Beyond the Gut: The Relationship Between Gluten, Psychosis, and Schizophrenia

JAMES GREENBLATT, MD & DESIREE DELANE, MS

Introduction

The National Institutes for Mental Health provide a succinct definition for schizophrenia as periods of psychosis characterized by disturbances in thought and perception and disconnections from reality; however, diagnosis is much less straightforward.  Schizophrenia represents a wide illness spectrum with symptomatic features and severity ranging from odd behavior to paranoia.  With a prevalence rate over the past century holding steady at 1% worldwide and immovably poor patient outcomes, schizophrenia delivers profound relational and societal burdens, proving to be a complex clinical challenge and an unyielding epidemiological obstacle.

Gluten as a Trigger for Psychosis

Although the role of food hypersensitivities in disease pathologies is highly controversial in the medical community, many recognize a parallel rise with dietary evolution in modern history.  Major shifts from ancestral diets largely absent of wheat or dairy to one with these as foundational components generate reasonable arguments on their implications for human health.  Industrialized food systems that streamline the way foods are grown, processed, and stored are often charged with altering their very nature down to its most infinitesimal molecules.  Yet, despite their diminutive size, micronutrients from food are essential to the complex processes and interactions that represent optimal health.

Intolerance to gluten represents one of the most prominent food hypersensitivities arising in recent history, delivering profound impacts to both physical and mental health.  As the most severe reaction to gluten, Celiac Disease (CD) affects a growing population of men and women in the United States.  Unfortunately, an estimated 83% of cases remain undiagnosed or wrongly diagnosed with other conditions. Like other autoimmune diseases, CD is a factor of underlying genetic susceptibility combined with environmental pressures.  Sometimes remaining non-symptomatic for years, CD progressively damages the lining of the intestine, eventually presenting with severe gastrointestinal symptoms including gas, bloating, diarrhea, and constipation.  One of the most dangerous consequences is that digestion and absorption become impaired, resulting in malnutrition and increasing requirements for several key nutrients.  Furthermore, chronic, subtle inflammation keeps the immune system on high alert, promoting an environment of oxidative stress in which free radicals wreak havoc throughout the body.  By elevating the body’s overall inflammatory status, CD and other immune-mediated food allergies trigger not only immediately apparent physical symptoms, but also biochemical imbalances that alter brain function.  Notably, data showing that CD is often incorrectly and inconsistently diagnosed suggests that mental symptoms are often misinterpreted or overlooked.

A separate byproduct of gluten metabolism poses another, possibly more dramatic and direct, threat to brain function.  Gliadorphin, a peptide fragment produced through the breakdown of gluten, directly accesses the brain and attaches to opiate receptors.  Neuropeptides including gliadorphin and casomorphin, a structurally similar byproduct of dairy, mimic and interfere with normal neurotransmitter communication, producing significant mental symptoms ranging from fatigue and brain-fog to hallucinations and aggression.  Like the opiate drugs morphine and heroin, food-derived opiates hold strongly addictive properties as they promote reward, sedation, and satiety.  Sensitive individuals are typically marked by excessive cravings and dependence on food sources of gliadorphin and casomorphin, that manifest in difficulties regulating mood and behavior when levels are depleted.  Fortunately, mental health practitioners have begun to recognize the contribution of neuropeptides in many psychiatric conditions.

Gluten, Gliadorphin, & Schizophrenia

Like Celiac disease, experts agree that schizophrenia has both genetic and environmental contributors, and evidence even suggests that overlapping genetic risk factors may underlie a shared susceptibility for schizophrenia and Celiac disease.  A 2004 Danish case-control study indicated that individuals with a history of Celiac disease may have a 3x greater risk of developing schizophrenia.  Additionally, short-term immune-related exposures during gestation or early life can have long-term consequences for the brain by inducing permanent DNA modifications.  Maternal or post-natal illnesses and infections have all been linked to a greater risk for psychosis and schizophrenia.  Excessive immune activation during these critical developmental periods can also influence the body’s response to potential food allergens.  From the other direction, schizophrenia and psychosis may invoke unique immune mechanisms influencing an individual’s reactivity to gluten. 

