This blog is about noticing connections and making things a little simpler to understand. Today’s post is going to be a good example; all those odd sounding things like Purkinje cells and neuroligins all fitting nicely together.
Today we see how a central hormonal dysfunction (testosterone/estradiol) can lead to an ion channel dysfunction (NKCC1/KCC2) at one end of the chain and at the other explains the absence of many Purkinje cells in the autistic cerebellum, which leads to some of the observed features of autism.
I am calling it the Purkinje-RORa-Estradiol-Neuroligin-KCC2 axis, or Purkinje-KCC2 axis for short.
We also get to see how melatonin fits in here and see why disturbed sleeping patterns should be expected in someone affected by the Purkinje- KCC2 axis.
I should point out that not everyone with autism is likely affected by the Purkinje-NKCC1 axis, but I think it will apply to a majority of those with non-regressive, multigenic, strictly defined autism (SDA).
We saw in a recent post how the enzyme aromatase acts in the so-called testosterone – estradiol shunt.
I suggested that lack of aromatase was leading to too little estradiol which then affected neuroligin 2 (NL2) which then caused down-regulation of the KCC2 cotransporter that takes chloride out of neurons. This then caused neurons to remain in a permanent immature state.
Digging a little deeper we find recent research that shows how the control loops that balance aromatase act through RORA/RORα, RORa (retinoic acid-related orphan receptor alpha.
The schematic illustrates a mechanism through which the observed reduction in RORA in autistic brain may lead to increased testosterone levels through downregulation of aromatase. Through AR, testosterone negatively modulates RORA, whereas estrogen upregulates RORA through ER.
androgen receptor = AR
estrogen receptor = ER
RORα (retinoic acid-related orphan receptor alpha.)
RORα certainly has a long full name. Retinoic acid is a metabolite of vitamin A (retinol).
RORα does some clever things.
RORα is necessary for normal circadian rhythms
ROR-alpha is expressed in a variety of cell types and is involved in regulating several aspects of development, inflammatory responses, and lymphocyte development
RORα is involved in processes that regulate metabolism, development, immunity, and circadian rhythm and so shows potential as drug targets. Synthetic ligands have a variety of potential therapeutic uses, and can be used to treat diseases such as diabetes, atherosclerosis, autoimmunity, and cancer. T0901317 and SR1001, two synthetic ligands, have been found to be RORα and RORγ inverse agonists that suppress reporter activity and have been shown to delay onset and clinical severity of multiple sclerosis and other Th17 cell-mediated autoimmune diseases. SR1078 has been discovered as a RORα and RORγ agonist that increases the expression of G6PC and FGF21, yielding the therapeutic potential to treat obesity and diabetes as well as cancer of the breast, ovaries, and prostate. SR3335 has also been discovered as a RORα inverse agonist.
RORs are also called nuclear melatonin receptors. Many people with autism take melatonin to balance circadian rhythms and fall asleep.
The reduced estrogen levels in women during menopause likely caused them not to sleep due to the effect on RORα.
So it would appear that some of what is good for menopausal women may actually be helpful for some people with autism.
Many Genes affected by RORα
Most exciting, the researchers say, is that 426 of RORA’s gene targets are listed in AutismKB, a database of autism candidates maintained by scientists at Peking University in Beijing, and 49 in SFARI Gene.
Therapeutic Effect of a Synthetic RORα/γ Agonist in an Animal Model of Autism
Autism is a developmental disorder of the nervous system associated with impaired social communication and interactions as well excessive repetitive behaviors. There are no drug therapies that directly target the pathology of this disease. The retinoic acid receptor-related orphan receptor α (RORα) is a nuclear receptor that has been demonstrated to have reduced expression in many individuals with autism spectrum disorder (ASD). Several genes that have been shown to be downregulated in individuals with ASD have also been identified as putative RORα target genes. Utilizing a synthetic RORα/γ agonist, SR1078, that we identified previously, we demonstrate that treatment of BTBR mice (a model of autism) with SR1078 results in reduced repetitive behavior. Furthermore, these mice display increased expression of ASD-associated RORα target genes in both the brains of the BTBR mice and in a human neuroblastoma cell line treated with SR1078. These data suggest that pharmacological activation of RORα may be a method for treatment of autism.
For those who like natural substances, some research from Japan.
Abstract
The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. In this study, we investigated the effects of isoflavones on RORα/γ activity and the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In doxycycline-inducible CHO stable cell lines, we found that four isoflavones, biochanin A (BA), genistein, formononetin, and daidzein, enhanced RORα- or RORγ-mediated transcriptional activity in a dose-dependent manner. In an activation assay of the Il17a promoter using Jurkat cells, these compounds enhanced the RORα- or RORγ-mediated activation of the Il17a promoter at concentrations of 1 × 10(-6)M to 1 × 10(-5)M. In mammalian two-hybrid assays, the four isoflavones enhanced the interaction between the RORα- or RORγ-ligand binding domain and the co-activator LXXLL peptide in a dose-dependent manner. In addition, these isoflavones potently enhanced Il17a mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin, but showed slight enhancement of Il17a gene expression in RORα/γ-knockdown EL4 cells. Immunoprecipitation and immunoblotting assays also revealed that BA enhanced the interaction between RORγt and SRC-1, which is a co-activator for nuclear receptors. Taken together, these results suggest that the isoflavones have the ability to enhance IL-17 gene expression by stabilizing the interactions between RORα/γ and co-activators. This also provides the first evidence that dietary chemicals can enhance IL-17 gene expression in immune cells.
Genistein is a common supplement. It is a pytoestrogen and unfortunately these substances lack potency in real life. In test tubes they have interesting properties, but they are poorly absorbed when taken orally and so unless they are modified they are likely to have no effect in the usual tiny doses used in supplements.
This is true with very many products sold as supplements.
Sometimes care is taken to improve bioavailability as with some expensive curcumin supplements, like Longvida.
Trehalose, a supplement referred to recently in comments on this blog, is another interesting natural substance that lacks bioavailablity. Analogs of this natural substance have been produced that are much better absorbed and are now potential drugs.
Purkinje Cells
Back in 2013 I wrote a post about Purkinje cells.
Pep up those Purkinje cells
These cells are some of the largest neurons in the human with an intricately elaborate dendritic arbor, characterized by a large number of dendritic spines. Purkinje cells are found within the Purkinje layer in the cerebellum. Purkinje cells are aligned like dominos stacked one in front of the other. Their large dendritic arbors form nearly two-dimensional layers through which parallel fibers from the deeper-layers pass. These parallel fibers make relatively weaker excitatory (glutamatergic) synapses to spines in the Purkinje cell dendrite, whereas climbing fibers originating from the inferior olivary nucleus in the medulla provide very powerful excitatory input to the proximal dendrites and cell soma. Parallel fibers pass orthogonally through the Purkinje neuron's dendritic arbor, with up to 200,000 parallel fibers[2] forming a Granule-cell-Purkinje-cell synapse with a single Purkinje cell. Each Purkinje cell receives ca 500 climbing fiber synapses, all originating from a single climbing fiber.[3] Both basket and stellate cells (found in the cerebellar molecular layer) provide inhibitory (GABAergic) input to the Purkinje cell, with basket cells synapsing on the Purkinje cell axon initial segment and stellate cells onto the dendrites.
Purkinje cells send inhibitory projections to the deep cerebellar nuclei, and constitute the sole output of all motor coordination in the cerebellar cortex.
In humans, Purkinje cells can be harmed by a variety causes: toxic exposure, e.g. to alcohol or lithium; autoimmune diseases; genetic mutations causing spinocerebellar ataxias, Unverricht-Lundborg disease, or autism; and neurodegenerative diseases that are not known to have a genetic basis, such as the cerebellar type of multiple system atrophy or sporadic ataxias.
Purkinje cells are some of the largest neurons in the human brain and the most important.
Neuronal maturation during development is a multistep process regulated by transcription factors. The transcription factor RORα (retinoic acid-related orphan receptor α) is necessary for early Purkinje cell maturation but is also expressed throughout adulthood.
The active form (T3) of thyroid hormone controls critical aspects of cerebellar development, such as migration of postmitotic neurons and terminal dendritic differentiation of Purkinje cells. T3 action on the early Purkinje cell dendritic differentiation process is mediated by RORα.
In autism we have seen that oxidative stress may lead to low levels of T3 in the autistic brain. We now see that low levels of RORα are also likely in autsim.
The combined effect would help explain the loss of Purkinje cells in autism.
Neuropathological studies, using a variety of techniques, have reported a decrease in Purkinje cell (PC) density in the cerebellum in autism. We have used a systematic sampling technique that significantly reduces experimenter bias and variance to estimate PC densities in the postmortem brains of eight clinically well-documented individuals with autism, and eight age- and gender-matched controls. Four cerebellar regions were analyzed: a sensorimotor area comprised of hemispheric lobules IV–VI, crus I & II of the posterior lobe, and lobule X of the flocculonodular lobe. Overall PC density was thus estimated using data from all three cerebellar lobes and was found to be lower in the cases with autism as compared to controls. These findings support the hypothesis that abnormal PC density may contribute to selected clinical features of the autism phenotype.
Estradiol – Neuroligin 2 to KCC2
We saw in a recent post how reduced levels of estradiol could lead to KCC2 underexpression via the action of neuroligin 2.
Conclusion
So in my grossly oversimplified world of autism, I think I have a plausible case for the Purkinje-KCC2 axis. I think that in addressing this axis numerous other issues would also be solved ranging from sleep issues to those hundreds of other genes whose regulation is at least partly governed by RORα.
The KCC2 end of the axis can be treated by bumetanide, diamox/acetazolamide, potassium bromide and possibly by intranasal IGF-1/insulin.
How to address the rest of the Purkinje-KCC2 axis?
· More RORα, or just a RORα agonist.
· More aromatase
· Genistein may help, but you would need it by the bucket load, due to bioavailability issues
· Estrogen receptor agonists
· Exogenous estradiol
The simplest is the last one and really should be trialed on adult males with autism. The dose would need to be much lower than the feminizing dose, so 0.2mg would seem a good starting dose for such a study.
Due to the feedback loops somethings may work short term, but not long term.
Great post Peter. One aspect of Purkinje cell loss that has not been satisfactorily answered for me is that from my understanding the studies on Purkinje cell loss were done on adult cadavers. So the question is whether the Purkinje cell loss happened before birth, or after birth and at what rate of loss at what age did it start to occur. Also, what causes Purkinje cell loss is an open question as well. It could be oxidative stress, but it could also be due to natural atrophy from a lack of stimulation via something wrong with the cerebellar tracts or perhaps or something more generally wrong in the cortex which diminishes communication with the cerebellum.
