Thursday, 27 July 2017

Targeting Dendritic Spines to Improve Cognitive Function and Behavior in Autism; plus Hair Loss/Graying

I have written several posts about dendritic spines and their varying shapes (morphology).  This sounds like a rather obscure subject, but it looks like it may be a key area where both behavior and cognition can be modified, even later in life.

Homer Simson after using a Wnt Activator 

Dendritic spines

In a typical neuron (brain cell) you have dendrites at one end and so-called axon terminals at the other. When neurons connect with each other, an axon terminal connects with a dendritic spine from another close by neuron.  Axons transmit electrochemical signals from one neuron to the dendrites of other neurons.  The junction formed between a dendritic spine and an axon terminal is called a synapse.

One neuron can have as many as 15,000 spines, some of which are picking up signals from axon terminals of other neurons.
The number and shape of these spines is constantly changing and not surprisingly defects in this process affect both cognition and behavior.
The other end of the neuron, with the axon terminals is much less studied.  The myelin sheath deserves a mention. This protective coating is constantly being repaired in a process called remyelination. MS (Multiple Sclerosis) is caused by damage to the myelin coating that does not self repair. A newly identified feature of autism is an abnormally thin layer of myelin. A lack of insulation along the axon will affect the flow of electrical signals.
Many factors are involved in dendritic spine morphology and plasticity. Many of the same factors are known to be disturbed in autism and other related dysfunctions (schizophrenia, bipolar, ADHD etc).
Recall that within autism there are two broad groups; the larger group has “too many” dendritic spines and the smaller group has “too few”. I am writing about the larger group. My post is a simplification of a complex subject.
Factors that influence dendritic spine morphology and plasticity include:- 

·        BDNF  (want less)

·        Estrogen  (want more)

·        Reelin (want more)

·        BCL2 (want more)

·        PAK1 (want less)

·        GSK3 beta (want more)

·        PTEN (want more)

All the above seem to work via

·        Wnt signaling (want less) 

BDNF is a growth factor within the brain, which tends to be elevated in most autism.
The female hormone estrogen seems to be reduced in male autism and this will have many effects via something called ROR alpha. There is also reduced expression of estrogen receptor beta.
Reelin is a protein that is critical in brain development and maintenance. Reelin is implicated in most brain diseases, including autism. It stimulates dendritic spine development. Reelin is found to be reduced in autism.
BCl2 is a very well-known cancer gene/protein. BCL2 is part of a broader family of genes/proteins that control cell growth/death. BCL2 is anti-apoptotic, meaning it encourages growth rather than cell death. You will find elevated BCL2 in cancers.  BCL2 is implicated in both schizophrenia and autism.
Bax is another key member of the BCL2 family. The BCL2 protein duels with Bax, its counteracting twin. When Bax is in excess, cells execute a death command. When BCL2 dominates, the program is inhibited and cells survive. In cancer you want more Bax.
Modulating BCL2/Bax has been proposed as an autism therapy in Japan.
BCL2 is found to be reduced in autism.
The Japanese proposed the use of Navitoclax, a drug responsible for inhibiting BCL2 production for the treatment of cancer. I think they want to activate BCL2 production. 
I covered PAK1 in some lengthy posts. This was what the Japanese Nobel Laureate at MIT was working on. In summary, a PAK1 inhibitor should be helpful in autism, schizophrenia and some cancer.  Some people with a condition called neurofibromatosis, where non-cancerous tumors grow, use a special kind of bee propolis that contains a substance called CAPE (caffeic acid phenethyl ester), that is a mild PAK1 inhibitor.

GSK3 beta plays a role in several key signaling pathways. Abnormal expression of GSK3 beta is associated with Bipolar disorder. One role played by GSK3 beta is in Wnt signaling, which then affects dendritic spines. A GSK3 beta inhibitor, like lithium, is a Wnt activator which will increase the number of dendritic spines.
PTEN is a tumor suppressor gene/protein that is also an autism gene.
PTEN deficiency results in abnormal arborization and myelination in humans. PTEN-deficient neurons in brains of animal models have increased synaptic spine density.
People with autism and PTEN mutations have large heads because they lacked enough PTEN to reign in cell growth (and head growth).  You would expect them to have increased synaptic spine density.
Note than in both autism/cancer genes (BCL2 and PTEN) the balance is shifted towards growth, which fits in with the broad concept of autism as a growth dysfunction.
Wnt signaling is a complex and only partially understood subject, that has been previously discussed in this blog.  The short version is that most people with autism and particularly the ones with large heads will likely have too much Wnt signaling as the result of their various metabolic “disturbances”. The best way to inhibit their Wnt signaling might be to counter their particular metabolic disturbances, so if you are one of the 2% of autism with a PTEN mutation, then increase your PTEN levels.  If this is not possible than any other way to inhibit Wnt might be effective.
In Bipolar, where GSK3 beta is a known risk gene, you want more dendritic spines and so you want a GSK3 beta inhibitor like lithium. 
I think lithium will have a negative effect on most autism. Within children diagnosed with autism, a minority may well better fit a diagnosis of bipolar.


Children with autism spectrum disorder (ASD) have higher rates of comorbid psychiatric disorders, including mood disorders, than the general child population. Although children with ASD may experience irritability (aggression, self-injury, and tantrums), a portion also experience symptoms that are typical of a mood disorder, such as euphoria/elevated mood, mania, hypersexuality, paranoia, or decreased need for sleep. Despite lithium's established efficacy in controlling mood disorder symptoms in the neurotypical population, lithium has been rarely studied in children with ASD.


We performed a retrospective chart review of 30 children and adolescents diagnosed with ASD by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria who were prescribed lithium in order to assess target symptoms, safety, and tolerability. Clinical Global Impressions - Improvement (CGI-I) ratings were performed by two board-certified child psychiatrists with expertise in ASD. CGI-I scores were dichotomized into "improved" (CGI-I score of 1 or 2) or "not improved" (CGI-I score ≥3).


Forty-three percent of patients who received lithium were rated as "improved" on the CGI-I. Seventy-one percent of patients who had two or more pretreatment mood disorder symptoms were rated as "improved." The presence of mania (p=0.033) or euphoria/elevated mood (p=0.041) were the pretreatment symptoms significantly associated with an "improved" rating. The mean lithium blood level was 0.70 mEq/L (SD=0.26), and the average length of lithium treatment was 29.7 days (SD=23.9). Forty-seven percent of patients were reported to have at least one side effect, most commonly vomiting (13%), tremor (10%), fatigue (10%), irritability (7%), and enuresis (7%).


This preliminary assessment of lithium in children and adolescents with ASD suggests that lithium may be a medication of interest for those who exhibit two or more mood disorder symptoms, particularly mania or euphoria/elevated mood. A relatively high side effect rate merits caution, and these results are limited by the retrospective, uncontrolled study design. Future study of lithium in a prospective trial with treatment-sensitive outcome measures may be indicated.

Hair Growth and Graying 
One surprising observation is the apparent connection between dendritic spine modification and modifying growth/color of human hair.
The same pathway is involved in signaling growth and coloring in the hair on your head and growing the dendritic spines on the neurons inside your head. I have mentioned this once before in a previous post. It is relevant because if a substance is potent enough to affect your dendritic spines you would expect it also to have a visible effect on the hair, of at least some people.
For example one reader of this blog uses a PAK1 inhibitor to treat her case of autism and she found that it has a hair graying effect.

EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling

Pigmented hair regeneration requires epithelial stem cells (EpSCs) and melanocyte stem cells (McSCs) in the hair follicle.

Thus far, only a handful of signals that regulate McSCs have been identified, including extrinsic signals, such as transforming growth factor beta (TGFB) and Wnts, which are provided by the epithelial niche. Wnt signaling induces activation of EpSCs to drive epithelial regeneration while coordinately inducing McSCs to proliferate and differentiate to pigment regenerating hair follicle

One known but uncommon side effect of my current favourite Wnt inhibitor, Mebendazole, is hair loss. Hair follicles require Wnt signaling and if there is too little Wnt signaling you will lose some hair.
BCL2 is a very important cancer gene/protein but it also plays a role in autism and in dendritic spine morphology.  Low levels of the protein BCl2 leads to premature graying.

The team then looked at what would happen if they 'knocked out' a gene in mice that is known to be important for cell survival.
Mice lacking this Bcl2 gene went grey shortly after birth.

