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Anxiety, Ammonia, and the NMDA Receptor

Discussion in 'The Gut: De Meirleir & Maes; H2S; Leaky Gut' started by Hip, Dec 30, 2009.

  1. Hip

    Hip Senior Member

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    This post is about the possible contribution of ammonia to chronic fatigue syndrome symptoms of anxiety, and the well-known "wired but tired" mental state in CFS.

    I have high anxiety (Generalized Anxiety Disorder, GAD) as one of my CFS symptoms. I believe anxiety symptoms are found in around 30% of CFS patients, so they are quite common. But even if a CFS patient does not have anxiety, nearly all CFS patients experience the "wired but tired" mental state; and I believe this "wired" state is a kind of low-powered version of the anxiety state.

    Indeed, on a good day, I merely feel "wired but tired", but on a bad day, when my internal anxiety levels go higher, my mental state swings up into full anxiety.

    So perhaps everyone with CFS is over-stimulated on the anxiety axis, but just to different degrees.

    But anyway, that is just a preamble.

    The question is: What is the anxiety axis, and what biochemical pathway(s) are over-revving it?

    I think the answer may lie, at least in part, in the NMDA receptors in the brain. It is well-known that the NMDA receptors found on neurons mediate anxiety behavior. Normally, the NMDA receptor is stimulated (switched on) by the brain's neurotransmitter glutamate. However, a number of other substances can also switch on the NMDA receptor.

    Presumably, any foreign chemical substance in the body that can stimulate the NMDA receptors, and that can cross the blood-brain barrier, will potentially generate a constant "wired" or high anxiety state. Such anxiety states will be generated irrespective of life circumstances: it is not a normal psychologically-produced anxiety, but biochemically-generated anxiety - and thus one you cannot directly control.

    Now, one chemical substance that is a HIGHLY POTENT activator of the NMDA receptors is ammonia. Ammonia can be produced in the body by various pathological processes, and it can cross the blood-brain barrier very easily.

    Many bacteria can produce ammonia. One example is proteus mirabilis, commonly found in in the gut/kidneys of people with urinary tract infections. Proteus mirabilis produces an enzyme called urease, which converts urea into ammonia. (Incidentally, Proteus mirabilis is also a sulfur-reducing bacterium that can produce H2S). There are other species of bacteria that can also produce urease, and so may potentially produce ammonia.

    So I wonder if there is another gut/kidney - brain connection in CFS, via ammonia produced in the gut or kidenys, that underpins the "wired but tired" and anxiety states of CFS.

    Interestingly, high-dose magnesium - one of the classic CFS palliatives - is a good blocker of NMDA receptor activation. I expect that is why magnesium is a calming supplement in general. Other blockers of NMDA activation (NMDA antagonists) include: zinc, taurine, progesterone, cats's claw (possibly), guaifenesin (possibly) and the drugs: memantine, ketamine, riluzole, dextromethorphan, amantadine, and also more obscure ones: nitrous oxide, xenon gas, and ibogaine.

    As many CFS patients can testify, these supplement can all help in reducing the "wired but tired"/anxiety state. The mental tiredness may arise, in part, from the NMDA overestimation itself, which exhausts the brain cells (and can cause brain cell death by excitotoxicity).

    But if ammonia is contributing to CFS symptoms (a big if), then rather than just trying to block the NMDA receptor with magnesium etc, perhaps there might be ways of stopping ammonia being produced at source (that is, tackling any ammonia-producing bacteria in the gut, kidneys, or perhaps even sinuses).



    (Note 1: I read that NMDA receptors are also over-stimulated by the immune system itself, whenever there is an infection within the brain. A part of the brains own immune system, the microglia, rather unfortunately secrete both glutamate and quinolinic acid - both powerful NMDA activators - as a byproduct of their operation. (Not a very clever design). Thus, in as far as CFS is a central nervous system infection, there may already be some NMDA over-stimulation going on, just from the the microglia, even before ammonia might contribute to the act.)