ReplyDeleteAs far as the bioavailability of genistein goes, there are a myriad of poorly absorbed vitamins and drugs that are being encapsulated in lipids under the premise of increasing bioavailability. Some of the science on this is sound from my reading in the past, nevertheless there seems to be a cottage industry of people creating liposomal preparations for just about everything not well absorbed.
That being said, I did a quick look for liposomal isoflavones and came up with this article:
https://mibellebiochemistry.com/app/uploads/2015/03/Lipobelle-Soyaglycone_Penetration-and-Metabolism-of-Isoflavones-in-Human-Skin_CT-2003.pdf
This is for cosmetic application of course (I could not find anything for oral use), but perhaps nobody has really tried out liposomal genistein due to demand whereas liposomal Vitamin C and lipsomal glutathione have much more demand (or at least more people believing in its effectiveness).
If you wanted to create your own liposomal Vitamin C, you might be able to create some yourself. There are a myriad of do it yourself videos on YouTube on how to create "lipsomal" this and "liposomal" using a sonicator which is not a super-expensive device to procure.
Hi Peter,
ReplyDeleteRelating to the purple ellipse in the diagram - oxidative stress.
From the following site: www.futurescience.com/deprenyl.html
"The three major natural antioxidant systems in the body are SOD, catalase, and glutathione peroxidase. Deprenyl raises SOD activity markedly, catalase activity slightly, and glutathione peroxidase activity none at all. The nutritional supplement N-Acetyl-Cysteine (NAC) raises glutathione peroxidase levels and should help to re-balance the body's natural antioxidant system in those using deprenyl".
So if the above is accurate, would combining Deprenyl with NAC provide the optimum re-balancing of the antioxidant systems and thereby clinical benefit to those on the spectrum that fall under the 'purple' ellipse?
I also found the statement - "Just because a substance is an antioxidant, doesn't mean it's good for you" - disturbing.
I can't speak to the accuracy of the above info, but if there is fact, it could warrant further exploration.
As Deprenyl is an MAOi, prescription will be hard to come by. Dr Knoll the formulater of the drug in the 60's started taking the drug in 1988 for life extension.
Any thoughts Peter or has this course been covered previously with no meri?
Regards,
D&G
D&G, it is much more complex.
DeleteLook at the diagram by Professor Sies in this post
https://epiphanyasd.blogspot.com/2014/11/why-not-cocoa-flavanols-for-autism.html
There are very many things involved. NAC is good, but so is activating nrf2. When people say oxidative stress, they also mean nitrosative stress.
https://epiphanyasd.blogspot.com/2016/12/nitrosative-stress-nitric-oxide-and.html
You also need GPx to work
https://epiphanyasd.blogspot.com/2016/12/refining-antioxidant-ros-rns-therapy-in.html
In our case I use NAC (boost GSH) plus broccoli powder (active nrf2). But other people find ALA is better or carnosine.
For nitrosative stress, calcium folinate looks interesting.
Deprenyl will do other things, it will affect dopamine levels. Possibly good and possibly bad.
Thanks Peter.
DeleteI did look at those posts.
Do you consider the activity level of SOD? Does it need to be, and if so how?
Also with respect to your ambivalence to Dopamine, does it also need to be considered particularly with respect to reward? Can ASD be looked upon a condition of 'lack of reward seeking'?
Do kids on the spectrum not engage in social activity because they don't derive a 'reward' as such like say social butterflies do from getting together and socialising.
The dopamine pathways to the frontal areas of the brain appear to me to be the most refined and recently evolved to distinguish us from other species. If these pathways were disturbed would it not yield someone with more rigid and less abstract thinking? I know in our son, the black and white world suits him fine. Doesn't dopamine also play a role in motor movement and picking up on social cues.
I'm not trying to understand this intellectually Peter, rather viscerally. Sometimes we all get bogged-down in the the complexity of the detail and it could help to take a step back.
Regards,
D&G
Peter, what did you use to dilute the insulin? I suppose I need about 5IU for the first trial. Since you've done that, could you please give instructions?
ReplyDeleteI did not dilute it. I used 100 IU/ml insulin and a spray that gives 0.14ml per dose; so my dose was 14 IU which is a low dose for intranasal insulin. Diluting is not a good idea since you may need a special substance, depending on the type of insulin. I gave a single spray in just one nostril.
DeleteI cannot measure my spray's single fixed dose. I have a regular nasal spray of 15ml leftover after disposing otrisalin normal saline solution. Do you know if this also gives 0.14 ml per dose?
DeleteI am really sorry for taking up so much of your time, thanks.
Petra, your product says it contains 107 doses so it must be 0.14 ml like the antihistamine spray I am using.
DeleteHi Peter, I found this paper which seems relevant to my son's kind of anxiety.
ReplyDeleteIntranasal Insulin to Treat and Protect AgainstPosttraumatic Stress DisorderWilliam H. Frey II, PhD
Stress has also been found to reduce the uptake and use of glucose by brain cells. In 1986,Sapolsky reported that glucocorticoids released in response to stress could damage neurons in thehippocampus. Multiple mechanisms are likely involved in this action, one of which is the inhibitionof glucose use in the hippocampus by glucocorticoids. Cortisol has been reported to reduce hippo-campal glucose use in healthy elderly adults on the basis of examination of the brain glucose use(cerebral metabolic rate of glucose consumption) response to hydrocortisone (cortisol; de Leon et al.,1997). It is likely that glucocorticoids also reduce the capacity of the hippocampus to survive neu-rological insults because glucocorticoids inhibit glucose transport 15% to 30% in both primary andsecondary hippocampal astrocytic cultures, and this could impair the ability of astrocytes to aidneurons by removing damaging glutamate from the synapse during times of neurological crisis(Virgin et al., 1991). Glucocorticoids released in response to major stress inhibit local cerebral glu-cose use throughout the brain and inhibit glucose transport in neurons; glia; and, possibly, endothelialcells in vitro (Sapolsky et al., 2000).Baker et al. (2005) have reported that mean CSF cortisol concentrations are significantlyhigher in combat veterans with PTSD than in healthy comparison subjects. Concentrations of CSFi corticotropin-releasing hormone and CSF cortisol concentrations werepositively and significantly correlated. The authors concluded that vet-erans with PTSD have a higher CNS exposure to cortisol than that ofhealthy comparison subjects.In a study assessing the cortisol response to a cognitive stresschallenge, patients with PTSD had 61% higher group mean cortisollevels in the time leading up to the cognitive challenge and 46%higher cortisol levels during the period of the cognitive challengecompared with controls (Bremmer et al., 2003). Most recently,glucocorticoids have been shown to induce PTSD-like memoryimpairments in mice (Kaouane, 2012).Intranasal insulin (40 IU) treatment of 26 healthy adult menminutes before they were exposed to the Trier Social Stress Test ina placebo-controlled, double-blind, between-subject design signifi-cantly diminished both the saliva and plasma cortisol response to thetest (Bohringer et al., 2008). Because intranasal insulin attenuatesthe hormonal response to stress in adult men, it may also be helpfulas a way to treat and even protect against PTSD. If so, it would bepossible to use insulin nasal sprays targeted to the upper third of thenasal cavity to treat individuals exposed to a traumatic stressful eventshortly after it occurred or even to treat individuals, such as militarypersonnel or first responders, who are at immediate high risk fortraumatic stress to help protect the brain against the damaging effectsof such stress.
Let you know my results as soon as possible.
Well Peter, let you know about my insulin trial, day 1.
ReplyDeleteI bought Humulin-Lilly 100IU, human insulin 10mL and put it in a 10ml (the only refillable I could find) nasal spray dispenser which makes 22 sprays per 1ml. 1ml is 100IU so to reach 14IU you need about 3 sprays, is this right, I am not sure if I did it correctly.
As soon as my son woke up, I gave him to spray once. After a few minutes he said he felt better. His nostril was a bit stuffed and after a while he sprayed two more times. I cannot establish the dose because as you put it, he may have taken something more than 40IU, but according to my calculations above (may proved wrong) he took 14IU totally.
It really made an impact on him. His energy levels got high, didn't enter into "freezing state" and was able to take quick decisions about what he was going to do for the rest of the day.
His executive functions and mood very much improved.
He didn't mention anything about "pain" or "fear".
Some side effects I noticed were that one nostril made a slight pink like bleeding, ommitted dinner (only ate some fruit) and couldn't go to sleep at his regular hours.
I intend to continue the trial to see if there is long term effect.
If you have any comments on my dose, or anything, please let me know.
Petra, all very interesting. You could even look at the effect of taking half the dose when he wakes up and half in the afternoon, to see what works best.
DeleteThere are good reasons to expect this to be an effective therapy.
Thank you Peter.
ReplyDeleteEven if the insulin positive effect lasts, as we know very well that lots of things help in the beginning and then stop, it doesn't mean that it can resolve the problem of his anxiety in the first place, which is supposed to raise cortisol concentrations in the brain interfering with cerebral insulin metabolism.
I really hate the idea of Ketamine for anxiety because I know my son reacts badly to psychodrugs. One evening he was very stressed and gave him 0,25 alprazolam which is a very small dose and I sometimes use it when my stress levels are too high. He became another person and felt much worse, so I have to be really careful with such drugs.
I forgot to mention that maybe some stimulants used for ADHD, or Parkinson's disease could help more than "sedatives", since he sometimes responds well to caffeine and nicotine.
ReplyDeletePetra,
ReplyDeleteTyler had suggested agmatine sulphate for my son, a mild nmdar antagonist, primarily as a cognition boosting intervention. On reading up, I noticed the word 'near death experience' in relation to agamatine use and that phrase scared the living daylights out of me! But goofy talk aside, it seemed to act on social anxiety and neuropathic pain amongst other stuff. I am still weighing my options, but you can read about it and see if it can be of any use to your son.. or take Tylers opinion.
Psycho drugs can be really harsh on some people..I took an alprax once and there was no sleep and horrible feeling for two days. I think my son will react in a similar manner. We metabolise brain drugs differently. So I can understand a little bit of your sons issues. I do not know if agmatine is relevant for your son but ge crossed my mind when I read about its uses.
Wishes
The "near death experience" is likely from some guy in the gym doing wayyyyyyyyyyyyy to much of it to get a good pump as agmatine sulphate's most popular use at the moment is for its nitric oxide properties in dilating blood vessels.
DeleteAnother interesting property of it when I first tested it on myself is that it gave me very intensely remembered dreams (I very, very, very rarely ever remember my dreams). Maybe that is what someone meant by a "near death experience".
I would not use very much it. The most I would use is a pinch of it on my son and a dash on myself (anglo cooking spoon measurements).
