New Experiments With Gluten

So I was feeling pretty good before my gluten experiment…..circadian rhythm was good – sleeping at 10 and waking up at 6AM…

My cells were filled with DHA, I had adequate vitamin A, D3 and a bunch of supplements to restore oral tolerance.

Anyway, I had some gluten over the weekend and then again earlier in the week – like 1/5th of a piece of bread and some other lectins….and it messed me up, big time.

This is even though I went to a GI doc and I tested negative for all of the antibodies associated with Celiac’s disease.

My memory went down, my mood became unstable and anxiety and fatigue went up.  Processing capacity went down and I had a hard time understanding normal speed audio.  The motor function also declined.  I also got a nice reminder that I used to have to deal with joint pain. My circadian rhythm got wrecked and my sleep was shitty, too.

I realized my glutamate levels were spiking and the OCD was coming back.  And then it hit me like a light bulb, in my gluten-induced haze.

Glutamic Acid Decarboxylase (GAD).

Glutamic Acid Decarboxylase converts glutamate to GABA.

If this protein isn’t working, you’ll have excess glutamate and too little GABA in various brain regions.   Glutamate is the main excitatory neurotransmitter and GABA is the main inhibitory neurotransmitter.

I then wondered whether gluten attacks Glutamic Acid Decarboxylase in susceptible people, and it seems like there is a connection (R, R2).

GAD antibodies decrease the GAD enzyme, which results in higher Glutamate and lower GABA.  The problem is getting off of gluten, casein, yeast or lectins doesn’t necessarily immediately reverse that right away.  I also don’t think that GAD antibodies are required for the problems, as other explanations are also adequate.

So I think it would be a good idea to check GAD antibodies after gluten consumption.

Interestingly, Vitamin D, particularly the active form (calcitriol) increases GAD67 and increases GABA (R), which may be one mechanism by which I felt relaxed when I took a mega dose of vitamin D3.

Where is Glutamate Decarboxylase/GAD Found?

Gluten, GAD, and The Pancreas

GAD (65+67) is found in your pancreas, where it’s needed for the release of insulin (R).  This could be one reason why we see the thin and anxious phenotype.  High glutamate and low insulin.  Glutamic acid decarboxylase is the common theme.

GAD67, which converts glutamate to GABA, is found in the hypothalamus, cerebellum (which controls motor function) (R) and various brain regions.

Gluten and The Circadian Rhythm

I’ve known people were dealing with circadian rhythm issues and that this was a root cause.

My explanation was because of stress-induced changes in the Per1 clock gene (R).  I also thought that undermethylation was not making the circadian rhythm work properly (R).  I’m still a fan of these theories, but I’d like to drop this new theory, which is significant for some people.

And for me, this could be the most significant because I was taking methylation supplements, was not stressed and my circadian rhythm was still affected. How?

In the hypothalamus, GAD (65+67) is found in the Suprachiasmatic Nucleus (SCN) (R), where GABA plays a central role in the circadian rhythm (R).

This means lower GAD will mess up your circadian rhythm, which will make you feel sleepy during the day, wired at night and cause you to get shitty sleep, among other symptoms.  I went to sleep later, slept 8 hours, but woke up feeling unrested.

Gluten, OCD, and Anxiety: The Role of CRH and Glutamate

headache_142814494

Glutamate is the neurotransmitter that causes OCD, or an inability to let go, and generalized anxiety.  That’s why magnesium, NAC, and memantine are  the best for OCD.

GAD is found in the Paraventricular Nucleus (PVN) of the hypothalamus, and lower levels of this are associated with depression by increasing CRH (R).

But why do people release CRH? I thought one of the main reasons was because people were undermethylated, which leads to increased CRH production.  Too little methylation of the CRH promoter (CRE), a region critical for CRH production, is a mechanism for the increased CRH response to stress in depressed rats (R). Undermethylation may possibly also cause lower GAD67 (at least in  the prefrontal cortex), which is unexpected (R).

That’s probably why we see MTHFR mutations associated with stressed and depressed phenotypes.

I also thought it was because of genes related to an increased stress response, of which there are many in 23andme that I’ve been researching.

I still believe in these causes, but now I realize that lower GAD from antibodies or general inflammation caused by gluten, casein, lectins, etc… could be a very significant cause for some people.

My stress response goes off to gluten and some lectins.  I thought that may have had to do with increased CCK being released by lectins, but this new explanation is an alternative explanation.

