In this blog, I attempt to explain why I believe that folic acid and other chemicals which modulate the action of the GABA(A) receptor, such as insecticides, phthalates, bisphenol A , methyl mercury and many others, are  responsible for contributing to the greatly increased incidences of autism and ADHD. I believe that these chemicals are also at least partly responsible for the increased incidences of type 1 diabetes and asthma, with supplemental folic acid in pregnancy possibly being the main cause. However, in order  to understand how these chemicals may be causing these illnesses, it will be necessary for the reader to first become acquainted with the intricacies of  the immune system response which I believe is aberrantly activated in these illnesses and many other diseases.

Since childhood, I have experienced mild to moderate symptoms of psychiatric disorders, with symptoms of Asperger syndrome (AS) predominating. It is common for people with AS to develop obsessive interests in ‘specialist subjects’ and these are often of a scientific nature. For over 20 years, my own specialist subject has been the study of the causation of psychiatric illness, in particular, schizophrenia and autism.

The early years were devoted mainly to schizophrenia research. What became increasingly clear was that schizophrenia was associated with an activated immune system ( . There was also a higher incidence of autoimmune diseases in the families of schizophrenics ( and an association with diseases not regarded as autoimmune, but which are nevertheless known to be inflammatory conditions, such as cardiovascular disease and type 2 diabetes (

The research therefore broadened into other areas to try to find a common factor which underlay these diseases, and the factor which emerged was activation of an immune system molecule called nuclear factor kappa beta (NF-kB). NF-kB has many functions, but one of its principal functions is the control of viruses and bacteria which establish latency within cells. To do this, it causes destructive molecules, known as ‘reactive oxygen species’ (ROS) to be produced inside infected cells. These molecules damage the cell walls of invading microbes.

However, it is also known that if excess ROS are produced inside cells as a result of processes unrelated to immune system activity, such as enzyme activity, this can cause aberrant activation of the NF-kB driven immune response ( and it would appear that some individuals are more genetically predisposed to such aberrant activation than others.

Viruses and bacteria gain entry into cells via specific cell membrane receptors. My research revealed that many diseases associated with NF-kB activation also exhibited receptor abnormalities, and these abnormalities were very often to be found in the receptors known to be used by invading microbes. Typically, there was reduced expression of these receptors, reduced sensitivity and, in some cases, blocking of the receptors by immune system antibodies. It seemed that the NF-kB driven immune response was attempting to protect cells from infection by microbes by closing down the receptors used by them to enter cells. In addition, cells expressing these receptors were often seen to be reduced in number, suggestive of an immune system mechanism called ‘apoptosis’ (programmed cell death). However, I could find no confirmation for these ideas in the medical literature. The insights appeared to be novel.

Schizophrenia is actually two closely related syndromes which can co-exist. Symptoms of the positive syndrome include delusions, auditory hallucinations and thought disorder, while the negative syndrome presents with blunted emotions, poverty of speech, lack of will, anhedonia and impaired intellect. Excessive dopamine transmission is the prevailing hypothesis for the positive syndrome, while the neurons of schizophrenics with predominantly negative symptoms show reduced numbers of serotonin receptors. Bipolar disorder, formerly known as ‘manic depression’, also presents with both positive and negative symptoms in the form of mania and depression.

Graves’ disease, also known as Basedow’s disease throughout much of Europe, is a thyroid disorder which also has a bimodal character. Typically, too much thyroid hormone is produced, as a result of autoantibodies binding to, and activating, the thyroid stimulating hormone receptor (TSHr). However, blocking antibodies are also seen at the TSHr which have the opposite effect and prevent thyroid stimulating hormone (TSH), secreted by the pituitary gland, from binding to its thyroid receptor. Sometimes, the blocking antibodies outnumber the stimulating antibodies and too little thyroid hormone is produced, and sometimes the ratio of stimulating and blocking antibodies is such that a normal amount of thyroid hormone is produced.