I also tried attenuating the blood pressure aspects of it with very small amounts of yohimbine (it is kind of the opposite of agmatine) based on a small chinese study on treating the hyperkinetic symptoms of opioid withdrawal where they combined agmatine and yohimbine together with good results (in rats though), but I could not really tell one way or the other if the yohimbine made a difference (generally, yohimbine would be the opposite of what you would want to give someone for autism, but this study suggested it helped balance some of the low blood pressure effects of agmatine).
I must also point out that agmatine is not really so much a drug, but an amino acid that is naturally produced in the body and found in small amounts at excitatory synapses in many parts of the brain (that have been found so far) and seems to be especially relevant to learning and memory.
DeleteThat does not mean that more is always better. 5-HTP is naturally produced in the body as well, but taking megadoses of the stuff will obviously have disastrous effects such as serotonin syndrome.
Tyler, adding zinc tablets with intranasal insulin, would that make any difference?
DeleteSupplements that affect nicotinic receptors are interesting.
Nicotinamide ribosome may be my next option. We read that a young adult Asperger's posting here found it beneficial.
If there is some form of mitochondrial myopathy involved, Nicotanimide Riboside on its own has solid research behind it in attenuating those problems. For whatever reason, Niagen's price has been lowered from $125 per 3 pack of 60 capsules each to $100. When I started buying it, the cost was $150. In spite of its expense, I believe it is really good at mitigating all sorts of health concerns stemming from a poor lifestyle or just getting old. In fact, every diabetic should probably be taking it, though since it is not a drug and NR itself is not patentable, you won't see too many doctors suggesting it anytime soon. Simply raising NAD+ levels won't cure much on its own, but I believe it will give other interventions a fighting chance from chronic cellular stress (ideally you would want to stop whatever is causing NAD+ to be overconsumed or underproduced in the first place).
DeleteAs to zinc and intranasal insulin, I think Peter has covered this topic extensively and I have nothing to add here as I have never trialed intranasal insulin or formal zinc tablets even though with ZMA he obviously get additional zinc supplementation.
Hello Tyler,
DeleteI wanted to know your opinion on use of common nootropics like piracetam, citicholine and galantamine. Can their be a downside? These are cheaply available OTC where we live.
Secondly, you are using lots of amino acids (BCAA, hydrolyzed collagen). BCAA therapy for autism has shown promise in a rare autism subtype and epilepsy and associated with deficiency in certain amino acids. I presume you are not using amino acid therapy to address deficiency but to block a kynurenine's entry into the brain. What about the hydrolyzed collagen? I am asking because it is suggested that balancing out the amino acid levels by adding all essential ones rather than specific ones would be wiser. So if I try to emulate your strategy, should I give a basic broad spectrum amino acid tonic to make up for the disturbance.
Could agmatine sulphate be given as a stand alone treatment. I beleive you are giving at least around thirty different drugs/supplements/dietary additives. That looks very intimidating.
Tyler, my son has what is called idiopathic autism and healthwise I cannot find a single anomaly (counting out his autism, of course) which could give me any idea whatsoever regarding an aberrant biochemistry. His latest basic blood works showed low normal cholestrol levels, marginally lower hemoglobin, creatinine and lymphocyte count. Everything else was perfect. In fact when.I requested his paed for a test he smiled and said that it seems I am spending too much time on the net and added that there usually are physical manifestations of metabolic disorders. So I do n ot have any clue except that I suffered a gi and strep infection in quick succession just before my pregnancy.
One important observation that when I trialled NAC (NAC, bumetanide, l. reuteri in rapid succession), it caused some discomfort but led to cognitive gains and much improved sustained attention...as it is my son does not have much stereotypy or obsessive behaviour, and at the end of a short one and a half/two month use of all three, I saw my son sitting in front of the computer screen alone cupping.his face in his palms..he looked so neurotypical..he was speaking out his bye byes unprompted apart from a greater interst in and focus on learning. Regarding NAC, since it downregulates glutamate transport to CNS in addition to its other properties, I feel interventions which tilt the e/i balance towards inhibitory should be more appropriate..hence an nmdar antagonist like mementine or agmatine (as you suggested) could be of potential benefit . Am I oversimplifying things?
I apologize for the very non specific and loose communication but please give your opinion on anything of relevance which you can glean from this. I am going round in circles and just want to move/inch forward.
Regards
Galantamine has worked well for us, particularly in association with Memantine. Build it up 1mg => 2mg => 4mg as some can only handle 2mg.
DeleteThe one nootropic that is likely to have a huge impact but you need to be careful dosing and tapering is phenibut, particularly if your son showed cognitive gains with NAC.
- EM
The word nooptropics is an oxymoron if you ask me, as most of those drugs have downsides that people who use them like to downplay. Of course that is a generalization, but the idea that you can make a normal healthy person smarter with drugs is basically a fantasy at this point in time. What people don't realize is that the human brain is already pretty much optimally organized for information transfer, among the many other amazing things it can do. That is why you have very, very, very few and true geniuses in the world relative to the number of people who have some sort of neurological impairment. Taking piracetam is like trying to make a formula one sports car go faster with stronger fuel. You might get a little more speed for less maneuverability and greatly increase your risk crashing. As for people with ID, drugs that address specific aberrant proteins that are causing problems, well then those drugs can obviously make a huge difference in those lives.
DeleteOn the hydrolyzed collagen, that just adds extra amino acids minus the aromatic amino acids to help increase protein synthesis in the liver in the morning (which will help cleave aromatic amino acids already in the blood). In studies where Acute Tryptophan Depletion (ATD) is used, they use a complex combination of free form amino acids mixed together which has the downsides of tasting awful and being super-expensive. Hydrolyzed collagen is largely tasteless and not too expensive. If you can get your kid to reliably eat jello, you could use the BCAA mix plus gelatin and serve your child jello instead as hydrolyzed collagen is just heat treated gelatin that breaks the protein bonds down enough that they won't recongeal from cold exposure. So yah you could do your own version which would be BCAA's plus a combination of amino acids, minus whatever aromatic amino acids you want to limit entry into the brain (tryptophan, tyrosine, phenylalanine).
Agmatine should probably be given stand alone. Sorry if I was not clear before. I don't mix the agmatine into his BCAA drink. Also I don't give 30 drugs/supplements to him in a given day either. I have trialed around that many, but getting my son to cooperate makes a lot of them difficult or impractical since he does not swallow pills so I have to stick to interventions that he will agree with and too many different things in a drink at a given time is impossible to mask by just adding more sweetener.
Also, BCAA's and hydrolyzed collagen are just protein really. You can get a lot of BCAA's in milk or cottage cheese, just they also have lots of aromatic amino acids as well (defeating the purpose of the therapy).
Last but not least, my son has idiopathic autism as well and at the moment has no health problems that his pediatrician could find. He had some diarrhea as a toddler, but either through my interventions (probiotic/prebiotic) or just growing out of it, he does not have those problems anymore, nor any of the common allergy issues many with autism face.
DeleteNevertheless, with idiopathic autism, the evidence as of right now suggests that the neurological damage was done very early in life, most likely before birth. That there often is a long laundry list of other strange health problems that come along with many autisms is tangential to the fact that neurodevelopment was thrown way off course long before anyone could do anything about it.
Now what can be done about all of this now? Well accepting things as they are and realizing that your child will always have challenges is what conventional wisdom suggests us parents do. For whatever reason, I am not wired this way so while many parents abandon their healthy children all the time for flakey reasons, I will never quit on my own children no matter their health status.
But to answer your question, my goal has been from around the beginning of all this after the first of three autism diagnoses and realizing the doctors and therapists were clueless (or even outright charlatans taking advantage of desperate parents at one school he was at early on) to first try and educate myself as much as possible about stopping any further neurological damage from ensuing (oxidative stress, excess neurotransmitters, including endogenous opioids, etc.) while at the same time spending a few lifetimes squeezed into the last 6 or so years working on something that will hopefully be able to literally rewire someone's brain (and reverse much if not all the neurological damage from autism and whatever other similar disorder that affects the brain). All of the advice I have given here on this blog is simply to halt the ongoing damage, not actually reverse anything. Of course, sometimes and in some people there can be drugs that reverse ID and some autism symptoms, as is the case with folate therapy and Roger Kulp, but I have little faith drugs will do much for autism unless in the future it can be diagnosed soon enough (perhaps even in the womb), and then treated. Till then preventative measures for prospective new mothers and fathers in taking care of their health is the best society can hope for. As for us parents who don't have a time machine handy to do things differently, the only other way of getting a good outcome is to literally reprogram someone's brain directly and that is where my hope lies right now as I already know how to do it with the tech I have discovered/invented, just I could use several million dollars and and some staff to move things along a lot faster or else I would have it all done already. The problem is that this all sounds like science fiction or else just a blatant lie or delusion on my part so I have had to do everything the slow, hard, and sort of dangerous way (danger to myself only). That is all I can say about it, other than when I get the tech released it will be universal, cheap, or perhaps even free. How it works, I am not going to say at the moment because there are still some big question marks I have to address before putting out something publicly that is both safe and effective. There is also the matter about literally rewiring someone's brain for nefarious purposes, but at the moment I think this will do a lot more good than bad but I could be wrong.
Em,
DeleteThanks for the suggestions. I will give galantamine a shot..starting very low as you suggested. I looked up phenibut and to be honest it looks a bit scary.. Not confident if I can handle the disciplined dosing as yet. It is available through i herb though it's not a very pure version I think.
Thanks
Hello Tyler,
DeleteCant thank you enough for taking trouble to respond with such a detailed explaintation. I will try my best to not be so chaotic and systematically put into practice your suggested interventions, including that of ensuring adequate soluble fiber intake to minimize inflammation.
Tyler, you have one more admirer in me in the way you seem to assimilate so much of theoretical information and actually give it the value of applicability and also whole heartedly share it with others. I also admire your deep commitment for family. Faith can move mountains and so can love. Therefore I am pretty sure you wil be successful in your 'brain rewiring
technology'. Seriously, I am in awe of you! I hope and pray you get the logistic support to push your project through.
Thanks for sharing your thoughts and experience with me. I do value it.
Here's wishing us parents lots of strength and hope (extra dose for those working overtime like you and Peter) and pride in our kids.
Regards
Hello Kritika,
DeleteJudge for yourself the purity of Phenibut available from iHerb.
http://www.tandfonline.com/doi/pdf/10.3109/15563650.2015.1059944
"A sample of the powder labelled phenibut was supplied by the patient and was analysed using gas chromatography – mass spectrometry. The purity of the powder was
98% 4-phenyl-2-pyrrolidinone, the lactam of phenibut. Nuclear magnetic resonance spectroscopy or NMS also confirmed phenibut."
