Thursday, 13 April 2017

Estradiol/Aromatase Deficiency in Autism, Schizophrenia and Bipolar

There was a rather complicated post in which I was linking some of the odd biological features of autism to something called RORα.

This was one of those posts that appeals to the scientist readers like Tyler.

Happy with his elevated estradiol level

Today’s post is more like the Psychiatrist's take on the same subject, so it is less complicated.

I was thinking that a logical way to treat boys, post puberty, and girls with autism would be to target RORα. In males this would be the treating aromatase deficiency.  You would start by measuring by measuring the level of testosterone and estradiol in both boys and girls.

My assumption is that there will be a substantial group of males who will have high testosterone and low estradiol.  In autism and its big brothers (and sisters) Schizophrenia and Bipolar, there are disturbed levels of these hormones.  One logical therapy would be estradiol, which is much less problematic for girls than boys.

Boys with genetically caused aromatase deficiency lack the female hormone estradiol, but are not treated with transdermal estradiol until after puberty.  Girls are treated with estradiol from a younger age.

Untreated males with aromatase deficiency have retarded bone age, but end up as very tall adults. They also have a problem with low bone density and so have weak bones.

Clinical Features of Aromatase Deficiency

Fetal life:
Masculinization of the mother during pregnancy
Masculinization of the mother during pregnancy
Genitalia at birth:
Severe clitoromegaly and posterior labioscrotal fusion
Normal male
Multi-cystic ovaries
Absent growth spurt
Absent breast development
Primary amenorrhea
Further enlargement of clitoris
Enlarged cystic ovaries
Normal development of pubic and axillary hair
Absent growth spurt
Normal pubertal development
Severe estrogen deficiency
Enlarged cystic ovaries
Continued linear bone growth
Tall, eunucoid proportions with continued linear growth into adulthood
Genu valgum


I have commented before that I think retarded bone age is a useful marker of some types of autism. You just need an X-ray of your hand and some interpretation that looks at the gaps between the small bones.

We have also seen in the comments section of this blog that numerous readers have low bone density problems in their families.

Extreme aromatase deficiency is very rare and is caused by mutations in the CYP19A1 gene.

We saw that RORα seems to be a hub for where things go wrong in autism (also schizophrenia and bipolar); I am not suggesting a problem with the CYP19A1 gene.

One approach in psychiatry research is to just try things, without bothering too much about the underlying science.  This has been the case with Estradiol, where there have been several very positive studies in schizophrenia and bipolar.  

Estradiol in Clinical Trials

Nobody is going get approval to use Estradiol in young boys, other than those who are promoting gender reassignment. These people want to chemically block puberty and then use high doses of estradiol to feminize the male body.

Estradiol is widely used in post-menopausal women, but also in clinical trials of middle aged women with schizophrenia or bipolar, where it appears to provide a clear improvement.

Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean = 35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 μg, transdermal estradiol 100 μg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo this study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.


It appears that the female reproductive events and hormonal treatments may impact the course of bipolar disorder in women. In particular, childbirth is known to be associated with onset of affective episodes in women with bipolar disorder. During the female reproductive events the sex hormones, e.g. estrogen, are fluctuating and particularly postpartum there is a steep fall in the levels of serum estrogen. The role of estrogen in women with bipolar disorder is, however, not fully understood.


The main objective of this review is to evaluate the possible relation between serum estrogen levels and women with bipolar disorder including studies of the anti-manic effects of the selective estrogen receptor modulator tamoxifen.


A systematically literature search on PubMed was conducted: two studies regarding the connection between serum estrogen levels and women with bipolar disorder were identified. Furthermore, four studies were found concerning the antimanic effects of tamoxifen.


Both studies in the estrogen studies showed very low levels of estrogen in women with postpartum psychosis and significant improvement of symptoms after treatment with estrogen. The four tamoxifen studies found that tamoxifen was effective in producing antimanic effects.


These results indicate that estrogen fluctuations may be an important factor in the etiology of bipolar disorder and it is obvious that more research on this topic is needed to clarify the role of estrogen in women with bipolar disorder.

Men also need to have a certain level of estradiol, but as they age, and particularly if they get overweight, they often end up with too much.  So the usual problem is too much estradiol.

