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Sunday, 25 September 2016

Excitotoxicity triggered by GABAa dysfunction




  
This blog, as you will have noticed, does rather meander through science of autism.  As a result there are some gaps and unanswered questions.

The blog talks a lot about the neurotransmitter GABA and the excitatory/inhibitory imbalance.  We have ended up with some therapies based on this that do seem to help many people.

The opposing (excitatory) neurotransmitter is glutamate which affects the NMDA, AMP and mGlu receptors.

It appears that in autism there is an unusually high level of glutamate, but another issue looks likely to be at specific receptors, for example mGluR5



This does get very complicated and lacks any immediate therapies. 

One very interesting insight was that you can repurpose the existing cheap generic GABAB drug Baclofen to treat NMDAR-hypofunction. 

This seems to work really well at low doses with many people with Asperger’s.  People with more severe autism do not seem to respond to low doses, however some do to higher doses.  The more potent version R Baclofen is a research drug.

GABAb-mediated rescue of altered excitatory–inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction



Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30–80 Hz) oscillatory abnormalities, phenotypes common to these disorders.

Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABAB-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits.



Excitotoxicity

We have touched on this subject on a few occasions but today, excitotoxicity is the focus of this post.
  
Excitotoxicity looks likely to be present in much autism and helps to connect all the various dysfunctions that we can read about in the literature.

It is a little scary because you cannot know to what extent this process is reversible.  It looks like in milder cases it should be treatable, whereas in extreme cases damage will be irreversible.

Excitotoxicity is the pathological process by which nerve cells are damaged or killed by excessive stimulation by neurotransmitters, particularly glutamate. This occurs when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) such as the NMDA receptor and AMPA receptor are overactivated by glutamatergic storm. 

Unfortunately you can trigger glutamate excitotoxity via a dysfunction in GABAA receptors.

For example if you severely inhibit GABAA receptors you kill brain cells, but it was the reaction in glutamate signaling that did the damage.  GABA is supposed to be inhibitory; in some autism it is not and then Glutamate gets out of balance.  This does lead to excess firing of neurons, which seems to degrade cognition, but it will tend towards glutamate excitotoxity.

When you see the cascade of events triggered by glutamate excitotoxity you will see how this really helps to explain biological finding in autism, even mitochondrial dysfunctions.

You can then trace this all back to the faulty GABA switch caused by too little KCC2 and too much NKCC1.

Then you can look at other neurological conditions that feature glutamate excitotoxity, like traumatic brain injury and neuropathic pain, and you see that the research shows low expression of KCC2.

This then suggests that much of autism would have been prevented if you could increase KCC2.  You would not just fix the E/I imbalance but you would avoid all the damage done by excitotoxity.

Just how early you would have to correct KCC2 expression is not clear.  For sure it is a case of better late than never, but how much damage caused by excitotoxicity is reversible?


Good News

The good news is that because KCC2 underexpression is a feature of many conditions there is plenty of research money being spent looking for answers.  When they find a solution for increasing KCC2 to treat neuropathic pain, or spinal cord injury (SCI), the drug can be simply re-purposed for autism.

The French government is funding research into increasing KCC2 to treat SCI.  They are starting with serotin  5-HT2A receptor agonists.  Regular readers without any memory loss may recall that back in the 1960 Lovaas was giving LSD to people with autism at UCLA.  LSD is a potent 5-HT2A receptor agonist.  The French are also looking at BDNF to upregulate KCC2 and then they plan to have a blind test where they try all the chemicals they have in their library.  The French are of course doing their trials in test tubes.

When I looked at this subject a while back, I looked for existing therapies that are known to be safe and should be effective.

Treating KCC2 Down-Regulation in Autism, Rett/Down Syndromes, Epilepsy and Neuronal Trauma ?




My conclusion then was that intranasal insulin was the best choice.



Excitoxicity in Autism




Autism is a debilitating neurodevelopment disorder characterized by stereotyped interests and behaviours, and abnormalities in verbal and non-verbal communication. It is a multifactorial disorder resulting from interactions between genetic, environmental and immunological factors. Excitotoxicity and oxidative stress are potential mechanisms, which are likely to serve as a converging point to these risk factors. Substantial evidence suggests that excitotoxicity, oxidative stress and impaired mitochondrial function are the leading cause of neuronal dysfunction in autistic patients. Glutamate is the primary excitatory neurotransmitter produced in the CNS, and overactivity of glutamate and its receptors leads to excitotoxicity. The over excitatory action of glutamate, and the glutamatergic receptors NMDA and AMPA, leads to activation of enzymes that damage cellular structure, membrane permeability and electrochemical gradients. The role of excitotoxicity and the mechanism behind its action in autistic subjects is delineated in this review










The influx of intracellular calcium triggers the induction of inducible nitric oxide (iNOS) and phosphorylation of protein kinase C. Increased iNOS enhances nitric oxide (NO•) production in excess, whereas protein kinase C activates phospholipase A2 which in turn results in the generation of pro-inflammatory molecules The subsequent generation of free radicals can inhibit oxidative phosphorylation and damage mitochondrial enzymes involved in the electron transport chain, which mitigate energy production .

Reactive intermediates such as peroxynitrates and other peroxidation products hamper the normal function of mitochondrial enzymes by impairing oxidative phosphorylation and inhibiting complex II of the electron transport chain. Moreover, lipid peroxidation products, such as 4-hydroxynonenal (4-HNE) can interact with synaptic protein and impair transport of glucose and glutamate, thereby decreasing energy production and increasing excitotoxic sensitivity

Overstimulation of the glutamate receptors, NMDA and AMPA, leads to the release of other excitotoxins resulting in the accumulation of glutamate. Indeed, excess glutamate concentrations results in an increase in calcium levels in the cytosol. This effect is attributed to the fact that excessive glutamate allows calcium channel to open for longer periods of time, leading to increased influx of calcium into cells. Calcium triggers inducible nitric oxide and protein kinase C that produce free radicals, ROS and arachidonic aid. Generation of these oxidants results in mitochondrial dysfunction and accumulation of pro-inflammatory molecules and finally cell death. Free radicals interact with the mitochondrial and cellular membrane to form lipid peroxidation. 4-HNE is a major destructive product of this process. Lipid peroxidation prevents the dephosphorylation of excessively phosphorylated tau protein, significantly interfering with microtubule function. It has also been shown to inhibit glutathione reductase needed to convert oxidised glutathione to its functional reduced form

The mechanism responsible for excitotoxicity and neuronal cell death is diverse. Experimental studies have shown that the apoptotic and/or necrotic cell death may be due to the severity of NMDA damage or can be dependent on receptor subunit composition of neurons (Bonfoco et al. 1995; Portera-Cailliau et al. 1997). Pathological events related to this mode of action can be loss of cellular homoeostasis with acute mitochondrial dysfunction leading to hindrance in ATP production. Moreover, glutamatergic insults can cause cell death by the action of one or more molecular pathways which involves the action of signaling molecules such as cysteine proteases, mitochondrial endonucleases, peroxynitrite, PARP-1 and GAPDH in the excitotoxic neurodegeneration pathway.

Intracellular calcium levels also rely on voltage-dependent calcium channels and Na exchangers . The Na?/Ca2? exchanger is a bi-directional membrane ion transporter, which during membrane depolarisation or the opening of the gated sodium channels, transports sodium out of the cell and calcium into the cell. AMPA-type glutamate receptors are highly permeable to calcium and its over expression can lead to excitotoxicity. The Ca2? permeability capability of AMPA-type glutamate receptors relies on the presence or the absence of the GluR2 subunit in the receptor complex. Reduced GluR2 expression permits the construction of AMPA receptors with high Ca2? permeability and contributes to neuronal defect and excitotoxicity. Another mechanism is the release of calcium from internal stores such as the endoplasmic reticulum and mitochondria. It results in mitochondrial dysfunction, reduction in ATP synthesis and ROS generation.

Voltage gated channels found in dendrites and cell bodies of neurons modulate neuronal excitability and calcium-regulated signaling cascades (Dolmetsch et al. 2001; Catterall et al. 2005). Point mutations in the gene encoding the L-type voltage-gated channels Ca v1.2 (CACNA1C) and Ca v1.4. (CACNA1F) prevent voltage-dependent inactivation of these genes. This causes the channel to open for longer time, leading to excessive influx of calcium.

Conclusion

Autism is a multifactorial disorder characterized by neurobehavioral and neurological dysfunction. Excitotoxicity is the major neurobiological mechanism that modulates diverse risk factors associated with autism. It is triggered by potential mutation in ion channels and signalling pathways, viral and bacterial pathogens, toxic metals and free radical generation. Over expression of glutamate receptors and increased glutamate levels leads to increased calcium influx and oxidative stress and progressive cellular degeneration and cell death. Genetic defect, such as mutation in voltage gated or ligand channels that regulate neuronal excitability leads to defect in synaptic transmission and excitotoxic condition in autism. Mutation in BKCa and Ca v1.2 channels also results in excess calcium influx Sodium, potassium and chloride channels also play important roles in maintaining homoeostasis of neuronal cells, and decreased channel activity leads to destabilization of membrane potential and excitotoxicity. Moreover, over expression of BDNF results in hyperexcitability. Excessive BDNF and NMDA receptor activity increases the neurotransmitter release and excitotoxic vulnerability. Given that autism is a multifaceted disorder with multiple risk factors, more precise studies are needed to explore the signalling pathways that influence emergence of excitotoxicity in ASDs.


Some relevant reading for those interested:-


GABAergic/glutamatergic imbalance relative to excessive neuroinflammation in autism spectrum disorders


Abstract

Background

Autism spectrum disorder (ASD) is characterized by three core behavioral domains: social deficits, impaired communication, and repetitive behaviors. Glutamatergic/GABAergic imbalance has been found in various preclinical models of ASD. Additionally, autoimmunity immune dysfunction, and neuroinflammation are also considered as etiological mechanisms of this disorder. This study aimed to elucidate the relationship between glutamatergic/ GABAergic imbalance and neuroinflammation as two recently-discovered autism-related etiological mechanisms.

Methods

Twenty autistic patients aged 3 to 15 years and 19 age- and gender-matched healthy controls were included in this study. The plasma levels of glutamate, GABA and glutamate/GABA ratio as markers of excitotoxicity together with TNF-α, IL-6, IFN-γ and IFI16 as markers of neuroinflammation were determined in both groups.

Results

Autistic patients exhibited glutamate excitotoxicity based on a much higher glutamate concentration in the autistic patients than in the control subjects. Unexpectedly higher GABA and lower glutamate/GABA levels were recorded in autistic patients compared to control subjects. TNF-α and IL-6 were significantly lower, whereas IFN-γ and IFI16 were remarkably higher in the autistic patients than in the control subjects.

Conclusion

Multiple regression analysis revealed associations between reduced GABA level, neuroinflammation and glutamate excitotoxicity. This study indicates that autism is a developmental synaptic disorder showing imbalance in GABAergic and glutamatergic synapses as a consequence of neuroinflammation.
Keywords: Autism, Glutamate excitotoxicity, Gamma aminobutyric acid (GABA), Glutamate/GABA, Tumor necrosis factor-α, Interleukin-6, Interferon-gamma, Interferon-gamma-inducible protein 16


Postmortem brain abnormalities of the glutamate neurotransmitter system in autism.



CONCLUSIONS:

Subjects with autism may have specific abnormalities in the AMPA-type glutamate receptors and glutamate transporters in the cerebellum. These abnormalities may be directly involved in the pathogenesis of the disorder.



Pathophysiologyof traumatic brain injury


General pathophysiology of traumatic brain injury
The first stages of cerebral injury after TBI are characterized by direct tissue damage and impaired regulation of CBF and metabolism. This ‘ischaemia-like’ pattern leads to accumulation of lactic acid due to anaerobic glycolysis, increased membrane permeability, and consecutive oedema formation. Since the anaerobic metabolism is inadequate to maintain cellular energy states, the ATP-stores deplete and failure of energy-dependent membrane ion pumps occurs. The second stage of the pathophysiological cascade is characterized by terminal membrane depolarization along with excessive release of excitatory neurotransmitters (i.e. glutamate, aspartate), activation of N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolpropionate, and voltage-dependent Ca2+- and Na+-channels. The consecutive Ca2+- and Na+-influx leads to self-digesting (catabolic) intracellular processes. Ca2+ activates lipid peroxidases, proteases, and phospholipases which in turn increase the intracellular concentration of free fatty acids and free radicals. Additionally, activation of caspases (ICE-like proteins), translocases, and endonucleases initiates progressive structural changes of biological membranes and the nucleosomal DNA (DNA fragmentation and inhibition of DNA repair). Together, these events lead to membrane degradation of vascular and cellular structures and ultimately necrotic or programmed cell death (apoptosis).

