Showing posts with label Tryptophan. Show all posts
Showing posts with label Tryptophan. Show all posts

Tuesday 7 September 2021

The Kynurenine Pathway in Autism and its modification using Sulforaphane or the probiotic Lactobacillus Plantarum 299v


 A pathway to somewhere, hopefully

Today’s post was prompted by our reader George’s observation that the probiotic Lactobacillus Plantarum 299v increased speech in his adult son.  This widely available probiotic is commonly used to treat IBS (Irritable Bowel Syndrome) and I did mention it in a recent post about Eubiotics.

Eubiotics for GI Dysfunction and some Autism

Increased speech is a target for many people treating autism and this probiotic is known to be safely used long term - so it is interesting.

Since I already had this probiotic at home, I made a trial and I observed a very similar effect to what happened several years ago when Monty started to use Sulforaphane / broccoli sprout powder. 

The effect of broccoli powder was a brief period of euphoria about 20 minutes later and a then a marked increase in verbalization.  The effect on mood was seen by some other readers, but not the majority. I recall back then a very happy parent who was feeding broccoli powder to his child via a G-tube. A gastrostomy tube, often called a G-tube, is a surgically placed device used to give direct access to your child's stomach for supplemental feeding, hydration or medication.  Some children with autism will not eat and so are fed via a G-tube.

Broccoli powder tastes pretty bad, but this is one problem you will not experience when taking it via a G tube.

I was surprised that even some people with mild autism found broccoli powder beneficial. In diabetics it improves insulin sensitivity and so reduces the amount of insulin they need to inject.

This post is about the science, but before reading all the science, I made my trial of Lactobacillus Plantarum 299v.  One capsule a day works very nicely. The science is optional.

I wondered what might be the shared effect of these two very different therapies - broccoli and L.P. 299v.  There is indeed a plausible explanation, the Kynurenine pathway.


Click on the graphic, to enlarge

This may all look rather complicated, but there are some terms we are already very familiar with. We know that Serotonin is the happy hormone and we know that Melatonin is the sleep hormone.

It all starts with Tryptophan, one of those amino acids. It is essential in humans, meaning that the body cannot synthesize it and it must be obtained from the diet. Good sources include milk, turkey and bananas. If you take bumetanide, you likely already eat a lot of bananas due to their potassium content.

95% of tryptophan is metabolized to Kynurenine, a very odd sounding word. So it must be that less than 5% becomes Serotonin and Melatonin. Two enzymes, namely indoleamine 2,3-dioxygenase (IDO) in the immune system and the brain, and tryptophan dioxygenase (TDO) in the liver, are responsible for the synthesis of kynurenine from tryptophan.

The so-called kynurenine pathway of tryptophan is altered in several diseases, including psychiatric disorders such as autism, schizophrenia, major depressive disorder and bipolar disorder.

The supplements Tryptophan and 5-hydroxytryptophan (5-HTP) are widely used for many conditions ranging from depression to autism.


The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+).


NAD+ is very important.


Increasing the level of NAD is itself an autism therapy in the research. 

New Preclinical Study Finds Niagen® Corrects Social Deficits in Mouse Model of Autism

First-of-its-kind preclinical study shows that Niagen® (nicotinamide riboside) resolves social deficits and anxiety-like behaviors in male mice

The amount of Tryptophan that ends up as the cute-sounding Picolinic acid is determined by how much of the enzyme ACMSD is present.

Quinolinic acid (QUIN) and Kynurenic acid (KYNA) are two neuroactive KP metabolites that have received considerable attention for their modulation of the NMDA receptor. While QUIN shows neurotoxic effects by over activation of the NMDA receptor, KYNA offers neuro-protection by blocking receptor function. Emphasis has been placed upon the importance of maintaining a balanced ratio between these two metabolites.

Picolinic acid (PIC) also shows antagonistic properties towards the toxic effects of QUIN via an unknown mechanism.  There are a number of biological factors that can potentially affect PIC levels and synthesis in the CNS including age, circadian rhythms and hormonal and nutritional factors.