In males, estrogen is produced in fat (adipose) tissue by the action of the enzyme aromatase on testosterone.  So it would not be surprising if males with five times more adipose tissue produced more estrogen/estradiol. This would might explain mild feminization of the body and the lack of more aggressive male behaviors.

Many males with schizophrenia and a substantial number with autism are on medication that causes weight gain. While there are is research on how to reduce this weight gain, if the weight gain causes more estradiol, there actually is some potential benefit.

"We found that testosterone alone can improve an aspect of memory known as spatial memory -- the kind of memory needed to drive, get dressed, use a knife and fork -- what you need to learn to navigate three-dimensional space," Asthana says. "But men with both testosterone and estrogen had better verbal memory."

Asthana thinks that new estrogen-like drugs that lack sex-hormone effects such as breast enlargement might be useful to preserve memory in aging men. He says he is planning to test this theory in human trials

An estrogen-like drug, raloxifene, was trialed unsuccessfully in women with Alzheimer’s, but not in men.

Estradiol is a research therapy for males with prostate cancer.

Estradiol in Autism

We saw in the science heavy earlier post that that children with autism do not have sufficient estrogen receptor beta expression to mediate the protective benefits of estrogen.

Estrogen receptor beta agonists, which are already known to improve brain plasticity and memory in animals, have been proposed to help reverse autism's behavioral deficits.

High testosterone, low aromatase and correspondingly low estradiol are features of autism and will compound the effect of reduced estrogen receptor beta expression.


There are far less issues with the use of estradiol in females with autism.  Given there have already been trials in Schizophrenia and Bipolar on females using estradiol, it is about time a psychiatrist made a trial in autism.

I think that via the effect on RORα, there will be numerous positive effects.  The risks and side effects will be exactly the same as in the previous Schizophrenia and Bipolar trials.

Having seen what, if any, positive effects the females with autism experience, it would be time to consider adult males.  Is there a behavioral benefit in small enough doses of estradiol that do not cause feminization?

It would also be useful to measure the level of estradiol in overweight males to get some benchmarks of what is “normal" today in males.

Later on, using bone-age and indeed estradiol levels it might be possible to identify a sub-group of autism who might be likely to benefit from this therapy.  There may even be familial markers, like problems associated with low bone density, which might predispose the person with autism to have low levels of estradiol.

The other issue is the lack of estrogen beta-type receptors in people with autism.


  1. Peter, Leptin seems to be elevated in some autism.

    Fluoxetine, spirulina and omega 3 fatty acids may improve leptin sensitivity.

  2. Hi everyone,

    Happy Easter!

    While there are a lot of papers about ASD, a few capture my interest, and I figure this one may be of interest to the community, so I wanted to share:

    It's called "Cluster of Differentiation 5 (CD5) Levels in the Plasma of Children with Autism Spectrum Disorder (ASD)"

    I'm going to look further into CD5 but if anyone has any insights, please share.

    Also, wanted to get the opinions of those who may know the answer to this question - P5P in theory is a good part of a treatment protocol, but at even low doses, my daughter complains of headaches so I don't use it. But it struck me, could the headaches themselves be telling me something? I know that headaches could be a normal side effect of P5P, but is there something more that it could be telling me about the nature of her condition? If anyone knows something beyond the standard side effect, it would be much appreciated.

    Thanks all!


    1. AJ,
      Is your daughter low on riboflavin? I remember reading many years ago that riboflavin is needed too when supplementing b6. Could it be supplementing the p5p has caused her riboflavin levels to dip and therefore the headaches? Riboflavin is often used as a treatment for migraines (it was very helpful for my son when he developed migraines a few years ago). My son responds to b6 but it took some time in figuring out how to see the good effects - maybe it was just a matter of the riboflavin balance for him? His OATs always showed a need for both b6 and riboflavin. Maybe you can find some ideas from this write up:
      Happy Easter to you as well

    2. Hi Tanya,

      Thank you so much for your response! I had no idea about the relationship between B6 (P5P) and Riboflavin. The fact that Riboflavin is used for headaches / migraines may be exactly the clue I was looking for.

      I'm going to go out first thing today, get Riboflavin, and give it to my daughter for a few days before starting P5P at very low doses and titrating up to where she should be slowly. If there are no complaints as I increase the P5P dose, then your insights will have resolved the issue.