Excitotoxicity and oxidative stress
TBI is primarily and secondarily associated with a massive release of excitatory amino acid neurotransmitters, particularly glutamate.854 This excess in extracellular glutamate availability affects neurons and astrocytes and results in over-stimulation of ionotropic and metabotropic glutamate receptors with consecutive Ca2+, Na+, and K+-fluxes.2273 Although these events trigger catabolic processes including blood–brain barrier breakdown, the cellular attempt to compensate for ionic gradients increases Na+/K+-ATPase activity and in turn metabolic demand, creating a vicious circle of flow–metabolism uncoupling to the cell.1650
Oxidative stress relates to the generation of reactive oxygen species (oxygen free radicals and associated entities including superoxides, hydrogen peroxide, nitric oxide, and peroxinitrite) in response to TBI. The excessive production of reactive oxygen species due to excitotoxicity and exhaustion of the endogenous antioxidant system (e.g. superoxide dismutase, glutathione peroxidase, and catalase) induces peroxidation of cellular and vascular structures, protein oxidation, cleavage of DNA, and inhibition of the mitochondrial electron transport chain.31160 Although these mechanisms are adequate to contribute to immediate cell death, inflammatory processes and early or late apoptotic programmes are induced by oxidative stress.11



Knocking down of the KCC2 in rat hippocampal neurons increases intracellular chloride concentration and compromises neuronal survival



Non-technical summary

‘To be, or not to be’– thousands of neurons are facing this Shakespearean question in the brains of patients suffering from epilepsy or the consequences of a brain traumatism or stroke. The destiny of neurons in damaged brain depends on tiny equilibrium between pro-survival and pro-death signalling. Numerous studies have shown that the activity of the neuronal potassium chloride co-transporter KCC2 strongly decreases during a pathology. However, it remained unclear whether the change of the KCC2 function protects neurons or contributes to neuronal death. Here, using cultures of hippocampal neurons, we show that experimental silencing of endogenous KCC2 using an RNA interference approach or a dominant negative mutant reduces neuronal resistance to toxic insults. In contrast, the artificial gain of KCC2 function in the same neurons protects them from death. This finding highlights KCC2 as a molecule that plays a critical role in the destiny of neurons under toxic conditions and opens new avenues for the development of neuroprotective therapy.


New understanding of brainchemistry could prevent brain damage after injury





Sciences de la vie, de la santé et des écosystèmes : Neurosciences (Blanc SVSE 4) 2010
Projet 
KCC2-SCI

The potassium-chloride transporter KCC2 : a new target for the treatment of neurological diseases




A decrease in synaptic inhibition –disinhibition- appears to be an important substrate in several neuronal disorders, such as spinal cord injury (SCI), neuropathic pain... Glycine and GABA are the major inhibitory transmitters in the spinal cord. An important emerging mechanism by which the strength of inhibitory synaptic transmission can be controlled is via modification of the intracellular concentration of chloride ions ([Cl-]i) to which receptors to GABA/glycine are permeable. Briefly, a low [Cl-]i is a pre-requisite for inhibition to occur and is maintained in healthy neurons by cation-chloride co-transporters (KCC2) in the plasma membrane, which extrude Cl-. We showed recently (Nature Medicine, accepted for publication) that these transporters are down-regulated after SCI, thereby switching the action of GABA and glycine from inhibition to excitation; this can account for both SCI-induced spasticity and chronic pain. KCC2 transporters therefore appear as a new target to restore inhibition within neuronal networks in pathological conditions. The present project aims at reducing spasticity and chronic pain after SCI by up-regulating KCC2. 
An important part will consist in identifying new compounds that increase the cell surface expression and/or the functionality of KCC2. Two strategies are considered. 1) Serotonin and BDNF will be tested on the basis of preliminary experiments and/or previous reports in other areas of the central nervous system indicating that these two compounds may affect the expression of KCC2. 2)Testing a large amount of compounds available in a library (“blind test”) to sort out KCC2-modulating molecules. This task can only be done in vitro on an assay that enables to easily visualize and quantify cell surface expression of KCC2, in response to these molecules (HEK293 cells). The few compounds isolated at the end of this task will then be tested on cultures of motoneurons (both mouse motoneurons and human motoneurons derived from induced pluripotent cells) and characterized further (potential toxicity, ability to cross the Brain Blood Barrier and effect on internalization and endocytosis of KCC2). 
The selected candidate compounds will enter into the in vivo validation phase aimed at increasing the expression of KCC2 following spinal cord injury (SCI; both contusion and complete spinal cord transection). The selected hits will be applied by intrathecal injections in SCI rats and their effects on KCC2 expression in the plasma membrane of motoneurons will be tested by means of western blots and immunohistochemistry. Their efficacy in increasing the cell-surface expression of KCC2 will also be tested electrophysiologically in vitro (i.e. their ability to hyperpolarize ECl). Functionally, their efficacy in reducing both SCI-induced spasticity and chronic pain will be assessed. 
Genetic tools will be used to increase the expression of KCC2 in some spinal neurons. This task will be done in collaboration with teams in the USA. Lentiviral vectors aimed at increasing KCC2 in the host cells, after parenchymal injection, have been developed in San Diego. A transgenic mouse model with a conditional tamoxifen-induced overexpression of KCC2 has been developed in Pittsburgh. The rationale for this part of the project is to use these genetic tools in the chronic phase of SCI to reduce spasticity and chronic pain. 
The last part of the project will focus on more fundamental issues regarding the relationship between the SCI-induced downregulation of KCC2 and the development of spasticity and chronic pain. 
The significance of the expected results goes far beyond the scope of SCI, since altered chloride homeostasis resulting from mutation or dysfunction of cation-chloride cotransporters has been implicated in various neurological disorders such as, for instance, ischemic seizures neonatal seizures and temporal lobe epilepsy. 


KCC2 escape from neuropathic pain






Activationof 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2.



 In healthy adults, activation of γ-aminobutyric acid (GABA)(A) and glycine receptors inhibits neurons as a result of low intracellular chloride concentration ([Cl(-)](i)), which is maintained by the potassium-chloride cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). Given the critical role of KCC2 in regulating the strength and robustness of inhibition, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance. We show that activation of 5-hydroxytryptamine (5-HT) type 2A receptors to serotonin hyperpolarizes the reversal potential of inhibitory postsynaptic potentials (IPSPs), E(IPSP), in spinal motoneurons, increases the cell membrane expression of KCC2 and both restores endogenous inhibition and reduces spasticity after SCI in rats. Up-regulation of KCC2 function by targeting 5-HT(2A) receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT(2A)R agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2).



Conclusion

Very little is certain in autism, in great part because only about 200 brains have ever been examined post mortem.  There are many theories, but very many more sub-types of autism.

GABAA dysfunction due to the faulty GABA switch never increasing KCC2 expression in the first weeks of life, triggering glutamate excitotoxicity and all that follows would go a long way to explaining my son’s type of autism. It might well explain 30+% of all autism.

Clearly other causes of excess glutamate would lead to a similar result.







145 comments:

  1. Well to answer a couple of the questions you brought up (great post BTW), first off there are a variety of methods for cleaving excess glutamate from the brain. The aspartic acid stuff I mentioned a while ago could be one of them (that was my original investigation even though it led me to its use for opioid signaling, though all I know is that it improved symptoms, just how it improved them is a matter of speculation and nothing proven at this point). Also, the typical autistic brain tends to not only have too much glutamate but also too much GABA even though the glutamate/GABA ratio also tends to favor excitotoxicity. Since Glutamate, Aspartate, GABA, and Glutamine all cycle back and forth among each other in the brain with various enzymes in various reactions and in a healthy brain there tends to be a fixed total concentration of the those 4 amino acids (i.e. if you add more of one you reduce some of the other), simply reducing glutamate in the diet likely won't do much because excess GABA will be converted into Glutamate as well. In other words, aside from Blood Brain Barrier permeability issues (which can let in excessive amino acids that are normally tightly regulated), getting the right balance via trying to hack these systems would likely best be done with enzymes or analogs of enzymes that convert one amino acid to another.

    Secondly, rTMS (Random Transcranial Magnetic Stimulation) seems to have receptor selective properties depending on the pattern and duration of stimulation. For instance, a pattern of stimulation called iTBS is thought to work by inducing LTP via disinhibition (disabling GABA receptors) which is normally part of the learning process (excitatory circuits where the brakes are let off a bit via reduced GABA action are biased to fire more strongly in the future). Conversely, another pattern of stimulation used to induce a virtual lesion for experimental purposes usually called cTBS is thought to work via the disabling of NMDA receptors, thereby making circuits that depend on them less likely to fire. In cases of excess noise in the brain (hello autism), cTBS can reduce the amount of overall glutamate signaling and thereby improve the signal to noise ratio. This is complicated and unintuitive, but the general idea here is that the effects of various rTMS protocols can be context dependent. Then there are other protocols including simple 1Hz tonic stimulation which is thought to increase GABA(A) receptor signaling and then there is another new one where you literally do an hour of 6000 pulses at 20Hz (50 pulses at a time every 30 seconds) that is thought to increase GABA(B) receptor signaling, even though 20hz stimulation is thought to be classically an excitatory frequency of stimulation.

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    1. Hi Tyler, aspartic acid could be useful for stopping excess glutamate from the brain, did you tried it in your son? I didn´t read it when you mentioned this theme. Regards, Valentina

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    2. Yes it is something that is actively done. If you Google "Aspartic Acid" you will find a lot of stuff warning of the dangers of neurotoxicity (via aspartame metabolism which is a bunch of bunk) even though it is one of the more abundant amino acids in the body. There are of course levels that can go too high and cause amino acid imbalances (this is true of supplementing any amino acid), but I think in adults on average you have about 4 grams of aspartate a day and studies going as high as 13 grams a day (via supplementation) showed no ill effects.

      My results are from a sample size of N=1, and other than clonidine and low-dose naltrexone in treating chronically overstimulated opioid receptors, I don't know of anything else besides this particular therapy which could improve symptoms for other reasons (i.e. therapy works but my hypothesis is wrong).

      If you don't want to do ZMA (even though Zinc and Magnesium are common supplements for autism) you can buy bulk L-Aspartic Acid (BulkSupplements is where I got mine) and mix it in peanut butter or jelly or something like that or else you can make a very salty solution with warm water L-Aspartic Acid and Baking Soda that dissolves to form monosodium aspartate.

      I do ZMA now, but originally used the above method. I would not do more than 8 grams of aspartate per day, but not enough won't give any results either.

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    3. Tyler, how much ZMA are you giving? How would you describe its effect?

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    4. Right now I give him 4 capsules a day (I would probably give him more but I don't want to overdo the zinc). An adult male recommended dose is 3 capsules for 2400 milligrams of ZMA, so 4 capsules is 3200 milligrams of ZMA. 485 milligrams comprise the zinc and magnesium by weight with the rest as aspartate, so you could roughly say he gets about 2700 milligrams a day which seems to do the job (my son is a very big 7 year old). If I give half of this self injurious behaviors start creeping up a lot more as well as general anxiety and impulsive rage. He was getting two doses of 4 grams a day with the old aspartic acid + baking soda method which had a pretty dramatic impact that was noticed by his teachers as he had a lot of aggression and SIBing issues at school prior to that (they are blinded by everything we do).

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    5. Tyler, very interesting re: ZMA. I had never heard about this supplement. I am interested in giving it a try - my son has a ganglioneuroblastoma tumor and some cancer sites recommend magnesium and potassium aspartate forms in possibly helping with cancer related fatigue. I am just curious how much do you think the b6 part of the mix helps? B6 is something that I have finally realized helps my kid, but it seems to be in cycles - really great for a couple of weeks, then those effects wear off, I pull it, add it back in, great results - cycle repeats. Trying to figure it out.
      ~Tanya

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    6. The key is the aspartate. ZMA just happens to be Zinc, Magnesium, and a lot of aspartate. There are other vitamins/minerals that are chelated with aspartate for better absorption but they have not been as popular lately for a number of reasons. As I stated before I use ZMA cause my kid does not do pills and it tastes not as bad as the L-Aspartic Acid + Baking Soda solution I was using before. If your kid does pills, you can just buy L-Aspartic Acid from BulkSupplements or somewhere else and then pack it in gelatin capsules as another option.

      Also, on the B6 they have is standard pyroxidine (the most common type found in vitamins). The most popular form of B6 that parents have used for autism which is a bit more expensive and is known as P5P under the hypothesis that the pyroxidine form of B6 is not metabolized to P5P in some individuals because of an enzyme deficiency (I use it though I will acknowledge the evidence for this hypothesis is probably selective to specific people and not terribly strong). If you exercise, you tend to use a lot of B6 as it is used in I think over 200 enzymatic reactions and can easily be depleted in times of stress (such as exercising or being sick or having inflammatory issues such as you might have with autism).

      I don't think it would matter much either way. B Vitamins, unlike Vitamin A and E which collect in fatty tissue, are all just flushed out of your system in a day if they are not used in the body or else stored by the liver.

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  2. Also, with respect to iTBS and cTBS specifically, the only difference between the two protocols is iTBS has 8 second gaps of rest after 10 bursts of 3 pulses at 50hz repeating at a rate of 5hz, whereas cTBS has no gaps of rest after each 3 pulse burst at 50hz at a rate of 5hz. This gap of rest is very important as the rate of calcium entry into a cell is as important as the load of calcium entering the cell beyond a particular threshold where you end up with different effects on the cell.

    Last but not least, LTP inducing protocols like iTBS have been shown in some studies of those with autism to have extended offline effects (i.e. the time after stimulation) that can be three times longer than the typical person which is one reason among many that almost all rTMS studies on those with autism follow low frequency inhibitory or dysfacilitatory (cTBS) protocols.