I found this situation of ‘pathological normality’ intriguing and did not believe it likely to  be a case of two different accidents cancelling out each other’s ill effects. These blocking and stimulating antibodies are seen in people who have never had thyroid disease and it seemed more plausible that they had evolved to act in concert during times of thyroid infection. The blocking antibodies would prevent microbes from entering thyroid cells through the TSHr. To compensate for the shortfall in thyroid hormone production from these cells, stimulating antibodies would bind to other TSHrs. If the compensation mechanism had simply relied on extra production of TSH by the pituitary, this could be self-defeating as more receptors would need to be expressed, increasing the risk of infection. The stimulating antibodies are much more powerful than TSH, so fewer receptors need to be expressed to compensate for the cells inactivated by blocking antibodies.

Translating this model to schizophrenia, kynurenic acid is created in the brains of schizophrenics to act as an antagonist at the glutamate NMDA receptor ( (  This increases dopaminergic transmission by reducing the number of dopamine transporter molecules, thus making dopamine bind to the D2 receptor for longer periods,  just as stimulating antibodies bind to the thyroid TSH receptor for longer periods than TSH. D2 receptor expression is modestly increased in most schizophrenic patients, but the increased length of occupany by dopamine may serve to restrict entry by pathogens. In schizophrenia, dopamine D1 and D5 receptors are seen to have reduced expression in the prefrontal cortex, and there is also reduced expression of serotonin 5-HT2A receptors. The functioning of dopamine and serotonin is tightly interdependent and these decreased receptor densities are probably responsible for negative symptoms.

Further research into the causation of other diseases revealed that this immune system mechanism, characterised by NF-kB activation, reduced receptor expression, and loss of cells expressing key receptors, was a common feature of  many non-communicable diseases. Examples of this are noradrenaline receptors and acetylcholine NACH receptors in Alzheimer’s disease (, insulin receptors in type 2 diabetes, serotonin 5-HT2A receptors in multiple sclerosis (, GABA(A) receptors in autism ( and acetylcholine NACH receptor blockade by antibodies in myasthenia gravis ( .

However, thus far, it is only in Graves’ disease and the psychiatric disorders that a dysregulated compensation mechanism is seen to cause symptoms of disease. More will probably be discovered, but it appears that the majority of diseases caused by chronic, aberrant activation of the NF-kB driven immune response are deficit syndromes, with no apparent compensation mechanism giving rise to disease. Cells malfunction due to reduced receptor activation and, when this situation becomes chronic, cell death often occurs. An example of this is Alzheimer’s disease, in which the early symptom of short term memory impairment is probably a result of reduced noradrenaline and acetylcholine  receptor expression. However, the more severe symptoms of advanced Alzheimer’s disease are a result of the death of neurons in which these receptors are underexpressed.

In the same way that abnormally excessive production of ROS within cells can activate NF-kB by mimicking its own actions, abnormal activation of receptors may also cause pathological activation of NF-kB. This can occur as a result of receptor hypofunction, which mimics the reduced expression and sensitivity of receptors or the blocking of receptors by antibodies to reduce infection by microbes, or by receptor hyperfunction, which mimics the compensation mechanism. I have called this ‘receptor activation’. An example of this is type 2 diabetes, which is usually caused by chronic overconsumption of food, particularly high glycemic index foods, resulting in chronically high levels of insulin receptor activation. This activates the NF-kB driven immune response in genetically predisposed individuals, which results in reduced expression and sensitivity of insulin receptors, leading to type 2 diabetes. However, in areas where famine is endemic, usually in the tropics, ‘tropical diabetes’ is seen, which may be the result of chronic reduced stimulation of insulin receptors ( Insulin receptor hypofunction is also seen in type 1 diabetes (, probably as a result of chronic reduced insulin secretion in that condition, and there is also an association between anorexia nervosa and later development of type 2 diabetes (

The onset of schizophrenia, usually in late adolescence or early adulthood, follows a period when there is greatly increased expression of dopamine receptors in the late stage of brain development and it is probably this surge in dopamine signalling which causes receptor activated illness in genetically predisposed people ( In autism, the onset of illness in early infancy, often after a period of normal development, follows a stage in the development of the brain when there is a peak in activity of the neurotransmitter, GABA ( I believe this causes receptor activation of an NF-kB driven immune response, resulting in reduced GABA(A) receptor expression.