 Source: The Physiological Action of Picolinic Acid in the Human Brain

Anthranilic acid (AA), once thought to be vitamin L, is very elevated in schizophrenia, and also in type-1 diabetes and arthritis.  AA is seen as a treatment target in these conditions. 

Now for the interesting part, the effect of the probiotic Lactobacillus Plantarum 299v on the Kynurenine pathway:


Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study


· There was an improvement in cognitive functions in group of depressed patients receiving probiotic Lactobacillus Plantarum 299v (LP299v) compared to the placebo group.

 · There was a significant decrease in kynurenine concentration in the LP299v group compared to the placebo group.

 · There was a significant increase in 3-hydroxykynurenine : kynurenine ratio in the LP299v group compared with the placebo group.

· Decreased kynurenine concentration due to probiotic could contribute to the improvement of cognitive functions in the LP299v group compared to the placebo group.


And, the effect of Sulforaphane on the Kynurenine pathway: 


Altered kynurenine pathway metabolism in autism:Implication for immune-induced glutamatergic activity

Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, Quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased Quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD.


QA = Quinolinic Acid

KP = Kynurenine Pathway


The increased concentration of QA in ASD is also likely to be associated with increased oxidative stress. We previously showed that QA can significantly potentiate oxidative stress in human primary neuron cultures and that oxidative stress markers are increased in children with ASD.  Recently, a clinical study effectively used sulforaphane derived from the broccoli sprout to treat ASD resulting in improved behaviour.  Interestingly, sulforaphane was shown to attenuate the effect of QA-induced toxicity in rat brain by enhancing the antioxidant, glutathione. This study is coherent with our current finding of increased QA in children with ASD and our previous work showing decreased glutathione in the children with ASD.  Hence, the possibility that sulforaphane may act by attenuating QA-induce oxidative stress in ASD warrants further investigation.



Too much Quinolinic Acid (QA) does appear to be a damaging feature of autism and is produced by a malfunctioning Kynurenine pathway (KP).

The exact relevance of each part of the KP in diseases of the brain is still a work in progress, but it is clearly disturbed in a specific way in each particular CNS disorder, autism being just one.

Modifying the KP does look like a useful therapeutic avenue to follow, but it is not so simple to understand all of it.

It appears that Lactobacillus Plantarum 299v may improve some people’s autism via a mechanism that includes modification of the Kynurenine pathway (KP). It may also be the case that sulforaphane / broccoli powder has an effect that counters the disturbed KP. For whatever biological reason, the visible/audible effects of the two therapies appear to be remarkably similar.

As usual, you do not have to fully understand biological pathways, like the KP, to benefit from them.  In effect, it is all a question of where all the Tryptophan from your diet ends up – and for some people it does seem to matter.

Lactobacillus Plantarum 299v and sulforaphane / broccoli are not wonder autism therapies for most responders, but if there is an incremental benefit available, you may want to take it.

Another low hanging fruit? 


Friday 28 February 2014

Vitamin D in Autism – too much or too little?

Reader’s of this blog will be aware that serotonin plays a major role in autism, and also in many other mental health conditions, like depression.

Vitamin D also regularly raises its head in discussions about autism.  You may recall the Somali autism clusters in Sweden and Minneapolis; researchers suggested that the Somali immigrants were not getting enough sun and therefore lacked vitamin D and so produced children with autism.  I did point out that another large Somali autism cluster exists in sun-drenched San Diego.
Even Martha Herbert talks about vitamin D deficiency and autism.

A while back we had a guest blogger, Seth Bittker, present his opposing view, that too much vitamin D added to food in the American diet may be contributing to the rise in autism there.
In same week that Seth has published his paper on this subject, yet another paper has appeared with the opposing view.  So who is right?

