Sunday, 3 January 2016

Vitamin A (and ATRA) Upregulate Oxytocin via CD38

 A familiar site to Maja, the confluence of the Sava and the Danube

Today’s post is to document an interesting discovery by Maja, one reader of this blog.  She is just ahead of some Korean researchers, who very recently published a paper in Experimental Neurobiology on the same subject.

Maja noticed that giving a small dose of fish oil produced the same benefits as those often claimed for Oxytocin; she then did some investigation and noted that an enzyme called CD38 upregulates oxytocin in the brain.  The level of CD38 is affected by inflammatory cytokines and certain vitamins.  In particular, all-trans retinoic acid (ATRA) increases CD38. All-trans retinoic acid (ATRA) is made in the body from vitamin A.  ATRA is also called vitamin A acid.

Maja suggested this paper:-

Deficits in social behavior in mice lacking the CD38 gene have been attributed to impaired secretion of oxytocin. In humans, similar deficits in social behavior are associated with autistic spectrum disorder (ASD), for which genetic variants of CD38 have been pinpointed as provisional risk factors. We sought to explore, in an in vitro model, the feasibility of the theory that restoring the level of CD38 in ASD patients could be of potential clinical benefit. CD38 transcription is highly sensitive to several cytokines and vitamins. One of these, all-trans retinoic acid (ATRA), a known inducer of CD38, was added during cell culture and tested on a large sample of N = 120 lymphoblastoid cell (LBC) lines from ASD patients and their parents. Analysis of CD38 mRNA levels shows that ATRA has an upmodulatory potential on LBC derived from ASD patients as well as from their parents. The next crucial issue addressed in our study was the relationship between levels of CD38 expression and psychological parameters. The results obtained indicate a positive correlation between CD38 expression levels and patient scores on the Vineland Adaptive Behavior Scale. In addition, analysis of the role of genetic polymorphisms in the dynamics of the molecule revealed that the genotype of a single-nucleotide polymorphism (rs6449182; C>G variation) in the CpG island of intron 1, harboring the retinoic-acid response element, exerts differential roles in CD38 expression in ASD and in parental LBC. In conclusion, our results provide an empirical basis for the development of a pharmacological ASD treatment strategy based on retinoids.

In December some Korean researchers also suggested that ATRA might be used therapeutically to increase Oxytocin.  Maja discovered that vitamin A can also be used, which makes sense.

The Korean paper reviews the existing literature and clinical trials on oxytocin in autism, and I suggest those interested should read it.

Some people clearly benefit from oxytocin, some do not and some suffer side effects.

In those that benefit from oxytocin, it might be simpler to upregulate the body’s own oxytocin via ATRA, or vitamin A.

Is this proof?

Of course there are other explanations possible for what Maja has noted.  She was using fish oil as a source of vitamin A, so it could be related to the other constituents.

However, I for one think it is highly plausible and does fit nicely with the ideas put forward by the Korean researchers and the earlier paper.

Vitamin A for all?

We know that autism genes include many for oxytocin, oxytocin receptors and indeed CD38, so anyone with those genes dysfunctional might benefit.

However, as we saw with biotin, more people may be affected to a lesser degree.

CD38 affects oxytocin secretion in the brain and CD38 is affected by inflammatory cytokines, so at times of elevated cytokine expression, CD38 and oxytocin might be reduced in people with no relevant genetic dysfunction.

You can have too much vitamin A, this is called Hypervitaminosis A.  You cannot suffer this condition by eating fruit and vegetables, but you can by eating too much preformed vitamin A from foods (such as fish or animal liver), supplements, or prescription medications; it can be prevented by ingesting no more than the recommended daily amount.

High intake of provitamin carotenoids (such as beta carotene) from vegetables and fruits does not cause Hypervitaminosis A, as conversion from carotenoids to the active form of vitamin A is regulated by the body to maintain an optimum level of the vitamin. Carotenoids themselves cannot produce toxicity.

So, too much cod liver oil can be bad for you, but you can eat carrots like Bugs Bunny and do no harm.  If you really overdo it, your skin may change colour to orange, something called carotenosis

You can buy vitamin A supplements as the preformed vitamin or as beta carotene.

Too much of a good thing?