The Paraventricular Nucleus (PVN) plays a role in Fatigue, Glucose sensing, Blood pressure, Temperature regulation, TRH release, Anti-Diuretic Hormone release (vasopressin), PRH release (precursor to prolactin) and Oxytocin.

In my clients, I see fatigue, low blood pressure, problems with glucose sensing, cold intolerance, lower ADH and perhaps lower oxytocin.

Studies show anxiety and depression are associated with gluten intolerance. Celiac patients were significantly more likely to have depression, state anxiety, social phobia, a panic disorder when compared to controls (R).

Gluten, Cognitive Dysfunction and Being In Your Head

brain_133874900

GAD67 is located in the prefrontal cortex (R), an area responsible for higher level cognitive function.  GAD67 is lower in Schizophrenia, in part from under-methylation (R).  Schizophrenia is often caused by gluten.  The prevalence of schizophrenia was lower in areas of lower grain consumption and a milk- and cereal-free diet improved schizophrenic symptoms (R).  Indeed, GAD antibodies are higher in schizophrenia (R).

If you’ve got lower GAD levels, this area will be overexcited, which means you won’t be able to focus, you will have anxiety and excessive analyzing.  You will not be able to shut down your analytical thinking.  You will be in your head.

ADHD symptoms were overrepresented in Celiacs and a 6-month gluten-free diet improved ADHD symptoms in 74% of these people (R).

Gluten, The Hippocampus, and Memory

GAD67 enzymes are located in the hippocampus and lower levels will cause over excitation, which may explain memory problems in the long term (R).

Prevalence of GAD Antibodies

My only problem with this theory is that the prevalence of these GAD antibodies are less than I would’ve expected.   I would like to check to see if my antibodies are high.

But, nevertheless, this can explain many of the issues with people who have Gluten Sensitivity or Celiacs.

In a study done in 2001, the prevalence of GAD65 Antibodies was around 5% in patients with neurological disease vs 1% of controls.  Prevalence of GAD67 Antibodies was 2% in patients with neurological disease vs 1% of controls (R).

In conditions connected with gluten, 86% patients with Stiff Person Syndrome were positive for anti-GAD antibodies, 11% for patients with idiopathic sporadic ataxia, and 40% for patients with gluten ataxia, and 60% for type 1 diabetes.  The study concludes that there’s a link with gluten-related diseases and GAD antibodies (R).

Confounding Variables

Gliadin has the capacity to activate cytokine production in monocytes and macrophages.  In mouse macrophages, gliadin increased TNFα, IL-12, IL-15, IFN-βiNOS, IP-10, and MCP-5.  It also stimulated lymphocytes (R).

TNF, Interferon gamma, and IL-1b inhibit GAD65 and GAD67 in rat pancreas cells (R).  It could be that gluten is causing systemic or local inflammation and that’s causing decreased GAD levels.

In Non-Celiac Gluten Sensitivity,  researchers found that mucosal TLR1, TLR2, and TLR4, which are associated with innate immunity, were elevated (but this requires a biopsy, which is invasive and not even available) (R).

It could be other people have different effects from different antibodies.  Gluten is associated with anti-ganglioside antibodies and TG6 in celiac’s disease, both of which are important for neurons (R).

It’s possible that gluten is messing with neurotransmitters. After 1 year on a gluten-free diet, patients with Celiac’s experienced a significant increase in major serotonin and dopamine metabolite concentrations (R).

Glutamate Decarboxylase/GAD SNPs

SelfDecode is the best gene analyzer around and helps you interpret your genetics from 23andme and ancestry

You might want to check if you have SNPs for lower GAD levels.

GAD1 is the gene that codes for GAD67 and the GAD2 gene codes for GAD65.

GAD1/GAD67 converts glutamate to GABA (R).

Rs3749034 – GAD1

The G allele=reduced GAD1 production in the DLPFC and hippocampus among people with schizophrenia….. by disrupting a binding site for two transcription factors (R).

GG=significant decrease in KCC2 (gene that helps GABA) production in the hippocampus (p < 0.004), compared with minor allele carriers.

GG= a robust reduction of cortical thickness in the left parahippocampal gyrus (PHG) (R).

Cortical thickness reductions of GG were only found in people with the COMT Val158Met versions of AG and GG, but not AA (R).

A g=increased risk of schizophrenia (R).

The T or the minor allele is associated with panic disorder (only in females) (R).

Rs3828275 GAD1….

TT is associated with post-traumatic seizures….which likely means higher glutamate and less GABA….CT is associated with intermediate glutamate levels (R).

Figure 1
http://www.ncbi.nlm.nih.gov/pubmed/22840783?dopt=Abstract

Rs1978340 GAD1 G>A

A=lower GAD1 (R).