The case for (even) more Vitamin D

The first paper is:- 

The authors make the following case:-
Serotonin and vitamin D have been proposed to play a role in autism, however, no causal mechanism has been established. Now, researchers show that serotonin, oxytocin, and vasopressin, three brain hormones that affect social behavior related to autism, are all activated by vitamin D hormone. Supplementation with vitamin D and tryptophan would be a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder.

After absorbing L-tryptophan from food, our bodies convert it to 5-HTP (5-hyrdoxytryptophan), and then to serotonin.
The supplements L-tryptophan and 5-HTP are widely available and have been used in ADHD and autism but there is no evidence that they are effective.  All that has been shown is that too little tryptophan is bad; there is nothing to show that abnormally large amounts do any good.
If you read the full paper there is an excellent explanation of the role of serotonin in autism.  It is beyond doubt that in many kids with ASD there is high blood serotonin, but low brain serotonin.
To fully treat autism, one thing to be done is to raise brain serotonin levels, without any nasty side effects.  SSRI drugs like Prozac, used to treat depression, do raise brain serotonin but often cause dependence and side effects (like suicidal thought).
It would be great if some vitamin D and tryptophan could do the job.

If you read the older literature, you will see that there is nothing new about the idea to supplement with Tryptophan in autism.  The results to date have been nothing special.
Here is a paper by Paul Whiteley and Paul Shattock:-

“It has been shown that a diet depleted of tryptophan is not beneficial for children with ASDs and that some symptoms are exacerbated. Presumably, the existing lack of available serotonin (and other tryptophan derivatives) was exacerbated under these circumstances. Supplementation with tryptophan would probably not be helpful in the majority of cases because the conversions along the important pathways are inhibited and tryptophan is likely to be converted along the IAG route, which would be unhelpful. Anecdotal clinical reports suggest that some children show benefits and others may get worse but no formal studies have been reported.

For this reason, and because tryptophan is a prescription-only drug*, we have looked at other methodologies. The active transmitter, serotonin, does not cross the blood brain barrier and so would be ineffectual in this respect. However, the precursor molecule 5-HTP does cross the blood brain barrier and reach the appropriate target areas. Some parents have reported impressive consequences, particularly with regard to sleep patterns; some physicians have been able to reduce the doses of e.g. risperidone (an anti-psychotic drug) by supplementing 5-HTP but, on the whole, the results have been less useful than would have been predicted.”

Vitamin D and Children with ASD
Children with autism are probably amongst the most “vitamin-supplemented” of any, since parents tend to give copious amounts of multi-vitamins and also vitamin D rich omega 3 fish oil.  It is hard to imagine that any of these children are deficient in vitamin D.

The case for too much vitamin D
In his paper, Bittker seeks to correlate the increase in vitamin D fortification in America with the rise in autism; he highlights groups that do not have vitamin D fortified food and where autism is far less prevalent.


So who is right?  Well for sure too little tryptophan or vitamin D is bad for you; but are abnormally high levels good or bad?  In the case of tryptophan, plenty of people have tried supplementation in autism and ADHD and we would probably have heard if it produced a great effect.

Do large amounts of vitamin D help with autism? I very much doubt it, but it would be very easy to do a trial, assuming you found some parents who had not read the Bittker paper.
The good thing is that raising the low level of brain serotonin seems agreed by everyone as a prime target of any autism intervention. For me, vitamin D and tryptophan is not the answer.


Monday 11 November 2013

Creatine, the Sub-types of Autism is Affects, and the Missing $26 million

Poly Genetic Theory of Autism

Autism appears to be the result of the expression of multiple abnormal genes acting in concert, likely initiated by some external factor(s).  This would explain why there are so many variants of autism and why there can seem to be autistic-like traits in close relatives.


Gene-based Autism Research
Several candidate genes have been identified, such as those linked to fragile X syndrome, tuberous sclerosis etc.  Researchers then follow the science from the target gene to identify a possible therapy.  At this point the researchers then seem to lose their scientific logic; they then try and apply their new therapy to all kinds of autism, i.e. the ones without the “faulty gene”.