Remarkably, the relationship between gluten and psychosis appears to go beyond Celiac disease.  Elevated levels of gliadorphin have consistently been measured in patients with schizophrenia, autism, attention-deficit-hyperactivity disorder, depression, and other psychiatric conditions.  Abnormally low activity of the dipeptidyl peptidase IV (DPP-IV) enzyme, involved in the breakdown of gluten, offers a potential link.  A clinical study in roughly 60 patients with schizophrenia or depression suggested that significant alterations in DPP-IV activity characterized patients with schizophrenia.  The prevalence of elevated gliadorphin and other opiate peptides in psychosis patients has led some researchers to believe that these psychoactive substances carry unique information to the brain that influence disease development.

Without normal breakdown of gliadorphin by DPP-IV, neurotoxic levels accumulate and produce psychoactive effects.  Significant behavioral alterations in animal models given food-based neuropeptides reflect symptoms of psychosis that were reversible by pre-treatment with opiate-blocking drugs.  Human patients with elevated urinary gliadorphin also demonstrate clinical behavioral improvements when gluten and other sources of “dietary morphine” are removed from the diet.  DPP-IV also modulates the activation and proliferation of CD4+ immune cells, providing an additional mechanistic explanation for the excessive inflammation characteristic of both Celiac disease and schizophrenia.  Finally, normal DPP-IV activity depends on adequate zinc and other nutrients, common casualties of poor intestinal function.

A New Approach to Schizophrenia Treatment

Despite evidence-based attempts to address the diverse spectrum of physical and mental impairments associated with schizophrenia, weak progress has been made over the last 100 years.  The rapid, clear clinical responses of antipsychotic drugs introduced in the 1950s and 1960s once appeared to offer miraculous promise to those suffering with psychotic illness.  At least 70 different medications have been developed targeting similar biochemical pathways and are firmly established as first-line therapies.  Modern antipsychotics can be profoundly useful with skillful use in the initial stages of illness, particularly for severe cases.  But it is no secret that these medications are rarely, if ever, totally effective, have no influence on negative or cognitive symptom categories, and bring debilitating side effects requiring further drug interventions.

A growing wealth of theory and data links nutrition and mental health, yet mainstream psychiatry remains stubbornly fixated on the status quo.  Clinical studies suggest that nutrient requirements in schizophrenia patients exceed generally recommended levels, whether due to poor diet, impaired intestinal function, or genetically induced metabolic differences.  A 2018 systematic review by Firth, et al., of 11 studies in early-stage psychosis patients found deficiencies in antioxidants, amino acids, and polyunsaturated fatty acids.  This recent evidence lends significant support for assertive nutrient-based approaches to schizophrenia treatment, particularly as preventive strategies in high-risk patients.

Normal mental processes require tightly-controlled amounts of B-vitamins, antioxidants, lipids, and many other dietary nutrients as key enzymatic components for neural growth, communication, and protection.  On top of the potentially toxic effects of gluten and its byproducts on some individuals, malabsorptive conditions resulting from food sensitivities or Celiac disease further reduce the bioavailability of these critical nutrients to the brain and exacerbate the biochemical imbalances that drive psychiatric illness.  Resulting from this malnourished state, neurotransmitter dysfunction and miscommunication dramatically alter sensory perception and distort a patient’s experience of reality, manifesting in abnormal behavior and social dysfunction. 

