Posts Tagged ‘GABA’
I think I am on the right track.
In the last post I speculated that ADHD and ADD were related in some way to GABA deficiency. I believe attention deficit disorder may be characterised by low glutamate levels with low dopamine levels, and attention deficit hyperactivity disorder may be characterised by high glutamate levels with low dopamine levels. I believe all types are characterised by low GABA levels, the same root cause that produces bipolar disorder and some types of autism in other individuals.
So here’s some research to back me up.
Dec. 4, 2003 — Children with attention deficit hyperactivity disorder (ADHD) may actually have different levels of certain chemicals in the brain than other children, a new study shows.
Using new imaging techniques, researchers found that children with the hyperactive form of ADHD had 2 1-2 times more of a brain chemical known as glutamate, which acts like a stimulant in the brain. In addition, the brains of children with this subtype of ADHD also had lower than normal levels of GABA, a chemical that has inhibitory properties in the brain.
Both of these chemicals are neurotransmitters that carry signals to and from nerve cells in the brain. Researchers say these differences may explain the behavior of children with poor impulse control.
“Glutamate is an excitatory amino acid that leads to easier stimulation and excited neuronal pathways,” says researcher Helen Courvoisie, MD, assistant professor of child and adolescent psychiatry at Johns Hopkins Medical Institutions in Baltimore. “GABA is an inhibitory neurotransmitter and inhibits those pathways in the brain.”
In addition to revealing differences in brain chemistry, the study also showed that these gaps correlated to the children’s scores on tests of language, memory, sensory, and learning skills. Brain Scans Reveal ADHD Differences
The study was small and limited, and is a few years old now. I do not know whether it has been followed up with any further studies.
Dr. Courvoisie spoke today at an American Medical Association media briefing on advances in neurology in New York.
“Children with adhd have problems that are associated with the part of the brain called the frontal lobes,” said Dr. courvoisie. “The frontal lobes are like the ‘boss of the brain,’ responsible for what we call executive functioning telling the brain and body what to do.” This area regulates impulse control, attention, movement and elaborating on thoughts.
“There are three types of adhd: attention-deficit, hyperactive and combined type,” explained Dr. courvoisie. “We focused on the hyperactive type to try to get the clearest picture of what was going awry with their executive function.”
“There is a partial malfunctioning of this ‘boss of the brain’ in adhd,” said Dr. courvoisie. “I describe it as having a poor manager, like the pointy-headed boss in the Dilbert cartoons he doesn’t know what he’s doing, he can”t run a good company and everyone becomes frustrated.”
adhd is characterized by difficulty concentrating and paying attention, and a high degree of restless and impulsive behavior. Although the problems may be less pronounced in adulthood, it is often a lifelong condition.
“The great increase in the diagnosis of adhd has created some controversy,” said Dr. courvoisie. “It is important to understand and identify the underlying neurology of adhd so that children with adhd can be appropriately treated. There are real deficients these are not just fidgety kids.” Imaging children with ADHD
Here is a link to the pubmed abstract, and another to the free full text of the study online. Something interesting of note is that glutamine as well as glutamate were elevated in both frontal areas of the brain in these children, while increased N-acetyl aspartate and choline were found in the right frontal area of the group.
Eggs contain high amounts of choline. I wonder if this is why some people react badly to eggs? My ADHD sister was sensitive to eggs when she was a child. I am ADD without the hyperactivity, unless I really push up my glutamate levels with B12/folate. I am not sensitive to eggs. The other difference between us is that she is left handed and I am right handed. Could brain laterality affect outcome?
Unfortunately the pubmed abstract does not contain the word ‘GABA’ which makes it difficult to find in searches. Courvisie has also done a similar study on children with bipolar disorder (full text here) and found that glutamate and glutamine were both elevated in the frontal lobes and basal ganglia. They also had elevated lipid levels in the frontal lobes but not the temporal lobes, while while N-acetyl aspartate and choline levels were normal.
If the main problem in ADHD is glutamate/gaba imbalance, one would expect to find that ADHD children are helped by epilepsy medications that enhance GABA signalling, like sodium valproate. So, whilst perusing pubmed, I also found the following mini-study:
We treated three boys with attention deficit/hyperactivity disorder (ADHD) associated with giant somatosensory evoked potentials (SEP). All responded well to extended-release valproate (EVA), a gamma-aminobutyric acid (GABA) enhancer. Improvement particularly involved hyperactivity and impulsivity. When methylphenidate previously was administered to two patients, symptoms worsened. EVA therefore may be preferable for ADHD with giant SEP. Favorable response of ADHD with giant SEP to extended-release valproate
It looks like a ketogenic diet all round then!
This post started out as a letter to a close relative who is on the verge of being diagnosed with cyclothymia, a mild form of bipolar disorder. The relative has been left out in the cold waiting for a referral to a psychiatrist. This person reminds me too much of myself five years ago, and I have been very worried.
Rather than reference this post with various science articles, I’m simply going to get it out there for now.
The most forward-thinking theory of bipolar disorder is that it is caused by a deficiency of GABA. GABA is a ‘calming’ and ‘regulating’ neurotransmitter. If you imagine GABA as the conductor of an orchestra, if you don’t have enough, all of the other neurotransmitters can get out of hand and start playing their own tunes, and they can swing in whatever direction they want. I believe that the most important thing you can do to control bipolar disorder is to raise your GABA levels.
