Important site to visit: http://www.ritalindeath.com/ THE UNIVERSITY OF CALGARY Application of the Exorphin Hypothesis to Attention Deficit Hyperactivity Disorder: A Theoretical Framework by Ronald Hoggan A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS GRADUATE DIVISION OF EDUCATIONAL RESEARCH CALGARY, ALBERTA APRIL, 1998 © Ronald Hoggan 1998 University of Calgary THE UNIVERSITY OF CALGARY FACULTY OF GRADUATE STUDIES 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. GLGP __________________ Date Abstract: 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. Preface 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. Acknowledgements 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. Dedication 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.... 21 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 Appendices: 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). DSM IV 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 practices. 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 little. 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 child. 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 circumstances. 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 system. 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 issue. 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 severity. 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 ADHD. 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 perspective. 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 (Hadjivassilliou.et al. 1996, 1997; Bye et al., 1993). A detailed discussion of this point is offered in Chapter 3. For the moment, it may be valuable to point out that there are at least 15 recurrences of one 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. Exorphins 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 functioning.” 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 identifying comorbid behavioral, psychiatric and educational conditions.” This problem may result from excessive reliance upon teachers’ reports on student behaviour. Differentiation 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 earlier. 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 studies. 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, 1970). 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 criteria. 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 factors. 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 school. Summary 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 prospects. 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 ADHD. 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 proteins. 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 protein. 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 proteins. 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 significance. 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 patients. 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 conditions. 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/Serotonin 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 (Era