      As far as blood tests, our daughter is 4 and we've never had one, so I have no idea what she's low / high on. She is so terrified of anything medical, that I can't imagine how we would do it. Honestly, I'm waiting for a device from a company called Seventh Sense Biosystems to be approved for regular blood draws and then I'm going to run every test possible. Painless, and not as scary looking as a needle, and it should be available soon

      The article you listed was also helpful in that it noted Zinc and Magnesium as well. I give my daughter both, and Magnesium L-Threonate specifically as its supposed to be more efficient at getting to the brain.

      Tanya, I want to say again, that I really appreciate your responding to my question. Your insights may allow me to give my daughter P5P, and hopefully that will lead to more improvements in her condition.

      Hope you have a wonderful Easter Tanya!


    3. That device sounds very interesting! I do not blame you at all at avoiding the stress of a blood test - most of them for vitamin levels are inconclusive anyway and just give a snapshot in time picture of things - plus you have to weigh the stress of that event against any benefit you would receive for the labwork. Especially if it is rabbit hole testing. The OAT however is a urine test - so pretty stress free. Yes you are right too about supporting with magnesium and zinc. I remember reading Dr Rimland's notations on people usng the b6/mag therapy running in to problems could indicate the need for zinc. I hope the riboflavin helps - if you are unsure you are seeing anything, might want to switch to the r5p form. That is the form we use from Thorne. Best wishes!

    4. Hello AJ,

      So happy to know that your daughter is responding well to supplementation. My son was doing OK with the methylcobalamin and some vit c, fisetin and Nigella oil routine (I was planning to slowly add in the folinic, Dmg, p5p, pqq+Co q10, omega 3s and basic multi with zinc to cover base) till my son fell ill with a bad cold and a round of antibiotics which left him really irritable with a disturbed digestion. Now these are the episodes that totally throw you off track with regards to monitoring effect of one's treatment protocol.

      After stopping everything for a week, I have resumed the methyl b12 and added in around 200 mcg of folinic. My specific query is about magnesium which has been touted everywhere as the safest intervention and is supposed to be added in to most autism supplementation regimes, along with b6 especially if you are trialing DMG. I have been giving around 100mg of magnesium as a glycinate twice daily and as I have been taking it myself, even at that low dose, it's causing me great discomfort within five minutes of consuming it. Last night it was like somebody has stuffed an inflated balloon in my stomach and trying to wrench it out now and then. My son too, within minutes of taking it started the odd looking through corner of eyes act, which is a big sensory indicator in his case of digestive discomfort. It would be helpful if you could tell me how much mag.threonate you are giving to your daughter, is she tolerating it well and is it making any perceptible difference. Magnesium is supposed to be calming but if I continue to see the opposite even after reducing the dose further, it means we can't tolerate Mg and I will have to let it go.


    5. Kritika, try a different form of magnesium. From what I remember, with compromised gut environment, the magnesium glycinate form can convert to oxalates - which does sound like the stomach symptoms you are describing. Try magnesium taurate.

    6. Tanya,

      You are right as ever. We tried the glycinate form on s compromised digestive system resulting from the course of antibiotics we took...both of us. Also, a hyper sensitive GI system is part of our rich family tradition/genetic make up. Its disheartening when the safest of intervention backfire on you.

      This is not end of the story though. Today, I left out the magnesium but with his oral mb12, I gave him just s little amount of folinic (around 200 mcg). But what i thought was a 'science based approach' again betrayed me. By evening, my kid was doing a perfect mad act, laughing like crazy for no reason and was asking for help for writing even simple numbers like 20. I do not know if its a random episode or related to folinic acid. In Peter's elder son Ted's words, he just became more stupid. I think i am getting blinded by all that science.

  3. Hi Peter, Happy Easter to all of you on this blog!

    Peter, I deeply appreciate what you are doing and thanks to you this Easter time is a lot happier for us.

    The brain GABA-benzodiazepine receptor alpha-5 subtype in autism may be relevant to my son's Asperger's.
    I remind you that my son cannot even tolerate 0.75mcg clonazepam longer than 4 to 5 days which may mean it builds up and probably interacts with a dysfunctional a5 subunit. This leads me to think there must be a mutation there.
    There is research on how to modulate this subunit with novel drugs other than benzodiazepines.
    If you happen to know more about this, please let me know.