One important neurotransmitter that is affected by GABA is glutamate. Glutamate is an ‘intelligence’ and ‘wakeful’ neurotransmitter. It’s almost like a volume knob. The more glutamate you have, the faster your brain goes and the louder all the neurotransmitters get. Too much glutamate can actually kill your brain cells. Manic highs are thought to be characterised by high levels of glutamate, characterised by racing thoughts and insomnia, while depressive lows are thought to be caused by low levels of glutamate. When we talk about depression in bipolar disorder, we are not necessarily talking about ‘sadness’, we are talking about a much wider range of symptoms that include grogginess and an increased need for sleep. Low glutamate levels are thought to be associated with some of the symptoms of fibromyalgia. People with unchecked bipolar disorder often describe having to sleep for several extra hours a day, sometimes not being able to get out of bed at all, and feeling hungover and being unable to wake up properly in the morning – very similar to fibromyalgia symptoms.
This isn’t the complete story of what is going on in the brain because bipolar disorder also affects dopamine levels – the ‘attention span’ and ‘pleasure/reward’ neurotransmitter. If you are unable to concentrate and are distracted easily (ADHD), and are unable to get any enjoyment out of the things you are doing, it is a sign that your dopamine levels are too low. Dopamine tends to rise when you are manic and fall when you are depressive.
High dopamine levels are an independent risk factor for bipolar disorder. This is because when dopamine levels become very high, thought becomes delusional and people experience hallucinations – very high dopamine and glutamate levels are thought to characterise schizophrenia. People who have naturally high dopamine levels are more likely to be at risk of delusional/manic episodes as their dopamine is more likely to go too high. A version of a gene called COMT, which causes high dopamine and low adrenaline levels, is associated with bipolar disorder.
However, if you have ADHD, you are to some extent protected from becoming delusional, as your dopamine levels are naturally low. I believe that people with ADHD can experience bipolar disorder quite differently to those who have naturally high dopamine. I believe that they can still have manic highs (insomnia, thoughts racing) caused by high glutamate in which they do not become delusional/hallucinatory, they just get carried away without crossing over into the ‘nuts’ category, as their low dopamine levels protect them from delusions. I believe attention deficit disorder may be characterised by low glutamate levels with low dopamine levels, and attention deficit hyperactivity disorder may be characterised by high glutamate levels with low dopamine levels.
There is a version of mania called ‘irritable mania’. Dopamine can convert quite easily to noradrenaline and adrenaline, which can trigger anger and aggression responses. I believe if you have the version of the COMT gene which causes low dopamine levels and high adrenaline levels, you will more likely experience irritable mania rather than regular delusional mania, in other words, rather than hallucinating or losing your ability to think logically, you will instead get really irritable and angry and lash out at the world. This kind of behaviour is frequently misunderstood as depression.
I believe there are people out there who have ADHD, whose low dopamine levels are protecting them from full-blown bipolar manic episodes. They therefore remain undiagnosed, even though they have the ‘seed’ of bipolar disorder within them, in that their GABA levels are too low and they are experiencing glutamate highs and lows. They will likely be diagnosed with unipolar depression or aggression disorders rather than bipolar disorder or cyclothymia, as they are less likely to recognise that something is wrong during their manic episodes – they simply feel too happy (or too angry), but don’t become delusional. As a result they are treated with drugs – SSRIs – that are totally wrong for their condition, or their aggressive behaviour gets them into trouble with the law, and rather than being diagnosed with a biochemical problem, they are regarded as criminals.
Though serotonin is thought of as the ‘happiness’ neurotransmitter, there’s a lot of evidence that dopamine is more important to happiness in bipolar than serotonin. Low serotonin levels tend to cause OCD and may be involved in aggression. SSRIs can trigger manic episodes in people with bipolar disorder, however. This may actually be because they cross react somewhat with dopamine receptors. Serotonin has multiple different purposes in the brain, and seems to be more of a regulator than a happy/sad neurotransmitter. We have recently observed in the media, the revelation that SSRI’s don’t actually help depression in most people. McManamy makes a very good argument as to why it is dopamine, not serotonin, that we need to worry about in bipolar disorder. Perhaps we need to re-examine our fixation with serotonin.
Raising GABA levels
Ultimately, the way to fix bipolar disorder is to raise GABA levels.
Firstly, a ketogenic diet or low carbohydrate diet can do this. This creates ketones, and the ketones increase several calming neurotransmitters in the brain, particularly GABA levels. This is why a ketogenic diet can help people with epilepsy, which is also caused by too much glutamate/too little GABA.
You can induce some of the effects of a ketogenic diet without having to be on one by taking vinegar. Believe it or not, the main ketone produced on a low carb diet is acetic acid, i.e. vinegar. A tablespoon or two of vinegar before every meal actually produces similar effects to low carbing, and will raise your GABA levels. Unfortunately vinegar is digested and destroyed very quickly, so the effect doesn’t last very long.
Valproate (valproic acid) works on bipolar disorder because it is very, very similar in structure to vinegar and ketones. It’s rather more potent because it takes the body longer to break it down than ketones or vinegar.
Alcohol is similar in structure to acetic acid and has a similar action on the body in that it raises GABA levels. It usually contains lots of impurities that can also make things worse, however, and its effect is very short-lived, and the alcohol withdrawal can actually make you feel worse. If you drink, you need to be very careful about how much you drink, what you drink, and you need to drink regularly, for example, one measure every evening, and be very self-controlled. I would stick to whisky, vodka or gin as they don’t contain the harmful impurities that are problematic for failsafers. Wine and beer contain amines, glutamates, salicylates and SLAs.
