Nefiracetam: The Highly Underrated Nootropic

What Is Nefiracetam?

I’m going to assume you’ve tried most of the more conventional nootropics. I’m talking about stuff like Piracetam, L-Theanine, caffeine, and so forth. For a long time, I stuck with these classics. After all, Piracetam is a favorite staple nootropic for a reason. But I want to share something with you guys that I only realized recently. You probably know this already, but it was groundbreaking for me when I was just getting acclimated to nootropics. The more obscure racetams are more effective than conventional racetams. They’re more potent (Coluracetam is active at doses as low as 5mg). Their effects on cognitive function are more robust. And in many cases, there’s actually more evidence supporting a nootropic effect for the obscure racetams, versus the conventional ones.

Heavy Hitting Nootropics

Coluracetam, Phenylpiracetam, and Nefiracetam – these are the heavy hitting nootropics. Take a look at the survey conducted in slate star codex, and ⅔ of these racetams are rated >7. They’re the top five most highly-rated nootropics. Coluracetam and Phenylpiracetam are more widely known than Nefiracetam.  I’m not sure why it was omitted from the survey. Probably because it’s more obscure. But today I want to discuss Nefiracetam in greater detail.

A quick survey of the biomedical literature reveals that more than 40 papers have been published about the cognitive enhancing effects of Nefiracetam. The evidence supporting its nootropic effects is actually much more compelling than for Phenylpiracetam and Coluracetam (which are great in their own right). Given the breadth of literature on Nefiracetam, it’s worth investigating further.

All About Nefiracetam

Nefiracetam is a racetam (obviously). It shares structural features with Aniracetam. Both are lipophilic (fat-loving) nootropics. They dissolve easily in fat or oil but aren’t miscible with water. Nefiracetam is currently under development by the Japanese pharmaceutical company, Daiichi Sankyo, for the treatment of neurodegenerative disease.

This lipophilicity is a property that’s used in Lipinski’s rule of five is used to predict whether a compound will be orally active in humans. The first Lipinsky rule pertains to the LogP or the partition coefficient. Drugs that are more lipophilic – like Nefiracetam – have larger partition coefficients and tend to be more suitable drugs. Lipophilicity is also a good indication of blood-brain barrier permeability. GABA isn’t really biologically active in the brain because it’s so water soluble. But Nefiracetam which avoids water and is fat soluble has excellent brain penetration.

Here are the two reasons that I added Nefiracetam to my armamentarium of nootropics:

1) Nefiracetam Increases Adult Neurogenesis

If you’re unfamiliar, neurogenesis refers to the creation of new neurons in the hippocampus. Believe it or not, you’re creating an average of 700 nascent neurons every single day. Here’s an excerpt from a paper published in Science that looked at neurogenesis in actual adult humans (not rodents):

We found that a large subpopulation of hippocampal neurons, constituting one-third of the neurons, is subject to exchange. In adult humans, 700 new neurons are added per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging.

Neurogenesis is suppressed by all sorts of noxious stimuli that we encounter from day-to-day. Radiation, chronic stress, excessive sugar consumption, and so forth are documented to suppress neurogenesis. It enhances neurogenesis or normalizes neurogenesis when it is suppressed. Ueda’s group modeled cognitive dysfunction by genetically engineering mice to be deficient in heparin-binding epidermal growth factor (Hbegf).

Neurogenesis was decreased in these Hbegf knockout mice, and genes related to NMDA-type glutamate receptors were also downregulated. It normalized the ensuing decrease in neurogenesis, which is not surprising given that it is a positive allosteric modulator of NMDA-type glutamate receptors. A positive allosteric modulator (PAM) is just a compound that indirectly increases the activity of a receptor. When the NMDA receptor interacts with Nefiracetam, it undergoes a conformational change. When it changes shape in this fashion it stays active for longer or is activated more easily.

This brings us to our next point:

2) Nefiracetam Prolongs the Open Time of Calcium Channels

Calcium channels play an important role in regulating membrane excitability and the development of action potentials. An action potential is just the signal that’s propagated from one neuron to the next. Nefiracetam was first discovered to be a calcium channel opener by Yoshii and Watabe in 1994. Specifically, it prolongs the open time of voltage-gated calcium channels.

Calcium channels play an indispensable role in long-term potentiation (LTP). Like Aniracetam, Nefiracetam acts on long-lasting L-type calcium channels. Predictably, inhibition of calcium channels prevents the learning enhancement caused by it. Nefiracetam potentiates autophosphorylation of an isoform of protein kinase C (PKCalpha). Glutamate receptors are actually required for the effect of it on PKCalpha. Activation of PKCalpha is probably the single most important mechanism that underlies Nefiracetam’s enhancement of learning and memory.

Nefiracetam And Neurotoxicity

We’ve established that Nefiracetam prolongs calcium channel opening. But this raises the question, could it exacerbate excitotoxicity? Excitotoxicity occurs when neurons are overstimulated. It eventually leads to cellular death. For example, if you bathe neurons in the neurotransmitter glutamate, you’d expect NMDA-type glutamate receptors to be triggered excessively. Under these conditions, too much calcium enters the cell, wreaking havoc.

Quinolinic is an endogenous neurotoxin – it’s produced in your brain naturally. It activates NMDA-type glutamate receptors. Quinolinic is a downstream product of the amino acid l-tryptophan, metabolized by the kynurenine pathway. Excessive NMDA receptor activation causes excitotoxicity.

As it turns out, long term consumption of Nefiracetam in humans and animal models has demonstrated no toxicity.  Some animals (like dogs) that metabolize it differently can develop testicular toxicity. Nefiracetam has been tested in clinical trials and no evidence of neurotoxicity has come to light. It actually protects against seizures induced by excitotoxins like veratridine and glutamate. You might expect to find the opposite – that Nefiracetam could have a pro-convulsant effect (lower the seizure threshold).

Nefiracetam blocks veratridine- and glutamate-related toxicity by preventing excessive sodium channel activation. This ultimately has a protective effect on the nervous system.

Nefiracetam Is A Potent Cholinergic Nootropic

Nefiracetam packs a serious punch. In addition to prolonging calcium channel opening, it affects both neuronal nicotinic and muscarinic acetylcholine receptors.

Here’s a quick and dirty summary of nefiracetam’s cholinergic effects:

  • Narahashi T., et. al found that nefiracetam caused a dual action on Acetylcholine-induced currents, depending on the concentration of Acetylcholine. Nefiracetam augmented currents induced by low concentrations of Acetylcholine but suppressed currents at high concentrations.
  • The drug, Scopolamine, blocks muscarinic Acetylcholine receptors. Because Acetylcholine plays such an important role in memory, blocking these receptors results in amnesia. The anti-amnesic effects of Nefiracetam are abolished by Scopolamine, hinting that muscarinic Acetylcholine receptors play a role in its nootropic effects.
  • Other evidence indicates that Nefiracetam may enhance Acetylcholine signaling presynaptically. In other words, it elicits more Acetylcholine release (in addition to glutamate release).

Final Thoughts

Nefiracetam has a lot going for it. It’s under development for Alzheimer’s disease in Japan, which indicates that it has clinically significant effects on Acetylcholine and calcium channels.

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