Phenibut is interesting, like a lot of drugs, it appears to have multiple modes of action that would indeed be beneficial to individuals with ASD.
One of those according to Wikipedia and others is ...
"It has been found to increase dopamine levels in the striatum,and it was suggested that phenibut may activate dopaminergic processes and that this may be involved in its effects".
I can read Russian so I really should read the literature.
Hope this helps.
Regards,
D&G
Hello Tyler,
DeleteI have to say I look at things a little differently.
You say "the idea that you can make a normal healthy person smarter with drugs is basically a fantasy at this point in time".
What do you mean by smarter?
Surely creativity in a sense? Don't certain drugs promote creativity? Walt Disney derived his inspiration for Fantasia after a trip on LSD. Steve Jobs was very vocal in attributing his genius to his LSD experiences.
So is it debateable to say that you can't make an otherwise healthy person smart with drugs?
I don't want to drift too far off topic but all these thought-bubbles in some inexpicable way evolve our cause closer to solution
Regards,
D&G
Phenibut is consistently shown to be the most "impactful" "nootropic" in that community and the dopaminergic effects could impact the effects of bumetanide etc.
DeleteCeretopic have the purest nootropics.
Intelligen and Stephen hawking and was it Bill gates too. However, I think Tyler is questioning the overall effect of these drugs on the well being of a person (well being as subjective a term as intellect) with non aberrant brain function. You gain some but in all probability you also lose some. Mermaid phenomenon!
DeleteD&G, if Kritika reads your link about Phenibut she is not going to like the fact that this relates to a man admitted to the intensive care unit.
DeleteIf Phenibut has a similar effect on GABAb receptors as Baclofen, then it should indeed help some people.
D&G, LSD is a very strong serotonergic. In fact a paper released a couple days describes how it works at the molecular level of the serotonin 2A receptor:
Deletehttps://www.sciencedaily.com/releases/2017/01/170126132541.htm
My main point was that our meat processor is largely optimized by evolution to be as intelligent as it given the constraints of earth biology. If you increase the size of the brain, you increase the transmission time between one side of the brain and another which slows down perceptive cycles. That we can do as much as we can with such a large brain owes a lot to some recent evolutionary changes/tradeoffs that allow specialized neurons to transmit information faster than other animals, as well as insulate long-distance connections more (myelin) so they can get good enough transmission speeds to respond to the world around us. And that extra myelination takes up a lot of space in the brain, which means less brain real estate for other things. Crows are incredibly smart animals, and yet they have no cortex as they are not mammals but descended from dinosaurs. Instead they have scattered collections of nuclei throughout their tiny brain and smaller more efficient neurons. This is the tradeoff they make for their intelligence in that they don't have the myelination of humans, but the distances one nuclei of neurons have to travel to another is always relatively short. Nevertheless, crows are very intelligent animals.
Simply dumping a bunch of stimulants into the brain or "nooptropics" as some people call them will not make you smarter. It is possible some of them might increase performance on a specific mental task, but usually at the expense of some other mental task.
So yes, you can't really make an intelligent person more intelligent with drugs and plenty of research done lately reaffirms this fact. That does not mean there are not a lot of substances you can take which will make an intelligent person less intelligent. Also, the aging process makes people less intelligent so there are drugs that can help improve the cognition of people as they age.
There are memory tournaments and other feats of intellect every year and you can read up on what people recommend or not for these people increasing their performance artificially if you are so inclined.
Hi Tyler,
DeleteThanks for the link and also the opportunity to discuss and bounce-things off.
Again, I look at things differently. I don't consider 'transmission speeds', but rather the quality of signal as being more influential. I would add that this is more the case as distance increases. And I would equate quality to a type of signal-to-noise measure. And yes the longer the run the more that signal needs to be insulated (myelin) against 'noise' from adjacent signals (MS comes to mind here).
I consider 'memory feats' to be on the lower rungs of intellect. Abstract thinking, creativity and the ability to learn, I rate much much higher up.
So what do we mean by a 'smarter brain'? Do we mean more efficiency? That is less biological resources used for the same outcome?
If the ageing process makes people less intelligent, then what mechanism is at play? Is it the reduction in dopamine as we age? Selegiline is used specifically by for this.
It's getting harder to call anything 'fact' anymore and the latest research for me wouldn't reaffirm anything. A case of research yields a certain result today and then doubt is cast on it tomorrow.
For example:
http://www.huffingtonpost.com.au/entry/turmeric-may-not-be-the-wonder-spice-people-think-it-is_us_587fdc40e4b00d44838cd188:
For me, break-through results are those often found serendipitously. Sometimes, it's not apparent those results are even break-throughs. But a fresh set of eyes coming from a different angle and ...
PS. Please feel free to shred any/all of my arguments apart.
Regards,
D&G
Hi Peter,
DeleteIf Kritika follows the link I provided I hope she more likely doesn't like the fact that this gentleman ingested 30g for recreational intent - typical therap. Dose is 500mg to 2g daily.
This is what makes it so hard for all of us trying to help our daughters/sons as the ill-conceived actions of a few lead to widespread sanctions on products that could ordinarily be researched for therapeautic benefit. Instances like this only seek to malign what could be a product with research potential.
Much like you did Peter, most people will draw an association between the product and harm and overlook the circumstances and therefore by extension any prospective benefit.
Regards,
D&G
D&G, the broader point is that many people seem to see prescription drugs as "bad", but supplements as "natural", "good" and "safe". There are some very potent substances sold as supplements, as that man in the case report discovered. People need to act responsibly, but many do not and this certainly makes it much harder for the responsible ones.
DeleteIt is odd how so many neurological drugs exist in Russia, but have not been taken up by Western medicine.
This also applies to some clever Japanese prescription drugs.
D&G,
DeleteYour comment about the nature of human intelligence has a nice texture..value assigned to various facets of human intelligence is highly contextual. Rating rungs of human intellect??? Cognition and emotions? Science seperates the two. I find science to be on the lower rungs of human pursuit for truth...of course I am not serious.
Personally, I find the quest for more, when it crosses a certain threshold, highly disturbing. This is precisely what looks so uncreative to me. Chasing an elusive dream towards perfection of human species. I am sure you are familiar with the Theseus's paradox.
I am sorry if I have taken creative liberty in distorting the intent of your comment a little. They are really thought provoking and intelligent.
This is quite an interesting article on LSD these days: https://quid.com/feed/not-your-grandmas-lsd
DeleteApparently they've started MDMA trials? https://erowid.org/chemicals/lsd/lsd_article4.shtml
Thanks for the links EM.
DeleteA thought provoking read but an equally frustrating one when you consider how many years of research were lost account of the sanctions imposed on these substances. Researching them could've led to innovative new classes of drugs and/or therapies, but we'll never know. Maybe now they can make up for lost time.
Tyler, no need to apologise. I enjoyed it. Keep doing what your doing ...
Regards,
D&G
Hello Peter,
ReplyDeleteCurrently, I am giving my son cytoflora+liverlife, half a tab biogaia gastrus and three days back started him on carnosine, 200 mg and plan to take it up to at least 600 mg per day (in the Chez study, they trialled 800 mg) and if he tolerates well, to the full 800 mg. I had some specific enquiries and would be grateful if you could give your opinion
1. My son is displaying lot of sensory behaviour...lot of chewing, paper, collars, anything he can get his hands on and then the need to squeeze or bang. Could this be related to gastrus? At half a tab, it does not help my stomach as much as five drops of bioamicus or one tab of macrobiome so I cant say what it is doing for my son. Should I increase the dose to one tab and see how it goes? Is chewing a sign of histamine related reaction? Also, his appetite seem to have gone down a little.
2. According to dr. Kelley, some sort of mitochondrial dysfuction is present in most autism. Is a trial of acetyl l carnitine and ubiquinol wise? There are combination products like mitosoectra or mito cell. They are expensive but they take away the headache of guesswork regarding new crop of deficiencies. Carnitine use will create a need for ubiquinol which will create some for b vitamins and then the whole methylation cocktail. So ironically, this monster of autism treatment has an insatiable appetite. The more you feed, the more he needs. There I go again into frivolity!
3. There was some talk of carnosine use leading to immediate benefits only to make the average autistic child end up in worse place. This was liknked to disturbance of copper homeostastis by histidine leading to its eventual deposit in tissues and alanine related net depletion of taurine and magnesium, resulting in prpblematic issues with certain enzymatic pathways. Do you see any merit in this theory.
4. Regarding speech deterioration in my son following bumetanide use, I read about similar observations from parents in relation to carnitine use. Cognitive gains but losing speech to eventually catch uo with the speech. Its difficult to say but I think functional speech is the final outcome of so many different developmental processes..cognitive enhancement and keeping engagement and interaction on as much as possible even through non verbal means and even though one sided intitially is going to be our best bet..
Spotlights on ma!
And I am seriously considering a well planned out retrial of bumetanide as I just went through my comments on your blog which unfortunately are the only records I have of my trial and they did confirm what I suspected. There were carry over effects of bunetanide for some time following disuse..in fact some positive effects developed a few days following suspension. So a little discontinuity does not have acute losses in my son.
Regards
Kritika, if you suspect mitochondrial disease this can be tested at a good hospital. Dr Kelley diagnoses based on lab tests, which of course are subject to different interpretation. Better to first test for it than start buying expensive supplements.
DeleteSensory issues and habits are a feature of autism. In some people these are severe. Potassium seems to reduce sensory overload in some people.
The more supplements you take, the more chance there is of making things worse.
I think some people are not drinking enough fluid when taking bumetanide. My drinks about 3 liters a day.
You need to try one drug/supplement at a time, or else you cannot judge the effect. Some will create a negative reaction and then you have to tell time pass before tying anything else.
Some people respond well to carnosine, you just have to find out of your son is one of them.
Peter,
DeleteThanks for responding. I think its crucial, as you reminded me, that I stick to few supplements which have clear benefits. Internet can be the sensible friend as well as the bad guy who can lead you astray with tantalizing promises. Right now my sitting duck act has left me with a cupboard full of supplements which I am not using and a nervous, bad feeling...I do not know about my son but I am sure to undergo multiple regressions unless I get a grip on myself.
Peter, my daughter also drinks 3+ liters of water every day. She is doing well with the addition of the second 1mg dose of bumetanide. She is speaking better, and social interaction has gone up another notch. It doesn't seem to matter even if the second dose is late in the evening, I can see the effect the following day. Interestingly, I see both these positive effects decrease if the second dose is missed. I am surprised by the quick response.
DeleteI currently give the potassium away from the bumetanide, and I have now noticed twice that if I give it along with the bumetanide, it does not seem to be very effective. A small amount of the hypersensitivity returns and a mild irritability as a consequence.