The scientists believe the same principle might apply in humans, which would explain why some people - such as TV presenter Philip Schofield - go grey in their 20s, while others keep their dark locks into retirement.

BCL2 is known to be reduced in the reduced in the brains of people with autism, as is another substance called Reelin.  Both Reelin and Bcl-2 are needed for dendritic spines to develop correctly.  

Autism is a severe neurodevelopmental disorder with potential genetic and environmental causes. Cerebellar pathology including Purkinje cell atrophy has been demonstrated previously. We hypothesized that cell migration and apoptotic mechanisms may account for observed Purkinje cell abnormalities. Reelin is an important secretory glycoprotein responsible for normal layering of the brain. Bcl-2 is a regulatory protein responsible for control of programmed cell death in the brain. Autistic and normal control cerebellar corteces matched for age, sex, and post-mortem interval (PMI) were prepared for SDS-gel electrophoresis and Western blotting using specific anti-Reelin and anti-Bcl-2 antibodies. Quantification of Reelin bands showed 43%, 44%, and 44% reductions in autistic cerebellum (mean optical density +/- SD per 30 microg protein 4.05 +/- 4.0, 1.98 +/- 2.0, 13.88 +/- 11.9 for 410 kDa, 330 kDa, and 180 kDa bands, respectively; N = 5) compared with controls (mean optical density +/- SD per 30 microg protein, 7.1 +/- 1.6, 3.5 +/- 1.0, 24.7 +/- 5.0; N = 8, p < 0.0402 for 180 kDa band). Quantification of Bcl-2 levels showed a 34% to 51% reduction in autistic cerebellum (M +/- SD per 75 microg protein 0.29 +/- 0.08; N = 5) compared with controls (M +/- SD per 75 microg protein 0.59 +/- 0.31; N = 8, p < 0.0451). Measurement of beta-actin (M +/- SD for controls 7.3 +/- 2.9; for autistics 6.77 +/- 0.66) in the same homogenates did not differ significantly between groups. These results demonstrate for the first time that dysregulation of Reelin and Bcl-2 may be responsible for some of the brain structural and behavioral abnormalities observed in autism.  


The development of distinct cellular layers and precise synaptic circuits is essential for the formation of well-functioning cortical structures in the mammalian brain. The extracellular protein Reelin through the activation of a core signaling pathway including the ApoER2 and VLDLR receptors and the adapter protein Dab1, controls the positioning of radially migrating principal neurons, promotes the extension of dendritic processes in immature forebrain neurons, and affects synaptic transmission. Here we report for the first time that the Reelin signaling pathway promotes the development of postsynaptic structures such as dendritic spines in hippocampal pyramidal neurons. Our data underscore the importance of Reelin as a factor that promotes the maturation of target neuronal populations and the development of excitatory circuits in the postnatal hippocampus. These findings may have implications for understanding the origin of cognitive disorders associated with Reelin deficiency.

While not everything relating to dendritic spines is variable, and hence potentially can be modified, much seems to be.
Rather like in this blog it took a few years to get a comprehensive view of the factors involved in neuronal chloride and extend the list of potential therapies, getting to the bottom of fine tuning dendritic spin morphology for improved behavior and cognition will be a complex task.
Much is already known.
Our reader AJ is busy looking at GSK3 beta inhibitors.
GSK3 beta is best known as a bipolar gene/protein, but it is becoming seen as an autism gene.

GSK3 is one of the few signaling mediators that play central roles in a diverse range of signaling pathways, including those activated by Wnts, hedgehog, growth factors, cytokines, and G protein-coupled ligands. Although the inhibition of GSK3-mediated β-catenin phosphorylation is known to be the key event in Wnt-β-catenin signaling, the mechanisms which underlie this event remain incompletely understood. The recent demonstration of GSK3 involvement in Wnt receptor phosphorylation illustrates the multifaceted roles that GSK3 plays in Wnt-β-catenin signaling. In this review, we will summarize these recent results and offer explanations, hypotheses, and models to reconcile some of these observations.
Recent advances indicate that GSK3 also plays a positive role in Wnt signal transduction by phosphorylating the Wnt receptors low density lipoprotein receptor-related protein (LRP5/6) and provide new mechanisms for the suppression of GSK3 activity by Wnt in β-catenin stabilization. Furthermore, GSK3 mediates crosstalk between signaling pathways and β-catenin-independent downstream signaling from Wnt.

it is known that glycogen synthase kinase 3β (GSK-3β) regulates both synaptic plasticity and memory. 
GSK-3β overexpression led to a general reduction in the number of dendritic spines. In addition, it caused a slight reduction in the percentage, head diameter and length of thin spines, whereas the head diameter of mushroom spines was increased.

Over the past 2 decades, neuroscientists have built a body of evidence that links not only bipolar disease, but other psychiatric disorders including autism and schizophrenia to abnormal brain development. In particular, they have found abnormalities in the numbers of synapses and in the shape of neurons at the points where they form synapses. Their studies have often implicated abnormal signaling in a brain pathway called Wnt, which is involved both in early brain development and later, more complex, refining of brain connections. The role of Wnt could help explain why lithium is effective: It blocks an enzyme called GSK-3 β, which is an inhibitor on the Wnt pathway. By boosting Wnt signaling, lithium could produce a therapeutic effect in psychiatric diseases in which the Wnt pathway is underpowered.

They then treated the mutant mice with lithium. Although the researchers acknowledge that rodents are an imperfect proxy for human mood disorders, they did observe that the animals’ symptoms markedly improved; studies of their brains also revealed normal numbers of spines. “That’s the key finding,” Cheyette says. “It suggests that lithium could have its well-known therapeutic effect on patients with bipolar disorder by changing the stability of spines in the brain.”

GSK3 has numerous effects.

Glycogen synthase kinase-3 (GSK-3) is a cytoplasmic serine/threonine protein kinase that phosphorylates and inhibits glycogen synthase, thereby inhibiting glycogen synthesis from glucose. However, this serine/threonine kinase is now known to regulate numerous cellular processes through a number of signaling pathways important for cell proliferation, stem cell renewal, apoptosis and development. Because of these diverse roles, malfunction of this kinase is also known to be involved in the pathogenesis of human diseases, such as nervous system disorders, diabetes, bone formation, inflammation, cancer and heart failure. Therefore, GSK-3 is recognized as an attractive target for the development of new drugs. The present review summarizes the roles of GSK-3 in the insulin, Wnt/β-catenin and hedgehog signaling pathways including the regulation of their activities. The roles of GSK-3 in the development of human diseases within the context of its participation in various signaling pathways are also summarized. Finally, the possibility of new drug development targeting this kinase is discussed with recent information about inhibitors and activators of GSK-3.  


The present study demonstrates that estradiol may trigger formation of new dendritic spines by activation of a cAMPregulated CREB phosphorylation. Induction of the CREB response requires activation of NMDA receptors, increased intracellularcalciumconcentrationsandcAMP-activatedPKA.These systems together then contribute to the CREB response, which in turn leads to the morphological changes seen with estradiol—i.e., spine formation. The biochemical and cellular routes leading from activated CREB to the morphological change in dendritic spine density are still uncharted.

Dendritic spines of the medial amygdala: plasticity, density, shape, and subcellular modulation by sex steroids.

The medial nucleus of the amygdala (MeA) is a complex component of the "extended amygdala" in rats. Its posterodorsal subnucleus (MePD) has a remarkable expression of gonadal hormone receptors, is sexually dimorphic or affected by sex steroids, and modulates various social behaviors. Dendritic spines show remarkable changes relevant for synaptic strength and plasticity. Adult males have more spines than females, the density of dendritic spines changes in the course of hours to a few days and is lower in proestrous and estrous phases of the ovarian cycle, or is affected by both sex steroid withdrawal and hormonal replacement therapy in the MePD. Males also have more thin spines than mushroom-like or stubby/wide ones. The presence of dendritic fillopodia and axonal protrusions in the MePD neuropil of adult animals reinforces the evidence for local plasticity. Estrogen affects synaptic and cellular growth and neuroprotection in the MeA by regulating the activity of the cyclic AMP response element-binding protein (CREB)-related gene products, brain-derived neurotrophic factor (BDNF), the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) and the activity-regulated cytoskeleton-related protein (Arc). These effects on signal transduction cascades can also lead to local protein synthesis and/or rearrangement of the cytoskeleton and subsequent numerical/morphological alterations in dendritic spines. Various working hypotheses are raised from these experimental data and reveal the MePD as a relevant region to study the effects of sex steroids in the rat brain.


CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. PTEN mutations in individuals with autism spectrum disorders (ASD) have also been reported, although a causal link between PTEN and ASD remains unclear. In the present study, we deleted Pten in limited differentiated neuronal populations in the cerebral cortex and hippocampus of mice. Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli. We observed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axonal tracts with increased synapses. This abnormal morphology was associated with activation of the Akt/mTor/S6k pathway and inactivation of Gsk3β. Thus, our data suggest that abnormal activation of the PI3K/AKT pathway in specific neuronal populations can underlie macrocephaly and behavioral abnormalities reminiscent of certain features of human ASD.  

Mutations in phosphatase and tensin homolog deleted on chromosome ten (PTEN) are implicated in neuropsychiatric disorders including autism. Previous studies report that PTEN knockdown in neurons in vivo leads to increased spine density and synaptic activity. To better characterize synaptic changes in neurons lacking PTEN, we examined the effects of shRNA knockdown of PTEN in basolateral amygdala neurons on synaptic spine density and morphology using fluorescent dye confocal imaging. Contrary to previous studies in dentate gyrus, we find that knockdown of PTEN in basolateral amygdala leads to a significant decrease in total spine density in distal dendrites. Curiously, this decreased spine density is associated with increased miniature excitatory post-synaptic current frequency and amplitude, suggesting an increase in number and function of mature spines. These seemingly contradictory findings were reconciled by spine morphology analysis demonstrating increased mushroom spine density and size with correspondingly decreased thin protrusion density at more distal segments. The same analysis of PTEN conditional deletion in dentate gyrus demonstrated that loss of PTEN does not significantly alter total density of dendritic protrusions in the dentate gyrus, but does decrease thin protrusion density and increases density of more mature mushroom spines. These findings suggest that, contrary to previous reports, PTEN knockdown may not induce de novo spinogenesis, but instead may increase synaptic activity by inducing morphological and functional maturation of spines. Furthermore, behavioral analysis of basolateral amygdala PTEN knockdown suggests that these changes limited only to the basolateral amygdala complex may not be sufficient to induce increased anxiety-related behaviors. 

Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors.

A meta-analysis of blood BDNF in 887 patients with ASD and 901 control subjects demonstrated significantly higher BDNF levels in ASD compared to controls with the SMD of 0.47 (95% CI 0.07-0.86, p = 0.02). In addition subgroup meta-analyses were performed based on the BDNF specimen. The present meta-analysis study led to conclusion that BDNF might play role in autism initiation/ propagation and therefore it can be considered as a possible biomarker of ASD.

Dendritic spines are major sites of excitatory synaptic transmission and changes in their numbers and morphology have been associated with neurodevelopmental and neurodegenerative disorders. Brain-derived Neurotrophic Factor (BDNF) is a secreted growth factor that influences hippocampal, striatal and neocortical pyramidal neuron dendritic spine density. However, the mechanisms by which BDNF regulates dendritic spines and how BDNF interacts with other regulators of spines remain unclear. We propose that one mechanism by which BDNF promotes dendritic spine formation is through an interaction with Wnt signaling. Here, we show that Wnt signaling inhibition in cultured cortical neurons disrupts dendritic spine development, reduces dendritic arbor size and complexity, and blocks BDNF-induced dendritic spine formation and maturation. Additionally, we show that BDNF regulates expression of Wnt2, and that Wnt2 is sufficient to promote cortical dendrite growth and dendritic spine formation. Together, these data suggest that BDNF and Wnt signaling cooperatively regulate dendritic spine formation.

Other Wnt inhibitors

Yet another anti-parasite drug, Niclosamide,  turns out to be a Wnt inhibitor. 

Not surprisingly, Niclosamide is now a candidate drug to treat several different types of cancer.  It is also thought to have great potential in suppressing the metastatic process of prostate cancer. Another extremely cheap drug, not available in the US.
Even the flavonoid quercetin can inhibit Wnt. 

Therapeutic Avenues

There certainly are many potential ways to fine tune dendritic spine morphology.
Some readers of this blog are already doing just that, perhaps not all realizing it. 
·        BDNF  (want less - TrkB inhibitor)

·        Estrogen 

·        Reelin (want more – statin via RAS activation)

·        BCL2 (want more – statin)

·        PAK1 (want less – PAK inhibitor, BIO30)

·        GSK3 beta (want more – GSK3 activator)

·        PTEN (want more – statin)

All the above seem to work via

·        Wnt signaling (want less – Mebendazole/Niclosamide etc)

If you inhibit GSK3 beta you activate Wnt. You need get things the right way around. 
Statins promote RAS signaling which appears to increase Reelin expression. 


Fine tuning dendritic spine morphology seems like a good target for those with MR/ID and also those with any kind of neurological disorder.
There appear to be many ways to achieve this.
It seems a plausible idea and in many ways seems more credible than the idea of a diuretic (bumetanide) raising some people’s IQ.
The big issue is which substances have sufficient potency, once they have crossed the blood brain barrier, to do anything at all.  This is an issue with all therapies targeting the brain, including bumetanide.
At least substances that can affect hair growth and color are making it through to the bloodstream, which is a start.
Does this mean that tuning your dendritic spines will inevitably make your hair turn grey or begin to thin?  I don’t think so. I think this will happen in people who have low to normal Wnt signaling to start with.
Do some people with naturally premature graying, or thinning, hair have low levels of Wnt signaling? Quite possibly. Are they more likely to have traits of bipolar/creativity? Look for actors with gray or thinning hair.
Do people with autism tend to have full heads of thicker hair, as well as bigger heads?
Do the minority of people with autism and small heads have thinning hair?
Some readers of this blog are already using statins to treat autism. As has been pointed out in earlier posts, other than lowing cholesterol, statins have potent anti-inflammatory effects and they also affect expression of RAS, PTEN and BCL2, all of which are implicated in autism and all affect dendritic spines. It seems plausible that these readers are already modifying dendritic spine morphology.


  1. Hi Peter,

    WOW! I have said many times how much I appreciate your insights, and I have to say, this post is TERRIFIC! Thank you, for this and everything you do.

    Peter, a few points I'd like to make, beginning with a lighthearted one - your comment about my looking for a GSK3 Beta inhibitor, while completely accurate, is more due to my not knowing what was coming in this post. In my best Homer voice, I say "D'OH!" and want to confirm that based on my daughter's tall stature and normal (maybe large, I don't know) head, that I will fall into the camp of those looking for a GSK3 Beta activator / Wnt inhibitor.

    I'll do a bit of research on what we have at our local pharmacies in terms of the anti-helminthic therapies (i.e. Niclosamide, Mebendazole, and Pyrvinium) and if they are OTC here. If so, then those in the US who want the drug and who live close to border can then make a day trip of it.

    Does anyone know offhand how one would best take such meds? That is, do you have to cycle on and off, or can you keep taking it?

    Also, I will do some research on different options for the other potential targets (i.e. Reelin, BDNF, etc.) and will post any interesting findings.

    I did ask a question on another thread that is very relevant to this subject. On Self-hacked, they list the following as GSK 3Beta inhibitors:

    Lithium (R)
    Zinc (R)
    Copper (potent) (R)

    Melatonin (R)

    Curcumin (R)
    Quercetin (R)
    Luteolin (potent) (R)
    Apigenin (potent) (R)
    Cinnamon (R)
    Angelica Sinensis (R)

    Many of us may be using at least one of these. I use Luteolin to control Microglial activation, I believe Tyler uses Apigenin to control IDO, and many may use Melatonin, Zinc, Quercetin, etc.

    Since they help in one way, but may decrease GSK 3 Beta, are we helping in one way and hurting in another, basically resulting in a net neutral outcome?

    Maybe the key is to combine a Wnt inhibitor with these other treatments so that we can block Wnt and Microglial activation or IDO, to benefit on both ends.

    Thanks in advance for anyone's insights!


