net result was that
these flawed studies undermined the solid results of much more defensible
methodologies employed by Dohan, et al, (1969); Singh & Kay (1974);
Reichelt (1997) and others, who had achieved positive results. The casual
attitude toward diet, as reflected in the published reports of  Vlissides
et al.(1986) and Davis (1978) would predict their equivocal 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 results of the weaker studies as legitimate refutations of the
earlier, more meticulous work.  Thomas Kuhn (1970)  has addressed a similar
question about scientists’ observations, by citing two experiments which
offer insight into the current question. Both reports show that human
subjects sometimes see what they expect to see. The first experiment he
cited was conducted by Bruner and Postman. They flashed playing cards 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 quickly identified the
usual playing cards correctly, but they identified 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 only
arose when the subjects were exposed to the anomalous cards for lengthier
periods of time. In other words, unless forced to study the issue, they saw
what they expected to see, and neatly fitted it into their current schema.
In another, similar experiment cited by Kuhn, subjects were given eye
glasses which turned their vision up-side-down. The subjects quickly
adapted to these lenses. Again, the notion that we see what we expect to
see was supported.   I suggest that in the absence of  the later work
demonstrating opioid peptides in these common foods, members of the
scientific community saw what they expected to see when they read
refutations of the therapeutic benefits of the gluten-free, dairy-free diet
in schizophrenia.
Consequently, the early work of Dohan et  al.(1969)  Singh and Kay (1976),
and others had been dismissed as one of the many “blind alleys” which are
common to science, and which are well recognized as valuable because they
exclude fruitless avenues for scientists who will follow. Thus, the
subsequent evidence from Mycroft et al. (1982), Fukudome & Yoshikawa
(1992), and Zioudrou et al (1979), about cereals and milk as sources of
psychoactive peptides, had little impact upon the thinking of  researchers
investigating schizophrenia and other mental illnesses. To most, it was a
closed issue.  Perhaps the  later work revealing exorphins in these foods
was interpreted as an attempt to shore up a faltering hypothesis.
Fortunately, a few researchers have continued to recognize the importance
of those clinical  trials and the subsequent findings about the
constitution of these food-derived exorphins. These latter few
investigators have pressed forward.
Connections to celiac, schizophrenia, and other intolerances
Celiac disease, or more correctly, the dramatic over-representation of
celiac disease among schizophrenics, was the first clue Dohan encountered,
about 1960 (Dohan, 1966), which eventually  led him to investigate the
gluten-free, dairy-free diet in schizophrenia. Since the diet had helped
alleviate psychiatric symptoms demonstrated by some celiac patients, and
since this food intolerance was over represented among schizophrenics,
Dohan considered the possibility that such a diet might also help
schizophrenics. Dohan dedicated much of his professional life to the
scientific investigation of this possibility (Hoggan, 1997a).  He, and a
team of health-care professionals, were the first to implement a trial of
gluten and dairy free diet as part of the treatment of schizophrenic
Dohan’s predilection for mystery stories may have served him well. He knew
he had come upon some very important clues to understanding schizophrenia..
He continued this work  to the end of his life.
“'The day before he died, we got a paper from a scientist in Norway,
Evidence and Arguments for Schizophrenia as a Dietary Disease and it was
the last thing I read  to him’ said his wife Marie. That night, she got as
far as Page 5. He died the  following morning." (Philadelphia Inquirer, Nov
14, 1991)  (Ronan, 1995).  
Dohan had experienced considerable frustration as he tried to disseminate
his findings. His work challenged conventional 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 arising out of consensus, rather
than scientific thought. Dohan’s ideas were not well received. Still, there
is a recent article suggesting an immunological connection between ADHD and
schizophrenia (Holden, Pakula, 1995).  
It is also interesting that a report  published in November of 1997
identified reduced perfusion of  the frontal cortex,   measured by photon
emission computed tomography,  in connection with schizophrenia. It is even
more interesting that the patient in question was subsequently diagnosed
with celiac disease, and following  institution of a gluten-free diet, the
psychiatric symptoms resolved  and there was a normalization of blood flow
to the frontal cortex (De Santis, Addolorato, Romito, Caputo, Giordano,
Gambassi, Taranto, Manna, Gasbarrini, 1997).   Such technological advances
threaten to discredit the current medical paradigm, but history continues
to repeat itself as 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-free diet in the
treatment of celiac disease, which was the first effective treatment to be
found for an illness that had been characterized as much as 2,000 years
earlier (Cooke & Holmes, 1984).  This disease had a childhood death rate
which was reported, more than a century 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 well
as a variety of psychiatric illnesses, but such a hypothesis may 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 fall prey to malignancies that could have
been prevented (Hoggan, 1997b).  The gluten and dairy-free diet has even
been shown to have therapeutic value in the treatment of malignancy
(Donaldson, Jundt, Ricour, Sarrazin, Lemerle, Schweisgtuth, 1975; Reading &
Meillon, 1984; Donaldson, 1977). 
Early descriptions of celiac children characterize them as whiny,
impulsive, attention seeking, sometimes angry, and a behavioral challenge
to their caretakers (Colquhoun & Bunday, 1981). 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 people
who have been diagnosed with ADHD. Anger and defiance are features often
reported in untreated celiac patients. Additionally,  celiac disease is a
condition where there is an overwhelming body of  evidence supporting the
involvement of exorphins. Increased intestinal permeability is a well
recognized feature of this disease, and Paul et al. (1985)  have stated
that when celiac children ingest gluten, there is a dose-dependent severity
of EEG abnormalities. Kozlowska (1991) has asserted that these
abnormalities are the same as those found in ADHD. 
Short stature is another point of convergence between ADHD (Spencer,
Biederman, Harding, O’Donnell, Faraone, Wilens, 1996) and celiac disease
(Arruchio, et al., 1988).  Celiac disease is primarily seen as a bowel
disease which is variously characterized by chronic constipation and/or
diarrhea (Fasano, 1996).  ADHD has also been associated with chronic
constipation (Snow, 1975) and with chronic diarrhea (Kalm 1983).  
Although not usually seen as a critical feature of celiac disease,
increased intestinal permeability is a consistent feature of this condition
(Arranz, Bode, Kingstone, Ferguson, 1994; Holm, Savilahti, Koskimies,
Lipsanen, Maki, 1994). The presence of IgG class  antibodies against
gliadin, one of the alcohol soluble protein groups in wheat, in virtually
all untreated celiacs, is one more indication of increased intestinal
permeability in this condition. These antibodies may also be found in the
circulation of many who suffer with other conditions, but they are found in
the sera of most untreated celiac patients (appendix seven). The
association of increased intestinal permeability with untreated celiac
disease is so well accepted that the more economic testing for such
permeability has sometimes been used to screen for celiac disease (Smecuol,
Vazquez, Kogan, Cabanne, Niveloni, Pedreira, Boerr, Maurino, Meddings,
1997; Vogelsang, Genser, Wyatt, Lochs, Ferenci, Granditsch, Penner, 1995),
although there are critics of such methods who assert that such screening
misses the milder cases of celiac disease (Catassi, Fabiani, Ratsch,
Bonucci, Dotti, Coppa, Giorgi, 1997).  This permeability  may explain the
increased incidence of atopy  commonly reported in celiac patients (Kitts,
Yuan, Joneja, Scott, Szilagyi, Amiot, Zarkadas, 1997; Stevens, Connolly,
Murray, McCarthy, 1990; Reading, Watson, Platt, Bird, 1971; Sandyk,
Brennan, 1983). It may also offer insight into similar comorbidities among
ADHD subjects (Biederman, Milberger, Faraone, Guite, Warburton, 1994;
Breakey, 1997; Mitchell, et  al. 1987; Stevens, et al. 1995; Aman, et  al.
1987; Stevens, et  al. 1996). 
There is evidence independent of the ADHD literature that atopy such as
recurrent serous otitis media should be investigated for dietary allergens
(Nsouli, et al, 1994). Despite a wealth of reports of increased inner ear
infections in ADHD, the possibility of  food intolerance  is ignored by
many of these investigators. 
If one can accept the possibility of increased permeability 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 ADHD, the
next step is to establish the likelihood that  incompletely digested
peptides, exorphins, may be over-represented in the ADHD subject’s gut,
leading to transport of significant quantities of exorphins into the blood.

