Friday 21 April 2017

The Excitatory/Inhibitory Imbalance – GABAA stabilization via IP3R

This blog aims to synthesize the relevant parts of the research and make connections that point towards some potential therapeutic avenues.  Most researchers work in splendid isolation and concentrate on one extremely narrow area of interest.

The GABAA reset, not functional in some autism

On the one hand things are very simple, if the GABAA receptors function correctly and are inhibitory and the glutamate receptors (particularly NMDA and mGluRx) function correctly, there is harmony and a  perfect excitatory/inhibitory balance.

Unfortunately numerous different things can go wrong and you could write a book about each one.

As you dig deeper you see that the sub-unit make-up of GABAA receptors is not only critical but changes.  The plus side is that you can influence this.

Today we see that the receptors themselves are physically movable and sometimes get stuck in the “wrong place”. When the receptors cluster close together they produce a strong inhibitory effect, but continual activation of NMDA receptors by the neurotransmitter glutamate - as occurs naturally during learning and memory, or in epilepsy - leads to an excess of incoming calcium, which ultimately causes the receptors to become more spread out, reducing how much the neuron can be inhibited by GABA. There needs to be a mechanism to move the GABAA receptors back into their original clusters.

Very clever Japanese researchers have figured out the mechanism and to my surprise it involves one of those hubs, where strange things in autism seem to connect to, this time IP3R.

I guess the Japanese answer to my question above is simple. YES,

A very recent science-light article by Gargus on IP3:-

Now to the Japanese.

I wonder if Gargus has read the Japanese research, because both the cause and cure for the GABAA receptors dispersing and clustering is an increase in calcium and both mediated by glutamate.  

The excitatory neurotransmitter glutamate binds to the mGluR receptor and activates IP3 receptor-dependent calcium release and protein kinase C to promote clustering of GABAA receptors at the postsynaptic membrane - the place on a neuron that receives incoming neurotransmitters from connecting neurons.

If Professor Gargus is correct, and IPR3 does not work properly in autism, the GABAA receptors are likely not sitting there in nice neat clusters. As a result their inhibitory effect is reduced and neurons fire when they should not.

Gargus has found that in the types of autism he has investigated IP3 receptor open as they should, but close too fast and so do not release enough calcium from the cell’s internal calcium store (the endoplasmic reticulum).

In particular the Japanese researchers found that:-

“Stabilization of GABA synapses by mGluR-dependent Ca2+ release from IP3R via PKC”
If the IP3 receptor does not stay open as long as it should, not enough Ca2+ will be released and GABA synapses will not be stabilized. Then GABAA receptors will be diffused rather than being in neat clusters.

The science-light version of the Japanese study:-

Just as a thermostat is used to maintain a balanced temperature in a home, different biological processes maintain the balance of almost everything in our bodies, from temperature and oxygen to hormone and blood sugar levels. In our brains, maintaining the balance -- or homeostasis -- between excitation and inhibition within neural circuits is important throughout our lives, and now, researchers at the RIKEN Brain Science Institute and Nagoya University in Japan, and École Normale Supérieure in France have discovered how disturbed inhibitory connections are restored. Published in Cell Reports, the work shows how inhibitory synapses are stabilized when the neurotransmitter glutamate triggers stored calcium to be released from the endoplasmic reticulum in neurons.

"Imbalances in excitation and inhibition in the brain has been linked to several disorders," explains lead author Hiroko Bannai. "In particular, forms of epilepsy and even autism appear to be related to dysfunction in inhibitory connections."

One of the key molecules that regulates excitation/inhibition balance in the brain is the inhibitory neurotransmitter GABA. When GABA binds to GABAA receptors on the outside of a neuron, it prevents that neuron from sending signals to other neurons. The strength of the inhibition can change depending on how these receptors are spaced in the neuron's membrane.

While GABAA receptors are normally clustered together, continual neural activation of NMDA receptors by the neurotransmitter glutamate -- as occurs naturally during learning and memory, or in epilepsy -- leads to an excess of incoming calcium, which ultimately causes the receptors to become more spread out, reducing how much the neuron can be inhibited by GABA.

