Summary (All Essential Benefits/Effects/Facts & Information)
Agmatine is a biogenic amine that is derived from L-arginine via decarboxylation (removal of a carboxylic acid group), and appears to be stored in neurons and released upon neuronal activation. Due to this and other properties, agmatine is a seen as a neurotransmitter or at least a neuromodulator. It's most relevant and interesting potential uses (research, overall, is preliminary) include the treatment of neuropathic pain, drug addiction, and protecting the brain from toxins and stroke.
Agmatine is known as a pleiotropic molecule, and has a large amount of direct mechanisms. These include inhibition of NMDA receptors and possibly also nicotinic acetylcholine receptors, and activation of imidazoline receptors; there is possibly activation of α2-adrenergic receptors but this is not 100% clear (some studies suggest that there is no effect). Agmatine also directly inhibits NOS enzymes (aside from iNOS, at concentrations too high to be concerned with) and may also inactivate these enzymes (more biologically relevant), but despite this apparent inhibition of Nitric Oxide metabolism it appears to directly act as a mimetic and circumvent its own inhibition; the result is somewhat of a regulation of nitric oxide in instances where it is improperly elevated. Other direct mechanisms include inhibition of calcium channels (fairly potent, with an IC50 value of 1.2µM) and inhibition of serotonin receptor subset 5-HT3.
Other mechanisms which are not ascertained if they are direct or vicariously through one of the aforementioned ones include activation of PI3K/Akt (found in multiple cell lines) and adenyl cyclase activation (noted in the prefrontal cortex, it is unsure if this is from serotonin or adrenergic receptors). A release of opioids (β-endorphins) has also been confirmed to be secondary to imidazoline receptor activation in the adrenal glands, and Ryanidine receptors are activated (which release intracellular calcium) although it is not sure if this causes or is a result of the nitric oxide interactions.
Agmatine has a large number of roles and mechanisms in the body. The primary four roles (that seem to be most important) involve positively influencing imidazoline receptors and α2-adrenergic receptors while inhibiting NDMA receptors and NOS enzymes
In regards to pain, there are mixed effects (as agmatine appears to have a modulatory role) but overall it appears to be analgesic. While agmatine in isolation can augment the perception of pain (by enhancing the signalling through a receptor known as ASIC3 that mediates pain associated with acidity), it appears to release β-endorphin and synergistically enhance the actions of any opioids. Due to the inherent release of a weak opioid and synergism with opioids, agmatine is able to reduce pain and pharmaceutically is synergistic with both morphine and fentanyl (increasing pain killing, reducing tolerance, and reducing addiction).
The ability of heat to cause pain in rats is normally reduced by cannabinoid signalling (such as Marijuana), and agmatine also appears to provide synergistic pain relief with cannabinoids. Other potential synergisms between agmatine and marijuana are not yet investigated, but it appears that anything through the CB1 receptor is augmented under the influence of agmatine.
Agmatine has both pro-pain and anti-pain mechanisms (technically speaking), but it appears that due to being very synergistic with established anti-pain pathways that the overall effect of agmatine injections into research animals is one of pain relief. The pain relief is fairly notable as well
For strokes, there are repeated studies in rats using injections of agmatine (around 100mg/kg) that suggest potent protective effects that near normalization of symptoms after 3-4 days with minor protective effects noted within a few hours. It is thought that this is due to modulating nitric oxide metabolism, as the increase in iNOS seen during stroke (which normally produces too much nitric oxide and damages tissue) is attenuated while the acute suppression of eNOS (which is protective) is preserved. Nitric oxide and its oxidative metabolite known as peroxynitrate are also attenuated, and this is thought to result in less overall damage.
When cognition and brain edema are tested after a stroke, they appear to be significantly reduced and almost normalized relative to control rodents.
Although there is no human evidence at this moment in time, agmatine appears to have potent protective properties against strokes
Another claim of agmatine supplementation are the anti-addictive properties, which appear to exist in rats who become addicted to opioidergic drugs (morphine, fentanyl, and oxycodone) where agmatine injections during drug administration reduce addictive effects. There is also a potential mechanism for agmatine to reduce Nicotine dependence (which needs to be explored further) and currently the only failure has been on cocaine, which is known to be low on a rewards scale in rats; cocaine may require a human study.
Agmatine may also help with alcohol and opioid drug withdrawal by reducing symptoms thereof.
Agmatine is potentially anti-addictive, and awaits human studies to confirm what is seen in rodent models
Overall, agmatine is a highly promising research chemical that will likely be important in the future. It's usage as a common supplement is limited by a lack of human trials at this moment in time, and although there are a few studies using oral ingestion here and there (which confirm that it does appear to be absorbed) the vast majority of studies use injections of agmatine. Future research will need to re-establish all the current observations following oral ingestion (or at least, more pharmacokinetic studies should be conducted including tissue distribution so we can make educated guesses on oral doses).