Digestive Enzymes
Susceptibility to celiac disease is a genetically transmitted trait which
has been associated with genetically coded immune system factors identified
as human leukocyte antigens (HLA) (Auricchio, Greco, Troncone, 1988). There
is a  significant association with HLA B8, which has also been demonstrated
in 10% to 30% of European populations (Ammerman, Cavalli-Svorsa, 1984).
Other HLA factors 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 also associated with celiac disease (Dohan 1972; Horvath, Horn,
Bodanszky, Toth, Varadi, 1983; Leung, Robson, 1996 ).
If these enzymatic deficiencies are genetically coded, and if they are
significantly associated with HLA B8, there may be cause to believe that a
large percentage of our children who are afflicted with ADHD, which also
appears to be influenced by genetic factors,  fall into the genetic
category which codes for HLA B8. If that is the case, then a failure to
cleave the peptide bonds within some of the exorphins, in combination with
increased intestinal permeability, may lead to absorption of these
macromolecular exorphins into the blood of ADHD sufferers.  Although
speculative, confirmation may result in changes to current perspectives on
many mental illnesses, including ADHD. It is a scenario which is possible.
Questions of relative risk are not answerable until the connections are
investigated but there is some interesting data which support such a
genetic possibility. Kaczmarski, Kurzatkowska  (1988) have reported a very
high familial incidence of cow’s milk intolerance in the families (34%) of
children with cow’s milk intolerance, and a 13.3% family incidence of
gluten intolerance was revealed in the families of children with celiac
disease. There appears to be a very strong familial pattern of food
intolerance,  which may also include patterns of digestive enzyme
deficiencies.  Similar familial patterns have also been observed regarding
ADHD patients (Biederman, Faraone, Keenan, 1992; Sandberg, 1996; Hechtman,
1996). Investigation of ADHD subjects for deficiencies of digestive enzymes
may thereby be very revealing.
Investigations of children of short stature has revealed that 5% to 20% of
these children have celiac disease (Arucchio, et al, 1988).  Growth
deficits in ADHD subjects have recently been reported to be independent of
the stimulant therapy, although these drugs had previously been blamed for
this problem, thus illuminating yet another connection between the two
The relative risk of malignancy is so dramatically greater among untreated
celiac patients, that regardless of whether the exorphin hypothesis proves
to be applicable to ADHD, it is a matter of some urgency to accurately
affirm or deny the possibility.  Rapidly increasing numbers of children who
are diagnosed with ADHD may predict an explosion in malignancy rates,
especially lymphomas and gastrointestinal adenocarcinomas.  If action is
not soon taken  and the possibility of frequent, underlying dietary
intolerance disease is either refuted or supported, our neglect 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
hypothesized above. Neither would the genetic coding for enzymatic
deficiencies constitute a critical feature of the application of the
exorphin hypothesis to ADHD. The foregoing is purely speculative, but the
evidence of atopy, food allergies,  food intolerances, and similar EEG
abnormalities in both celiac disease and ADHD is compelling. This evidence
suggests both increased intestinal permeability, and perhaps, enzymatic
deficiency in both ADHD and celiac disease. The genetic, atopic, and
dietary factors which have been identified in celiac disease and ADHD have
offered the opportunity for such speculation, but this should not be
construed as a critical feature 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, and there may be
many cases of untreated celiac disease among those suffering 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
differential 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 American blood donors, and approximately the same
incidence among Italian school children (Catassi, et al., 1996).  Occult
celiac disease may well constitute a significant portion of ADHD.
Undiagnosed cases of milk protein intolerance, and other protein
intolerance diseases may also comprise a significant percentage of ADHD
cases. There is also some evidence suggesting that intestinal permeability
is a feature of most cases of ADHD which will be discussed shortly. For
now, it might be valuable to examine the rates of intestinal permeability
that have already been reported in the literature.
The same population of healthy blood donors who showed a 1:250 incidence of
celiac disease, demonstrated an incidence of antibodies 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 donors. Those with anaemia, and
other such conditions which are much more common in food intolerances,
would be excluded from giving blood. Testing a random population would be
much more informative.  An examination of a random population in Iceland
revealed that 15%  of those tested demonstrated elevated antibodies against
gliadin, suggesting that 15% of the general population may have increased
intestinal permeability. A majority  of these folks are not likely to have
celiac disease, but the antibodies indicate that they are mounting an
immune response to the most common food in our Western diet  These
antibodies imply that macromolecules 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 folks probably do not have celiac
disease, some features of gluten intolerance may be present, and may offer
important insights into ADHD. 
Neurological Manifestations
 Another area of research, which converges with the exorphin hypothesis,
but was not shaped by it, is some work from the fields of neurology and
gastroenterology,  which have explored celiac-associated: epilepsy;
psychiatric disturbances; aphasia; depression; central and peripheral
nervous system demyelination; cerebrovascular disorders; neuromuscular
disorders; and immune system down-regulation through peripheral and central
action.  Untreated celiac disease has a reported association with some
instances of all 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 consistent with, but not exclusive to
schizophrenia, bi-polar disorder, and autism. Many of the symptoms
described by Shannon (1922) in what was, perhaps, the earliest report of
the treatment of ADHD symptoms with dietary exclusion, are symptoms found
in ADHD patients, celiac patients, and in a variety of mental disorders
which may be implicated in the Exorphin hypothesis. Shannon described these
children as neurotic. Similar psychiatric symptoms are reported in more
than 70% of celiac children (Kozlowska, 1991). 
Comorbidities in ADHD include language and learning problems reported at
32% and 74% respectively (Mitchell, et al. 1986) . It is of more than
passing interest that progressive aphasia and dysarthria  have been
reported in some  cases of  untreated celiac disease (Skully, Maark,
McNeely, McNeely, 1988). In such cases,  language competence usually
improves following institution of a gluten-free diet  In celiac disease, we
may deduce the possibility that exorphins were somehow involved in the
interference with language competence. Of course, other factors in celiac
disease may, partly or wholly, be  the cause of such language and learning
problems.  Nonetheless, the possibility of exorphin involvement seems quite
arguable. The same also seems possible in the large number of cases of
ADHD, where there are comorbid language learning problems ( Mitchell et
al., 1986; Biederman et  al. 1996).
Depression has recently become a concern in ADHD. A number of  reports
suggest an important association (Biederman, Mick, Faraone,1998; Faraone,
Biederman, Weber, Russell,  1998; Katz, Wood, Goldstein, Auchenbach,
Geckle, 1998; Faraone, Biederman, Mennin, Wozniak, Spencer, 1997).
Selective serotoinin re-uptake inhibitor, anti-depressant medications are
reported to be effective when used in the treatment of some cases of
depression in ADHD (Findling, 1996).  Depression has also been asserted to
be  the most prevalent symptom of celiac disease (Cooke & Holmes 1984) and
reported as very common by others ( Addolorato, Stefanini, Capristo,
Caputo, Gasbarrini, 1996; Holmes 1996; Pellegrino, D’Altilia, Germano,
1995; Hallert, Astrom, Walan, 1983) which is thought to be a function of
central monoamine metabolism dysfunction (Hallert, Martensson, Allgen,
1982) or due to reduced  serotonin binding sites on the platelets of celiac
patients (Chiaravalloti, Marazziti, Batistini, Favilli, Ughi, Ceccarelli,
Cassano, 1997). Coleman (1971) has reported low platelet serotonin in 88%
of the hyperactive children tested.  The implicit connection is compelling.
Molecular Mimicry
Neuropathic presentations of celiac disease also include central and
peripheral nervous system demyelination. A variety of explanations have
been postulated for these presentations. The suggestion which may prove to
be of greatest significance is the notion that molecular mimicry could
underlay an autoimmune attack upon myelin basic protein. 
The concept of molecular mimicry arises out of a theoretical 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 reflecting such an increase  ( Medline
search, March, 1998). The molecular mimicry perspective argues that the
incursion of polypeptides into the circulation leads to selective antibody
production. These antibodies are sensitized to specific amino acid
sequences present in the invading peptide or in a combination of the
invading peptide and tissues to which they have bound. If similar amino
acid sequences are present in protein structures within body tissues, the
same antibodies may attack these self cells, resulting in  autoimmune
damage to the tissues in question (Tuckova, Tlaskalova-Hogenova, Farre,
Karska, Rossmann, Kolinska, Kocna, 1995; Oldstone, 1987). 
The invading peptides, if derived from a common food which is usually
consumed on a daily basis, such as dairy products or gluten, may thereby
incite autoimmunity and perpetuate it as long as such dietary practices
continue.  This, of course, would apply to many of the autoimmune
conditions which have been associated with celiac disease, including
neuropathies. It may also apply to neuropathic and other autoimmune
conditions which are often found in ADHD, some of which may have suggested
the earlier name for this condition: “minimal brain damage” (Mitchell et
al., 1987).
 Delayed myelination and delayed development of  CNS morphology have also
been suggested as features of   ADHD (Castellanos, 1997;  Castellanos,
Giedd, Rappoport, 1994; Hynd, Semrud-Clikeman, Lorys, Novey, Eliopulos,
1990; Semrud-Clikeman, et al. 1994; Ucles, Lorente, Rosa, 1996). These are
also consistent with the concept of  molecular mimicry resulting from
increased intestinal permeability, combined with consumption of cereals
and/or dairy products.  Delays in neuron, glia, dendrite, and brain
development have also been associated with opioid peptides (Hauser, et al.,
1989; Zagon, et al., 1991; Zagon, et al., 1984).  
Another autoimmune condition, thyroiditis is an ailment which is commonly
associated with both ADHD and food intolerance disease.  Brucker-Davis,
Skarulis, Grace,, Benichou, Hauser, Wiggs, Weintraub, (1995) report a 60%
incidence of ADHD among persons with resistance to thyroid hormone. Another
group reports a 5.4 % incidence of thyroid abnormalities in ADHD, as
compared to an incidence of less than 1% in the general population (Weiss,
Stein, Trommer, Fefetoff, 1993).  Freeman (1995), Counsell, Taha, Ruddell,
(1994) and Collin, Salmi, Hallstrom, Reunala, Pasternack, (1994) all report
an increased coincidence of autoimmune thyroiditis in association with
celiac disease.  
Brain morphology and perfusion
The general size and conformation of the brain, as well as the supply of
nutrients to the brain also provide important areas of interest. Longer
chain fatty acids pass through the blood brain barrier (BBB) by simple
diffusion, and lipids provide much of the basic structure of the membranes
and myelin of the brain (Zeisel 1986), which  can indirectly alter
neurotransmission.  The electroencephalogram (EEG) is used to measure some
of the  brain's electrical activity in ADHD (Satterfield, Schell, Nicolas,
Backs, 1988) along with other instruments such as magnetic resonance
imaging (MRI), (Castellanos, et al. 1994; Hynd, Semrud-Clikeman, Lorys,
Novey, Eliopulos,  1990) which can be used to determine quantities of blood
supply to various parts of the brain, and topographic EEG mapping, which
can be used to suggest the  extent of  myelination, and relative shape and
size of various regions of the brain, as well as identifying characteristic
patterns of pathological electrical activity ( Uhlig et al., 1997).  
Hypoperfusion, of some parts of the brain, has been reported in ADHD
(Castellanos, et al., 1994) and celiac disease (De Santis, et  al. 1997).
Cerebrovascular disorders have long been identified in celiac disease (
Rush, Inman, Bernstein, Carlen, Resch, 1977).  The possibility of a
connection seems worthy of investigation.  The cortical atrophy reported in
long term follow up studies of subjects who experienced lengthy periods of
stimulant therapy as youngsters may be the result of  reductions in blood
supply as a function of their ADHD condition, rather than a deleterious
result of either stimulant therapy, or substance abuse.  Alterations to
vascular health and dilation may result from the same underlying cause in
both celiac disease and ADHD.  In keeping with the exorphin hypothesis, an
increased risk of cerebral vasculitis has also been reported in legal and
illegal uses of opiate drugs (Brust, 1997). 
Metabolically 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 inferred in regional
hypoarousal. Celiac disease has also been demonstrated to exert an
important effect upon vascular dilation (Rush, et  al. 1977; Bye,
Andermann, Robitaille, Bohane, Andermann, 1993;  Tiacci, D'Alessandro,
Cantisani, Piccirilli, Signorini,  Pelli, Cavalletti, Castellucci, Palmeri,
Battisti, Federico, 1993;  Rush , Inman , Bernstein , Carlen , Resch, 1986)
) so it may be reasonable to suspect that the reduced blood supply may
result from the action of exorphins upon vascular walls in some regions of
the brain. 
This  may also support the perspective suggesting a reduced state of
arousal in some regions of the brain, as lowered glucose metabolism has
been reported in "medial frontal, parietal, and occipital
areas"(Semrud-CIikeman M, Filipek P, Biederman J, Steingard R, Kennedy D,
Renshaw P, Bekken K, 1994).  Additionally, according to Castellanos et
al.(1994): "Functional imaging techniques used to pinpoint the specific
anatomic substrates of ADHD have implicated striatial hypoperfusion and low
global glucose metabolism, particularly in frontal regions" (Castellanos et
al., 1994).
Altered brain morphology in ADHD supports the perspective that the problem
is "rooted in the processes of the cerebral cortex and some subcortical
structures" (Levy, Ward,  1995). This information may prove valuable to
future diagnosticians.  Therapeutic interventions in nutrient delivery to
neglected parts of the brain in ADHD may already be a feature of one type
of intervention.  Levy reports  that “ hypoperfusion of the caudate and
central frontal lobes, accompanied by relatively hyper-perfused occipital
lobes tended to be reversed by methylphenidate" (Levy, Ward, 1995).
Neuromuscular disorders have recently been reported as the presenting
feature of some cases of  celiac disease (Hadjivassiliou et al., 1996,
1997; Cooke & Holmes 1984). Perhaps similar problems may also have
significance in the increased awkwardness reported in ADHD (Kinsbourne,
1975). In both celiac disease and ADHD, there are reports of many disorders
involving morphological and functional changes to the central and
peripheral nervous systems. In celiac disease, dietary intervention has
been demonstrated to result in improvement or resolution, in most cases  of
these symptoms. In a few anecdotal reports (see appendices one and five,
Colquhoun & Bunday, 1981 ), 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 dairy, can be
demonstrated  as the cause of attentional problems and abnormalities in CNS
morphology and perfusion in celiac disease, the assertion of similar
possibilities in the context of ADHD does not seem unreasonable.
Essential Fatty Acids
Another factor which has an impact on brain morphology, and thus,
presumably, brain function,  is essential fatty acids. They are "either of
2 fatty acids that the body requires, cannot make from other substances and
must therefore get from foods" ( Erasmus 1996).  The names of these two
EFAs are linoleic acid (LA; 18:2w6) and alpha linolenic acid (LNA; 18:3w3).
The former is commonly identified as omega 6, while the latter is commonly
referred to as omega 3. 
Reduced essential fatty acid (EFA) levels have long been recognized as
over- represented among ADHD patients (Aman, Mitchell, Turbott, 1987;
Colquhoun & Bunday 1981; Mitchell, et  al. 1987; Stevens, Zentall, Deck,
Abate, Watkins, Lipp, 1995; Wainwright 1992 ).  According to Colquhoun and
Bunday (1981),  "A 1932 description of behaviour in children with coeliac
disease who have a fat malabsorption problem could be one of the earlier
descriptions of hyperactivity".  There is thus cause to suspect that many
of the soft neurological signs associated with ADHD (Martin, Welsh, McKay,
Bareuther, 1984) may be associated with EFA deficiency (Mitchell et  al.
1987), as has been suggested to apply to celiac patients with neuropathic
symptoms (Cooke & Holmes, 1984).  It is these neurological signs which led
to the early characterizations of ADHD as "minimal brain damage" (Mitchell
et  al., 1987) although it was many decades before definitive evidence of
altered morphology of the brain, other than reports 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 only about 5%  of ADHD children show solid evidence of brain
damage (Mitchell et al. 1987).  There  are developmental and morphological
abnormalities, but the term ‘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, if
any, remedial value in the treatment of ADHD patients (Aman et al. 1987;
Wainwright 1992). The explanation for this situation remains unclear
(Mitchell et al. 1987; Stevens et al. 1995),  but  speculation of
malabsorption, or reduced ability to convert fatty acids to longer chain
unsaturated fatty acids,  and increased metabolism of , or impaired
systemic or cellular transport of EFAs,  have all been included  in some of
these discouraging reports (Mitchell et al. 1987; Stevens et al. 1995; Aman
et al. 1987; Colquhoun & Bunday 1981; Homan, Johnson, Hatch, 1982; Stevens
Zentall, Abate Kuczec, Burgess, 1996; Wainwright 1992; Ziesel 1986).  The
possibility of microvillous damage, perhaps resulting from
dietary/autoimmune dynamics, seems to have been given little, if any,
attention. The microvilli are the site of absorption of fats, for lymphatic
transportation to the liver. As fats are not water soluble, they can not be
absorbed directly into the circulation (Hoggan 1997c). 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 all of this is that the established  connection
between EFA deficiency and ADHD (Mitchell et al. 1987; Stevens et al. 1995;
Aman et al. 1987; Colquhoun & Bunday 1981; Homan, Johnson, Hatch, 1982;
Stevens Zentall, Abate Kuczec, Burgess, 1996; Wainwright 1992; Ziesel 1986)
may suggest  an answer to one previously unexplained anomaly in ADHD. The
high male to female ratio  in ADHD  has been suggested to be a function of
gender differences in EFA requirements (Colquhoun & Bunday 1981).  As one
group put it: "Male animals require approximately three times as much EFAs
as females for normal development" (Mitchell et al. 1987). 
 An additional factor related to essential fatty acids is that exorphins
(opioid peptides) from  milk and wheat can block PGE  formation from
dihomogamma-linolenic acid (DGLA) (Mitchell et al., 1987).   PGE is a
series 1 prostaglandin involved in a variety of immune and circulatory
functions (Erasmus, 1996). This may provide another clue to the etiology of
some of the reported increases in immune system anomalies (Warren, Odell,
Warren, Burger, Maciulis, Torres, 1995; Mitchell, et al, 1987; Stevens et
al. 1995) and abnormalities in neurotransmission in many cases of ADHD
(Hoshino, Ohno, Yamamoto, Kaneko, Kumashiro, 1985; Greensberg, Coleman,
1976; Halperin, Newcorn, Kopstein, McKay, Schwartz, Siever, Sharma, 1997;
Coleman, 1971 ) and celiac disease (Chiravalloti, et al. 1997; Hallert, et
al. 1982). 
EFAs have a significant impact on phospholipids in the brain.  Ziesel
(1986) tells us that: "Essential fatty acids needed by the brain are
obtained from the diet  They traverse the blood-brain barrier by
translocation through endothelial cell membranes. Phospholipids are
synthesized within the brain from these fatty acids and glycerol. Fatty
acids are also precursors for the synthesis of prostaglandins, which are
important neuromodulators".  Thus, EFA deficiencies, as found in ADHD, are
likely to impact upon brain structure, neurotransmission,  as well as
immune system function. Such deficiencies of essential fatty acids are also
widely recognized as a  common feature of   celiac disease.  
Others have shown that long chain, 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 cerebral gray
matter, and the retina (Wilens, Prince, Frances, 1995).  The ingestion and
metabolism of these fats is critical to brain and nerve function, hence the
term 'essential'. The variety of neuropathic symptoms often reported in
ADHD may find at least some explanation 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 also provide a greater understanding of
etiological factors in the  identified sub-categories of ADHD.  While omga
3 deficiencies predominate among those presenting with hyperactivity
(Mitchell et al. 1987), behaviour problems, temper tantrums, sleep,
learning, and health problems, are parallelled by findings in animal
studies (Stevens et al., 1996) further re-reinforcing the suggestion of a
relationship.  Additionally, animal 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 fish, marine animals, and some organs,  require long
term deficiency  before the composition of the brain is altered
(Wainwright, 1992). If the postulated connection exists, it is chronic, and
is thus unlikely to be remedied by interventions of  short duration, as are
often employed in dietary investigations, if it can be remedied at all.  
Conversely, "A high rate of speech difficulties was found among the
children with low arachidonic acid levels" (Mitchell et al.,1987). These
latter are synthesized  from 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 (Scully, et al., 1988) which slowly
resolved after several months of excluding gluten from the diet, reflects a
deficiency in omega 6. The description is very consistent with the
explanation provided by Mitchell et  al. (1987)   If so, perhaps the cause
of language learning problems in some cases of ADHD is associated with a
similar problem with absorption of EFAs. 
 There is also evidence that "....cognitive and linguistic problems appear
to precede hyperactivity" (Sandberg 1996). Perhaps, with a greater
understanding of EFA deficiencies, the specific presentations of individual
ADHD patients'  EFA levels may provide a means of differentiating
sub-groups, ultimately revealing a food intolerance disease, or losses in
absorptive capacity.  
An interesting contradiction comes to us from Aman et  al. (1987) who
report: "The subgroup analyses... failed to indicate a differential
response for individuals who were initially low or high on these
substances," thus undermining the therapeutic use of EFAs in ADHD. But this
result may be interpreted in another manner.  If malabsorption is occurring
in varying degrees, due primarily to variations in microvillous morphology,
or reduced bile delivery to the duodenum, or both, then a more EFA
deficient child would be less likely to benefit from supplementation. This
would be true because the more deficient individual would likely be
experiencing a  more pervasive malabsorption pathology, rather than a
dietary insufficiency of EFAs.  On the surface then, it is probably quite
correct to say that EFA supplementation 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 reinforce the notion of a
pathological connection. Colquhoun and Bunday(1981) state: "Since an EFA
deficiency itself leads to a defect in fat absorption which will exaggerate
the deficiency, a vicious circle could result". 
There is also the possibility of reduced cholecystokinin (CCK) production
in the duodenum (Tortora & Anagnostakos, 1989, p.751), due to damage caused
by food intolerance (Domschke, Bloom, Adrian, Lux, Bryant, Domschke, 1989).
Absence of this hormonal messenger, which signals the gall bladder to
contract in response to fat consumption, could also lead to both a
deficiency in EFAs, as well as a failure to respond to supplementation
(Minich, Vonk, Verkade, 1997).
Malabsorption due to slight damage to the mucosa of the small intestine
would be very likely to have a large impact upon fat absorption, since fats
are absorbed at the microvilli, into the lymph system, rather than through
the intestinal wall into the circulation, as with other nutrients (Hoggan,
1997c).  The microvilli extend, with the exception of  brush border
enzymes, furthest into the intestinal lumen, and may sustain damage more
quickly than the underlying structures. 
Deficiencies in dietary intake of EFAs appear to have been ruled out in
most of these reports connecting EFA deficiency and ADHD, and we are left
to explore  other explanations for this deficiency.  In our exploration, we
may find evidence to suggest some features of malabsorption diseases
associated with food-protein intolerance.  In fact, there is considerable
evidence connecting gluten and dairy consumption with ADHD.
Gross measures of brain volume, and of perfusion may suggest pervasive
underlying pathologies at the level of neurotransmission.  Abnormalities in
neurotransmitter function in attention deficits have long been asserted
(Raskin, Shaywitz, Shaywitz, Anderson, Cohen, 1984), and diet can readily
be demonstrated to influence neurotransmission (Ziesel, 1986) which is
important for undernourished children, whether from dietary insufficiency,
or from malabsorption or from metabolic abnormalities.  There is also
evidence that:  "Even when gross malnutrition is not present, subtle
changes in diet may modulate brain function" (Ziesel, 1986).  
An important shared  characteristic of neurotransmitters is that they are
almost exclusively derived from dietary protein or amino acids (Lovenberg,
1986).  Serotonin is a monoamine neurotransmitter which is widely
distributed through the brain, as well as the rest of the body (Tortora
&Anagnostakos, 1989).   For some researchers, the question is not whether
neurotransmitter dysfunction is a facet of ADHD, but which
neurotransmitters are pathologically involved. Dopamine, noradrenaline, and
serotonin appear to be the primary suspects (Sandberg, 1996).  
Interestingly,  refined sugar may also influence central serotonin levels.
It is a substance which has long been suspected to be an initiator of
hyperactivity symptoms. This has been repeatedly refuted in controlled
studies.  Although  more refined sugar consumption has been reported among
ADHD subjects, it appears to reduce activity levels  among both normal
controls and experimental subjects (Rapoport, 1986) and it has been
demonstrated to reduce performance on school achievement tests (Egger,
Stolla, McEwen, 1992). Perhaps sugar is at work in attentional deficits,
rather than in hyperactivity. The hyperactivity might follow, as something
akin to a rebound reaction.
It seems that "dietary alterations in precursor availability can modify
neuronal activity" (Young, 1986).  The availability of tryptophan through
increased insulin production, in response to sugar ingestion, increases
uptake of competing large neutral amino acids  into muscle cells. This
increases the relative serum concentration of tryptophan, which is
resistant to insulin.  The relative increase in serum tryptophan, following
a rise in insulin,  leads to a competitive advantage to tryptophan,  for
transport across the BBB. Increased tryptophan has been asserted to lead to
increased levels of serotonin in the brain (Krassner, 1986; Fernstrom 1986;
Wurtman, 1986; Ziesel, 1986).   Increased tryptophan can also lead to
drowsiness, and induction of endorphin analgesia (Ziesel, 1986).  Poor
attentional performance would seem consistent with this scenario.
Although a bit of a digression, the importance of which will become
apparent shortly,  it has also been shown that "oral or intravenous
administration of gluten exorphins A5 and B5 can influence the regulation
of postprandial insulin  release"(Fukudome, Shimatsu, Suganuma Yoshikawa,
1995; Scott, Cloutier, Kleemann, Woerz-Pagenstert, Rowsell, Modler, Kolb,
1997; Scott, 1996). 
Thus,  consumption of sugar or gluten should, other conditions being equal,
predict reduced activity levels.  It is of interest to note that
hyperactive children appear more likely to consume greater quantities 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 considering some of the symptomology of
There is also familial evidence to suggest that serotonin deficiency may be
involved in aggressive behaviour, and a poor long-term prognosis for that
behaviour (Young, 1986; Halperin, Newcorn, Kopstein, McKay, Schwarn,
Siever, Sharma, 1997).  There appears to be something of a contradiction
here.  Hypoarousal is not easily associated with aggressive behaviour. To
add to the confusion, sugar has recently been demonstrated to alter EEG
patterns among subjects with food-induced ADHD (Uhlig, Hoshino, Hashimoto,
Okano, Kumashiro, 1993).  These are the contradictory findings reported in
the literature.  If the in- vivo action of exorphins is factored into this
array of conflicting reports, perhaps some of that contradictory complexity
will be reduced. 
Dopamine, another monoamine neurotransmitter, has repeatedly been
implicated in ADHD (Raskin et al. 1984; Hanna, Ornitz, Hariharan, 1996),
and is thought to be involved in maintaining normal alertness (Raskin et
al. 1984) and executive control (Castellanos, 1997).  Krassner provides us
with a more complete explanation: "Dopamine is thought to be involved with
emotions through the limbic system, motor function through the basal
ganglia, some pituitary hormones through the hypothalamus, and inhibition
of the vegetative nervous system through the autonomic ganglia"(Krassner,
As was mentioned earlier, dietary precursor availability can affect
neuronal activity (Krassner, 1986).  Variations can occur in
neurotransmitter release, as a function of variations  in diet  " thereby
allowing one's nutritional state to affect one's behaviour"(Wurtman, 1986)
and  specific neuronal cells can synthesize neurotransmitters if the
precursor is available in the diet" (Lovenberg, 1986).  Tyrosine is the
amino acid precursor of dopamine and epinephrine. "Brain tyrosine levels
are most conveniently increased by ingesting pure tyrosine alone or with a
carbohydrate  (to lower plasma levels of competing LNAA)" (Lovenberg,
1986).   Meals high in protein and carbohydrates also tend to raise
tyrosine levels in the brain (Ziesel, 1986).   Thus, the reported inverse
relationship between urinary epinephrine levels and both fidgeting and
aggression among normal children (Hanna et al., 1996) offers some
interesting insight when we look at reports that  ADHD subjects show
significantly lower urinary levels of  epinephrine than in controls (Hanna
et al., 1996). Abnormalities in iron absorption may suggest an explanation
for this dynamic. 
Sandstead (1986) has suggested, on the basis of animal findings, that iron
may be required for dopamine receptor function in the caudate nucleus.
Monoamine neurotransmitters, principally dopamine, appear to affect
neuronal communication in regions of the brain involved in executive
functions (Castellanos, 1997) which, by definition, is a problem for ADHD
patients (DSM IV).  Given the issues surrounding problematic uptake in iron
supplementation associated with ADHD (Olki, honig, Helu, Howanitz, 1983;
Lozoff, Viteri, Urrutia, 1982), in conjunction with evidence of iron
requirement for receptor function (Sandstead, 1986), this may be a very
important interface of two dietary issues in ADHD and celiac disease, as
will be discussed shortly.   
Although peptides are not monoamines they do function as neurotransmitters,
"Dietary protein serves as the ultimate 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 inhibited by peptidergic modulation (Russell, De
Villers, Taljaard, 1995).  The peptides derived from gluten and dairy may
or may not be involved in such modulation. We may hope for further research
in this regard. Stein and Sammaritano (1984) offer the possibility that “
some hyperkinetic children differ from normal children in their amino acid
and protein metabolism”. 
Kapusta et al.  (1989) have identified exogenous and endogenous peptides as
regulators of kidney function. Urinary dysfunction is reported as very
common in ADHD (Maizels, Gandhi, Keating, Rosenbaum, 1993).
The data on monoamines provide quite convincing evidence for the belief
that there may be an interplay between diet and behaviour which is mediated
by alterations in neurotransmission.  This can be important at all levels
of under-nutrition (Zeisel, 1986 ).  Malabsorption is one means by which
under-nutrition may occur in a clinically obscure fashion ( Hoggan, 1997a;
Mineral deficiencies
ADHD signs and symptoms in mineral deficiencies are well described
(Krassner, 1986; Sandstead, 1986; Lovenberg, 1986).  At the level of
neurotransmission, "Neurons are unique biochemical units that have the
ability to produce an electrical current by causing intracellular 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
function"(Sandstead, 1986).  
Since the parathyroid gland is involved in regulation of calcium and
magnesium metabolism, there is another connection with food intolerance
provided by the report that IgA class endomysium antibodies, which are a
very specific indicator of celiac disease, can cross-react with parathyroid
tissue (Kumar, Valeski, Wortsman, 1996), and low magnesium levels have also
been associated with functional hypoparathyroid (Bertelloni, 1992).  Recent
investigations reveal that the incidence of magnesium deficiency was found
in 95% of ADHD patients studied, and that remediating that deficiency can
result in significant improvements in ADHD symptoms (Starobrat-Hermelin,
Kozielec, 1997; Kozielec, Starobrat-Hermelin, 1997).  Similarly, all
adult-diagnosed celiac patients demonstrate some level of bone
demineralization, compared to the general population, regardless of dietary
compliance  (Green, 1997). Many celiac subjects who demonstrate diminished
calcium levels show improvements to serum calcium  after  magnesium
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 &
Holmes,1984). One report asserts that all of a group of celiac patients who
underwent magnesium supplementation demonstrated significant bone
remineralization (Rude & Olerich 1996).  
     Some dietary deficiencies of trace minerals may also affect
neurotransmitter function (Lovenberg, 1986).   For instance, iodine
deficiency can have a devastating impact on brain maturation and function
(Sandstead, 1986).
The proximal duodenum is the site of most iron absorption (Cooke & Holmes,
1984; Barton, 1997). Coincidentally, it is usually the site of earliest
damage induced by protein intolerance disease (Barton, 1997). It is well
established that iron deficiency, during critical stages of development,
can lead to permanent or long-standing intellectual and behavioural
deficits (Bushnell, 1992). Iron deficiency symptoms  have been reported as
including hyperactivity and attention deficits (Anderson, Hrboticky, 1986;
Sandstead, 1986).  Some treatment interventions such as  intramuscular iron
therapy, produced significant improvement in behaviour...."(Olki, Honig,
Helu, Howanitz, 1983). Yet there is a dissonance in reported findings. One
group states: "We are unable to explain the discrepancy in the treatment
results between our observation of a response with intramuscular iron and
the lack of response with oral iron"(Olki et al., 1983). 
The rationale presented for oral iron supplementation is: "Oral iron was
used because it is the treatment of choice, with a therapeutic response
parallel to that of intramuscular iron, and because of the slight risk
associated with parenteral administration of iron" (Lozoff, Viteri,
Urrutia, 1982).  In spite of the rhetoric, oral iron did not help. We are
left to wonder why.  Lozoff et  al. (1982) suggest the possibility of
malabsorption, but found no other evidence to support such a possibility
and therefore dismissed  it.  Many cases of celiac disease are identified
through investigation of the singular presentation of iron deficiency
anemia  which is resistant to oral supplementation (Volpe, Festini, 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 can cause selective
malabsorption of iron (Volpe et al., 1997).  The asserted association, in
some cases of iron deficiency, of deficiency of vitamin B12 and folic acid
(Bushnell, 1992) should also increase suspicion of malabsorption, but iron
deficiency alone should significantly elevate suspicion of  malabsorption
disease (Carroccio, Iannitto, Cavataio, Montalto, Tumminello, Campagna,
Lipari, Notarbartolo, Iacono, 1998).
Another problem can lurk in our desire to provide children with a healthy
diet   We may err  in what we feed them: " too much fibre in the diet will
render available iron unabsorbable" (Bushnell, 1992).  This is arguably the
result of phytic acid entering into combination with the iron, thus forming
a bond which cannot be broken by the enzymes in the gut (Lindeberg, 1997).
In support of this suggestion, iron deficiency is also reported as overly
common where "cereals and legumes are the primary source of energy and
protein" (Sandstead, 1986).
Further to the relationship between iron deficiency and ADHD, Cantwell is
reported  to have  " detected 'soft' neurological signs as long as six
months after treatment for iron deficiency anaemia at 6 to 18
months"(Lozoff, et al., 1982).  Also, learning disabilities and attention
deficits are sometimes attributable to iron deficiency anaemia (Bushnell,
Other trace minerals
Copper deficiency may also be implicated in some brain damage  (Sandstead,
1986). While 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 malabsorption may compromise adequate copper
levels. Hence, copper deficiency may underlay some facets of ADHD related
to delayed myelination. Copper deficiency is also reported in celiac
disease (Cooke & Holmes, 1984).
Zinc deficiency has also been reported in ADHD.  Zinc deficiency indirectly
inhibits some  normal essential fatty acid processes through inhibition of
specific enzymatic  activity (Mitchell, et al., 1987; Colquhoun & Bunday,
1981).   Zinc deficiency, as with iron deficiency, can also result from
elevated levels of fibre with phytic acid in the diet, as with cereals and
legumes (Sandstead, 1986).  Animal studies in zinc deficiency have revealed
developmental delays as well as alterations in neurotransmitter
concentrations (Sandstead, 1986). Zinc deficiency may also be involved in
inhibition of growth and is also reported in celiac disease (Cooke &
Holmes, 1984).
In total then, mineral deficiencies, individually, or in combination, may
result in  some ADHD symptoms, and many of these are suggestive of dietary
deficiency, or metabolic abnormalities. Patients with celiac disease appear
to suffer similar deficiencies in most or all cases.
Electroencephalograms, ADHD, and Exorphins
Perhaps some of the most compelling evidence supporting the postulated
connection between gluten/dairy pathology  and ADHD may be found in the
study of patterns of electrical activity in the brain (Kittler, Baldwin,
1970; Ucles, Lorente, Rosa, 1996; Zamerkin, Liebenauer, Fitzgerald, King,
Minkunas, Herscovitch, Yamada, Cohen, 1993).  This is important evidence
which supports  a connection between ADHD and gluten intolerance, and which
may signal the action of exorphins in the CNS. Exorphins have been shown to
bind to CNS opiate receptors in rats.  
Perhaps the earliest work which showed improvement in ADHD subjects' EEG
patterns, in response to diet, was conducted by Kittler et  al.(1970 ).
While they recognize that EEG patterns have long been known to be abnormal
in some allergic children, they also believe that improvements of such EEG
abnormalities had not previously been connected to dietary changes in those
with learning problems.
The EEG abnormalities in food-induced autoimmunity such as celiac disease
also has a surprisingly long history in Europe, although I can find no
reports of such work published in English.  In a translation from German,
Paul et  al. (1985) tell us that Sidor & Mitarb and Karczewska & Mitarb
suspect this mechanism to be  the direct effect of the gluten upon the
central nervous system and hence on the brain wave curves, 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 children studied showed pathological EEG changes which increased
with increased duration of  gluten consumption, and that the long-term
compliance with a gluten-free diet decreased the probability of
pathological 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 psychological signs in celiac children
reflect a direct or indirect influence of gluten ingestion, and that damage
to the intestinal mucosa is always accompanied by pathological brain waves
in the celiac children studied.  Several interpretations for this are: 1.
People with damaged small intestines absorb more toxic substance, resulting
in the pathological changes, or; 2. Toxic,  gluten-derived proteins and
peptides may cause the pathological changes; 3. Both of the above dynamics
contribute to the pathological changes. 
Kozlowska (1991) has reported a very similar incidence of EEG abnormalities
in 71% of the celiac children studied. She has identified these
abnormalities as the same as those found in ADHD. 
The importance of the startling report from Uhlig et  al. (1997) is
difficult to over-emphasize.  It provides objective evidence for a
connection between food intolerance and ADHD.  This group has reported
their recent finding that topographic mapping patterns can be manipulated
by changes to the diet among ADHD subjects.  Refined sugar, milk, and
gluten proteins were most frequently implicated in the ADHD-specific
abnormalities identified in topographic EEG mapping.
Of course, there is always the semantic difficulty that if similarly
pathological  EEG  patterns are present in two conditions, then the
patterns are sometimes discredited as characteristic of one condition. For
instance, one report  indicates that some EEG patterns under specific
conditions may be characteristic of ADHD, but under other circumstances
could include some other categories of mental illness (Levy, Ward, 1995).
The converse argument, that there is overlap between these conditions,
also seems  supported by the same evidence.  But perhaps the work of Ulig
et  al. (1997) in demonstrating EEG changes associated with dietary factors
among ADHD subjects  will finally facilitate an end to such debates.
Published replications of this group’s findings may finally induce
pediatricians, teachers, and parents to engage in a careful search for
dietary pathogens prior to leaping for easy pharmacological answers.
Schmidt et  al. (1997) claim that a "biochemical rationale for the allergy
hypothesis is still lacking".  This may not be accurate. If we harken to
Paul et  al.(1985) again, they have asserted that in celiac children, 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 need 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 can enter the blood, then a condition
of permeable intestine may suffice. Animal and human studies demonstrate
that a variety of forms of gluten-induced damage can occur in the absence
of celiac disease (Hadjivassiliou, Gibson, Davis-Jones, Lobo, Stephenson,
Milford-Ward, 1996; Thibault, Coulon, Roberge, 1988; Levine, Briggs,
Harding, Nolte, 1966; Hudson, Purdham, Cornell, Rolles, 1976; Doherty,
Barry, 1981 ). This principle may also apply to a variety of mental
As mentioned earlier, Husby et  al.(1985) have demonstrated that many
apparently healthy adults are allowing the passage of gliadin proteins into
the blood. Antigliadin antibodies found  in the sera of 15% of a random
sample in Iceland (Arnasson, et al, 1992), and 4.75% of healthy blood
donors in the USA (Not, et al. 1996) suggest that many of us absorb partly
digested proteins  into our blood. Fukudome and Yoshikawa have
characterized 5 distinct opioid-acting sequences of amino acids in the
pepsin 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). Others have also isolated such
peptides in casein, one of the proteins in  milk (Mycroft, Wei, Bernardin,
Kasarda, 1982).  
Perhaps originating with Dohan et  al. (1966), and being continued by
Reichelt et  al. (1997) the investigation of dietary proteins in
gluten-containing cereals and milk, as regards a variety of mental
illnesses, 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 manifestations. Clinical trials have shown that
some schizophrenics benefit from the dietary exclusion of gluten and dairy
(Dohan, et al.,1969; Singh & Kay, 1976; Reichelt, Sagedal, Landmark,
Sangvic, Eggen, Helge, 1990a; Reichelt, Ekrem, Scott, 1990b ). Other work
shows that many  autists benefit from the same diet (Reichelt, Knivsberg,
Lind, Nodland, 1991). 
Lovenberg (1986) has  indicated that  diet could influence behaviour
through " the presence of psychoactive substances in food. Such compounds
may bypass neurotransmitter synthesis to directly activate 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 thought
to either be transported to the brain, and function in a manner similar to
opiates (Zioudrou, et al., 1979) resulting in reduced alertness of some
parts of the brain, or to inhibit the breakdown of other peptides, thus
resulting in elevated levels of endogenous opioid peptides within the brain
(Hole, Lingjearde, Morkrid, Boler, Diderichsen, Saelid, Ruddd, Reichelt,
In support of this hypothesis, it has been demonstrated that "children
diagnosed as having ADD of some severity excrete peptide-containing
complexes in the urine” (Hole, et al., 1988).  As was previously discussed,
there is considerable overlap between these groups, and there also seems to
be some relationship between the patterns 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 gliadin peptides (Atkins, 1986)
provides such a breach. 