AA=increased GABA levels (R).

Since GAD1 levels are believed to be lower with the A allele, the study speculates that GABA production by the GAD1 gene is actually reduced in the A allele carriers and that a compensatory change such as excessive production by GAD2 or a decreased breakdown by GABA transaminase may be causing this unpredicted increase in GABA (R).

The compensation could also be occurring in certain places that were tested, whereas others may be decreased but their techniques may not have been sensitive enough to detect it, or it could be that GABA is present in cells, but still result in a relative deficit of GABA synaptic transmission (R).

Rs3791878 GAD1

GG is associated with post-traumatic seizures…which likely means higher glutamate, less GABA….GT is associated with intermediate glutamate levels (R).

rs769391 GAD1….

Not on my 23andme. AA is associated with post-traumatic seizures…which means higher glutamate and less GABA….AG and GG are equally normal (R).

Figure 2

http://www.ncbi.nlm.nih.gov/pubmed/22840783?dopt=Abstract

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25 COMMENTS

  • Rob Clements

    “Schizophrenia is often caused by gluten.”

    Bold claim. I’ve come across one study indicating this based on an assumption, involving few people who were not part of a study but more or less theoretical in that they were admitted for psychiatric illness during a time period where wheat consumption was slightly higher than it was a short time beforehand.

    This was also documented during WW2 which certainly could have played a role in admission rates and government funding for the mentally ill.

    I’ve actually never come across a study as farfetched and loose as that one in the thousands I’ve gone through. And one would be hard pressed to conduct one.

  • BPip

    I have the GAD snps (and MANY SOD snps) – chronic anxiety my whole life. To the point of not functioning.
    I became very ill – body and mind completely ‘burnt out’. Hormone profile non-existent (as a female)…with super high testosterone levels. Adrenal hormones deficient too – i had NO stress response which meant i collapsed with every ‘fright’…i.e a sudden knock on the door, dogs barking etc. Life became impossible!! I’ve been suicidal my whole life…thankfully i’m stubborn and don’t give in too easily, despite REALLY wanting to.
    Deficient in Vit D also.

    I gave up gluten – anxiety improved. Lessened lectins, anxiety improved. Took good quality generic supplements to compliment various symptoms – felt stronger, better, finally putting on weight (addison’s weight loss)
    High dose vitamin D – wonderful!!! Sunshine is limited in Ireland so i got a sunbed – wonderful!! Light therapy – wonderful!
    I’ve improved so much i’m able to do something during the day rather than sweating profusely and feeling too anxious to move.
    A few basic changes have changed my symptoms hugely!
    Vit D and sunlight therapy are so under-estimated. Vit D receptors in the brain and all body cells…why is this?! It’s much more functional than just calcium/bone health!
    I was 45kg at my worst – now i’m 50kg and counting! It took years for me to figure out that all i needed was a few basic adjustments.
    It’s worth giving up gluten for sure! I agree with you Jo….the links you’ve made. Brilliant article.

  • Dr. Scott Burtis

    “Glutamate is the neurotransmitter that causes OCD, or an inability to let go, and generalized anxiety. ” To be more precise, a deficiency in GABA is a bigger contributor, as agonists of the GABA-B receptor typically result in clinical improvement. (https://www.ncbi.nlm.nih.gov/pubmed/22169948, https://books.google.com/books?id=IKhSRR6LI6EC&pg=PA16&lpg=PA16&dq=gabab+ocd&source=bl&ots=6f4QSp_0z-&sig=rwPlxyg0UGi1Q0E5xLbvcpRc758&hl=en&sa=X&ved=0ahUKEwjsptyX-JXUAhXMy4MKHUggBRoQ6AEITDAH#v=onepage&q=gaba(b)&f=false), etc. The increase in glutamate at the expense of GABA mediated Gaba-B receptor activity is the likely tie-in.

  • Lainey Kelly

    I’m interested in your comment that calcitriol increases GAD67 and increases GABA. I ‘discovered’ SelfHacked trying to find information on how elevated calcitriol and GAD65 antibodies might be connected or possible in a patient. Can’t find any literature/studies on that at all! Do you have any more information on the relationship between calcitriol and GAD67 (or any insights into my own pathology combination involving GAD antibodies and hence decreased GABA but also calcitriol sometimes double the upper limit – no cancer, no granulomatous disease, but likely Borrelia or relapsing fever suggested by WB positivity)?

    1. Remy

      I think the high calcitriol must be protective somehow.