Because these diseases are being caused by chronic, aberrant activation of the NF-kB driven immune response, which is being activated by processes which mimic its own actions, I have called them ‘Immune Mimicry Diseases’ (IMDs) and have written a much more detailed blog titled ‘Integrative Theory of the Causation of Non-Communicable Diseases: Immune Mimicry Disease (IMD) Theory’. The first half of the paper is a general exposition of IMD theory, while the second half deals with the specific etiologies of  schizophrenia, multiple sclerosis, cardiovascular disease, porphyria, diabetes, obesity, Alzheimer’s diseae, autism and ADHD. A link to the blog can be found at the end of this article. NF-kB driven diseases are known to be caused by a combination of genetic and environmental/lifestyle factors. The most important genetic factors may be immune system abnormalities which predispose to aberrant NF-kB activation, enzyme variants and receptor variants. The most important enzymes involved probably belong to the cytochrome P450 superfamily.

Environmental and lifestyle factors which contribute to IMD pathogenesis include microbes which establish latency inside cells, lack of immune challenge in infancy (the ‘hygiene hypothesis’), lack of vitamin D, chemical pollutants, environmental metals, food and chemical intolerance/sensitivity, pro-inflammatory diet, lack of physical exercise, psychological stress and abnormal gut microbiota. Lack of immune challenge in infancy due to oversanitised living conditions and lack of vitamin D may both exert their influence by affecting the developing immune system in a way that makes it more prone to dysfunctional NF-kB activation later in life. A diet high in fats, refined carbohydrates and chemical additives is known to be pro-inflammatory and will contribute to NF-kB activation, as will a diet which is low in antioxidants.

Chemical pollutants, particularly molecules which bind to the intracellular aryl hydrocarbon receptor (AHR) and are metabolised at the nuclear membrane by cytochrome P450 enzymes, liberating highly reactive hydroxyl radicals in the process, are known to activate NF-kB, and this could explain much environmental illness, particularly in people with P450 enzyme polymorphisms.  NF-kB driven diseases are more common in cities than in rural areas (  and this is probably due to air pollution, principally from motor vehicle exhausts. Vehicle pollution includes polycyclic aromatic hydrocarbons, benzene and metal oxides, all of which induce cytochrome P450 enzyme activity by binding to the AHR.

My research into the causation of autism convinced me that it, too, had a bimodal character, with autism symptoms being the deficit syndrome and ADHD symptoms resulting from a dysregulated compensation mechanism. There is pronounced co-morbidity between autism and ADHD ( and overlapping genetic influences ( Both autism and ADHD have a pre-school age of onset and the sex ratio of four affected boys for each affected girl is the same in both conditions.

The greatly increased incidence of both autism and ADHD is due in large part to increased awareness of these conditions,  broadening diagnostic criteria and sociological factors. However, there is also a belief that this is not sufficient to explain all of the increase and that some environmental factor must also be responsible. I found the temporal association between increasing folic acid supplementation in pregnancy and increased rates of autism/ADHD to be of particular interest. There appears to be only a little preliminary evidence to support a causative association (, but there is evidence of folate receptor blocking antibodies ( and variants of enzymes involved in folic acid and folate metabolism ( ( Other chemicals which have been implicated in the autism ‘epidemic’ include insecticides (, phthalates ( and mercury (

Further research revealed a crucial fact: folic acid (, phthalates ( , methyl mercury ( and a variety of insecticides, including organophosphates ( , organochlorines ( and pyrethroids ( are all either antagonists of the GABA(A) receptor, or otherwise inhibit its functioning. This is unlikely to be coincidence, and if it is not coincidence it must be causal. Moreover, autistic children have been shown to have reduced activity of the enzyme paraoxonase 1, which is responsible for metabolising organophosphate insectcides ( (  ( . Scores of chemicals with widely differing structures are also known to modulate GABA transmission, either as boosting or suppressing factors. These include some food additives and perfumes ( and some metals, including zinc ( Increasing food fortification with zinc, particularly in breakfast cereals, is therefore an additional cause for concern.  Aluminium also modulates  GABA(A) transmission ( and the action of the GABA transporter ( It is used to clarify drinking water and in bakery products.

There is reduced expression of GABA(A) receptors in autism ( (, which is suggestive of an NF-kB driven deficit syndrome. Moreover, onset of autism symptoms in early infancy follows a peak in GABA signalling as GABA is involved in early brain development ( This is reminiscent of the onset of schizophrenia in late adolescence and early adulthood coming after the peak of dopamine signalling in late adolescence, when the expression of dopamine receptors is greatly increased.