    Unfortunately, there seems to be a cottage industry of rTMS outlets popping up these days for treating depression and many other neurological diseases, but I am skeptical the people running them are doing any good because finding the right spot to stimulate is not completely the same for everyone and coordinates of stimulation in research studies for rTMS use fMRI to identify and localize the proper brain area for stimulation (and rTMS tech is orders of magnitude cheaper than fMRI which is at a minimum of 3 million dollars just for the scanner).

    So the potential for rTMS in treating broad based receptor issues for autism on the lateral surfaces of the brain is clearly there, just I have not seen anyone really push for this kind of research for therapeutic reasons as all of the research on rTMS with autism (and I have read most of the notable papers in this area already) tend to focus on specific metaplasticity inducing effects of specific brain areas such as the semi-famous guy you may have heard of (and whose name I cannot remember) who got rTMS treatment as an adult and then claimed that it led to a permanent reduction in his symptoms. I believe his account, but my point here is that using rTMS for therapeutic purposes to broadly affect specific receptors throughout large areas of the brain is not an area of research anyone seems to have explored yet.

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  3. Hello Peter,

    A very useful post, almost a synthesis, and did succeed in educating even blockheads like me on the wider neurological context within which the role and interconnectedness of neurotransmitters, ion channels and transport, receptors and co transporters has to be understood. Will have to re read a few times to really appreciate how the E/I imbalnces act out so as to result in various neurological disorders and the way ahead and possibly out.

    Again, on a reflective note, it's all so complicated that one cannot help but feel deeply reverential towards the ways of nature. Perhaps, we were meant not to understand but follow nature. But now nature has left us and our over smart ways behind and we are almost our own now.

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  4. For those who haven't seen this TedTalk on glutamate and diet.

    https://www.youtube.com/watch?v=iL4SD5f2toQ

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    1. Reasonable people can agree to disagree, but even though she is a doctor she is woefully ignorant of how glutamate is processed in the body. The whole "bound glutamate" or "free glutamate" she talks about is total nonsense as the blood brain barrier is very stubborn about letting "free glutamate" across. Also, if MSG caused autism, you would of had massive increases in autism in Asia over the last century.

      Really this is just another facet of the whole "clean food" movement which is really just the gentrification of ingestibles that fulfills the same biases people have to health when it comes to having a "spot free" house, even though now the "hygiene hypothesis" might as well be accepted as medical fact now by knowledgeable scientists when it comes to immune disorders including asthma and allergies. Poor "dirty people" eat whatever they can afford and the sophisticated "clean people" shop at Whole Foods and Trader Joes. These are all just examples of people playing to some very primal biases almost all human beings have that lead them to believe in "facts" which have no scientific basis.

      And while I sympathize with her as I do any autistic parent, I still do find it annoying when certain doctors put on their white coat as a symbol of authority and spew unscientific nonsense (e.g. Dr. Oz) as it decreases the signal to noise ratio for serious researchers to get the attention and resources they need in tackling real medical problems like autism.

      That is not to say that many "processed foods" are not good for you because they have been overheated causing byproducts like AGEs (Advanced Glycation Endproducts which are linked to obesity and diabetes), or that excessive intake of fructose is not handled well by many individuals, but the whole "clean food" movement which this woman espouses does not see the forest for the trees when it comes to why some, but not all, or even a majority, of processed foods are potentially unhealthy, leading to many parents employing restricted diets in their otherwise healthy children leading to the kind of malnutrition you typically only find in very impoverished countries.

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    2. Lot of ideological biases seem to be piggybacking on not only autism treatment movements bit also most affliction that ail us today, and in many parts of the world we are witnessing a resurgence of traditional or even a return to nature type lifestyle patterns, especially amongst those who can afford it.

      But because there seems to be some indirect association between the current state of human health and well being and modern living, which would include processed food, preservatives and then the whole organic inorganic thing, as long as it's not deeply restrictive or nutritionally deficient, there might be a remote merit in going for healthy eating. And if these isolated voices take away the steam from hardcore scientific autism treatment actions, it only reflects poorly on the earnestness and conviction and desire to reach out and speak, of the genuine white coat variety.

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    3. Pretty much 99.9 percent of the food we eat are farmed animals or else domesticated plants (i.e. not natural stuff you would find trying to survive in the tropical rainforest). Even though most of these foods are not GMO's, they still have unnatural levels of gene expression which are either enhanced or repressed through selective breeding which if done long enough, often achieves the same results you would get by directly hacking the genome of the plants themselves thereby making them GMO's. The bananas you eat are nothing like the original banana plant that was domesticated for human use through lots and lots of inbreeding. Many crops now yield more energy and are easier to digest than older crops, at the expense of less vitamin and mineral content.

      The point is that human beings have been making major changes to the world ecosystem for millions of years and have adapted the world and its other species for our benefit whether we like it or not. What is the "perfect diet" for maximizing longevity in human beings is a very open ended question, but when people tout eating "clean food" with a glass of wine (alcohol is carcinogenic and mutagenic and not "healthy" for you at any amount), it really makes me roll my eyes.

      Focusing on minimizing damaging environmental insults like air pollution or light pollution and avoiding foods with strong scientific causal harm associated with them such as excess fructose (via sugar) or trans fats (which are largely banned nowadays) will potentially do a lot more good than focusing on whether a particular food is "clean" or not which has no scientific rationality.

      Delete
  5. When the "serious researchers" you speak of actually offer a treatment for my child, I will take their advice. Until then, I'm willing to listen to someone with a Ph.D. in biochemistry who is only suggesting I feed my kid healthier food. It certainly can't hurt.

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    Replies
    1. Its called translational medicine, where research is converted to clinical practice. There are some researchers who do this, including Dr. Naviaux with Suramin, the guys at Stanford with NAC etc. Let's also not forget Knut's work that Peter has posted about here. Its obvious that the mainstream doctors have dropped the ball here, and it only makes me even more grateful for people like Peter.

      I thought that what's needed to feed my kid healthy food is common sense, not a phd in biochemistry.

      Delete
    2. Not to get into a big debate about this stuff because there are plenty of other boards where people argue these topics incessantly, but before someone can give themselves or their child "healthy food" you first must define what "healthy food" is in the first place and be able to explain why a particular "healthy food" decreases mortality and also increases longevity which is very hard to do in human beings since there are very few long-term comprehensive studies on human nutrition and the only research projects that do exist with a significant timeline like the Framington Heart Study have only started gathering the kind of data to answer these questions very recently.

      Last but not least, if someone with a PhD in biochemistry makes a bold claim such as their child's autism was cured by "clean food", the fact that there is not an army of other people with PhD's in Biochemistry shouting her down on YouTube does not necessarily mean that the vast majority of her professional peers agree with her opinions at all, especially since if someone becomes popular on the internet for some fad, you could have 10 Nobel Prizes to your name and disagree with said popular celebrity person, and the next thing you know you have your inbox filled with hate mail from random anonymous strangers saying you are the dumbest person on earth and that the Nobel committee only gives Nobel Prizes out anymore to "idiots" like yourself (the critical researcher) these days. It is a lose-lose proposition for professionals to try and talk down "pop medicine" which unfortunately allows charlatans or else people who simply have extraordinary confidence in their own intellect (perhaps because they have an advanced degree that allows them to think that way) while also lacking the introspective judgement to critically evaluate their own ideas before trying to present them to others as fact.

      And restrictive diets can sometimes hurt. It depends on the diet of course and what she proposes in the video I think is basically neutral anyways in that it won't do much other than hurt your pocketbook which all of us parents of kids on the spectrum are willing to do for anything we believe even has a scintilla of a chance in helping our children.

      Delete
    3. Almost always a discussion on any topic, if it as much as even remotely touches upon environmentalism, tends to become hugely judgemental. Well, I am guilty of holding a doctorate in ecology and can go on and on arguing and counter arguing, but I have a child on the spectrum and therefore I do not have the luxury to get into academic debates. I also am guilty of being an opportunist, enjoying the gifts of modern lifestyle but ideologically and emotionally siding with the Greens. Though, going through the initial sections of Patricia Lemer's Outsmarting Autism really upped my irritability levels.

      And holding a PhD does not take away from one the right to be stupid.

      Delete
    4. I have to say that I find this type of infighting to be extremely discouraging. We are all here because we are trying to help our children, ourselves, or someone else we love with autism. In many cases (certainly mine), the many medical professionals we have consulted have told us there is no therapy available, so we have had to set out on our own to find solutions. I hold a Ph.D. in History, but unfortunately my knowledge of science is weak, so I have to rely on others who can make sense of the scientific literature. And, I am willing to listen to anyone who offers viable ideas about potential points of intervention, and I am willing to try anything that seems safe (most importantly) and reasonably likely to help. I would guess that many of you have tried things that the "serious researchers" would deem scientifically misguided or even irresponsible (which is exactly what I was called by a respected mainstream autism expert when I suggested trying Atorvastatin with our child). So, why can't we come together and share ideas or experiences about what has worked or not worked? If you think something I or someone else offers is BS, then ignore it and move on.

      Delete
  6. Tyler, why did you stop with the aspartic acid? Do you think that ZMA, zinc and magnesium aspartate is safer, did you get better results in your son?Valentina

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    1. The reason was practical. The liquid concoction is quite salty and very hard to mask in a made up beverage. It was also quite a bit of a chore as I would have to microwave a little bit of water to warm it up, then pour in the aspartic acid, then the baking soda, swish it around for a while till it totally dissolved, and then finally put it in a drink I pre-make at night for the next day. My son won't do pills.

      With respect to ZMA, they come in capsules and I just dump them in a drink as ZMA is mostly tasteless (at least compared to monosodium aspartate).

      Delete
    2. tyler, I have 2 questions, First could I use magnesium and zinc aspartate separeted, because 4 capsules makes zinc increase too much, I have read that only 40 mg elemental zinc is convenient. Is that true? About my son, his behaviour is more related to hyperexitability, repetitive movements only just for looking at someone strange or something intresting for him in computer, tv or playing at school. For this reason I think that excess glutamate or an imbalance with the other neurotransmitters has altered him and I dont know if can be reversable or at least improved. So do you think that ZMA or aspartic acid could help in his situation? Thankyou. valentina

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    3. Yes you can do that, but unfortunately every single supplier of magnesium aspartate I tried to find had it out of stock unless I wanted to buy quantities of it for thousands of dollars from bulk suppliers in China. This was 3-4 months ago, so for all I know things have changed and Magnesium Aspartate can be bought somewhere on the internet. So this is why I eventually went with ZMA.

      Also, another thing you might want to look into is a ketogenic diet which I have yet to try in my son because he is a carb king and I have yet to find enough pure fatty foods that are palatable to him which he is willing to eat. Also because he goes to a public school and I can't control what he manages to snack on while he is there because if he refuses to eat the fatty stuff in the hopes of holding out for carbs, they are not going to prevent him from doing so which ruins the ketogenic diet. I might try it next summer to see if it helps.

      Here is a good overview of the ketogenic diet that i read today:

      http://blogs.scientificamerican.com/mind-guest-blog/the-fat-fueled-brain-unnatural-or-advantageous/

      I already know plenty about ketosis, but this seemed like a good article for others to peruse who are not as familiar with the science behind it.

      Also, with regards to hyperexcitability (which I assume is your second question), my son has similar behavior with visual and motor stimulation. Autism severity in several studies has been shown to be directly correlated with how active the somatomotor cortex and the visual cortex happen to be, likely due to GABAergic deficits that could happen at multiple stops of visual processing in the brain (it is hard to say at this time to say definitively where the floodgates are opened). The visual cortex seems to be optimized for processing natural scenes (i.e. when you are out in nature) and explaining the evidence for this would take quite some time, but perhaps turning his room into a jungle of sorts (lots of plants) and maybe even having some sort of natural sounds track on autoloop could help him get enough stimulation that he does not seek out the kind of visual stimulation that makes him irritable.

      A famous neuroscientist named Henry Markham and his wife (also a neuroscientist) have a child with autism and have devoted much of their recent research in this area. He recently put out a followup paper to his "Intense World Theory":

      http://journal.frontiersin.org/article/10.3389/fnhum.2010.00224/full

      where his conclusions were that it is probably best to restrict the amount of background sensory stimulation for those with autism, rather than try and help them cope with all the distractions of the real world. If you can imagine kids with autism living in the 1800's on the frontier, many of them might not have any of the types of environmental stimulation human beings take for granted these days (noise pollution, light pollution, large numbers of people in gatherings, etc.). I don't (can't) do this myself as my son has 3 young kids and keeping the house quiet is near impossible and what happens at school is beyond my control (I wish I could homeschool him).

      Delete
    4. Here is another article I read today which coincidentally describes much of what I just explained above:

      https://spectrumnews.org/opinion/q-and-a/questions-for-rafael-yuste-how-to-rewire-neurons-with-light/

      Also I might add that visual cortex neurons fire sparsely in natural visual scenes, but in experimental situations where flashing gratings are used, neurons tend to fire more coherently and strongly with each other (which according to this researcher can cause problems if this happens too strongly). I have literally several hundred bookmarks not organized very well on neuroscience papers and I thought I had the one about natural scenes but can't find it at the moment so you can just take my word for it or look it up yourself if you are interested.