    (Note 2: Perhaps there are also other NMDA agonists at play, in addition to ammonia, glutamate and quinolinic acid, that further underpin the "wired but tired" or anxiety states of CFS).
    end, Sidereal, kurt and 4 others like this.
  2. brenda

    brenda Senior Member

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    Hip

    Dr David Jernigan

    http://beatinglymedisease.blogspot.com/

    says that amonia is the main problem in Lyme - and I expect any bacterial infection and treatments include neutralising the amonia. However it is hugely expensive to stay at his clinic for treatment but I may buy his book and try his herbs. He cured himself from Lyme apparently.
    end, Jarod and Lotus97 like this.
  3. liverock

    liverock Senior Member

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    Hip,

    According to Dr Amy Yasko's Methylation Cycle, most ammonia problems are caused by animal protein intake which is up regulated in the body due to CBS polymorphisms.

    Getting rid of this ammonia by the urea cycle uses up tetrahydrobiopterin (BH4), which in turn can cause anxiety problems.

    PWC's in particular are faced with this problem, because of the need for an adequate protein diet to ensure a good supply of amino acids for cell regeneration.

    If you are not familiar with the Yasko Methylation Cycle, it was originally designed to treat autistic children and this site puts it all together with diagrams.

    http://www.heartfixer.com/AMRI-Nutrigenomics.htm

    As mentioned previously, I dont think its a good idea to restrict animal protein too much for PWC's. I dont do well on a low protein diet, so taking carnitine and using an FIR sauna to sweat out the ammonia (which helps preserve BH4 which would normally be used during the normal excretion method via the urea cycle), has been found to help.

    http://www.ncbi.nlm.nih.gov/pubmed/1845745

    .
    Jolie, kurt, Rolo and 2 others like this.
  4. JanisB

    JanisB Senior Member

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    I've been on the Yasko protocol for a year and have successfully reduced my ammonia production.

    You can measure urinary ammonia with a urine amino acids test (available from Doctor's Data, Metametrix, Genova). You can also get a rough reading (e.g. low, medium, high, no numbers) using the Reams home testing kits.

    Yucca taken with protein foods helps to mop up ammonia. So does activated charcoal, taken apart from food.

    The urea cycle has to be supported properly. Sometimes one can see if it is working properly with the urine amino acids. If not, plasma aminos will give additional information. If not working, some interventions, depending on where the problem lies, are arginine, ornithine, citrulline, magnesium, BH4 (prescription), bioptern (not prescription but only available from practitioners except in tiny 25 mg doses.)

    I've gotten great results with Yucca, charcoal, and biopterin. My gut still has dysbiosis but the buggers don't show up on stool tests. I recently read about the biofilms protocol being used in autism and I'm certain my gut has chlostridia or pseudomonas that is hiding from stool tests, DNA stool tests, and EAV testing because the byproducts show up on organic acid testing. I am hoping to introduce this protocol.

    Still, with ammonia lowered substantially, I have fewer symptoms. That feeling of raw nerve endings has gone away. I am calmer as well.

    Good luck in getting your ammonia levels down.
    DREBS, Jarod, kurt and 2 others like this.
  5. pamb

    pamb Senior Member

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    Hi,

    Just want to say thanks for this. Anxiety is the symptom my husband - and I - have the most difficulty coping with. He has been taking charcoal, but not between meals and yucca and biopterin. Can you tell me any more about the dosages that work for you JanisB?

    thanks,
    Pam - wife of CFS sufferer
  6. Hip

    Hip Senior Member

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    More on the subject of ammonia and anxiety:

    A hypothesized explanation for the connection of generalized anxiety disorder and stomach ulcers (the latter we now know are caused by the bacterium Helicobacter pylori in the stomach wall).

    Statistics show that people with stomach ulcers often experiences anxiety states. People have often causally said that "anxiety promotes stomach ulcers", but in reality the reverse is more likely: that the chemistry of stomach ulcers actually causes anxiety states in the brain.

    Here's how:

    Helicobacter pylori makes the enzyme urease, which converts uric acid into ammonia. Now there are significant quantities of uric acid in the stomach wall, so therefore:

    Helicobacter pylori + uric acid in stomach wall = lots of ammonia.

    Now, ammonia is one of the most potent activators of the NMDA receptor - the brain cell receptor that mediates anxiety states. So once ammonia is generated within the stomach wall by Helicobacter pylori, if this ammonia then gets into the bloodstream and into the brain, it will activate the NMDA receptor on neurons, thereby switching on your "anxiety circuits"

    SO the fact that generalized anxiety disorder is a common co-morbid condition with peptic ulcers may be because of the ammonia generated by Helicobacter pylori.