Chapter 4
A Model for Exorphin-Induced  ADHD
Understanding ADHD from the perspective of the exorphin hypothesis may be
aided by a concrete representation. Whenever such models are proposed,
however, there are necessary distortions due, in part, to gaps in pertinent
data. Nonetheless, provision of such a model offers to enhance
understanding of the concept underlying this document, and is included
despite the inherent risk. 
Testing for anti-gliadin antibodies has rendered a range of positive
results. The lowest incidence reported  in a random population is  2.3%
(Catassi, Ratsch, Fabiani, Rossini, Bordicchia, Candela, Coppa, Giorgi,
1994), while the highest reported incidence is 15%  (Arnason, et al.,
1992). When coupled with the reported incidence range of ADHD, there is an
interesting, although not completely congruent picture, as the most common
figures suggest ADHD in  2% to 10% of school aged children (Rowe, 1988,
Boris & Mandel, Castellanos, 1997).  The comparison becomes striking when
we revisit the proportion of celiac children who demonstrate
ADHD-appearing, EEG patterns (Paul et al., (1985);  Kozlowska, (1991) which
suggest that about two-thirds of celiac children exhibit such
abnormalities. If we can assume that the 70% proportional incidence of ADHD
symptoms found in celiac disease could also occur in a population
demonstrating anti-gliadin antibodies, then the reported incidence of such
antibodies in random populations, 2.3% to 15% would suggest an incidence of
ADHD at 2% to 11%, which is surprisingly close to what has been reported.
It is such points of convergence that form the central thrust of this
thesis. Of itself, one such point may not be interesting. Several such
points of convergence must begin to pique our interest, and a significant
number of such points may demand consideration. Table 1 offers an outline
of twenty significant points of convergence which may be found between ADHD
and food intolerance disease. It also offers seven significant points of
convergence between elevated anti-gliadin antibodies and ADHD.
Table 4.1 Points of Convergence


