Vitamin A May Be A Viable Therapy For Autism (human Study)

Haidut has made several posts previously on autism, including on the potential therapeutic role of vitamin D and the potential causative role of serotonin.

Vitamin D May Be A Viable Therapy For Autism (human Study)
Children Conceived In Winter Have Much Higher Risk Of Autism
Gut Dysbiosis May Cause Autism Through Cortisol And Serotonin
Children With Autism Have High Serotonin Levels
Serotonin Causes Autism; Blocking It May Treat Autism

Some evidence below that deficiencies of vitamin A may be involved as well and that supplementation of vitamin A can reduce serotonin levels and improve autism symptoms.

Update: information on dose below

Brain Res Bull. 2017 Nov 6;137:35-40. doi: 10.1016/j.brainresbull.2017.11.001. [Epub ahead of print]
Vitamin A improves the symptoms of autism spectrum disorders and decreases 5-hydroxytryptamine (5-HT): A pilot study.
Guo M1, Zhu J1, Yang T1, Lai X1, Liu X1, Liu J1, Chen J1, Li T2.

Autism spectrum disorders (ASD) are complicated neurodevelopmental disorders. Many studies have demonstrated that children with autism have multiple nutritional deficiencies and increased serum 5-hydroxytryptamine (5-HT) levels. In our previous study, 77.9% of autistic children were found to have vitamin A deficiency, and the concentration of vitamin A was negatively associated with the CARS score. In the present study, we sought to test whether vitamin A supplementation could improve autistic symptoms and decrease serum 5-HT levels. The DSM-V criteria and CARS score were used for symptom description and symptom assessment of the patients, respectively, before and after vitamin A supplementation (VAS). Serum retinol and 5-HT levels, mRNA levels of RAR α, β, and γ and TpH 1 expression were detected in autistic children before and after VAS and in normal children. Serum retinol levels in children with ASD were significantly lower than in control children. Serum 5-HT levels in children with ASD were higher than in control children, which were correlated with symptom severity of children with autism. After VA supplementation, the children with ASD exhibited significant improvement in autism symptoms. Serum retinol concentrations of children with ASD were significantly increased, and serum 5-HT levels were decreased. Moreover, statistically significant changes were observed in mRNA expression levels of RAR α, RAR γ and TpH 1 after VAS compared to baseline. This study suggested that VA supplementation may improve symptoms and reduce 5-HT levels in children with ASD, indicating that VA supplementation is a reasonable therapy at least for a subset of children with autism.

"Children with autism were requested to complete an interview with a developmental pediatrician and submit to a baseline blood collection. Then a single vitamin A supplementation (VAS) at a dose of 200,000 IU (WHO, 2011) was performed in the thirty-three ASD patients. All evaluations and blood collection were conducted again 6 months after VAS, based on the principle that a single, large dose of vitamin A is well absorbed and stored in the liver, and then mobilized, as needed, over an extended period of time."

The WHO document they are referring to is this one:

Guideline: Vitamin A Supplementation in Infants and Children 6–59 Months of Age - NCBI Bookshelf

 

Very interesting. I feel as though Vitamin A might be a wee bit misunderstood. It is generally the feeling that vitamin A deficiency is not an issue in Western countries. @Travis made that point in another thread recently. Maybe full on deficiencies are rare, but that doesn't mean it's not possible that peoples health is suffering to some degree by sub-optimal levels of this vitamin. It also doesn't mean that we wouldn't benefit from more. Women are told not to supplement with vitamin A during pregnancy. There is a great fear of it causing birth defects. When I looked into the history of this fear and the teratogenic effects of vitamin A, the evidence seemed weak in my opinion. From what I remember it was based of a New England epidemiological study and did not differentiate between synthetic form of the vitamin and other forms. Perhaps the rise in autism is in part due to this fear of vitamin A during pregnancy that has taken over? I'm not saying it is or isn't, just throwing the question out there.

There are other nutrients that we benefit from that would be very difficult to actually become deficient in. Glycine is a non-essential amino acid and clearly people would benefit from getting more of this in their diet. Another one is niacin, which the body can make, yet seems to be beneficial if supplemented. I am under the impression we can make taurine as well, yet there seems to be benefit from supplementing that (I don't know much about taurine). I think my point is an obvious one.