In times gone by, children used to be given a tablespoon of cod liver oil daily, as a good source of vitamin D and vitamin A.  These days that amount of both vitamins would be seen as excessive.  Excess of both vitamins is bad for you, but easy to achieve, by accident, while trying to do a good thing.

Maja’s Dose

Maja achieved her positive results with a modest dose of fish oil (using 40% of one capsule) giving 3-4000 IU of vitamin A.

This is actually quite a high dose of vitamin A, if you look at the maximum safe dose.

I think many people are giving kids with autism much larger doses of fish oil and thus far too much vitamin A and D.  This has been raised as an issue by Seth, another reader of this blog.


CD38 has many other functions other than regulating oxytocin. In people who have an oxytocin dysfunction due to an upstrean CD38 dysfunction, correcting the lack of CD38 might be particularly beneficial.   

CD38 is used as a prognostic biomarker for leukemia.  This is a complex area of science.  In essence, it is an accepted fact that increased CD38 expression is associated with favorable prognosis in adult acute leukemia.

Leukemia is associated with Down Syndrome. 

Not surprisingly, both vitamin A and ATRA can be beneficial in treating leukemia.
ATRA (All Trans-Retinoic Acid) for acute myeloid leukaemia (AML)

CD38 expression is apparently easy to measure.

Perhaps in those numerous oxytocin trials for autism, they might want to bother measuring CD38?

The Recent Korean Paper

Here is what the Koreans have to say about Oxytocin:-

CD38 is a transmembrane antigen that has been studied as a negative prognostic marker for chronic lymphocytic leukemia [72]. CD38 participates in the oxytocin secretion in the brain and affects maternal nurturing and social behavior [73]. Plasma levels of oxytocin are strongly reduced in CD38 knockout mice (CD38-/-mice) and subcutaneous oxytocin injection or lentiviralvector-mediated delivery of human CD38 into the hypothalamus rescued social memory and maternal care in these mice [73].

CD38 transcription is highly sensitive to cytokines and vitamins, including all-trans retinoic acid (ATRA), a known inducer of CD38 [75]. In a study on lymphoblastoid cell lines in patients with ASD and their parents, ATRA exhibited an upmodulatory potential on CD38 mRNA [75]. Although there have been almost no follow up studies on ATRA and ASD treatment, there is a possibility that substances affecting CD38 expression, such as ATRA, may be potential therapeutic candidates


  1. Peter why do say that 3000/4000IU is a high dose of Vitamin A? Do you mean for children? 1 IU Vitamin A as beta carotene is equal to 0,6 mcg, 3000IU is 1800mcg(1,8mg) and 4000IU is 2400mcg(2,4mg), please correct me if I am wrong. This amount of vitamin can be found in many supplements per tablet. For example Solgar Omnium has 2,5 mg beta carotene per tablet and the recommended dose is 2 tablets daily.

    1. Petra, beta carotene is not preformed vitamin A and you cannot overdose on it. The body only converts the amount of beta carotene to vitamin A that it wants to. If you give actual vitamin A, or fish oil, this all becomes vitamin A in your body, so you can overdo it.

      Table 2. Recommended Dietary Allowance (RDA) for Vitamin A as Preformed Vitamin A (micrograms [μg] of Retinol Activity Equivalents [RAE]/day)

      Life Stage

      Age (μg/day) maximum dose

      Infants 0-6 months 400
      Infants 7-12 months 500
      Children 1-3 years 300 600 maximum
      Children 4-8 years 400 900 maximum
      Children 9-13 years 600 1700 maximum
      Adolescents 14-18 years 900 2800 maximum
      Adults 19 years and older 900 3000 maximum

      IU is equivalent to 0.3 microgram (μg) of retinol, and 1 μg of retinol is equivalent to 3.33 IU of retinol

      So 4000IU equals 1,200 μg (mcg) which is above the RDA, but below the suggested safe maximum of 1,700 in a 9-13 year old.

      Some cod liver oil provide 13,000 IU of vitamin A per serving. Too much.

    2. Peter, do you think it would be possible to create the melatonin effect in a similar way to oxytocin?
      I've read in the consumer's lab page, where they trial the effectiveness of supplements for various disorders, including autism, that an adult can have as much as 20mg melatonin a day in order to have its antioxidant properties especially when it comes to mitochondrial disease. Melatonin is a synthetic hormone and I'm a little reserved to trial that much.
      Anyway, so what would be your recommended dose of beta carotene if you don't want the get the orange face?

