Below are some abstracts of research done on the link between dietary issues and autism.
Iacono G, Cavataio F, Montalto G, Soresi M, Notarbartolo A, Carroccio A: Persistent cow's milk protein intolerance in infants: the changing faces of the same disease. Clin Exp Allergy 1998 Jul;28(7):817-23.
Abstract: II Divisione di Pediatria, Ospedale Di Cristina, Universita di Palermo, Italy.
BACKGROUND: Recent research has shown that cow's milk protein intolerance (CMPI) often persists beyond 4 years of age. AIMS: To evaluate the clinical and immunological characteristics of a group of infants with persistent CMPI. PATIENTS AND METHODS: Twelve infants (6 m, 6f) with persistent CMPI were followed up from birth until a median age of 5 years. The patients underwent CMP challenge each year to evaluate CMP-tolerance. As controls we followed 26 infants (12 m, 14 f) with CMPI that resolved within 1-2 years. RESULTS: A family history of atopic disease was found in 10/12 patients with persistent CMPI and in 10/26 controls (P<0.01). Clinical presentation changed over time: at onset symptoms were prevalently gastrointestinal, while at the end of the study there was an increased frequency of wheezing and constipation and a higher frequency of delayed reactions to CMP-challenge than at study commencement (9/12 vs 2/12; P<0.007). 11/12 infants with persistent CMPI and 3/26 controls (P<0.0001) presented multiple food intolerance. During the observation period 9/12 infants with persistent CMPI and 2/26 controls showed atopic disease: asthma, rhinitis, eczema (P < 0.0001). CONCLUSIONS: Persistent CMPI forms are characterized by: (a) considerable importance of familial atopic disease; (b) change in CMPI manifestations over time and more prolonged delay between CMP consumption and manifestation of symptoms; (c) very high frequency of multiple food intolerance and allergic diseases.
Teschemacher, H. et al: Milk protein-derived opioid receptor ligands. Biopolymers. 1997 / 43 (2) / 99-117.
Abstract:
Rudolf-Buchheim-Institut fur Pharmakologie, Justus-Liebig-Universitat, Giessen, Germany.
Milk is mammalian characteristic and is of particular importance for humans: Mother's milk or its substitutes from cows' milk are absolutely essential nutriments for the neonate and cows' milk also represents a basic foodstuff for adults. However, in addition to their well-known nutritive role, milk constituents apparently are also able to carry specific information from the milk producer's to the milk receiver's organism: Thus, a number of milk protein fragments has been shown to behave like opioid receptor ligands able to address opioidergic systems in the adult's or in the neonate's organism. With respect to the proteins, which they are derived off these peptides have been named alpha-casein exorphins or casoxin D (alpha-casein), beta-casomorphins or beta-casorphin (beta-casein), casoxin or casoxin A, B, or C (k-casein), alpha-lactorphins (alpha-lactalbumin), beta-lactorphin (beta-lactoglobulin) or lactoferroxins (lactoferrin). Only casoxins and lactoferroxins display antagonistic properties; the other peptides behave like opioid receptor agonists. Most of the information available so far has been collected about beta-casomorphins. These peptides obviously can be released from beta-casein in the adult's or in the neonate's organism, where they might elicit opioid effects in the frame of a regulatory role as "food hormones". Several synthetic beta-casomorphin derivatives have been shown to be highly specific and potent mu-type opioid receptor ligands which frequently have been used as standard tools in opioid research.
Fukudome, S. et al: Release of opioid peptides, gluten exorphins by the action of pancreatic elastase. FEBS Lett. 1997 / 412 (3) / 475-479.
Abstract: Food Research Laboratory, Nisshin Flour Milling Co. Ltd., Saitama, Japan.
The release of opioid peptides, gluten exorphins A, which have been isolated from the pepsin-thermolysin digest of wheat gluten, with gastrointestinal proteases was examined. High levels of gluten exorphin A5 (Gly-Tyr-Tyr-Pro-Thr) immunoreactive materials were detected in the pepsin-pancreatic elastase digest by a competitive ELISA. From this digest, gluten exorphin A5, B5 and B4 were isolated. This means that these peptides are released in the gastrointestinal tracts after ingestion of wheat gluten. The yield of gluten exorphin A5 in the pepsin-elastase digest was larger than that in the pepsin-thermolysin digest. The gluten exorphin A5 sequence is found 15 times in the primary structure of the high molecular weight glutenin. The region from which gluten exorphin A5 was released by the action of pancreatic elastase was identified using synthetic fragment peptides.
Scifo R, Cioni M, Nicolosi A, Batticane N, Tirolo C, Testa N, Quattropani MC, Morale MC, Gallo F, Marchetti B: Opioid-immune interactions in autism: behavioural and immunological assessment during a double-blind treatment with naltrexone. Ann Ist Super Sanita 1996;32(3):351-9.
Abstract: Servizio di Psichiatria, Istituto OASI per lo Studio del Ritardo Mentale e l'Involuzione Cerebrale, Troina (Enna), Italy.
The emerging concept of opioid peptides as a new class of chemical messengers of the neuroimmune axis and the presence of a number of immunological abnormalities in infantile autism prompted us to correlate biological (hormonal and immunological) determinations and behavioural performances during treatment with the potent opiate antagonist, naltrexone (NAL). Twelve autistic patients ranging from7 to 15 years, diagnosed according to DSM-III-R, entered a double-blind crossover study with NAL at the doses of 0.5, 1.0 and 1.5 mg/kg every 48 hours. The behavioural evaluation was conducted using the specific BSE and CARS rating scales NAL treatment produced a significant reduction of the autistic symptomatology in seven ("responders") out of 12 children. The behavioural improvement was accompanied by alterations in the distribution of the major lymphocyte subsets, with a significant increase of the T-helper-inducers (CD4+CD8-) and a significant reduction of the T-cytotoxic-suppressor (CD4-CD8+) resulting in a normalization of the CD4/CD8 ratio. Changes in natural killer cells and activity were inversely related to plasma beta-endorphin levels. It is suggested that the mechanisms underlying opioid-immune interactions are altered in this population of autistic children and that an immunological screening may have prognostic value for the pharmacological therapy with opiate antagonists.
Hadjivassiliou M, Gibson A, Davies-Jones GA , Lobo AJ, Stephenson TJ, Milford-Ward A: Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996 Feb 10;347(8998):369-71.
Abstract:Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK.
