Agmatine - The Neurotransmitter That Can't Make Up Its Mind.

Agmatine is an aminoguanidine compound that was discovered in 1910 by Albrecht Kossel; a well-known German Chemist from that time [1]. Since that time a whole lot of research has been conducted on it and its original classification as a "protein" and further, an "amino-acid altering substance" has been refined and further called a "neuromodulating neurotransmitter" [2] [3]. However, one could argue that is an inappropriate definition for this compound, as most of its activities are on blood vessels [4]. Uniquely though, Agmatine *does* have a primary action in the cardiovascular system but achieves its actions by altering neurotransmitters [5].

AGMATINE & Its Many Many, Contradictions 

Agmatine, as I've discussed before in many of my articles, is often thrown into PreWorkout formulas and the claim is usually something along the lines of "it enhances the pump" or "maximizes the pump produced by Arginine". This is found on countless PWO's in the bodybuilding industry. Unfortunately, many people (even fitness buffs) are blind to the inaccuracy of the claims and simply, the fact that Agmatine is a NITRIC-OXIDE INHIBITOR [6]. So why include it right? Well because in some studies it DID increase endothelial nitric oxide synthesis [7], which could promote a workout pump, however this effect is limited by opposing actions; such as Agmatine's alpha-2 stimulation [8] and NMDA-receptor blockade [9].  The direct nitric-oxide inhibiting action of Agmatine is present within neurons and in some studies, the skin [10]. However the indirect inhibiting actions are present everywhere. So essentially these 'other actions' inhibit nitric oxide while in some cases in the cardiovascular system the nitric oxide is increased. 

Confusing right?

That is [part] of the reason for this title.

It is ...a neurotransmitter that can't make up its mind. It contradicts itself (proverbially).

AGMATINE Does TWO Different Things At The Same Time to the Alpha-2-Adrenergic (Adrenaline) "Receptor".

A study published in the year 2000 noted (and other studies confirmed) that Agmatine is both an antagonist (blocker) and a positive allosteric modulator (enhancer) of the alpha-2D-adrenergic receptor.

That is an interesting conundrum. Basically this substance (Agmatine) is doing two totally different things to the same receptor at the same time.

Perhaps the correct explanation is "site-specific", perhaps it blocks some alpha-2D receptors and modulates others - but that doesn't really explain anything and that would be a first for any substance in this family of compounds and really, in general. You don't *often* see a substance that offers two opposing actions at the same site and meanwhile has the ability to differentiate in neuronal and cardiovascular locations.

That makes this "neurotransmitter" even more contradictory, to itself.

I also found another interesting tidbit, in that study Agmatine was confirmed to have alpha-2 agonistic actions AND serotonergic actions (increasing serotonin). YET, it only acted on the 5-HT1A/1B sites and was "indirect". Normally, that would produce further cardiovascular effects as we know that 5-HT1A [11] and 5-HT1B "receptors" play great roles in the human cardiovascular system [12]. 5-HT1A, primarily by reducing Anxiety and Stress can lower blood pressure when activated and 5-HT1B activation (especially chronic) contributes to heart disease and myocardial inflammation [13] [14].

So what's the DEAL? Is Agmatine USEFUL?

Agmatine appears to have some use in lowering blood pressure. But as a workout agent, its actions in the nervous system contradict what we know about exercise performance. Alpha-2 activation decreases adrenaline which would blunt energizing effects of stimulants [15] and would probably cause less fat to be burned (at least in theory) [16]. Now, you could argue that because Agmatine "enhances" the pump while lifting, that this effect would offset the other effects - I suppose if you are an ultra-motivated person (like me) that could be the case - but in reality, I've heard of many reports where its not.

NMDA antagonism by Agmatine might reduce Testosterone production, considering stimulation of the receptor boosts Testosterone levels in Humans and Animals [17] [18].

These two actions aren't exactly favorable, but those aren't the lowest point for Agmatine.

Agmatine can also reduce motivation by its Imidazoline-agonist effects [19].

So it has a triple-negative effect in that regard.

HOWEVER...

1.) Agmatine is not used much on its own thus we don't have a lot of information for comparison, its mostly included in PreWorkout & Nitric Oxide "blends" so most people don't supplement with it solo.

2.) Agmatine-containing products often have good reviews and maybe more frequently than bad. So there is some contradiction and it may be some time before we figure out whether Agmatine is really valid as workout supplement.

So, What Is MY Favorite PreWorkout Supplement?

I honestly prefer using standalone herbs and building my own stack, usually including NutraBio's Creatine, Ceretropics Caffeine + NALT and then Arginine silicate (Nitrosigine) and B-Vitamins.

But...when I do go for a known PWO its NutraBio's incredibly powerful PRE-Extreme.

Thanks for reading and don't forget to follow me on Google+.

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