Peter, I also wanted to thank you and the commenter who posted the paper on pantethine and the ketogenic diet. The only B vitamin that I felt might have been of value was the pantethine, though I gave a very small amount. I would like to try it, but then I have to come in with all the other B vitamins too, isn't it? I was so happy to be rid of them, not looking forward to doing it again. What dose of pantethine would be good to try?
DeleteRG, plenty of people seem to use pantethine to reduce cholesterol without side effects. In the study below 600mg was effective.
DeleteWith luck this will not affect the other B vitamins and might be enough to help the ketosis. It would be an experiment.
Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942300/
Thank you Peter, I'll give it a try. Especially because my daughter's cholesterol is very high, especially LDL and lipoprotein A. Her C reactive protein is also high. At Mayo, they wanted her to go in to their Lipid Clinic, I am not sure what they would have done there, we'll get a chance to try it when we go back in a couple of months. At the very least, she can now easily get a statin prescription.
DeletePeter, just making a hypothesis here.
ReplyDeleteI can see my nephew consume large amounts of sunflower seeds daily and thought I should search a bit.
Sunflower seeds can provide caffeic acid phenethyl ester (CAPE), which as you say may be beneficial for SHANK3 partial deficiency in autism.
CAPE is an antioxidant, anti-inflammatory, antifungal agent, shown to be protective for ongogenesis, nigral dopaminergic neurons and maybe for aldehyde toxicity in autism.
You told me that 2ml ethanol might work positively for my son, does this have something to do with Shank3 deficiency or dopaminergic function?
I read that CAPE is abundant in thyme, sage, spearmint, ceylon cinammon, star anise, apple souce, barley and rye and of course in Propolis Bio-30.
What impressed me is that thyme oil (cape) is used to treat toenails fungus. Children with 22q13 deletions have hypoplastic/dysplastic toenails and while I was reading an article about that I saw a picture illustrating affected toenails which were exactly like my son's. Both my son and nephew never take off their socks and must feel some kind of huge dysphoria on their feet, toes, toenails.
I remember Tyler discussing about spearmint benefits but I don't remember it this discussion was relevant to what I am saying.
I feel something pointing at Shank3, propolis etc. for oxidative stress and possibly less anxiety.
Do you think all these things may be connected?
Petra, small amounts of ethanol will affect the subunit expression of GABAa receptors, which might explain why your son becomes more NT when he has some alcohol.
DeleteI think the fact that your son and nephew have unusual toenails most definitely does tell you something useful, but there are multiple possible reasons. I would raise this with your research doctor who might find this a challenge.
CAPE from any source does look to have therapeutic potential, but it looks like you need quite a lot of it.
There are connections and coincidences so you do have to be careful, but I think you might find something useful by exploring the genetic cause of the unusual toenails.
Note that SHANK3 in autism is usually associated with severe MR/ID, which is not your case.
Do the sun flower seeds make your nephew feel better?
It is my hypothesis that small amounts of alcohol in homeopathic tinctures are probably a large reason for their occasional "success".
DeleteI wonder if this is the case with Cytoflora and Liverlife type mixtures too, which are 20% alcohol by volume.
- EM
I think so too..but its more than that at least for the homeopathic meds. The effects are very distinct with each remedy. I use different remedies for cough, fever, allergy and nasal congestion for my son and I tested by substituting one for the other. It does not work.
DeleteThank you Peter and Tyler for your replies.
ReplyDeletePeter, I am afraid challenges are all ours.
I'll try to find out if my nephew really feels better by eating sunflower seeds.
Intranasal insulin trial day 5, 3 shots during the day, so far I can see improvements with my son's "rigid thinking" which is in fact a cognitive issue and also better mood.
Late in the evening whenever he gets too stressed, he smokes a cigarette which makes him active. As soon as he smokes he does stretching exercises and then stationary bike for quite some time.
He quitted the idea of alcohol this week.
I found this paper about smoking and energy homeostasis in diabets.
"An alpha7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes."
'The results show that alpha7 nAChRs play a central role in regulating biological parameters associated with diabetes and support the potential of targeting these receptors as a new therapeutic strategy for treatment.'
Maybe there is a good basis on approaching ASD as if it is some kind of diabets in the brain.
Hi AJ,
ReplyDeleteIf you happen to read this I wanted to share with you that I ramped up my cytoflora dose to five dropperful, twice a day, a dose used by bioray to assess and claim significant improvements in a study/survey carried out by them. My very objective conclusion is that it has by no means a dramatic impact, at least in my son. There seems to be a mild increase in awareness and receptivity but I am not really sure if it is cytoflora or the liverlife. Not discounting its efficacy though, as its possible that in kids with severe dysbiosis and gi issues, it might have more pronounced effects.
In conclusion, if pocket is extra warm, give it a try. Do not expect a miracle.
Hi Kritika,
DeleteThanks for letting me know! I'm still trying whatever I can find that has some chance to work, but still not successful. I've been giving my daughter he fenugreek leaf tea for a while now, in the hopes of its anti-purinergic qualities, but haven't seen anything yet. I will be trying Sytrinol next and keeping my fingers crossed. I have Bumetanide and Clonazepam on my radar too - need to talk to my daughter's doctor and make a case, but not 100% optimistic she'll agree. Some doctors are very focused on drugs that have been approved for a specific purpose. Still also waiting for the Naviaux paper - If it isn't free text, I'm going to buy it as I think it may have key findings. Really hope the anti-purinergic pathway is effective for a lot of ASD kids.
Have a great day Kritika!
AJ
A very interesting study on opioid withdrawal and a therapy suggested for it based upon an existing drug called probenecid (an anti-gout drug) came out today.
ReplyDeletePress Release:
https://www.sciencedaily.com/releases/2017/01/170130110911.htm
Paper:
http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4281.html
My original investigations into aspartate and agmatine for dealing with some of the worst behavioral issues with severe autism (SIB, aggression, etc.) were inspired by a wide variety of literature that shows how opioid withdrawal symptoms and long-term opioid addiction being very similar to the symptoms of severe autism (sensory sensitivities, hyperkinesia, mood swings, etc.). This study was very interesting because it is another recent paper showing how the immune system indirectly acts as the regulator of these types of symptoms (at least with opioids) which eventually have an upstream effect on behavior and the brain itself.
So after reading this I did a quick search on pannexin-1 (the protein blocked by the anti-gout drug probenecid) and came up with this:
https://www.sciencedaily.com/releases/2013/01/130109081153.htm
In this study, they found that mice lacking pannexin-1 displayed autism like symptoms and that their brains lacked true plasticity due to excess synaptic glutamate being released (pannexin-1 helps regulate a feedback loop to prevent excess glutamate from being released during learning).
So based upon what I already know and intuit from these two studies, this sounds a lot like a situation where excess and chronic opioid signalling could be causing pannexin-1 channel desensitization.
On the surface, it would sound like probenecid would be a terrible idea for autism as the older study suggests that it will directly cause "autistic symptoms". However, if there is a situation where this pannexin-1 channel is dysfunctional because of chronic overstimulation, thereby leading to desensitization, then reducing the activity of this microglial signalling pathway might restore healthy pannexin-1 channel activity, leading to greatly improved autism symptoms.
Another thing to consider here is that you can have the exact same situation with pannexin-1 dysfunction if you have opioid signaling is too low or too high so you might have different forms of autism affected by this immune cell channel, but which require different drugs to modulate its function to a healthy state.
For those here who have had to deal with dyskinesia (hyperkinesia) symptoms in their child as a side effect from drugs, or else just because their child has extreme motor problems, here is an interesting study where the takeaway is that successful treatment of these problems might involve drugs/interventions that both push the accelerator and the brake of the basal ganglia at the same time:
ReplyDeletePress Release:
https://www.sciencedaily.com/releases/2017/01/170127152613.htm
Paper:
https://www.jci.org/articles/view/90132
Whereas typical hyperkinesia or hypokinesia therapies would only target one pathway at a time whether it be the direct pathway via D1 receptor agonists (to push the accelerator) or D1 receptor antagonists (to push the brake) or else the indirect pathway via D2 receptor agonists (to push the brakes) or D2 receptor antagonists (to push the accelerator).
This sounds very counterintuitive to employ two different drugs which in a sense cancel each other out, but that happens to be the takeaway here from this research which may be of interest to visitors to this blog who have to deal with these side-effect conundrums of dopamine medications that strongly influence one striatal pathway or the other.
Tyler, the subject of involuntary movements is thrilling for me. It is so complex, this study may be it is a little scary, but could be effective. About my son,I tell you when entered 5htp, only 50 mg a day, he started to show new tics and diskynesias that have stopped during only BCAA 2g. What do you think?
DeleteValentina
Serotonin levels have classically been thought to be inversely related to dopamine because their synthesis depends on the same enzyme, but really serotonin is quite complicated and in spite of 10's of millions of prescriptions being filled in the United States every year for serotonin medications, the fact is nobody really knows exactly what serotonin actually does in the brain (things are more straightforward with what it does in the gut).
DeleteOriginally, I added in 5-HTP with the BCAA therapy due to strongly blocking tryptophan in the brain, but if I had missed one 5-HTP dose, things would be very bad at school. I didn't know as much about how serotonergic receptors work at the time, so I don't use 5-HTP anymore.
The question is, does anything improve with 5-HTP for your son and if so, sometimes rather than stopping a successful treatment with undesirable side effects, you first try and address the side effects before giving up on it. I don't really know enough about your situation to say much else, other than if the BCAA is helping, then perhaps it is not 5-HTP at all, but something else that the BCAA's address (like dopamine).
Tyler, I agree with you about serotonin, it has been said that akathisia, chorea and movement disorders can be produced by high serotonin and can be treated with anti serotonin agents. In fact, bcaas have antiserotonin activity by blocking triptophan.It seems that changing 5htp for NR would be a safer option but more difficult to get and follow a constant treatment.
DeleteValentina
Hopefully I did not mislead you here. The 5-HTP will not increase NAD+ in the brain if that is why you were supplementing it, rather tryptophan will because it is converted either into 5-HTP or L-Kynurenine which follow separate pathways, one being called the serotonin pathway and the other being called the kynurenine pathway. To summarize and generalize (there are other metabolites in these pathways but we don't need to get into them right now):
DeleteTryptophan -> 5-HTP -> Serotonin -> Melatonin
Tryptophan -> L-Kynurenine -> Kynurenic Acid
Tryptophan -> L-Kynurenine -> Quinolinic Acid + Vit B6 -> NAD+
And for dopamine:
Phenylalanine -> Tyrosine -> L-DOPA -> Dopamine
or just
Tyrosine -> L-DOPA -> Dopamine
The Nicotanimide Riboside (NR) directly raises NAD+ levels which helps cells and their mitochondria deal with stress when they cannot produce enough NAD+ on their own. Since you are blocking tryptophan and kynurenine into the brain with BCAA's, I feel you should use NR to safely get around Pellagra type symptoms. You can also just use regular Niacin, but that won't raise NAD+ levels, though it will increase NADH which can be recycled back into NAD+ via the NAD salvage pathway enzyme NAMPT. So to put it bluntly, NR is sort of a wonder substance for what it can do with elevating NAD+ levels which are very important in disease and aging (and perhaps some autisms).