    P.S. if the ability to turn one's hair gray is a sign of a Wnt Inhibitor, then I suggest that my wife may be a potent Wnt inhibitor, with my jet black hair now showing a few streaks of silver ;-)

  2. Peter, thank you for the write up about dendrites and hair loss. As I already mentioned, you can't use a meta-analysis to judge certain chemicals or proteins in the brain. Just because a certain chemical or protein (BDNF in this discussion) is elevated in the blood of autistic patients, it doesn't mean that these patients don't need it and it should be reduced. You are making a big mistake by labeling "want less" or "want more" based on meta-analysis studies. Brain often upregulates certain things as an intrinsic neuroprotective mechanism. For instance, BDNF is found consistently elevated in cases of brain injury (traumatic or inflammatory) and bacterial meningitis:

    Subjects with higher BDNF also had better outcomes following a brain injury, which is expected since BDNF triggers neural regeneration, reconnection, and dendritic sprouting. Why autistic children show elevated BDNF remains to be investigated further. It could be a neuroprotective mechanism following a brain injury, or birth hypoxia, or childhood infection, which resulted in chronic brain inflammation. In this case advising to reduce BDNF doesn't make sense. Or, it could be a result of maternal infection or some faulty genetics, which upregulated BDNF and created "an overconnected brain". In this case, suggesting to reduce BDNF would make sense.

    1. As I mentioned in the post, I am simplifying things. If you do not do this you get completely lost, as many clever researchers do in their (over)complex papers. For example the E/I imbalance in autism, there are numerous different types, all with multiple possible causes and so therapies. I picked just one and hardly mention the others.

      If you are lacking in BDNF or indeed NGF, I think having some more might help. Too much BDNF around birth looks like part of the problem in autism.

      I am not seeking to lower my son's BDNF, I am just noting the implications that his likely elevated BDNF have. In this case elevated BDNF appears to cause overly dense dendritic spines, which suggests less would be better. Changing BDNF would also affect other things.

  3. HI Peter, How does this relate to your posts such as Types of Excitatory/Inhibitory Imbalance in Autism, Fragile-X & Schizophrenia for example. Or the use of sulforaphane, PPARy or anti-inflammatory treatments.

    1. It does not relate directly to them. Although everything is ultimately interrelated, I think you can consider fine tuning dendritic spines as a discrete subject.

      Just note that something that is anti-inflammatory might also affect dendritic spines (statins, quercetin etc).

  4. I had a controversial idea on macrocephaly autism based upon some recent research that is controversial in and of itself dealing with so-called Neanderthal genes:

    Press Release:


    I read the paper and one particular gene they looked at was GPR26. I did a quick search on this gene and autism and came across this paper:

    The results pertaining to GPR26 are in this paragraph:

    "In order to distinguish primary versus secondary MeCP2target genes, we performed ChIP on cerebella from threeMECP2-Tg, Mecp2-null and WT mice. We found thatMeCP2 binds to the promoter regions of the activated targetGpr26 and the repressed target Lrp1b (Fig. 4). Gpr26Figure 2. RNA ISH demonstrates that Prlf2 is highly upregulated in MECP2-Tg cerebellum compared with WT (A). Prlf2-expressing cells were counted onsections throughout the cerebellum (B)(P,0.004).2434 Human Molecular Genetics, 2009, Vol. 18, No. 13
    encodes the G protein-coupled receptor (GPCR) 26, a consti-tutively active orphan GPCR that is predominantly expressedin the brain (30) and that has been shown to be downregulatedin glioblastoma (31). In the hypothalamus, Gpr26 wasactivated by MeCP2 (upregulated in MECP2-Tg and downre-gulated in Mecp2-null mice) (19). Lrp1b encodes the low-density lipoprotein-related protein 1B (deleted in tumors). Itis expressed in the adult brain and was originally describedas a putative tumor suppressor in lung cancer cells. Inaddition, it can bind to amyloid precursor protein (APP) anddecrease its processing to amyloid beta peptides (32). Lrp1bis also repressed by MeCP2 in the hypothalamus (19)"

    One way of thinking about this is that overexpressed so-called Neanderthal genes may be actively dampened or even silenced in normal development, but because of some improper developmental signaling such as excess serotonin in utero, these Neanderthal genes in macrocephaly subtypes of autism are allowed to proceed as normal. This would cause a hyperactive visual system (and perhaps auditory and sensory systems) that the downstream areas of the human brain cannot handle/filter just as if ancestor primate genes were not silenced, then we would all have monkey like tails.

    It is also interesting the heat map they have for the expression of Neanderthal genes almost exactly mirrors the fMRI images shown in many papers I have seen on temporal and occipital lobe hyperactivity in autism.

  5. Hi everyone,

    Has anyone actually been using anti-helminthic therapy (mebendazole, nicloasamide, pyrviuium)? I would like to find out from those who have been using it, what their experience has been? And also, very importantly, how often they are using it and at what dosage?

    It sounds like an interesting option, but since the normal use would be very short term, I'm hoping to see what results people have been having, with their dosage and frequency of use.



    1. AJ, I am just in the early stages with this. Since your daughter is still young you might want to consider what Ling is doing with Ponstan. This is the idea of Knut, the researcher, to alter the course of autism is very young children. It seems to have an impact in Ling's case.

  6. Interesting, especially the part about cAMP, which strongly influences PKA levels.

    According to wikipedia and other research PKA is necesarry for reward perception, something that people with ASD (myself included) definatly have huge problems with.

    Why go hang out with friends and be social on a friday night if you cant imagine how good the reward of social interaction actually can feel.

    Another thing that is HUGELY overlooked is overactivation of the immune system in ASD.
    Think about it from a simple perspective: if your body is constantly fighting 'false alarm' attacks, it will not be able to relax and enjoy things in daily life.

    As someone who is sensitive to alcohol and has a drinking aversion I found out that low cAMP-PKA individuals are less likely to drink alcohol and are more sensitive to its sedative effects.

    The times that I do drink like lets say 12 beers, the next day i wake up i am CURED from my aspergers/asd.

    I have been researching this and there are tons of people with ADHD/ASD feeling the best version of themselves and fully emotional capable.

    So I have been narrowing down what happens during a hangover, thee are multiple things:

    * cortisol: during a hangover cortisol levels are far higher than normal, coincidence that i jump out of bed while i normally have a hard time getting out? I think not, the cortisol awakening response in asperger is impaired showing elevated acth levels but lower than normal cortisol, definatly a genetic dysfunction somewhere in cortisone->cortisol, hence acth keeps trying so hard.
    Not to mention cortisol is immunosupressive, which i think can benefit some including myself.

    * glutathion: alcohol lowers glutathion, but during a hangover the enzymes responsible for GSH production work overhours, pulling the necessarry glutamine out of muscles in an attempt to raise GSH.
    I suspect some of the mood effectd during a hangover come from this, just look how effective NAC and sulforapgane are.

    * PKA: PKA activation increases ABOVE baseline during hangover.
    Incredibly important in reward perception and signalling molecule.
    Luteolin for example is a PDE4-i, which increases cAMP and thereby PKA.
    Rolipram has actually been shown to be effective in certain autism subtypes.
    Also I personally have chronically LOW free fatty acid, my doctor always is impressed by this but in the case of autism this can be bad, especially when you eat healthy every single day, only coconutoil, oliveoil, nuts, etc.
    Individuals with LOW PKA AND cAMP have their HSL (hormone sensitive lipase) impaired, these people have a harder time staying lean even when eating healthy, this is why forskolin can help with this, it induces cAMP.

    AMPA/NMDA ratio and upregulation.
    Hangovers increasr ampa and nmda receptors, im pretty sure this means less aspartic acid floating around with no receptors to attach to? Which seems a good thing.


    My stable blood levels throught the years:

    - slightly elevated ast (d-aspartic acid gives me headaches, impaired sleep and crazy dreams)
    - slightly elevated alt (beta alanine gave me hugeeee fear symptoms, taurine is a miracle for me, they both use the same transporter)
    - very low gamma gt (impaired glutamine usage? L glutamine boosts my mood)
    - verly low alkaline phosphatase
    - elevated ldh
    - elevated ck

    - low free fatty acids (i definatly have low cAMP and PKA)

    - prolactin somewhat high but still in the range


    Now to my latest supplement i am taking currently, cordyceps!

  7. Now to my latest supplement i am taking currently, cordyceps!

    So far this has helped tremendously with apathy and anhedonia, it was cordyceps that made the link for me clear what i am deficient in.