BACKGROUND: Antigliadin antibodies are a marker of untreated coeliac disease but can also be found in individuals with normal small-bowel mucosa. Because neurological dysfunction is a known complication of coeliac disease we have investigated the frequency of antigliadin antibodies, as a measure of cryptic gluten sensitivity, and coeliac disease in neurological patients. METHODS: Using ELISA, we estimated serum IgG and IgA antigliadin antibodies in 147 neurological patients who were divided into two groups. There were 53 patients with neurological dysfunction of unknown cause despite full investigation (25 ataxia, 20 peripheral neuropathy, 5 mononeuritis multiplex, 4 myopathy, 3 motor neuropathy, 2 myelopathy). The remaining 94 patients were found to have a specific neurological diagnosis (16 stroke, 12 multiple sclerosis, 10 Parkinson's disease, 56 other diagnoses) and formed the neurological control group. 50 healthy blood donors formed a third group. FINDINGS: The proportions of individuals with positive titres for antigliadin antibodies in the three groups were 30/53, 5/94, and 6/50 respectively (57, 5, and 12%). The difference in proportion between group 1 and the combined control groups was 0.49 (95% CI 0.35-0.63). Distal duodenal biopsies in 26 out of 30 antigliadin-positive patients from group 1 revealed histological evidence of coeliac disease in nine (35%), non-specific duodenitis in ten (38%), and no lesion in seven (26%) individuals. INTERPRETATION: Our data suggest that gluten sensitivity is common in patients with neurological disease of unknown cause and may have aetiological significance.
D'Eufemia P., Celli M., Finocchiaro R., Pacifico L., Viozzi L., Zaccagnini M., Cardi E., Giardini O: Abnormal Intestinal Permeability in Children with Autism. Acta Paediatrica,1996; 85: 1076-1079.
Abstract: Institute ofPediatrics, La Sapienza University of Rome, Italy.
We determined the occurrence of gut mucosal damage using the intestinal permeability test in 21 autistic children who had no clinical and laboratory findings consistent with known intestinal disorders. An altered intestinal permeability was found in 9 of the 21 (43%) autistic patients, but in none of the 40 controls. Compared to the controls, these nine patients showed a similar mean mannitol recovery, but a significantly higher mean lactulose recovery (1.64% +/- 1.43 vs 0.38% +/- 0.14; P < 0.001). We speculate that an altered intestinal permeability could represent a possible mechanism for the increased passage through the gut mucosa of peptides derived from foods with subsequent behavioural abnormalities.
Lucarelli, S., Frediani, T., Zingoni, A.M., Ferruzzi, F.,Giardini, O., Quintieri, F., Barbato, M., D'Eufemia, P., Cardi, E.: Food allergy and infantile autism, Panminerva Med., 1995 Sep; 37(3): 137-41.
Abstract: Department of Paediatrics, University of Rome La Sapienza, Italy.
The etiopathogenesis of infantile autism is still unknown. Recently some authors have suggested that food peptides might be able to determine toxic effects at the level of the central nervous system by interacting with neurotransmitters. In fact a worsening of neurological symptoms has been reported in autistic patients after the consumption of milk and wheat. The aim of the present study has been to verify the efficacy of a cow's milk free diet (or other foods which gave a positive result after a skin test) in 36 autistic patients. We also looked for immunological signs of food allergy in autistic patients on a free choice diet. We noticed a marked improvement in the behavioural symptoms of patients after a period of 8 weeks on an elimination diet and we found high levels of IgA antigen specific antibodies for casein, lactalbumin and beta-lactoglobulin and IgG and IgM for casein. The levels of these antibodies were significantly higher than those of a control group which consisted of 20 healthy children. Our results lead us to hypothesise a relationship between food allergy and infantile autism as has already been suggested for other disturbances of the central nervous system.
Lensing P, Schimke H, Klimesch W, Pap V, Szemes G, Klingler D, Panksepp J: Clinical case report: opiate antagonist and event-related desynchronization in 2 autistic boys. Neuropsychobiology 1995;31(1):16-23.
Abstract: Department of Physiological Psychology, University of Salzburg, Austria.
Event-related desynchronization and visual orientational behavior were examined in 2 autistic boys to determine if blockade of endogenous opioid activity facilitates cognitive processing at a cortical level. Before naltrexone, the boys showed no selective alpha blocking during exposure to either mother's pictures or white light. Unlike normals, they exhibited strong alpha band enhancement at temporocentral recording sites. Two hours after administering 0.5 mg/kg naltrexone, mother-as well as light-related alpha blocking appeared at occipital, occipitotemporal, and prefrontal sites. These effects were gone 24 h after dosing in one child, but persisted in the other. A parallel increase in visual pursuit in a social context was observed. These results affirm that autistic gaze aversion can be caused by excessive opioid activity interfering with corticothalamocortical processing of visual stimuli.
Kurek M, Czerwionka-Szaflarska M, Doroszewska G: Pseudoallergic skin reactions to opiate sequences of bovine casein in healthy children. Rocz Akad Med Bialymst 1995;40(3):480-5.
Abstract: Department of Gastroenterology, Academy of Medicine, Gdansk.
Skin tests with opioid peptides naturally occurring in cow's milk: beta-casomorphin-7 and alpha-casein (90-95), were performed in 25 healthy children. Wheal and flare reactions, similiar to histamine and codeine were observed in all children. The area of these reactions was concentration dependent. Pretreatment with H1 antagonist--cetirizine significantly inhibited the skin response to both peptides. Beta-casomorphin-7 and alpha-casein (90-95) are noncytotoxic histamine releasers in humans.
Knivbserg A.M., Reichelt K.L., Nodland M., Hoien T.: Autistic syndromes and diet. A four year follow-up study. Scand J Educat. Res. 1995, 39: 223-236.
Abstract: Dietary intervention was applied to 15 subjects with autistic syndromes, with pathological urine patterns, and increased levels of peptides found in their twenty-four-hour urine samples. The peptides, some of which are probably derived from gluten and casein, are thought to have a negative pharmacological effect on attention, brain maturation, social interaction and learning. Our hypothesis was that a diet without these proteins would facilitate learning. Social behaviour, as well as cognitive and communicative skills, were assessed before diet. The subjects were closely followed for a year, after which their urine was retested blind, and the assessment of behaviors and skills was repeated. Further retesting was made four years after the onset of dietary intervention. Normalization of urine patterns and peptide levels was found after one year. Likewise, a decrease in odd behaviour and an improvement in the use of social, cognitive and communicative skills were registered. This positive development continued through the next three years, though at a lower rate. These promising results encourage further research on the effect of dietary intervention.
Bouvard MP, Leboyer M, Launay JM, Recasens C, Plumet MH, Waller-Perotte D, Tabuteau F, Bondoux D, Dugas M, Lensing P, et al: Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study. Psychiatry Res 1995 Oct 16;58(3):191-201.Abstract: Service de Psychopathologie de l'Enfant et de l'Adolescent, Hopital Robert Debre, Paris, France.