Here is all you really need to know about Pellagra which might never happen even without NR or Niacin, but I recommend it to be on the safe side, as well as NR's great benefits to mitochondria which seem to be compromised severely in many autisms:
https://en.wikipedia.org/wiki/Pellagra
BTW, Valentina where do you live? There is Niagen from Chromadex (the original source) and many third party formulations that all contain Chromadex's NR.
DeleteIf you are worried about the price, just do one a day as the adult dose is two capsules a day. The human studies on variable doses of NR that finished up recently (albeit they were funded by Chromadex) suggested using more than 2 a day for an adult was a waste of money. I suppose higher doses might be warranted for severe mitochondrial myopathies or other diseases that could benefit from exogenously supplied NAD+, but Chromadex's own research suggested only two a day should suffice for an adult.
For a 3 pack at 100 dollars which gets you 180 capsules, that comes out to 55 cents per capsule or 55 cents per day.
Tyler, I am waiting for the godfather of my son who lives in Usa,he is the one who brings me all the suff for his work trips to Punta del Este, where I live now, a city and resort of southeastern Uruguay.But now he is not travelling and is complicated. Sure for March I have the NR, but should I keep 5HTP when I get NR ? today my son is very calm, very good.
DeleteValentina
Oh Uruguay, the country with the best elite footballer to capita ratio in the world while I live in one of the countries with one of the worst elite footballer to capita ratios in the world (then again the USA has no elite footballers so I guess our ratio is 0). So I guess you can't just order from Amazon.com then. I assumed you were an American as your English is better than many Americans (definitely better than my Spanish which is non-existent).
DeleteTyler, very funny! I assumed that if you liked football you would get it right away. Sometimes it complicates me a bit to understand complex ideas and translate them at the same time, I miss things.
DeleteValentina
Hello Peter,
ReplyDeleteAfter being on carnosine, 400mg once a day, today I was got the dreaded call from his school. He had peed in his pants and was crying and not letting anyone change him...his aide was late today. He was even being little bit aggressive. When I went to pick him up he had gone to sleep and all this drama played out between eight to eight thirty. He has not been himself lately at home too..now I do not know whether its the cytoflora or carnosine. At his therapy center too he looked upset, anxious, lost and wanted to go home. Actually, the alcohol content in bioray products is enough to give me nausea..even the smell is potent ..so I am wondering if its this or that or that. Cytoflora, liverlife, carnosine or another that..biogaia gastrus, one tab a day now. Will start eliminating one by one and lower the dose too. At this rate, it will take me a lifetime figuring out what works and what doesnt and at what dose. Not fair at all!
Kritika, forgive me if you have addressed this before - but are you certain your son does not have histamine issues? I do remember you mentioning he is very sensitive - like my son - and even reacted in the past to certain homeopathics. What has been happening lately with your son might be a sign of histamine problems. I just found information that if there is a problem metabolizing/degrading histamine due to low DAO availability or problems with other histamine degrading genes, that high dose NAC can be a problem. Also, the Biogaia Gastrus is a strain that increases histamine. And liver life has certain mushrooms as an ingredient that can raise histamine. I read on the selfkacked page- the author shared a link that carnosine can inhibit DAO enzymes - although this was in a study involving pigs. I think maybe you have some red flags here to consider. And you say he hasn't been himself lately - histamine does activate the stress pathway (HPA) - also stress=excessive urination. Even the alcohol content in that liverlife releases histamine.
ReplyDeletehttp://ajcn.nutrition.org/content/85/5/1185.long
Hello Tanya,
DeleteI was actually about to spiral down onto that conclusion..I still do not understand histamine/mast cell aspects, all the implications clearly although I have a vague idea. I continued gastrus though I know the second reuteri strain mediates an anti-inflammatory response through histamine production, becuase my son has really picked up imitating from videos..today he was even trying to sing along on the 123 song. Things went pretty bad after I think I increasedv his cytoflora+liver life dose and the carnosine to 400 mg. Surprisingly, cognitively there is no decline, he was writing even his hindi letters, but he is on a short fuse. Its like he is feeling physically uncomfortable in settling down and focussing.. something got inside him. He even had a slight alcohol hangover kind of look in the eyes..sunken eyes, pale face. Even a little lack of energy interspersed with momentary bouts of looney jumping. Do you understand..its histamine..isnt it? This is the first time I have seen that look..he has been so healthy always and quite regulated behaviourally.
What do you suggest..stop everything. Allopathic anti allergens do more harm than good for him so will have to consult his homeopath.
Or should I exclude the carnosine and liver life and just go with a low dose of cytoflora and biogaia protectis drops. Bioamicus reueteri had been gentle and beneficial for him.
Should I stop all these peripheral treatments and instead focus on those addressing major dysfunctions like e/I imbalance.
Tanya, you had once mentioned that when your son was younger you focussed more on gi/inflammation issues? Could you elaborate? And liver health now..through what measures?
Everything was going perfect around November last year..I thought that at this rate he will make huge strides in progress and now its a small setback. Feeling a little low after the issue at his school. Windmills of our mind!
And I am sorry if I have left you breathless with the load of my queries.
Warm regards
Kritika, I would stop all of those supplements - go with an assumption that they are making things worse. Give his nervous system and liver a break. Put on the histamine glasses and investigate things through that lense for a bit and see if it resonates with you to experiment further. Look at the e/i through histamine issues.. Another thought - the erections could be related to high histamine too. Histamine issues can cloud your view on what helps or doesn't because with histamine it is all about thresholds and all the variables in any given day that can breach that threshold (from stress to food to supplements to pollens etc). You may need to determine if certain foods are triggers, there are certain genes involved in breaking down histamine that have specific nutrient co-factors so of he is low in any of those it can affect processing (either low in DAO enzymes for gut issues or b2, b6 and even pantethine, SAMe for nervous system issues)..Unfortunately, a lot to consider with this, so not likely to see magic bullet type response with just one thing - but I think it is important enough to at least rule out or give it a fair trial. I wish I would have known the significance of this when my son was younger - would have saved a lot of unnecessary trips down biomed rabbit holes that mostly made things worse.
Deletei had to focus on GI and allergy inflammation issues with my son because those were his crisis health issues. I have to switch focus to what I knew - his proper diagnosis of something, anything. I cpuld not experiment with any cookie cutter "autism" treatment because he was just too sensitive. And try to aid liver metabolism or at least not make things worse by avoiding certain supplements drugs and even some foods and trying things to aid methylation (glycine in form of DMG helped some but only in cycles). Anyway, I am still learning myself. Evolving .Had to learn the hard way on many things. Hope this helps and makes sense? I never feel like I sound coherent when typing on my son's ipad - but mostly on the go and have no choice :)
http://physrev.physiology.org/content/88/3/1183
Tanya,
DeleteToday I reduced the cytoflora dose (two droppers) and the liverlife (just a few drops) and did away with the carnosine. I gave him his gastrus. And he was so communicative, happy, smiling and laughing back, pulling me for a joint act of 'walking in the jungle'. He was struggling hard to speak and was emphatic with his yes and nos'. He was still having that need to pinch and bang though. He almost communicated that to us in a happy sort of way seeking our understanding and cooperation. Excuse me dad, can I pinch you a little..my fingers itch.
Tanya, now I do not know if this enhanced communication is because of or despite of the pre/probiotics and the carnosine. The wonderful interaction that I got to experience today ...was it the carnosine effect? Or because I removed it and reduced the bioray product dose too, reducing the overall histamine load.
I think I will remove gastrus tommorrow too and see if that affects his communication and budding dancing interest. Liverlife is not really useful for my son so that can go off too. I will just keep a low dose of cytoflora and watch.
I had for the past few days started giving him around 200 mg of picrorhiza (kutki) powder as it is a potent liver/digestive aid apart from.numerous other benefits. It is also rich in apocynin which has been found to prevent the effect of histamine induced toxicity on dopaminergic neurons.
As you said, its about thresholds..I have to accept that mega doses of drugs/supplements might not work for my son..I already knew it. But you suddenly helped me see why..its a total shift of perspective. Your comments always make so much sense to me. I look forward to reading more of them. As for the magic bullet, I am almost jealous of parents whose kids start 'talking up a storm' after a spoonful of coconut oil.
Thank you so much Tanya...the world seems so histaminey to me now. Flowers? Yuck! And your typing on the I pad is at least respectable unlike me, on a mobile phone, that too not an iPhone but an android and yes, mostly on the go.
Hi everyone,
ReplyDeleteJust wanted to share an interesting paper abstract relevant to ASD.
http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2016255a.html
Also, wanted to share the following - there is an interesting clinical trial listed here for ASD:
https://clinicaltrials.gov/ct2/show/NCT02901431?term=NCT02901431&rank=1
It's interesting because it uses a drug called RO5285119. I looked into it and it's a Vasopressin 1a receptor antagonist.
Here's a trial result of a V1a receptor antagonist:
http://www.medscape.com/viewarticle/825711
So my first question was, are there any natural V1a receptor antagonists that I can get a hold of? And it looks like there may be one ... California poppy!
https://www.ncbi.nlm.nih.gov/pubmed/1535715
I've ordered some and want to trial it, but just wanted to share my research and thoughts with everyone. If anyone has any input (other V1a receptor antagonists) or why California Poppy is good, bad, etc, please share.
Have a great evening everyone!
AJ
Interesting reads AJ. I studied vasopressin a bit a while ago due to desperation in finding a bed wetting solution. As I am sure you well know, vasopressin in the periphery is called ADH or anti-diuretic hormone. There is a lot of animal research suggesting vasopressin to have similar surprising social effects like its sister molecule oxytocin so I am also surprised vasopressin has not gotten the same level of attention as oxytocin.
DeleteHi AJ,
DeleteI looked at california poppy a few years ago for my daughter's sleep difficulties, but stayed away when I read somewhere that it could cause hallucinations, though mild. It is often recommended as an alternative to opium.
Peter,
ReplyDeleteCan histamine lead to increased cognition..shorter response time, better grasp but the gains offset by decreased ability for sustained attention?