    - tonic
    - immunomodulation, but in most cases according to pubmed it works immunosupressive, with exception to a few interleukins, including il10!, which is necesarry for oxytocin! Remember reuteri atcc 6475, works by lowering il17 and increasing il10.
    -AMPA amplification, cordyceps induces a potent antidepressant affect without working throuhj serotonin, this effect is within a few hours of first dose.
    - contains cordycepin, a compound nearly identical to adenosine, it is very unique.
    - increases cAMP and PKA
    - increases dopamine and tyrosine hydroxylase both in the gut and the brain without affecting serotonin


    Why is there so little discussion about cAMP and PKA, autism shows low PKA in the frontal cortex.
    Rolipram has been used in a study with autism before with some success, now rolipram has nast side effects, what about a combination of a pde4-i and forskolin.
    This could also be beneficial to the autism subtype with the RORA mutation since forskplin increases aromatase.

  8. Speaking of cognitive enhancement, a paper came out today that showed that the enhanced learning effect of dietary restriction is not dependent upon mTOR, insulin, autophagy, or other life-extending pathways, rather the cognitive enhancement is separate from life-extending benefits of dietary restriction and dependent instead on the kynurenine pathway and its synthesis of kynurenic acid which impairs learning:

    Press Release:


    Kynurenic acid of course is linked to schizophrenia and depression, but it also is thought to be an endogenous dampener of NMDA receptors that helps prevent excitotoxicity such as from quinolinic acid, another metabolite of the kynurenine pathway.

    Now there are many very interesting conclusions in this research that intersect with many topics Peter has covered. For me, even though the research is on C. Elegans, an organism with only 302 neurons, whereas the human brain has billions, I feel it might be an answer to some strange improvements in the behavior of my son in the past when his appetite decreased significantly. In particular, one time he pretty much starved for two weeks and would not eat much food at all to the point we were about to seek medical supervision. He was quite chubby before his anorexic behavior so he lost some weight which the pediatrician at his checkup said was great even though I said "but, but, he starved for two weeks and that is good". His anorexic behavior was driven by some pathogen he acquired from a classmate who went to school and got pretty sick. My son got sick as well and then had this several week disinterest in food, however, his SIB pretty much disappeared during that time and he was very calm and more verbal. I have had many hypotheses about why, but this latest one sounds like it might explain some problems in light that BCAA therapy improves his cognitive symptoms and even though some people use it for suppressing excess dopamine in the brain, my original reason for its use was to suppress kynurenine into the brain since L-Kynurenine uses the same amino acid transporter as the BCAA's and other aromatic amino acids.

  9. Now, I was working under the presumption that quinolinic acid reduction was the reason for an improvement in my son's results, especially since glutamatergic signaling seems to be excessive rather than dampened (such as in schizophrenia).

    Now it is also possible that L-Tryptophan in some people with autism would improve symptoms if the increased kynurenine as a result of L-Tryptophan supplementation ended up producing more Kynurenic Acid which would reduce the effects of excessive glutamate signaling. However, with activated microglia, kynurenine tends to favor the quinolinic acid path, but much of this has been speculation.

    So one thing parents could do if they follow my reasoning here is to test supplement increasing doses of L-Tryptophan over the course of a week or two to see what happens. About 90% or more of L-Tryptophan is converted to L-Kynurenine with the remaining 10% or so being converted to serotonin, of which about 90% of the serotonin produced is secreted by enterochromaffin cells in the intestines with the remaining 10% being produced in the major serotonin expressing neurons in the brain such as the dorsal raphe nucleus. So, if you have a hyperactive autistic child and the L-Tryptophan improves symptoms, the obvious conclusion most would make is that the increased serotonin would be what improved symptoms, but what if instead it was Kynurenic Acid balancing out hyperactive glutamatergic signaling in the brain at NMDAR receptors which are though to be hyperplastic in autism. On the other hand, if symptoms became worse (such as increased hyperactivity and SIB), it might suggest Quinolinic Acid problems, which means you might want to try BCAA therapy and restricting dietary tryptophan and perhaps supplementing a small amount of 5-HTP back into the body to make up for the tryptophan inhibition. Of course, almost all protein (aside from gelatin/collagen) has significant amounts of tryptophan so restricting tryptophan itself can be seen as impractical (which is generally why you need to fast to reduce tryptophan/kynurenine levels in the blood), but BCAA's of course competitively block tryptophan/kynurenine's access to the brain via the BBB for 3-4 hours if the BCAA's are ingested a half hour or so before a meal containing tryptophan.

    I thought that in light of this research this might be an easy way to test what type of intervention could help out in this area with respect to autism. Of course, this research may have nothing to do with humans in the end, but it is likely these mechanisms or at least similar ones are evolutionarily conserved.

    The main point is that with respect to autism, for intellectual delay especially, there are real reliable cognitive boosting interventions at the moment and this research, even though on a very primitive organism, suggests that normalizing the excitation/inhibition ratio might be doable via modulation of the tryptophan/kynurenine pathway.

  10. Hi everyone,

    Interesting new research out today:

    Social interactions light up
    Neurophysiological phenomena that underlie the symptoms of autism remain unclear. Genetics-based mouse models of autism have suggested that there is an increase in the neuronal excitation/inhibition (E:I) balance. An optogenetically driven increase in this E:I balance leads to social deficits in mice. Using mice lacking CNTNAP2, a gene known to be associated with autism in humans, Selimbeyoglu and colleagues now show that real-time optogenetic modulation of the E:I balance rescued social behavior deficits and hyperactivity in these animals. This study highlights the potential for modulating neural circuits in the brain as a strategy for treating autism.
    Alterations in the balance between neuronal excitation and inhibition (E:I balance) have been implicated in the neural circuit activity–based processes that contribute to autism phenotypes. We investigated whether acutely reducing E:I balance in mouse brain could correct deficits in social behavior. We used mice lacking the CNTNAP2 gene, which has been implicated in autism, and achieved a temporally precise reduction in E:I balance in the medial prefrontal cortex (mPFC) either by optogenetically increasing the excitability of inhibitory parvalbumin (PV) neurons or decreasing the excitability of excitatory pyramidal neurons. Surprisingly, both of these distinct, real-time, and reversible optogenetic modulations acutely rescued deficits in social behavior and hyperactivity in adult mice lacking CNTNAP2. Using fiber photometry, we discovered that native mPFC PV neuronal activity differed between CNTNAP2 knockout and wild-type mice. During social interactions with other mice, PV neuron activity increased in wild-type mice compared to interactions with a novel object, whereas this difference was not observed in CNTNAP2 knockout mice. Together, these results suggest that real-time modulation of E:I balance in the mouse prefrontal cortex can rescue social behavior deficits reminiscent of autism phenotypes.

    Have a great day!


    1. Yes this is very interesting research and unfortunately my paper fairy was not working so I have yet to read anything more than the abstract (maybe try again in a few days).

      One caveat that is important here is that in mice the medial prefrontal cortex when mapped to the human brain is a rather large area, whereas in the human brain the medial prefrontal cortex comprises a much more segmented area and is typically referred to as dorsal medial prefrontal cortex, anterior medial prefrontal cortex, and ventromedial prefrontal cortex. In mice, the term "medial prefrontal cortex" refers more to the area in humans that is commonly called the cingulate cortex as in mice the prefrontal areas are much smaller and not as expanded as in humans. For instance, only primates have what you might call an anterior medial prefrontal cortex, an area greatly expanded in humans which is thought to giving us the ability to do mental task switching (i.e. hold multiple thoughts in our mind at once).

      In autism, the dorsal anterior cingulate cortex (which in mice would be considered medial prefrontal cortex), seems to behave aberrantly in communicating with other autism hotspots like the amygdala and the anterior insula, both areas of the brain involved in shifting attention and socialization.

      I have to actually read the paper to speculate much further, but another thing to consider here so you don't get your hopes up too much is the medial prefrontal cortex in a mouse is kind of like saying "prefrontal cortex" as in humans our lateral prefrontal cortex is much larger (i.e. we have more surface area on our brains), and many studies with regards to improving autism symptoms such as with rTMS focus on the dorsolateral prefrontal cortex which doesn't really exist in a meaningful way in mice. Of course producing genetically modified monkeys would take quite a long time as it would be years before they would even be ready for this experiment, but until that happens I would not draw too much from this experiment.

      Then again, once I read the paper I might be surprised.

  11. Coincidentally with regards to my last post about a Tryptophan challenge maybe giving some clues as to therapy directions might want to go, here is some very compelling research (in mice) that just came out today which describes how L. Reuteri helps dampen down inflammation and it turns out it does so via metabolizing tryptophan:

    Press Release:

    I can't dig up the paper yet (Google searched and everything), so the link may appear in a few days, but the press release suggests that controlling gut inflammation may benefit from the combination of L. Reuteri AND Tryptophan.