 

This is really interesting and I have been wondering if women who aren't diagnosed with hypothyroidism also tend to be lower in vitamin A although that won't necessarily be something that most doctors focus on. They will look at your TSH and if you're outside the range they'll prescribe you some levothyroxine, with of course no discussion about nutrients. They will, however, make sure you're getting plenty of iron! Most prenatal vitamins do contain vitamin a but this is what I found on a website discussing the standards of prenatal vitamins:

• Vitamin A - 770 mcg (Note: The safest form of Vitamin A is beta-carotene or other carotenoids.)

And then most women these days don't eat liver. I guess milk provides a certain amount, assuming that the mother even drinks milk or eats dairy in general! Now so many people are drinking almond and coconut milks.

 

@Koveras do you happen to have full access to this study and be willing to post it? Or at least any information regarding the dosages of vitamin A?

 

"Children with autism were requested to complete an interview with a developmental pediatrician and submit to a baseline blood collection. Then a single vitamin A supplementation (VAS) at a dose of 200,000 IU (WHO, 2011) was performed in the thirty-three ASD patients. All evaluations and blood collection were conducted again 6 months after VAS, based on the principle that a single, large dose of vitamin A is well absorbed and stored in the liver, and then mobilized, as needed, over an extended period of time."

The WHO document they are referring to is this one:

Guideline: Vitamin A Supplementation in Infants and Children 6–59 Months of Age - NCBI Bookshelf

 

Wow! That is a large dose. Retinil, here I come!

 

By the way, thank you!!!

 

Makes sense for a prenatal vitamin as there may be some risks to the fetus of excessive vitamin A during pregnancy

http://www.nejm.org/doi/full/10.1056/NEJM199511233332101#t=article

 

Yes, perhaps for the general population, but (and please correct me if I'm wrong) isn't a hypothyroid person more likely to be deficient in vitamin a? And futhermore, unable to process carotenoids into VA?

 

Thanks, this is really amazing result, especially the reductions in serotonin. Given that these were children, I think an adult would need a 2-3 times higher dose to achieve similar reductions in serotonin. A single dose of 400,000 IU - 600,000 IU retinol ester is not that high but could cause mild toxicity symptoms in some people. Adding 400 IU - 800 IU vitamin E as a single dose to that hefty dose retinol should protect from the side effects, which should be mild anyways given that this is supposed to be a single dose.
That hefty vitamin A dose reduced both serotonin and TPH1 expression by about 40%, which is a solid result considering it was just a single dose and the effects continued throughout the 6 months. Those serotonin and TPH1 reductions were measured 6 months after the vitamin A administration. So, it is likely that serotonin and TPH1 were even lower during those 6 months after the vitamin A administration but before the blood collection took place.

 

Arghh, so true about the SSRI's. Autism websites are teeming with parents who are giving their children fish oil and ssri's. It's truly unfortunate and I wish that RP was more well-known. Unfortunately people in general, but even moreso with parents of autistic children, can be very defensive if you tell them what they've been putting all their hopes in is wrong. Especially when they've already invested a lot of money in it. It's cognitive dissonance, they are invested so they don't want to question it now because that would mean it was all wasted.

Anyways I was thinking that I heard an interview with Ray where he says that Vitamin A can compete with thyroid in hypothyroid people so he wouldn't take too high of a dose until thyroid is in good shape (paraphrasing obviously.) So I wonder if there is also a connection there with autistic folks; thyroid is not optimal so VA is deficient.

 

Another paper from the same group as above

Mol Nutr Food Res. 2017 Dec 21. doi: 10.1002/mnfr.201700754. [Epub ahead of print]
Vitamin A Deficiency Induces Autistic-Like Behaviors in Rats by Regulating the RARβ-CD38-Oxytocin Axis in the Hypothalamus.
Lai X1,2, Wu X1,2, Hou N1,2, Liu S1,2, Li Q1,2, Yang T1,2, Miao J2,3, Dong Z2,4, Chen J1,2, Li T1,2,4.