A natural alternative to valproate that you can buy in the shops, is the herb valerian, which contains valeric acid. All herbs come with some risk and side effects, but valerian is known to increase GABA in the same way as vinegar and valproate, again, having a very similar structure. A popular over the counter remedy you can get from most pharmacies is ‘Kalms’, and this contains valerian. Take the Kalms Stress version, and avoid the Kalms Sleep version, unless you want to, uh, fall asleep and get a hangover. If you take valerian, you must not under any circumstances get pregnant, as it is similar in structure to valproate, which can cause deformaties and some types of autism in foetuses.
You can actually obtain GABA itself online, though you have to order it from America because it’s illegal to sell in the UK. I have tried taking GABA, though not recently. I found it gave me very vivid dreams.
Another alternative is glutamine, an amino acid that opposes glutamate. The brain makes GABA from glutamate, glucose, and glutamine. You don’t always want to oppose glutamate, but I find it very helpful if I am grumpy or sugar-craving after meals. Theanine is another amino acid with a similar effect. It is found in tea, which is why tea makes you feel calm (however, tea also contains salicylates which will have longer lasting adverse effects).
A secondary regulatory neurotransmitter that interacts with GABA and that might help is taurine.
Two other herbal remedies that raise GABA by rather complicated drug-like actions are kava kava, and scullcap/skullcap.
There is a strong possibility that herbal remedies will make you feel hungover. I would test them all one at a time and see how they make you feel. Don’t take ten things at once!
Calcium is also thought to raise GABA levels through ion channel signalling mechanisms, though it will also raise glutamate levels and dopamine levels. Magnesium opposes the effects of calcium on glutamate. I tend to take calcium when I want to stay awake, use my brain, and extend my attention span, and magnesium when I need to sleep. Do not underestimate the usefulness of calcium! It can make a big difference to your mental state.
Allegedly, if you have the patience for it, relaxation techniques like yoga and meditation can also raise GABA levels. This is probably why perennially moody stars like Madonna and Gwyneth Paltrow witter on about yoga so much. I find that going and sitting somewhere dark and quiet and reciting a mantra/some lyrics/some poetry in my head can help calm me down sometimes.
Lowering glutamate levels
Mania and hypomania aren’t just characterised by happiness, they are also characterised by irritation and anger. As I mentioned, this is because high dopamine levels can convert easily to the closely related neurotransmitter, adrenaline. When you are feeling angry and stressed, this is as much a sign of mania as happiness is. Mania symptoms also include having a racing brain, feeling as though your thoughts are very intelligent and well-crafted, having insomnia, having nightmares and poor sleep, waking too early feeling fantastic, and buzzing about the place feeling really hyperactive.
Vitamin K actually protects against high glutamate levels and helps the body to use up excess glutamate by converting it into the bone-building/clotting protein GLA. I find it very useful for calming me down, helping me sleep, and stopping me from feeling angry. The type of vitamin K you need is a version called K2. I use a Vitamin Research Products brand, which is ideal as you can open the capsule and portion out smaller doses. You can buy it online in the UK from nutricentre. It might make you quite sleepy if you overdo it, but it is very valuable to have around as it works quite quickly. Don’t take it for an extended period though (i.e. every day for a week), as you may give yourself a cold or unbalance your mood in other ways by inducing vitamin A and vitamin D deficiency, which are used up by the same bone-building processes.
Theoretically, B6 should help you to lower glutamate by converting it into GABA. Unfortunately I find it gives me brain fog – perhaps because it lowers glutamate too much.
Raising glutamate levels
You should only ever try to raise glutamate levels when you have brain fog, hangover symptoms, and you can’t wake up in the mornings, otherwise there will be trouble!
I find the best thing is a dose of B12. I use a Metabolics brand ‘adenosylcobalamin’ product, also available from nutricentre. It will make you feel much better, but you should never take a whole capsule as it can trigger mania, anger, and insomnia. I also get strange trapped nerve sensations in my shoulders and neck if I take too much. I take the tiniest sprinkle I can, and even that can make my heart pound sometimes.
Some people find that folic acid is also useful. It depends on your genes. I would only take very small doses (50-100mcg, a quarter to half a tablet) to trial it, as it triggers hypomania and dependence in me very easily. I find I tend to need increasing doses each day to stay free of brain fog and then have an awful comedown if I stop taking it. It might be useful in a very, very small dose.
It is easy to overdo these supplements, so remember that you can calm down high glutamate levels with vitamin K. You might end up falling asleep at your desk though! It’s always best to err on the side of caution with these supplements.
Raising dopamine levels
This would be useful if you are having concentration problems or feel like you don’t care about doing anything. Calcium supplements are supposed to increase dopamine levels. I do find that a glass of goat’s milk helps me to concentrate on my writing.
Avoiding neurotransmitters in foods
There came a point in my late 20’s when a low carbohydrate diet just wasn’t having a strong enough effect on me anymore, and I started going downhill again until I found the failsafe diet. It IS very important to avoid neurotransmitters in foods, be they amines or glutamates. Salicylates mess with dopamine levels, trigger a type of glutamate receptor called an NMDA receptor that is thought to be involved in depression, and inhibit GABA production by blocking calcium ion channels. Salicylates tend to cause brief happy-high feelings just after you eat them, then cause depression, ADHD and brainfog the next day. While ever your GABA levels are too low, neurotransmitters in foods will just send you whatever which way they can, so you will always be up/down/angry/confused.
The worst offending foods are chocolate, cheese, pork, tomato, citrus fruits, grapes, other tropical fruits, broccoli and dark leafy greens. You must avoid all the listed additives, especially colourings and flavourings and (obviously) MSG and flavour enhancers because they will give you ADHD and contribute to depression. Check the food labels of everything before you buy it, including vitamins. They are sneaky and get everywhere. Better still, don’t buy food that’s in packages, it’s always got some crap in it.