Hi everyone,
ReplyDeleteI have a question for the community and would really appreciate your input - so the more I read about Naringin, the more I think it has the potential to be helpful to some with ASD, and I want to trial it with my daughter (who can't take capsules) but it is terribly bitter. Before someone notes this, I'm aware not to use any meds around Nraingin given its impact on metabolizing other substances.
My question is this - mixing Baking Soda into the liquid I would also mix Naringin in (say juice or tea) can dramatically reduce the bitterness of Naringin, but I don't know if it would also inactivate it so that it won't actually work. Does anyone know if baking soda normally inactivates substances (e.g. by binding to and), and that's how it affects flavor, or if one would still benefit from substances mixed with baking soda.
So in essence, my question is, by mixing baking soda with Naringin, am I likely to make the Naringin useless?
Thanks much in advance if anyone knows the answer to this.
AJ
P.S. I've tried fixing the flavor with agave nectar, juice, etc and the bitterness remains after a few seconds
AJ, an alternative to synitrol/naringin capsules could be this old-folk home-made cholesterol remedy drink. It is very popular in certain parts of Europe, where many people swear by it, including some doctors. I now believe that the supposed effects are due to naringin that gets extracted in the process.
DeleteThere are many versions of the recipe and they all involve about a kilo of either whole lemons or whole oranges, washed well and chopped up in pieces or thin slices, which are then brought to boil in about 1-2 litres of water and left to cool, then sieved. Some recipes recommend simmering oranges/lemons on a very low heat for a couple of hours (in which case you would need 2 litres of water per kilo of citrus fruit) and some say to add the fruit to boiling water and take the pot off heat as soon as it reaches the boiling point again (in which case you only 1 litre of water, as it won’t evaporate). Some say boil for 20 min, but don’t let temp of water go over 60 degrees celsius. Once cooled, the mixture is sieved by pressing hard to squeeze out as much as possible, leaving only dry pulp, and put in a fridge.
Each recipe always has something else added to the mix, either a large bunch of rosemary, or parsley, celery root, or loads of garlic cloves, even ginger. This add-on ingredient largely determines the taste of the drink, ½ glass of which should be taken first thing in the morning, and one later in the day. I have tried both the rosemary and garlic versions, and both taste fine from an adult perspective :) but I guess even if only citrus fruits are used you would get the benefit of naringin. Worth a try?
I could not find any recipes in English but these pics could give you an idea of the process:
http://www.coolinarika.com/recept/napitak-od-limuna-i-cesnjaka-za-snizavanje-masnoce-u-krvi/
http://www.coolinarika.com/recept/anti-trigliceridi-limun-i-celer/
Peter, what is the connection between increasing KCC2 and nicotine replacement therapy, if there is any?
ReplyDeleteI have been using intranasal insulin for enhancing KCC2 for 10 days. During the first day insulin improved his motor coordination and as I said helped with "rigid thinking" and mood. The following days intranasal insulin seemed not enough to rescue "pain" issues. I think cognitive gains have lasted but he needed something on top of it. It was a coincidence that my husband, during pain episode, told my son to smoke a cigatette. It worked with muscle pain and motor functions. Yesterday he used e-cigarette and also helped him.
Maybe pain comes from a kind of movement disorder, due to lack of dopamine, which may be an ASD core symptom or side effect from olanzapine.
I would appreciate your views on my results.
Petra, there is a known connection between neuropathic pain and KCC2, as discussed in this recent paper, where they modify chloride levels:-
DeleteChloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871741/
In this study they injected their KCC2 gene therapy into the spinal canal and produces complete and long-lasting relief from nerve injury-induced neuropathic pain by restoring Cl− homeostasis.
This then raises the issue of whether these “viral vectors” used to restore chloride homeostasis in the spinal cord of mice could do the same in the brain.
I think you have again noted something very interesting with nicotine.
The alpha-7 nicotinic receptor has been suggested as another trigger to flip the “GABA switch”, in other words down regulating NKCC1 and upregulating KCC2.
https://www.researchgate.net/profile/Sherry_Leonard/publication/272624246_The_human_CHRNA7_and_CHRFAM7A_genes_a_review_of_the_genetics_regulation_and_function/links/569d60ba08ae16fdf0797711.pdf
“The early switch of chloride channels, regulating the change of positive to negative stimulation and accompanied by down regulation of NKCC1 and up regulation of KCC2, is controlled by the
expression of a7nAChR (Liu et al., 2006). The switch does not occur in murine models with decreased Chrna7 expression.”
Sequential Interplay of Nicotinic and GABAergic Signaling Guides Neuronal Development
http://science.sciencemag.org/content/314/5805/1610
Nicotine is an agonist of alpha-7 nicotinic receptor.
Galantamine is a positive allosteric modulator of the alpha-7 nicotinic receptor and might be an alternative to cigarettes.
Galantamine is a Russian Alzheimer’s drug sold
elsewhere as an OTC supplement and used by some with autism.
Memantine is very similar and has been used off-label for years in the US for autism.
You might also want to read this, mentioned in an old post:-
Acetazolamide and midazolam act synergistically to inhibit neuropathic pain
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914558/
Several readers of this blog use Acetazolamide/Diamox.
A word of caution on the nicotine, but some very interesting science that I have a hunch might suggest a more permanent way of inducing downregulation of NKCC1 and upregulation of KCC2:
DeletePress Release:
https://www.sciencedaily.com/releases/2017/02/170202085656.htm
Paper:
https://gupea.ub.gu.se/bitstream/2077/48662/6/gupea_2077_48662_6.pdf
This study/thesis was done on rats and was inspired by a weird observation of a rat used in another nicotine study that after 3-4 months of abstinence from nicotine, the rat began to display odd behavior of lacking inhibition or fear. So in this study they had a little over 100 rats subjected to nicotine exposure and then had them abstain for 3-4 months and very reliably the same strange lack of fear and uninhibited behaviors occurred.
What was also found was that the reason for these behavioral changes occurring was that GABAergic communication switched from inhibitory to excitatory. The paper makes no mention of NKCC1 or KCC2, rather several other mechanisms are suggested so it is entirely plausible NKCC1 and KCC2 may be involved in what is going on, just that the doctoral student was unaware of this information.
So lets just say hypothetically that this disinhibition may be because of the GABA chloride switch from long-term abstinence from nicotine exposure. What if something similar is happening in autism. What if this switch is not even developmental as we all assume and has something to do with excess dopamine signaling via excess nicotinergic signaling (this is just all hypothetical so don't assume I actually think this is true myself). And what if things could work in reverse where nicotonergic antagonists (rather than agonists like nicotine or Chantix) could reverse GABAergic neurons from being depolarizing to hyperpolarizing.
Another thing to think about with respect to this study and pregnant mothers is that many women around the world still use tobacco products or other forms of nicotine administration (E-Cigarettes). Much of the time women addicted to nicotine will begin abstaining from nicotine consumption upon learning of a pregnancy. What if the fetus had been exposed to nicotine and then this abstention effect ended up locking in changes that didn't manifest until after birth (the period of abstention was 3-4 months, but rats have much shorter lives than humans and much faster metabolisms). There could even be some sort of antibody or micro RNA like effect to nicotine exposure that explains this as well where a woman who has smoked all her life even decides to quit smoking before getting pregnant and paradoxically causes this sort of effect in her fetus that leads to dysregulated neuronal chloride homeostasis. My wife smoked for many years before meeting me and marrying me. It had been several years (that I know of) that she had stopped smoking before getting pregnant with our first child (and most severe case of autism), so this thought kind of went through my head here.
DeleteNote, these are just hypothetical ideas and not something I seriously give any credence to at this time, but it is interesting to think about as pretty much all of the studies I have seen on smoking and autism are only focused on smoking during pregnancy, not whether the mother had ever smoked or the period of abstention prior to pregnancy.
Tyler, I had quitted smoking about one year before my pregnancy with the idea of protecting my fetus from nicotine exposure. Now we are challenged with a paradox outcome.
DeleteHi everyone,
ReplyDeleteHere is a VERY interesting paper:
http://www.nature.com/articles/srep40740
The big quotes are:
"We propose that deficits in IP3-mediated Ca2+ signaling represent a convergent hub function shared across the spectrum of autistic disorders – whether caused by rare highly penetrant mutations or sporadic forms"
"In summary, the results presented here have significant mechanistic and translational relevance that support the involvement of Ca2+ signaling disruptions in ASD"
I'm going to start digging into this further, but if those who are far more capable than I in this regard can also dig into this, and provide your insights, it would be much appreciated.
Have a great evening all!
AJ
AJ, this is what I came up with:-
Deletehttps://epiphanyasd.blogspot.com/2015/10/is-dysregulated-ip3r-calcium-signaling.html
Peter this new study concerning IL-1b and sleep induction and sleep deprivation:
ReplyDeletehttps://www.sciencedaily.com/releases/2017/02/170202141838.htm
reminded me of an old post you made on cognitive dysfunction and the immune system:
https://epiphanyasd.blogspot.com/2015/02/inflammation-leading-to-cognitive.html
What this study showed is that IL-1b is critical in inducing sleepiness and proper brainwave patterns during sleep (as measured by EEG). Obviously, if someone is sick then sleep is pretty much always a good thing. This is just something that is implied as common sense, but what drives people to "take a rest" has not been completely clear. What I find interesting here is that when people are pseudo-awake (sleepy but not quite asleep) then you obviously have cognitive dysfunction just as it is unwise to drive a car after being sleep deprived. Could some of autism's cognitive problems be the result of chronic and excessively elevated levels of IL-1b in the blood, even when there is no actual infection for the immune system to fight?
Just some food for thought.
Thanks Tyler, it does get complicated. Another point to remember is that inflammation affects neuroligin-2 and KCC2. This helps explain why allergy and hence more IL-6 reduces cognitive function in my son, even though I am blocking some Cl- entry with bumetanide, I then have more NKCC1 transporters and less KCC2 transporters, so Cl- concentration goes up.
DeleteSo for multiple reasons too much inflammatory signaling of any kind is bad for autism, SIB and cognitive function.
This also might explain why some people's severe SIB goes away with nicotine patches. It is neuropathic pain that prompts the SIB and nicotine is lowering the Cl- level and halting the pain.
It is well established that epilepsy rate is high in people with severe autism and chloride neuronal regulation may at least partially contribute to this. From what is known about neuropathic pain and KCC2/NKCC1 involvement, I would suspect that many people with severe autism may suffer from neuropathic pain, just as from epilepsy. It might affect those with the most impaired communication skills and while it is hardly possible not to recognize grand mal seizure, pain presentation in autism may be atypical. I mean, it does not look like what doctors and caregivers expect from a person affected by pain. “Challenging behaviours” can be the only visible sign. Thinking how many people can’t communicate the pain and are given neuroleptics or behavioural therapy is really scary to me.