The effect of month-long naltrexone (NTX) treatment at a daily oral dose of 0.5 mg/kg/day was contrasted with placebo (PLC) in a double-blind study with conjoint clinical and biochemical evaluations of therapeutic effects. Modest clinical benefits were achieved with both PLC and NTX, with marginally better overall results following NTX, and degree of improvement appeared to be related to plasma chemical profiles. Massively elevated levels of beta-endorphin were observed in all children with assays using C-terminal antibody but not with an N-terminal antibody assay. In addition, 70% of the children exhibited abnormally low levels of adrenocorticotropic hormone, and smaller subsets exhibited elevated norepinephrine (60%), arginine-vasopressin (50%), and serotonin (20%). The best clinical responders exhibited the clearest normalization of the elevated plasma chemistries, especially in C-terminal-beta-endorphin and serotonin. There was some evidence of therapeutic carry-over effects in both clinical and biochemical measures in those children who received NTX before PLC. The results suggest that NTX only benefits a subgroup of autistic children, who may be identified by the presence of certain plasma abnormalities. These results suggest a possible linkage between abnormal plasma chemistries, especially those related to the pro-opiomelanocortin system, and autistic symptoms.
Reichelt K.L. Knivsberg AM, Nodland M, Lind G: Nature and consequences of hyperpeptiduria and bovine casomorphin found in autistic syndromes. Develop Brain Dysfunct. 1994, 7: 71-85. [No abstract available]
Gardner M.L.G.: Absorption of intact proteins and peptides. Physiol of gastrointestinal Tract 3rd edit (edit: LR Johnson) Raven press, New York 1994: 1795-1820.
Leboyer M, Bouvard MP, Launay JM, Recasens C, Plumet MH, Waller-Perotte D, Tabuteau F, Bondoux D, Dugas M: Opiate hypothesis in infantile autism? Therapeutic trials with naltrexone [Article in French]. Encephale 1993 Mar-Apr;19(2):95-102.
Abstract: Service de Psychiatrie Adulte, Hopital Pitie-Salpetriere, Paris.
The opioid hypothesis suggests that childhood autism may result from excessive brain opioid activity during neonatal period which may constitutionally inhibit social motivation, yielding autistic isolation and aloofness (Panksepp, 1979). This hypothesis has now received strong support and is currently based on three types of arguments: (1) similarity between autistic symptomatology and abnormal behaviors induced in young animals by injections of exogenous opioids, such as increasing social aloofness and decreasing social vocalization; (2) direct biochemical evidence of abnormalities of peripheral endogenous opioids being reported in autism and (3) therapeutic effects of the long lasting opioid receptor blocking agent naltrexone in autism. In this article, we give description of open and double-blind studies of naltrexone in autism. Naltrexone has been tested in several open studies. We performed an open trial with naltrexone in 2 autistic girls, displaying serious self-injurious behavior, reduced crying and a marked preference for salty and spicy foods, symptoms that could be related to a dysfunction of the opioid system. With dosages of 1 mg/kg/day, we observed an immediate reduction of hyperactivity, self-injurious behavior and aggressiveness, while attention improved. In addition, social behaviors, smiling, social seeking behaviors and play interactions increased (Leboyer, Bouvard et Dugas, 1988). Campbell et al. (1988) has also reported a tranquilizing and a stimulating effect in 6 out of 8 children with autism. We did confirm these preliminary results in a double-blind study performed on 4 children with autism. In a cross-over double-blind study, three dosages of naltrexone (0.5, 1 and 2 mg/kg/day) and placebo were compared. (ABSTRACT TRUNCATED AT 250 WORDS)
Fukudome S, Yoshikawa M: Gluten exorphin C, A novel opioid peptide derived from wheat gluten. FEBS 1993; 316: 17-19.
Abstract: Research Control Department, Nisshin Flour Milling Co., Ltd., Nihonbashi, Tokyo, Japan.
A novel opioid peptide, Tyr-Pro-Ile-Ser-Leu, was isolated from the pepsin-trypsin-chymotrypsin digest of wheat gluten. Its IC50 values were 40 microM and 13.5 microM in the GPI and MVD assays, respectively. This peptide was named gluten exorphin C. Gluten exorphin C had a structure quite different from any of the endogenous and exogenous opioid peptides ever reported in that the N terminal Tyr was the only aromatic amino acid. The analogs containing Tyr-Pro-X-Ser-Leu were synthesized to study its structure-activity relationship. Peptides in which X was an aromatic amino acid or an aliphatic hydrophobic amino acid had opioid activity.
Bidet B, Leboyer M, Descours B, Bouvard MP, Benveniste J: Allergic sensitization in infantile autism. J Autism Dev Disord 1993 Jun;23(2):419-20. [No abstract available.]
McLaughlin P.J., Zagon I.S.: Endogenous opiod systems and clinical implications for infantile autism. Proceedings of the International Symposium on Neurobiology of Infantile Autism, Tokyo , 1990, Neurobiology of Infantile Autism, Excerpta Medica 1992.
Lensing P, Klingler D, Lampl C, Leboyer M, Bouvard M, Plumet MH, Panksepp J: Naltrexone open trial with a 5-year-old-boy. A social rebound reaction. Acta Paedopsychiatr 1992;55(3):169-73.
Abstract: School Psychology of Upper Austria, Linz.
The neurobiological rationale for an opiate antagonist pharmacotherapy of autism is presented. Naltrexone efficacy in decreasing autistic behaviour and in increasing social-affiliative behaviour was explored in a 5-year-old autistic boy. Naltrexone (0.5 mg/kg 3 times peer week) was effective in immediately decreasing gross motor activity and stereotyped behaviour and caused a delayed increase of crying, smiling and rough-and-tumble play. This single case presents preliminary evidence that a therapeutically valuable rebound reaction is possible and that the human opioid system modulates social-affective processes. The possibility of psychological factors being instrumental in achieving this effect is discussed as being suitable for future clinical trials.
Kurek M, Przybilla B, Hermann K, Ring J: A naturally occurring opioid peptide from cow's milk, beta-casomorphine-7, is a direct histamine releaser in man. Int Arch Allergy Immunol 1992;97(2):115-20.
Abstract: Department of Dermatology, Ludwig-Maximilian-University, Munich.
beta-Casomorphine-7, a naturally occurring product of cow's milk with opiate-like activity, was studied for possible direct histamine liberation activities in humans. It was found to cause concentration-dependent in vitro histamine release from peripheral leukocytes of healthy adult volunteers. Intradermal injection of beta-casomorphine-7 induced a wheal and flare reaction in the skin similar to histamine or codeine. Oral pretreatment with the H1 antagonist terfenadine significantly inhibited the skin responses to beta-casomorphine-7. The intradermal injection of an opiate receptor antagonist, naloxone, inhibited in vitro histamine release and skin reactions only in a 100-fold excess over beta-casomorphine-7. These findings suggest that beta-casomorphine-7 can be regarded as a noncytotoxic, direct histamine releaser in humans. The clinical relevance of these findings deserves further studies.
Fukudome S, Yoshikawa M: Opioid peptides derived from wheat gluten: their isolation and characterization. Federation of European Biochemical Societies (FEBS) 1992; 296: 107-111.
Abstract:Research Control Department, Nisshin Flour Milling Co., Ltd., Tokyo, Japan.