Nutritional and other integrative therapies provide the body and brain with optimal and familiar tools for self-healing.  By addressing the origins of symptoms first, medications can be employed as second-tier strategies that support rather than direct treatment.  The treatment paradigm for schizophrenia must be expanded to adopt strategies for early recognition and prevention and incorporate holistic therapies that empower patients to be involved in their recovery.  Long-term dietary changes, including removal of gluten, and nutritional supplements facilitate recovery and promote resilience and self-care.  The integrative care model for mental health care aims not at just the absence of disease, but for healthy minds, bodies, and futures with hope for independence, happiness, and fulfillment.

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References

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DIETARY INFLUENCES ON BEHAVIORAL PROBLEMS IN CHILDREN

James Greenblatt MD, Author of Finally Focused (www.finallyfocusedbook.com), Chief Medical Officer and Vice President of Medical Services at Walden Behavioral Care

It is well known that our food choices play a role in our long-term physical health. It is less recognized that nutrition can have profound effects on our mental health and our behavior. Overall, malnutrition in childhood can affect the brain throughout the lifespan, while specific food components can affect our short-term well-being. Sugar, wheat, and milk are among the most common dietary triggers for ADHD symptoms. Fluctuating blood sugar levels and partially-digested foods can also cause a wide range of symptoms from fatigue to hyperactivity. This article will discuss the dietary influences on behavioral problems in children, review how laboratory testing can be critical in identifying food sensitivities, and how to enhance digestion for maximum absorption of nutrients.

One of the most debated treatments for ADHD is the Feingold Diet, introduced in the early 1970’s by pediatrician and allergist Ben Feingold, MD. He initially suggested that children who are allergic to aspirin (which contains salicylates) may react to artificial food colors and naturally occurring salicylates. The Feingold Diet eliminates artificial food additives like flavorings, preservatives, sweeteners, and colors to reduce hyperactivity. The research over the years on the Feingold Diet has been mixed – some studies show no behavior change and some show increases in hyperactivity when children consume artificial ingredients. A landmark study conducted in the UK on three hundred 3-year-old and 8/9-year-old children in the general population found artificial colors or a sodium benzoate preservative (or both) in the diet resulted in increased hyperactivity (McCann et al., 2007). This study led the European Union to ask manufacturers to voluntarily remove several artificial food colors from foods and beverages or to add a warning label that the artificial food color “may have an adverse effect on activity and attention in children” (Arnold et al., 2012). Conversely, in the US, the FDA reviewed the study and determined that a causal relationship between consumption of color additives and hyperactivity in children could not be definitively established (Arnold et al., 2012).

Genetics often play a role in how a child’s ADHD symptoms are exacerbated. The children most likely to be affected by food additives have a genetic inability to metabolize the compounds. Genetic tests were conducted on the 300 UK children from the artificial food color study. Children with specific variations in the HNMT gene, which helps break down histamine in the body, had stronger behavioral reactions to artificial food colors than children without this variation (Stevenson et al., 2010). This means that in some children, food additives spur the release of histamine that in turn affect the brain.

The Barbados Nutrition Study was a longitudinal case-control study that began in the late 1960’s and investigated the physical, mental, and behavioral developmental effects of infant malnutrition. The 204 participants of this study experienced a single episode of moderate to severe malnutrition during their first year of life. Data was collected on these children through adulthood and compared to data from healthy children. By the end of puberty, all children completely caught up in their physical growth. However, cognitive and behavioral issues persisted into adulthood.

The consequences of malnutrition in infancy manifested in many ways. IQ scores of the children with a history of malnutrition at age 5-11 were significantly lower than those of the control children. 50% of the malnourished children had scores at or below 90 while only 17% of the control children had scores this low (Galler et al., 1983). According to teacher reports, attentional deficits, including shorter attention span, poorer memory, and more distractibility and restlessness, were found in 60% of the malnourished children compared to only 15% of the controls. They also had worse social skills, general health, sleepiness in the classroom, and emotional stability (Galler et al., 1983). When the children were reassessed on these measures at age 9-15, a history of early malnutrition was still associated with behavioral impairment at school, especially attention deficits (Galler & Ramsey, 1989).