The above table demonstrates that ADHD and celiac disease have much in
common. It also shows a number of conditions associated with gliadin
antibodies, despite the fact that these antibodies are non-specific and
have therefore not inspired much investigation outside the realm of celiac
The process involved in the exorphin hypothesis, as it relates to ADHD is
shown on the following pages. There are some cases, perhaps many, of ADHD
that probably do not derive from these dietary factors. Many such cases
would likely fall outside the genetic coding for the HLA factors most
suspect in the case of food intolerance disease and thus, food-induced
Only further research will plot the precise boundaries of food-induced
ADHD. That some cases of ADHD are caused or exacerbated by dietary factors
is undisputed. Some may believe that those numbers are very small, as is
suggested by the research conducted within a pharmacological paradigm. Work
cited earlier, which has moved to the periphery of that paradigm, has
demonstrated 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 directly investigating exorphins. As one may unwittingly
substitute one source of exorphins for another, trials involving single
substance and single food-group exclusion, are unlikely to identify at
least some of the cases of ADHD resulting from exorphins.    In the
interim, as we await more research which directly investigates the exorphin
hypothesis,  it seems useful to offer the following outline of the
postulated process of the action of exorphins  in ADHD:
Stage One
Figure 1      HLA-B8 distribution in Europe (Ammerman & Cavalli-Sforza,
1984)  in relation to the starting point of cereal grain cultivation (Lutz,