Four opioid peptides were isolated from the enzymatic digest of wheat gluten. Their structures were Gly-Tyr-Tyr-Pro-Thr, Gly-Tyr-Tyr-Pro,Tyr-Gly-Gly-Trp-Leu and Tyr-Gly-Gly-Trp, which were named gluten exorphins A5, A4, B5 and B4, respectively. The gluten exorphin A5 sequence was found at 15 sites in the primary structure of the high molecular weight glutenin and was highly specific for delta-receptors. The structure-activity relationships of gluten exorphins A were unique in that the presence of Gly at their N-termini increased their activities. Gluten exorphin B5, which corresponds to [Trp4,Leu5]enkephalin, showed the most potent activity among these peptides. Its IC50 values were 0.05 microM and 0.017 microM, respectively, on the GPI and the MVD assays.
Dubynin VA, Maklakova AS, Nezavibat'ko VN, Alfeeva LA, Kamenskii AA, Ashmarin IP: Effects of systemically-administered beta-casomorphin-7 on nociception in rats. [Article in Russian] Biull Eksp Biol Med 1992 Sep;114(9):284-6.
Abstract: The influence of food-derived heptapeptide beta-casomorphin-7 (beta-CM-7) on pain sensibility of white rats was studied by tail flick test. As shown for doses 10 and 20 mg/kg intraperitoneally, injected beta-CM-7 induced significant analgesia; lower peptide concentration (5 mg/kg) was ineffective. As a whole, there is a significant positive correlation between the intensity of analgesia and the quantity of administered exorphine. These changes of pain sensibility were observed for one hour after injection of heptapeptide; further measurements showed no significant difference of time reaction between control and experimental groups of rats. It was found out that animals with high native level of pain sensibility (4-8 sec) made the main contribution to manifestation of analgesia.
Bouvard M.P., Leboyer M., Launay J.M., Kerdelhue B., Dugas M.: The opiod excess hypothesis of autism: A double-blind study of naltrexone. Proc. of the Intern. Symp. on Neurob. of Inf. Autism, 1990, Neurobiology of Infantile Autism, Exerpta Medica 1992.
Teschemacher H, Koch G: Opioids in the milk. Endocr Regul 1991 Sep;25(3):147-50.
Abstract: Rudolf-Buchheim-Institut fur Pharmakologie, Justus-Liebig-Universitat Giessen, Germany.
In various studies, the milk has been screened for the presence of free or precursor-bound opioids. In fact, various opioid receptor ligands with agonistic or even antagonistic activity were found. Besides the alkaloid morphine, peptides derived from alpha-casein (alpha-casein exorphins), beta-casein (beta-casomorphins; beta-casorphin), alpha-lactalbumin (alpha-lactorphins) and beta-lactoglobulin (beta-lactorphin) were among the agonists. In addition, certain peptides derived from k-casein (casoxins) or from lactoferrin (lactoferroxins) were found to behave like opioid antagonists. Although a functional role in the mammalian organism for all of these compounds appears to be well possible, evidence has only been presented for the functional significance of beta-casomorphins, so far. These peptides might play a role in reproduction or nutrition in the female, in the newborn's or in a milk consumer's organism, respectively. Thus, opioids related to milk might represent essential exogenous extensions of the endogenous opiodergic systems.
Risebro, B.: Gluten-free diet in infantile autism. Tidsskr Nor Laegeforen 1991 Jun 10;111(15):1885-6 [Article in Norwegian]
Reichelt K.L., Knivsberg A.M., Lind G., Nodland M.: The probable etiology and possible treatment of childhood autism. Brain Dysfunct. 1991, 4: 308-319. [No abstract available]
Longoni R, Spina L, Mulas A, Carboni E, Garau L, Melchiorri P, Di Chiara G: (D-Ala2)deltorphin II: D1-dependent stereotypies and stimulation of dopamine release in the nucleus accumbens. J Neurosci 1991 Jun;11(6):1565-76.
Abstract:
Institute of Experimental Pharmacology and Toxicology, University of Cagliari, Italy.
In order to investigate the relative role of central delta- and mu-opioid receptors in behavior, the effects of (D-Ala2)deltorphin II, a natural delta-opioid peptide, and PL017, a beta-casomorphin derivative specific for mu receptors, were compared after local intracerebral and intraventricular administration. Intracerebral infusion of the two peptides was done bilaterally in the limbic nucleus accumbens and in the ventral and dorsal caudate putamen of freely moving rats through chronic intracerebral cannulas. After intra-accumbens infusion, the two peptides elicited marked but opposite behavioral effects: while (D-Ala2)deltorphin II evoked dose-dependent motor stimulation characterized by locomotion, sniffing, and oral stereotypies, PL017 elicited motor inhibition with rigidity and catalepsy. These effects were site specific because they could not be evoked from the ventral or from the dorsal caudate. Low doses of naloxone (0.1 mg/kg, s.c. ) blocked the effects of PL017 but not those of (D-Ala2)deltorphin II, which instead were reduced by high doses of naloxone (1.0 mg/kg) and by the putative delta-antagonist naltrindole; this drug failed to affect the catalepsy induced by PL017. Therefore, while (D-Ala2)deltorphin II effects were delta-mediated, PL017 effects were mu-mediated. Blockade of dopamine D1 receptors by SCH 23390 abolished (D-Ala2)deltorphin II effects, while blockade of dopamine D2 receptors by raclopride or by haloperidol was without effect. Local application by reverse dialysis of (D-Ala2)deltorphin II (5 microM) to the accumbens resulted in a naloxone-sensitive increase of extracellular dopamine concentrations; these effects could not be evoked from the caudate, nor by PL017 in the accumbens. Intracerebroventricular administration of (D-Ala2)deltorphin II or of PL017 elicited behavioral effects qualitatively similar to those obtained from the accumbens.
If deltorphin II is indeed present in the urine, this may explain why low doses of naloxone are often only moderately effective at reducing autistic behaviors.
Fukudome S.-I. and Yoshikawa M.: Opioid peptides derived from wheat gluten: Their isolation and characterization. FEBS Letters 1991, 296: 107-111.
Abstract: Four opioid peptides were isolated from the enzymatic digest of wheat gluten. Their structures were Gly-Tyr-Tyr-Pro-Thr, Gly-Tyr-Tyr-Pro, Tyr-Gly-Gly-Trp-Leu and Tyr-Gly-Gly-Trp, which were named gluten exorphins A5, A4, B5 and B4, respectively. The gluten exorphin A5 sequence was found at 15 sites in the primary structure of the high molecular weight glutenin and was highly specific for delta-receptors. The structure-activity relationships of gluten exorphins A were unique in that the presence of Gly at their N-termini increased their activities. Gluten exorphin B5, which corresponds to [Trp4,Leu5]enkephalin, showed the most potent activity among these peptides. Its IC50 values were 0.05 microM and 0.017 microM, respectively, on the GPI and the MVD assays.