      In this study, http://www.ncbi.nlm.nih.gov/pubmed/23302101, they actually decreased the GAD65 antibodies by giving the children calcitriol.

      I just tested positive for these antibodies as well and am interested in learning more about how to treat.

      1. Lainey Kelly

        Remy, I have some symptoms that would suggest I may have a variant of Stiff Person Syndrome … for that the first treatment is anti-convulsant medications which increase GABA and/or Valium for the same reason.

        My combination of elevated ACE and elevated Calcitriol has doctors looking for Sarcoidosis but I think that the restriction I have round my diaphragm (and bronchial thickening) would be enough to elevate ACE and many (but not Australian mainstream doctors) would know that D1,25 can elevate in many immune/infectious diseases.

        I would love to be able to test enough to see if GAD67 antibodies are present/absent when Calcitriol is very elevated in summer and see what patterns emerge but most doctors, if they even know what these tests are, are very unwilling to order them.

  • Scompy

    Gluten and casein both have 25-40% glutamic acid by dry weight. If you have a gene mutation that doesn’t allow good conversion of glutamate to GABA, there’s going to be more concentration of glutamate in the blood all of the time is my guess. Taurine binds to the NMDA receptors like glutamate, so this has been my friend to eat foods higher in taurine content to minimize glutamate’s impact on those receptors all of the time. Another angle might be the liver’s ability to produce taurine is stifled, driving up overall blood-glutamate concentration.

    The last angle I want to share is highly significant with glutamate… I read a study in the past that said glutamate invokes the release of insulin when there is no glucose present (study was something like 300% higher). Think of that… a person that cannot convert glutamate to GABA that good may just have higher blood-glutamate levels all of the time, so when new glutamate comes into the body in the form of gluten, casein, MSG, etc., then it over-shoots insulin higher… that of course leads to brain fog, lethargy, etc. Then if you get a person eating a higher carb diet on top of the glutamate-intake due to GAD1 mutations,..blamo. That’s where I see it. NMDA receptors appear all throughout the cardiovascular system and may work as the gating-controls for many functions. The irony would be if glutamate-NMDA binding is also the same gate for how taurine is made in the liver.

  • Ole

    Gluten Psychosis: Confirmation of a New Clinical Entity

    http://www.npif.no/images/pdf/nyheter/Gluten-psykose.pdf

    Non-celiac gluten sensitivity (NCGS) is a syndrome diagnosed in patients with
    symptoms that respond to removal of gluten from the diet, after celiac disease and wheat
    allergy have been excluded. NCGS has been related to neuro-psychiatric disorders, such
    as autism, schizophrenia and depression.

  • Lynn D

    Now need to look at Phenibut after scanning the comments. Have been trying so much to gain weight/muscle…
    About 20 yrs ago wanted to heal families digestive issues. Dr said try no milk as even though son had no allergies on skin test (wish we’d known to look at it next day for delayed). Thought of when a kid got stomachaches from milk and sandwhiches (would pull the liverwurst out and eat that ). So did a trial of no milk, wow, better energy, then wheat free, less joint pain and more energy. 1 child turned from sweet to mean (was Totally addicted ). Tried going back to wheat, not good, sourdough works better than whole wheat. Lat year someone gave me Einkorn(supposedly oldest wheat variety), and no reactions. Had been SCD for ~4yrs and it helped except started too many high oxalates. In the SCD book, mentions the person hybridizing wheat to make it easier to harvest and also more grain, but found that it also lengthened? the starch and that the starch wraps around the gluten, amking all hard to digest. when the starch was removed (really wonder how that was done), the gluten was digestable in the study. Read a book on making bread the old way and wonder if that would be ok, since it goes thru so much predigestion. (am homoz , NC, Hm for the listed snps, neg for HLA celiac gene test). Would really be nice to reduce anxiety but espec the flat blaw get sometimes daily.

    1. Ole

      Phenibut isnt something you’d want to use for this reason due to addiction risk. It builds a tolerance incredibly fast and withdrawals are hell (ive never been through it so i dont know) But i have been through benzo withdrawal (prescribed by Dr) and that was hell.

      Phenibut is really good to kill stress, feel normal and boost appetite once a week or twice a month.

      Long term effects, like with most supplements and drugs: Unknown

  • Guin

    More GAD1 SNPs from 23andme to check out:

    GAD1 rs10432420 A AA +/+
    GAD1 rs12185692 A AA +/+
    GAD1 rs2058725 C TT -/-
    GAD1 rs2241165 C TT -/-
    GAD1 rs3749034 A GG -/-
    GAD1 rs3791850 A GG -/-
    GAD1 rs3791851 C CT +/-
    GAD1 rs3791878 T GG -/-
    GAD1 rs3828275 T TT +/+
    GAD1 rs701492 T CT +/-

    I posted my results as an example–I didn’t investigate each rs number yet. Maybe this will help?