It’s also rather important to avoid caffeine. Caffeine is a weak substitute for dopamine and adrenaline. It affects me in the same way as folic acid, and I need increasing amounts to stay free of brain fog and feel like I can wake up in the mornings. The adrenaline it creates will contribute to you feeling angry and stressed.
Ultimately, if you have bipolar disorder, the drugs you will be prescribed are lithium, valproate, or lamotrigine. They do help. Sometimes there is no natural solution. If you do not have the self control to manage your problems with the methods I describe above, you NEED to be on prescription drugs for your own safety.
Following on from a previous post in which exposure to methylation supplements like folate during pregnancy appears to increase the risk of food chemical intolerance symptoms in children by causing DNA hypermethylation, there are also hints that DNA hypermethylation can be harmful in a different way:
ScienceDaily (Aug. 1, 2008) — Autopsies usually point to a cause of death but now a study of brain tissue collected during these procedures, may explain an underlying cause of major depression and suicide.
The international research group, led by Dr. Michael O. Poulter of Robarts Research Institute at The University of Western Ontario and Dr. Hymie Anisman of the Neuroscience Research Institute at Carleton University, is the first to show that proteins that modify DNA directly are more highly expressed in the brains of people who commit suicide.
These proteins are involved in chemically modifying DNA in a process called epigenomic regulation. The paper is published in Biological Psychiatry.
The researchers compared the brains of people who committed suicide with those of a control group who died suddenly, from heart attacks and other causes. They found that the genome in depressed people who had committed suicide was chemically modified by a process that is normally involved in regulating the essential characteristics of all cells in the body. As Poulter explains, “We have about 40,000 genes in every cell and the main reason a brain cell is a brain cell is because only a small fraction of the genes are turned on. The remaining genes that are not expressed are shut down by an epigenetic process called DNA methylation.”
The rate of methylation in the suicide brains was found to be much greater than that of the control group. Importantly, one of the genes they studied was shown to be heavily chemically modified and its expression was reduced. This particular gene plays a major role in regulating brain activity. “Interestingly, the nature of this chemical modification is long term and hard to reverse, and this fits with depression,” says Poulter.
“The whole idea that the genome is so malleable in the brain is surprising. Finding that epigenetic mechanisms continue to influence gene expression is pretty unusual,” says Poulter, who is also a professor in the Department of Physiology and Pharmacology at Western’s Schulich School of Medicine & Dentistry. “These observations open an entirely new avenue of research and potential therapeutic interventions.” The research was funded through the Canadian Institutes of Health Research. Autopsies Reveal Changes To DNA In Major Depression And Suicide
The gene in question that becomes hypermethylated is the GABA-A receptor. Here’s the associated abstract:
BACKGROUND: Epigenetic mechanisms may be involved in the reprogramming of gene expression in response to stressful stimuli. This investigation determined whether epigenetic phenomena might similarly be associated with suicide/depression.
METHODS: The expression of DNA methyltransferase (DNMT) mRNA was assessed in several brain regions of individuals who had committed suicide and had been diagnosed with major depression relative to that of individuals who had died suddenly as a result of factors other than suicide.
RESULTS: The DNMT gene transcripts’ expression was altered in several brains regions of suicides, including frontopolar cortex, amygdala, and the paraventricular nucleus of the hypothalamus. Importantly, an increase of both mRNA and protein expression was found in the frontopolar cortex. In addition, although transcript abundance of various forms of DNMT was highly correlated in normal control subjects, this coordination of DNMT isoform expression was diminished in suicide brain. Further, within the frontopolar cortex, gene-specific aberrations in DNA methylation were apparent in the gamma-aminobutyric acid (GABA)(A) receptor alpha1 subunit promoter region, the transcript of which is underexpressed in suicide/major depressive disorder (MDD) brains. Indeed, three cytosine/guanosine sites were hypermethylated relative to control subjects. Finally, we found that DNMT-3B mRNA abundance was inversely correlated to alpha1 mRNA abundance.
CONCLUSIONS: These data show that DNMT mRNA expression was altered in suicide brain, and this change in expression in the frontopolar cortex was associated with increased methylation of a gene whose mRNA expression has previously been shown to be reduced. These observations suggest that epigenetic mechanisms may be associated with altered gene expression in suicide/MDD. GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes
Why is this important to failsafers?
Well, ketosis (low carbing) raises GABA levels. GABA levels are thought to be deficient in people with bipolar disorder and autism. The manic/depressive swings associated with bipolar disorder are thought to be caused by the subsequent deregulation of glutamate. During manic phases, glutamate levels are too high, and during depressive phases, glutamate levels are too low. I will write more on this subject soon.
Salicylates are thought to interfere with DNA methylation – they are thought to protect against DNA hypomethylation. Does this go as far as increasing the risk of DNA hypermethylation? It would not surprise me.
In the brain, salicylates are thought to act on excitatory NMDA receptors (a form of glutamate receptor). They are also thought to block GABA release by acting on calcium channels.
I did a B12 trial earlier this year. I found that B12 seemed to be useful in helping me recover from food chemical reactions (particularly amine hangovers), but the B12 gave me insomnia, irritability, palpitations, and caused weight gain, which are as bad in their own way as eating the amines in the first place.
B12 seems to have glutamate-agonist properties. I wondered whether taking it with a glutamate-antagonist might help neutralise some of the negative side effects. B6, K2, glycine, glutamine, theanine, and just being in ketosis are all potential options. I know from past experience that some of these have side effects too. B6 just gives me brain fog. Glycine makes me depressed. Glutamine doesn’t do much of anything apart from being very good at neutralising sugar cravings. Theanine had an effect but wore off very quickly, probably because the body breaks down theanine into glutamate. Ketosis makes me calm, but it isn’t strong enough to counteract the effects of the B12.
The last remaining option is vitamin K. I’ve been led to believe that vitamin K is supposed to protect against glutamate toxicity (if only I could find a pubmed study showing that I’d feel more confident about saying it). Vitamin K certainly makes me feel calm. The effect is like being in ketosis, but different. Vitamin K makes me feel drugged, like I’m on Valium. I find it hard to get worked up about anything. It also makes me feel stupid and I get very forgetful. It does not help me to control my weight, if anything, I’ve felt in the past that I’ve gained weight while taking it, though my hunger and blood sugar regulation feels under better control. K2 is supposed to help produce energy so WAPF members have blamed chronic fatigue syndrome on K2 deficiency. K2 has never made me feel more energetic. Pantothenic acid was always much better at that.
I can’t take vitamin K2 regularly because I had deep vein thrombosis a few years ago, and when I take vitamin K2 for more than a few days, the site of my DVT starts hurting and swelling. Vitamin K is involved in clotting, and old DVT sites usually have some fibrin still stuck to the inside of the leg vein just waiting to cause trouble. The only other thing that does that to me is calcium carbonate supplements. I’ve never managed to induce it with vitamin K1, but then, vitamin K1 is very hard for the body to absorb.
During this trial I took between 500mcg and 1.5mg of the Vitamin Research Products brand of vitamin K, which is largely the K2 MK4 variant, along with the adenosylcobalamin I was already using. I did not take the supplements every day, only when I had eaten something I knew I would react to.
What happens when I take B12 and K2 together?
Well, I feel calm. It doesn’t negate the positive effects of the B12 on amine hangovers, but it stops the slightly manic, overstimulated feeling and the insomnia. It doesn’t stop the weight gain. I also managed to pick up a couple of veruccas after years of not having any, possibly something to do with a K2/A antagonism (vitamin A arrests the growth of Human Papilloma Virus and was thought to help that poor tree root man who was in the news a while ago).
But I fall asleep.
I literally can’t keep my eyes open. It takes a couple of hours to kick in. At first, I couldn’t figure out what was going on, so I just thought I must have slept badly or I was just tired. But that’s not the case. I’ve been trying this one out for a couple of months now, and every single time it’s knocked me out. Great at bedtime, not so great on a Sunday morning when you want to recover from Saturday’s cheating.
Vitamin K, along with glutamate, help to form a protein called gamma-carboxyglutamate protein, or Gla protein for short. Gla protein is involved in bone formation. The only suggestion I can find in pubmed that Gla might have anything to do with sleep is this abstract:
The venom of a fish-hunting cone snail (Conus geographus) contains a novel toxin, the “sleeper” peptide, which induces a sleep-like state in mice when injected intracerebrally. We demonstrate that this peptide contains 5 mol of gamma-carboxyglutamate (Gla) in 17 amino acids. The amino acid sequence of the sleeper peptide is Gly-Glu-Gla-Gla-Leu-Gln-Gla-Asn-Gln-Gla-Leu-Ile-Arg-Gla-Lys-Ser-Asn-NH2. Gamma-carboxyglutamate in a neuroactive toxin
The effect is quite different from the effects of GABA and melatonin – they send me into light dream sleep. Melatonin is particularly awful, as it induces a hypnotic not-quite-asleep state in me with vivid dream/hallucinations and a big hangover the following morning. The B12/K2 combo doesn’t do this. The sleep is proper, deep sleep. My partner has problems getting into deep sleep, and he also reported feeling like he got deeper sleep after taking K2. He’s usually very skeptical of vitamins, but he seemed quite impressed in this case.
Yippee, I discovered something unknown to science. A phenomenal new sleep drug. Are there any researchers who would like to take this up?
Unfortunately unless I plan on giving up all my IQ points and turning into a sloth, I think I may have to pass on taking B12/K2 regularly. I went on a five day food chemical binge recently, and B12/K2 failed to stop me feeling awful, though they limited my symptoms. I spent far too much time asleep. But at least I have a backup plan for those days when my diet slips.
Having had some relatively helpful improvements taking methyl-B12, and some fairly awful experiences taking other methyl donors like folate, especially when trying to come down off them, I’ve been meaning to get round to doing another isolated B12 trial for a while. Earlier this year I did one. It lasted for around two and a half months.
The RDA for B12 is only about 2.4 micrograms in the US and 1 microgram in the EC. There have been calls from some quarters to increase the RDA by 500% to around 5 micrograms, a dose that is easily obtainable in the diet if you eat meat, but very difficult to obtain if you only eat eggs and dairy, and very variable in different types of fish. I get several hundred times the RDA of B12 in my diet daily. I do not have absorbency problems with B12, because I can feel the effects and side effects of B12 when I take a relatively small dose.
Yasko’s nutrigenomics protocol (which I will critique at a later date), tests for a number of genetic variations in the capacity of the body to reduce (recycle) oxidised B12, the theory being that if you have a poor capacity to recycle B12, you will have a higher dietary requirement than other people.
There are various types of B12 – cyanocobalamin, adenosylcobalamin, hydroxycobalamin, and methylcobalamin. All are active in the body. Cyanocobalamin is thought to be the least useful to the body but is the type usually found in vitamin supplements. B12 is used by the body to detoxify cyanide (i.e. cyano-), so this does make sense. Hydroxycobalamin is the type typically found in meat, along with some adenosylcobalamin. Apparently methylcobalamin is only found in significant amounts in milk, suggesting it may be required by infants and young animals. The body also uses B12 to detoxify sulphites to some extent, forming sulfitocobalamin – thought to be a toxic compound in its own right.