To combat this effect, the receptors are somehow continually re-clustered, which maintains the proper excitatory/inhibitory balance in the brain. To understand how this is accomplished, the team focused on another signaling pathway that also begins with glutamate, and is known to be important for brain development and the control of neuronal growth.

In this pathway glutamate binds to the mGluR receptor and leads to the release of calcium from internal storage into the neuron's internal environment. Using quantum dot-single particle tracking, the team was able to show that after release, this calcium interacts with protein kinase C to promote clustering of GABAA receptors at the postsynaptic membrane--the place on a neuron that receives incoming neurotransmitters from connecting neurons.

These findings show that glutamate activates distinct receptors and patterns of calcium signaling for opposing control of inhibitory GABA synapses.

Notes Bannai, "it was surprising that the same neurotransmitter that triggers GABAA receptor dispersion from the synapse, also plays a completely opposite role in stabilizing GABAA receptors, and that the processes use different calcium signaling pathways. This shows how complex our bodies are, achieving multiple functions by maximizing a limited number of biological molecules.

Pre-activation of the cluster-forming pathway completely prevented the dispersion of GABAA receptors that normally results from massive excitatory input, as occurs in status epilepticus -- a condition in which epileptic seizures follow one another without recover of consciousness. Bannai explains, "further study of the molecular mechanisms underlying the process we have uncovered could help develop treatments or preventative medication for pathological excitation-inhibition imbalances in the brain.

"The next step in understanding how balance is maintained in the brain is to investigate what controls which pathway is activated by glutamate. Most types of cells use calcium signals to achieve biological functions. On a more basic level, we believe that decoding these signals will help us understand a fundamental biological question: why and how are calcium signals involved in such a variety of biological phenomena?"

The full Japanese study:-

·        Bidirectional synaptic control system by glutamate and Ca2+ signaling

·        Stabilization of GABA synapses by mGluR-dependent Ca2+ release from IP3R via PKC

·        Synaptic GABAAR clusters stabilized through regulation of GABAAR lateral diffusion

·        Competition with an NMDAR-dependent Ca2+ pathway driving synaptic destabilization

GABAergic synaptic transmission regulates brain function by establishing the appropriate excitation-inhibition (E/I) balance in neural circuits. The structure and function of GABAergic synapses are sensitive to destabilization by impinging neurotransmitters. However, signaling mechanisms that promote the restorative homeostatic stabilization of GABAergic synapses remain unknown. Here, by quantum dot single-particle tracking, we characterize a signaling pathway that promotes the stability of GABAA receptor (GABAAR) postsynaptic organization. Slow metabotropic glutamate receptor signaling activates IP3 receptor-dependent calcium release and protein kinase C to promote GABAAR clustering and GABAergic transmission. This GABAAR stabilization pathway counteracts the rapid cluster dispersion caused by glutamate-driven NMDA receptor-dependent calcium influx and calcineurin dephosphorylation, including in conditions of pathological glutamate toxicity. These findings show that glutamate activates distinct receptors and spatiotemporal patterns of calcium signaling for opposing control of GABAergic synapses.

In this study, we demonstrate that the mGluR/IICR/PKC pathway stabilizes GABAergic synapses by constraining lateral diffusion and increasing clustering of GABAARs, without affecting the total number of GABAAR on the cell surface. This pathway defines a unique form of homeostatic regulation of GABAergic transmission under conditions of basal synaptic activity and during recovery from E/I imbalances. The study also highlights the ability of neurons to convert a single neurotransmitter (glutamate) into an asymmetric control system for synaptic efficacy using different calcium-signaling pathways.

The most striking conceptual finding in this study is that two distinct intracellular signaling pathways, NMDAR-driven Ca2+ influx and mGluR-driven Ca2+ release from the ER, effectively driven by the same neurotransmitter, glutamate, have an opposing impact on the stability and function of GABAergic synapses. Sustained Ca2+ influx through ionotropic glutamate receptor-dependent calcium signaling increases GABAAR lateral diffusion, thereby causing the dispersal of synaptic GABAAR, while tonic mGluR-mediated IICR restrains the diffusion of GABAAR, thus increasing its synaptic density. How can Ca2+ influx and IICR exert opposing effects on GABA synaptic structure? Our research indicates that each Ca2+ source activates a different Ca2+-dependent phosphatase/kinase: NMDAR-dependent Ca2+ influx activates calcineurin, while ER Ca2+ release activates PKC.

Taken together, these results lead us to propose the following model for bidirectional competitive regulation of GABAergic synapses by glutamate signaling. Phasic Ca2+ influx through NMDARs following sustained neuronal excitation or injury leads to the activation of calcineurin, overcoming PKC activity and relieving GABAAR diffusion constraints. In contrast, during the maintenance of GABAergic synaptic structures or the recovery from GABAAR dispersal, the ambient tonic mGluR/IICR pathway constrains GABAAR diffusion by PKC activity, overcoming basal calcineurin activity. One possible mechanism of dual regulation of GABAAR by Ca2+ is that each Ca2+-dependent enzyme has a unique sensitivity to the frequency and number of external glutamate release events and can act to decode neuronal inputs (Fujii et al., 2013xNonlinear decoding and asymmetric representation of neuronal input information by CaMKIIα and calcineurin. Fujii, H., Inoue, M., Okuno, H., Sano, Y., Takemoto-Kimura, S., Kitamura, K., Kano, M., and Bito, H. Cell Rep. 2013; 3: 978–987

Abstract | Full Text | Full Text PDF | PubMed | Scopus (24)See all References, Li et al., 2012xCalcium input frequency, duration and amplitude differentially modulate the relative activation of calcineurin and CaMKII. Li, L., Stefan, M.I., and Le Novère, N. PLoS ONE. 2012; 7: e43810

Crossref | PubMed | Scopus (29)See all References, Stefan et al., 2008xAn allosteric model of calmodulin explains differential activation of PP2B and CaMKII. Stefan, M.I., Edelstein, S.J., and Le Novère, N. Proc. Natl. Acad. Sci. USA. 2008; 105: 10768–10773

Crossref | PubMed | Scopus (44)See all References) in inhibitory synapses.

Tight control of E/I balance, the loss of which results in epilepsy and other brain and nervous system diseases/disorders, is dependent on GABAergic synaptic transmission (Mann and Paulsen, 2007xRole of GABAergic inhibition in hippocampal network oscillations. Mann, E.O. and Paulsen, O. Trends Neurosci. 2007; 30: 343–349

Abstract | Full Text | Full Text PDF | PubMed | Scopus (194)See all ReferencesMann and Paulsen, 2007). A recent study showed that the excitation-induced acceleration of GABAAR diffusion and subsequent dispersal of GABAARs from synapses is the cause of generalized epilepsy febrile seizure plus (GEFS+) syndrome (Bouthour et al., 2012xA human mutation in Gabrg2 associated with generalized epilepsy alters the membrane dynamics of GABAA receptors. Bouthour, W., Leroy, F., Emmanuelli, C., Carnaud, M., Dahan, M., Poncer, J.C., and Lévi, S. Cereb. Cortex. 2012; 22: 1542–1553

Crossref | PubMed | Scopus (14)See all ReferencesBouthour et al., 2012). Our results indicate that pre-activation of the mGluR/IICR pathway by DHPG could completely prevent the dispersion of synaptic GABAARs induced by massive excitatory input similar to status epilepticus. Thus, further study of the molecular mechanisms underlying the mGluR/IICR-dependent stabilization of GABAergic synapses via regulation of GABAAR lateral diffusion and synaptic transmission could be helpful in the prevention or treatment of pathological E/I imbalances, for example, in the recovery of GABAergic synapses from epileptic states

DHPG = group I mGluR agonist dihydroxyphenylglycine.

On a practical level you want to inhibit GABAA  dispersion and promote GABAA stabilization. How you might do this would depend on exactly what was the underlying problem.

If the problem is IP3R not releasing enough calcium, you might activate PKC in a different way or just increase the signal from Group 1 mGluR. If the problem is too much calcium influx through NMDA receptors due to excess glutamate, you could increase the re-uptake of glutamate, via GLT-1, using Riluzole.  You could block the flow of Ca2+ through NMDA receptors using an antagonist.

The Japanese used dihydroxyphenylglycine (DHPG) as their Group 1 mGluR agonist.  DHPG is an agonist of mGluR1 and mGluR5.  We have come across mGluR5 many times before in this blog.  Mavoglurant is an experimental drug candidate for the treatment of fragile X syndrome.  It is an antagonist of mGluR5.

We have seen many times before that there is both hypo and hyper function possible and indeed that fragile X is not necessarily a good model for autism.

The selective mGluR5 agonist CHPG protects against traumatic brain injury, which would indeed make sense. Although, that research suggests an entirely different mechanism.

The calcium released by IP3 works in complex way together with DAG (diacylglycerol ) to activate PKC (protein kinase C).

Ideally you would have enough calcium released from IP3, but you could also increase DAG. It depends which part of the process is rate-limiting.

Diacylglycerol (DAG) has been investigated extensively as a fat substitute due to its ability to suppress the accumulation of body fat.  Diglycerides, generally in a mix with monoglycerides are common food additives largely used as emulsifiers. In Europe, when used in food the mix is called E471.


On the one hand things are getting very complicated, but on the other we keep coming back to the same variables (IP3R, mGlur5, GABAA etc.).

It is pretty clear that some very personalized therapy will be needed.  Is it an mGlur5 agonist or antagonist? Or quite possibly neither, because in different parts of the brain it will have a good/bad effect.

It does look like Riluzole should work well in some people.

A safe IP3R agonist looks a possibility. As shown in the diagram earlier in this post,IP3 is usually made in situ, but agonists exist.

In effect autism could be the opposite of Huntington’s disease. In Huntington’s,  type 1 IP3 receptors are  more sensitive to IP3, which leads to the release of too much Ca2+ from the ER. The release of Ca2+ from the ER causes an increase in concentrations of Ca2+inside cells and in mitochondria.

According to Gargus we should have reduced concentrations of Ca2+inside cells in autism.

I suspect it is much more complicated in reality, because it is not just the absolute  level of Ca2+ but rather the flow of Ca2+; so it matters where it is coming from. I think we likely have impaired calcium channel activity of multiple types in autism and the actual level of intracellular calcium will not tell you much at all.

As the Japanese commented, it is surprising that glutamate is the neurotransmitter that controls the clustering, or not, of GABAA receptors.  This suggests that you cannot ignore glutamate and just “fix” GABA.


  1. I remember there was a study of Riluzole vs Placebo for ASD, but I can't find publications...

    1. Jane, if you click on "current projects" you can see that this researcher is doing several very interesting studies. They just seem to take a very long time.

    2. Hi Peter,

      First, thank you for a terrific blog post. I've learned a lot from this one. I'm trying to wrap my head around the opportunities that may arise from this (i.e. methods to impact IP3R, PKC, etc.)

      Also, I went on the site you linked at Holland Bloorview, and was really glad to see so much good research being done, and even happier to see it's being done here in Canada (and nearby enough to me that I'm signing up for the first clinical trial at Holland Bloorview that's applicable to my daughter).

      Finally, I had an idea Peter that I wanted to run by you. Would you consider doing an interview with Dr. Anagnostou, using your own questions and some submitted by the community, and then providing the transcript (or summary)as a blog post? I would suggest a call versus e-mail as she may say something that piques your interest, and you'll have the opportunity to go down avenues we hadn't foreseen.

      Just a suggestion, but if she's open to it, it would be super interesting and educational for all. From her background info on their site, she seems extremely well qualified, and may provide insights we otherwise may not have access to.

      Thanks Peter!


  2. Peter, about Gaba a5 you say that we may need inverse agonist. I don't know how relevant this may be but in the case of hepatic encephalopathy they used Flumazenil to reverse paradoxical behavioral activation by some benzodiazepines. It is a benzodiazepine antagonist and I thought I should let you know in case you see relevance.

  3. Wow this is a very complicated system and process Peter. Petra that is an interesting case. Personally, I notice that my son has many types of seizures with different sorts of triggers. Some of my sons seizures are related to a state of excitement. For example, he is on a swing and is happy and laughing excitedly as he is being pushed on the swing. Suddenly, I notice the laughing stops and a concerned look sweeps his face. We get off of the swing and he sits with me. I hear clicking in his throat and I know he is having a type of seizures. It is not tonic clonic but could have been. The ketogenic diet helps somehow to reduce the severity, duration of the seizures. I have to take all of these precautions and avoid these over heightened states of excitement but in our playing and enjoying ourselves, I sometimes forget. He is ok and has no post-ictal activity and does not need to sleep and it is a few seconds long. Then there are the seizures where it is a response to another altered state within in his body (illness, low blood sugar?, allergic response?)- with these it is more of a shock, I notice ear/s turning red, dialated pupils, fidgeting, eyes blinking and moving but mentally not there. Then there are the illness related seizures where the body temperature rises too high too fast and the compensatory mechanism is not working properly. I often wonder if the seizures have many different causes with him. The ketogenic diet helps with all of them except the ones related to body temperature spikes too high too fast. If he gets hot from being outside and the increase in temperature is slow then he is ok. He also gets seizures if there are multiple triggers excitement and temperature, and unknown physiological responses-molecular/biochemical cascade. I theorize the autism late speech regression (occurred at 3.5-4 years of age) was a neurologic injury that occurred with pharmaceuticals and adjuvants in XXXXX. The pharmaceutical VPA, and adjuvants xyz in the XXXX. I believe that the mutagenic x adjuvant changed the expression of gene/s that have to do with expressive speech and VPA likely could have contributed but in what way I don't know. I am not sure how VPA in pregnant mice contributes to autistic offspring. Now if you combine mutagenic adjuvent x in a developing brain with VPA what is the likelihood of injury? Also, this case (my child) had elevated levels of ammonia in his labwork. Because of the cognitive change (zombie stare, no response, inability to function in daily living, the elevated ammonia) we titrated off. After titrating off of VPA the layers of the onion soon revealed a different child. Now a child with both epilepsy and autism.

  4. Hi Tanya,

    Just a quick note to say thanks again for your response to my question about the P5P headaches my daughter was having. I started giving her Riboflavin based on your response, and have been titrating her P5P up. Today I gave her P5P doses pretty close to the ones that used to give her headaches ... and she didn't complain of anything. I've been giving her increasing doses for days (with Riboflavin, after having started Riboflavin by itself)

    I'll see how she's doing as time goes by, but it looks like you were right! Not only am I happy about being able to give her P5P, but doubly happy as we may be addressing something we didn't even know she may be suffering from, which is that she may have been low on Riboflavin.

    So a big heartfelt thanks Tanya, for responding to my question, with what looks like great advice!

    Hope you have a great rest of your weekend!


    1. Hi AJ, I'm glad to hear it is helping your daughter too!

  5. Peter, I am quite sure that, at least in my son's case, there is calcium dysfunction.
    This presents as some kind of hypocalcemia induced seizure and may lead him have muscle contractions mainly in his hands. I think hand flapping may be also connected to this.
    According to the doctor this can't be a permanent hypocalcemia as it would need high amounts of calcium for him to recover the incident and he seems to recover without it. As you mention serum calcium may be normal during blood tests.
    I wonder if this "hypocalcemia" has something to do with sodium dysfunction because salty food can sometimes rescue part of the episode.
    Autistic behaviours such as stimming, freezing, inability to express what is happening and sensory overload come together with extremely cold feet obviously with bad circulation and bath salts relieve him.
    If anyone on this blog has experience with such behaviours, I would be grateful to have his feedback.

    1. Petra, does your son have histamine/mast cells issues? Just anectdotal info. to share here, but many consider salt, esp sea salt, as a natural antihistamine - so it's interesting at tmes you see some relief with salt. Also , the cold feed - Raynaud's ? Many people in the histamine and mast cell groups have this symptom. My son finds instant relief too with bath salts as well as a soak in a baking soda (bicarbonate sodium) baths.

    2. Hi Tanya, thanks for your response.
      Yes, my son occasionally shows signs of allergy such as rhinitis and eye allergy. I didn't know that sea salt is a natural antihistamine. There are nasal products with sea water and I am going to find out.
      I use baking soda soak every evening because otherwise he cannot overcome cold feet discomfort.
      I also made an appointment with a rheumatologist to investigate it further.
      I'll let you know what happens.
      Tanya, have you ever considered using fluoxetine for OCD? I think it can help considerably. It's extremely difficult to escape OCD whithout medication.

    3. And the baking soda ia also a natural antihistamine remedy too - it helps when my son is having a food senstivity reaction as well as for hives. Have you ever tried any mast cell stabilizers? Are you suspecting dysautonomia/ POTS (Postural Orthostatic Tachycardia) as far as the cold feet symptoms go? I know so many people with mast cell activation have this issue. My son at one point had blood pooling in his hand. I think it is a good idea to check in with a rheumatologist. Yes please keep me posted what happens. You are right - OCD is tough. We did try fluoxetine - briefly. I tried it to be diplomatic with his doctor - she really insisted giving a tiny dose a short trial and I reluctantly agreed because I figured I had to give her suggestions a try if I wanted her to be open to trying other things I have read on Peter's blog. I stopped after two weeks. The tiniest of dose made my son just want to stay in bed all day. I really do feel a lot of his OCD moments are connected to histamine/mast cell activation. He does have trauma related anxiety that is situational with certain triggers (school, anyone who acts like a behavior therapist to him). Stress is a huge mast cell trigger for him - if not the biggest. When he had the issue with the blood pooling that was actually a year ago when he was still in school. I have been staying on track and focusing on mast cell/histamine treatments specifically b6 and his symptoms are steadily improving. Also avoiding stress triggers (so he's being homeschooled) I just had to figure out the effective way to dose those B's for him (without b12 and folate) and other supports and it appears to be making a difference. slow and steady and giving things time. I was considering the low dose clonazepam if that might in some way help with trigger type of anxiety but at this time I'm not interested in putting him back in school just to see if it works. Just do not want to rock the boat now...

    4. Tanya and Petra, my son shows this behaviors, OCD, anxiety , fears,sensory overload,hand clapping when he is engaged or very interested or sensory overloaded, not hand flapping. He is doing histidine, and low dose b6.

    5. Valentina, I presume you have seen the research on histamine/histidine and tics/Tourette's. If not here are some links.

      Histidine decarboxylase deficiency causes Tourette syndrome: parallel findings in humans and mice

      Histamine control of Tourette syndrome

  6. Hi Peter, does bumetamide fit anywhere into this since it has a GABA effect (although due to chloride not calcium)?

    1. It all gets called E/I imbalance, but it is a different dysfunction to the one that bumetanide treats.

  7. For anyone interested in perhaps an alternative way of modulating the endocannabinoid system without actually ingesting/smoking cannabis or synthetic cannabinoids, some very interesting research came out today that shows that TRPV1 agonists will cause endogenous production of anandamide (an endogenous cannabinoid) which then recruits a specific type of macrophage which regulates the immune system into downregulating inflammation in the gut.

    Press Release:


    In autism, gut inflammation is more often than not comorbid with autism (greater than 50% in one study I remember). Also, there is evidence that a hyperactive immune system can compromise the health of someone with autism both in the gut and the brain to the point that anti-inflammatory substances/drugs, antioxidants, and endogenous antioxidant support (B-vitamins, etc.) can really make a big difference in those with autism.

    One anecdotal and strange thing about my son is that he absolutely loves salsa even though he won't touch pretty much any other vegetable unless it has salsa on it (like on a burrito bowl). Recently, my wife will buy salsa for herself and unless she hides it well, my son will open the salsa and eat it like crazy just with his hands. The salsa is not very hot, but I wonder if he would like that salsa even more because if he gets some gastrointestinal relief from capsaicin, he may find consuming large quantities of salsa to be pleasurable in that way. Of course, I love hot and spicy food myself and can easily knock down the hottest chicken wings BW3's has and I even get a bit of a buzz from it all (maybe these endogenous cannabinoids have something to do with it), just that 12 hours later I am usually regretting all the super spicy chicken wings I just ate for reasons that do not need explaining.

    Really, I am just scratching my head in light of this research because my son absolutely avoids vegetables, but he will knock down plain salsa (no chips) like crazy and I wonder if this research might explain why. Maybe I should give him Huevo Rancheros for breakfast everyday (he loves eggs too) or just let him dive into the salsa liberally at every meal and see if it helps/hurts his symptoms.

    It is odd because sometimes pizza sauce will make him hyper but that could just be because of the extremely high sugar content most pizza sauces contain.

    Does anyone else have a child with autism who also has a strange salsa/capsaicin spicy food preference?

    1. Tyler,

      My son loves spicy food as well and gorges on those savory spiced mixes which we in India call 'namkeen', especially the 'navratan' mix, a standard snack and loyal tea time companion in Indian households. Namkeen literally translates into salty and 'navratan' means nine gems so it includes grain legume mix with generous helping of spices. My son also has some kind of dietary wisdom and keeps on varying preferences from sweet and chocolaty to hot and spicy to light and fruity depending on his bodily requirements. So I let him decide. As for spicy, I can't survive without the very very hot spices, raw green chillies, cinnamon, cardamom, black pepper and hedonistic pursuits aside, if I go without my dose of spices and condiments for long, I end up with a bad headache...and it's linked to digestive issues and blood circulation I guess. So it's a case of spirit desires and the flesh does too. Of course, capsacin is known to increase bioavailability of certain nutrients and things might be acting synergistically. Therefore you do have a point there.

      Tyler, I would be grateful if you could tell me the amount of perilla oil which I should start with for my son. He is five, 24 kg. I am particularly concerned about the rosmarinic acid which is supposed to act beneficially at a low concentration and might affect one adversely at higher quantities. I also want to share that like your kids, mine also has problems with sleep, basically sleep initiation which seems to have been genetically passed on from me where when the world around you slows down preparing for slumber, you feel all ready for action. This has a major downside when you are inhabiting an early to bed and early to rise world and its painful to force him out of bed at six thirty in the morning. Feel tempted to try melatonin but not feeling comfortable. I have started giving him magnesium glycinate, 100 MG Bill dailg...too early to say anything but I feel it gives me as I consumed it too, some bad kind of feeling..gut as well brain. Any tips about how to manage sleep issues would helpful.

  8. I use capsaicin, red pepper flakes, on top of food because my son loves it and I know it's helpful for nociception.
    I would like to modulate endocannabinoid system without cannabis for it's anti-inflammatory potential and many times thought we might need an agonist to fight inflammation particularly arthritis like symptoms.
    On the other hand its signaling modulates anxiety and I am not quite sure if an agonist or an antagonist would help. I mean that there are people who find cannabis anxiolytic, but some others can have panic attacks and become too self conscious, if you know what I mean. It's not as easy as to give cannabis and that's fine, it needs clever modulation.
    If you have any ideas, please let us know.

  9. Hi Valentina thanks for sharing. Have you seen improvements in those symptoms since starting histidine? Are you giving zinc with it? I have not tried histidine yet.

    1. Tanya, I answered you in the current post about Zinc, I had lost your comment!

    2. yes I saw - thank you Valentina! I think I will give histidine with zinc a try soon. I am glad it stopped your son's tics


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