    Note that activation of the NMDA receptors can be caused by other mechanisms, so ammonia is unlikely to be the cause of all cases of anxiety disorder.

    Treatment: Ammonia can be partially eliminated by dietary health supplements such as arginine alpha-ketoglutarate, and L-carnitine. So if people with peptic ulcers found that their anxiety disorder improved or was eliminated by taking these supplements, it would help support the Helicobacter pylori - ammonia hypothesis of this particular anxiety disorder.

    It is also possible that, if similar urease-generating bacteria colonize the kidneys (where there is also plenty of uric acid), this may also result in an anxiety disorder, by the very same mechanism of the urease enzyme converting uric acid into ammonia.

    Proteus mirabilis is once such bacterium that has a propensity to colonize the kidneys: Proteus mirabilis causes upper urinary tract infection (I believe Proteus mirabilis is responsible for 10% of upper urinary tract infection).
    Rolo likes this.
  7. sela

    sela Senior Member

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    has anyone tried l carnitine for anxiety? what about biopterin?
  8. dannybex

    dannybex Senior Member

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    Interesting Janis. I recall reading y ou had the Metametrix GI Profile test and it turned up nothing? I finally got my results back and was somewhat disappointed in the lack of specificity on the report. I had one parasite (but they couldn't identify it except to say it was 'an ingested protozoan and not a human parasite'!), and they also found mycoplasma species (but not specific) and also streptomyces (again not specific strains).

    I'm not sure if these produce ammonia or not -- my regular doc is on pregnancy leave, so the doctor filling in for her was going to get back to me on more specific treatments (has me on beta glucan and strong probiotics for now, along with a homeopathic for the mycloplasma and general environmental detox.)

    I've had increasing muscle spasms and back pain...but don't know if this is due to 'die off' reactions or not. If anyone has a clue, I'd appreciate the feedback...but I guess I could try and call and get through to the doc's office? :)

    I do have charcoal, but always wonder if it steals (adsorbs) nutrients from the last meal...or the next one, so have never found the right time to take it. :confused:

    Hip -- it's my understanding that manganese (not magnesium) along with b-6 helps convert glutamate to gaba. Also taurine may help...

    best to all,

    Dan
  9. Athene

    Athene Never give up

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    Thank you for this really interesting info.

    A few questions for anyone whose brain works better than mine:
    Do free form amino acids raise ammonia, or only proteins that need digesting?
    I had my uric acid measured and it was well below normal - would that mean I have too much ammonia?

    BTW Dannybex I wrote to Kirkman Labs to ask their experts if charcoal traps and removes nutrients and they said yes, it traps just about any nutrient as well as just about any drug or poison. There's a very short list indeed of things it doesn't attach to. I have been avoiding it since then, which is a big shame as it helped so much.
  10. dannybex

    dannybex Senior Member

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    Athene -- I wonder if taking it right at the end of the day -- right before bed -- maybe 3 hours after a meal would be 'safest'?

    Not sure about the uric acid level's connection to ammonia, but low uric acid is very common with PWC's. There is a way (or ways) to raise it, but can't remember right now...and I should be in bed myself! :)
  11. Marco

    Marco Old blackguard

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    Interesting.

    Generalised anxiety has been a major and growing problem for me.

    In the earlier years, I had extensive GI examinations for IBS and upper gastro pain identical to stomach ulcers. Biopsy was clear but I was dependent on Tagamet for many years until the upper GI pain just 'disappeared'.

    In subsequent years anxiety has been a more prevalent issue.

    By co-incidence I've just resumed taking magnesium and am trying to balance the dosage.

    I wonder if anyone has reported being successfully treated for H Pylori and is this affected any co-existing anxiety issues?
  12. Athene

    Athene Never give up

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    Dannybex,
    I guess your idea about charcoal sounds the safest way to use it. The trouble is, if you take it 3 hours after a meal, I think a lot of the damage will already have been done, i.e. a lot of the nasty substances, like H2S and all the rest, will already have been absorbed into the body tissues.
    This isn't something I've read, it's only my supposition. I suppose we need to experiment, but the trouble is, how do we tell if it's sucking up nutrients or not?
    How frustrating!
  13. drjasonjones

    drjasonjones Guest

    Hope this helps

    Hope this helps you. There are many "feel good" hormones and neurotransmitters in the body. One is Serotonin. Even though serotonin is housed in the brain it is produced in the small intestine (85%+ is produced in the small intestine). Gut issues will inhibit the production of serotonin, hence increasing the likelihood of anxiety/stress. Raising serotonin levels with diet and nutrition is not that difficult, but it depends heavily on the status of your current gut health.

