I was just going to briefly discuss some issues that could be relevant, in my opinion, to the potential for the use of purine nucleotides and L-methylfolate, a reduced folate that is available by prescription (with the brand name of Deplin) or over-the-counter (as L-methylfolate, with the trade name of Metafolin, etc.), as adjunctive strategies, used under a doctor's supervision, for dealing with depression. The most basic thing is that the use of adenosine 5'-monophosphate (AMP) is likely to allow for more flexibility in dosing, over the long term, than the use of adenosine 5'-triphosphate (ATP) disodium is, primarily because the hydrolysis of ATP, by a variety of ectonucleotidase enzymes (and also intracellular nucleotidase enzymes, in the intestinal epithelial cells) and esterase enzymes in the luminal fluid of the small intestine, supplies significant amounts of inorganic phosphate. I don't like to mention brand names on here, and I have no financial ties whatsoever to any supplement or pharmaceutical manufacturer or to any other company or commercial interest. The Bluebonnet nucleotide complex is, in my opinion, still the only over-the-counter supplemental source of AMP that provides a meaningful amount of AMP [(
http://www.google.com/products?q=nucleotide+bluebonnet&hl=en&aq=f)]. The phosphate is likely to be absorbed more rapidly than the phosphate that is derived from the hydrolysis or, rather, phosphorolysis of polyphosphates that are present in meats, for example. In my most recent postings on the nutritional aspects of phosphate, I was trying to convey that the use of supplemental sources of phosphate has the potential to be problematic, especially but not only when the supplementation continues for more than a few weeks. And I think that supplementing with any source of phosphate without close supervision by a doctor (this would be of absolutely crucial importance and would include the use of blood tests, every couple of weeks, to monitor serum phosphorus, and the use of urinary phosphorus tests to monitor urinary phosphate excretion) has the potential to be extremely hazardous. Sources of supplemental phosphate can elevate serum phosphorus in very unpredictable ways, and the key point is that AMP provides one third as much phosphate as ATP does. Some of the articles I cited in past postings show that the serum phosphorus levels can rise slowly, over many months, and then suddenly increase exponentially, with potentially devastating consequences to kidney function or to the functioning of any tissue, in which the precipitation of calcium phosphate can cause serious damage. This includes any tissue in the body. So I wanted to reiterate and strengthen my warnings about the significant potential for danger that can accompany any use, whatsoever, of a source of supplemental phosphate. Some ATP disodium supplements also contain calcium phosphate binders and silicates, and these excipients can supply significant amounts of calcium that could, in my opinion, either prevent or augment the adverse effects that excessive phosphate intakes can produce, and the effect (prevention or augmentation) would be expected to depend on the dosage and the timing of the administration/intake of the excipient. Messing around with that stuff and worrying about supplements that are loaded up with calcium doesn't sound very good to me, for reasons I've discussed, at length, in the past.
Part of the point with this is that the use of supplemental gluconate, glutamine, creatine, citrate, or adenosine or inosine or other supplements that supply organic anion substrates can, in my opinion, significantly limit the amounts of oral AMP that one can tolerate, and this can become very problematic and puzzling. I've mentioned this in the past, but I want to emphasize that it's very important, in my view, to consider the fact that many nutrients and drugs compete with phosphate and with bile acids, for example, for transport by nonspecific organic anion transporters, in the kidneys and liver. In essence, there tends to be a limit to the total supply of "organic anion transporter (OAT) substrates" (these transporters are very numerous and include the ATP-binding cassette family of transporters, and that family of transport proteins includes the multidrug resistance transport proteins, as in mdr1, mdr2, etc.) that one can ingest, and it can become necessary to "decide" which nutrient one wants to supplement with and to limit the dosages of the other OAT substrates. I've been aware of this for a long time, and many articles discuss the crucial importance of this in the context of liver disease or in relation to kidney-related pharmacology. But it took me a long time to realize that, for example, the dosages of magnesium gluconate, creatine, and glutamine that I'd been taking had been causing me to be unable to use dosages of AMP that I'd wanted to use, in relation to antidepressant augmentation, under my doctor's supervision. The dosages of the individual supplements were not high and were actually fairly low (well, I'd been taking 24 grams of glutamine and about 800 mg of creatine monohydrate, but the amounts of gluconate from magnesium gluconate are likely to have been excessively high), but the total "mass" of OAT substrates (this "mass" includes all of the citrate and glutamate and whatnot that glutamine is metabolized into, and it includes creatinine and other degradation products of creatine and also includes the extra phosphate that can accumulate intracellularly, in response to exercise, in a person who's taking creatine, given that the extra creatine phosphate can, in my opinion, tend to "dump" more phosphate during exercise) was high and was causing me to be unable to tolerate enough AMP. I was noticing that my plasma volume or, less specifically, extracellular fluid volume was high, and this was most obvious during exercise. One manifestation of this can be "water retention" that is obvious at the end of a workout, etc. Uric acid (urate) and other purines that are derived from AMP (and from the guanosine 5'-monophosphate in that nucleotide supplement) also compete with phosphate and with bile acids for transport. I've reduced the dosage of glutamine to 4-8 grams per day and reduced the dosage of creatine monohydrate to about 400 or 500 mg per day (I may reduce this further) and have been able to tolerate more AMP, etc. I also stopped taking magnesium gluconate. If one were taking a small dose of magnesium gluconate, this might not be an issue. But what's a small dose. To supply 30 mg of magnesium, one has to take in something like a gram of gluconate (derived from the magnesium gluconate, after one has ingested it).
