If you’re taking nootropic supplements, it is probably because you’re seeking a competitive edge on the cognitive front. In order to get the most benefit from tweaking one’s own neurochemistry, you should have a basic passing understanding of how the brain and it’s neurochemistry works. Caffeine may help you get a few more hours of work done and delay the inevitable tiredness brought on by heavy mental and/or physical exertion but there’s a point at which the caffeine molecule no longer serves as an ally.

As a result, learning how to use supplements wisely can be a great boon. One topic that’s very important when it comes to understanding how nootropics work and how to get the most out of them would be the subject of the glutamatergic system. Glutamate, or glutamic acid, is one of the most common of all amino acids found in the body, especially within the nervous system where it is not only the most widely found neurotransmitter but also the primary excitatory neurotransmitter.

Glutamates Role in the Brain

Glutamate plays an ancillary role in postsynaptic neuronal excitatory responses which have an important role in the formation of memories, learning processes and any basic neural communication. Glutamate overactivity can lead to a dangerous overstimulation that can be neurodegenerative and neurotoxic causing neuronal damage through the over-firing of neurons. This process of over-activity is known as excitotoxicity.

Racetams & Excitotoxicity

In general, the classic racetam drugs exhibit neuroprotective properties (in other words they should not lead to excitotoxicity). Only three studies in regards to piracetam (or it’s analog leveteracetam) have been completed on excitotoxicity. Leveteracetam, however was shown not to decrease excitotoxicity (as compared to VPA, valproic acid, in a study by Goffin, Bormans, Casteels, Bosier, Lambert, et al. in the June 2008 edition of the journal Neuropharmacology).

Contradictory to the above study, an earlier study from June 2007 by Euda, Doi, Tokumaru, Takaki & Willmore, leveteracetam was indeed shown to significantly suppress artificially evoked glutamate overflow. The study further showed that the neuroprotective benefit in regards to the dangers of excitotoxicity extended beyond mere reversal of symptoms of glutamate excess.

Considering the, scant at best, research that’s been done on this topic, one should not consider the case closed by any means. Keep in mind that all the studies involved moderate (i.e. within the typically recognized therapeutic window of dosing) use of the racetams. As a rule, despite the glutamatergic effect of the racetams, there have been no cases of the classic racetams being found to be anything but neuroprotective in regards to the brain at suggested dosages.

One of piracetam’s mechanisms of action is through improving efficacy of AMPA receptors, which are excitatory glutamate receptors. When AMPA receptors are exposed to glutamate, calcium ions are allowed to flow through the cell membrane. This is believed to facilitate learning & memory processes but it can also be bad. Elevated calcium influx is toxic and can be cytotoxic (cause cell death).

Glutamate excitotoxicity can even be caused by food. Glutamic acid is an enzyme that’s related to MSG (Monosodium Glutamate).  MSG was once a common flavoring additive, working as a preservative and flavoring ingredient. Several studies have shown that too much MSG in your food can actually lead to brain cell death & excitotoxicity.

Protection Against Excitotoxicity and GABA Kindling

A chelated magnesium supplement can be a good way to protect against excitotoxicity and brain damage from heavy metals. Magnesium acts as a calcium channel buffer. As a result, it slows down the glutamate evoked calcium influx and could potentially allow avoidance of cell death. Memantine, another nootropic is also said to be neuroprotective against excitotoxicity. Agmantine, related to memantine, is an NMDA antagonist. NMDA and AMPA are two of the excitatory receptors activated by the glutamatergic response.

While there is no current evidence to suggest that racetams may exacerbate the possibly excitotoxic situation, the more recent AMPAkines like Sunifiram and Unifiram may be a possible danger. Exercise especial caution when augmenting AMPAkines like Sunifiram or Unifiram with any stimulants (even caffeine). Addition of l-theanine or other mild GABAergics like Picamilon could possibly be helpful to raise the GABA inhibitory system in response to the neuronal excitation.

Studies have shown that racetams may be able to protect from high calcium concentrations. In one study it was suggested that piracetam and noopept could suppress voltage-activated calcium and potassium currents as well as up-modulate and/or down-regulate Ca2+ (Calcium ion) influx within the neurons.

Memantine and agmantine can also be very helpful in dealing with withdrawal from alcohol which may involve GABA kindling, a situation whereby GABA downmodulation results in increasingly worse excitotoxic situations. This can occur with severe alcoholism, phenibut, GHB or benzodiazepine and barbiturate abuse.

GABA & Excitotoxicity

Abusing GABAergic drugs and substances like alcohol and benzodiazepines may lead to excitoxicity. The brain naturally produces the neurotransmitter, GABA to counter-act glutamate’s excitatory response. When the GABA system is abused, it becomes down-regulated, causing the brain to produce less GABAergic activity. In response, there is a higher level of glutamatergic activity leading to excitotoxicity. In the worst case scenario, seizures and brain damage can happen as seen in the case of patients withdrawing from substances like alcohol “cold-turkey”. In summary, abusing GABAergic substances extensively can be excitotoxic in nature.

Always research any supplements before adding them to your nootropic regimen. Understanding the basics of how these compounds work and how they work together, which includes some of their multiple actions is vital to safe and effective use. Despite the relative safety of the nootropics and especially the classic racetams, it always best to consult with your physician before undertaking any major dietary, exercise or supplementation change.