    1. Joseph M. Cohen

      GAD1 snps don’t mean anything unless you know what they’re doing….

      1. Guin

        Duh. I’m working on that.

  • MachineGhost
    1. Joseph M. Cohen

      no

  • Paul

    Quality post, convinced me even further that gluten is poison. Will keep staying as far away as possible from it. Thank you so much for the quality and insight of your post, I wouldn’t be the same person today if it wasn’t for self hacked. Bravo!

    1. Joseph M. Cohen

      🙂

  • lordilol

    ah so for how long you take restore 4life?
    it needs some time to restore microbes no?
    or its just a lie and gardon was in fact marketing some shit.

    1. Joseph M. Cohen

      it could’ve helped in other ways…not sure…maybe it helped him….

  • lordilol

    just from a person of no food sensitivity perspective,
    i ate 1kg cottage cheese 0.5% fat and 1 litter goat milk today.
    no adverse effect.
    but
    one few times i ate plenty of full wheat bread.
    in the 500g range
    i thought i am going to to die.
    i dont have food sensitivites.
    you feel like you are on something, like something fills your body, and its absolute crap. your gut fills with gas. fuck.
    and it wasnt a one time occurance, it repeats with grain consumption.
    i ate today 2 slices of bread at work, and no adverse effect though.
    well only when i eat a ton(grain) i feel like i am at my death bed.
    shit, and then when i ate sugars and fat alot, i feel even worse when its combined with grains.

  • Deltrus

    Phenibut, a GABA B agonist, is the only thing that ever made me feel normal. Memantine doesn’t work that well for me (I can barely feel it at 20mg/day). Phenibut has 1 day tolerance so I’m trying to get ahold of baclofen which supposedly can last much longer without getting tolerance.

    Phenibut makes me react much better to food, I get dizzy if I don’t eat and I feel energetic when I eat. It makes my muscles relax when normally they are stringy and tight, it makes my body feel comfortable when normally it just feels “off”. Normally I feel like I am in the bottom of a trench in time, with the future and past out of vision, but with phenibut, it feels like past, future, and present are in one continuum. It feels like I am on the peak of a mountain of time and can “see” clearly around me. I can notice facial expressions and social cues which are normally pass in 1/10 of the time it would have taken me to register them. My ADHD symptoms get cured.

    I have the exact same GAD genes as you.

    I have so much trouble with staying away from lectins, gluten etc. I have no energy, no motivation, no concentration, so it is so hard for me to make a good diet. And the rest of my family has so much variety in food, usually with lots of wheat.

    This study is relevent: http://www.sciencedirect.com/science/article/pii/S0091305715000295

    Guanfacine is related to clonidine and also has other nootropic effects. I’m looking into getting that.

    If I went completely off of gluten, lectins etc, how long do you think it would take for GAD antibodies to normalize?

    What do you think would be the difference between taking gaba agonists (such as baclofen) and having increased GAD enzyme? Wouldn’t increased GAD enzyme also result in increased GABA receptor tolerance? Or is it like ADHD with dopamine, where tolerance occurs but enhanced neurotransmission is still retained?

    1. Joseph M. Cohen

      Just out of curiosity, did you get prescription memantine?

      How do you know you have the antibodies? I’m not sure I even have them. It’s just an interesting idea and it fits in various ways.

      1. Deltrus

        Memantine was from Ceretropic.

        I don’t know if I have the antibodies, I guess I’m just speculating. I guess I got too caught up in your speculation.

        I think I’m actually going to make an appointment with you to discuss some things. I’ve waited long enough.

        1. Joseph M. Cohen

          I spoke to someone else who bought from them and he said he couldn’t either feel anything. I’m starting to question the reliability of that. I’ve got some from them that I’m going to try.

    2. Ole

      Exact same effects i get from phenibut. Ive been on prescription benzos and none of them make me feel normal or allow me to tolerate food to such a great degree, so i doubt its a gaba thing.
      I stay away from lectins and other bad foods and im fine but on phenibut i can eat a horrible diet and be better than i am on a strict lectin free diet. Effects last for nearly 3 days from when it kicks in. Benzos kill anxiety far more than pheni does. Pheni just makes me feel like i used to do all my life up until when i became “broken”.

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