You may want to investigate and get tested for an MTHFR defect. I tested positive homozygous mutation for the 677 variation of the MTHFR defect. I haven't started a protocol yet, as my problems are massive and detailed in my thread.
Hmm, definitely seems very relevant for people with a plethora of seemingly unrelated symptoms. Note that an MTHFR defect would inherently affect multiple organ systems and thus is not likely to be the case if the problems are merely neurological.
Another bit of evidence to suggest Glutamate -agonists might be the key to treating several sub-groups of ADHD.
http://www.nature.co.../tp201411a.html
This study found that a lot of us have lower Glutamate than the baseline population, and that significantly lower levels were all involved in greater symptoms of inattention.
Man, I really wish all of us could be on some glutamate -agonists right now... If only we could figure out which ones would be the most effective tho'? Fasoracetam is one possible compound, but is it the right one?
Dr Hakonsson has been testing that stuff for close to 5 years now, but haven't published anything that suggests any results from administering it to patients. Yet I do believe I read that he's got plans to launch it as a drug to combat ADHD somewhere around 2017.
I do wonder... do you guys know what the most logical reason is why those of us with ADHD-PI, without hyperactivity, are actually hypO-active? Is it that our brains have some extra impairments, that inhibit our ability to generate heightened adrenal levels, to compensate for the low uptake of dopamine and norepinephrine? What's the general theory here anyway? Why are we different from the Hyper-active guys?
Glutamate is definitely an understudied area of AD(H)Dm, and that is an excellent study. However I'm wary to assume any single one neuro-circuit is responsible for the disorder. Quite a few studies have all pointed to different areas of the brain, and the most relevant area (both in terms of logical function and observed deficits) seems to be the Prefrontal-Cortex. I also very strongly have come to believe that there is NO single AD(H)D disorder, but an array of disorders with different causes that create similar symptoms. This theory best explains the lack of consistency in studies observed deficits as well as how patients respond to various ADHD so dramatically (Ritalin works for many, but it also fails to work for many). I have the same feelings in regards to most psychiatric disorders.
As for your question, there is no definitive answer. My best guess is that ADD aka ADHD-PI is primarily mesolimbic pathway dysfunction, with minor dysfunction in the prefrontal cortex. This combination would produce a syndrome of erratic response to reward/punishment, with only minor self-regulation issues (compromised ability to direct internal attention). ADHD-PH (Primarily Hyperactive) is more likely a case of mostly just severe prefrontal cortex dysfunction. This in theory produces a syndrome of severely compromised ability to self-regulate which affects not only internal behaviors but external behaviors as well (the PFC's purpose of "gating" impulses is disrupted), and so you have a child who not only has trouble controlling their attention, but they have great difficulty controlling their impulsive actions.
The reason why it's so difficult to pin down despite modern advances in scanning technologies is that the brain is capable of adapting to selective impairments, particularly the developing brain in toddlers to children around 12 years of age. Other areas of the brain may develop differently in order to "take up the slack" of the dysfunctional components; albeit not as effectively (additionally, some areas may not intentionally develop differently, but are forced to due to the dysfunctional pathways). The result of this is that brain scans show minor (and major) abnormalities everywhere, obscuring the origin of the problem. Once the child is an adult, reversing the defects may not be possible, as the brain will have developed differently than it should have, and thus may not perform better (or may even perform worse, explaining why some ADHD patients react adversely to stimulants, even mild doses) if the root problem is corrected too late.
Symptoms of excess Acetylcholine would fit ADD-PI as well, low dopamine and everything.
Regarding the Glutamate angle - maybe taking precursors like Glutamine, Ketoglutarate or Glycin could be enough to lessen symptoms if that was the case?
I for one get a relief in symptoms when taking Modafinil, which increases Glutamate, Histamine, Dopamine and Serotonine in various parts of the brain - with Acetylcholine being pretty much the only transmitter it doesn't (directly) affect.
Cholinergics on the other hand make my symptoms worse instantly.
Guess I'm gonna try both angles - Glutamate precursors and maybe a TCA like Anafranil (chlomipramine) to lower ACh.
Maybe even (carefully) combine them with low dose Modafinil?
It's too damn bad there are very few if any selective Acetylcholine antagonists or even Acetylcholine-esterase activators available...
Precurors are rarely good drug targets. The problem is that there are too many factors in the body preventing precursors from affecting levels of the chemicals derived from them, such as rate-limited enzymes, neurochemical transporters, etc. At best they may cause very temporary increases in neurotransmitter activity, that rapidly stabilizes. Most studies suggesting sustainable positive improvement from precursor supplementation have quality issues, and such studies are few and far between. They can be helpful when one is unsure if they're are getting insufficient amounts from their diet however.
If you want to target the Glutaminergic system, there are several agents that are available. Sunifiram is a good glycine receptor agonist, but I've found it to be a bit too potent for comfort. Sarcosine is a milder glutaminergic agent, acting as a mild glycine reuptake inhibitor, which to me seems like a better (and safer) target.
Modafinil is definitely on my list of things to try, as it has some very interesting observed activity, very diverse in it's actions, yet still mild enough to avoid severe side-effects. The only deterrent for me is the cost and difficulty obtaining in some countries (apparently Canadian customs are pretty tough on these things), unless you live in the EU or India.
As for acetylcholine, I am skeptical of it being very relevant to ADHD. There isn't much evidence implicating those circuits (and the studies I've found seem to implicate a deficit, rather than an excess of it), and I haven't heard of any widespread success of the very common acetylcholinergic nootropics (piracetam, etc) in ADHD users (for ADHD symptoms) on the forums. Furthermore, acetylcholine antagonists are very risky to play around with, as getting the dose (or potency) wrong can cause paralysis affecting the respiratory muscles, and thus death.
LongeCity
