MAJOR UPDATE (MUST READ):
I've been doing an incredible amount of research lately, and I have made a breakthrough. I'm piecing together results from various studies, and I may have discovered the penultimate link between a single neurological malfunction and ADHD (as well as several other disorders). What is this link? The NMDA receptor, and more specifically, calcium ion release (which it facilitates).
One of the things that has been confounding ADHD researchers is that several receptors and neurotransmitters have been observed to be dysfunctional in patients (which is odd, as it's highly unlikely that several distinct gene polymorphisms, each affecting one neurotransmitter system, could all come together so frequently) As it turns out, the NMDA receptor directly modulates several neurotransmitter systems, dopamine included. The glutaminergic system is the largest neurotransmitter system in the brain, of which NMDA plays a large role in. NMDA in turn directly connects to several other neurotransmitter circuits, which in turn influence other systems. Pretty much every neurotransmitter circuit in the brain is interconnected with each other, so a disruption in one can cause smaller disruptions in others. However, the NMDA circuit has the most direct connections and thus has the most signifigant influence.
Moving on; disrupted NMDA signalling has been observed in ADHD test case rats (specifically that NMDA receptors are overactive), however the authors of the few studies which have noticed this connection seem to have not appreciated the magnitude of this discovery, as a lot of what we know about the glutaminergic system's interactions with other systems is fairly new as well.
My own personal experience supports this hypothesis; my trials with Sunifiram, a potent glycine agonist (glycine are one of several receptors on NMDA neurons) found that it actually made my ADHD symptoms worse even at lower doses (thus excluding ODing as the explanation); causing increased brain fog and attention wandering. This is consistent with the theory that my condition is caused by overactive NMDA neurons; taking a glutaminergic agonist would in theory worsen the problem.
Another coincidence I recalled was that I've heard of some people with ADHD taking Memantine (an NMDA antagonist) to prevent Adderall tolerance (which is actually a real, separate phenomena). They all report it makes their stimulant medication work much better, but what if it's actually directly treating the core of their problem (partially or fully), giving the perception that it's just enhancing the stimulant when in actuality it's working alongside it (as well as preserving their response to it). This seems to be supported by the few cases I've run into of ADHD people using Memantine alone with success. As an NMDA antagonist, Memantine would indeed correct the problem of NMDA overactivity, but taking too much could push the problem in the opposite direction (underactivity).
Just to top it off, NMDA dysfunction also explains the extremely variable response to stimulants amongst ADHD patients. Returning to the use of Memantine to prevent tolerance (as blocking NMDA receptors does reduce the buildup of tolerance to certain drug classes), it makes sense that some patients with greater NMDA activity would experience more rapid tolerance to their meds than patients with lower (but still elevated) activity.
So we know that NMDA signalling has been observed to be a problem in ADHD patients as I have guessed. Now, what could cause that issue? I haven't established a single clear cause (and there may actually be multiple reasons why it's dysfunctional), however I recalled a very strange coincidence. It is fairly well known that supplementing zinc and/or magnesium often helps ADHD people from a mild to moderate degree. Guess which two ions are involved in modulating (normalizing) NMDA receptor signalling? Zinc and magnesium. Both ions play a role in preventing an NMDA receptor from activating in response to lower signals. Now, studies have disagreed whether ADHD patients consistently have depressed levels of those minerals, however it's possible that they may have normal serum (systemic) levels, but disrupted transporters which move them into the brain. If that is the case, then such patient's condition would be further aggravated if they also had lower than optimal dietary intake of them.
I also found that comparing other diseases where NMDA neurons are already suspected of involvement was also insightful. Note that NMDA's involvement in Schizophrenia is now very accepted by the research community, and several glutaminergic agents are being trialed alongside antipsychotic. Note the parallel where both NMDA and Dopamine seem to be involved in the pathogenesis? However get this: in schizophrenia's case the situation is flipped; NMDA receptor activity has been observed to be significantly depressed which (in line with my theory) causes increased dopaminergic activity, which in turn produces the psychotic behavior. This explains why antipsychotics do partially work; they're like painkillers, they treat the symptoms but not the problem. In this case, they counteract the increased dopaminergic activity, however they do not correct the disrupted NMDA activity. This explains why some symptoms of schizophrenia still persist with treatment, and additionally why ADHD patients also experience similar unresolved issues despite stimulant treatment.
After noticing this connection, I began to wonder if Bipolar disorder also shared this link. As I expected, it does (other studies have also noted that bipolar patients have elevated calcium in the CSF. NMDA activation causes a flood of calcium ion release). This makes sense, as the current overcomplicated explanations just seem unlikely (how is it that a disorder seemingly involving several completely unrelated gene polymorphisms all occurring together in a very specific way is not extremely rare?). It could very well be the exact same issue as ADHD, except a more exacerbated form. Overactive NMDA signalling in turn disrupting prefrontal cortical activity (just like ADHD, but to a far more significant extent), possibly rendering the PFC almost disabled, which would naturally in turn cause random mood swings. The prefrontal cortex is highly involved in mood regulation, as it serves to suppress the more raw emotional activity of the amygdala. Intrigued, I delved deeper. Lithium is the most common treatment for Bipolar. Doctors aren't entirely sure how it works, but guess one of the hypotheses. If you guessed that it has been observed to have NMDA-antagonist activity, you are correct 
. What a coincidence, huh?
Now, the first question that popped into my mind was: "Why hasn't someone noticed this yet? It seems like NMDA signalling would be a pretty obvious suspect.". The tricky part is, definitively deciding what is the root of the problem is very difficult, as I mentioned before, all of these neurotransmitter systems are interconnected. The dopaminergic system for example does actually loop back to the glutaminergic system (particularly the NMDA circuit). So it would be difficult to notice "Hey, this is where the problem is starting" just by looking at raw activity. Plus, since psychiatric medicine was originally very much "Try drug first, make theory after if it works", it's only recently that researchers are pursuing new avenues, considering the possibility that the original hypothesis was wrong.
So, wrapping things up this poses the extremely interesting possibility that if NMDA overactivation lies at the core of ADHD. I am personally extremely excited, and am going to obtain some Memantine to test the hypothesis on myself. It's a fairly well tolerated drug, and thus shouldn't pose serious risks if your liver and kidneys are fully functional. I will of course, continue to post.
For those of you who are not keen on trying an Anti-Alzheimer's drug without seeing some more case reports, some other more proactive things you can try are supplementing a combo of Magnesium and Zinc (be cautious with Zinc though, too much can be neurotoxic so try to keep the dose at 15-20 mg at most. Supplement it at night so that it doesn't interfere with copper absorption during the day).
Edited by GetOutOfBox, 03 June 2014 - 04:21 AM.