      Delete
    5. Hi Tyler,
      We did the SCD a while back for a year and a half, which I think can compare to the ketogenic diet, and the results were good (for example he would sit down the full length of the meal). Eventually we had to stop it because he goes to public school and they were putting a lot of pressure to give him the same snacks as the other kids. We introduced potatoes/rice again and the increase in hyperactivity has been dramatic.
      Many times I'm considering going back on it, but it's a very hard diet to adhere to. Also we think he was too skinny (although eating enormous amounts of fat).
      I will try ZMA shortly.

      Delete
  7. Peter, I am a bit confused here. I thought Abha Chauhan's work showed protein kinase C to be low in autism. Whereas, the paper above seems to say that it is increased due to increased intracellular calcium. Going on from there, how does verapamil usage affect all this?

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    Replies
    1. Chauhan was talking about regressive autism.

      Look at this chart:-

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432855/figure/F1/

      Reduced Activity of Protein Kinase C in the Frontal Cortex of Subjects with Regressive Autism: Relationship with Developmental Abnormalities

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432855/

      She also found protein kinase A was low in regressive autism but not early onset autism.

      It clearly is a work in progress.

      Verapamil should reduce signaling from L-type calcium channels, which may be over-expressed or just over-activated in some autism.

      There is an old paper by Catterall, which shows that PKC inhibits Cav1.2.

      http://www.pnas.org/content/97/22/12334.full.pdf

      This would mean that PKC and verapamil have a simuilar effect on these calcium channels. Perhaps people with low PKC have too much Cav1.2 activity? Perhaps some people with low PKC might feel better with some Verapamil?

      Delete
  8. Peter, with regard to KCC2, Bumetanide was effective from the start and Diamox has been very successful. The only thing is that the catamenial seizure is not responding. I am trying to decide between increasing the Diamox dosage starting a week before through to the 10th day, or increasing Bumetanide from our current 1mg once per day to 1mg twice a day. Could you weigh in on this please?

    ReplyDelete
    Replies
    1. Bumetanide seems to be very well tolerated, so I would try 1mg twice a day. This is the dose we use.

      In our case Diamox seemed to be less well tolerated, but for others it may be just fine.

      Probably try one and then the other.

      Delete
  9. I think vitamin e, in the form of alpha and mixed tocopherols, can rescue to some extent my son's excitotoxicity.
    However, I have to be careful with the dose as it may bring adverse effects. The dosage I am trialling is low, about 200IU once a week, or maybe ten days.

    ReplyDelete
  10. Thankyou Tyler, very interesting all the information, will look at natural scenes and visual cortex, if you find your bookmarks let me know, his problem is not so common in autism, specially because he was diagnosed HFA, I haven't been able to find anything that really helps or works in this matter. About homeschooling, this is something that really crossed my mind, but always find advantages and disadvantages.Valentina

    ReplyDelete
  11. Hi Peter, any thoughts or experience with readers using l-theanine to reduce glutamate induced neurotoxicity? Pubmed search yielded some results, here is one with schizophrenia: https://www.ncbi.nlm.nih.gov/pubmed/25896423, I could not find any studies with autism and theanine. I am thinking of trying GABA or l-theanine and am leaning more towards l-theanine.

    ReplyDelete
    Replies
    1. I have tried L-Theanine in the past for the reasons you have suggested in my son and it to date is the single worst intervention so far for him. I have multiple hypotheses for why it caused such severe problems, but it literally made him psychotic and go into a rage after about an hour or so after ingesting it.

      Now why did L-Theanine cause this behavior when it is supposed to upregulate GABA production in the brain? Well, one obvious possibility is that because it is metabolized to L-Glutamate and Ethylamine (at least in the liver, but I remember reading a while back this breakdown happens in the brain as well). Another possibility is that because of paradoxical GABA activity in autistic brains, the upregulation of GABA is only transient and then GABA is converted back to Glutamate without there being any upregulation of activity in detecting increased production of Glutamate (there are very complex feedback loops between GABA, Glutamate, Glutamine, and Aspartate).

      I also scoured many different forums for case use examples of Theanine and a minority of users expressed that they had rage and extreme anxiety issues with Theanine.

      If I were you I would try it out because all of our kids are different, but don't be too surprised if it ends up being the worst intervention you have ever employed.

      Also, GABA supplementation classically is believed to not cross the Blood Brain Barrier but in the last several years there have been some human studies that suggest things are not so cut and dry. Nevertheless, I think with regards to raising GABA levels L-Glutamine supplementation has been shown to be effective in that regard. Nevertheless, increasing GABA or L-Glutamine levels is going to increase Glutamate levels as well (at least temporarily). There is a big question as to whether it is just the GABA/Glutamate ratio that matters or whether absolute levels of one or the other matter as well. In several studies I have read on the subject, the GABA/Glutamate ratio is low relative to controls but the absolute amount of GABA levels are really high relative to controls so in this case more GABA just means more Glutamate (which means more fuel for the fire).

      Delete
    2. L-theanine is used by some people to regulate hyperactive behaviour in autism and ADHD. I recall reading that at Johns Hopkins they found in people with mitochondrial disease it raised cognition. Since nobody knows for sure what is going on inside a particular person's brain, there is no way to predict whether L-Theanine will help or even if there is any glutamate induced neurotoxicity. The only way to know if L-Theanine is beneficial is to try some.

      You can try GABA, but if it does not much cross the blood brain barrier it may do little.

      If you have excitotoxicity triggered by GABAa dysfunction, then you would treat the GABAa dysfunction with bumetanide.

      Delete
  12. Peter,

    Even I was wondering about theanine. Read some positive reports about helping in calming down and focussing. Taurine and theanonine combination has also been deemed as effective.

    Statred with 600 mg of NAC, as fluimucil on son and myself. Felt lightheaded for a while (more likely due to lack of sleep) and plan to continue for three days before doubling the dose. Have stopped all homeopathic meds for now and might add on as needed.

    Fluimucil, the batch I tried, did not give off any smell but on tasting gave off a mild sulfurous odour/flavour which I believe is alright. But it was not pleasant tasting at all and for my son had to be crushed a little to make it dissolve in his juice. If this works, I will go for NAC sustain.

    Again, getting into the drug collecting mode, which I have to switch off as I have a pattern of getting bogged down with so much of information collection and getting every possible intervention in hand before I start, that the actual process gets indefinitely delayed.

    Regards

    ReplyDelete
  13. Peter, I'd like to add a second low dose clonazepam and need to know how you give it during the day.

    ReplyDelete
    Replies
    1. Petra clonazepam has a very long half life (about 30 hours). You could give a second dose during the day and that is what is done when using high clonazepam. I would try increasing the single daily dose, which is much easier to do and should work well.

      If you give too much then there will be a negative effect.

      I would increase the dose a small amount and then it will take 3 days to reach a stable, higher, concentration.

      Delete
    2. Peter, we are on .025mg once a day of the low dose clonazepam. Since we had clear good results with this and also because I was going to add in Diamox soon after, I didn't try increasing the dose. Now, this has been our history with things that work, I see good results and there are so many more therapies waiting in the pipeline, that I don't experiment further with dosage. Bumetanide, Sytrinol, clonazepam are all examples.

      I have been tempted by clonazepam especially because it does bring about a lovely calmness in about 1/2 an hour. Does this make sense or could it be a placebo effect?

      Delete
    3. I think you might be at the lower edge of where clonazepam is effective and so you get the best effect straight after the dose. So I would increase slightly the dosage and see if you get the calm effect all day long.

      If you get past the upper edge of where it is effective and into the negative effect area you will see that this negative effect starts very soon after taking the dose and then fades away over a few hours until the concentration is back in the zone where the effect is positive.

      If you have 0.025mg doses made up by the pharmacy, you could even try a second dose every other day for example. So 0.025mg once a day, then twice a day and then back to one a day etc.

      We currently use 0.035mg once a day.

      Delete
    4. Thanks Peter, I'll try it and report back.

      Regarding the others, are there any that you stagger deliberately such as verapamil and bumetanide? Do you give the clonazepam by itself alone or with any of the others? Do you mind sharing your schedule on this? It feels like I am running every half an hour to give something, and its become almost impossible to do so without missing some doses here and there?

      Do you think the mirtazapine can be given with verapamil and/or Diamox? I am currently doing 3.75mg of mirtazapine.

      Delete
    5. I am only a beginner but this is how I do it:
      I've got a digital scales, which cost 22 euros, and the salesman told me it's quite reliable, next more reliable is 60 euros and didn't want to spend so much.
      I weighted the 0,5 mg clonazepam pill and found it a little bit more than 0,20 gr. According to some calculations I concluded that I needed 0,03 gr., about 1/7 of the pill.
      I give this dose for two weeks and only once we had some irritability which didn't last long, with no serious consequences..he just explained that he felt fear.
      Peter, am I doing it right, or I am just having the Bumetanide effect? I think I have the maximum effect of clonazepam after about 5 hours.

      Delete
    6. Petra, you are giving 0.071mg of clonazepam, so twice the dose I use and almost three times the dose RG uses. Your son is an adult male probably nearly twice the weight of my son. I think the dose should be about right, but it might not be optimal. You just try a bit more for a week and then a bit less for a week.

      Delete
    7. RG, at breakfast I give verapamil, bumetanide, atorvastatin, NAC, Biogaia in tablet form. In water I give potassium, effervescent NAC and broccoli powder. In the middle of the day is more NAC and Verapamil. At about 6pm is NAC, verapamil, bumetanide as tablets and a glass of water with clonazepam, potassium and effervescent NAC. In addition in summer we have antihistamine nasal spray and we also have a low dose of steroid inhaler to prevent asthma. It is quite a lot, but all do have an impact.

      Fortunately my son enjoys swallowing tablets and will drink strange tasting concoctions just for verbal encouragement.

      Delete
  14. I remember theanine was suggested as mast cell stabilizer as well:

    https://www.ncbi.nlm.nih.gov/pubmed/21344174

    Maybe it is worth a trial in autism + mast cell activation?

    Perhaps the answer for the second question as usual is that it's not so simple, but if we talk about glutamatergic storm and glutamate receptors, then what do you think about NMDAR antagonists, memantine or amantadine?

    My country was invloved in multinational memantine trial that failed. According to local psychatrist all families included decided to continue memantine later. This may say not so much about its efficacy, but I also talked to another reasearcher who saw significant cognitive improvement in a very small minority of children in the study. It was noticed by their school teachers, decreased on withdrawal and was not covered by the trial endpoints. Apparently best seen in children with ID.

    All this got lost in the final conclusions and the "failed" label.

    Well, I have not tried memantine nor l-theanine. Tyler's exeprience is not encouraging and reminds me poor effects of my own attemt to modulate glutamate by boosting GAD activity with its cofactor P5P.



    ReplyDelete
    Replies
    1. Agnieszka, I would not be put off by Tyler's negative experience. He had a good result with Picamilon, I recall. When I tried Picamilon, to "increase" GABA, we had an immediate negative effect. Some kids with autism likely have the opposite dysfunctions. The good thing is you just need one pill to find out.

      You could indeed use this as part of a broader diagnostic test, which many one day trials. Seeing what gives a negative reaction could be insightful to figure out someone's sub-type.

      Memantine is also an L type calcium channel blocker. It resolved the GI issues of one reader's child. So memantine might be having a positive effect in different children for different reasons.

      Galantamine is very similar to memantine and both are used as cognitive enhancers by some NT adults.

      I think in some cases this is fine tuning the brain. In autism I think we are looking for more profound improvement. Most likely a small number of people with autism really should have memantine and the same may well be true for theanine.

      Delete
  15. Hi Peter,

    Have you seen this trial of Ganaxolone by the MIND institute?

    https://clinicaltrials.gov/ct2/show/NCT01725152

    and this:

    https://clinicaltrials.gov/ct2/results?term=ganaxolone&Search=Search

    ReplyDelete
  16. Here are the results from the phase 2 trial in FX:

    http://ir.marinuspharma.com/releasedetail.cfm?releaseid=977308

    ReplyDelete
  17. Sorry to comment in this choppy way. Ganaxolone seems to increase allopregnanolone without actually having any hormonal effect.

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    Replies
    1. RG, it is interesting and shows how key GABAa is to fragile X and epilepsy. There are clearly many different types of GABA dysfunction and the more safe drugs that are available the better it will be. It would be interesting if Hardan, who trialled Pregnenolone in adults with autism, would compare the effect of this new drug. Is their effect the same or not?

      Delete
    2. I wonder especially if it would be even more effective at micro doses like the low dose clonazepam?

      Delete
  18. Hello Peter,

    Day third on 600 mg NAC and to be honest and critical, no amazing moment to report. Generally OK, average rating on behaviour, probably a little less hyperactive than he was on days just prior to NAC but we have seen better days. So these were not the best of days, nor the worst. One observation, he looks a little more sleepy, was dozing off while we were coming home, which he had not done for the past six months. But it could be the weather. The interpretation :

    1. He does not suffer from oxidative stress

    2. He had oxidative stress but large part of it was already treated with homeopathic detox meds, which is why the dramatic changes we got when we started them, were not replicated again

    3. NAC dose is too low. He is 21 kg,(heavy boned, taken after my Pathan husband)

    What do you suggest, doubling the dose, 600 in morning and 600 in eveming or splitting 600 mg into two. As it is my son did not have much issues with disregulation, stereotypy or aggression. I have a feelong that supportive medicine will not do much as he is already not too much messed up, and we need something to target neurological issues.