Figure 4.1   HLA-B8  Distribution in Europe					


This is the first element of the model. While the HLA-B8 group does not
include all of those who have celiac disease, it is a genetic marker which
is highly associated with gluten intolerance. As such, the European
distribution of this genetically 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 of exposure 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
B8, population displacement is also a probable contributor.  

Stage Two
Only a small fraction of the 10% to 30% of Europeans who have HLA-B8 would
have celiac disease, so that is probably not the cause of this genetic
trimming. The increased intestinal permeability associated with the genetic
group demonstrating HLA-B8, in conjunction with gluten consumption, is
probably at the root of some alterations to the intestinal wall which do
not include villous atrophy. With increased permeability, the intestinal
wall allows absorption of undigested and partly digested proteins and
peptides into the blood. 

Stage Three
There is a lot of evidence suggesting that these peptides can also lead to
psychiatric disturbances.   Some of the peptides in question are well
established as exogenous opioids, or exorphins, which have a function
similar to morphine and may thus be expected to cause altered behaviour,
just as we would expect such alterations in those who are under the
influence of morphine most of the time.
The exorphins may effect the brain by causing inappropriate conservation of
endogenous opioids, since increases in opioids can inhibit opioid
breakdown. exorphins may thus impact upon behaviour without breeching the
BBB (Reichelt et al, 1988). 
It may therefore be postulated that the morphine-like properties of
exorphins, or inappropriately conserved  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 between food
intolerance and ADHD.  As vasoactive peptides, they may play a role in
reduced blood supply to parts of the brain. They may anaesthetize parts of
the cortex involved in speech production and/or language learning and/or
mathematical learning. And  they may interfere with some executive
functions through reducing activation and perfusion of those parts of the
Our limited grasp of neurotransmitters makes it difficult to imagine
exactly how changes from attachment of endorphins and other endogenous
peptides, to competition with these latter,  and attachment of exorphins
may explain the behavioural and attitudinal changes 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 model in such a simplistic, three stage form may suggest a
superficiality which is inappropriate. The process outlined is a highly
complex one, and the finite representation herein may incorporate some
errors, and lead to misunderstanding. This should  impugn the author, not
the hypothesis.
The web on the following page offers yet another visual perspective which
may 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 celiac disease. Figure 4.2  is thus offered as an
imperfect representation of these associations of symptoms and signs of
celiac disease and ADHD. 


  Our next step will be to discuss both the limitations and future
directions suggested by the application of the exorphin hypothesis to ADHD.
Chapter Five
Applications,  Recommendations, Limitations, and Implications 
That exorphins function similarly to morphine, and can be derived from
dairy and grain products is well established. That the removal of these
substances from the diets of patients with some forms of mental illness has
produced significant improvements is also reported. That food intolerance
disease often leads to similar mental disturbances is also reported. There
are many points of convergence between reported features of ADHD and
similarly recognized aspects of food intolerance disease.  There are also
points of convergence between ADHD and the mental illnesses implicated in
food intolerances. Finally, there is a rich literature which variously
connects dietary interventions with improvements in small minorities 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
compelling body of evidence suggesting that exorphins may be at the root of
much of this widespread mental illness which afflicts from 2 % to 10% of
school children, and has life-long implications for their futures. 
If one accepts the notion that ADHD may often be the result of opioid
peptides derived from gluten, dairy, and perhaps, other dietary proteins
passing through a permeable intestinal wall into the circulation and then
directly or indirectly impacting on the brain,  hence influencing
behaviour, then it is important to understand what may be done to help
alleviate this problem.
   There is some suggestion of a detoxification dynamic at work in some
successful dietary interventions in ADHD. "In several children the initial
improvement produced by the diet was preceded by a deterioration in
behaviour" (Egger, Carger, Graham, Gumley, Soothill, 1985). Such initial
deterioration might represent withdrawal from dietary exorphins, and it is
important to anticipate such a response. Withdrawal from an addictive
substance with analgesic function might erroneously  be characterized as a
negative response to a short-term dietary intervention and should 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 reconstruction of the intestinal mucosa. The long
period of gluten challenge, of up to two years, required in some cases of
celiac disease (Chartrand, Seidman, 1996) may well be the result of a
healed mucosa  functioning in a protective fashion, preventing harmful
proteins, peptides, and toxins from entering the blood. The expectation of
a rapid response to dietary intervention, although it sometimes happens in
ADHD and celiac disease, is  misplaced. There is also the learning phase,
in such interventions, which many food intolerance patients can attest to.
In the early stages of compliance with such a diet there are many painful
“learning experiences” resulting from mistakes. 
Applications to Education
The postulated process involved in the causation of ADHD, however
interesting,  may be less important to parents and teachers than the result
of the dietary exclusions it suggests. The most valuable test of such ideas
must take place in real people who suffer from the debilitating effects of
this condition. Fortunately, the dietary exclusion of gluten and dairy is
perfectly safe. Additionally, the exclusion of these foods may lead to more
than  improvements in psychological health.  For many, it may also lead to
a vastly  improved quality of life through increased vigor. 
Trials of fad diets, however, may not be the answer. All too often,
compliance is difficult, and may wane over time, if there are only
subjective, arguable results reported. This problem can be addressed by
several means.  Assuming that thyroiditis and hypoglycemia have been ruled
out, serum testing for gliadin antibodies is an inexpensive, non-invasive
test. For less than the cost of a month’s supply of stimulant medication,
such testing would clearly identify intestinal permeability, suggesting
both the need for dietary intervention, and the specific nature of one of
the appropriate exclusions.
Serum antibody testing for celiac disease, in the form of IgA
anti-endomysium as well as IgG and IgA antigliadin antibodies ( see
appendices four and six, regarding serological testing), in combination
with testing for IgA deficiency, although more expensive than the first
option suggested, offers a valuable tool both for excluding celiac disease,
and for identifying  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
associated autoimmune diseases which should lead to further testing to
definitely rule it out. The presence of  IgG antibodies, if there is no IgA
deficiency, suggest a permeable intestine. As has previously been
discussed, such intestinal permeability 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 hand, they are speaking to us in the only
language they have, about an illness which they do not understand. It is up
to us to come to understand it.  
Teacher preparation programs should include discussion and opportunities
for contemplation of some of the ethical issues associated with teacher
participation in evaluations of students toward ADHD diagnoses. These
programs should also provide instruction related to the diagnostic and
treatment processes  currently employed with cases of suspected ADHD.
Entering employment as knowledgeable teachers, they will thus have a choice
about whether to participate in the process in a knowledgeable manner, or
to exclude themselves on the basis of their own ethical determinations on
the topic. 
As knowledgeable participants in the process, they will be in a position to
ask if  testing for thyroiditis and hypoglycemia has been conducted. Such
prior testing 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 initiating an evaluation process which is aimed at possible stimulant or
other chemical therapies.
Recommendations for Future Research  
While several options are available,  I will tentatively outline one
construct which would provide the opportunity to confirm or deny the
application of the exorphin hypothesis to ADHD. Of course, part of my
personal journey toward the implementation of a test of this hypothesis
would be to learn more about the design of such investigations. In the
interim, the following outline suggests,  in broad strokes, a process that
might produce a meaningful, objective test of the application  of the
exorphin hypothesis to ADHD:
The Investigators
Such an undertaking would necessitate a group of professionals 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 psychologist who has expertise
in the area of  ADHD, a dietician knowledgeable in the realm of gluten-free
and dairy-free diets, and a teacher who is well versed in these diets, and
able to communicate on related issues with parents and children. Other
personnel would be necessary to draw, centrifuge, and ship serum to a
laboratory for testing, and to conduct administrative tasks. Other 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
diagnosed with  ADHD by an appropriate health care professional. Both child
and parents would need to be willing  participants, and willing to express
a commitment to comply with a strict diet. The cooperation of  parents and
teachers would also be required, for completion of appropriate assessment
instruments, and discussions with the psychologist.   School records would
likely be helpful, and would also be requested.
 Those volunteers with Reye’s syndrome, a history of a  hypoxic anoxic
event, heavy metal toxicity, significant head trauma, or central nervous
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 repeatedly
been reported in the context of occult celiac disease, and would therefore
not be an appropriate element of  the differential diagnosis for the
purpose of the proposed investigation. 
Establishment of a Baseline
Each student would need a baseline assessment, which would include testing
for hypoglycemia and thyroiditis, as recommended by Block (1997), as well
as IgG and IgA gliadin antibodies. Abnormalities in glucose tolerance or
thyroid function would result in the exclusion of such subjects with
recommendation that they seek medical follow-up. The results of antibody
testing would be withheld until the end of the investigation.  
Current use of stimulant or other medications would be noted, and any
dietary or other treatments currently employed would require investigation,
and possible exclusion of the subject, where appropriate. Current practices
of dietary supplementation such as the use of multivitamins would also
require attention, especially regarding  the nature of binders used. It
might also be useful to standardize supplements for all participants during
the course of the study. A uniform starting date for the trial would be
useful, especially if it could be coordinated with school reporting
periods,  and end prior to, or begin after occasions where there is greater
temptation to “break” the diet, such as during the Christmas holiday. 
 Extensive instruction, regarding the diet and its many pitfalls, would  be
necessary, and should be conducted by the teacher and a qualified
Terminal assessments
At the end of the 60 days of compliance with a gluten-free, dairy-free
diet, another 10 ml of blood would be drawn for IgG and IgA serum antibody
testing. Reports from parents and teachers would also be gathered, to see
what, if any, improvements had been observed in the children.  I would
anticipate that the baseline antibody test results  would vary in three
general ways, and the terminal tests would vary in four ways.
Baseline tests:
1. Some of the subjects would demonstrate no abnormal presence of gliadin
2. Some subjects would demonstrate elevated IgG antibodies
3. Some subjects would demonstrate elevated IgA antibodies, along with
elevated IgG antibodies.
Terminal tests:
1. Those with no abnormal antibody levels at baseline would likely show
similar terminal test results, although some members of this group may show
improvements in their ADHD symptoms.
2. Many of those with elevated IgG antibodies, at this stage, might show
some reduction of  antibody levels, although IgG levels are very slow to
respond to exclusion of gluten from the diet.  A significant number  would
likely present  with a positive response to the diet, as gliadin and/or
dairy proteins would offer an explanation for many cases of  increased
intestinal permeability in this group.
3. Those with reductions in their levels of IgA gliadin antibodies would
likely represent the group who showed the greatest number of subjects with
the most improvement of their ADHD symptoms as a result of  the diet. 
4. Those who showed terminal elevations of IgA gliadin antibodies might
reasonably be suspected of dietary indiscretions (perhaps unintentional)
during the 60 day diet period, although some of these might show
improvement in their ADHD symptoms, as a result of reductions in  gluten
and dairy proteins in their diets.
Selection bias:
It is important to recognize that the test group for such a trial would not
be representative of  the ADHD population. A number of selection biases
would, of necessity, shape this group. Such a trial would attract both
parents and children who are quite motivated, as the diet requires quite an
adjustment. Once one is accustomed to the diet, it is relatively easy, but
the initial adaptation is difficult  because it is a challenge to be
constantly  wary of hidden sources of both types of proteins which are rife
in processed foods. 
Such an investigation would likely be attractive, primarily, to parents and
children where the symptoms 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 economic, social, and time-use challenges of a gluten-free, dairy -free
diet would also be likely to be over-represented in this group. Such an
initial foray into this research would probably not be inviting to a
representative sample of ADHD subjects, and the results, regardless of how
positive, could only be taken as a herald for further research in this
area. Still, such a clinical trial could offer great insight into the murky
world of ADHD. 
Other Research possibilities
As was mentioned earlier, there are many other possible avenues to
investigate this question. Naloxone has been demonstrated to block
exorphins. It blocks 70% of psychoactive peptides derived from gluten, and
100% of those from dairy products. This offers an exciting research
opportunity.  If this or a similar opioid-blocking drug can be demonstrated
to be safe for such usage, and it induces  improvements in symptoms of a
significant number of ADHD subjects, the central notion of this thesis will
be supported. Such results can provide  a much clearer picture of both the
etiology of many cases of ADHD, as well as offering reasonable treatments
for this condition, which will not engender the risk  inherent in stimulant
and other chemical therapies. 
Following Naloxone screening, and antibody testing, clinical trials of
gluten-free/dairy-free 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 incarcerated might well benefit from such dietary
restrictions, and their periods of incarceration might provide a very
important service to society and to these youngsters. 
Epidemiological work, perhaps in the form of anitbody testing in large
groups of ADHD children, would also be revealing. Perhaps this is the tool
that may identify many of those ADHD patients who will benefit from dietary
 Further refinement of urinary peptide filtration and characterization may
also provide a diagnostic tool for some sub-types of  ADHD, as well as
providing a clear indication of who may benefit from dietary interventions.
Investigations of the application of the exorphin hypothesis to ADHD might
also be conducted in a variety of manners and methods which the author has
not considered.