Delete“Autism”+”neuropathic pain” search in PubMed brings you null with regard to clinical papers.
I once had a thought that my son suffers from periodic neuropathic pain. I haven’t fully explained his recurrent episodes, but maybe it is periodic calcium channelopathy that comes with massive mast cells degranulation and inflammatory mediators release, this via further KCC2/NKCC1 dysregulation can lead to peripheral neuropathic pain and headache. Do you think it is plausible?
Agnieszka, before finding an efficient therapy in the form of verapamil, during allergy driven self-injury my son would always hit the upper part of his right leg. Maybe this was just a convenient part of the body, but maybe he actually felt pain there.
DeleteI think most SIB that is reported is directed at the head. It was suggested that degranulation of mast cells might cause pain.
There is some logic in hitting the part of your body that hurts.
I expect the explanation will vary somewhat from case to case and that channelopathies, mast cells etc will all play a role. If you could correlate a positive behavioral response to bumetanide to the existence of self-injury then you could make a good case for the involvement of neuropathic pain driving the SIB.
A problem with SIB is that once it becomes established, it just becomes an acquired behavior that then reoccur for other unrelated and possibly quite minor reasons. It is hard to lose this behavior once it has been discovered.
Agnieszka and Peter, have wondered about neuropathic pain as well in my son - but not sure. When he is having a fit reaction, in the past he has pinched himself down his legs. I am looking more in to histamine intolerance because we still have lingering issues in spite of verapamil and using anti histamines and other measures. So if there is an inability to degrade histamine, and h1 and/h2 blockers used, wpuld all that histamine overwhelm the other histamine receptors and intensify pain?? I found this information that h3 blockers used for neuropathic pain treatment. Interesting. excuse amateur questions - still learning.
Deletehttp://onlinelibrary.wiley.com/store/10.1111/cns.12279/asset/cns12279.pdf;jsessionid=27BE51016CB7C3EAB159BE96E03AE189.f01t04?v=1&t=iyqbvhso&s=ff9615752ab2558824835c8d0383f5b67f33b7c2
Peter, thank you very much. I am going to work on that direction.
ReplyDeleteThis may sound strange, Asperger's can sense things differently, but before I got back your reply, my son had started complaining about his spinal cord, saying that there may be something connected to pain there.
In the past he said that many times before and we visited the doctor to see if there is scoliosis or something like that. Doctor said there is no scoliosis but when he had an operation and needed local anesthesia, the anesthesiologist said that there must be something wrong with his spinal cord because he had trouble doing his job, but didn't explain further.
I saw him many times press his side parts of spinal cord seeking relief and it cracks there.
He also finds relief when he is not in "freezing" mode and can do some exercises that seem to address to his spinal cord, such as stretching, push ups, sit ups and back exercises.
Do you think this may be relevant to spinal cord neuropathic pain?
Petra, I am no expert on neuropathic pain, but I do not think where he feels the pain is necessarily the location of the problem.
DeleteI was thinking that if your son responds to bumetanide, it is just a case of the NKCC1/KCC2 imbalance having effects elsewhere in the body. As you reduce intracellular chloride, by whatever means, you should improve both his Asperger's and any neuropathic pain.
So you might look at Acetazolamide/Diamox, even Dr Frye in the US is using smallish doses (60mg) doses.
If nicotine is effective, you could try small pieces of a nicotine patch to give a small continuous dose.
Ok, I have found acetazolamide 250mg. How much should I start with? Give it with or without the rest of treatment?
ReplyDeleteI would try one quarter of a tablet, once a day. Try it for a few days and then decide if it is helpful.
DeleteI would continue with his other treatments.
Hello Peter,
ReplyDeleteI have stopped everything (bioray products, Biogaia gastrus, carnosine) and my son is still displaying the pinching, flopping himself impact fully on the bed repeatedly. But doing well with learning and awareness. This almost looks cute but I know my child is uncomfortable and this could in all probability turn into a major crisis. It's spring here. In India, specially in Delhi we have six major seasons, ranging from 'brain freezing' cold to vaporizing heat. With each turn of weather, my son used to display sensory behavior without the cognitive loss, rather a little enhancement. His therapist advised to wait it out. I knew seasonal changes trigger allergies, seasonal changes trigger sensitivities in my son, allergies involve histamine production but it was actually Tanya who made me sort of compose the sentence... My son displays sensory issues and sometimes deteriorating behavior as and histamine is the cause for this. This is so helpful and probably I might stock on some very verapamil as a contingency measure. And probably try and manage it through CAM therapies. And evaluate drug reactions in that light too. Moderation, thresholds, total load and the works.
I presume some of the strategies like bumetanide and clonazepam can be tried out irrespective of histamine status.
Regards
Kritika, it seems that any inflammatory condition may block the effect of bumetanide, the inflammation itself leads to higher intracellular chloride.
DeleteYou need to differentiate between histamine intolerance, when you cannot degrade histamine, and just allergic reactions that cause histamine to be released from mast cells. If he has allergies you need to treat these first and do your bumetanide trial when he is allergy free.
Clonazepam is different and the effect should be there regardless of allergy. It takes 3 days to show effect, if he is a responder. So this might be best to try first.
So, allergic reactions produce histamine and in some histamine produces an allergic reaction or sort of because it can't be degraded. Actually my son started the disruptive behavior this time after the first half a tab of gastrus. I do not know whether he is allergic to it or intolerant to histamine production involved with gastrus... And this histamine intolerance behavior got accentuated with the seasonal allergy? Could be be having both? And the behavioral manifestations of both could be same? Tanya was suggesting histamine intolerance. There must be tests available to find out if one is histamine intolerant. I am just doing loud thinking.. will look up.
DeleteThanks Peter
Kritika, my son did not tolerate Biogaia Gastrus but responds well to Biogaia Protectis. The second bacteria in Gastrus was also not tolerated by some other commenters. It can take 10 days to get back to normal.
DeleteSo better not to use Gastrus. I think your Bioamicus is very similar to Protectis.
Tanya,
ReplyDeleteHow did you zero in on histamine intolerance issues in your son? I understand there are no reliable tests available..the most reliable biopsy being a very expensive one and mostly it is through following an elimination diet to see if it helps. Then there is the confusion between food allergy and histamine intolerance. In fact, some opine that its not even a real medical condition but sychosomatic in nature. My son does not have any problem whatsoever with histaminey foods but as you said, once you breach a threshold, that is when the problem starts appearing. Then there is something called sensitivity to vasoactive amines. My head is spinning. Gluten, caesin sensitivity, sensitivity to tannins, flavonoids..should I teach my child photosynthesis now!!!
I will be mindful about what to give to my son but if you can suggest anything I would be grateful.
Warm regards
Kritika! I had a long paragraph typed in this little box, went to copy and paste a link, and returned to find my comments vanished. arrgh. Maybe this is a sign. haha
ReplyDeletePlease feel free to email me and I will gladly share tanyastatum@gmail.com
Tanya, I absolutely get it. Will contact you hoping its not too much of a trouble. As a parent, maintaing propriety is the last thing on my mind when it comes to seeking help from someone whom I find to be really wise, but still did not want to be a pest.
DeleteWarm regards
Hi Peter,
ReplyDeletePlease help me understand this better. I have been reading about RORs and there is a lot written about cholesterol binding of these receptors and the use of statins. I am unable to really understand the conclusion, do statins upregulate the activity or vice versa? I am especially keen on figuring this out as they seem to play a role in regulation of lipoprotein A, which my daughter has been shown to have very high levels of.
http://atvb.ahajournals.org/content/24/4/637.full
"However, this apparent contradiction can be accounted for by the in vitro model used. The modulation of the RORα transcriptional activity by statins has been assessed in in vitro studies with LDL serum-free medium.1 However, total depletion in intracellular cholesterol has detrimental effects, leading to cell death. In vivo inhibition of cellular synthesis of cholesterol by statins results in increased uptake of circulating LDL cholesterol, leading to a compensation of decreased intracellular cholesterol synthesis. Therefore, it is most likely that in vivo statin treatment does not result in total depletion of cellular cholesterol, allowing RORα to be active. Thereby, in vivo statin treatment is unlikely to impair the protective effects of RORα in the vascular system."
DeleteYour daughter probably needs more RORα, because she has high levels of cholesterol and inflammation. The paper is saying that the theoretical effect of the statin reducing cholesterol and so reducing RORα activity does not occur in the real world. So in effect though the statin reduces cholesterol there is still plenty left to maintain RORα activity.
So statins should still be good for your daughter. More RORα activity would also be good.
RG, more recent papers suggest things rather differently. Quite often things seem to work in reverse. The more recent paper suggests that less RORα is good for heart disease.
DeleteInhibition of RORα/γ suppresses atherosclerosis via inhibition of both cholesterol absorption and inflammation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034492/
So in this study they are doing the opposite of what was done in the study in my post where they used an RORα agonist in the animal model of autism with a good effect.
I think they will have to trial things in humans to see what actually happens.
So the conclusion is that statins are good but when it comes to RORα it is unclear whether your daughter needs more or less, because that data is contradictory, but she is unlikely to be at optimal point now.
Hi Peter,
ReplyDeleteMy son who is 4.5 years old now recently had some very good gains( He is flying through ABA programs he was stuck on for months - his main issue is lack of attention & lack of speech).
What we tried new is: Leucovorin which I beleive is folinic acid (Not Methyl folate - this I think is what DAN doctors suggest), and we tried low dose AC Chelation for around 5 weeks - with ALA & DMSA (micro doses). Cant say for sure which helped.
Question is : Our DAN was suggesting HBOT and may be IV chelation, wanted to check if you or any other readers have tried these, IV chelation seems a little risky, so not sure about it. And HBOT will probably be one of the most expensive ones we try, but we are ok with the expense part.
For other readers: I just wanted to share that some parents found folinic acid (Leucovorin) more helpful than Methly Folate (Deplin in US).
Thanks
BK
BK, my son has not used IV antioxidants, but his Grandfather has been using IVA ALA for several years to treat diabetic neuropathy and finds is very effective and free of side effects. Chelation is no more than treatment with antioxidants.
DeleteIV ALA should give an improvement, if oral ALA gave an improvement, and should be more effective as with neuropathy treatment.
Leucoverin (calcium folinate)in addition to helping people with genetic folic acid deficiency is effective in treating nitrosative stress.
People with autism usually have oxidative stress and may also have nitrosative stress.
HBOT does not seem to help most people. There have been numerous clinical trials. I think there is a big parental placebo effect, because of the cost.
Hi Peter
DeleteThanks for quick reply
I will check about IV ALA but my DAN uses EDTA iv not sure if you heard about it
Thanks
BK