SCOPE:
Vitamin A (VA) is an essential nutrient for the development of the brain. We previously found that children with autism spectrum disorder (ASD) have a significant rate of VA deficiency (VAD). In the current study, we aim to determine whether VAD is a risk factor for the generation of autistic-like behaviors via the transcription factor retinoic acid receptor beta (RARβ)-regulated cluster of differentiation 38 (CD38)-oxytocin (OXT) axis.

METHODS AND RESULTS:
Gestational VAD or VA supplementation (VAS) rat models were established, and the autistic-like behaviors in the offspring rats were investigated. The different expression levels of RARβ and CD38 in hypothalamic tissue and serum retinol and OXT concentration were tested. Primary cultured rat hypothalamic neurons were treated with all trans retinoic acid (atRA) and recombinant adenoviruses carrying the rat RARβ (AdRARβ) or RNA interference virus RARβ-siRNA (siRARβ) were used to infect neurons to change RARβ signal. Western blotting, chromatin immunoprecipitation (ChIP) and intracellular Ca2+ detections were used to investigate the primary regulatory mechanism of RARβ in the CD38-OXT signaling pathway. We found that gestational VAD increased autistic-like behaviors and decreased the expression levels of hypothalamic RARβ and CD38 and serum OXT levels in the offspring. VAS ameliorated these autistic-like behaviors and increased the expression levels of RARβ, CD38 and OXT in the gestational VAD pups. In vitro, atRA increased the Ca2+ excitability of neurons, which might further promote the release of OXT. Different CD38 levels were induced in the neurons by infection with different RARβ adenoviruses. Furthermore, atRA enhanced the binding of RARβ to the proximal promoter of CD38, indicating a potential up-regulation of CD38 transcriptional activity by RARβ.

CONCLUSIONS:
Gestational VAD might be a risk factor for autistic-like behaviors due to the RARβ signal suppression of CD38 expression in the hypothalamus of the offspring, which improved with VAS during the early-life period. The nutritional status during pregnancy and the early-life period is important in rats. This article is protected by copyright. All rights reserved.

 

Acute effects of vitamin A on the kinetics of endotoxin in conscious rabbits. - PubMed - NCBI

A "fairly low" dose of Vitamin A caused a 50 percent reduction of endotoxin-halflife in rabbits! And it doesnt seem to make a difference if the Vitamin is given before or after endotoxin/ food .


BACKGROUND:
Vitamin A reduces the pathophysiological effects of endotoxin in animals, but the mechanism and the lowest effective dose are not clear.

METHODS:
An intravenous bolus of endotoxin 20 microg. kg(-1) was given to 30 rabbits. In 10 of them, 1000 IE. kg(-1) retinyl palmitate was injected intravenously 1 h before the endotoxin and in another 10 rabbits 1 h after the endotoxin. A one-compartment open model was fitted to the time-concentration profile of endotoxin in plasma.

RESULTS:
The half-life of endotoxin was half as long when vitamin A was given for prophylaxis (median 35 min) and for treatment (33 min) than in the controls (67 min; p < 0.004). The plasma concentrations of immunoglobulin G and M endotoxin-core antibodies, the leucocyte count and the acid-base balance did not differ between the groups during the experiment, but the pyrogenic reaction was more pronounced in the controls.

CONCLUSION:
A fairly low dose of vitamin A reduced the half-life of endotoxin.

 

Yep, VA is powerful stuff and really interesting because of its multifaceted effects, not least in maintaining our intestinal barrier.

I wouldn’t be surprised if VA deficiency is much more common than first thought. A lot of studies simply use serum retinol tests to judge VA status when this is clearly a very limited tool. Serum retinol is homeostatically controlled and only really relevant when hepatic stores are severely depleted. Therefore, people can have serum retinol ‘within range’ but, when put through something like a relative dose response test, actually be shown to have VA deficiency.

 

Can someone calculate the HED of the above study . My HED calculator doesnt work anymore and I dont know about IE either...

 

Vitamin A and Response to Endotoxin - Full Text View - ClinicalTrials.gov
I found another clinical trial about Vitamin A and endotoxin. Unfortunetly i cant find the results ,eventhough they claim the study has been completed in 2014...