This really goes back to our current limited understanding of the brain, medicine is more art than science, and we should perhaps suspend logic and accept this trial and error approach as valid.  At least call it trial and error.

Creatine is an organic acid produced naturally in the body.  It helps to supply energy to all cells in the body. This is achieved by increasing the formation of adenosine triphosphate (ATP).

Creatine is not an essential nutrient, as it is manufactured in the human body from L-arginine, glycine and L-methionine.
Its main use as a supplement/drug is among people wanting to develop their muscles, like athletes and bodybuilders.  Taking the standard dose of 5-10 mg has the same effect as eating a very high protein diet.  In people with muscle wasting diseases, Creatine is also used.  What I found interesting was the research showing an effect in depression.  There are marked similarities between conditions like depression and ASD.
We will return later in the post to another reason that Creatine may be relevant to autism; it appears to be something the research community did not notice.  Now back to those professional researchers:-
Creatine Deficiency
Science has identified three types of Creatine deficiency and all three lead to mental retardation and/or autism.  Two types are very rare, but are treatable; the third type is far more common, affecting about a million people worldwide, and is currently untreatable in humans.  In mice, this third type has been “cured”, but the money is not yet available to develop and test a human version of the therapy.
1.      AGAT 
AGAT (L-Arginine:glycine amidinotransferase) is an enzyme.  This enzyme is needed for the body to produce Creatine.  AGAT deficiency will cause Creatine deficiency  and lead to mental retardation and autism.
For those regularly following my blog, please note the following: It has been suggested that AGAT activity in tissues is regulated in a number of ways including induction by growth hormone (GH) and thyroxine (T4).

The actual genetic mutation associated with AGAT involves a tryptophan codon being converted to a stop codon at residue 149.
You may recall in my post on serotonin, we learnt about its precursor tryptophan and how it appears to be degraded in the autistic brain.

2.     GAMT
GAMT (Guanidinoacetate N-methyltransferase) is another enzyme required to produce Creatine.  As with AGAT deficiency, if you are deficient in GAMT, autism and mental retardation will follow.

If diagnosed, defects of Creatine biosynthesis are treated with Creatine supplements and, in GAMT deficiency, with ornithine and dietary restriction of arginine through limitation of protein intake.
3.     X-linked Creatine deficiency
The final type of Creatine deficiency is much more common, but is much more difficult to treat.  The defect is the Creatine transporter that should allow the Creatine into brain cells, where it plays a critical role in the brain’s energy needs.  No matter how much Creatine you give to people with this disorder, they cannot use it, because their Creatine transporters (CRTs) are defective.

Fortunately, thanks to Dr Joseph Clark, Professor of Neurology at the University of Cincinnati, there is light at the end of the tunnel.  Dr Clark has been researching the Creatine metabolism for some years.  Very unusually, he has been sharing his experiences with us, via his blog.
To cut a long story short, the good doctor has figured out that by using an analog (a modified version) of Creatine called cyclocreatine he could normalize the function of mice with  X-linked Creatine deficiency.  All he now has to do, is to make it work in humans, fully test it and get it FDA approved.  The problem is there is no more money.  In his blog post he tells us that all he needs is:-
$26 million and three more years

Here is the official report from the University:- 
Peter’s thoughts on Creatine
I started looking at Creatine because it appears to stimulate IGF-1 (insulin-like growth factor 1).  This is not a fact well-known to endocrinologists, but it is very well known to athletes and body builders.  They take Creatine orally and it stimulates muscle growth.  Research has even measured the change in IGF-1 in muscle tissue resulting from Creatine supplementation.

In a recent post I pointed out that IGF-1 is itself being used in autism trials, as is a novel Australian analog of IGF-1 [1-3] called NNZ-2566.  The big advantage of NNZ-2566 is that it is taken orally.