    3. Petra, I do not know about another way to stimulate melatonin, however it does seem that quite beneficial effects can occur in some people with autism at 10mg. This is being studied. The risk is that if you give melatonin, the body may stop producing its own. This is what happens in people with a functioning thyroid, who then take additional thyroid hormone T3/T4.

      I think the best way to see if you can benefit from Maja's discovery is to give vitamin A itself. Perhaps in some people they have plenty of beta carotene but the body just does not convert enough to vitamin A. It may be unlikely, but certainly is possible.

      My son loves to eat raw carrots, so I doubt he is short of beta carotene. It is very cheap to buy 5,000 IU tablets of vitamin A, you can cut them in half of course.
      So I will try it for a week or two and see if it has any effect. It would be interesting for those people who currently use oxytocin, to see if vitamin A is an effective alternative.

    4. Hi Peter, my son has always been a picky eater, especially after 12, so he rarely eats food containing beta carotene or vitamin A, except for some spices, milk and a small amount of onion, tomato, garlic in his lentils soup. The only vegetable that he eats is broccoli capsules.
      When I first used Omnium I did it for its SFN exracts as I was expecting broccoli sprouts powder from Australia, and saw an immediate effect on him. It is very similar to Oxytocin effect but could not connect it then. He is very affectionate and compasionate in many aspects. Of course I can only speculate that beta carotene created the effect, but still Omnium has a good amount of it.
      I'll try Vitamin A itself, just in case he cannot metabolise beta carotene into vitamin A. The only suitable product I found is Sogar Vitamin A 5000IU in dry tablets but it's out of stock for the time being. All the other products have 10000IU in jelly form and cannot be splited.
      Peter, in your articles you mention many things about calcium channels dysfunctions in autism and not being familiar with it, just in case there is also something wrong with my son's disorder, do you think 64mg of calcium(bisglycinate, ascorbate, D-calcium pantothenate) and also vitamin D 5 μg would be a problem?
      Thank you very much

    5. Petra, one reader's child had a very bad reaction to calcium supplements. If your son drinks milk, he should not need extra calcium. Often vitamin D has been added to milk and other products.

  2. Thank you so much for documenting this discovery. It was a good read.
    I am also taking Vitamin A that is why it interest me a lot.

  3. Offtopic (so feel free to delete this if you want), but I am sure you would be very interested in this:

    I read some stuff about this group a while back as they are working on the MeCP2 gene (I am 99% sure you know what it is). So essentially they found that in a model of Rett Syndrome if they restored the function of the KCC2 chloride cotransporter, then GABA function returned to normal (rescuing the diseased mice). The way they did this was to directly treat the nerve cells with IGF-1 (as far as longevity is concerned it is a hormone you want to minimize, but obviously not too much as is the case with Rett Syndrome).

    Anyways, you can read the rest of the article. The paper they linked is on public embargo (not released to the public) so you might have to wait several weeks to read it on or wherever you happen to get the full text of papers that interest you.

    1. Thanks Tyler it is interesting. I think it shows how different causes can lead to common dysfunctions. We want less KCC1 and more KCC2. People with Rett have highly disturbed growth factors, but always in the same direction. People with autism can have high IGF-1 (like my son) or low IGF-1, or just average. It would seem that people with Rett should try bumetanide, just like those with Down Syndrome, and of course autism.

  4. This is very interesting. I have been supplementing a product called Niagen for about two years now to my 6, soon to be 7 year old son. Niagen's active ingredient is called Nicotanimide Riboside. Unfortunately, even though it is a natural substance (found highest yet in trace amounts in milk) and is not patented, the company that sells Niagen bought up all the patents on manufacturing the stuff industrially.

    cADPR is produced from the breakdown of NAD+ which Nicotanimide Riboside (NR) directly raises which is why it is primarily being marketed as an anti-aging supplement, though it has been trialed successfully in treating one form of mitochondrial myopathy (because it uniquely raises NAD levels without triggering genes which then lower NAD levels as simply supplementing plain Niacin seems to do).

    Now, in the paper cited on Wikipedia cADPR gets produced via NAD+ and two enzymes produced from CD38. After some cursory reading, with one type of heritable mutation the functionality of these enzymes reduces the effectiveness of producing cADPR to only 30% of normal.