The hypothesis which emerged is that prenatal exposure to GABA(A) antagonists causes a reduction in GABA signalling in the developing brain of the foetus. This forces the GABA system to become more sensitive. When this sensitised GABA system reaches a peak of activity in early infancy, the combined effect of this peak of GABA activity, heightened sensitivity of the GABA system and genetic predisposition may cause aberrant receptor activation of NF-kB ( ( This aberrant immune system reaction results in GABA(A) receptors becoming underexpressed and hypofunctional. This reduced GABA signalling results in the symptoms of autism, possibly in conjuction with brain changes, including the death of neurons, such as the GABAergic Purkinje cells (

In addition to the above mentioned chemicals, two drugs taken during pregnancy have also been associated with a higher incidence of autism. These are the anticonvulsant medication, valproic acid, and thalidomide ( The therapeutic action of both drugs is exerted through the GABA(A) receptor. However, unlike the other chemicals, valproic acid and thalidomide act as agonists at the GABA(A) receptor, potentiating its action, rather than suppressing it. This could result in a prenatal receptor activated disease process in GABAergic neurons, resulting in autism commencing before birth. Valproic acid has recently been reported to activate NF-kB (

If ADHD is the positive syndrome, then the symptoms must result from excessive GABA signalling, but perhaps without increased expression of GABA(A) receptors. Medication which improves ADHD symptoms increases production of dopamine in the brain. Activation of the dopamine D4 receptor decreases GABA signalling ( and genetic alleles of the D4 receptor are associated with ADHD symptoms ( It is therefore plausible that the compensating mechanism is reduced activation of the dopamine D4 receptor and that this compensation mechanism has become excessively activated in ADHD ( .

Further evidence that ADHD is the positive syndrome of autism and that both are caused by prenatal exposure to chemicals which modulate GABA(A) receptor  transmission are the association of a folate pathway enzyme variant in ADHD (, an association with prenatal exposure to organochlorine pesticides in ADHD ( and evidence of high urinary concentrations of organophosphates in ADHD ( There is also evidence of phthalate involvement ( and mercury involvement ( in ADHD.

In conclusion, the modern ‘epidemics’ of autism and ADHD are the negative (deficit) and positive (compensation) dimensions of the same disease process. The huge rise in the incidence of this disease process in recent times is probably  due to a combination of increased awareness of the conditions, broadening diagnostic criteria, sociological factors and prenatal exposure to chemicals which disrupt GABA(A) receptor functioning. Although there is only a little preliminary evidence implicating folic acid supplementation in pregnancy as a cause of this disease process, the circumstantial evidence does reinforce this hypothesis.

Moreover, it is very possible that the harmful effects of folic acid supplementation in pregnancy are not limited to autism/ADHD. Over the same time scale as the emerging autism/ADHD epidemic, there has also been a growing asthma epidemic affecting children more than adults, and there is evidence for maternal folic acid supplementation as a cause ( ( The GABA(A) receptor has recently been shown to exist in airway epithelial cells and GABA(A) agonists have been successful in relieving airway constriction (

In addition, there has been a significant increase in the incidence of type 1 diabetes in recent years, a disease which is usually diagnosed in children. Antibodies to the GABA synthesising enzyme, glutamic acid decarboxylase (GAD), are frequently seen in this disease ( and activation of the GABA(A) receptor in pancreatic islet cells causes insulin secretion ( . Moreover, GABA has been shown to exert protective and regenerative effects on islet beta cells, reversing type 1 diabetes in severely diabetic mice (, suggesting that the proposed mechanism for the pathogenesis of autism may also be responsible for the beta cell death seen in this disease (

About the Author:
William Davidson is 58 and  lives in Scotland, UK. In common with many Asperger sufferers, he has a fascination with scientific specialist subjects, in particular the study of the etiology of non-communicable diseases. His main blog, which explains how non-communicable diseases, such as autoimmune diseases, psychiatric illnesses, neurological diseases and many others  are being caused by a combination of genetic, environmental and lifestyle factors all contributing to the aberrant activation of NF-kB, can be found at: