Retinoic acid makes #20 for our schizophrenia/Alzheimer's risk factor list.

It can affect Vitamin D and Thyroid receptors, transcribe proteins, and affect fetal development. ADHD may have alcoholic sperm as an underlying causal factor.

How could I forget Retinoic Acid metabolism? I was focused on mitochondrial dysfunction and the citric acid cycle doesn’t directly use vitamin A - and the list was already long. Adding aberrant Retinoid metabolism didn’t make it shorter, but it added a lot of clarity.

• This post is a summary of key points from my findings related to Retinoic acid in schizophrenia. That got long, and the bulk is remaining in a document for now. See it for a more complete discussion of the science and for the reference list.

• See this recent Substack post, Experimental design and (20) variables, for the narrative regarding the experimental design aspects of such a long list of variables.

The list is a summary of the previous post, Rest in peace Dr. Zelenko, which has a variety of topics in addition to an expanded discussion of the list of schizophrenia risk factors - drumroll - which may also be indicating increased risk for Alzheimer’s dementia eventually. People with schizophrenia have a much higher risk for later Alzheimer’s dementia and histamine excess also has increased.

That post got long too and is available in a Word document, Rough Times Ahead, with tabbed subtitles available for navigation. Fetal Alcohol Syndrome and ADHD are discussed along with common risks including self-injury and suicide. Other possible physically based causal factors for suicidal urges are discussed including medication withdrawal, secondary hyperparathyroidism, and alcoholism. Retinoid excess and/or histamine excess can also lead to severe mental disorder and possibly suicidal urges.

#20 Either deficiency of retinoids or excess Retinoic acid can be a causal factor in symptoms of schizophrenia. (114, 116)

“The first line of evidence firmly connecting retinoids to schizophrenia is that retinoid toxicity or deficit has repeatedly been shown to result in symptom presentations that, though more severe in extent, resemble the stigmata of schizophrenia, e.g., thought disorder, mental deficit, enlarged ventricles, agenesis of the corpus callosum, microcephaly, and a variety of major and minor congenital malformations, among which craniofacial and digital anomalies are prominent.” (116)

Lack of vitamin A and carotenoids as a risk factor for schizophrenia:

Absence of the Retinoid Receptor leads to impaired hippocampal signaling. Vitamin A deficiency can cause worse relational and spatial memory in an animal model, reversible with supplementation. (114) Errors in transport proteins can also affect nutrient availability as seen with the dysbindin allele effects on schizophrenia. Whether retinol may not be able to cross the Blood Brain Barrier (BBB) to reach the brain to be activated there into retinoic acid, is a question by a review team (Reay & Cairns, 2020, 114)* regarding schizophrenia and abnormal retinoid metabolism. *They do an excellent job at explaining the complexity of retinoid metabolism and how it relates to schizophrenia. Many excerpts are included in the main document, with much appreciation for the clarity they add. (114)

Multiple gene alleles may be involved with schizophrenia phenotype (what is observed) rather than being able to point at one gene as a problem genotype (what the DNA says). (114) The differences may lead to low levels or excess, (116), or may cause other problems indirectly because other nutrients have metabolic gene differences.

Excess active Retinoic acid can cause symptoms of schizophrenia

The overactive Retinoic acid problem may have a few causes so treatment might require avoiding vitamin A and carotenoids in the diet or medications, and if the enzyme that deactivates Retinoic acid is deficient, possibly medicinal use of the enzyme to break it down might help, or use of Retinoic acid receptor antagonists have been found helpful in some animal studies to reduce harm in glyphosate research on teratogenic effects.

“A reporter gene assay revealed that GBH treatment increased endogenous retinoic acid (RA) activity in Xenopus embryos and cotreatment with a RA antagonist rescued the teratogenic effects of the GBH.” (117)

Alcohol use can cause low levels in liver and eyes of the drinker and excess in the testes:

Alcohol use in excess or chronically may be causing low retinoid levels in the liver and eyes and elevated levels in other tissues including the testes. (113) Fetal alcohol effects from the father’s use during sperm production may lead to multiple gene differences due to retinoic acid effects on the sperm. Those gene differences might cause a heterogenous mix of gene alleles in the child, and ADHD possibly. ADHD symptoms were seen in the offspring of animal studies with alcohol-exposed males. Alcohol use by the pregnant woman would lead to worse physical and mental effects associated with Fetal Alcohol Syndrome from more direct retinoic acid activation during the embryogenesis and physical formation of the fetus and its eyes and brain. Small eyes and microcephaly are seen in more severe FAS - and glyphosate exposed animal embryos. (117)

Glyphosate excess during pregnancy is a teratogen causing birth defects similar to FAS, due to causing an increase in activated Retinoic Acid.

Glyphosate is a widespread residue found in foods, and urine samples of 80% of US citizens screened in a recent study. "CDC finds glyphosate in 80% of US urine samples—as reported by 0% of "our free press"" - Mark Crispin Miller, (Substack)

CYP enzymes are involved in Retinoid metabolism which makes glyphosate residue a potential factor for disrupted function.

Teratogenic effects caused by glyphosate in an animal-based study led to deformities of the Rhombomere domain (117) which likely leads to malformation of dendritic spines (complex route involving Eph receptors, see the document if curious), a physical issue seen in patients with schizophrenia. (118)

An experiment where the cohort has symptoms due to deficiency or excess, would likely find no clear results.

An experiment designed to test vitamin A supplementation for patients with schizophrenia/schizoaffective disorder would likely get the 'average’ problem - some patients would be helped, and others would be made worse, and the statistical total would be no benefit, or maybe even harm, possibly a small benefit. It would depend on the population mix and what their varied causal factors were.

The patients might all have other various deficiencies or imbalances from the list and their symptoms might not improve much until more of the list of issues is resolved in some way for each of them.

ADHD may be Fetal Alcohol Syndrome by another name - due to alcohol exposed sperm at conception, but in a pregnancy without further alcohol exposure.

Breaking news - Fetal alcohol syndrome effects that are less visibly severe than FAS when a woman drank during the pregnancy, are likely to be happening due to a father-to-be’s use of alcohol in the ~74 days prior to conception. It takes that long to make a sperm. (38) The DNA of the alcohol exposed sperm may be negatively affected by the alcohol and the testes are one of the tissue types which receives an elevated quantity of retinoids during alcohol use, while the liver and eyes become depleted. (113)

Larger amounts of alcohol in animal-based studies definitely caused an increase in behavioral differences in the offspring, similar to ADHD. A survey-based study with humans found that weekly drinking by the husband as reported by the wife, was associated with an increased risk for ADHD in the children. (38)

What about the long term Retinoic Acid activation in a male exposed FAS child?

Did the Retinoic acid activation change that occurred during sperm production remain in the sperm and the child? Will it leave them sensitive to excess Retinoic Acid activation throughout their life?

The research question that could affect the children’s future risk for schizophrenia or Alzheimer’s dementia is whether the change in the sperm DNA left a lifelong increase in Retinoic Acid conversion in the child’s liver. Health problems do seem to worsen for adults with an FAS diagnosis, but the long-term effects have not been studied much compared to more immediate effects on the children. (34, 35, 36)

The problem of schizophrenia (and autism and FAS) is heterogeneity - wide variance in the gene changes seen in the populations with the diagnosis “schizophrenia” (or “autism” or “FAS”). One treatment plan is not going to help a population with varying metabolic differences. Each individual will need to have their own metabolic issues evaluated and treatment designed to cope with the variety. Some can balance other gene alleles, leaving a non-problem, or lesser problem.

Night blindness in alcoholics was successfully treated with vitamin A supplementation, however if excess Retinoic acid is being delivered to other parts of the body - is that really a good idea? Alcohol is causing increased activation of retinoids in some areas of the body while causing a decrease in retinoid level in the liver and in the eyes, apparently leading to night blindness in many alcoholics. (112) High dose supplementation helped the night blindness – but what was the extra vitamin A supplementation doing to the “lungs, trachea, kidneys, and testes”? (113) The increased retinoic acid might be causing gene changes in the sperm while the levels are elevated.

Vision is a blessing to treasure and protect. Photo by Vincent Chin on Unsplash, thanks for sharing!

This post is about saving lives - preventing histamine excess that can cause suicidal urges, or other panic and anxiety or mania. If we can identify who is low in vitamin A and supplement it, that would help reduce schizophrenia symptoms and likely reduce risk of self-harm - and - if we can identify who is overactive in Retinoic acid and treat that in various ways, then they also might have improvement in schizophrenia symptoms and decreased risk of suicide.

Methyl folate helps break down histamine and may help to take daily. Retinoic acid and food sources can increase histamine along with any seasonal allergy type allergens that are an individual problem, or an infection, or chronic inflammation. (Histamine foods to avoid or that may help document)

Suicidal urges or self-harm are a concern with histamine excess which would be more likely with over-active Retinoic acid and also a difference in methylation ability can affect histamine breakdown, adding to an excess risk. Both FAS and ADHD have increased risk for suicide, self-harm, and other risky behavior or addiction problems. (1, 61)

There has been an increase in grade school children and adolescents committing suicide and ADHD is a risk factor, more frequent among the suicide victims than peer average. (94) What if an excess of carrots was a problem? Odd thought, but worth knowing whether something is helping or harming. Low calcium or vitamin D may also lead to self-harm urges with secondary hyperparathyroidism - solution, simply take or eat adequate calcium and vitamin D (and magnesium and vitamin K2 to help with D metabolism and bone density).

Alcoholism also can lead to suicidal depression and altered vitamin A metabolism is part of the problem. Hopefully while avoiding making babies when chronically drinking, I wonder if Retinoic acid antagonists would help an alcoholic’s personal health? Not drinking too much would help more. The B vitamins and balanced cannabinoids also would be helpful, and magnesium and a trace mineral complex.

The list of nutrient deficiencies or imbalances that may be involved in schizophrenia is long - and got longer. Retinoic acid interacts with several of the other issues.

Both excess and lack of Retinoic acid/retinoids can lead to symptoms of schizophrenia. (116)

Vitamin D and Thyroid Receptor interactions: Retinoic acid interacts with the Vitamin D and Thyroid receptors via Retinoid X Receptor (RXR) activation. Retinoic acid can also activate peroxisome proliferator-activated receptors beta/delta (PPARβ/δ). Excess might lead to increased gene transcription of products affected by any of those receptors in addition to effects from proteins transcribed by Retinoic Acid Receptor (RAR) activation. The Retinoic Acid Receptor alone is estimated to be able to transcribe 10-15,000 different genes and their proteins. (114)

Excess Retinoic acid is not a small problem if you have it as an adult and is a worse risk for a developing baby as it directly can affect the formation of the infant’s brain and body - visible deformities can occur. Vitamin A and carotenoid deficiency can also be a severe problem for a developing fetus or older child or adult as it is needed for immune function in addition to night vision. Immune deficiency similar to AIDS can occur. The severity of a measles infection can be worse or even deadly with Vit. A deficiency.

Zinc: Activated Retinoic Acid transcribes genes, and zinc finger transcription proteins can be involved - making zinc deficiency an additive risk factor to low vitamin A. Zinc deficiency would also worsen a retinoic acid excess as zinc finger transcription proteins are involved with regulation of activated Retinoic Acid. (114)

1. Low vitamin D (can also be low magnesium or excess glyphosate) or gene differences in the Vitamin D Receptor (VDR). (47) VDR gene alleles are also seen in bipolar disorder. (48) Low vit D is a factor in Toxoplasmosis risk. (76)

   Excess Retinoic Acid might effect Vit D Receptor transcription of proteins. (114)

2. Low iodine/hypothyroidism / excess fluoride, bromide and perchlorates. (55)

   Excess Retinoic Acid might affect Thyroid Receptor function. (114)

3. Zinc deficiency prenatally or later in life. (69, 70, 71, 72, 73)

   Zinc finger transcription proteins are regulators of activated Retinoic Acid, so a deficiency of zinc may worsen an excess of RA, (114), as is seen in Fetal Alcohol Syndrome.

4. Excess copper in relation to a low zinc level - may be dietary or genetic - the copper/zinc transport protein dysbindin would be needed as a treatment if that was an underlying factor. (Dysbindin:56, 57, 58, 81),

5. Low manganese and iron were found along with elevated copper. (80, 57)

6. Low trace minerals or excess, or imbalance - it is complex - some with individual impact: Zinc, Cobalt, Chromium, “Zn, Co and Cr”; or in combination with a group of minerals: Selenium, Lead, Phosphorus, Tellurium, Copper, and Thallium,  “including Se, Pb, P, Te, Cu and Tl”, or a few that might affect it either individually or in a combination of minerals “such as Cs,” Cesium. Most were low or moderately low, a few were in excess (lead, iron). (83) Elevated iron is seen in chronic inflammation and adds to risk. Lead is a neurotoxin - avoid it.

7. Low Cesium is also seen in Alzheimer’s. The research team speculate that it may chelate misfolded proteins. “The potential relationship between Cs and Schizophrenia may be due to its chelating proteins, such as amyloid-β (Aβ) and apolipoprotein (APOE) and adjusting oxidative status in the brain 27.” (83)

8. B vitamins – gene methylation difference and/or pyroluria may be factors in chronic deficiency. Low methyl folate and methyl B12; possibly methylation gene differences. (55)

9. Low B6, folate and methyl B12 can lead to increased C-reactive protein levels which is associated with schizophrenia. (46, 55)

10. Low B6, (82)

11. B6, B8 (Inositol), and B12 supplementation helped. (85)

12. Low niacin – or a need for more than average for an unknown reason at this time. (45)

13. Vitamin C supplementation helped, along with standard medication. (88)

14. Cofactors: Alpha lipoic acid helped, “(100 mg/d) for 4 months” and standard med. (86)

15. CoQ10 supplementation found no difference – adherence taking the supplements may have dropped off. Blood levels of CoQ10 in the treatment group were raised at 3 months and not at 6 months compared to the control group. (87)

16. N-acetylcysteine – an amino acid, used to form glutathione, along with glycine and glutamate. Doses of 600-1000 mg once or twice a day were used. (91) Also see NAC – N-acetylcysteine.

17. Low DHA/EPA, omega 3 fatty acid: Supplementation helped most in early stages, fewer patients advancing to worse psychosis was observed, particularly helpful for adolescents with a baseline low DHA. Symptom improvement was seen for patients with a long-term diagnosis of schizophrenia. (43)

18. Low 2-AG (CBD equivalent) in relation to anandamide (THC equiv.). (49)

    There is a genetic risk for low 2-AG (CBD equivalent) in relation to anandamide (THC equivalent). (49) Providing CBD may help particularly in early stages of the condition. (50) The genetic difference that might make someone more susceptible to developing schizophrenia may involve a gene difference in Cannabinoid Receptor Type 2. (75) CBD/2-AG is the main agonist for them. (51, 77) People with Cystic Fibrosis or a BHMT gene allele can’t make cannabinoids for different reasons, and both would be low in both 2-AG and anandamide. They also have an increased risk for social anxiety conditions later in life. The risk was reduced when treatment with cannabinoids was given in early infancy (animal-based study, cystic fibrosis model). (52)

19. Glutathione levels were found to vary, with a wider range than the control, more elevated, and more low levels than in the non-schizophrenia group, but overall the average glutathione level was not significantly different in the schizophrenia group. (88)

Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

The full Reference list is in this Word document, Rough Times Ahead, with tabbed subtitles available for navigation.

Additional references are in a new one: Retinoic acid in schizophrenia, document