Nitric Oxide Supplements (and a surprising neurotransmitter)

    This week brings six updates to, two of which are unrelated to nitric oxide metabolism (and will be covered quickly): Arachidonic acid and serrapeptase.

    Arachidonic acid (AA) is the opposite to fish oil in plasma membranes, and both AA and fish oil create signaling molecules known as eicosanoids; the ratio of AA eicosanoids to fish-oil eicosanoids mediates the benefits of the omega 3:6 ratio and the benefits of both arachidonic acid and fish oil.

    It appears that, in vitro, incubating a muscle cell with higher levels of AA causes production of eicosanoids that can induce muscle protein synthesis. Because of this, plus the fact that it's a relatively novel pathway, AA is touted as a muscle builder. Trials have not yet confirmed these claims, although it does appear that AA can increase joint pain, inflammation, and DOMS.

    Serrapeptase is in a similar situation; there's theory behind its actions, but not enough evidence to either recommend it or disprove its efficacy. Serrapeptase is an enzyme that, following (limited) absorption, appears to confer antiedemic and anti-inflammatory properties. Not much of it reaches the blood, although that which does appears to be enzymatically active; no studies have attempted superloading in order to see if the limitations of serrapeptase supplementation can be overridden by merely taking more.

    Neither claims about arachidonic acid nor serrapeptase can currently be disproved, but there is not enough evidence to support their supplemental usage either. Arachidonic acid is limited in a sense by antagonizing the benefits of fish oil, and serrapeptase is not well absorbed.

    The other cluster of updates involves nitric oxide metabolism. This includes the three commonly used dietary supplements that are in the urea cycle: L-arginine, L-citrulline, and L-ornithine, and the arginine metabolite agmatine.

    As a general statement, ornithine is distinct from both arginine and citrulline as it is not involved with the nitric oxide cycle, and instead just sequesters ammonia while producing urea. Ornithine is an ammonia buffer, and thus is primarily seen as an anti-fatigue agent, or useful in clinical situations where ammonia toxicity is a concern (e.g., renal failure or hepatic encephalopathy).

    Arginine is the substrate from which nitric oxide is created, but this may be a false positive; the enzyme that creates nitric oxide is already saturated, and adding further substrate should not logically induce any changes. That being said, arginine does increase nitric oxide at times, and this appears to be due to extracellular arginine concentrations; this leads to the assumption that the ability of arginine to act on the alpha-2-adrenergic receptors stimulates nitric oxide; however, arginine is weak at doing this (the EC50, aka the concentration that half-activates the receptor, is 1mM, but supplemental arginine only reaches roughly half of that). So although required for nitric oxide production, it is mechanistically weak and unreliable at inducing it.

    Surprisingly, arginine appears to be quite beneficial for those with impaired glucose tolerance and type 2 diabetes. It appears that in these instances, the arginase enzyme (which converts arginine into ornithine) is increased and may cause a relative deficiency of arginine; thus supplemental L-arginine does appear to fairly reliablu improve blood-vessel health and nitric-oxide production.

    Finally, L-ornithine and L-arginine are mimicked and outperformed by L-Citrulline. Citrulline converts to arginine in the body, and arginine can convert to ornithine; citrulline has been noted to increase levels of all three amino acids in the body, is better absorbed with fewer intestinal side effects, and lasts longer in the blood than does L-arginine (as conversion of citrulline to arginine has a rate limit, extra citrulline forms a free floating "pool" in the blood waiting for conversion).

    Arginine has unreliable benefits for nitric oxide production, while ornithine has somewhat more reliable benefits for reducing fatigue and ammonia concentrations; citrulline is better at both of these goals and is likely the best supplement option.

    Agmatine is a very interesting, novel neurotransmitter. First of all, it activates production of nitric oxide via the alpha-2 adrenergic receptors more potently than arginine does, and is likely to be better for producing nitric oxide.

    Agmatine has roles as an NMDA antagonist, a neuronal nitric oxide inhibitor (not related to "the pump" in any way), and a serotonin receptor signal enhancer, and is an activator of both alpha-2-adrenergic receptors and imidazoline receptors. Agmatine may directly block calcium channels, and can indirectly inhibit potassium channels.

    The above mechanisms underlie its therapeutic benefits. Agmatine is useful in drug addiction (being shown to abolish anxiety with alcohol withdrawal and fentanyl self-administration, and reducing conditioning effects of meth), is synergistic with opioids like morphine (increases analgesic effects, reduces tolerance and addictive properties), and is synergistic with antidepressants, most notably SSRIs. Agmatine is also highly effective in treating neuropathic pain, and is theoretically synergistic with marijuana for this role as well.

    Finally, agmatine is neuroprotective against excitotoxicity and stroke and has inherent anti-anxiety and anti-depressant effects. The latter two are likely due to agmatine enhancing signaling of naturally occurring anxiolytic and antidepressant compounds. There are, finally, some memory-enhancing effects that are context dependent. Behavioral and procedural memory appear to be enhanced, while spatial memory is unaffected; emotional fear conditioning is actually impaired. It was suggested by a few authors that "higher-up" processing is beneficially influenced, which correlates with high concentrations of agmatine in the cerebral cortex and hippocampus.

    Neurological effects appear to follow a bell-curve pattern, maxing out at an estimated 500 mg human equivalent for somebody around 150 lbs (based on the limited evidence using oral agmatine in rats). The neuropathic pain reduction is dose dependent.

    The limitations of the current evidence for agmatine include:

    • A ton of studies use injections rather than oral intake. Although the oral studies seem to suggest it has good absorption, a proper bioequivalence study has not been conducted.

    • Very limited human evidence; a lone study for neuropathic pain.

    • For many neural effects, it is antagonistic with arginine and citrulline. For neural and cardiovascular effects, it is antagonistic with yohimbine and rauwsolcine; all four are popular supplements.

    Overall, agmatine is an incredibly promising dietary supplement for both cognitive health/enhancement as well as an ergogenic, since it is possibly a better nitric oxide stimulator than arginine itself, yet it appears to prevent the toxicity associated with nitric oxide in the brain. Although it requires more human evidence and there are still a few studies that need to be conducted, agmatine appears to be worth looking into.