I used a Metabolics adenosylcobalamin supplement in capsule form. I chose this over hydroxycobalamin purely because I could not obtain hydroxycobalamin in powder form. Each capsule contains 1 milligram (1000 micrograms) of B12. This is an enormous dose, approximately 100,000 times the EC RDA. I have taken very large doses of B12 on a number of occasions. I experience some rather peculiar effects from a large dose of B12. I often become twitchy and very anxious and stressed. I also get the most excruciating ‘trapped nerve’ pain down the side of my neck. I had no intention of taking large doses of B12, instead I broke open each capsule and sprinkled a tiny amount on my tongue. I could make one capsule last over a week. This means I was still taking quite a large dose, but not large enough to give me nerve pain.
B12 does some very interesting things to me. Firstly, it makes me feel more intelligent. I feel wittier, brighter, more cheerful, more motivated, and more chatty. It makes me just a wee bit too happy. It also seems to have the peculiar effect of turning me into social dynamite. Gee, I never knew I could be so funny and entertaining that people ask me for my phone number and email address [the slight problem with this is that I never answer my phone unless I know who is calling!]. It also gives me more energy. Food chemicals, alcohol and stress often leave me feeling drained and fibromyalgic, and B12 seemed to negate some of this.
I have an online friend who tried taking B12 and after a couple of weeks experienced a seizure – I think complex partial. She is doing a nutrition degree and after researching this she discovered that B12 has the ability to depress a form of glutamate decarboxylase (GAD67) that converts glutamate into GABA. The symptoms I am going to describe make perfect sense in this context. Interestingly, the Japanese regard glutamate as making you more intelligent, which has something to do with why they eat miso soup for breakfast. Though I imagine several thousand Japanese commuters who’ve just eaten miso soup for breakfast won’t be in the best of moods.
The downside changes B12 makes to my personality are that I become a lot more irritable and emotional. Some people like melodrama in their lives. I don’t. I cry more easily. I become stressed more easily. I become more judgemental. I have a very low tolerance threshold for anger. The thing about being irritable is that irritability is completely invisible when you are on your own or things are going your way. Then someone crosses your path and confounds you, the dog does something naughty, a driver does something stupid on the road, and instead of coping and carrying on you get disproportionately cross about it. Exploding unpredictably might be something that earns you a little respect and fear, but it’s an extremely unattractive personality trait.
B12 also seems to ease my chronic back pain. The back pain is related to a lot of things. Food chemicals play a very significant part in it, particularly amines, which are always vile, but also salicylates. Propionates (E282) have me in absolute agony after a sneaky build up, and gluten and A1 casein give me a chronic low-level ache. But it’s also a repetitive strain type injury. It’s partly because we have an awful mattress that needs replacing – when we had a foam mattress a couple of years ago my back was great. I spend too much time using a laptop on my lap. I can’t sit at desks for very long as my former DVT leg starts to swell up and hurt because the valves in my leg vein are permanently damaged. So instead I sit on the sofa with my legs on a footstool or folded to one side and hunch a bit over my laptop, which puts pressure on the top third of my spine and my neck. Also, I have Lara Croft boobs, which sounds great if you don’t have them, but in practice they give me back pain. If someone offered me a reduction to a B or a C cup I would take it without hesitation because at my minimum BMI I was still a 32D. I also have lower back problems as well as upper back problems. I’m not sure which is worse. If I stand or walk around all day my upper back is a lot better, but I feel like someone’s been pile driving my spine into my pelvis. I can make the bottom of my back make an audible cracking sound by wriggling around a bit. B12 doesn’t get rid of my back pain entirely but it does seem to help lessen it. So does sunlight. So does a ketogenic diet.
I also experienced improvements in my skin. B12 did not make my skin perfect, but it seemed to lessen some of the bumps and red patches that flare up on my skin after I eat amines, additives or caffeine. However, I did experience some tinnitus.
B12 significantly improves my amine/salicylate tolerance. As well as damping down skin reactions the day after eating food chemicals, it also lessened the hangover/brain fog symptoms I get. However, this leads to problems because I feel I can cheat. My skin actually got significantly worse in practice because I felt I could get away with more and obviously I couldn’t. B12 seems to prevent some of the skin problems that flare up when I take folate or other methyl donors. However taking a multivitamin and some B12 still left me feeling significantly foggier and itchier than if I had done nothing at all. Unfortunately B12 does not negate food reactions, not even in a very high dose. I still feel off the day after eating something bad, however, a whole capsule megadose did come in very handy recently when I had no choice but to eat a curry (lovely red colouring and spices in it) with some friends. I have done this a few times now and I am usually wiped out for the whole of the next day. In this case I still made lots of silly mistakes and was very cross (not great when you have a four hour drive to make on hangover day). But I wasn’t bedridden, as I have been on previous occasions.
I often have problems waking up in the morning, especially after consuming food chemicals, and B12 seems to help quite a lot with this. I feel like I need less sleep and I wake up faster. In fact I generally feel more awake. It’s something I first caught on to after eating some clams one night and bouncing out of bed early the following morning. Clams are very rich in B12. Something else that helps me to wake up in the morning is tonic water. Tonic water contains quninine, a stimulant, which may also be, interestingly, a folate antagonist.
Returning to the notion of B12 as having glutamergic effects, this makes sense. Some anti-narcolepsy stimulants like provigil are thought to have glutamergic effects as well as raising monoamine levels. What is curious is that some people also experience drowsiness when they consume glutamates. I have been kept awake by glutamates and I have been sent to sleep by them (and I have been made totally autistic and spaced out by them). This may have something to do with the way glutamate interacts with other neurotransmitters at different times of the day. B12, however, always kept me awake and did not make me any more autistic than normal.