Shattock P. Kennedy A, Rowell F, Berney T: Role of neuropeptides in autism and their relationships with classical neurotransmitters. Brain Dysfunct 1990, 3: 328-346. [No abstract available]
Reichelt K.L., Ekrem J., Scott H.: Gluten, milk proteins and autism: Dietary interventions effects on behavior and peptide secretion. J Appl Nutrition 1990, 42: 1-11. [No abstract available]
Marchetti B, Scifo R, Batticane N, Scapagnini U: Immunological Significance of Opioid Peptide Dysfunction in Infantile Autism. Brain Dysfunction,3: 346-354,1990. [No abstract available]
Leboyer M, Bouvard MP, Lensing P, Launay JM, Tabuteau F, Arnaud P, Waller D, Plumet MH, Recasens C, Kerdelhue B, Dugas M, Panksepp J: Opioid Excess Hypothesis of Autism. Brain Dysfunction 1990; 3: 285-298. [No abstract available]
Knivsberg A.M., Wiig K., Lind G., Nodland M., Reichelt K.L.: Dietary intervention in autistic syndromes. Brain Dysfunc. 1990, 3: 315-327. [No abstract available]
Cade R. et al.: The effects of dialysis and diet in schizophrenia. Psychiatry: A World perspective 1990, 3: 494-500. [No abstract available]
Barthelemy C, Bruneau N, Adrien J, Roux S, Lelord G: Clinical, Biological and Therapeutic Applications of the Functional Analysis of Autistic Disorders. Brain Dysfunction, 3: 271-284, 1990. [No abstract available]
Herrera-Marschitz M, Terenius L, Grehn L, Ungerstedt U: Rotational behaviour produced by intranigral injections of bovine and human beta-casomorphins in rats. Psychopharmacology (Berl) 1989;99(3):357-61.
Abstract: Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden.
The biological activity of beta-casein derived beta-casomorphin peptides was evaluated by injecting bovine beta-casomorphin-5 (Tyr-Pro-Phe-Pro-Gly), the homologous sequence in human beta-casein (Tyr-Pro-Phe-Val-Glu) and the corresponding N-terminal tetrapeptides into the left substantia nigra of rats. Their ability to produce rotational behaviour was compared to that produced by three reference compounds, morphine, D-ala2D-leu5 enkephalin and U50,488H, ligands for mu, delta and kappa types of opioid receptors, respectively. The relative potencies of beta-casomorphins and morphine were compared to those tested in two in vitro assays for opioid activity: (1) inhibition of the electrically induced contraction of the isolated myenteric plexus-longitudinal muscle of the guinea-pig ileum and (2) displacement of 3H-dihydromorphine binding to brain membranes. The same ranking order of potency was found in all three assays, the peptides from human beta-casein being about 10-fold less potent than those from bovine beta-casein. The effects of both morphine and bovine beta-casomorphin-5 in producing rotational behaviour were antagonized by naloxone; however, approximately 10-fold more naloxone was required to antagonize the beta-casomorphin-5 effect than that of morphine. The present data are discussed in the light of the recent observation that high concentrations of beta-casomorphin-like peptides are found in the cerebrospinal fluid and plasma of women with postpartum psychosis.
Ramabadran K, Bansinath M: Opioid peptides from milk as a possible cause of sudden infant death syndrome. Med Hypotheses 1988 Nov;27(3):181-7.
Abstract: Department of Anesthesiology, New York University Medical Center, NY 10016.
Milk from breast or baby formula is the exclusive source of nutrition for newborn infants. Short chain opioid peptides such as beta-casomorphins have been isolated from breast milk as well as baby formula. These biologically active peptides are absorbed from the gastrointestinal tract. In infants predisposed to respiratory apnea because of abnormal autonomic nervous system development and respiratory control mechanisms, opioid peptides derived from milk might be one of the etiological factors for sudden infant death syndrome and near miss sudden infant death syndrome.
Paroli E: Opioid Peptides from Food (the Exorphins). World Review of Nutrition and Dietetics 1988; 55: 58-97. [No abstract available]
Hole K. et al.: Attention deficit disorders: A study of peptide-containing urinary complexes. J Develop Behav Pediatrics 1988, 9: 205-212.
Abstract: Department of Physiology, University of Bergen, Norway.
In several behavioral disorders, we have observed that abnormal amounts of peptides and protein-associated peptide complexes are excreted in the urine. The gel filtration patterns of these excreted substances have some specificity for the different disorders. The urinary excretion of peptide-containing complexes was studied in 91 boys and 13 girls (mean age 9.4 years, range 1-23) with the clinical diagnosis of attention deficit disorder (ADD), with or without hyperactivity. The gel filtration of urine precipitate showed patterns in all patients that were different from those seen in 36 normal controls. Sixty-four patients had increased benzoic acid-glycoprotein-peptide complexes in the late peaks. The symptoms of all these patients fit the criteria for diagnosis of attention deficit disorder with hyperactivity (ADDH). Thirty-five patients showed reduced amounts of uric acid complexes in the late peaks. Clinically, this group, with the exception of three patients, fit the criteria for diagnosis of attention deficit disorder without hyperactivity. Five patients showed reduced amounts of all urinary complexes; four of these were hyperactive. Moderate exercise in control children did not change the urinary pattern. One urinary peptide fraction from hyperactive patients, purified to homogeneity, increased the uptake of 14C[5-HT] in platelets. Strict clinical, neuropsychological, and psychophysiological selection of the patients reduced the heterogeneity of the patterns. Although more studies are needed, the findings seem promising for the possibility of developing biochemical tests that may be helpful diagnostically.
Dohan, FC: Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophr. Bull. 1988 / 14 (4) / 489-494.
Abstract:Medical College of Pennsylvania, Eastern Pennsylvania, Psychiatric Institute, Philadelphia, 19129.
This brief overview proposes a testable oligogenic model of the inheritance of susceptibility to idiopathic schizophrenia: "abnormal" genes at each of a few complementary loci. The model is based on my assumptions as to the likely genetic abnormalities at possibly four or five interacting loci that would permit exorphins, the opioid peptides from some food proteins, especially glutens and possibly caseins, to go from gut to brain and cause symptoms of schizophrenia. Exorphins may reach the brain cerebrospinal fluid (CSF) in harmful amounts because of their genetically increased, receptor-mediated transcellular passage across the gut epithelial barrier plus decreased catabolism by genetically defective enzymes. A schizophrenia-specific, genetically enhanced affinity for exorphins by opioid receptors influencing dopaminergic and other neurons would permit sustained dysfunction at low CSF exorphin concentrations. Tests of each postulated genetic abnormality are suggested. This model is supported by a variety of evidence, including a significant effect of gluten or its absence on relapsed schizophrenic patients, the high correlation of changes in first admission rates for schizophrenia with changes in grain consumption rates, and the rarity of cases of schizophrenia where grains and milk are rare.
Sahley TL, Panksepp J: Brain opioids and autism: an updated analysis of possible linkages. J Autism Dev Disord 1987 Jun;17(2):201-16.
Abstract:
Considerable clinical evidence suggests that autistic children lack the normal ability or desire to engage others socially, as indicated by their poor social skills and inappropriate use of language for communicative purposes. Specifically, these children seem to lack normal amounts of social-emotional interest in other people, leading perhaps to a decreased initiative to communicate. This paper summarizes experimental evidence supporting a neurological theory, which posits that autism, at least partially, represents in the brain, such as brain opioids. These substances modulate social-emotional processes, and the possibility that blockade of opioid activity in the brain may be therapeutic for early childhood autism is discussed.
Kahn A, Rebuffat E, Blum D, Casimir G, Duchateau J, Mozin MJ, Jost R: Difficulty in initiating and maintaining sleep associated with cow's milk allergy in infants. Sleep 1987 Apr;10(2):116-21.
Abstract: To confirm that sleeplessness in infants can be related to an undiagnosed allergy to cow's milk proteins, 71 infants were studied. Group I consisted of 20 infants referred for chronic insomnia that had appeared in the early days of life. Group II was made up of 31 infants admitted for skin or digestive symptoms attributed to cow's milk intolerance; 13 of these infants were shown to sleep as poorly as the infants of group I. Group III consisted of 20 infants with no history of sleep disturbance or milk allergy. The three groups of infants were comparable for sex and age. Laboratory tests revealed immunologic reactions to milk in all the infants in groups I and II. The sleep of the insomniac infants (group I, and the 13 "poor sleepers" in group II) became normal after cow's milk was eliminated from the diet. Insomnia reappeared when the infants in group I were challenged with milk. We conclude that infants with clinically evident milk allergy may suffer from sleeplessness and that when no evident cause for a chronic insomnia can be found in an infant the possibility of milk allergy should be given serious consideration.
Meisel, H: Chemical characterization and opioid activity of an exorphin isolated from in vivo digests of casein. FEBS Lett. 1986 / 196 (2) / 223-227.
Abstract:
The in vivo formation of an opioid peptide (exorphin) derived from beta-casein has been proved for the first time. It was isolated from duodenal chyme of minipigs after feeding with the milk protein casein. The exorphin has been identified as a beta-casein fragment by end-group determinations and qualitative amino acid analysis of the purified peptide. This peptide, named beta-casomorphin-11, displayed substantial opioid activity in an opiate receptor-binding assay.
Alpers DH: Uptake and fate of absorbed amino acids and peptides in the mammalian intestine. Federation Proc. 1986; 45:2261-2267.
Abstract:Intraluminal and brush-border digestion of proteins results in a mixture of amino acids and small peptides. Thirteen brush-border peptidases have been described. Despite all of these enzymes, some peptides escape digestion and are absorbed intact. The assimilated products of protein digestion can follow multiple paths: absorption into the blood as amino acids or small peptides, metabolism within the enterocyte, incorporation into proteins of the enterocyte, and incorporation into proteins to be secreted into plasma. Unlike other tissues, the intestinal mucosa is not very responsive to metabolic regulation as regards amino acid uptake or regulation of protein synthesis. Most effects after dietary manipulation or drug or hormonal stimulation are modes (two-to fivefold increases). This constitutive metabolism of amino acids in the intestinal mucosa is consistent with its essential role in absorption. The mucosa also is a major contributor to apolipoproteins, which are probably the quantitatively most important proteins secreted from the intestine. Alterations in apoprotein secretion have been noted after fat feeding, and are both transcriptionally and translationally regulated. Although the fractional renewal rate of protein in the intestine is the highest of any tissue in the body, the quantitative importance of alterations in protein synthesis or secretion to the fate of intracellular amino acids is not known.
Svedberg, J.et al: Demonstration of beta-casomorphin immunoreactive materials in in vitro digests of bovine milk and in small intestine contents after bovine milk ingestion in adult humans. Peptides 1985 / 6 / pag.825-830.
Abstract: Healthy young volunteers ingested one liter of cows' milk; then the contents of the small intestine were aspirated through an intestinal tube at various times and assayed for the presence of bovine beta-casomorphin immunoreactive materials. Considerable amounts of beta-casomorphin-7, but no beta-casomorphin-5 and only small amounts of beta-casomorphin-4 or -6 immunoreactive materials were found. Chromatographical characterization showed that most of the beta-casomorphin-7 immunoreactive material was not identical with beta-casomorphin-7, whereas the major part of the beta-casomorphin-4 or -6 immunoreactive materials might be identical with their corresponding beta-casomorphins. Analogous results were obtained for in vitro digestion of bovine milk which had been designed as a rough imitation of the gastrointestinal digestion process. A regulatory influence of beta-casomorphins as "food hormones" on intestinal functions is suggested.
Saelid G, et. al.: Peptide-Containing Fractions in Depression. Biol Psychiatry 1985, 20: 245-256.
Abstract: A mixture of peptides and glycoproteins has been found in benzoic acid-precipitable material from urines of psychomotorically agitated and retarded endogenous depressive patients. This complex mixture of compounds is fractionated on a Sephadex G-25 gel, from which the different peaks are further separated on Biogel P2. The G-25 elution profiles ultraviolet absorbance, 280 nm) from depressive patients deviated from the normal pattern. The increase in hydrolyzable ninhydrin-colorable material of the P2 fractionation step encountered in psychotic depression was several-fold that of the normal population. Neurochemically active peptide-containing fractions were found. As explanation of these findings, it is probable that a genetically determined peptidase insufficiency is present, causing a peptide overflow when the secretion outstrips the breakdown. This model could easily combine more psychodynamic models with the genetic-biological models. The variability of the peptide patterns could possibly reflect the considerable clinical variability of the syndrome. Furthermore, the presence of a group of active compounds with different neuropharmacological activities might reflect the composite nature of the depressive syndrome.
Rix KJ, Ditchfield J, Freed DL, Goldberg DP, Hillier VF: Food antibodies in acute psychoses. Psychol Med 1985 May;15(2):347-54.
Abstract: Antibodies to a variety of foods, and in particular cereals, were measured in serum from 100 patients with acute psychoses and 100 elective surgical patients. For 13 out of 14 foods to which non-IgE antibodies were detected the schizophrenics had slightly more antibodies than the controls. There was an association between a possible secondary mania and the presence of IgE antibodies to wheat or rye. However, neither the schizophrenia nor the mania findings can be regarded as evidence for food allergy causing psychiatric disorder, since the immunological findings in both cases may represent consequences of the illnesses or their treatment, rather than causes of the illness.
Chang, KJ, Su YF, Brent DA, Chang JK: Isolation of a specific mu-opiate receptor peptide, morphiceptin, from an enzymatic digest of milk proteins. J. Biol. Chem. 1985 / 260 (17) / pag. 9706-9712.