Behavior problems reported by teachers when the participants were aged 5-11 significantly predicted conduct problems at age 11-17 (Galler et al., 2012). Age at 5-11, children malnourished as infants had lower performance on 8 out of 9 academic subject areas. 37 children (36 malnourished, 1 control) were below the expected grade for their age (Galler, Ramsey, & Solimano, 1984). Compared to control children, previously malnourished children at age 5-11 had significantly worse scores on parent-rated measures of good behavior (no antagonism between mother and child, obedience), social skills, mother-child relationship, frustration level, eating habits, sleeping habits, and school avoidance. Compared to their siblings, previously malnourished children had significantly worse scores on social skills, good behavior, helpfulness, mother-child interaction, eating habits, toilet training, and language (Galler, Ramsey, & Solimano, 1985). When the children were reassessed on these measures at age 9-15, the same results were seen, especially for aggression and distractibility (Galler & Ramsey, 1989). Problems with self-regulation, displayed as reduced executive functioning and aggression toward peers, persisted through adolescence (Galler et al., 2011).

Years later when the subjects were aged 37-43, attention problems were assessed using an adult ADHD scale and a computerized test of attention-related problems. There was a higher prevalence of attention deficits in the previously malnourished group relative to controls. 69% of the previously malnourished participants had at least one test score that fell within the clinical range for attention disorders (Galler et al., 2012). Previously malnourished participants also had worse educational attainment and income across the entire 40-year study (Galler et al., 2012).

Multiple connections have been made between sugar, hyperactivity, and the risk for ADHD. In group of almost 400 school-age children, researchers found that children with the greatest “sweet” dietary pattern had almost four times greater odds of having ADHD compared to those who ate sweets (ice cream, refined grains, sweet desserts, sugar, and soft drinks) less often (Azadbakht & Esmaillzadeh, 2012). In a similar study on 1,800 adolescents, having a “Western” dietary pattern (higher intakes of total fat, saturated fat, refined sugars, and sodium) more than doubled the odds of an ADHD diagnosis (Howard et al., 2011). Likewise, a study on 986 children, average age 9 years, found a high intake of sweetened desserts (ice cream, cake, soda) was significantly associated with worse inattention, hyperactivity-impulsivity, aggression, delinquency, and externalizing problems. In contrast, a high-protein diet was associated with better scores on these measures. A high level of sweetened dessert consumption was also associated with lower scores on tests of listening, thinking, reading, writing, spelling, and math (Park et al., 2012).

Certain foods may not only influence behavioral and physical symptoms, but may also modify brain activity. When children aged 6-15 with food-induced ADHD consumed provocative foods, they showed an increase in beta activity in frontotemporal regions during EEG topographic mapping of brain electrical activity (Uhlig et al., 1997). Beta waves are involved in normal waking consciousness and tend to have a stimulating effect; while too much beta can lead to anxiety.

A food sensitivity to a protein found in milk or a protein found in wheat is a prevalent but neglected cause of ADHD. Milk and milk products like cheese and butter contain a protein called casein. Casein is different from lactose which is a milk sugar. Grains like wheat, rye, and barley contain a protein called gluten. During digestion, casein becomes casomorphin and gluten becomes gliadorphin. For most people, these proteins are further broken down into basic amino acids. For some with ADHD, they have inactive dipeptidyl peptidase IV, a zinc-dependent enzyme that breaks down both casein and gluten, leaving these opioid peptides substances to build up.

Children with ADHD who have high levels of casomorphin or gliadorphin often have severe, uncontrolled symptoms. Both casomorphin and gliadorphin are morphine-like compounds which attach to opiate receptors in the brain. These substances can act like an addicting drug in susceptible children and cause fatigue, irritability, and brain fog. A child with high levels of casomorphin may have strong cravings for milk products (ice cream, yogurt) and may become irritable when he or she doesn’t eat these types of foods. The Gluten/Casein Peptide Test is a simple urine test that can measure levels of casomorphin and gliadorphin. If a child has high levels of casomorphin or gliadorphin, they should try to eliminate casein or gluten. Supplementation with DPP-IV enzymes can also be beneficial and often required for clinical improvement.