    1. Petra, what benefit do you see from the micro dose clonazepam? So are you doing a cycle dose like 4 days on 3 days off since he cannot tolerate more than 4 days? Or are you no,longer using? Since clonazepam is a substrate of cyp3a4 enzyme is he taking in any high amounts of cyp3a4 inhibitors like garlic which could be causing the negative side effects? Just curious in hearing everyone's experience with this. thanks so much for sharing.

    2. We tried Low dose clonozepam and first time started at .3mcg and at .35 mcg it gave hyper activity and regurgitation so stopped. Next time we started at .1 mcg and increasesd slowly. At .35 mcg it gave hyper activity as well as verbal stimming so stopped. Such a disappointment.

    3. Hi Tanya,
      I used LDC several times for my son. Each time I could see some kind of alertness and presence in his environment which could also be described as less stereotypy/stimming.
      I could also see this happen on the third day as the dose builds up.
      My son is the type who shows paradoxical reaction to benzodiazepines and although this dose is absolutely tiny, as it was building up, he ended up with anxiety and aggression.
      I also noticed that tea or coffee or probably other food, might have interacted with clonazepam.

    4. Petra, there are not many obvious ways to reduce the effect of GABA alpha 5. It should give cognitive enhancement and also perhaps be anti-depressant.

      There is an old Russian drug Pipofezine, a tricyclic antidepressant that is a Pyridazine class drug. Some Pyridazine class research drugs have been found to be inverse agonists of alpha 5. Nobody seems to have tested the Russian drug.

    5. Salempeacock,the half-life of clonazepam is long and you need to keep the same dose for 3 days to reach a stable level. For a 10 year old child 25mcg is a good place to start. If the dose is slightly too high there are very clear negative behavioral effects. I think you mean you were giving 35mcg, which in a very small child is too much.

      The effect is not transformative and perhaps it was not noticed as the dose was increased.

    6. Peter,
      What may be the dosage for a 12 kg 3 year old child? We dissolved.5 mg tablet in 100ml water and started from 1 ml daily. Waited for 4 days and increased to 1.5 ml and like that reached 3.5 ml.

    7. Salempeacock, I would have thought you would need between 1ml and 1.5ml, but it is very individual and does seem to be affected by any other drugs he might be on.

      You might want to try 0.7 to 1.0ml. This will be difficult to measure. It might be best to cut the pill in half so that the volumes are easier to measure (so 0.25mg in 100 ml and start at 1.5ml for several days).

      The fact that he had a negative response at the higher dose does tell you something, because in typical people I doubt it has any effect at all, at what is a sub-clinical dose.

      I am not sure what effect you would see in a 3 year old, it all depends how severe is his autism. At that age people with severe autism cannot do much.

      Does he respond to bumetanide?

    8. Thanks Peter. I have got .25 mg tablets. Will try that. We tried bumetanide.5mg twice daily for 40 days with no effect. The next batch of bumetanide was delayed so couldn't try 1 mg daily. Meanwhile we started leucovorin calcium and only recently reached 20 mg. We are supposed to try that dose for 3 months. After that we plan to try bumetanide and clonazepam.

    9. Peter,
      My grandson has moderate autism I think. Occasionally his intelligence gives us a shock. By watching video he taught himself to recite and read alphabets and numbers, colours and shapes when he was two. So I think any positive effect can be identified. He can speak and has a very good vocabulary (picture cards and ABA) including prepositions but has little functional speech. Still not responding to his name. Very affectionate and hugging type even with newly introduced persons. May be that's why oxytocin had no effect. We tried it for a month.

    10. Peter, could you elaborate on why not much can be done for severe autism at young age eg in a 3 year old child?

    11. Agnieszka, my point is not that you cannot treat a 3 year old with severe autism, but rather you may have difficulty judging the result.

      This is for two reasons. The first is that in people with severe early onset autism the disease is still progressing, and so a child at 3.5 years can be seen as more "autistic" than he was a 3.0 years. So you might give an effective therapy at 3.0 years and see no improvement, but you did stop things getting worse.