The release of IGF-1 is stimulated by growth hormone GH.  Secretion of growth hormone (GH) in the pituitary is regulated by the hypothalamus, which release the peptides Growth hormone-releasing hormone (GHRH) and Growth hormone-inhibiting hormone (GHIH) into the blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.
Stimulators of growth hormone (GH) secretion include:
  • peptide hormones
    • GHRH  through binding to the growth hormone-releasing hormone receptor
    • ghrelin through binding to growth hormone secretagogue receptors
  • sex hormones
    • increased androgen secretion during puberty (in males from testis and in females from adrenal cortex)
    • estrogen
  • clonidine and L-DOPA by stimulating GHRH release

·         α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine 
      (Interestingly clonidine is a drug used for ADHD, or autism-lite, as I call it)

Factors that are known to cause variation in the levels of (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake. The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals. These are chemicals found in both household and industrial products that are known to interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of normal cell metabolism. 
Based on my earlier primary research, I am pretty sure that in the sub-type of autism I am dealing with, there is a deficiency of either GH or TRH, in the brain.  As I result, I am interested in mention of these hormones.

 SHANK3 deficiency
(also known as 22q13 Deletion Syndrome or Phelan-McDermid Syndrome)

IGF-1 is being trialled at Mount Sinai Hospital in New York in autistic children with SHANK3 deficiency.  In true “art” rather than “science” approach, the plan is then to trial IGF-1 on children without SHANK3 deficiency.

Here is a good explanation.
If you live in the Big Apple:-

Where Can I Get Testing?

The Icahn School of Medicine at Mount Sinai offers genetic testing for Phelan-McDermid Syndrome/22q13 Deletion Syndrome and for SHANK3 mutations. A blood sample is needed to conduct the test. For more information about testing, visit The Seaver Autism Center, call (212) 241-0961  

It appears that SHANK3 deficiency accounts for about 1% of autism cases.
If, as is hoped, IGF-1 turns out to be a useful therapy in SHANK3 deficient children, it will be tried on all ASD kids.  If it works, then what was the relevance of SHANK3 in the first place?   It seems pretty odd to me.  I think most likely our current understanding of genetics is so basic, as to be flawed.

I am working via observation, rather than genetics; I know what circumstances produce near neurotypical behaviour, I just need to understand what is going on biologically.  This is how I ended up with TRH and/or GH.

Well if the Mount Sinai study is successful, as it probably will be, we should find Dr Clark in Cincinnati and give him $26 million.  Then we put creatine and cyclocreatine in a pill and give it to ALL people with ASD, since 99% will never get their sub-type diagnosed. 

Either the creatine, the cyclocreatine or the extra IGF-1 will do some good, depending on the sub-type – something for everyone. And no needles.


Monday 4 November 2013

Central Serotonergic Hypoactivity in Autism & Degradation of Tryptophan

Today’s post has an impressive title and a year ago I would not have understood it, but it summarizes exactly what may be going on inside the autistic brain.  It fits into the wider puzzle of hormonal imbalances in autism that then manifest themselves into behaviours ranging from qwerky to extreme self-injury.

Human emotions and behaviours are influenced by parallel signals from the nervous system (i.e. the brain) and the endocrine system.  The two systems are interconnected and so your state of mind in controlled by hormones that you cannot directly control and the nervous system which you can learn to control.  For example, you can make yourself happy, unhappy, or depressed with the power of your mind.  You can train yourself to overcome fear.  Some people are clearly very much better at doing this than others; but the potential to do so lies within all of us, autistic or neurotypical.  This also explains why singing makes you happy and rapidly reduces cortisol, your stress hormone, as we learnt in an earlier post.
So on the one hand we need to understand any in-built hormonal disturbances in autism and then see how to best tackle them using the hormonal system and the nervous system.  This may sound like fantasy but the more you learn about it, the more plausible it becomes.

Most people have heard of Serotonin; it is frequently thought of as the “happy hormone”.