Malnutrition can negatively affect behavior and cognition, but certain nutrients can have detrimental effects on children as well. Louise Goldberg, pediatric dietitian, put it succinctly: “Food allergies and sensitivities can come at children with a one-two punch - first making them agitated, and next robbing them of nutrients that might rein in their behavior” (Peachman, 2013). We are biochemically unique and have different physiological and psychological responses to different foods. The right food for one child may the wrong food for another. For instance, peanut butter on whole wheat toast may be a nutritionally-balanced, energy-boosting snack for one child, while this snack would be harmful to a child who cannot tolerate neither nuts nor wheat. Medical testing can clarify which nutrients a child is sensitive to. Fortunately, eliminating offending substances can rapidly improve physical and behavioral symptoms.

References:

Arnold, et al. (2012). Artificial food colors and attention-deficit/hyperactivity symptoms: Conclusions to dye for. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics, 9(3), 599-609.

Azadbakht & Esmaillzadeh. (2012). Dietary patterns and attention deficit hyperactivity disorder among Iranian children. Nutrition, 28(3), 242-249.

Galler et al. (1983). The influence of early malnutrition on subsequent behavioral development I. Degree of impairment in intellectual performance. Journal Of The American Academy Of Child And Adolescent Psychiatry, 22(1), 8-15.

Galler et al. (1983). The influence of early malnutrition on subsequent behavioral development II. Classroom behavior. Journal Of The American Academy Of Child And Adolescent Psychiatry, 22(1), 16-22.

Galler & Ramsey. (1989). A follow-up study of the influence of early malnutrition on development: Behavior at home and at school. Journal Of The American Academy Of Child And Adolescent Psychiatry, 28(2), 254-261.

Galler, Ramsey, & Solimano. (1984). The influence of early malnutrition on subsequent behavioral development III learning disabilities as a sequel to malnutrition. Pediatric Research, 18(4), 309-313.

Galler, Ramsey, & Solimano. (1985). Influence of early malnutrition on subsequent behavioral development: V. child’s behavior at home. Journal Of The American Academy Of Child Psychiatry, 24(1), 58-64.

Galler et al. (2011). Early malnutrition predicts parent reports of externalizing behaviors at ages 9-17. Nutritional Neuroscience, 14(4), 138-144.

Galler et al. (2012). Infant malnutrition predicts conduct problems in adolescents. Nutritional Neuroscience, 15(4), 186-192.

Galler et al. (2012). Infant malnutrition is associated with persisting attention deficits in middle adulthood. The Journal Of Nutrition, (4), 788.

Galler et al. (2012). Socioeconomic outcomes in adults malnourished in the first year of life: a 40-year study. Pediatrics, (1), 1.

Howard et al. (2011). ADHD Is Associated with a "Western" Dietary Pattern in Adolescents. Journal of Attention Disorders, 15(5), 403-411.

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McCann et al. (2007). Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: A randomised, double-blinded, placebo-controlled trial. The Lancet, 370(9598), 1560-1567.

Niederhofer. (2011). Association of Attention-Deficit/Hyperactivity Disorder and Celiac Disease: A Brief Report. Primary Care Companion For CNS Disorders, 13(3), pii: PCC.10br01104.

Park et al. (2012). Association between dietary behaviors and attention-deficit/hyperactivity disorder and learning disabilities in school-aged children. Psychiatry Research, 198, 468-476.

Stevenson et al. (2010). The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms. The American Journal of Psychiatry, 167(9), 1108-15.

Uhlig et al. (1997). Topographic mapping of brain electrical activity in children with food-induced attention deficit hyperkinetic disorder. European Journal of Pediatrics, 156(7), 557-61.