      The second reason is that if a child is non-verbal, remains in his own world, and has no basic skills, but has yet to develop stereotypy, self-injury or seizures, it is hard to have any benchmarks for "improvement".

      If a child speaks in single words and overnight starts to speak in 2-3 word sentences everyone will notice and the new therapy is likely the cause.

    12. Thanks. That's in line with the results of the last bumetanide RCT and with what I was told when asked about off-label French experience with bumetanide for children 2-3 years old compared to older ones.

  4. Came across some very interesting new research regarding a SHANK3 study on mice that showed that D1 expressing neurons in the basal ganglia (direct pathway neurons) in control mice and SHANK3 mice increase locomotor activity while D2 expressing neurons in the basal ganglia promote repetitive behaviors in SHANK3 mice when they are hypoactive:

    Press Release:


    This suggests a much more complex scenario where even if dopamine levels are not excessive (which leads to hyperactivation of D1 expressing neurons and increased locomotor activity), repetitive behaviors will still ensue due to D2 expressing neurons failing to activate properly, leading to a lack of inhibitory drive from the indirect pathway of the basal ganglia.

    So to sum things up, it is suggested that in SHANK3 related autism, to correct repetitive behaviors requires that D2 expressing neurons are upregulated artificially somehow and that simply increasing dopamine won't fix the repetitive behaviors (in fact they can become worse), but rather will lead to an increase in hyperactivity just like with control mice.

    So if one were to make a human therapy for this, one might consider doing your best to normalize dopamine transmission along with D1 pathway by avoiding D1 agonizing drugs or excess dopamine in the brain, while at the same time increasing D2 pathway neurotransmission via mglur5 agonists as well as calcium channel activators. Of course, the challenge of selectively enhancing D2 neurons while not activating dopamine transmission in other areas of the brain is a big challenge with drugs. Either way, specifically addressing repetitive behaviors will involve increasing D2 basal ganglia receptor neurotransmission one way or another.

    I have noticed this paradox in my son where when he is hyper sometimes he is less involved in repetitive behaviors and more engaging, however when he is calm he might be fixated on his eye bad playing the same video he likes over and over again. At speech therapy both scenarios cause big problems as hyperactivity makes it hard for him to focus, while being calm yet engaged in repetitive behaviors makes it hard for him to shift his attention. When everything seems balanced with regards to his activity level (i.e. activity level slightly above average bu not more than that), he has good therapy sessions, while if he is too hyper or too engaged in repetitive behavior stuff, then things can be frustrating for the therapist.

    1. Tyler,

      I have the same observations with my son... You had seen this kind of response with broccoli sprouts as well , I suppose. I an currently trying out methylcobalamin and at 1000 mcg once every three days seems to be doing some good... Happy, assertive and best of all claiming independence. Marked increase in understanding and a newly acquired sense of maturity where he is pushing me away to do copy basic words on his own and even at the therapy excercises...its like, ma i do not want you to watch me doing stuff. But sitting tolerance has gone down drastically and while earlier he had started to sit for fifteen twenty minutes strsight with his tab, watching videos, not the same ones repeatedly but different numbers, he is just on the move now. As a lay observation, increased brain energy that is not being channelized perfectly... So some good stuff but some bad too. I plan to trudge on and just give the full protocol a decent try...mb12, folinic, NAC, DMG and add in the Mg-B6, a decent multi, EPA,DHA and see how it goes. Some perills oil and some Pqq+coq10. Very very slow...and low.

      Any insights are welcome.

    2. I do some of those interventions as well, but I don't think they are going to do any wonders for pretty much all people with autism even though addressing oxidative stress/methylation issues may be a prerequisite for other interventions working. My son also has this independent streak of pushing me away and I attribute that mostly to socialization and "dealing with people" being stressful for him. For my son this behavior has always been off and on.