Limitations of the Model
Far too little is known about several stages of the process postulated
here; the application of the exorphin hypothesis to ADHD. It is a
theoretical construct which requires a great deal of further research. Not
all published reports on the topic of ADHD were investigated. It was just
too large a task. The process of  selecting the literature that would be
examined was conducted by a person with a bias..... the author. 
A further limitation lies in the difficulty in implementing such dietary
interventions. Gluten and dairy proteins pervade the food supply in
industrialized nations, and often do so in occult forms.
It is also a challenge to investigate or implement such dietary
interventions in the context of an under-informed medical community.
Nutritional issues are given little or no attention in most of our medical
training programs, and dietary issues are often dismissed as a result of
such deprecation by some adherents to conventional medical wisdom.  
Despite these limitations, the impressive body of evidence which suggests
and supports this perspective imparts an urgency to the call for further
research in this venue.  
Implications of Ignoring the Model
This section presupposes that clinical trials will support this model for
understanding ADHD. The need to investigate this possibility with
appropriate clinical trials has some very serious implications for ADHD
patients, their families, and their communities.  Increased mortality among
ADHD patients has been reported (Boyle, Decoufle, Holmgreen, 1994), but
this may reveal only the tip of the iceberg, as the maximum age included in
this report was 19 years old at the time of death. If exorphins are the
underlying pathogen in many or most cases of ADHD, then risks of
malignancies (Hoggan, 1997b) and the host of neurologic and other
debilitating sequelae associated with celiac disease (Holmes, 1996) and
elevated gliadin antibodies associated with a great variety of neurological
disease (Hadjivassiliou et al., 1996, 1997)  may include adults who have
previously or who currently  suffer from ADHD.  It is not just a case of
these dietary  pathogens having a stratifying socio-economic impact. In
addition to social losses in productivity, increased costs of medical care
and education, there is the spectre of substance abuse, and the social
costs of treating  all these ailments.  This group who suffers from ADHD
may, through the search for answers to their ills,  light the path to
improved mental and physical health for every industrialized 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.

Exploration of the exorphin hypothesis, as applied to ADHD, offers a safe,
non-invasive, non-chemical approach to this pervasive problem. What remains
to be done to investigate this application of the exorphin hypothesis is
carefully constructed clinical trials.  It may offer an  improved
life-expectancy, quality of life, and understanding, which may accrue to
ADHD subjects, their teachers,  families, pediatricians,  and their
cultures. It is a window of opportunity for all participants. Failure to
explore this hypothesis may result in continued social, familial, and
individual costs of this condition, and the associated illnesses mentioned
We are not just discussing 2% to 10% of the school children who have
difficulty settling to their work, or focussing their attention. We are
talking about a large segment of the population, perhaps as much as 30%,
which is increasingly inundated with gluten and dairy proteins in almost
all or our processed food. Their immune systems are compromised. They are
more likely to suffer from malignancy, autoimmunity, neuroses, or
psychoses, or perhaps all of these. 
Teachers can participate in fostering social wellness, or continue to aid
in the process that masks symptoms of treatable ailments so the illnesses
will continue to go untreated and, in some cases, result in deadly and
debilitating sequelae.  




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Appendix One:
Kate and Frank  Vincent							
15 May 1997
55 Riverview  Street
Murwillumbah 2484

Dear Ron,

	A moment's peace ! Lewen is at school! Thank you for your letter, I
will 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 expressing some of
these last five years with Lewen will be a relief of sorts - I know you
will understand the deep meaning of that.   
	We have all been emotionally and physically drained as well as
socially deprived . Funny really, all I had to do was skip the bread isle
of  the supermarket!  But no bread and jam or toast or cake with my tea is
just not cricket - I mean I'm English for Christ's sake!   Change is always
confronting but the benefits speak for themselves.   Thank you once again
for your interest in Lewen.
PRE-LEWEN:	Two children, Sarah 10, Nicholas 9.   Civilized, balanced,
socially active.  OK.  So we sat  around our table and discussed having
another addition to the family…everyone in favor, we'd share
everything…waited. nine months passes…a very anxious expectant family.

LEWEN:   Born 18/12/91, three weeks late, dry birth due to ruptured
membrane four days earlier.  Consequence - Lewen is born with HIB
meningitis.  Life-threatening situation, antibiotics, oxygen, humidicrib.
First feed eight hours later is disastrous as is every other feed for next
nine months.   Child would suckle one mouthful, arch his little back into a
ball, then pull away; then try to suckle again; hated feeding generally.
It looked like feeding was somehow very painful for him. Help from
chemists, doctors, specialists, clinics, etc. led us to try everything on
the market  At six weeks, paediatrician's synopsis, "most extraordinary!",
can offer no advice.  Constantly on the move, loud, a restless sleeper
waking every couple of hours till age three and burning rubber the moment
his feet touch the floor.  
	At eleven months an evening meal  abandoned as we rush screaming
child to hospital, suspecting food poisoning; turns out to be a stool which
had blistered his bottom in a cup-sized ring, quickly relieved with paw paw
ointment.   Walking by nine months, he managed to climb to top shelf and
drink bleach at age one.  Trees around house cut down to keep him off the
roof, (two storey at front), safety harness attached to 20 metre lead, a
bell attached to his clothes, neighbours on the lookout, Lewen's first
first year of life was intense, ours desperate.
	On the positive side, Lewie has a fantastic memory; even though he
doesn't  seem to dwell on anything and it is surprising the detail he can
communicate when it suits him.   He is very dexterous and loves building
things.   Kathe, our good neighbour, said he seemed to be driven, as though
trying to take his mind off whatever is upsetting him.  He was like a
butterfly on speed!   More in-depth medical merry-go-round and allergy
testing with no more help.  He was totally over the top, could not still or
concentrate for more than a minute on anything, showed little affection
even though there were four of us craving it; we were beginning to suspect
autism.   One paediatrician's advice at eighteen months, "This is a
behavioural problem, perhaps we should consider foster care!"
	New GP in town (20 others), who listens, observes, understands.
Places Lewen on Serfontain Clinic waiting list for assessment.  At age two,
Lewen is diagnosed as chronically hyperactive (ADHD).   Gov't. regulations
are four years minimum before he can be given medication for the condition!
With a stack of documentation supporting Lewen's condition, we appeal to
the Health Dept. and wait.  He began medication (dexamphetamine) at three
years of age.   Yesssssssssssss!  

LEWEN MEDICATED:   What an immediate change!   He could actually watch a
five minute TV program and turned the pages of a book as though
re-discovering them instead of speed reading.   A much happier kid, more
affectionate, and although there was an initial weight loss, he regained it
and actually put on weight.   He was still a tornado but at least his
concentration improved immensely.   It was great but no panacea.
	Christmas 1995 we miss script renewal by four days, we spend five
days over Christmas with Lewen unmedicated.   Disaster!  Day five, mother
hospitalised for ten days with nervous exhaustion.   Camping holiday
postponed, teenagers 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 him prior to him going; we
weren't sure if we had a bored genius or struggling child!   If there was a
problem, they would let us know.  (Medication was given at 6am, 8:55am, 3
pm.)    It is now May and Lewie is doing well at school and loving it.
Wants to learn, becoming more social, the class clown and popular.
GLUTEN-FREE:  Kathe once more to the rescue with wads of info on ADHD and
its link with gluten tests.   In the meantime we decided to go ahead
anyway, particularly as there appeared to be suspect family 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.
He began to laugh a lot more, appetite improved, overt affection to all
family members.   Were we just imagining it?   We decided to withhold
medication to see what would happen.  Nothing!   No outrageous behaviour,
just a really pleasant kid albeit still a live wire.   Rather than let him
feel different, it was one in all in; a gluten-free family.
	Six weeks have passed with interesting results.   Relenting after
constant harassment from Nick we smuggle him in some bread buns and hide
them in the freezer.   Somewhere along the way, Lewie discovered them and
we immediately noticed a change in his behaviour.   Three-year-old Brent
asked, "Is Lewie medicated, Mum?"   Serves us right, but it did demonstrate
to especially Nick, now fourteen, the importance of staying gluten-free and
that in all probability, he was also affected.
	We were lucky enough to see the dramatic results on a five year
whose system is more sensitive to change.   We know we are all going to
benefit because we have witnessed it in Lewen.   It is now six since we
first 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 at least
try it.   It really does work.  Shame about all those foods denied but a
new adventure shopping and surprisingly better value for money and
healthier.  Kate considers herself a fantastic cook, but to be suddenly
told that she couldn't use the BROW (barley, rye, oats, wheat) products to
cook with, she was devastated!  Six weeks later however, she can now make
absolutely anything she made before - but now all gluten-free!  She finds
being gluten-free no problem at all!
	Cheers, Ron - and thanks!