As we have learnt in this blog, the human body is not like any man-made invention, it seems to function in quite irrational ways.  Serotonin is found mainly in the intestines and less than 10% is in the brain (and CNS), but it is not the same serotonin.  Serotonin cannot cross the blood brain barrier.  In autism serotonin in the blood (produced in the intestines) tends to be elevated, but the level of serotonin in the brain appears to be reduced.  So there appears to be a failure in the entire serotonin system, the one for the brain and the one for the blood.
Drugs that lower brain serotonin are often used to treat the symptoms of autism.  Even Temple Grandin admits (on her own website) to being on a low dose of Prozac to control her anxiety.  In spite of a long list of side effects, many children with ASD living in the US are prescribed this serotonin lowering drug.  Prozac is a heavily prescribed antidepressant drug and is a selective serotonin reuptake inhibitor (SSRI).

Somewhat bizarrely, Prozac is linked to an increase in suicidal tendencies.  As is often the case, many drugs have secondary or tertiary modes of action; you will experience all of them.
In the language of your doctor, low brain serotonin would be called central serotonergic hypoactivity, but don’t go asking him to test it, because he cannot.  All he can do is measure the level of serotonin in the blood or urine, and probably tell you that it is slightly elevated and not to worry.

Researchers have known about this serotonin paradox in autism for many years.  To my surprise a researcher at Yale University even made a mathematical model to better understand it. 

Since the early 1960s, the most consistent pathophysiological finding in autistic individuals has been their statistically elevated blood 5-hydroxytryptamine (5-HT, serotonin) levels. However, many autistic individuals have normal blood 5-HT levels, so this finding has been difficult to interpret. The serotonin transporter (SERT) controls 5-HT uptake by blood platelets and has been implicated in autism, but recent studies have found no correlation between SERT polymorphisms and autism. Finally, autism is considered a brain disorder, but studies have so far failed to find consistent serotonergic abnormalities in autistic brains. A simple mathematical model may account for these paradoxes, if one assumes that autism is associated with the failure of a molecular mechanism that both regulates 5-HT release from gut enterochromaffin cells and mediates 5-HT signaling in the brain. Some 5-HT receptors may play such a dual role. While the failure of such a mechanism may lead to consistent abnormalities of synaptic transmission with no alteration of brain 5-HT levels, its effects on blood 5-HT levels may appear paradoxical.

 The figure below sums up what appears to be going wrong.

A great all-in-one overview
If you only want to read one paper on serotonin and autism, and one that is not too science heavy, the one for you is:-

If you have more interest, then read on …

Research on Serotonin in the Autistic Brain
A recurring problem in all brain research is the lack of physical samples.  You cannot just open up someone's head and take a brain biopsy.  Research is either carried out on the tiny number of autistic brains donated to medical research, or it is non-invasive (MRIs and EEGs etc.), or it is very indirect.  An example of this latter type is the following paper from Belgium, home of kriek, a beer made from cherries and French fries served with mayonnaise.

"Some studies have suggested that disorders in the central serotonergic function may play a role in the pathophysiology of autistic disorder. In order to assess the central serotonergic turnover in autism, this study examines the cortisol and prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.Q.>55) and 22 matched healthy volunteers. Serum cortisol and prolactin were determined 45 and 30 minutes before administration of 5-HTP (4 mg/kg in non enteric-coated tablets) or an identical placebo in a single blind order and, thereafter, every 30 minutes over a 3-hour period. The 5-HTP-induced increases in serum cortisol were significantly lower in autistic patients than in controls, whereas there were no significant differences in 5-HTP-induced prolactin responses between both study groups. In baseline conditions, no significant differences were found in serum cortisol and prolactin between autistic and normal children. The results suggest that autism is accompanied by a central serotonergic hypoactivity and that the latter could play a role in the pathophysiology of autism."
Tryptophan and DHEA
Just to complicate things a little further, I now introduce you to Tryptophan and DHEA.

Tryptophan is an essential amino acid, meaning that it is essential for human life, cannot be synthesized by the organism, and therefore must be part of your diet.
Tryptophan functions as a biochemical precursor for the following compounds:

The disorders fructose malabsorption and lactose intolerance cause improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood and depression

What you will not find on Wikipedia, is that perhaps Tryptophan is in fact also a bona fide neurotransmitter in its own right.