      Also, core autism features likely start manifesting themselves in utero and then snowball from there so the strategy I have always employed is do whatever I can to first keep the snowball from growing (oxidative stress/inflammation issues shown in autism specific research), and then working on specific fixes or at least workarounds to developmental problems that at this time can't just be rewound. So this is where looking at direct neurotransmitter interventions or drugs that affect specific classes of synapses for areas of the brain commonly shown to have differences from a typical brain (striatum, visual cortex, motor cortex) or else hope you hit a home run with indirect methods of modulating other neurotransmitters such as focusing on the opioid or endocannabinoid systems which have strong downstream effects on catecholamine function. In addtion, there are other technologies that are rapidly being improved for directly modulating cortical function like rTMS and tDCS, plus the project I have been working on for the last 3-4 years that allows precise targeting of cortical and subcortical areas of the brain (basically the whole brain) that I have pretty much been working on every day and night when family life itself is not getting in the way (the gruntwork has taken a lot longer than I thought as I hoped to have this released over a year ago, but it is just me working on this so things move at the pace I can safely handle as the time to do this often comes from cutting sleep). I have made a lot of new discoveries in that time which has added to the delay as incorporating/understanding them takes time. How useful it will be in treating core symptoms of autism and for how many people is obviously an unknown until a lot of other things happen (investment, money for clinical trials, etc.). I am not a formally trained scientist so the way a lot of this stuff has worked is that I discover something and then try and figure out what is going on which is kind of the opposite of how things are supposed to work in that usually you go to school to be formally trained and then try and use that knowledge to discover/invent something new (or at least just publish lots of papers to advance your career). In my particular case, this is all flying by the seat of your pants so you might want to take what I am saying with a grain of salt, even though my personal efforts are serious and real.

    3. Tyler,

      First, I am sure none of the regular readers of this blog need salt,pepper or sugar for that matter when it comes to your communications especially regarding the 'brain device' (in absence of a better term) you are developing. Secondly, with regards to formal scientific training is concerned, well..I have a doctoral degree and publications but believe me, you will be greatly disillusioned about the practise of science in so called temples of higher education/research. Those who get involved in the rat race are a desperate lot and science is the first casualty when it comes to embarking on this hard and long journey towards s successful scientific career. Of course, exceptions are there. But do note, result manufacturing is a reality so one has to keep the salt sprinkler close when examining a scientific research.

      Supplements that I am using with my son are unlikely yo do any wonders but I wonder if anything else will. I do not know how to identify his specific neurological dysfunctions and target them via drugs. And though stuff like TMS looks promising, i have not received any feedback on a good practitioner where I live.

      And about the independent streak... I think right now with my son it's not a social issue but newly found confidence. He is rearing to go...on the worksheets when he knows the stuff. Today he even held down his special educators hand with his left hand while attempting a new Hindi letter formation with his right. She was pleased. Social stress is an autistic reality which will probably accompany him through life but this habit of trying to figure things independently might have a genetic origin in my case and probably your case too.

    4. A relative of mine who is a neuroscientist at a very prestigious university here in the states finally got a paper published that it took him 3 years to finish the experiment and another 3 years to get the research published. He has several other first author papers to his name, but the work he put into this paper was ridiculous from my perspective, so getting myself into formal science is not something I will ever be doing unless someone comes up with an immortality pill because these days assuming you are going for a professor track, you will likely be in your 40's before that ever happens and I am 41 right now.

      Science is way too competitive from my vantage point and since too much competition tends to bring out the worst qualities in people as politics, which self-evidently destroys everything good in the universe, ends up consuming any institution with a zero-sum reward structure where the only way to win is for everyone else to fail. The old saying "science advances one funeral at a time" is more true than ever unfortunately.

      All of that being said, I was not trying to poo poo supplements as obviously I have advocated the use of many of them here on this blog, just I was saying I tend to think of their use in strategic terms, not in the sense that I am genuinely hopeful using a handful of broadly interactive compounds are going to cure autism. That does not mean that I don't hope for this or think it is impossible, just that my experience on this journey has been very humbling, as I am sure it has been for most people who read this blog.

      As to your son, independent perseverance (which can be seen by some as a handicap in autism) can be a big plus if you can provide an environment with minimal distractions which includes people. There was a study a while ago you may have seen which showed that autistic youth may work better with a robot (controlled by a human on the other end) than with a live human instructor in the same room. Maybe for some kids they would do better with this kind of setup with just a covertly placed video camera to monitor progress. Of course, learning to interact with other people and develop social skills is important, but maybe all other work besides formal social skills training would be better administered by non-human interfaces as human interaction itself can be very stressful to some with autism, just as a co-worker who just ate several pounds of garlic lasagna will inevitably distract and causes stress to anyone who has to be near them.