    This is very interesting because Tryptophan is found in large quantities in casein rich dairy foods and ironically avoiding dairy foods might induce a tryptophan deficient diet in the gut. On the other hand, even though the entire GFCF diet is controversial as macro studies have shown no improvement in symptoms, what if a lack of an inflammatory response to pathogens in the gut could cause problems in some with autism and reducing tryptophan and L. Reuteri numbers might balance the gut to be more pro-inflammatory. These are just ideas off the top of my head and I have never employed the GFCF diet for my children nor believed in it scientifically, but it is common for macro studies to drown out subset responders with noise and this dichotomy between believers in GFCF and those who don't believe in it or even feel it makes symptoms worse could be explained by this research if the effects of L. Reuteri and Tryptophan translate from mice to humans.

  12. I was able to finally find a link to the L.Reuteri/Tryptophan. Here it is:

  13. Hi everyone,

    The following is a potentially interesting paper that just came out today, called "Neuroplastin deletion in glutamatergic neurons impairs selective brain functions and calcium regulation: implication for cognitive deterioration"

    I'll have to do some digging into Neuroplastin, PMCAs, and ATP2B2. If anyone has any insights from this paper that could be relevant, please share!


    1. I just finished reading the paper. Upon first glance, it would seem that in autism the levels of neuroplastin would be higher than normal as many people with autism have a hyperactive hippocampus and often superior spacial memory (linked with NP). On the other hand, in the discussion section there was a reference to a couple papers finding low levels of neuroplastin to be associated with autism (PMCA2) and poor social behavior (I have not read those papers).

      Of course, in autism usually multiple hits are indicative of increasing severity of symptoms so it is of course possible a regulatory gene or genes could both cause decreased neuroplastin in learning areas leading to intellectual disability, while some of the other more common autism candidate genes cause the hyperactivity in the same brain areas, thereby causing some researchers to report false positives for GWAS studies.

      Of course the problem with this scenario is as you increase the number of genes interacting in this way you increase the magnitude of complexity of getting to the bottom of things where a strong association between one symptom and a gene can mask a deficit caused by another gene when you only look at general statistics such as the so-called excitation/inhibition ratio in a particular part of the brain.

    2. Hi Tyler,

      Thanks for reviewing and your insights!

      I think one of the best things that could happen for us ASD parents and our kids is for some sort of diagnostic that would help differentiate our kids in some meaningful way, like is done in cancer now. For example, in breast cancer, a patient can be HER2 positive, or triple negative, etc. If we had a way to differentiate our kids so that they could receive the treatment they need, it would make life so much easier.

      I guess that's why, at the end of the day, there is so much trial and error that is done - as my daughter may be low on something that your son has too much, and vice versa.

      Have a great day Tyler!


  14. Here is another potential explanation for circadian sleep problems in people with autism that deals with D1 receptors in the superchiasmatic nucleus of the hypothalamus:

    Press Release:


    The important takeaway here is that interventions like melatonin may help reset the circadian clock, but that if there is an excess of D1 receptor activity in the superchiasmatic nucleus, then people with this issue are going to be extra sensitive to light resetting their biological clock.

    So as far as interventions go in keeping circadian rhythms in optimal form for people with this particular problem (under the assumption this research applies to humans), you will obviously want to be extra-judicious about artificial light in the evening hours, and you will want to look at ways of limiting dopamine release of which there are legion (caffeine, exercise, upbeat music, etc.).

    Of course this sounds like some advice from Captain Obvious, but for more severe cases of sleep problems with those with autism who often tend to have high dopamine levels, being extra-judicious in light of this information might significantly improve sleep quality in some people.

  15. Hi everyone,

    I just found this and it could be yet another piece in the ASD puzzle:

    "Disruption of a neuron structure called the primary cilium leads to defects in brain development resembling those seen in neuropsychiatric disorders"

    Have a great Monday everyone!


  16. Hi everyone,

    To anyone who has used PONSTAN... would you kindly provide information about your experience (how long until improvement, what kind of improvement, extent of improvement, etc.), including dosage used (Mgs per Kg would be ideal)?

    I will be going to a new doctor soon and wanted to talk about bumetanide (maybe even low dose SSRI), but now want to also bring up PONSTAN and would love to have some real world experience with it to share.

    Thanks very much for anyone who shares their experience.


  17. Came across a study today which was done with the Biogaia Protectis strain (L. Reuteri 17938) that dealt with a metabolite of L. Reuteri and Glycerol called "reuterin" which acts as a natural antibiotic to pathogenic strains such as C. Difficile that is comparable to vancomycin in reducing populations of C. Difficile.

    Press Release:


    Now obviously this research is interesting because the specific strain used is literally the same strain I use (one of them as I use Biogaia Gastrus while I think Peter uses Biogaia Protectis which only has the L. Reureri 17938 strain), but considering we don't know exactly what the mechanism of improvement in various autism and comorbid to autism symptoms may be for those who have had success with Biogaia, however, in light that glycerol production in the intestinal tract is highly variable between people, adding some glycerol with Biogaia supplementation could significantly increase the efficacy of Biogaia Protectis in some people. Really, there is no way to know for sure, but it is entirely possible many of the improvements with Biogaia Protectis may be from normalizing the populations of various strains in the microbiome via antibiotic metabolites like reuterin. If there is already a problem in producing glycerol in the intestinal tract (which could be partially the result of intestinal dysbiosis to begin with), then L. Reuteri won't be able to be as effective as it needs to be in helping regulate other pathenogenic species of bacteria like C. Difficile.

    Much of this is just speculation on my part, but I think trying out glycerol supplementation for Biogaia users might be worth a try as glycerol is added to just about every processed food as a preservative and thickening agent and is totally non-toxic, even in large quantities. Some people even use it for vaping into their lungs as a substitute for polyethylene glycol.

  18. Hi everyone,

    The following is a very interesting paper, showing that OTA could be a culprit in some ASD - the P-values are significant:

    Role of mycotoxins in the pathobiology of autism: A first evidence.
    De Santis B1, Brera C1, Mezzelani A2, Soricelli S1, Ciceri F3, Moretti G1, Debegnach F1, Bonaglia MC3, Villa L3, Molteni M3, Raggi ME3.
    Author information

    Gene-environment interaction is an emerging hypothesis to expound not only the autism pathogenesis but also the increased incidence of neurodevelopmental disorders (such as autistic spectrum disorder, attention-deficit, hyperactivity disorder). Among xenobiotics, mycotoxins are worldwide contaminants of food that provoke toxicological effects, crucially resembling several symptoms associated with autism such as oxidative stress, intestinal permeability, and inflammation. Here, we focused on a group of mycotoxins to test their role in the manifestation of autism, try to explain their mechanism of action, and discuss possible preventive and therapeutic interventions.
    Autistic children (n = 52) and healthy children [n = 58 (31 siblings and 27 unrelated subjects)] were recruited and body fluids and clinical data collected. The diagnosis of autism was made according to DSM V criteria, then with GMDS 0-2, WPPSI, and ADOS. Ochratoxin A (OTA), gliotoxin, zearalenone, and sphingosine/sphinganine ratio were determined by LC analysis in sera and urines. Statistical analysis was performed by the Wilcoxon Rank Sum (Mann-Whitney) test and Spearman test.
    By comparing the results of autistic patients with those of unrelated controls, a significant association was found for OTA levels in urines (P = 0.0002) and sera (P = 0.0017), and also comparing patients with siblings and unrelated controls together (P = 0.0081).
    Our results are the first describing a possible role of OTA in the pathobiology of autism. Recalling the male prevalence of ASD (male/female = 4-5/1), it is noted that, in animal models, OTA exerts its neurotoxicity especially in males. Moreover, in vitro, OTA increases microRNA-132 that is dysregulated in autistic patients and involved in reciprocal regulation of the autism-related genes MeCP2 and PTEN. A personalized diet coupled with probiotic administration, especially OTA adsorbing Lactobacillus, could ameliorate autistic symptoms in OTA-positive patients.