This is a very important issue, in my opinion, because AMP is, in my view, probably the most "important" over-the-counter compound that could, in my view, be of sigificance in relation to adjunctive antidepressant strategies that researchers could test and that one could discuss with one's doctor. Methylfolate, for example, has the potential, in my view, to gradually contribute to the decreases in the intracellular purine nucleotide levels that can result, in my opinion, from the use of any number of medications that produce any sort of excitatory effect, whatsoever, on neurotransmission. On a personal level, I've found that none of the antidepressant augmentation strategies, such as Deplin (prescription L-methylfolate), has been nearly as useful, in the long term, without the concomitant use of AMP, but that's just been my experience. It's important to remember that the accumulation of uric acid, produced by purine degradation, can become problematic in the long term and could, in my opinion, contribute to soft tissue calcification, and the safe way to go would be to monitor one's urinary uric acid levels and not just to monitor serum uric acid (serum urate) levels with blood tests. The "excitation-induced decrease in purine nucleotide concentrations" in neurons and astrocytes is a general phenomenon and could even occur in response to the pathological, stress-induced increases in the firing rates of noradrenergic neurons in the locus ceruleus or other adrenergic cell groups (i.e. the A1, A2, and A3-A6 and C1, etc., adrenergic cell groups in different parts of the medulla oblongata). I'll try to put up some better references, but here are some of the countless articles discussing the neuronal-excitation-induced increases in extracellular fluid adenosine levels [Latini and Pedata, 2001: (
http://www.blackwellpublishing.com/specialarticles/jnc607.pdf); Rosenberg and Li, 1995: (
http://www.ncbi.nlm.nih.gov/pubmed/8548307); Schubert et al., 1997: (
http://www.ncbi.nlm.nih.gov/pubmed/9369970); Matsumoto et al., 1982: (
http://www.ncbi.nlm.nih.gov/pubmed/1352728); Hagberg et al., 1987: (
http://www.ncbi.nlm.nih.gov/pubmed/3585332); Frenguelli et al., 2007: (
http://www.ncbi.nlm.nih.gov/pubmed/17459147)(
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920548/pdf/jnc0101-1400.pdf); Hagberg et al., 1986: (
http://www.ncbi.nlm.nih.gov/pubmed/2875423)]. When there's the kind of excessive noradrenergic transmission that can lead to the derangements and "decreases" in noradrenaline (norepinephrine) "levels" that have been associated with the worsening of depression or of anxiety disorders, there is the distinct potential, in my opinion, for increases in glutamate release, by glutamatergic neurons that provide synaptic inputs to the noradrenergic or dopaminergic or serotonergic neurons, to also occur and to have the potential to contribute to the excessive increases, as can be induced by stress, in the firing rates of the noradrenergic neurons or other groups of neurons.
The point is that, in my opinion, exogenous AMP, for example, has the potential to replenish some of these losses, even if the effect is not as great as one would like it to be (as it would be in response to intravenous inosine, for example, or an adenosine prodrug or source of intravenous adenosine that would release adenosine very, very slowly into the bloodstream). But I can't make any statements about the efficacy or safety of any of these supplements, and I definitely wouldn't expect any of the supplements to be effective by themselves, without conventional prescription medications, in the treatment of depression or anything else. I'll reiterate the extreme importance of discussing these details and concepts with your doctor.