  5. Tyler,increasing D2 receptor neurotransmission to adress repetitive behaviors by using a calcium channel activator or mglur5 agonist is something that our logic wouldn´t allow us to do, or at least to me,but may be is the reason why the problem with dopamine is so complex and we can´t fix it.I can understand an mglur5 antagonist in my son,for his dyskinesias and upregulated d2 receptors by risperidone, but the reason of his repetitive behahviors could be that d2 receptors are hypoactive from the first time? I also noticed this paradox in my son.To BCAAs, what would you add to help with this imbalance?

  6. Came across an interesting paper I had in the queue for well over a week that discusses epigenetic effects from the paternal line whereas dim light exposure at night (which reduces melatonin output) can cause hypoimmunity to male offspring several generations later:

    The research used Siberian Hamsters which have the benefit of very regular and accurate circadian rhythms, so this does not necessarily mean it applies to humans, but my hunch is the same mechanism or a similar mechanism of epigenetic modification in response to chronic dim light exposure at dark applies in humans as well.

    Now what on earth does this research have to do with autism? Well in male offspring of dim light exposed at dark hamsters, there was considerably less melatonin receptors and less glucocorticoid receptors. There were also indicators of reduced immunity overall as well. Combine this with maternal immune activation and you get a double hit of immune dysregulation from the mother and father which could lead to increased rates of autism in male offspring. It is also interesting that late night blue light exposure from computer screens has only been a recent phenomena in western nations and that in areas where this kind of lifestyle has been extra common (like Silicon Valley) there have been reports of increased pockets of autism (this is of course hard to verify due to some of these areas being wealthier and therefore more likely to have children tested).

    I know myself that my lifestyle as a software engineer in the past had me staying up late at night working more often than not so it makes me wonder if these kind of mechanisms have a bit to do with me having so many sleep challenges with all of my children as well as 3 autism diagnoses on top of that. My wife had many, many environmental risk factors now associated with autism risk so perhaps combinatorial risk factors (like the ones I just suggested) may have added up here. Of course, I can't send a message back in time and tell myself to get more sleep and to go to bed early, but maybe looking at this type of research more closely in humans could let future generations know about one more environmental risk factor they may want to consider in terms of mitigating risk to the health of their future children and even grandchildren.

    1. Tyler,

      Non human instructor... Well, not sure about my son but I would be the most willing candidate and am certain can master the universe if one removes human entities from the practice of learning. A significant percentage of human population, passing off as so called neurotypicals, find performing with, under or in front off live human object not only stressful but deeply limiting of their potential, demanding modification of individual working style and even outright unexciting. Obviously, crippling social or performance anxieties or even inability to participate fully in group activities requiring cooperation can be very autism this might make one completely dysfunctional. So as parents, encouraging social exchanges including ones associated with learning should be one of our priorities though respite through solitary engagement for enhancements or fine tuning of skills should be allowed to anybody who needs it...autistic or not.

      As for distractions, who needs garlic breath... the crafty human face with dancing/shifty eyes is enough. So says the misanthrope in me.

    2. Haha. On a semi-related note, many violinists (or just stage performers) have used beta-blockers to deal with performance anxiety and some people have used them off-label for treating related autism issues. Of course beta-blockers have long-term side effects so simply dimming down the sympathetic nervous system is kind of a brute force solution to social anxiety problems.

      Even though there are probably a legion of researchers working on this problem, I have thought about the evolutionary mechanism of performance anxiety as it relates to the little I know about neuroscience and see it as more of a protective mechanism for people to avoid situations where the price of being wrong on something in front of your whole tribe could mean exile (social exclusion) or even death. This would mean you would only be willing to step up and lead on an issue for your tribe if you were supremely confident in your judgement because there are grave risks in being wrong. Of course in today's world there is little penalty for being "supremely confident" and wrong at the same time, which is why this type of person who is both confident and ignorant at the same time often rises to the highest levels of political power. In the distant past if you were wrong about something that cost people their livelihoods or even lives, you and your family members would definitely suffer the wrath of others. Nowadays, since people have short attention span and memories, all you need to do to avoid punishment for false promises in politics is demonize your opponent so that the "tribal" attention is focused on your competitor. That person then does the same to you which results in a perverse system where anyone with useful opinions have their voice drowned out by the noise of the loudest who routinely use new scandals to make the public forget about their old ones.