The downside of feeling awake is that B12 also gives me insomnia. Quite bad insomnia. It takes me a couple of hours to get to sleep. I’ve heard some people say that this ‘wears off’ as you get used to the B12. I have news: like hell it does. Two and a half months later I still had insomnia like this. Also, in the process of falling asleep I experience unpleasant heart palpitations and skipped heart beats, and hypnic jerks – little tiny myoclonic seizures as you’re falling asleep. One night shortly after I started the experiment, I had a hypnic jerk in the night that was so bad it threw both of my arms forward and I actually sat up in bed. My partner has JME and he had symmetrical arm seizures like these before we got him medicated properly. The palpitations and hypnic jerks did lessen, but they were still more frequent than usual. I also had a few moments when I was awake that felt like twitches or electric shocks, or, almost as though I had missed a second when I was doing something or watching something move. This is not good, in fact, it’s quite scary. Having a lapse like that when you are holding a kettle, cooking, or driving, is a fairly bad idea.
Apart from the irritability and the reduced tolerance of stress, the biggest downside to taking B12 was the weight gain. I have had very stable weight for a long time now, but I gained around five pounds during the two and a half month period I was taking the B12. This was not just because I ‘cheated’ more. On occasions when I tried taking a whole capsule, I would usually wake up the next day a pound or half a pound heavier. Though B12 did increase my appetite, I did monitor my calorie intake, and as usual, the weight gain was disproportionate – particularly as I was much more active than usual. It was real weight – fat – not muscle or water – and it did not come off of its own accord. B12 did not negate the weight gain I experience when I eat amines either, instead it contributed.
Something important to note is that during this experiment, I felt really very good for the first 2-3 weeks, then I started to feel less good and old symptoms started filtering through again – so either my body started to get used to the B12, or something else was missing or being depleted. A couple of years ago I would have come to the second conclusion, these days I am inclined towards the first.
I dreaded ending the trial but I could not continue to gain weight at the pace I was going. I have experienced awful withdrawal symptoms from taking methyl donors, and as B12 feeds into the methylation cycle, I was expecting to experience them again when coming down off B12. But I didn’t. This was totally astonishing. When I stopped taking B12 I just felt really, really calm and relaxed. I felt glad and relieved to have ended the experiment and to have stopped feeling so short tempered and unpredictable. If I became stupider again, I didn’t notice it. But then, when you’re stupid you don’t pick up on things, that’s the whole definition.
Would I take B12 over doing a ketogenic diet? And here, by a ketogenic diet, I mean a diet that is carbohydrate and calorie controlled – it tends to lose its effect if I reach a metabolic equilibrium.
No I wouldn’t. A ketogenic diet causes very similar improvements to how I feel and my various chronic symptoms, with the exception that it is not as good at negating reactions to food chemicals. However a ketogenic diet makes me feel a lot more motivated and energetic than B12 does. It also comes with the advantage that I remain very calm and stress-free and not prone to emotional swings. On a ketogenic diet, which reduces the impact of glutamate, I feel like I can cope with anything.
I have decided not to take B12 permanently due to the negative side effects, which are pretty much as bad in their own way as being off failsafe. Perhaps in the future I will find a way to counteract the glutamate-agonist response (B6, K2, glycine, glutamine, theanine, or ketosis are all potential options). However, I do believe I will find it most useful if I take B12 when I am forced to eat off-diet, in order to counteract strong negative reactions to food chemicals.
You can take your vitamins and throw them down the toilet. Folate makes me manic and gives me eczema. B12 makes me feel a little bit too happy, very intelligent, too awake (great first thing in the morning, terrible problem at night), makes me easily stressed and irritable, and makes me gain weight quickly. After having stable weight for months and months, I suddenly gained several pounds in the space of a two month B12 (adenosylcobalamin) trial earlier this year. On the plus side it actually helped my residual winter eczema somewhat – though not as much as getting some sunshine has.
The weight gain that B12 causes I suspect is connected to B12’s ability to depress a form of glutamate decarboxylase (GAD67) that converts glutamate into GABA. And of course glutamate stimulates weight gain through insulin production. More on the B12 trials in another post.
So the upshot of this is that I’ve been back on a diet for a few weeks now to get rid of the weight. I’m on a ketogenic diet. Properly. Last year I did a moderate version that included a small portion of rice every day. I tried this because without any carbohydrate at all I tended to just flake out and feel starved. I couldn’t really sustain the rice version for long as I tended to feel just a little too hungry all the time. Of course this means I don’t have much variety in my diet right now. Largely I’m living on lamb, chicken, fish, shellfish, eggs, and A2 dairy (butter, cream, cream cheese), and Woodlands organic sheep’s milk yoghurt, which has turned out to be a life-saver (at last! a yoghurt that doesn’t give me headaches and cravings!). I’m not hungry at all. This probably sounds like a scary anorexic diet, but I am getting enough calories and vitamins, I assure you. I’m also feeling better than I have in years. Literally years, because I haven’t really done failsafe gluten-free for very long before, and I haven’t done it ketogenic like this. All my leftover aches and pains have gone – I suspect gluten and A1 milk bother me rather more than I liked to think they do. This time I have no real hunger, so I feel as though the diet is sustainable and I plan to stay on it for at least six months – or until I get back down to my minimum healthy BMI, because I like being slim.