Tryptophan as an evolutionarily conserved signal to brain serotonin: molecular evidence and psychiatric implications.


The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated, including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signaling amino acid. Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances, such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of psychiatric disorders and symptoms associated with low availability of tryptophan. 

This paper is open access, it gets quite technical but here is a summary of the conclusion. 

Our findings support a possible mitochondrial dysfunction as a result of impaired tryptophan metabolism in cells from patients with ASDs
Although approximately 99% of the dietary tryptophan intake is metabolized via the kynurenine pathway, tryptophan is also the main precursor for both serotonin and melatonin
Melatonin plays a critical role in the regulation of the circadian rhythm, and anomalies of this rhythm have been associated with some of the signs in the autistic spectrum, like seizures or sleep disorders
Serotonin is a neurotransmitter involved in multiple aspects of brain functions, ranging from the regulation of mood to the control of appetite and social interactions and its production has been reported as deficient in ASD brains.
Tryptophan levels have been demonstrated to directly influence central nervous system (CNS) serotonin levels and behavior, and altered tryptophan transport has been described in fibroblasts from boys with attention deficit/hyperactivity disorder (ADHD)
Patients with ASDs, on average, are less capable of utilizing tryptophan as an energy source than controls.
Decreased tryptophan metabolism in patients with ASDs may alter metabolic pathways involved in the regulation of the early stages of brain development (first month of gestation), mitochondrial homeostasis and immune system activity in the brain.
Disruption of such pathways can primarily be caused either by insufficient serotonin production by placental cells, mitochondrial dysfunction and/or impaired balance between quinolinic and kynurenic acid in fetal cells. The combined effects of these events could lead to abnormal organization of neurons , particularly in specific brain regions, determining the imbalance between the short- and long-term circuitry that has been considered to be one of the fundamentals of the ASD neuropathology
Even though the ideal target tissue, brain, could not be investigated, our observation of decreased tryptophan metabolism in cells from patients with ASDs may provide a unifying model that could help explain the genetic heterogeneity of ASDs.
Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid, and kynurenic acid, which are involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid is the structural precursor of NAD+, a critical energy carrier in mitochondria. Also, the serotonin branch of the tryptophan metabolic pathway generates NADH. Lastly, the levels of quinolinic and kynurenic acid are strongly influenced by the activity of the immune system. Therefore, decreased tryptophan metabolism may alter brain development, neuroimmune activity and mitochondrial function. Our finding of decreased tryptophan metabolism appears to provide a unifying biochemical basis for ASDs and perhaps an initial step in the development of a diagnostic assay for ASDs.

DHEA  (didehydroepiandrosterone) It is the most abundant circulating steroid in humans, importantly for us to know it is also produced in the brain.  It has a variety of potential biological effects in its own right, binding to an array of nuclear and cell surface and acting as a neurosteroid.

Faulty serotonin--DHEA interactions in autism: results of the5-hydroxytryptophan challenge test. 



Autism is accompanied by peripheral and central disorders in the metabolism of serotonin (5-HT). The present study examines plasma dehydroepiandrosterone-sulphate (DHEA-S) and the cortisol/DHEA-S ratio following administration of L-5-hydroxytryptophan (5-HTP), the direct precursor of 5-HT, to autistic patients.


Plasma DHEA-S levels were determined both before and after administration of 5-HTP or placebo, on two consecutive days in a single blind order in 18 male autistic patients and 22 matched healthy controls.


The 5-HTP-induced DHEA-S responses were significantly higher in autistic patients than in controls. In baseline conditions, the cortisol/DHEA-S ratio was significantly higher in autistic patients than in controls. Discussion: The results suggest that autism is accompanied by a major disequilibrium in the serotonergic system. The increased Cortisol (neurotoxic) versus DHEA-S (neuroprotective) ratio suggests that an increased neurotoxic potential occurs in autism.