Abstract: Specific radioimmunoassays have been developed for the measurement of naturally occurring morphiceptin and beta-casomorphin. These peptides and related exorphins were isolated from an enzymatic digest of caseins by chromatographic techniques including gel filtration, hydrophobic column and multiple-step high pressure liquid chromatography. Three exorphins were purified and characterized in their radioimmunological, biological, and chemical properties. They were identified as morphiceptin, beta-casomorphin, and 8-prolyl-beta-casomorphin. Since morphiceptin is a highly specific mu-agonist and can be derived from a milk protein, it is possible that morphiceptin is an exogenous opioid ligand specific for mu-receptors in the brain and gastrointestinal tract.
Takahashi M, Fukunaga H, Kaneto H, Fukudome S, Yoshikawa M: Behavioral and pharmacological studies on gluten exorphin A5, a newly isolated bioactive food protein fragment, in mice. Jpn J Pharmacol 2000 Nov;1984(3):259-65.
Abstract: Department of Pharmacoinformatics, School of Pharmaceutical Sciences, Nagasaki University, Japan. takahashi@net.nagasaki-u.ac.jp
Central effects of gluten exorphin A5 (Gly-Tyr-Tyr-Pro-Thr), a fragment from wheat gluten, were studied on the pain-inhibitory system, emotionality and learning/memory processes in mice. Orally administered gluten exorphin A5 produced neither an antinociceptive effect nor an effect on morphine analgesia. Intracerebroventricularly (i.c.v.) administered gluten exorphin A5 produced mild but significant antinociception in a dose-depepndent manner, while not affecting the morphine analgesia. On the other hand, oral gluten exorphin A5 suppressed the endogenous pain-inhibitory system, i.e., antinociception induced by socio-psychological- (PSY-) stress (SIA) using a communication box; intraperitoneal gluten exorphin A5 abolished both footshock- (FS-) stress-induced antinociception (SIA) and PSY-SIA; and i.c.v. gluten exorphin A5 suppressed FS-SIA, but rather potentiated PSY-SIA. This peptide given by these routes was without effect on forced swim-SIA. In addition, oral gluten exorphin A5 tended to prolong the retention time on open arms in the elevated plus-maze test. Finally, oral gluten exorphin A5 when given during the post-training period of learning/memory processes significantly increased the latency into the dark compartment in the one-trail step-though type passive avoidance test, indicating that the peptide also facilitates the acquire/consolidation process of learning/memory. Thus, gluten exorphin A5 has been found to produce various effects not only in the peripheral nervous systems but also in the central nervous system.
Pfeiffer CC: Schizophrenia and wheat gluten enteropathy. Biol Psychiatry 1984 Mar;19(3):279-80. [No abstract available]
Lindstrom LH, Nyberg F, Terenius L, Bauer K, Besev G, Gunne LM, Lyrenas S, Willdeck-Lund G, Lindberg B: (1984) CSF and plasma beta-casomorphin-like opioid peptides in post-partum psychosis. Amer. J. Psychiat. 1984, 141: 1059-1066.
Abstract:
The authors measured opioid receptor-active components in the CSF of 11 women with postpartum psychosis, 11 healthy lactating women, and 16 healthy women who were not lactating. Activity that eluted with 0.2 M acetic acid 0.7-0.9 times the total volume of the column (fraction II activity) was significantly higher in the CSF of both healthy and psychotic women in the puerperium than in that of the lactating women. Very high levels of fraction II activity were seen in four psychotic patients. Material from these patients was further characterized by electrophoresis and high-performance liquid chromatography: The material migrated as bovine beta-casomorphin. Receptor-active material with the same characteristics was also found in the plasma of these four patients. The authors conclude that certain cases of postpartum psychosis are associated with the occurrence in plasma and CSF of unique opioid peptides probably related to bovine beta-casomorphin.
Huebner FR, Lieberman KW, Rubino RP, Wall JS: Demonstration of high opioid-like activity in isolated peptides from wheat gluten hydrolysates. Peptides 1984 Nov-Dec;5(6):1139-47.
Abstract: Because of a possible relationship between schizophrenia and celiac disease, a condition in some individuals who are sensitive to wheat gluten proteins in the diet, there has been interest in observations that peptides derived from wheat gluten proteins exhibit opioid-like activity in in vitro tests. To determine the origin of the peptides exhibiting opioid activity, wheat proteins were fractionated by size (gel filtration), by charge differences (ion exchange chromatography) and by differences in hydrophobicity (reversed-phase HPLC). These fractions were hydrolyzed by pepsin or pepsin and trypsin and the resulting peptides separated by gel filtration chromatography. The separated peptides were tested for opioid-like activity by competitive binding to opioid receptor sites in rat brain tissue in the presence of tritium-labeled dihydromorphine. The peptides showed considerable differences in activity; while some peptides exhibited no activity, 0.5 mg of the most active peptides were equivalent to 1 nM of morphine in the binding assay. The most active peptides were derived from the gliadin fraction of the gluten complex.
Dohan et. al: "Is Schizophrenia Rare if Grain is Rare?" Biol Psychiat 1984; 19(3): 385-399.
Abstract: If, as hypothesized, neuroactive peptides from grain glutens are the major agents evoking schizophrenia in those with the genotype(s), it should be rare if grain is rare. To test this, we analyzed the results of our clinical examinations (e.g., kuru) and observations of anthropologists on peoples consuming little or no grain. Only two overtly insane chronic schizophrenics were found among over 65,000 examined or closely observed adults in remote regions of Papua New Guinea (PNG, 1950-1967) and Malaita, Solomon Islands (1980-1981), and on Yap, Micronesia (1947-1948). In preneuroleptic Europe over 130 would have been expected. When these peoples became partially westernized and consumed wheat, barley beer, and rice, the prevalence reached European levels. Our findings agree with previous epidemiologic and experimental results indicating that grain glutens are harmful to schizophrenics.
Loukas, S. et al: Opioid activities and structures of alpha-casein-derived exorphins. Biochemistry 1983 / 22 (19) / 4567-4573.
Gardner MLG: Evidence for, and implications of, passage of intact peptides across the intestinal mucosa. Biochemical Society Transactions 1983; 11: 810-812. [no abstract available]
Morley, JE: Food peptides. A new class of hormones? J. Am. Med. Assoc. 1982 / 247 (17) / 2379-2380. [No abstract available]
Reichelt KL, Hole K, Hamberger A, Saelid G, Edminson PD, Braestrup CB, Lingjaerde O, Ledaal P, Orbeck H: Biologically active peptide-containing fractions in schizophrenia and childhood autism. Adv Biochem Psychopharmacol 1981; 28: 627-643.