And I’m calm. Totally calm. Ambien calm. It’s like someone found the centre of my emotional balance and nailed me there. No stressing out over minor things. No irritation. I’m also highly motivated. Hence less posts and more stuff getting done around the house. Like painting walls and constructing furniture and spring cleaning and unpacking boxes that are still left form the house move last year – all the stuff that normally tires me out just thinking about it. I’m not manic however – I’m just happy in a good, balanced way.
No vitamin could ever do this or has ever done this for me. The minor improvements I saw in myself on the B12 (which approached megadoses on occasion) are nothing in comparison to the sledgehammer effect of ketosis. And ketosis comes without the unpleasant side effects. My sleep is fine. I’m waking up fine. I feel sharp. And I’m losing weight instead of gaining it.
And why it’s relevant to failsafers!
Our objective was to study brain amino acid metabolism in response to ketosis. The underlying hypothesis is that ketosis is associated with a fundamental change of brain amino acid handling and that this alteration is a factor in the anti-epileptic effect of the ketogenic diet. Specifically, we hypothesize that brain converts ketone bodies to acetyl-CoA and that this results in increased flux through the citrate synthetase reaction. As a result, oxaloacetate is consumed and is less available to the aspartate aminotransferase reaction; therefore, less glutamate is converted to aspartate and relatively more glutamate becomes available to the glutamine synthetase and glutamate decarboxylase reactions. We found in a mouse model of ketosis that the concentration of forebrain aspartate was diminished but the concentration of acetyl-CoA was increased. Studies of the incorporation of 13C into glutamate and glutamine with either [1-(13)C]glucose or [2-(13)C]acetate as precursor showed that ketotic brain metabolized relatively less glucose and relatively more acetate. When the ketotic mice were administered both acetate and a nitrogen donor, such as alanine or leucine, they manifested an increased forebrain concentration of glutamine and GABA. These findings supported the hypothesis that in ketosis there is greater production of acetyl-CoA and a consequent alteration in the equilibrium of the aspartate aminotransferase reaction that results in diminished aspartate production and potentially enhanced synthesis of glutamine and GABA. Response of brain amino acid metabolism to ketosis
There are a number of different studies by Daikhin and Yudkoff that have confirmed the above hypothesis in different ways. They can be found in pubmed. I won’t repeat them all here.
Here is a study that found other differences:
The ketogenic diet (KD) is an established treatment for medically refractory pediatric epilepsy. Its anticonvulsant mechanism is still unclear. We examined the influence of the KD on the CSF levels of excitatory and inhibitory amino acids in 26 children (mean age 6.1 years) with refractory epilepsy. Seventeen amino acids were determined before and at a mean of 4 months after the start of the KD. Seizures were quantified. Highly significant changes were found in eight amino acids: increases in GABA, taurine, serine, and glycine and decreases in asparagine, alanine, tyrosine and phenylalanine. However, aspartate, glutamate, arginine, threonine, citrulline, leucine, isoleucine and valine/methionine remained unchanged. A significant correlation with seizure response was found for threonine (P=0.016). The GABA levels were higher in responders (>50% seizure reduction) than in nonresponders during the diet (P=0.041). In the very good responders (>90% seizure reduction), the GABA levels were significantly higher at baseline as well as during the diet. Age differences were found with significantly larger decreases in glutamate and increases in GABA in connection with the diet in younger children. Our results indicate that the KD significantly alters the levels of several CSF amino acids that may be involved in its mechanism of action and the increase in GABA is of particular interest. The ketogenic diet influences the levels of excitatory and inhibitory amino acids in the CSF in children with refractory epilepsy
Glutamate and aspartate are both ‘bad’ neurotransmitters for people with food chemical intolerance (aspartate is involved in salicylate reactions on NMDA receptors). Ketosis appears to reduce aspartate levels by moving glutamate production away from aspartate and towards GABA and glutamine. Other glutamate-opposing amino acids like taurine, serine and glycine are raised too. GABA and glutamine are both ‘good’, calming neurotransmitters for failsafers.
The ketogenic diet has been studied for many years in relation to intractable epilepsy in children. It has also been hypothesised to help bipolar disorder:
The ketogenic diet, originally introduced in the 1920s, has been undergoing a recent resurgence as an adjunctive treatment for refractory epilepsy, particularly in children. In this difficult-to-treat population, the diet exhibits remarkable efficacy with two-thirds showing significant reduction in seizure frequency and one-third becoming nearly seizure-free. There are several reasons to suspect that the ketogenic diet may also have utility as a mood stabilizer in bipolar illness. These include the observation that several anticonvulsant interventions may improve outcome in mood disorders. Furthermore, beneficial changes in brain-energy profile are noted in subjects on the ketogenic diet. This is important since global cerebral hypometabolism is a characteristic of the brains of depressed or manic individuals. Finally, the extracellular changes that occur in ketosis would be expected to decrease intracellular sodium concentrations, a common property of all effective mood stabilizers. Trials of the ketogenic diet in relapse prevention of bipolar mood episodes are warranted. The ketogenic diet may have mood-stabilizing properties
When the researchers say that anticonvulsant interventions help bipolar disorder, one example is the prescribing of sodium valproate for people who have bipolar disorder. I have a close friend with epilepsy who is familiar with both valproate and ketosis. Valproate is an acetone mimic that produces effects on the brain that are identical to ketosis. The difference is that valproate comes with a range of side effects that a ketogenic diet doesn’t have.
If valproate is used for bipolar disorder it naturally follows that ketosis would help too.
Unfortunately no studies have yet been conducted to back up the use of a ketogenic diet for bipolar disorder. Which is a dreadful shame. It has helped (as in ‘effectively cured whilst diet is maintained’) three members of my family who have bipolar tendencies but are just short of official diagnosis – something that Prozac didn’t do for their depression.