It is concluded that disequilibrium in the peripheral and central turnover of serotonin and an increased neurotoxic capacity by glucocorticoids are important pathways in autism.
Mice Studies
For the mice lovers amongst you, they also get their vitamin P (Prozac).

Serotonin Defects Identified in "Autistic" Mice

Serotonin modulators mitigate some BTBR behaviors
The researchers tested the effects of acute doses of fluoxetine (Prozac) (an SERT blocker), risperidone (a 5-HT2A receptor antagonist), and buspirone (a partial 5-HT1A receptor agonist) on social and repetitive behaviors of BTBR mice. These three compounds regulate serotonin activity and have inconsistent, limited, and sometimes harmful effects in rodent models of and people with autism. Only buspirone and fluoxetine were found to make BTBR mice significantly more social: treated mice spend proportionally more time socializing with a strange mouse than do saline-treated controls. Interestingly, BTBR mice treated with either buspirone or fluoxetine show a reduced interest in social novelty: when introduced to a second stranger mouse, they do not show a preference for either stranger. In contrast, the saline-treated controls spend more time investigating the newer mouse. Compared to either buspirone- or fluoxetine-treated mice and saline-treated controls, Risperidone-treated mice spend less time investigating strange mice and novel surroundings.
Regardless of treatment, BTBR mice spend comparable amounts of time burying marbles (an index of repetitive behavior). However, eliminating from the analysis one saline-treated control that did not bury any marbles suggests that risperidone-treated mice bury significantly fewer marbles than the saline-treated controls.
In summary, Daws and her team concluded that the autism-like behaviors of BTBR mice are likely due in part to an altered hippocampal SERT serotonin transporter and/or an altered 5-HT1A serotonin receptor. These findings may lead to the identification of additional therapeutic targets for treating human autism.
There was a lot of science in this post and it was clear that the mechanisms involved are only very partially understood by researchers.
It is clear that interventions increasing central (brain) serotonin levels are likely to reduce autistic behaviours.  Prozac was mentioned, but there is a much wider class of drugs called serenic, many of which could potentially be helpful.  As mentioned earlier, the big problem with most of the drugs created for psychiatrists is side effects.  Autism is supposed to be very common, but you would not think so by looking at way new drugs are developed.  As a result, the drugs currently used in ASD and the majority of those in the pipeline are ones developed for other conditions (depression, bi-polar, psychosis , anxiety, ADHD, schizophrenia, Alzheimer’s etc.) many of which share some similar characteristics, but are essentially different conditions, with the exception of ADHD.  It is akin to trying to fix your Ford car with a parts bin filled with Toyota components; it is possible, but not a wise idea.
In my opinion, all the hormone dysfunctions in autism can eventually be traced back to damage caused by oxidative stress and neuroinflammation.  The brain has just adjusted to find a new homeostasis, which happens to be an autistic one.  The list of metabolic disturbances in autism is long and getting longer; but they are just consequences.  I very much doubt it is ever going to be possible to go hormone by hormone, neurotransmitter by neurotransmitter “correcting” them.   I think the best solution is to go further back up the chain and look at how hormones and neurotransmitters themselves are jointly regulated.  I do not believe anyone fully understands the molecular basis on which this is carried out, but as I have pointed out earlier in this blog, you can get the right answer for the wrong reasons and also without showing your workings.  As long as it works, perhaps understanding why does not matter.  A much less intellectual approach might indeed prove effective.
I will continue with my problem solving, but less intellectual, approach and see where it leads.

Just to show how all the hormones are interrelated, I added the paper below from Japan.  They investigate the relationship between Oxytocin and Serotonin:

Evidence That Oxytocin Exerts Anxiolytic Effects via Oxytocin Receptor Expressed in Serotonergic Neurons in Mice

"It is thus possible that oxytocin modulates not only anxiety-related behavior but also social behavior via serotoninergic transmission. These observations may provide new insights into psychiatric disorders associated with disruptions in social and emotional behavior, including autism, anxiety disorders, and depression."