    There are people who megadose with Niagen even though for health maintenance the studies the company has done suggested optimal dosage is 250 milligrams a day. There are people who megadose this stuff and have not had any big negative side effects that have been reported (that I am aware of).

    So running under the hypothesis that due to the inefficiency of the enzymes, in utilizing the available NAD+ you could perhaps hack around this problem by boosting NAD+ by some large amount (333% in the case of the nonsense mutation I mentioned above). How much NR you would need to do this, well I have no idea off the top of my head, but in addition to the intervention cited in this topic about Vitamin A, perhaps a far higher dose of NR than is typical might address this CD38 problem in an indirect way?

  5. Thank you very much, Peter.
    This picture of Belgrade in Serbia would be excuse for my poor English.
    Optimal dose of retinol is hard to determine. More or less, this is recommended: multivitamin/mineral supplement that provides no more than 2,500 IU (750 μg) of preformed vitamin A (usually labeled vitamin A acetate or vitamin A palmitate) and no more than 2,500 IU of additional vitamin A as β-carotene.
    Tolerable upper intake level for preformed vitamin A for children 9-13 years is around 5 500 IU.
    To determine a real level of vit A in serum is hard because of its deposits (mostly in the liver).
    I don`t give my child extra D vitamin, she gets it through other supplement (Cardiovitamin, in my country) - 200 IU of D3 vitamin. The supplement of fish oil I use has only A vitamin in it, cause I don`t want extra D vitamin (during the summer, my child usually gets worse).
    Now I can`t understand how I didn't notice earlier the need for the retinol. I used to give her the small amount of it in the CLO which maintained the basic level.
    As soon as I stopped that, in 2-3 week, the sights of deficiency has occurred: hyperkeratosis, itchy eyes, instability in the dark; dermatitis seborrhoica of the scalp and strabismus exacerbate. But, what surprised me is a loss of eye contact, foggy and uncooperative behavior, abdominal cramps, apathy, and a call from teacher because "something went wrong".
    All of that disappeared in with supplementation. The very first day I noticed better eye contact and better mood.
    Does she has vitamin A deficit or something else (irregularity of the CD38 gene....)? I don`t know. Would the retinol supplementation help other kids in the same way? I don`t know.
    I am going to speak with the researcher from The Institute for Medical Research, and informe you after that.

  6. Hello peeps,
    33 year old male with asperger syndrome here, would like to share my experience with nicotinamide riboside (2x 250mg/day) both on empty stomach, together with broccomax/sulforaphane (3x 2tablets hour after a meal - HDAC inhibition/gluthatione production/phase II detox in liver).
    My experiences so far have been VERY VERY good, other supplements i take besides this i take in the evening (magnesium biglycinate and ksm-66 ashwagandha).
    Planning on adding sodium butyrate next with Miyarisan (Clostridium Butyricum).
    The effect so far on niagen + broccomax have been AMAZING, no other supplements gave me these effects so far, im so much more social, actually starting to have some desires now to go out and meet ppl, even my environment is noticing it.
    And I havent even used them so long yet, only about 3 weeks in so far, looking very promising!!!

    1. Thank you for that! Did you start niagen + broccomax at about the same time? What about vit D3, also around that same time? tx

    2. Hi Nat,
      No I did not, I started it during the summer after reading so much positive things about it regarding antiaging on
      I allready felt back then in the summer that niagen was doing something positive but I was on 2x 125mg a day, it was not untill 2x 250mg/day for me that I started to notice huge benefits.
      Both mood wise and energy during the day wise, I feel far far less drained after either mentally or physical activities.
      As for the Sulforaphrane, I feel it helps me so far being more social and outgoing, keep in mind I have only been using is 3 weeks so far! I know theres such a thing as the placebo effect, but the people around me are noticing that im improving so much aswell, and best of all for me personally completely side effect free.
      I think HDAC inhibition is very very usefull for autism/autism spectrum disorders, apparantly from what ive read it is the pathway to gene regulation, sulforaphane is also a HDAC inhibitor, not sure how strong though.
      For example I notice when i started eating alot of full fat yoghurt and goat cheese my mood also was improving alot (I do still take a fair bit of oliveoil aswell, but ive been increasing my satured fat consumption). For me personally all the increased fat intake I have been using over the past months and slowly cutting down a bit on the carbs has even made me lose quite alot of bodyfat and I feel so much healthier overall.
      My HDL gone from 1.1 to 1.6 and my LDL is very low now and total cholesterol is mid range.
      Before I started this diet my LDL was low, total cholesterol was low and HDL was low.