      Perhaps this extreme form of "social anxiety" for people with autism is an exaggerated form of a protective instinct to prevent people from talking the talk when they can't walk the walk. Of course, if you are 100% right about something which could help your tribe and you are too afraid to speak up, you will stay marginalized and with low social status and the tribe will suffer from your lack of insight so anxiety versus confidence is always going to be a push/pull mechanism in communities where accountability matters (unlike modern western nations). In very large societies like mine, even outright fraudsters usually get very lenient punishments from society while people of the wrong social class get long prison sentences for being in possession of small amounts of drugs they use to self-medicate themselves to avoid the pain of their very hard lives. Promising people the world while delivering nothing or just stealing from people outright favors a much different personality type than the measured, somewhat shy personality type associated with autism.

      And while there now may be drugs for "social anxiety" now and even named disorders concerning the matter, the last time I checked there are no drugs for a lack of "responsibility, accountability, and humility" or disorders concerning the lack thereof unless you consider these the traits of sociopathy which seems to be an actively sought after trait in executive positions of industry and government these days. Our last two presidential candidates were pretty much a case study in sociopathy/psychopathy as I am sure are just about all other so-called leaders around the world from the looks of things and these trends seem to be getting worse rather than better regardless of whatever political persuasion these so-called leaders claim to represent.

      Maybe what the world needs are leaders who are more autistic even though modern western forms of government pretty much preclude that from ever happening, since there is no longer any dichotomy nor balance between being right and being vocal.

  7. Tyler, the last paper you came across about doapamine is about the SHANK3 related autism,probably my son doesn´t have it, but I notice this parodox bahaviour you mentioned in your son. In this context BCAAs could be not helping with repetitive behaviors and OCD.Repetitive and dyskinesic movements are mixed.I posted a comment above,couldn´t express myself clear because I have so many doubts, but if d2 neurotransimission is hypoactive, BCAAs could be interfering. Could you clarify it to me?

    1. Tyler, I thought you could answer my last question about BCAAs and d2 hypoactive neurotranssmision.I don´t know if there is an answer.Anyway, I thank you very much for all.

    2. I don't think bcaa's are relevant here because they address a different problem. This research on SHANK3 with repetitive behaviors is challenging from a therapy standpoint because you need a drug that us selective for a specific type of cell because even though d2 receptors promote the indirect pathway, dopamine also targets the d1 receptors which effects the direct pathway more strongly. A small nucleus of cells latreal to the posterior area of the hypothalamus called the subthalamic nucleus is the most commonly targeted brain area in modulating the indirect pathway for deep brain stimulation which more or less are just electrodes injecting current at a rate of 130hz to interrupt it's function since the indirect pathway reigns supreme in Parkinson disease since the sources of dopamine for the basal ganglia are not available due to the die off of dopamine expreasing neurns in the substantial nigra and ventral tegmental area. In huntingtin's disease, the opposite seems to occur which instead of hypokinesia which you have in Parkinson's disease, you have hyperkinesia which often manifests itself as chorea which you are very familiar with as a side effect of chromic risperidone treatment. So there are multiple nodes in the indirect pathway beginning with the striatum and ending with the medial pallidum which happens to be the second most popular area of DBS research due to it being the final inhibitory output nuclei to the thalamus from the indirect pathway.

      Since proper functioning of the basal ganglia depends on the right amount of dopamine, bcaa's definitely can help with the problem of excess dopamine in the brain but this specific SHANK3 problem here which may exist in a subset of autism cases will need another vector of attack in up upregulating the indirect pathway to reduce repetitive behaviors, which are one of the legs of the three legged stool that is autism.

    3. Ok, the improvement in my son is undeniable,in a cognitive level and his observation power is amazing. Also his dyskinesias are almost nonexistent, even though there are days that reappear. But repetitive movements is something that he still do when he is in front of TV. I don´t know if it is the kind of game or movie, because there are days that he doesn´t move , but other days, specially when he plays a football ps4 game ,he can´t controll himself. Until today,now he is 11, we haven´t been able to solve this problem.Repetitve movements in front of TV were his hallmark since he was 1 and the only reason why, later, we realized of his diagnosis.


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