    Infections in the GI tract are also common. 80% of your immune system is located in the gut. Ideally you will have a ratio of 85% good bacteria to 15% bad bacteria in the gut. You need the good and the bad. Restoring this ratio is also very important and can be done over a period of time.

    NMDA receptors are primarily located in the brain stem and upper neck region of the spine. These receptors are typically stimulated in those with chronic pain and fatigue. This cycle must be stopped. I have found that specific upper neck adjustments by a chiropractor is definitely part of the process.

    Last but not least, nutrition is absolutely crucial for CFS and at the same time so is detoxification. Toxins attach themselves to the out walls of the human cells and create a cascade of events that lead to inflammation, hormonal resistance and actually more toxicity.

    Again, hope this helps.
  14. richvank

    richvank Senior Member

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    Hi, Athene.

    Ammonia is produced whenever amino acids, either free form or from proteins, are broken down and burned to produce energy. The nitrogen that is left over from this process is in the form of ammonia, which is normally carried to the liver (if it originates in the muscles, where much of the breakdown of amino acids occurs) as part of the glutamine molecule and is processed by the urea cycle in the liver to form urea, which passes to the kidneys via the blood and is excreted in the urine. The breakdown of excess amino acids is a normal process in the body. However, in CFS, according to the GD-MCB hypothesis, amino acids are broken down at a higher rate than normal to produce energy, because the use of the normal energy sources, carbohydrates and fats, is hindered by a partial block at aconitase, early in the Krebs cycle. Since both carbs and fats have to enter the cycle at acetyl-CoA, which is not far before this partial block, they cannot be used by the cycle at normal rates. Amino acids, on the other hand, can enter the cycle at later points, beyond the partial block. Thus, the cells resort to burning amino acids, as occurs in starvation (in that case because carbs and fats are just not available, so the body burns amino acids from its muscle protein as a last resort to preserve life, as in the Holocaust survivors). Note that this process requires transamination reactions that convert one amino acid to another, so that they can be fed into the Krebs cycle. These reactions require vitamin B6 as a cofactor. B6 is often found to be low in PWCs, and I suspect that it gets worn out in these reactions. This then hinders the utilization of amino acids for fuel, also.

    Another source of ammonia in the body, which can be major in PWCs, because of the high prevalence of gut dysbiosis in CFS, is the breakdown of amino acids by unfriendly bacteria in the gut. This ammonia enters the blood and also places a load on the urea cycle in the liver.

    Dr. Yasko has suggested that another significant source of ammonia in autism (and presumably also in CFS) is that some people have upregulating polymorphisms in the CBS enzyme, and that leads to greater flow from the methylation cycle into the transsulfuration pathway. In the presence of excess flow, she has suggested that there is a reaction that breaks down cystathionine or cysteine to produce ammonia and sulfur compounds. In this case, the nitrogen in the ammonia would originate from the amino acid methionine.

    Uric acid is a horse of another color. It gets its name because it is also excreted in the urine, but it is not related to the breakdown of amino acids or protein. Rather, it comes from the breakdown of the purines (guanine and adenine). It's true that uric acid is often found to be low in CFS. Dr. Cheney has suggested that it's because uric acid is an antioxidant, and it is oxidized because of the state of high oxidative stress in CFS. I would like to suggest a different explanation. The synthesis of purines in the body requires the help of folate. Because of the partial block in the methylation cycle, which is linked to the folate metabolism, folate metabolites drain from the cells into the blood via the socalled methyl trap mechanism. One of the results of this is lowered production of purines, and hence, lowered production of uric acid from the breakdown of purines. The body has a mechanism of recycling purines when they are in short supply, and I think that is what accounts for the low uric acid in CFS. This is the opposite of the situation in gout, which results from too high a level of uric acid in the blood.