    1. Hi AJ, Dr. Stephen Genuis (Edmonton) is big on mycotoxins contributing to chronic illness including neurodegenerative conditons (you can find him and his research on pubmed) as well as environmental toxicity. This paper by Frye et al also mentions mold as possible factor briefly but focuses on aluminum mostly-

    2. Hi Anon, thanks for letting me know about Dr. Genuis' work!

      I just went out yesterday and bought BioGaia Protectis as it appears that various strains of Lactobacillus can adsorb OTA. I have to do some research to see what other ways there are to minimize the impact of OTA.

      I'll definitely go through Dr. Genuis's papers to see if there are any other ways to impact mycotoxins.

      Do you (or anyone else on the board) have any other suggestions that you know of? This would be very helpful.

      Thanks Anon!

      P.S. Anon - please give yourself a name at the end of your posts so we can differentiate you from others.


    3. Tyler, AJ and Anonymous - great findings!


    4. Hi All, here is a link to most of Dr. Gs work: He places a large importance in removing mycotoxins then treating. that means evaluating where the child lives and spends time as well. If the child was born and lived in a house with mold at any point in time it can trigger an immune cascade. He also treats mycotoxin load and i believe uses testing to determine what it is. Great PLains Lab in the states is coming out with a mycotoxin profile by end of this month and it will be available as a urine test. In terms of treatment I am not sure and you might find it in some papers of his I have not gone through all of them yet. AM

    5. AM, I am intrigued. I wonder how his work compares with Dr Ritchie Shoemaker's work and testing recommendations? Will have to check the link you provided - thanks so much. And good to know Great Plains will be offering this lab. We did a biotoxin panel yrs ago for my son - markers Dr Shoemaker recommends - family history here with my grandmother's lupus and the mold connection. Also my son has very high IgE allergy to certain molds. I think it has improved somewhat over the years.

  19. Hello Peter,

    My question is not related to medical treatment for autism. I am increasingly getting convinced that each kid has a fixed upper ceiling and there is only as much that he learn at a particular age. So whether you start therapies at two years of age moving slowly through the drills or start at four and move fast forward because you can now, at five years of age, the child developmental outcome will be same. And probably therapists know about it but prefer the slow long route due to obvious reasons. I hope I am making myself clear. Any thoughts?

    1. Kritika, I am sure all therapists want the best for the children they support. I have asked many of them if they think everyone benefits, and they all replied that yes they all benefit, without exception, but to widely varying degrees. I think parents give up on paid for therapy that does not yield clear results. What counts as a clear result is very subjective and depends on how realistic are the expectations.

      If a child is non-verbal, parents expect speech and they may disregard small steps made towards communication, which is the first step towards speech.

      I think that each child does have a limit based on biological factors, that vary with age. So a particular 4 year old may have no comprehension of prepositions, but if you try again at age 6 he rapidly does master them. So no point wasting hours of time, frustration and money when he is 4 years old teaching him something that is too complex, at that time.

      While your question was not about medical intervention, my firm opinion is that the correct medical intervention raises the cognitive competence of the child so that he then is able to benefit from more advanced therapy.

    2. Yes Peter,

      That is what I meant....speech therapy is one such area where parents spend lot of resources even when the child is just not ready or its physically impossible for the child to produce speech. A lot has to be going on up there before a child talks. But then in autism you never know so there is a lot of parental guilt involved in not opting for standard therapy.
      In autism world, deciding to postpone 'speech therapy'...sacrilegious!

      You are absolutely right about correct medical intervention aiding in making other therapies more effective. Only, the process of finding the correct therapy could be hazardous for your (child's) health. As they say..the road to hell is paved with good intentions.

    3. Kritika, medical therapy for autism is currently experimental and therefore is discouraged. Many people could potentially benefit, but due care and caution is needed to avoid problems. I do not see this situation changing very soon. Autism is the manifestation of hundreds of possible causes and you expect your doctor to get things right first time. You can see why most doctors would not want to even try to treat autism, the exception is when it is their child.

    4. Peter,

      With all due respect, I beg to differ. Parents do not expect doctors to get things right in the first place. We do expect caretakers of our health to at least read up and take interest in at least the researches that make it to headlines, at least listen to what the parent is saying, at least give referrals for specialists, at least write up tests that the parents wants their child to be evaluated for to at least know whats going on if something is indeed going on and at least acknowledge that medical causes and therapies are not all in the parents head just as autism is not all in their 'childs head'!!!

      Deeply disappointed in modern medical practitioners and now getting disillusioned with special educators also because of their highly limited thought process and treating their profession as 'just a job'. Even a garbage disposal job gets done better when the personnel treat it more than 'just a job'. Maybe an exaggeration....but yes, I really think so.

    5. Kritika- My hope is that maybe you could find a special educator that is different. I just want to let you know that some doctors are medically diagnosing it as probable or potential autism in that they are begining to understand that there is more to the picture. There is hope but I wish that it was happening sooner....Jaded mom.

    6. Jaded mom,

      I have had a similar, bitter experience with benign supplements. My son displayed symptoms of liver and digestive issues and even an episode of SIB..all on only a few days or maximum weeks of being on them. Is that medically normal....these reactions to supplements? Obviously something is off. Its not only oxalates or amines or other loaded variables that are being affected by these chemicals but blood pressure and blood sugar levels too which might wreak havoc in a biologically sensitive child. I am pursuing lab tests not to really find a cause per se..I am quite realistic there..but to rule out certain issues lest they make my sons life physically uncomfortable. Our paed has never mentioned the word autism..deficits in certain all he speaks of for which I am grateful.

      As for special educators, their lack of education reflects in their action and words. My son suffered from a urination problem and a period of pain was followed by almost a loss of toilet much so, he wet his pants one day on way to his therapy center. And the poker faced educators stared blankly while one of them offered..'sometimes its sensory'. Bravo son for pinching and biting and hitting . You gotta protect yourself from fools...the most dangerous creed on earth. Sorry for this but I will not let any half educated dimwit subject my child to daily drills of carrying and dumping objects from one place to another, months on end. Which neurotypical child will endure this.

      Well, let us keeps our hopes and heads high. I am sure medical research will not let us down.


  20. Kritika and Peter you are right. In the U.S., early intervention services are provided by the state governments as soon as the diagnosis is received. Overwhelmed and most often shell-shocked parents are told they need X many hours of speech and X many hours of behavior therapy started at such a young age - I don't know any other dev. delay dx that is started so rigidly and so intensely at such a young age (often times before the age of 2). The very real down side: the stress creating new health problems when the baseline medical issues are not addressed. My son always presented with high medical needs form of autism - of course the "therapists" didn't rcognize this, they just like to label,it "task avoidance behavior". It might be different now, but early intervention services when my son was diagnosed at age 2yr 4 mos. had zero understanding of this and what they provided made things so much worse.

  21. Hi everyone,

    Maybe another piece of the puzzle is progranulin.

    The relevant paper just dropped (not necessarily about ASD):

    The story is here:

    Given the impact on the brain of specific dementia patients, I was curious if progranulin levels had ever been measured in ASD... and it was. Apparently progranulin levels are low in ASD patients:

    What might low progranulin levels result in? Check out the following paper:

    "During aging, Grn−/− mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn−/− microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn−/− mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency."

    I get that this isn't directly related to ASD, but there are some interesting potential connections (ASD has low levels of progranulin, low progranulin affects microglial pruning, OCD like grooming from low progranulin levels) - if anyone has any insights from the above on ASD, please share. I'll do more digging and post any insights I have, but wanted to share just in case anyone was interested.

    I'm curious to dig a bit more into the C1qa gene to see if anyone has studies the impact of modulating the activity of this gene.

    Have a wonderful night all!


  22. Hi everyone,

    Another new paper that may be of interest - we have seen many papers that show that ASD kids have increased cytokine levels, but this one also identifies Il-9 levels as being elevated.

    Have a great day everyone!


  23. Fresh off the press: "Dementia and low brain serotonin may be linked"

    >> This new study on persons with early stages of memory decline showed conclusively that serotonin loss was causing the memory loss rather than the other way round... In a normal brain when a message comes via a neuron, the neuron releases serotonin at its end. This is detected by the next neuron receiving the message. Once the message is propagated, there is a serotonin transporter SERT that picks up the serotonin and takes it back to the message-sending neuron. This shows up as the flow of the chemical serotonin. The serotonin neurons and transporters reduce with age in normal persons. As the neurons die with age, the SERTs also reduce in number. One group of drugs that improve brain serotonin levels are the drugs that block the brain's reuptake of serotonin (known as SSRIs or Selective Serotonin reuptake inhibitors)... But these drugs need adequate number of serotonin transporters or SERTs in the brain to work, and that was missing among those with cognitive decline. That is probably why SSRIs do not show as much success as expected.