    And I carried out a critical assessment of his other issues, particularly GI onrs, and have decided that I might be actually searching for problems where there might be none. All my nt niece and nephews have worse GI status and we as kids used to move around with a discomfortable belly bloat after huge glass of milk was forced down our throat and nobody cared. Actually falling sick or getting hurt was an invitation for a long drawn sermon from ma. And here is my prince, every littl mosquitoe bite being caressed and soothed. Basically, I was getting too paranoid and reading too much into things and I think I can solve this indigestion issues with a big plum and orange, as for now.

    I do not know whether it is a good thing but my son can really gesture quite well where he is hurting. Yesterday it was tummy and chest and he moved my hand over it till his gas problem was eased.
    One important concern i had was about neuropathic pain which you mentioned somewhere. He is communicating his discomfort about even the slightest stirrings in his penis now, just before falling asleep or just as they occur through the day. He will whine or speak out..ma, nunu. I do not know how to help him except to tell him it's alright. I was wondering if it's not a problem of erection but he is just neurologically wired to record a sensation as uncomfortable. Could this be a possibilities? Can sytrinol dampen certain sensations? Or can anything else?

    Finally, I have received burinex from our good old Asian neighbour Taiwan. Neatly packed, right in time and a simple, efficient online site where you get to track your order on a day to day basis. And because they have most medicines, it could be a very convenient method of drug procurement in future.

    Please suggest on nac usage, the simple discomfort based cause of his erection problem and when to start burinex. I hope bumetanide works..if it doesn't then I will be in a fix. Intuitively I feel antioxidants, probiotics and amino acids will have only minor effects on him if any..not in any way disregarding their benefits.


    Regards








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    Replies
    1. NAC dosage is too low for the desired effect. There is no harm in trying 1800 - 2400mg a day for a few days given a half life of just under 6 hours.

      Delete
    2. I would try 1800mg of NAC split in 3 or more doses for a few days. If there is no behavioral impact, I would then assume there is no oxidative stress.

      You could try sytrinol and see if it helps.

      To trial bumetanide the researchers use 1mg twice a day for a month or more. In our case it took a couple of weeks to show effect. You do need to give potassium and make sure the K + blood level stays within normal limits.

      Delete
    3. Peter,
      Pardon me for repeating a question which you have probably already answered before but can I keep one half of a fluimucil tab for later use..will it not start breaking down?

      And does NAC cause a mild diuresis
      ? We noticed this in our son today, late evening till night.

      Delete
    4. Hi Kritika,

      I called an old friend of mine whose son had similar issues when he was very young. He was also an asd child. She used a cold towel and very soon he learnt enough to go to the bathroom and wet a washcloth and use it himself. Over time, it all went away apparently. This might be a good behavioral solution until you fix it from inside. She did recommend you consult an urologist first just to be sure because one of her friends' children had an internal structural issue, she couldn't remember the details.

      Delete
    5. Thank you so much RG. Yes, consultation with a urologist is due and probably a neurologist. One of my husband's neurotupical cousin used to have painful erections as a child which went away at puberty. And apparently, my son does try to cool himself off by standing just next to the AC with his pants down.

      I will try the wet towel thing..see how he responds but I do not know how he can do this at school..

      Once again thank you for relating the other child's case..n is not=1 thank God.

      Delete
    6. Em, RG,

      Starting 1800 mg NAC from today. Thanks. Please keep advising.

      Delete
    7. Kritika, you can break fluimucil in half but wrap up the unused half and use the same day. We have no diuresis with NAC.

      Delete
    8. Kritika, I think the idea of the cold towel is to contract the blood vessels, and reduce circulation.

      For school, maybe you could keep washcloths in individual zippered plastic bags in the fridge and send a few in a lunch bag with an ice pack. This way they could be used outside his clothes, perhaps? Sorry Kritika, I am out of my depth here, you should experiment. The key seems to be to apply something cold enough.

      Delete
    9. RG,

      Yes, I know the idea of cooling it off is to bring about blood vessel contraction ..what else..

      Today, his lead therapist agreed that what we are brushing off as behavioural of sensory could have a physical or physiological basis. And this has been going on for almost a year now.

      I personally am feeling it could be something regarding foreskin..I hope it gets resolved and also that the solution be non surgical. Will visit a urologist soon. Once this is sorted out, I think behavioural part will be easier to deal with. Little guy was trying out deep breathing exercises (not more than three inhalations) on my insistence.

      And thank you for the detailed answer to my other question. You have been a great help.

      Delete
    10. Sorry RG,

      I meant a cold washcloth or towel when I used the phrase wet towel. And at his age, 4.7, and with his condition, read autistic, he can in no way open up a box with cold napkins inside, go off to the washroom, and do the works. With 40 neurotypical kids keeping a watchful eye. No way!

      Delete
    11. Kritika,

      I am sorry to hear about your son's issues and I don't have a good advice for this, just wanted to share my NAC experience.

      I did not see immediate effects on NAC, but tried to collect some daily data about my son and over the time it was clear for me that he does better on NAC.

      When I read Stanford study in details I could see that NAC impact on irritability was clear early in the study, but it was not until 3 months of NAC use when they saw some other effects eg hyperactivity decrease. And they used 2700 mg daily as far as I remeber.

      Anyway my son's sensory driven behaviors reduced and some - eg pressing his body against surfaces - disapperared totally on Bumetanide. Well, I was later told by one of French doctors involved in Bumetanide studies that it is quite common on this treatment.



      Delete
    12. Hello Angeiszka, Peter,

      First, about the discomfort part. Son was physically last examined around a year back, things were normal and the paed showed me how to clean it by pulling back the foreskin a little. But now something seems different..even my husband and therapist are not clear. So the first priority is to get this thing sorted out..festive season so a senior urologist I wanted to consult is not available for a few days.

      Now the NAC experience. Five days completed out of which last two were on 1800 mg. I quit after 600mg for three days, but my child is braving on. It truly is horrible and my son makes pukey faces while consuming it but somehow manages to empty the glass. He is such an agreeable child.

      As for the effects, he generally looks happy but he is like that usually. No meltdown, easy to control, happy, affectionate, responsive. Follows most instructions. Therefore I was wondering what if NAC is helping with oxidative stress but in absence of too many autistic mannerisms, the effects are not that explicit.

      Or maybe its too early to draw a conclusion. One observation that I made today was that while he was attempting some writing work, he still held onto his erection and was uncomfortable but he tried to smile a little. But of course it could be a one off instance..will have to wait and watch.

      Another observation, after his third NAC dose today, he got really charged up but not in a zoned out way. Energized, happy, hyperactive but present and settled after an hour or so. I do not count it as an adverse effect as usually these periods are sometimes indicative of progress in case of my child.

      So that is it. Probably in a few days time I will get a clearer picture. After that I want to begin burinex.. at least few days before the school reopens so that I can work out a schedule around his diuresis pattern.

      Thanks for all your suggestions.

      Wishes

      Delete
    13. Angeiszka,

      How are you giving NAC to your son? Is he able to swallow tablets? I am sure my son will be able to do so if we teach him but that will take time and NAC 600 is quite large and I am not even sure if it's helpful so do not want to spend much time on this right now.

      Peter, Angeiszka,

      You had once responded to one of my queries regarding intermittent drug usage and had referred to a study where NAC when used three days a week seemed effective in maintain its benefits when used on a long term basis..supplementation with melatonin and selemethionine was another way. Can I try three days a week strategy after this trial with 1800 mg is over which I plan to carry out for five days? Should I try longer..

      Actually I am still not sure what to look for.. irritability..my son has none beyond what normal kids of his age have. Anxiety..I would not affirm to that as he is willing to seek out new experiences and tries to tolerate uncomfortable sensations like a thermometer under the arm if i try and persuade and reason out.

      If I can sum up, autistic behavioural problems that he faces are basically lack of sustained focus, big problems with language, both receptive and expressive, and immature social behaviour. So all his major deficits are in areas which define what autism is.

      I feel I am repeating this account of his condition..please bear with me.

      Delete
    14. Hello Kritika,

      You can see how I struggled with giving NAC to my son two years ago straight under Allergies & Autism section here. Finally he drinks Fluimucil or occasionaly PharmaNAC mixed with Sando-K (effervescent potassium) 3-4 times daily, including at school.
      I used to add fresh lemon juice for better taste, but when my son was on the summer camp they had no way to get lemons into the backcountry camp (or thought I was overacautious mother probably) and it turned out that it was not really needed. Over the time my son got used to drinking this mixture and I don't worry about hydration and potassium thanks to this solution.

      I haven't tried intermittent NAC dosing yet.

      Using NAC continuously I can see similar effects as you described:"easy to control, happy, affectionate, responsive." As my son's behavior also has been naturally fluctuating, I think that sometimes I can assess treatment effects only after longer time periods.

      NAC is antioxidant, but also is supposed to target glutamatergic transmission in a different way:

      "Cysteine supplied by NAC treatment can also be oxidized to cystine, a substrate for the glutamate-cystine antiporter. This antiporter allows for the cellular uptake of cystine, which causes the reverse transport of glutamate into the extracellular space. The non-vesicular glutamate released into the extracellular space stimulates the type 2/3 metabotropic glutamate receptors (mGluR2/3), which in turn inhibits the vesicular release of glutamate, thereby resulting in decrease in glutamatergic neurotransmission (18) and the E:I ratio."

      Maybe this explains differences in how people respond to NAC.

      Hope your urologist will be able to help your son, wish you all best with this.

      Delete
    15. Angeiszka,

      Read about your struggles not only with NAC, but other trials as well. The trials and tribulations of mothers with child on the spectrum! Seriously, I hope you and the other intelligent contributors to this blog can come up with a autism treatment guide for the dummies.

      Thanks for all your suggestions ..will keep them in mind.

      Best wishes for your son

      Delete
  19. Peter,

    I wanted to reiterate, that although any enhancement in cognition would be a desirable outcome, for my son, at present, even at his current condition levels, if we could somehow dampen his sensitivity, I feel we can bring about big improvements. I spent half an hour working on him on sight words and he really picked up fast..made him write numbers, precursive amidst moments of focus disturbed by periods of distress as he held onto his erection. It's distressing to me as well to see him struggle so much. RG has mentioned somewhere her daughter wanting her feet feet squeezed hard in response to stress. In my case it's stress that brings about erection but erections in themselves without the stress are equally uncomfortable to my son.

    ReplyDelete
  20. Peter, thinking about my son's epileptiform activity,can bacterial and viral infection be stimulating seizures for excess glutamate?, here the immune system plays a key role? he is taking valproate. Valentina

    ReplyDelete
    Replies
    1. Valentina, I do not know the answer to that one.

      Delete
    2. Hi Valentina, the opposite might also be true. I know of a child who was treated by Dr. Mike Smith of Chicago Rush Hospital. He was given Depakote and steroids and in six months had a clean EEG and all medications were stopped. Incidentally, his near psychotic meltdowns also went away.

      Delete
    3. Thankyou Peter and RG, I will see if can get more info in this case.Valentina

      Delete
    4. Hi again Valentina,

      Did your son’s epileptiform EEG clear on valproate?

      In my son awake EEG improved on Bumetanide and his epileptiform sleep discharges disappeared now - he’s also on Diamox and mitochondrial support according to dr Kelley’s paper.

      Diamox has many interesting mechanisms of action and both Diamox and Bumetanide target neuronal chloride concentration (NKCC1 etc), Peter has written a lot about this.

      Chloride regulation in neurons seems affected by inflammation: “Concomitantly with the inflammation, changes in expression of NKCC1 and KCC2 co-transporters have been observed that resemble the immature brain”.

      http://www.epilepsybehavior.com/article/S1525-5050%2810%2900695-5/fulltext

      I think the infection/EEG relation is not that clear what can be seen in this report by Prof. Evangeliou team about a child whose intractable epilepsy and EEG improved much after acute GI infection:

      “Ketosis and EEG improvement following viral gastroenteritis in patient with West syndrome.”
      https://www.ncbi.nlm.nih.gov/pubmed/24479997

      So my reply to your question is not very practical, I am sorry, seems like I have the same questions. For the time being I appreciate the effects of the above treatments in my son without having all answers.

      Delete
    5. Agnieszka, how are you doing? I am glad to hear you! It seems that we have the same concerns, I wonder if we are the only ones in this blog whose sons have epileptiform discharges, not epilepsy. I really wanted to stop valproate but after doing a small trial with topiramate I returned to valproate,not only improves the EEG but also his behavior. Still, the upgaze appears from time to time, think that it is the hallmark of this discharges that are our sons share. Now it seems that he has a virus, he vomited and doesn't feel well. I don't know exactly but valproate could be excacerbating viral issues. I am thinking of adding acyclovir or another antiviral herb. Regarding Bumetanide,here can get acetazolamide, Diural, but I dont know if it is the same or if need a prescription. If I understood right Prof Evangeliou's papers,couldn't read the link properly, the improvement of epilepsy following acute viral infection, means that the virus had a positive immunological effect in epilepsy? perhaps you can e mail me.Valentina

      Delete
    6. Hi Valentina,

      My son has now best ever EEG - on acetazolamide (generic Diamox). Since April there has been almost no upgaze. Acetazolamide is used in calcium channelopathies and it was suggested that paroxysmal upgaze is oculomotor calcium channelopathy - maybe this explains what happened.

      Yes in Prof Evangeliou's paper they described a child whose epilepsy got better after viral infection and you can find more such reports. Among possible explanations they suggest immunological mechanisms, including anti-inflammatory cytokines (IL-10) or ketogenic effect of fasting during infection.

      Delete
  21. Hi Peter, wanted to tell you that I am very interested in investigating this theme, the role of inflamation, the immune system in the epileptiform state, I think that it is an area that hasn,t been well considered in autism, It is so related to my son that it scares me Valentina

    ReplyDelete
    Replies
    1. Valentina, I forgot to mention this earlier, the only definitive way I know of to look for viral or bacterial infection in the brain is through a lumbar puncture. The testing can be very detailed. A spinal tap can also yield a lot of other useful information that could guide overall treatment.

      Delete
  22. Off-topic Peter:

    Have you written any posts on Cyclosporine? Would be interesting what you think of this compound.


    Joel

    ReplyDelete
    Replies
    1. Joel, I have not written about it.

      As an immunosuppressant, I think it very likely that Cyclosporine will help some people with autism (the people that respond to TSO, perhaps the people that respond to very high dose Biogaia Gastrus etc). People with severe mastocytosis or severe ulcerative colitis and autism should ask about trying it.

      Cyclosporine does have plenty of side effects listed, so it will not be good for most people.

      Delete
    2. Cyclosporine not only has plenty of side effects listed, the drug actually has serious side effects and can cause severe infections with irreversible damage, as it's a potent immunosuppressant. So anybody who uses it has to be very careful about monitoring the side effects under medical supervision.

      Delete
    3. Kritika, some of the most interesting drugs are off limits due to side effects. Suramin and Rapamycin are examples.

      If you have severe ulcerative colitis you may already be on drugs with nasty side effects, like steroids.

      This comes back to linking the therapy to the severity of the autism (and comorbidities). Some people with severe autism + UC have aweful quality of life. The two conditions are linked.

      Delete
  23. Hi Peter,

    I recently learned from my psychiatrist that she is trying to get funding to test a research compound, OSU6162 on autistic patients. Hopefully I might be able to participate. Interestingly, it is among other things a partial agonist at the 5-ht2a receptor.
    Joel

    ReplyDelete
  24. Peter, do blood glutamate levels accurately reflect brain levels? I was reading a paper recently on estrogen and progesterone being neuroprotective by reducing glutamate levels and they tested this with blood levels. I was trying to figure out how to interpret this with regard to my daughter's catamenial epilepsy, since it is precisely on the high estrogen days that she has seizures.

    ReplyDelete
    Replies
    1. RG, I think you are just seeing the effect of natural steroids on the sub-unit expression of GABAa receptors. Remember that over the monthly cycle in females the structure of the GABa receptor actually changes, instead of anxiety, in your daughter the consequence is increased seizure risk.

      " In late diestrus (high-progesterone phase), enhanced expression of deltaGABA(A)Rs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. "

      Dancing the Delta Shuffle: Neurosteroids Regulate GABAA Receptor Expression
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1363372/

      So progesterone good, estrogen bad for seizures.

      Delete
  25. Hi Peter and fellow readers,
    My son is currently taking the following:
    MORNING BEFORE SCHOOL
    1mg Bumetanide
    1 PharmaNAC tablet
    0.1mg extended release Clonidine
    1 BioGaia Gastrus tablet
    AFTER SCHOOL
    1 PharmaNAC tablet
    5:00 PM
    0.1mg Bumetanide
    7:00 PM
    0.1mg Clonidine regular form (for sleep)

    1. He has been on the Bumetanide for nearly a month with no side effects, but no real gains.
    2. The NAC helps his vocal repetitiveness (repeating his weekly schedule over and over)
    3. BioGaia no side effects, no gains
    4. Clonidine helps with calming down his body and sleep

    Nothing seems to help his extreme anxiety. Our world has become so small. It is hard to go anywhere outside of school, therapy and the pool. He uses familiar movies as a lifeline and needs them 100% of the time outside of school/therapy.
    Can anyone suggest anything to help? I have tried essential oils (very temporary), SSRI's, beta blockers, even Benzos.
    Any ideas for supplements, drugs or testing is greatly appreciated.
    Thank you!!
    Christine

    ReplyDelete
    Replies
    1. If bumetanide doesn't seem to have much impact on GABA(A) expression then it may be worth exploring GABA(B) interventions like Baclofen or Pantogram Aktiv or reducing the glutamate side of the equation (why 0.1mg at 5pm btw?)

      Other interventions that occasionally work is Niacin (check flush) and the very easy Inositol (pretty much sugar).

      For us magnesium seemed to help, especially epsom salt baths?

      Delete
    2. Hi Christine,

      have you tried verapamil? 20mg once, sometimes twice, a day has done wonders here. Not so much for general anxiety (that is a very minor issue nowdays) as for near-eradication of debilitating fears that stuck around for many years.

      In the past we did have anxiety, it was helped by combination antihistamines, 5-htp and calming massage. Also I think a course of antibiotics for strep throat played a role. Something like Qigong massage for autism is easy to learn and can be done at home for free. The book+instruction dvd can be ordered on amazon.

      Also, how long has your son been on NAC for? It sometimes can take quite a while to show effect, but saying that there is not guarantee it will work for anxiety.

      Delete
    3. Em, what would you suggest to reduce the glutamate side of the equation?

      Verapamil seems a good idea, but there is a risk of interaction with clonidine.

      Delete
    4. Christine, what kind of autism does your son have? If it is more like Asperger's then Baclofen 5 to 10mg two or three times a day might help. If it is more like classic autism this dose may not help. Verapamil might help depending on what the underlying dysfunction is. The good thing is a verapamil trial needs just a day.

      Sometimes the comorbidities help to narrow down the options, things like allergies, GI issues, dermititis. Even physical things like height, weight, head size, which come down to growth being up or down regulated.

      Delete
    5. First, thank you SO much for everyone's reply.
      We have not tried Verapamil. Perhaps we should.
      We have been on NAC for about 3 months and as I said, it has helped with the OCD like part of repeating things.
      My son has classic autism -- development was always off. We tried Baclofen and he had no effects other than constipation.
      He has seasonal allergies that respond to claritin or Zyrtec. GI was an issue for most of his life. He cycled between constipation and diarrhea but that improved on Memantine. We discontinued using it this summer in order to see if he could sustain the improved GI without it and he has.
      I have never tried 5HTP. Calming massage helps a lot, but is very temporary.
      In terms of physical appearance he is skinny with very defined calf muscles due to being in constant motion and toe walking. Hair, skin and nails are normal. His head is maybe a bit larger than average, but not noticeably. He does have dark circles under his eyes for his age. No asthma or seizures. --Christine

      Delete
    6. Peter,
      I read your post about Biotin and Niacin and wonder which one you would recommend for reducing anxiety. I read up on the flushing potential with Niacin but think it can be avoided if the child is kept well hydrated and the dosing isn't too high. Biotin sounds more benign but wondering if it helps anxiety? Thanks as always!! Christine

      Delete
    7. Christine, I think your best bet now is a verapamil. Only a small number of people really benefit long term from biotin or niacin, or other B vitamins, there has to be an underlying relates dyfunction.

      Easier to obtain is the ZMA supplement that Tyler refers to in the first comments on this post. It has addressed anxiety in his child. The mechanism is quiet different to verapamil. It is a body builder supplement.

      Delete
    8. Thank you Peter.
      My son's doctor would prescribe Verapamil if I provided the research. He has allowed Memantine, Baclofen and Bumetanide off label.
      Do you think I should continue with Bumetanide? It has been about 3 1/2 weeks. Should I have seen the effect by now?
      In terms of Bumetanide, I remember you saying its effect seemed to make Monty more present and aware. My son's anxiety has increased a bit since we have been on it. Is it possible in your opinion, that with increased awareness a kid can become more anxious? Just a thought... If the child's awareness increases, but they still don't feel capable of expressing themselves or fitting in, might that cause a spike in anxiety? My thought is that it may take time for him to adjust to the new state of increased awareness???
      --Christine

      Delete
    9. Christine, does your son currently suffer from allergy ? If he does I would trial bumetanide again when he is allergy free. If he is allergy free I would give it another couple of weeks and reassess the situation.

      The increased awareness becomes higher IQ. So school should notice a cognitive change.

      There is no literature on verapamil and autism, just what is in this blog. There was a study in bipolar. Having GI problems may be one marker for verapamil use.

      Delete
    10. There is some literature out there on verapamil for anxiety and panic disorders, would you doctor be willing to prescribe on those grounds?

      I have just come across this super interesting article on ketamine for anxiety, agression ... also been talked about as helpful in severe depression and OCD

      http://www.npr.org/sections/health-shots/2013/03/25/174928768/how-an-unlikely-drug-helps-some-children-consumed-by-fear

      Delete
    11. Peter,

      What actually do you mean by cognition? It is definitely not the same as I.Q. Can cognition be measured?

      My limited understanding says that increased cognitive ability should enhance functionality which might or might not be related to a higher IQ.

      What do you think of cognition in a person who has genius level IQ but crippling anxiety and sensory issues make him absolutely non functional.

      I really am confused about this and I hope I do not have to deal with anxious behaviour that cannot be reasoned out, and a not so smart but a relaxed, functional infividual would be my choice, if I had to make one.

      Delete
    12. Christine, here are several on Verapamil for treatment of panic disorder and mania/anxiety, including anxiety-reducing effects in schizophrenic patients:

      http://www.sciencedirect.com/science/article/pii/0278584691900659

      http://ajp.psychiatryonline.org/doi/abs/10.1176/ajp.145.4.431

      http://psycnet.apa.org/psycinfo/1985-12636-001

      Anxious mice and calcium blockers:

      http://medind.nic.in/ibi/t01/i4/ibit01i4p267.pdfhttp://europepmc.org/abstract/med/9653816
      http://europepmc.org/abstract/med/18195452

      hth

      Delete
    13. Peter and Nat, thank you for your help! Kritika, thank you for your thoughts as well. I tend to agree that a person's crippling anxiety can impede them from being able to demonstrate what they are capable of if not for the constant state of worry and fight or flight.
      I will review all of the articles above -- really appreciate it!
      Peter, my son has had a bit of a runny nose and coughing the past month, and I have been giving him claritin which is helping. I think I will continue with Bumetanide for another month and perhaps by November the allergies will subside and we can get a better idea of the effects of Bumetanide.
      --Christine

      Delete
    14. Christine, have you thought about candida? My son had terrible anxiety and dark circles under his eyes until we started an anti candida protocol. He'd never had a lot of yeast flares, just one or two, but he stimmed a lot and was always very tense and anxious when his routine was interrupted. What we do is rather involved but if you are interested in details please let me know. Surprisingly candida turned out to be a big underlying problem so for the past two weeks we have been doing the "detox" and the results have been dramatically reduced anxiety, improved skin/hair and no more dark circles, etc. BIG desire to start talking more and saying new words despite motor issues. It's been a longer than usual process, especially with all the die off symptoms, and there are quite a few. Last month, prior to the candida detox we'd started a large dose of Klaire Therbiotic powder (100 billion) and another large dose L. reuteri probiotic separately. He did tremendously well with the bigger doses and the additional detox has only made things better. However, all that said, my son does not have severe autism. His issues are mostly from birth/neonatal insults and include apraxia, SPD, and the ever present food allergies due to "leaky gut" from overuse of antiobiotics in infancy. Literally, probiotics have made the greatest impact on recovering my son and there are so many studies, as Peter has put forth, now proving the influence of gut bacteria on neurochemical balance and brain function. It's astounding. The L. Reuteri we use is a product available on amazon, Microbiome, and it's a much larger dose than the drops but it has definitely made my son a much happier, more engaged little person and communication is now no longer an issue. It opened his world up to others in so many ways. And if you haven't tried it, broccoli sprout powder may do wonders, it did for us last spring. Much better mood, reduced ox stress, etc. I loved it and wanted to keep it in our arsenal forever but my son decided he hated the taste and now rejects anytime I give it to him in a sippy cup (he's 3). It was the first real biomed that actually worked with no side effects, other than a funky smell/taste. Hope you find something that helps soon! :)
      MKate

      Delete
    15. Hi MKate,
      I see some similarities with my son, so I'm interested in some details!
      We saw some improvement as well with probiotics (vivomixx in our case).
      Thanks

      Delete
    16. MKate,
      I really appreciate your response!
      I would say that my son falls directly in the middle of the spectrum. He is verbal (mostly to get needs/wants met and scripting from movies). He is never aggressive. His issues are mainly verbal repetition -- incessant repeating of his daily and weekly schedule and when holding a device (iPad) saying over and over "I have the iPad". He struggles with transitions (increased agitation). He doesn't engage with toys. He watches familiar movies in his downtime and struggles to part from them. His sleep is erratic. He has a lot of dyfluency when he tries to talk and it causes him to speak much too loudly in order to get his words out. He likes being around his peers, but doesn't know how to engage so he asks for hugs from them (which they very warmly oblige). He is able to do basic math -- subsitizing numbers to 10. Composing/decomposing numbers up to 10, etc... He can read at about a 1st or 2nd grade level but is very anxious and struggles to make true meaning out of language unless he has had an emotional experience tied to the language. His fine motor skills are very weak. He is potty trained. His GI issues have been gone for several years. He is rarely sick and is a handsome/fit 12 year old boy.
      In terms of candida, I don't know what to think. There was a time many years ago that we tried Diflucan and Nystatin and they did nothing. He is now taking BioGaia Gastrus (per this blog) and I'm not sure if it is doing anything. I feel it can't hurt. I had tried the broccoli sprouts (Enduracell) and they seemed to help for a time and then stopped. Perhaps I should try again.
      Yesterday his anxiety was SO bad that I had to give him a 1/2 Clonidine and 1/2 Lorazapam along with some Rescue Remedy in order to help him calm down. About 10 minutes later he was good and ready to sit down for homework. I don't however feel like Benzos are a good long term choice (only in really tough times).
      Again, keep the suggestions coming. I will rethink candida. I appreciate you taking the time to write.
      --Christine

      Delete
  26. Peter, do you think that baclofen could work in my son? here it is called Diafen, with valproate has any interaction? do you get it without prescription? Valentina

    ReplyDelete
    Replies
    1. Valentina, based on comments on this blog, including from a UK paediatrician, people with Aspergers-type autism are more than 50% likely to respond to moderate doses of baclofen. This is a huge response rate yet there are no clinical trials.