    On taking charcoal, it would seem to me that bedtime, well after dinner, would be a good time to take it. By then, most of the nutrients will have been absorbed, and the charcoal will be in a good position to bind the toxins that come into the gut with the bile and make sure that they are carried out in the stools. Most of the processing of toxins by the liver occurs in the wee hours of the morning.

    Best regards,

    Rich
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  15. Athene

    Athene Never give up

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    Thank you so much for all this info, Rich.
    I'll try the bedtime charcoal treatment, and re-read the other info a few times to try to get my poor old head round it properly!
  16. Mark

    Mark Acting CEO

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    Just to quickly say that this is happening to my sister right now, she is in hospital after collapsing earlier this week. She has been "wired-but-tired" and anxious, which was (initially at least) explained by stress. They have now found a urinary infection. This thread really helped me understand what she is going through, thanks everyone. The explanation of how the anxiety is a consequence not a cause may be really useful.

    I have been trying to explain to my family for many years that she has ME/CFS, she too has been sick for (about) 15 years but far worse than me, with severe IBS so bad they thought it was Crohn's, but a top UK specialist drew a blank in the end after some years trying. She lost about half her body weight in a couple of years or so.

    She blatantly has ME/CFS/XAND but I still can't convince my family. They get angry whenever I try. They think I'm just "off on one" and I'm making connections that aren't really there. It is so unbelievably frustrating, they say the doctors have told them it is a post-natal condition plus BPD and IBS and there is a sort of explanation for it, it has nothing to do with ME/CFS, and even though they have never been able to help her (apart from treating secondary stuff) and she has no proper diagnosis apart from a few ideopathic conditions, and no answers after 15 years, they still won't accept it has anything to do with ME/CFS.

    Just wanted to share my frustration - anyway I'm hoping the info and connections in this thread and one other I found the other day, relevant to her, may help a little to convince them...I have been making some apparent progress on other fronts lately so maybe some day soon they will understand. Still fighting a lot of sadness and frustration with this at the moment though.

    ETA: I don't think I'm even going to try talking to them about charcoal...:rolleyes:
  17. glenp

    glenp "and this too shall pass"

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    Proteus Mirabilis

    Quote:
    Many bacteria can produce ammonia. One example is proteus mirabilis, commonly found in in the gut/kidneys of people with urinary tract infections. Proteus mirabilis produces an enzyme called urease, which converts urea into ammonia. (Incidentally, Proteus mirabilis is also a sulfur-reducing bacterium that can produce H2S). There are other species of bacteria that can also produce urease, and so may potentially produce ammonia.
    End Quote


    I had this bug in my bone and often wonder if it might not be chronic. I don't think there is a test for it? I also have many respiratory infections and someone mentioned 10% of respiratory infections to be by this bug it would make sense if it was coming and going? Does anyone else know of it in respiratory track or bone and roots of teeth etc.? It was very difficult to get rid of the first time and I often think it may still be smoldering . Could it be in mucous secretions from the nose, does anyone know?

    Glen
  18. johnniehaz

    johnniehaz

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    i'm not sure if anybody is still following this thread, but I have something to add on the issue of ammonia toxicity. I have anxiety issues that are biochemical in origin rather than psychological. I had tests done recently in the UK (Acumen) for DNA adducts, and they came up with aluminium blocking the expression of a gene called 'glutamine synthetase'. The blurb that came with the results says, 'this enzyme takes up ammonia and....converts glutamate into glutamine....Glutamine is also the preferred form of transport for ammonia. Normal genetic expression of glutamine synthetase is essential for clearing waste nitrogen (as ammonia) by the production of glutamine....there may be implications here for the mental aspects of chronic fatigue.' So there would be an explanation here for my anxiety problems - looking into heavy metal toxicity might be a help for others. Out of interest, I've had hair mineral analysis before, and no excesses showed up.
    Ailsa and Gestalt like this.
  19. Hip

    Hip Senior Member

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    That is very interesting, as glutamate as well as ammonia can activate the NMDA receptors. Overstimulation of the NMDA receptors can lead to anxiety. Glutamate is a neurotransmitter, but glutamate can also be produced as a by-product of microglia operation. Microglia form part of the brain's immune system. Chronic microglial activation is found in brain inflammation and in many neurological diseases.

    So if glutamine synthetase in the brain were low (due to aluminum in the brain), this would impede the clear out ammonia and glutamate. Then ammonia and/or glutamate (from microglia) can both activate the NMDA receptors, leading to anxiety.