    It appears PKC inhibitors activate SERT's. They are Quercetin and Luteolin (strongest), followed by Curcumin, Reservatrol, and Skull Cap. Interestingly, EGCG activates PKC. I tried EGCG on my son a few weeks ago, and it made him more autistic, more locked in his own world, waving with his hands in the air like a magician, counting all day long. Now it is clear why EGCG did it. Lack of serotonin activity is perhaps the most important cause of autism. My son is currently taking 5mg of SSRI Lexapro and 500mg of Quercetin every day. I noticed positive effect on his social interactions and anxiety from both.


  24. You do realise that SSRI's are SERT INHIBITORS?? Quercetin and luteolin according to what you write above are SERT ACTIVATORS, thus LOWERING the usefullness of an SSRI...

  25. Besides, most people with autism have increased serotonin, you are poisoning your kid with an SSRI, all your doing is dulling his emotions and not solving the root of the problem.
    SSRI's are well known for causing apathy and sexual dysfunctions, sometimes even permanent after discontinueing them, ask yourself, is this really what you want for your kid?
    The common thing alot of parents seem to do is just to dull their kids out so they can get some rest, disgusting...

    1. SSRI's are not SERT inhibitors, nor SERT activators but something else entirely. In fact one problem with SSRI's and their rampant use and abuse is medical science is still not sure what they actually do, though the conventional wisdom is that they block serotonin's reabsorption into the presynaptic serotonin expressing neuron, thereby increasing the levels of serotonin in the synaptic space of the synapse which increases the odds of a serotonin molecule binding to the postsynaptic serotonin receptors. This of course makes them a dirty drug in many ways and why their use should be treated with caution, especially in children.

      The naive explanation of course for SSRI's is that they increase serotonin signaling but considering neurons are sensitive not just to the volume of a particular neurotransmitter but the rate and temporal aspects of signaling, this is why an intervention like 5-HTP is likely safer in the long run.

      Also, dosage matters here and I think 10mg is an adult dose which means 5mg is likely wayyyyyyyyyy too high for a child (the low-dose studies I have seen I remember being much lower).

      One older extended family member in my family has been on SSRI's for over 2 decades and this person is basically addicted to them now. Even worse, it has changed her for the worse to the point I can't trust her with my children without supervision anymore. Serotonin is important in distinguishing the meaning of things and if you broadly raise serotonin signaling in the brain, everything will seem like it has meaning which sounds great on the surface until you realize that someone who cannot prioritize their grandchildren's needs over those of some random stranger because the random stranger is as meaningful to them as their own grandchildren, then you end up sometimes with some very strange and seemingly incomprehensible behavior.

      The serotonergic system in most autisms seems to be messed up in many ways, especially in regars to maternal inflammation and obesity, so it is an open ended question still what is the best course of treatment. SSRI's in some form may be proven to be a good intervention in the end, but I would not bet my money on it.

      That being said, I think you are wrong about a lot of parents drugging their kids up just to get some rest, rather I think they believe that if their child is calm to the point of sedation that it means "progress" in terms of symptoms. Benzodiazepines and other GABAergics will calm people with autism as well, but they also lead to cognitive decline over time.

      The tough reality here is there have been no major breakthroughs in neuropsychiatric medicine in 6 decades or so, so while it is always interesting to see new research using old drugs, as a parent you don't want to keep repeating the mistakes of the past with the abuse of neuropsychiatric medicine in children who may even be old enough and cogent enough to advocate for themselves.

    2. Aspie1983, that is simply untrue, you are obviously not informed on the issue on serotonin levels in the blood versus its metabolism in the CNS, or the mechanisms of action of SSRIs.

      Your senseless attack on parents is totally inappropriate and I am surprised it has been approved.

    3. Thank you, Aspie, Tyler, and especially Anonymous. I accept criticism only when the critic offers a better solution, which Aspie didn't. It is easy to poo-poo all SSRI's based on some personal experience with a specific SSRI, which at some high dose caused some problems. My relative took several SSRI's and some reduced libido, some caused ticks, and some were totally fine and helped a lot. Unless Aspie can be more specific which SSRI's caused problems and at what dose, his reply is weak and not deserving serious attention. Should I listen to some guy on internet or to my psychiatrist/neurologist, a fellow of UCLA, who has treated thousands of children in his 43-year career? It is hard for a person without an autistic child to understand the dilemma that we parents of autistic children face: leave things alone and hope that a child will recover on his/her own or take a risk and treat it with something that FDA doesn't approve for this condition. I have constant anxiety over my son's future: will he be living in a group home, abused by caregivers, or be independent, have a job, and may be even a family? Impotence from SSRI's you say, Aspie?


    4. V, there currently is no “one-stop shop” to go to for autism treatment. You have a small group of clinicians in the US, each convinced that their therapies really work, but they are often not the same therapies. One doctor who attended UCLA 40 years ago may think anti-virals and SSRIs are they key, another thinks leucoverin, B12 and NAC are they key. They may both be right sometimes, but they are not treating the same autism. Different dysfunctions will require radically different therapy and almost nobody has their autism biologically diagnosed with any precision.

      Doing nothing and hoping for the best, is quite a rational conclusion, but not the one I opted for.

  26. Maybe someone can help me with this. I have used vitamin C with Quercetin in the past. Well the nightmare was too much amine and not enough enzyme to break it down......nightime vomitting episodes. They occurred at in the winter. He was not getting much sunlight-Vit.D, not a lot of zinc, and was being exposed to electrosmog at school. We live in Minnesota. I believe these things to seriously impair enzyme function. At the time I did not know. So I decided he was dealing with a stomach virus possibly so I kept him home and used C+biofizz (powder C with quercetin). Shortly after, he threw up everywhere and i had given him amines(avocados/water kefir) that day too because he has a taste for them--I did not know yet. Anyway, I realized what was going on and I was looking for DAO enzyme.....No where to be found-shortage. My son is on a bunch of different supplements used for different things depending on what is going on. It is a balancing act where I often don't use pharmaceuticals because in our case --both myself and my son are highly sensitive people. I find these compounds are not balanced with the designs of nature and often will effect something somewhere else and they are too strong. We have to take something with the wisdom of a shaman and the balance of that which has been provided us. So if I give a small amount of amine it is ok, if I give a small amount of vitamin c with quercetin it is ok. Start small, learn from your mistakes, listen. While I would have loved to have access to my own personal ability to order labs to see what is floating around in my son........How will I really know if what I find is necessarily the cause, because it could be more than one or more lab tests could explain? I have had to learn to accept his disability and at the same time not give up that maybe there are explanations for the regression. I do know he has inflammation. He reacts to toxins from insect bites by getting a seizure and small rise in temperature. The seizures are short and I do not seek to prevent them as the point of them is to bring oxygen to his brain and it seems to work for him. He will sleep because they wear him out and then when he awakes he is better than he was before. I feel if I try to stop the seizure he may not get the oxygen where he needs it when he needs it. I also fear that he might develop a tolerance to the anticonvulsant triggering a need to eventually have a longer seizure to evoke the same response, while dealing with all of the side effects of anticonvulsants. Anticonvulsants always made him have more seizures more often, longer seizures, and I dealt with a decline in folinic acid, a cognitive decline. My son had what appeared to be a stroke that went ignored by the hospital neurologist and I was told it was nothing to worry about that one side of his face was off, his speech was altered, and his leg was dragging on one side of his body. No tests were ordered and nothing was done when we were there to learn the ketogenic diet. It is all very upsetting. Asking for tests to look for biomarkers was denied. I will never trust the medicines with the metals, the vaccines with the metals, the doctors ignoring things ever again period. Very few doctors during our hospital stay ever really understood my concerns. The ones that did we spoke in a very private confident manner. It was like a secret the knowledge they shared and it is so depressing that they cannot just share what they know is helpful out loud for others to hear and know My hope is that I can get rid of metals in places they interfere....but how will I know where they are? My hope is to find the areas of dysfunction but how will I know when there are so many possibilities and no doctor willing to look without paying a private physician? My hope is to use meridian photonic therapy to retrain the bodies flow of photon energy signalling and intracellular atomic communication. My hope is to repair inflammatory membrane and vessel damage............I first have to find the dysfunction............Jaded Mom.


Post a comment