Abstract: It is well documented that peptides have a major role in the effective functioning of higher animals at all levels from enzyme stabilization to homeostatic mechanisms governing essential functions such as eating, sexual behavior, and temperature regulation. The effects of exogenously administered peptides on neurotransmitter release, uptake, metabolism and behavioral consequences are also well established. We have attempted to extend these findings by postulating peptidergic neurons as transducers of multisignal inputs, and that development of pathological states may be due to genetically-determined reduced levels of activity of key peptidases, leading to excretion of regulatory peptides into the circulation. We have been able to demonstrate that, in schizophrenia and autism (in well defined clinical cases), the patterns of peptides and associated proteins from urinary samples differ considerably from each other and from normal controls. In addition to this, further purification of the material obtained has led to the discovery of a number of factors capable of modulating the function of major neurotransmitters. Some of these are in the final stages of characterization as peptides, while the remainder are also probably peptides, as purification has been followed by both biological testing and chemical analysis for peptidic material. We have outlined a number of parameters which we consider relevant in any attempt to put psychiatric disorders on a biological foundation. Any new advances in the neurochemical understanding of such disorders must take into consideration the observations of several different disciplines including genetics and psychology. However, at this stage of research it is far too early to speculate on the relevance of the various biological activities to the etiology and symptomatology of schizophrenia and childhood autism.
Trygstad OE, et al: Patterns of peptides and protein-associated-peptide complexes in psychiatric disorders. Br J Psychiatry 1980 Jan;136:59-72.
Abstract: Peptidic neurones may be considered as multisignal intergrators and transducers. When formation or release of peptide outstrips genetically determined breakdown capacity, overflow of peptides to the body fluids and urine may be expected. In this paper, pathological urinary chromatographic patterns of peptides are shown for genetic, functional and mixed disorders. Part symptoms of the disorders may be induced with the biologically isolated and purified peptides as well as with chemically synthesized peptides.
Ross-Smith, P, Jenner FA: Diet (gluten) and Schizophrenia. J. Hum. Nutr. 1980 / 34 (2) / 107-112.
Four aspects of clinical evidence for an association between gluten and schizophrenia are examined. The scientific evidence for the role of gluten is set out. Finally, reference is made to other dietary approaches.
Zioudrou C, Streaty RA, Klee WA: Opioid peptides derived from food proteins. The exorphins. J. Biol. Chem.1979 / 254 (7) / 2446-2449.
Abstract: Peptides with opioid activity are found in pepsin hydrolysates of wheat gluten and alpha-casein. The opioid activity of these peptides was demonstrated by use of the following bioassays: 1) naloxone-reversible inhibition of adenylate cyclase in homogenates of neuroblastoma X-glioma hybrid cells; 2) naloxone-reversible inhibition of electrically stimulated contractions of the mouse vas deferens; 3) displacement of [3H]dihydromorphine and [3H-Tyr, dAla2]met-enkephalin amide from rat brain membranes. Substances which stimulate adenylate cyclase and increase the contractions of the mouse vas deferens but do not bind to opiate receptors are also isolated from gluten hydrolysates. It is suggested that peptides derived from some food proteins may be of physiological importance.
Panksepp J: A neurochemical theory of autism. Point of View, North-Holland Biomedical Press, Jul 1979.
Hole K, Bergslien AA, Jørgensen H, Berge O-G, Reichelt KL & Trygstad OE:(1979) A peptide containing fraction from schizophrenia which stimulates opiate receptors and inhibits dopamine uptake. Neuroscience, 4, 1139-1147. [No abstract available]
Dohan FC: Schizophrenia and neuroactive peptides from food. Lancet 1979 May 12;1(8124):1031. [No abstract available]
Brantl V, Teschemacher H: Naunyn Schmiedebergs Arch Pharmacol 1979 Apr 30;306(3):301-4. A material with opioid activity in bovine milk and milk products.
Abstract: Chloroform-methanol extracts of lyophilized milk, of commercially available dried milk or baby food and of casein digests were tested for opioid activity on the guinea-pig ileum longitudinal muscle-myenteric plexus preparation. Compounds with opioid activity--which proved to be resistant to peptidases--were detected in certain batches of baby food, casein digest, and cow milk in considerably varying amounts.
Ashkenazi et. al: Immunologic reaction of psychotic patients to fractions of gluten Am J Psychiat 1979; 136: 1306-1309.
Abstract: Production of a leukocyte migration inhibition factor by peripheral blood lymphocytes in response to challenge with gluten fractions was studied in hospitalized patients with schizophrenia and other psychoses compared with normal individuals and with children and adolescents with celiac disease. The schizophrenic and other psychotic patients could be subdivided into two groups, one that responded in the leukocyte migration inhibition factor test as the celiac patients did and one that responded as the normal control subjects did. The psychotic and schizophrenic patients did not show any evidence of malabsorption. The authors speculate that gluten may be involved in biological processes in the brain in certain psychotic individuals.
O'Banion D, Armstrong B, Cummings RA, Stange J.: Disruptive behavior: a dietary approach. J Autism Child Schizophr 1978 Sep;8(3):325-37.
Abstract: The effect of particular foods on levels of hyperactivity, uncontrolled laughter, and disruptive behaviors was studied in an 8-year-old autistic boy. The floor of the child's room was taped off into six equal-sized rectangles to measure general activity level. Frequency data were recorded on screaming, biting, scratching, and object throwing. A time-sample technique was used to record data on laughing. Data were gathered during four phases. During an initial 4-day period the child was fed a normal American diet. A 6-day fasting period followed, during which time only spring water was allowed. The third phase lasted 18 days and involved the presentation of individual foods. During the final phase of the study the child was given only foods that had not provoked a reaction in the third phase. Results showed that foods such as wheat, corn, tomatoes, sugar, mushrooms, and dairy products were instrumental in producing behavioral disorders with this child.
Singh MM, Kay SR: Wheat gluten as a pathogenic factor in schizophrenia. Science 1976 Jan 30;191(4225):401-2.
Abstract: Schizophrenics maintained on a cereal grain-free and milk-free diet and receiving optimal treatment with neuropleptics showed an interruption or reversal of their therapeutic progress during a period of "blind" wheat gluten challenge. The exacerbation of the disease process was not due to variations in neuroleptic doses. After termination of the gluten challenge, the course of improvement was reinstated. The observed effects seemed to be due to a primary schizophrenia-promoting effect of wheat gluten.
Dohan FC, Grasberger JC: Relapsed schizophrenics: earlier discharge from the hospital after cereal-free, milk-free diet. Am J Psychiatry. 1973 Jun;130(6):685-8. [No abstract available]
Goodwin MS, Cowen MA, Goodwin TC: Malabsorption and cerebral dysfunction: a multivariate and comparative study of autistic children. J Autism Child Schizophr 1971 Jan-Mar;1(1):48-62. [No abstract available]
Dohan FC: Is celiac disease a clue to pathogenesis of schizophrenia? Mental Hyg 1969; 53: 525-529. [No abstract available]
Dohan FC: Wheat "consumption" and hospital admissions for schizophrenia during World War II. A preliminary report. Am J Clin Nutr. 1966 Jan;18(1):7-10. [No abstract available]
Cooke WT, Smith WT: Neurological disorders associated with adult celiac disease. Brain 1966, 89: 683-722. [No abstract available]
Dohan FC: Cereals and schizophrenia: data and hypothesis. Acta Psychiat Scand 1966; 42: 125-152. [No abstract available]
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