    So adding this all together: if you have chronic microglia activation, this may lead to anxiety (especially if you have low levels of glutamine synthetase in the brain). And if you have ammonia in the brain, this can lead to anxiety (again, especially if you have low levels of glutamine synthetase in the brain).

    Note that some vaccines (such as tetanus vaccine) contain aluminum hydroxide, which can accumulate in the brain. Use of aluminum hydroxide shows statistically significant increases in anxiety.

    Apple pectin can help remove aluminum from the brain.

    Vitamin E can reduce microglia activation.



    You may be interested in the non-standard anti-anxiety approach I used to cure my extremely high levels of anxiety:

    After many years with horrible anxiety, I finally figured out that my anxiety was created by a brain inflammation. As soon as I tried taking an anti-inflammatory supplement (that targeted NF kappa-B inflammation), most of my anxiety vanished (within a day).

    I use the herbal extract called curcumin to block the NF kappa-B mediated inflammation. You take curcumin in three daily doses of 500 to 1000 mg. You have to take it in divided doses to work: a capsule at breakfast, one at lunch, one at supper time, and one before bed. This is because the plasma half-life of curcumin is short: 3 to 6 hours, so you need to take it 4 times a day to keep up your anti-inflammatory blockade. Another good NF kappa-B blocker that can be used in place of curcumin (or in addition, if you want) is Citricidal grapefruit seed extract drops taken three times a day at the maximum dose.


    You might also want to try a different anti-inflammatory: one that targets COX-2 mediated inflammation. In this case, take cat's claw herb, 1000 mg, on the same dosing schedule. Propolis at 1000 mg can be used in place of cat's claw, as propolis is also a good COX-2 inhibitor. (If neither NF kappa-B or COX-2 inhibitors bring relief, then consider trying a 5-LOX anti-inflammatory, such as the 5-LOXIN extract of Boswellia serrata. You may also try all 3 of these together, since more than one inflammatory mechanism can be at play. )

    The idea of these anti-inflammatory approaches to anxiety treatment is that they block the mechanisms that create the biochemistry of anxiety in the brain in the first place. That is, they treat the actual cause of anxiety. They stop anxiety at source.

    However, if these anti-inflammatory approaches to stopping anxiety do not work (or only work to a certain degree) then you may have to use palliative anti-anxiety treatments.

    The palliative anti-anxiety natural supplements I found useful are: inositol (10 to 15 grams daily). And take these when needed: vitamin B1 (100 mg), vitamin B6 (50 mg), vitamin B5 (1 gram), L-tyrosine (500 mg); taurine (1000 mg), L-carnitine (500 mg), picamilon (100 mg), arginine pyroglutamate (2 grams), theanine (200 mg)). Some anti-anxiety herbs include: ashwagandha, Bacopa monniera, chamomile (especially the apigenin extract of chamomile), lavender, passionflower. Holy basil can dramatically improve anxiety in some people (holy basil is potent COX-2 inhibitor, however, thus its anxiolytic mechanism may actually be as an anti-inflammatory rather than a palliative; holy basil also lowers cortisol, and high cortisol is another source of some people's anxiety states - but watch out if you have low cortisol).

    The antihistamines cetirizine (Zyrtec) and loratadine can reduce anxiety symptoms. Dose is 10 mg daily.

    Transdermal magnesium cream used twice daily is also good. Transdermal magnesium is often used in autism, where there are very high levels of internal mental anxiety. Magnesium lowers NMDA receptor activation. (You can make your own cheap transdermal magnesium cream, simply using Epsom Salts mixed with some hand cream). Oral magnesium may help, but most people reach bowel tolerance (they get diarrhea) after about 500 to 1000 mg. The magnesium content of Epsom Salts (magnesium sulfate MgSO4) is 20%, so 5 grams of Epsom Salts provides 1 gram of magnesium.

    More info here.
  20. jen jen

    jen jen

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    Hi
    I live in the U.K and was reading about ammonia causing problems in the brain. I wondered if you could tell me where I couls get the home testing kits from?
    As in to test if u have a problem with amonia. What would u recommend taking supplement wise to help this
    many thanks

    also can you take activated charcoal at night if you are taking zolpidem and amitryptyline

    jen

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