    3. I'll be buying sodium butyrate and Miryarisan next.
      Im pretty sure this will help me tons.
      Ill keep you all updated and share my experiences.

    4. Aspie1983, thanks for sharing you experiences. You might also want to try potassium. One adult with ADHD recently sent a comment that it solved his problems whereas years on various ADHD drugs did not help. Potassium supplements are cheap and any effect would be within 10-20 minutes. Potassium ion channel dysfunctions seem to be common in autism.

    5. Hi Peter,

      Which supplement or form of potassium would you recommend as Ive seen most potassium supplements only contain 99mg.
      Besides, I allready spend so much on supplements, especially niagen and broccomax are very expensive.
      I allready eat quite healthy, and has my potassium and sodium has been checked by bloodtests about a year ago, both were nice in mid range.
      Calcium somewhat high up in the range but still within limits and magnesium low-medium ish.

    6. Hi Aspie,

      This is the one I use, its 200mg:

    7. Aspie 1983, just use a cheap one. In the US they are all very weak to stop people being stupid with them. I buy a 500mg effervescent tablet. The RDA is over 3 grams a day.

    8. Aspie1983 another question if you don't mind, wondering if you have tried the plain nicotinamide/niacinamide, as opposed to the (much more expensive) nicotinamide riboside/Niagen patented form?

    9. Hi Nat,
      I have tried the flush version (nicotinic acid), which did make me sleep like a rock.
      The flushing apparantly is due to histamine release, I didnt find it very uncomfortable allthough I think some can.
      The danger apparantly with most forms of vitamin b3 is that it has downside, such as possible insulin resistance in higher (effective dosis they use to lower LDL) ->

    10. Yes I know that the RDA is pretty high, the problem with getting all the potassium from foods ( vedgies are high in em - I used to eat 400-500gram vedgies a day, i felt healthier but had tons of constipation so I stopped that, basically my stools were like a solid rock).

      Peter, I want to try vitamin A first, can you give me any recommendations on which form to try? Im pretty sure beta caratoen is a bad version.
      By the way I have tried seriously so many oxytocin raising drugs/supplements, including viagra/sildenafil/vardenafil which I have had pretty good social mood boost with but it the effects do not seem very stable and reliable often.

    11. Hi Peter,
      I got a potassium gluconate supplement at home right now, says 550mg of potassium gluconate (90mg potassium), how many tablets would you recommend for a first try?

    12. A banana has about 400mg of potassium so that would be about 4 of your tablets, but the potassium in a banana is absorbed gradually. In Europe people take effervescent tablets with 500mg of potassium. So you could take 4 or 5 90mg tablets with a full glass of water. Most of your tablet is gluconate rather than potassium.

    13. Thanks for the reply Peter,
      I have tried 5 tablets twice daily with a meal, so took 900mg in total in addition to what I get from my meals.
      Maybe some minor relaxation I noticed, nothing major though it seems so far, will try it for a few more days.
      Im still going strong on the sulforaphane and niagen btw, ive even ordered a sprouting jar now, as I seen a video where the sulforaphane from broccoli sprouts is far far better absorped than from broccomax, and at about 1/8th the price.
      With regards to ATRA, I have found one of the only natural sources of retinoic acid is colostrum, which my mother (who has crohn desease ) has had great results with, so if someone was wondering and wanted to try, worth a shot id say.

  7. Forgot to add, I take 2x 5000iu vit d3 a day too and ubiquinol 200mg/day

  8. Small update, ran out of niagen just under a week ago, quite a noticable difference in my mood and energy( in a negative way ).
    My niagen is coming in on monday and will let you all know how I feel again once im back on it.

  9. Does anyone know anything about the research being carried out into a substance derived from vit a called atra? It has apparently been very effective in repairing damaged lungs in mice? Atra now being spoken of as 'cure' for copd/emphysema-but I can't find out much else about it.

    1. The mouse studies were twenty years ago and the human trials were at UCLA ten years ago. In the end they concluded that ATRA was not of benefit to humans. The study was called FORTE, but there is not much information available now.


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