							Kate and Frank

Appendix Two:

At 08:15 AM 1/17/98 +0000, you wrote:

Sender:  Celiac/Coeliac Wheat/Gluten-Free List
Poster:  Carol Leather <carol@X-CALIBRE.DEMON.CO.UK>
Subject: Overweight and temper tantrums summary

Hi everyone,

Sorry I've taken a while to summarise all the replies to my last posting
regarding my son's behaviour problems but I've been feeling pretty 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
although I have it. Many of you wrote with similar experiences and
advised me to get him checked out. I took him to the doctor's yesterday
and she has agreed it may be a possibility (but coeliacs only get
diarrhoea, was her first comment!) and will now organise blood tests.

Some stories 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 there's
been substantial heling from lack of gluten intake." Thanks Chris for
your reassurance that I was not the only overweight coeliac.

My thanks also to DÄLynne your story sounded so much like ours. Ben has
had similar violent outbursts at school and once picked up a chair and
threatened the teacher with it!

jill mentioned that her child also seemed ever hungry but did not gain
weight as did Kathy in her reply.

If I mention everyone who responded this post will be too long to read,
so can I say thanks to you all.

I'll be away from the computer next week when i go in for my gallstone
operation but will eagerly await the time when I can catch up on all
your posts. Speak to you soon.

Carol Leather
An English Coeliac

Appendix Three:
A speech I gave at the 1997 Annual General Meeting of the Calgary Chapter
of the Canadian Celiac Association: 

             Gluten is a Dubious Luxury of Non-Celiacs


                       Ron Hoggan

(Note: In this paper I use the term "gluten"  generically, as we celiacs
use it, to refer to all 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 compelling 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 is but a brief moment in
evolutionary terms. Remember too, it is only a small population located in
the Near East, that has 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 (5), 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 articular damage(3).
Additionally, ancient Egyptians, who consumed a diet 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 few elements of
modern implications of this issue.

W.J.Lutz (4) has offered an alternative perspective on the "French
Paradox." (The "French Paradox" 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 similarly compelling data on the rates of breast cancer

A study done in China produced what the investigators 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 reliable predictors of
cardiovascular disease. They were very surprised to find that wheat
consumption, and perhaps, reduced fish consumption, were the strongest
predictors of levels of SHBG which would indicate 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

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(10). 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 molecular 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 all 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

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 is
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.
I 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 I have written which suggests (among other
things) that gluten may be implicated in a great many cases of
lymphoma(14). Gluten has been demonstrated to interfere with the celiac
patient's ability to mount an immune response to malignancies(15,16,17). In
my paper, I have postulated a dynamic whereby gluten may have a similar
effect in others who are simply sensitive to gluten.

We hear all the time about pollution in the industrial world being the
source for modern man's high incidence of cancer. It is the chemical
additives, we are told, in the food we eat, that causes much of the
problem. Dietary fats have also come under attack. I would like to suggest
that the evidence from antiquity, 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, all point to the strong
possibility that gluten is a dangerous substance to many more people than
just celiacs.


1. Eaton B, Konner M, Shostak M, " Stone Agers in the Fast Lane: Chronic
Degenerative Diseases in Evolutionary Perspective" _The American Journal of
Medicine_ 1988; 84:739-749

2. Eaton S, Konner M, "Paleolithic Nutrition" _NEJM_ 1985; 312(5): 283-289

3. Eaton S, Nelson D, "Calcium in evolutionary perspective" _Am. J.
Clin.Nutr._1991; 54: 281S - 287S

4. Lutz W J, "The Colonisation of Europe and Our Western Diseases" _Medical
Hypotheses_ 1995; 45: 115-120

5. Lindeberg S, et al. "Cardiovascular risk factors in a Melanesian
population apparently free from stroke and ischaemic heart disease: the
Kitava study" _J Intern Med_ 1994 Sep.

6. Lewin R, "A Revolution of Ideas in Agricultural Origins"  _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 globulin 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 Celiac
HLA"_Gastroenterology_ 1996; 111: 318-324

11. Ostenstad B, Dybwad A, Lea T, Forre O, Vinje O, Sioud M, "Evidence for
monoclonal expansion of synovial T cells bearing  V Alpha 2.1/V beta 5.5
gene segments and recognizing a syntehtic peptide that shares homology with
a number of putative autoantigens"

12. Lindeberg, Staffan, personal correspondence Feb, 1997

14. Hoggan R, "Considering Wheat, Rye, and Barley Proteins as Aids to
Carcinogens" _Medical Hypotheses_ In Press 1997.

15. Maclaurin 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 Lymphoma"  _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: 
Predictive Value of Serology Testing in Celiac Disease 
Presented by Dr. Vijay Kumar at Mt. Sinai Medical Centre,
 Nov. 9, 1996
 American Celiac Society/Dietary Support Coalition 
Mystery Golden Key Conference
condensed by 
Ron Hoggan

Dr. Kumar has been working on serological testing for celiac disease over
the last 15 years, and was presenting after having been up all night trying
to catch a flight from Buffalo after a severe snow storm. We were all
pleased by his dedication, as his presentation was both informative and
compelling. He began by asking some fundamental questions, which challenged
several common beliefs about the diagnosis of celiac disease, beginning
with: "Can we effectively diagnose celiac disease by its clinical
presentations?" The answer came in the data he cited from Campbell &
Davidson in their survey of 1300+ celiac patients. The first item indicated
that celiac disease may present with a broad variety of symptoms, and are
easy for clinicians to miss. The second item indicated that the majority
had visited 5 or more doctors prior to diagnosis. The third item indicated
that it had taken an average of 5 to 10 years, after initial presentation,
for celiac disease to be diagnosed. Clearly, the answer to Dr. Kumar's
question was that celiac disease can not be diagnosed by its clinical
presentations. What would be the value of histological, or any other
evidence, if it could be diagnosed on the basis of clinical presentation
alone? He mentioned the considerable risk of misdiagnosis as well. While
clinical presentation may help in identifying the possibility of celiac
disease, it can not, reasonably, be the sole criteria for an accurate
diagnosis. "Why do we need an early diagnosis of celiac disease?" was his
next question. The answer was twofold. First, young children may not grow
and develop properly if they have unidentified celiac disease. Normal
development, for many of these children, requires that they be on a
gluten-free diet, thus recieving adequate nutrition. Second, untreated
celiac disease is associated with a very high risk of lymphoma, and the
gluten free diet plays a protective role against lymphoma. It reduces the
risk to almost the same as the general population, after 5 years on a
strict diet  He cautioned that less than 5 years may not yeild
statistically significant reductions in risk. Similar risk factors for
malignancy are at work in dermatitis herpetiformis. Histopathology gained
acceptance in the mid-sixties, to aid in the diagnosis of celiac disease,
because of the problems with diagnosis on the basis of clinical
presentation. This is where a biopsy is taken from the small intestine, and
the morphology is examined to determine the status of villi in the patient.
Slides were shown, first demonstrating normal morphology of healthy villi,
then demonstrating total villous atrophy, along with crypt hyperplasia, and
increased density of intraepithelial lymphocytes. These were the criteria
proposed in the mid-sixties, but such morphology alone is not diagnostic of
celiac disease. Many other diseases like parasitic infections, immune
deficiency disorders, and nutritional deficiency disorders, all look quite
similar. At that time, ESPGAN (European Society of Gastroenterology and
Nutrition) proposed a strict set of diagnostic criteria for celiac disease.
First, characteristic flat or damaged villi were to be demonstrated.
Second, after a gluten-free diet for an extended period of time, when the
patient was feeling normal, a second biopsy should be taken, showing villi
of normal appearance. Finally, a gluten-containing diet would be
re-instituted, and if after a period of about 6 months, if villous atrophy
was demonstrated at biopsy, then the diagnosis of celiac disease was
confirmed. In many of the patients he has seen, there are poblems getting
them to eat enough gluten to confirm the diagnosis for the third biopsy.
Then there is the limitation that initially, patients need to be identified
as needing the biopsy. Yet another limitation of this approach is that when
a biopsy is taken, it is removed from a small, localized area. It may miss
a region of typical celiac intestinal lesion and take the sample from a
region showing very mild symptoms which are difficult to identify. These
histological criteria are on a continuum, showing flat villi at one end,
and normal villi at the other. Yet another limitation arises in the three
recent reports which identify celiac disease in patients with normal
histopathology. Pathologists apparently read them as normal biopsies. He
cited papers from 1982, 1993 and 1996. Dr. Kumar used the iceburg metaphor
to describe the current status of recognition of celiac disease, where the
vast majority of celiac disease remains undiagnosed. We are seeing only
typical celiac disease. This is where weight loss, diarrhea, short stature,
very typical manifestations, lead to the biopsy, where the histology
reveals characteristic damaged villi. What remains under the surface is two
large groups: 1) silent celiac disease where the the patient presents with
mild, atypical manifestations like low levels of iron and low haemoglobin
levels. Some patients only present with aphthous ulcerations in their
mouths but if they are tested, many of them demonstrate characteristic
histopathology; 2) Then you have situations where patients who really have
celiac disease, but if you test them, they show normal histopathology. What
can be done, then? When it was first identified, in the 1960's that the
gliadin proteins in wheat were the toxic entities 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 reporting results may not be as good as
another lab reporting results. Dr. Kumar reported on his own lab results in
anti-gliadin antibody tests. He indicated that 5% to 10% of those
demonstrating IgG anti-gliadin antibodies do not have celiac disease.
Rarely, on the other hand, are IgA anti-gliadin antibodies demonstrated in
non-celiacs. These antibodies are detected by very simple methods. The
consensus in the field is that IgG antibodies are more sensitive, but not
specific, and IgA antibodies are more specific but less sensitive. The next
antibody identified in the literature was the antireticulin antibody. We
don't really know what protein antigen this antibody is developed in
response to. The name is a serological term, but it reacts to substances
called reticulin which is in the tissues surrounding the tubules in the
kidney. There are five types of reticulin antibodies. 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, their antibody levels will eventually disappear and become negative.
The third type of antibody, reported in 1984, was the endomysial antibody.
It is named in reference to the endomysium which is the lining of the
muscle fibers. These, and the antireticulin antibodies are primarily of IgA
class. In situations where patients are IgA deficient, they will make IgG
antibodies. Patients with celiac disease demonstrate this antibody with
virtually 100% frequency. On a gluten-free diet, these antibody levels
become normal, or negative. They are a very sensitive, very specific marker
of celiac disease. It takes varying periods for these levels to become
normal. They reappear very quickly on a gluten challenge. He then reported
on 133 celiac patients, 132 of whom showed IgA antiendomysium antibodies
when eating gluten. The one who did not was IgA deficient, and was positive
for IgG endomysial antibody. IgA is the more sensitive marker. All of the
133 patients eventually demonstrated negative levels of antiendomysial
antibodies. When rechallenged with gluten 130 once again became positive
for antiendomysial antibodies. Other studies indicate that if the other 3
were challenged with a high gluten-containing diet, they would have
demonstrated antibodies too. Another group of 31 showed abnormal biopsies,
but endomysial antibodies were not demonstrated. On a gluten-free diet, the
the villous morphology returned to normal, but could not be induced again
on gluten challenge. Neither were antiendomysial antibodies detected. It
appears that these were not cases of celiac disease. A single biopsy can be
misleading without additional evidence. Yet another group of patients in
Italy, reported in 1996, demonstrated symptoms suggestive of celiac
disease. They tested positive for antiendomysial antibodies, but did not
display abnormalities in villous morphology. The question is, are these
patients celiac or not? They demonstrated typical symptoms, which resolved
on the gluten-free diet, and the endomysium antibodies also disappeared on
the diet  Upon gluten challenge, these symptoms returned, and the high
antibody levels returned also. The clinical manifestations, including
diarrhea, steathorrea, and abdominal cramping, are convincing evidence that
these are cases of celiac disease in the early stages of immune response
which, with time, will develop typical histology of celiac disease.
Follow-up studies have demonstrated just this. There are certain HLA
markers which are associated with celiac disease. Nine of ten celiac
patients in another study did not have these markers. That means that the
genetic markers we currently associate with celiac disease are also
problematic. Lymphocyte density was also within the normal range. This
indicates that these individuals 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. If allowed to continue, Dr. Kumar was confident that the
typical histopathology of celiac disease would eventually be demonstrated.
He went on to show a study reported in _Acta Paediatrica_ where patients
who demonstrated antiendomysial antibodies and normal mucosa, were
re-biopsied three years later, and demonstrated villous atrophy. Quantity
of gluten intake seems to be the primary variable, and where increased
intake occurs villous atrophy follows. Examples reported as recently as
1994 indicate that diagnosis may still be slow among elderly patients, even
where there is a threat to life. This demonstrates that diagnosis of celiac
disease continues to be a very slow process in many cases. A simple
serological test could help immensely. Among family members of those with
celiac disease, symptomatic or asymptomatic celiac disease is present in
10% to 15% of first degree relatives. This is cd associated with short
stature, autoimmune disorders and cardiac abnormalities. A simple
serological test should be considered for family members. Dr. Kumar
presented a compelling case for the value of serological screening for
celiac disease. He indicated that the biopsy remains the gold standard for
diagnosis, but I walked away from his presentation convinced that the
serological 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 risk, be more
reliable than the biopsy, and it is less invasive. 