      It is a prescription drug but that paediatrician had no problems with side effects or tolerance. More usually higher doses are given.

      You have to ask your doctor about interactions with other drugs.

      Delete
  27. The best tasting NAC imo is Jarrow NAC Sustain, which also needs a lower dosage for the same effect from our trials.

    ReplyDelete
    Replies
    1. I agree it is the best NAC, and not the most expensive. They now make ALA sustain which may be interesting for people using alpha lipoic acid

      Delete
    2. How do you give J. NAC Sustain to your kids? The tablets are quite big and seem difficult to swallow?

      Delete
    3. I had always assumed swallowing pills would be an issue, so always avoided it. Some people wisely teach their kids to swallow pills. At the age of 10, I discovered my son has no problem whatsoever swallowing pills. Giant NAC sustain pills get swallowed down even with no water. So I may be better at tying shoe laces, but he is the master pill swallower.

      I think if you start with small pills and then starting giving bigger ones, it becomes achievable. The same is true with liquids you can start with something OK tasting and gradually add less nice things and in the end you are very happy to drink broccoli "juice" medicine.

      This is true with brushing teeth and dentists, as I just read in another blog. Giving up is the easy option and then you will have a adult who cannot brush his teeth and goes to hospital to patch up his teeth one a year. Soon therafter he will have no teeth. I was really surprised people give up on brushing teeth. I can understand blood draws being a struggle, but even that can be overcome and become routine.

      Delete
    4. Hello Peter,

      After being on NAC 600 mg, three times a day for two days, my son developed lot of uncomfortable gas and I was compelled to skip his last 600mg today. I feel behavioural issues brought about by stomach discomfort may outweigh NAC s benefits under the circumstances. Should I go slow, lower the dose?

      Actually, we are having aberrant weather conditions in Delhi, with high humidity levels and heat unusual for this time of the year. Most people are on the edge and not feeling too comfortable and therefore it would become more difficult to segregate NACs effects on son's behaviour especially in absence of stereotypy and OCD, which would have been easier to assess.

      I also have a nagging doubt that drugs which take a long time to bring about minor changes in variables which are assessed subjectively might not really be very effective. I feel the improvement should either be rapid, taking not more than 10-15 days, significant and/or measurable or quantifiable. I might be wrong.

      Peter, since you asked Christine for a physical description of her son, I thought i might offer mine as well. My son is a pleasant looking child with healthy, fast growing hair and nails, clear skin, clean well set teeth, sparkling eyes, height and weight in the higher percentile, head large but not abnormally so, baby faced..not the hard lined one, slight hirsutism on the back and upper arms. Does that indicate upregulation of growth? What are the implications if you see any?

      And yes, teaching healthy habits like brushing teeth, washing hands, the good ones like cleaning up and putting things away, and the necessary ones like swallowing pills, tolerating blood draws, taking temperature can be procrastinated at your own peril. The later you do it, more difficult it will be. Although some times kids just learn when they are ready. And the trick is to be firm but responsive and always on the child's side.

      Delete
    5. Agnieszka, I missed this comment of yours earlier. Have you tried a special cup that trains to swallow. I have heard of parents using this successfully. Something like this:

      https://www.amazon.com/OralFlo-RC-02-Oralflo-Pill-Swallowing/dp/B000NJJ3C4/ref=sr_1_1_a_it?ie=UTF8&qid=1477020384&sr=8-1&keywords=pill+swallowing+cup

      I am not sure if it was this exact one or something similar.

      When my daughter was much younger and couldn't swallow pills, I used to mix especially funky meds in a bit of honey, scoop it up in my finger and put it in her mouth. The honey hits the middle of the tongue and is such a strong sweetness that pretty much all other tastes are buffered. Maybe worth trying with NAC.

      Delete
  28. Peter, I've always wanted to ask you this. With so many blood pressure meds, how do you handle Monty's blood pressure? Does it ever drop? Yesterday my son said that he didn't feel well and I found him low 6/9. He experienced dizziness and saw neurological symptoms such as facial spasm and risus sardonicus.
    I'm sure this can't be only due to Bumetanide. Behaviour was ok.

    ReplyDelete
    Replies
    1. Petra, Bumetanide lowers blood pressure by reducing the total amount of fluids in the body. If you drink additional water the fluid content will remain the same and there should be no effect on blood pressure. We have had no problems with this, but one parent did tell me that their child refused to drink extra fluids and then felt unwell. I think your son should try increasing his fluid intake.

      Delete
    2. Hello Petra,

      I have started giving my son NAC with mixed results.
      He never had serious behavioural issues but after NAC he seems a little unregulated mood wise..could be physical discomfort due to NAC or some independent cause, little upset but then back to happy, not zoned out but just loud from inside.. something bothering him.

      But cognitively, very responsive, almost learnt the vowels after few repetitions, a conscious effort to focus. Almost enjoying the process.

      Can you recall what immediate and long-term effects you had observed in your son with NAC. It would be of great help. And any negatives?

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    3. Hi Kritika,
      I am sorry to hear that your son is having side effects after giving Nac, I know how fragile people on the spectrum are.
      My son had a slight amygdalitis and took him weeks to recover.
      I am not sure if I can help you with all your meaningful questions, still remaining with no definite answers.
      I sometimes think that if I knew how Nac affects my son, I may have solved the mystery of his didorder.
      My son used Nac while recovering from an operation and being a complete wreck. At that time doctor advised us not to use medicines for a better outcome, but he was on painkillers almost every day and I know Nac helped him detoxify.
      The outcome of the operation was excellent and even the doctor asked me what supplement I used in order to advise other patients on that.
      According to the facts I concluded that Nac is a great antioxidant with numerous properties.
      When it comes to behavioural changes, it certainly gave some long periods of stability, on the basis of survival, but on the other hand it failed to rescue periods of extreme build ups, where anxiety/OCD/cognitive dysfunction reoccured. I think it helped with SIB though, not as much with aggressiveness and mood swings.
      All in all, I would recommend moving on to Bumetanide and low dose Clonazepam for more stable results. Then you could see if Nac adds to the treatment.

      Delete
  29. Hello Peter,

    Yesterday and today my son was on 1200 mg NAC, after being on 600 mg and 1800 mg for three and two days, respectively. I plan to again increase to 1800 mg for three more days and watch. On Wednesday i have an appointment with his paed for his vaccination and for an preliminary examination to determine any physical problem. Probably I can ask him to write some basic tests before I start bumetanide.

    I hope NAC will not interfere with the vaccination.

    And for the behavioural update, he seems a little over the top, assertive, a little moody but overall happy, but pinching us hard when physically uncomfortable. He pinched me on getting an erection after waking up and then on getting an insect bite. He does not react with this kind of mild aggression on getting external injuries but I have noticed pain or irritation caused by internal causes make him really irritable. He also seems a bit itchy.

    But on the upside, he again laughed through his initial discomfort and tried to ignore his erection to focus on work. To my pleasant surprise, on asking what is b.a.g, m.a.g and t.a.g., words i have not taught him before, he could speak out the word correctively..he is using some phonetic logic. Also I was making him write numbers in order and and the good part is that after twenty when he started making mistakes, writing 27 after 25, the moment I pronounced 26, he immediately corrected his mistake. He was being alert and focussed. So there is this marginal increase in ability to stay on task.. NAC? I do not know.

    I am also concerned about his sensory issues..till two years of age we could easily take him to malls. Now Although he still enjoys the experience, cannot stay in one place for long and probably gets overwhelmed, thus making any purchase a rushed affair. Will he outgrow this stage?

    Getting impatient to try potassium-magnesium and bumetanide but i feel it's wiser to wait a few days, assess NAC, get the shots, electrolyte levels and then make the next move.

    ReplyDelete
  30. Hello Peter,

    I was concerned if NAC might, in some cases cause itching. My son seems to develop a little skin irritation on the areas which were earlier affected by insect bites or dried up little wounds. He is scratching those very areas with previous insults. I have run out of homeopathic med for allergies, it worked well for mild itchiness and was effective for about three to five hours. Should I give Allegra?

    Anybody else experience mild skin irritation with NAC?

    ReplyDelete
    Replies
    1. Kritika, NAC has a very short half so stop NAC for a day and see if the itching stops. Some people do not tolerate NAC, but most seem to have no negative reaction. If you google NAC + itching you will see that some people do indeed experience itching.

      Delete
    2. Hello Peter,

      I am not sure whether I should mention it here but after noticing certain cognitive improvements in my son, which my husband also observed (again a list which I will spare you) I thought I better share my apprehension here.

      When we started homeopathy on my son, one of the med given to my son was Nat sulphate, a detoxifier. And did my son improve! I remember in those early days, at night he used to pass wind at least once, smelling of H2S, exactly the same smell as with NAC and I took it as an indication of the drug being metabolized or assimilated and therefore effective. And indeed it was so. He is still on Nat sulf, but the smells have gone and so have the big jumps, perhaps indicative of tolerance. As with allopathic compounds, some kind of feedback mechanisms seem to be operating on all kinds of interventions and I have now a list of homeopathic drugs which worked for longer time, shorter durations or not at all.

      Now, my major concern is that I am definite, nac will stop working after time. Should I start pulsing it from now onwards or continue till I feel it has stopped working and then stop, give a break and restart.

      I think I am done with my querying about NAC and would like to thank you for being so patient.

      Delete
  31. Hello Peter, Angeiszka,

    Had read up NAC beneficial effects on autistic and nt individuals and also side effects.

    Could not find clear accounts of positives except for reduction in stereotypy, irritability and obsessive behaviour in autism. In someone, whose oxidative stress manifests as something different from the above commonly cited autistic behaviours, I wonder what would be the outcome.

    As for for the side effects, Candida and its behavioral impacts, a relation which this blog dismisses, stomach irritarion and mild itchiness have been reported as some of the common ones.

    In my son, I have finally nailed the behaviour I am observing. It's amplification. Every experience seems amplified, tiredness, happiness, erectile discomfort, itchiness, hyperactivity, responsiveness, naughtiness, attention seeking and demanding behaviour,even cognition and focus. He was laughing in his sleep.

    I do not know what to make of this. Or whether it's related to NAC at all. Probably I should have tried bumetsnide first as NAC is said to impact gaba and if gaba is working in an aberrant manner, the effects of NAC might not be optimum.

    Angeiszka, I believe you had also experienced mixed behaviours, especially hyperactivity in your child following NAC initiation and had similar apprehension. What do you have to say about mine and what is,the dose you are giving to your son who I believe is seven or eight.

    Sorry for incessant querying.

    ReplyDelete
    Replies
    1. Hi Kritika,
      I know you were speaking to Angeiszka, but I thought I would throw my two cents in as well.
      My son has been taking NAC for several months now. For the first several weeks he was also very gassy. I didn't get concerned because I figured it was just his body adjusting to a new supplement. I'm guessing it is likely to cause bloating or gas in many people who try it. Unless your son appears to be in real discomfort, I say let his body adjust.
      Initially it really helped my son's verbal repetitiveness. It's effects seem to be diminishing as (once again) his body is adjusting. We have seen this is medication as well. Like your son, my son has periods of behavioral amplification and I have seen that over the last week or two. It is all a guessing game. Is it allergies (Fall in Chicago can really stir them up)? Is it NAC?, Is it Bumetanide? Is it hormonal changes? Is it a growth spurt? Is it a hidden source of pain (tooth ache, splinter, etc...)? It is hard to say.
      My son takes (2) PharmaNAC effervescent tablets/day. I would say pull back on the NAC and see what happens. Try it again after a few weeks and see if the amplified behavior returns.
      One other thing to note (and this is difficult for us parents): Sometimes to get to the good outcome we have to allow our children's bodies some time to adjust and then integrate the neurological and physiological changes. You have to go through a period of adjustment prior to seeing the effects.
      That is what I am doing with Bumetanide.
      If you have never seen any positives with NAC, than perhaps it just isn't for your son. But, if you have seen any improvements and then they went away or something else popped up, it may be worth another trial down the line.
      Warmly,
      Christine

      Delete
    2. Hi Christine and Peter,

      Please keep on giving your valuable suggestions as I have just forayed into this area of medical interventions for autism, having spent the last two years concentrating mostly on various psycho behavioural therapies.

      I plan to continue fluimucil 600 tabs, morning and evening, for a longer time as I feel that is the only way I can assess it's overall impact. Of course, unless the side effects become unbearable. I know it's pretty subjective, howsoever clinical and objective assessment we may try to attempt. We are dealing with an individual who is psychologically and physiologically so sensitive and fluctuating that a baseline behaviour against which to assess improvement or deterioration becomes quite a difficult task.

      Now, this is where I am understanding what Peter has always meant about value of using cognitive measures as indicators of improvement. Not that they are very easy to quantify.

      Peter,

      My son's paed, whom I consulted today following an examination, felt that the penile discomfort might be resolved, most probably in three months time, once his foreskin starts retracting better and has advised certain simple topical treatments. We can only wait and hope the discomfort ends. We can keep on working on the excitability part simultaneously.

      Got him to write certain basic tests..he as well as I feel that chances of inborn errors of metabolism are rare as there are other indications ..well at least I will have some test results that might be helpful later on.

      Regards

      Delete
    3. Hello Peter,

      My son's basic blood works are in and everything seems perfect, cholesterol on the lower end, potassium on the higher end and rest almost in the middle. Only highlights wrere on Hb 11.9 and creatinine 0.33 mg/dl, probably because of vegetarian diet.

      Should I start bumetanide from tomorrow and with his high K+ levels, what do you suggest regarding supplementation. I am slightly nervous here.

      And FYI, I had stopped the NAC for two days and his slightly extreme behaviour continued but the slight cognitive enhancement was preserved as well.

      I am now really reflecting and introspecting about subtle psychodynamics at play here. Would you think it possible that expectation of improvement after an intervention raises the bar for a parent and the sheer parental confidence in the child's capacity is sort of sensed by him/her and then sets him for better success. Too esoteric a thought but sometimes it feels like that.

      Regards

      Delete
    4. Kritika, I would add potassium to his diet (a banana for example, contains about 400 mg of potassium); I am also giving 250mg potassium with each 1mg of bumetanide. You could just give two bananas a day extra, this is zero risk.

      People lose different amounts of potassium through diuresis, so there is no one-size-fits-all solution.

      It is best to use teacher or therapist feedback to assess interventions, just don't tell them you are trying something new. There is a big parental placebo effect.

      Delete
    5. Peter,

      My son stopped eating bananas..thinking of supplementing with 250 mg potassium plus prunes and an extra orange. Does that seem OK..are there any overt symptoms of K levels falling?

      Delete
    6. Kritika, there are symptoms:-muscle cramps, weakness, palpitations, or feel faint. One orange contains about 250mg of potassium, so better eat two.

      He also needs to add back all the fluid lost by diuresis, otherwise there will be other problems. My son drinks about 0.4 l extra per bumetanide pill.

      Delete
    7. Peter,

      Have given him 1mg burinex crushed in fruit juice..feeding him two oranges. Does that seem fine.

      It's been fifteen minutes...the pamphlet says peak diuresis should be over in one to two hours. I selected late evening for the first dose.

      Delete
    8. Hello Peter,

      My son did have good amount of diuresis..almost one and a half litre. Not very inconvenient as he is a cooperative child..drank sufficient water. His diuresis pattern almost pergectly followed the pharmacokinetic graph of the drug. Inititation of diuresis 30 min, peak between 1-2 hours and finally finished off in three hours.

      Now three hours is quite a lot of time so I will have to schedule it either at noon or evening, if that is alright.

      Please do tell me if I can supplement with a little amount of potassium-magnesium along, say around 100 mg K+, just to be on the safe side. Can that be harmful in any way? I was concerned about possibility of sudden fall in electrolyte levels with all that diuresis.

      Delete
    9. Kritika, the potassium supplement we use does also have a smaller amount of magnesium. It works fine for us.

      Delete
    10. My son's blood pressure dropped again yesterday, not as much this time, low normal I think and fortunately he told us that he was feeling dizzy.
      This happened in spite of his drinking with Bumetanide 2 glasses of water,1 big fresh orange juice, 2 cups of green tea, 1 big iced coffee and eating a banana.
      I've got a liquid supplement for intensive potassium therapy which is practical and cheap, 4.5 euros. I gave him a tablespoon equal to 780mg all together and a big bag of salty chrisps. Then he felt fine.
      Is it ok if I give something salty when blood pressure drops? Shall I add back magnesium?
      There is also something about coffee that I've noticed happening after Bumetanide. Before he didn't use to gain benefit out of a cup of coffee, but now he likes a little because it makes him feel more alerted.

      Delete
    11. Hi Petra,

      What would your advice be to me on precautions related to bumetanide use. It's been only two days but I am little in comfortable especially after reading your experience. Should I give around 250 mg K with 1mg bumetanide as a safety measure..his potassium levels are towards the higher side so i do not know what a safe conservative dose would be.


      Delete
    12. As I remember, after a few weeks on Bumetanide, my son's potassium dropped about 0.5, remaining in the normal to low means, but without supplementation, just through diet. I read, probably in this blog , that it's better to keep normal high levels, so I think 250 mg plus dietary seems safe. I suppose we need to measure during the first two/three months to adapt according to results.
      Doctor once told me that he didn't care about possible blood pressure drop, it can't bring irreversible damage, but I have to be careful in case he falls and has an accident. On the other hand there are so many old people on high doses of diuretics and never take extra potassium and can handle very well.

      Delete
    13. Petra,
      What do you mean in case he falls..my son is running, jumping , climbing and of course falling all the time. Please could you elaborate.

      Delete
    14. Kritika,
      I didn't mean to scare you.
      It's just an "if chain" referring specifically to my son, who has a medical history of orthostatic hypotension like symptoms.
      He has a hyperactive brain and a slow body and can't connect them both due to high levels of stress and other underlying unknown dysfunctions.
      I am not at all sure if Bumetanide causes this blood pressure drop, but it's blood pressure medication and I have to investigate by measuring regularly.
      The if chain goes like this: when blood pressure drops, people usually feel dizzy and if they feel dizzy, they may faint and if they faint, they might have an accident...and so on.

      Delete
  32. Hello Kritika,

    I think that you need to judge the intervention as generally helpful to continue it long term. If there are any unwanted effects, then the question is if they are disturbing enough to quit. You can stop NAC for a few days and see what happens. Sometimes it may be the only way to assess the individual response.

    I know some people who don't tolerate NAC, but never seen myself any serious issues or problems which would not resolve within few days after NAC withdrawal.

    NAC effects in my son were not immediate and rather mild in terms of behavioral changes. In fact I thought that it did not affect stereotypy in him until I quit and could see reemergence of hand flapping which I forgot at all. Irritability also returned then. So in our case two withdrawal trials helped to judge this intervention.

    I did not see clear relation (=without other factors potentially influencing behavior e.g. eating a packet of crayons) between NAC dose and hyperactivity while I definitely saw such using carnitine for example.

    I view influencing oxidative stress with NAC (if well tolerated) as a kind of long-term prophylactic intervention which may reduce the risk of various immune insults consequences or other drugs toxicity. This is just my unproven opinion based on NAC mechanisms of action.

    Fyi my son was tested for GI Candida overgrowth on several occasions with negative results. He has just turned nine and uses 1800-2400 mg daily. I also found NAC helpful myself.

    Hope this helps.

    ReplyDelete
    Replies
    1. Hello Petra, Angeiszka, Peter

      Your replies have been too helpful as I my thoughts are exactly the same as yours regarding NAC use ..giving a dose as a long term prophylactic at a level the effects due to discomfort do not outweigh the benefits. So for me after trialing one more day at 1800 mg, I will probably come down to 600 mg and then reassess after starting bumetanide.

      Amplification! As I mentioned earlier, sound sensitivity amplified..was covering his ears at the sound of traffic. Now whether it's a direct result of NAC or indirect effect due to stomach issues which cause sensory sensitivity on my son, is hard to say.

      But just now, I am back from a bad shopping experience where my son aggressively pinched the salesman. His stomach was bloated and gassy almost ballooned up, and I should not have taken him but I keep on pushing his boundaries which helps me assess his disregulation. This aggression was new for me and I asked him if his tummy was paining and he said 'ya'.

      I made him control his behaviour for some more time but after that the entire mall started becoming smelly..diffusion of gas!

      So basicslly, NAC's side effects which I find disruptive, I feel are not caused by some profound changes in the brain but simple physical discomfort. The amplification of intensity of sensory experiences I think I can handle and I remember the slight increase in focus I had observed had taken place at 600 mg. So after tomorrow I will lower the dose.

      I am so greatful for your responses. Cannot thank you enough.

      Delete
    2. Your son may have high sulphur sensitivity. It causes bloating and very smelly gas when NAC or similar sulphur compounds are given (eg ALA)

      Delete
    3. Em,

      My son consumes lot of sulfur rich vegetables and legumes with no signs of any serious sensitivity and in India we joke about diet related detective work as revealed by the noxiousness of the person's fumes. Sorry for being gross. Could the dose of nac be too high as I had moved rapidly up to 1800 mg.

      Gastrointestinal sensitivity to weather, food and sleep run in my family and in me it manifests as severe gasteroentitis twice a year with the turn of weather. So I was not reading too much into it except for 1800 mg being too big a dose to be without negative effects.

      Do you suggest quitting nac altogether or lowering the dose? Are the other kids on high dose NAC completely free of any digestive issues whatsoever? If they are, then it calls for reassessment of the decision to continue NAC.

      If indeed he is reacting to sulfur then out go my options of ala, nac and broccoli powder.

      Delete
  33. Hello Peter,

    Just read your observations about sensory exhilaration resulting in temporary elimination of autistic mannerisms.

    We too have observed, that not only sensory flooding, especially with those based on movement which might be a affecting vestibular and proprioceptive processing, but also sunlight and natural settings seem to normalize my son's behaviour.

    What might be happening..you have given some hormonal relationship. It also could be about vision. Shrinking of visual field and too much of visual input of the two dimensional kind? Movement sort of simulates and produces a wider visual field and a multi dimensional visual signal.

    Tyler had made a brilliant comment about our visual cortex adapted to process natural settings. Natural settings not only affect the visual senses but studies have shown better regulation of blood sugar, which was attributed to inhaled polycyclic aromatic hydrocarbons. Lowering of cortisol levels and boosting of immunity when with nature or even viewing a natural scene have all been established through research. Not to speak of sensory fulfilment that comes from handling nature..soil with the deep smell of humus, the meshy algae, green fragrant juices of crushed leaves and the crackle of dried leaves. It's a tragic loss of an entire way of subtle sensory living which could have been beneficial for our kids.


    ReplyDelete
  34. Hello Peter,
    I've found L rhamnosus GR-1 with L reuteri RC-14 probiotic.
    It's officially for vaginal infections. There is also research for men's urinary track and candida albicans.
    I've just taken one myself to see how it feels.
    Do you have any information about it? How similar would this be to L rhamnosus JB-1?

    ReplyDelete
    Replies
    1. Petra, it is just a case of trying it.

      I am going to try Lactobacillus reuteri NCIMB 30242 which looks interesting and is available.

      I will also try Lactobacillus Johnsonii which is sold without saying which type it is, some types have been shown to have very interesting effects.

      Delete
  35. I hope they add to your son's course of improvement...needless to say that you give me lots of homework.
    The thing is that I don't have an easy access to interesting types of probiotics in Greece. We have problems ordering abroad. I bought this one from Macedonia. Still I could go to great lengths to find the probiotics I need and that's a promise.
    It's too early to say but the one I referred to feels good, both in me and my son.

    ReplyDelete
  36. There is a probiotic company doing business in southeast Europe called JGL and I bought Lactogyn from them (Lrhamnosus GR-1+Lreuteri RC-14).
    They also have another product called Normia LGG+BB12. This is for intestinal health and immune system.

    ReplyDelete
    Replies
    1. Thanks Petra, they are from Croatia and make prescription drugs as well. They are much less expensive than western producers. Normia looks good as well, particularly for people with eczema and so likely asthma and then worth trying for some autism perhaps.

      Delete
  37. I am curious about this and what is going on with it in Children with Autism. It plays a role in a lot of what is talked about on this Blog. I wonder if environmental contaminates aren't playing a role here in some of what we are seeing going on with our children in terms of Glycine but I haven't found much. I have to add the broccoli sprouts powder but I am wondering if I can just grow the sprouts or would you have to eat so many sprouts that you my as well supplement..
    https://pubchem.ncbi.nlm.nih.gov/compound/glycine#section=Biomolecular-Interactions-and-Pathways

    ReplyDelete
    Replies
    1. You certainly can grow the sprouts. They do not taste bad, but I think most people find it less bother to buy the powder. The environment certainly plays a role. The immune system does not get exposed to the wide mix of bacteria because we are "too clean" and some of the very many chemicals introduced to the food chain probably have some negative effects. Like lead in gasoline used to lower the IQ of kids living near busy roads.

      Delete

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