This is an interesting article [Halaris and Pleitz, 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17927294)], and the authors discuss the effects that the administration of exogenous agmatine, an arginine metabolite, can have on the brain. Apparently, significant amounts of agmatine can be made from arginine, either outside the brain or in the brain, by the decarboxylation of arginine by arginine decarboxylase (ADC). ADC converts arginine into agmatine in a single enzymatic step. The authors discuss some of the research showing antidepressant or anxiolytic (anti-anxiety) effects of agmatine in animal models of depression or chronic stress, etc. (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=agmatine+psychiatric+OR+antidepressant+OR+anxiety+OR+anxiolytic+OR+neuroprotective+OR+pain+OR+antinociceptive). I have no idea if agmatine actually has antidepressant effects in people, and it's important to remember that these types of physiological substances are not a substitute for medical treatment for anxiety or mood disorders. Even under a doctor's supervision, the uses of some of these things would, in my opinion, only potentially have value as adjunctive treatments, etc. None of them has been proven or approved to treat any condition or disorder.
Some people have also suggested that agmatine could be responsible, at least in part, for the growth hormone (GH) releasing effects of arginine. I can't immediately find an article in which someone suggests that, but I'm sure various people have suggested it. Agmatine exerts, among other actions, alpha2-adrenoreceptor (alpha2-AR) agonism, meaning that it activates alpha2-AR's, in a manner similar to clonidine. Clonidine is known to release GH by acting as an alpha2-AR agonist. The anxiolytic effects of agmatine could also be the result of its alpha2-AR agonism. Yohimbine, an alpha2-AR antagonist, is sometimes referred to as an "anxiogenic" drug and has been shown to block or reverse many of the effects of agmatine (the alpha2-AR agonism can contribute to the potentiation by agmatine of the morphine-induced antinociceptive effects, etc.) (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=clonidine+agmatine). Agmatine also exerts antagonism at NMDA receptors (NMDA-R), and that action could account for the anxiolytic, antidepressant, and antinociceptive effects. Halaris and Pleitz (2007) noted that agmatine evidently doesn't bind to a polyamine binding site (there are multiple polyamine binding sites on different NMDA-R subunits) on the NMDA receptor. I'm not sure which polyamine binding site the authors are referring to, but presumably they mean the ifenprodil-sensitive binding site. Agmatine is also an agonist at imidazoline receptors (I1 and I2 imidazoline receptors) (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=imidazoline+agmatine).
Halaris and Pleitz (2007) had suggested that agmatine might be useful in treating anxiety disorders or depression but subsequently began to favor the use of agmatinase inhibitors in the treatments of those conditions. Agmatinase is an amine oxidase enzyme that degrades agmatine to putrescine and urea. Thus, the idea would be that inhibition of agmatinase would slow the breakdown of agmatine and prolong its actions. This sounds rational, on a superficial level, given that agmatine does appear to have a short duration of action (even though its formation from endogenous arginine pools would presumably be somewhat ongoing). But agmatine aldehyde (AGALD) is known to be an inhibitor of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS). The slowing of agmatine turnover could increase the extent of the AGALD-mediated inhibition of nNOS. The inhibition of iNOS would tend to be desirable but could conceivably be undesirable under some circumstances. As a rationale for the use of agmatinase inhibitors and not agmatine itself, the authors note that agmatine may have a narrow therapeutic window and may begin to enhance glutamate release, an effect that would tend to be undesirable, at dosages slightly higher than the dosages that are neuroprotective and that produce therapeutic effects. At 50-100 mg/kg, given intraperitoneally, agmatine was shown to be neuroprotective. In contrast, a dose of 150 mg/kg did not produce neuroprotection. The authors also noted that 80-100 mg/kg, which are in the higher range of dosages used in animal studies, can cause transient uremia in animals (they mean an elevation in serum urea that is not (likely to be) associated with kidney toxicity; this is a misuse of the term, really, given that, in the true uremia that occurs in people with renal failure, there are elevations in the serum concentrations of urea and also of other metabolites that are excreted renally or that have accumulated abnormally, such as in response to metabolic toxicity from uremic toxins, etc.). The urea is formed from the degradation of agmatine by agmatinase. The authors discuss similar effects associated with uremia, such as lethargy and loss of appetite, in a primates given 30 mg/kg by intravenous injection [Piletz et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/15028571)]. At dosages approaching 200 mg/kg, given intravenously, in rodents, Piletz et al. (2003) noted that large (dangerous) reductions in mean arterial blood pressure had been noted. If one scales those dosages (http://hardcorephysiologyfun.blogspot.com/2008/12/equations-for-animal-food-intake-and.html) using the scaling factor of 7.14, for young rats, or the most conservative, blanket scaling factor of 10, one gets 7-14 mg/kg bw or 5-10 mg/kg bw for a human (given intraperitoneally). The monkey weighed 12 kg (Piletz et al., 2003), and that gives a scaling factor of 1.70 (17.65 mg/kg bw i.v. for a human). Those translate into potentially-therapeutic, intraperitoneal dosages, for a 70-kg human, of 350-700 mg or 490-980 mg. The scaled monkey dosage of 1235.5 mg (i.v.), for a human, was associated with lethargy and adverse effects. The upper range of dosages, approaching 100 mg/kg i.p. in animals (which is the range of 700-980 mg per dose, scaled to humans), were associated with adverse effects in some studies, according to Halaris and Pleitz (2007). Those dosages are by parenteral routes of administration, and the Cmax and AUC values would be expected to be lower in response to oral dosing (due to a higher first-pass effect in the liver or even the lungs (the lungs exert a first-pass limitation of bioavailability following i.v. dosing)). That would theoretically mean that oral doses could be higher, but the point is no one knows what the oral dosage range would be. Additionally, the urea issue would still be a dose-limiting factor, regardless of bioavailability.
I do that kind of analysis to get a sense of things for myself and to hopefully discourage anyone from being reckless with something like agmatine, given its complex pharmacological effects. There might be tachyphylaxis to the central hypotensive effects, but the transience of that type of effect wouldn't necessarily show up in everyone to the same degree. A person taking any number of medications could have serious complications from something that has strong hypotensive effects. I give these warnings because I see that agmatine is being sold as a supplement, although it's evidently not widely available. But this is the type of thing that could be especially problematic without a doctor's supervision, even though one should always discuss these things with one's doctor before one takes any supplement. I'm not saying agmatine is necessarily likely to have any usefulness at all (it may not, and I have no idea if it would or not), but I will say that lots of drugs have narrow therapeutic windows. It's worthwhile to take that information, provided by Halaris and Pleitz (2007), seriously, though, because an excess of urea can elevate serum sodium (and an excess of glutamate release would probably not be desirable). Agmatine has also been shown to be capable of lowering blood pressure, an effect that could be the result of its activation of imidazoline or alpha2-ARs. I was going to discuss agmatine in relation to polyamine metabolism, more broadly, but I don't have time at the moment.
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