Appendix Five

Date: Sun, 26 Apr 1998 16:16:53 Ä0400 (EDT)
To: Ron Hoggan <>
From: George & Gayle Kennedy <>
Subject: ThesisÄ appendix?


You asked for it, so, as you have deadlines for your thesis, I'll take half
an hour (How about an hour and a half!!!) and tell you a little bit about
Clint, our older son, and the saga of his gluten sensitivity and the small
part that ritalin plays in the story.

It all begins before he was born.  As our first child, I didn't know what
normal/abnormal in utero babies were like, so I assumed all the activity in
my abdomen was normal.  People thought I was exaggerating and making a fuss
when I would jump and bend over backwards sometimes when he would kick and
stretch before he was born.  I had no choice Ä he needed more room and was
hyperÄactive even then, and was very strong.  With a second pregnancy,
second son, I found how easy it is to carry a normal child. No extra
bending backwards, no jumping around because I was so severely kicked.

After he was born, Clint was a difficult baby.  At five days he came home
from the hospital, fully able to support his own weight on his legs Ä to
stand Ä as long as I kept him from falling over.  Our best friend and
neighbor was a doctor whose son was born three days later.  He simply could
not believe that Clint could stand at that age.  But when the doctor held
him, he found that it really was true.

He was always hungry, and never satisfied, and cried constantly.  George
and I walked the floor for hours, holding and patting and soothing and
trying to be good parents.  There were no pediatricians anywhere around,
and as he appeared to be a 7 1/2 pound healthy baby, we thought WE must be
doing something wrong.  He was not nursed, and for years I felt guilty
about that, but now that I know that he and I are both sensitive to gluten,
I know that even if he had been nursed he would have been fussy.  The OB
had suggested putting him on food early, as he seemed fussy, so we started
with rice cereal, then added probably oatmeal, (my memory is hazy on this
sequence) and eventually pabulum, which, I believe, contains wheat.  No
particular additional problem with rice cereal, but no solution either.
Some time after introducing pabulum he had a time with severe diarrhea.  I
think he had had that problem earlier, but I did not realize that it was
abnormal.  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 cereal for a
month or so Ä so I did just that, and the thrush went away. I believe we
also eliminated formula (cow's milk based) for a few days.  Then I put him
back on regular baby pabulum, etc.  The thrush did not return.  I do not
recall any virulent diarrhea from that time on, but it has been 44 years,
and it's hard to reconstruct.

At three months he learned to suck his thumb Ä pacifiers did not work with
him Ä and he finally was quiet   George and I were so glad he wasn't crying
we didn't care about the thumb.  All along, he gained weight and looked

  He never crawled, but slid around on his stomach like a salamander, and
got where he wanted to go.  He sat at the usual age. I know now that
crawling is good for motor development, but I didn't know it then. At 14
months he walked, and started talking.  By the age of 18 months he had an
astonishingly large vocabulary Ä well over 250 words.  I lost count after
that, but he has always been eager to increase his vocabulary Ä even to
this day.

 At 14 months we moved, and sublet an apartment in Evanston, IL.  Clint was
so active we didn't dare spend much time in the apartment.  He was so
active NOTHING was safe Ä nor was he.  He and I must have walked 10 miles a
day Ä Clint being in and out of his stroller Ä just to keep him busy and
out of harm's way.

Once he was walking I could not take him anywhere because he was so very
active.  Going to anyone else's home was a nightmare, I never could follow
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 Ä just seemed to have no control over what he did.
As a result of this I had very few social contacts during his waking hours,
and was too tired when he went to bed to have many friends or much social

When he entered kindergarten he was given an IQ test Ä I have only limited
faith in those tests Ä and was found to be at the top end of the scale.
Great Ä or at least encouraging.  He did not, however, learn to read Ä in
spite of having parents who read to him constantly.  By the end of first
grade we knew we were in trouble.  His three 1/2 years younger brother was
already reading more words than he could handle.

I have not talked about the nightmares.  From probably age 2 on Clint had
severe nightmares.  He would awaken screaming and I'd go in to his room,
pick him up, rock him and hold him until he would finally wake up, have a
drink of water, slowly realize that he was safe and all was normal, then he
would go back to sleep.  That eventually became sleep walking and/or
screaming nightmares. Those continued well into adultÄhood.  In addition he
ground his teeth at night and by the time 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
will not even try to sleep without it.

He did not learn to read in first, second, third, and fourth grades, altho
he and I worked at home and he eventually had a basic reading vocabulary.
It was agony for both of us, and sounding out a new word was painful and
extremely frustrating for him.  Fifth grade he was blessed with a newly
graduated teacher who took a liking to him and tried to be of help.  She
would send home assignments for us to do together, and kept me informed
about his work and what areas needed help.  That began to build some badly
needed self confidence.  Recess and gym class were never comfortable,
probably because he had never really learned how to play quietly with other
boys without being too aggressive or too active.

A couple of things that have been left out.  In first grade Clint became
fascinated with math.  He would put himself to  sleep at night reciting
addition tables, then subtraction, and still in first grade was teaching
himself to multiply.  By second grade he was dividing.  [He's really good
with  computers!]

All this time we were moving from one town to another, one school system to
another, one group of friends to another.  Letting him go to preÄschool or
early grade birthday parties was a nightmare, as he might accidentally
break a birthday toy before the birthday child had a chance to play with
it. Things were spilled, furniture tipped over.  He just did not know how
to play with other children.

I kept taking him 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 engineer, that's probably
the reason.  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 spent as much time as he could, playing with his kids.  He did
not participate in the reading classes, but I can't fault him for that, as
he had other things on his mind.

After first 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. SelfÄesteem plummeted.

I had read about dyslexia in an article in the Saturday Review of
Literature, and decided that that was the problem.  I also read about
autism in Life Magazine and wondered if Clint was autistic, as he was so
distant and difficult to reach at times.  The dyslexia article gave
suggestions about how to help those children learn, and I did everything
they suggested, plus adding my own exercises and aids.  The improvement was
painfully slow.

Finally I read about ritalin and talked about that with the MD, who decided
we could try it.  That made a difference.  I was, however, really very
uncomfortable with using a strong drug that seemed to affect the brain, and
in spite of a calming effect in the classroom, I decided not to continue
with that.  I don't know how I had the nerve to discontinue the medication,
except that it seemed to turn him into a robot instead of my brilliant, if
nonÄreading, son.

By seventh grade I finally had enough money to make an appointment at the
University of Minnesota Child Development center.  They spent a whole day
giving Clint tests.  He thought it was a ball, and at the end of the
afternoon, when the professors were telling us what they had learned, he
was busy showing me all the various block patterns he had put together for
their tests, etc.  The decision was that he was dyslexic and brilliant.
[I could have told them that!]  It was wonderful to have my positive
feelings confirmed.  They said that I should continue with what I had been
doing, as it was obviously working, and that perhaps adolescence would make
a change.

[It is interesting that young celiacs frequently have a remission during

By the end of 7th grade he was reading a bit better.  I would read
mysteries to him and leave off the ending Ä some excuse about having to go
iron or wash dishes.  The book would stay next to the bed, and he would
struggle 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 beginning 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 day.  And spelling is a mystery even now.
I assume that visual memory and small muscle coordination are problem

He was accepted by Cornell University and managed to graduate from the
College of Liberal Arts in three years plus two summer sessions at the
University of Minnesota.  He knew we were really stretching to pay for Ivy
League college education, and therefore took too many classes at once.  But
we promised the tuition money from the 4th undergraduate year for graduate
school, so he then went to Northwestern University for and MBA.

 As each college year began he would return to campus in good health,
eating good meals with very little bread Ä we didn't go in for sandwiches,
doughnuts, spaghetti, hamburgers, and pizza at my house.  By the end of the
school year he would return looking haggared and exhausted, a little slow
of speech and definitely not relating well to others.  In addition he had
very little stamina for sports.

He is a handsome fellow.  However, after graduating with his MBA, he could
not get a job Ä did not interview well Ä much too intense and driven, I'm
sure.  He went into the Peace Corps, lived in hot climates, ate bread and
strong tea with lots of sugar, and came home after 2 years looking like
death warmed over.  He got and lost two jobs.

By then I was becoming aware that my lifetime of feeling a little different
from others had turned into steatorrhea and constant irrational anger Ä
another of Clint's symptoms.  Fortunately one of the many doctors that I
saw over a ten year period finally said that maybe it wasn't in my mind.
Maybe I had Whipple's disease.  I went to the library.  Ah, blessed
library!  There, after reading about Whipple's and thinking the profile
didn't fit, I continued reading in the area of gastroÄerterological
illnesses and came to celiac.  The lights went on, the bells rang!  I took
myself off gluten and within three days I felt as though I had just been
born.  I had always managed to cope with people and jobs and school, so my
problems had never been as severe as Clint's, but I was not an easy person
to be around.  [I'd like to think that I am a little bit like him in
intelligence, but that's never been tested...]

So then I learned about a nutritionist in Washington, DC, where my mother
was living, and made an appointment with her.  She recommended the ELISA
test Äand Dr. Jaffe, who developed that test, actually administered the
test himself.  A charming man.  With those test results I was told to
remove milk protein and milk sugar [butter is ok] and remove a few other
foods from my diet Ä many of which have now been added back.  I was also
given a large list of vitamin and mineral supplements to take to make up
for a leaky gut.

Next step was to convince Clint to try my new found solution.  After
returning from South America, 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 hypoglycemia test, when I knew that he was about to explode with
anger at me, and the doctor and the nurse, and everyone else in the waiting
room, and only years worth of extreme selfÄcontrol kept the professionals
from seeing what was happening.

So then we drove across the USA together and as he drove I read the book
Brain Allergies by Philpott, and another book about PsychoÄNutrition by
Carlton Frederichs aloud to him.  Each time we came across any symptom that
seemed related to him, we wrote down the offending food or the helpful
vitamin or mineral supplement.  When we arrived home, I 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 first time in my life, I
woke up to the sound of Clint singing downstairs.  I simply couldn't
believe my eyes when I saw him.  The almost gray pallor that had always
been his coloring was gone and he was rosy cheeked and smiling.  The
transformation was nothing short of miraculous.  Of course we continued the
glutenÄfree, vitaminÄheavy process for a second day.

The next day was Sunday, and I announced that I was going to attend church
as a kind of public acknowledgement of my feelings Ä we were not a church
going family.  Clint said he would go with me.  George said he'd come, too.
After the service I went to talk with a friend, George went to talk with
another friend, and Clint went to congratulate the soloist.  He asked her
to go the theatre the following weekend, but she said she was going home to
the farm for the summer Corn and Clover Festival (Hinckley, MN Ä population
about 1000, max.).  Somehow Clint managed to be invited to go along for the
weekend.  A year later they were married and now I have two lovely
grandsons.  She cooks glutenÄfree most of the time for the whole family,
tho she spoils herself and the boys once in a while.

After Clint's transformation, I realized that for years I had managed our
whole family in a way that tried to keep him calm and nonÄbelligerent.  By
the time he was himself, or cured, 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 all just glad that the disease had been cured and Clint had become the
person that had been hiding inside the difficult shell all those years.

If you are interested in details, it is extremely important for Clint to
avoid gluten and also to remember to take BÄComplex and extra niacin in
order to stay healthy.

There, that's the long story of Clint Kennedy.  He's a delightful 44 year
old man who runs 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 like him.  He accepts
that he is glutenÄsensitive and is very careful about his 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.  Eventually that will probably catch up with
him, and it concerns me.  He also will not get involved with this LIST, but
now does keep a file of information that I forward to him from the LIST.
And I send recipes to his wife, Karen.

Anything else you need to know?  I hope this has been helpful.

I'll be home until tomorrow around noon (I suppose that's 8 AM your time)
and would be interested in your response.  Think I'll send a copy of this
to Clint.

Best of luck with the thesis.  I think it would be a lot shorter with


Appendix Six:

reprinted with permission
Appendix Six continued.....

reprinted with permission