Nootropics are substances that enhance learning and memory while being safe and protective of the brain.

The term nootropics means “towards the mind” and is defined a class of molecules that specifically target higher-level, integrative activity in the brain.

To be considered a true nootropic, a substance must meet ALL of the following characteristics:

  • Enhance learning and memory
  • Protect the brain from physical or chemical injury
  • Enhance the firing mechanisms of neurons
  • Have few side effects and extremely low toxicity
  • Prevent the disruption of memory formation from conditions which tend to disrupt it.

*Amphetamines like Adderall and wakefulness-agents like Modafinil are NOT considered nootropics.

History of Nootropics

In 1963, scientists at UCB Pharma in Belgium were modifying the inhibitory neurotransmitter GABA in pursuit of creating a sleep-aid. Instead they accidentally discovered a molecule with properties so profound and unique that in order to classify it, the creation of an entirely new class  of compounds was required.

That molecule, which would later be known as Piracetam, was able to prevent the disruption of memory formation in rats when they experienced a loss of oxygen (hypoxia) or were electroconvulsively shocked (ECS). It was also shown to bring back higher-level brain function to oxygen-deprived rats, nearly double as quickly as the control. 1)Giurgea, C., Mouravieff-Lesuisse, F., and Leemans, R.: Correlations electropharmacologiques au cours de l’anoxie oxyprive chez le lapin en respiration libre ou artificielle. Rev. Neurol. (Paris), 122:484-486, 1970.

What piqued their attention was not only that it was able to do all of that and more, but that it did so while being extremely safe and while showing no activity on over 30 psychopharmacological tests, including behavioral tests demonstrating that it was neither a stimulant nor a sedative. 2)Giurgea, C., Moyersoons, F., and Evraerd, A. C.: A GABA related hypothesis on the mechanism of action of the antimotion sickness drugs. Arch. Int. Pharmacodyn. Ther. 166:238-251, 1967.

Piracetam appeared to act directly on higher brain, integrative activity, increasing efficacy, and decreasing deficits. After studying these properties for 9 years, in 1972 Corneliu Giurgea coined the term nootropics, meaning “towards the mind.” 3)The “Nootropic” Approach to the Pharmacology of the Integrative Activity of the Brain C. GIUIRGEA, M.D. 1972

Nootropics are not to be confused with cognitive enhancers. While all nootropics are cognitive enhancers by definition, not all cognitive enhancers are nootropics (most are not).

This means substances like central nervous stimulants, including amphetamines like Adderall/Concerta/Ritalin are NOT nootropics and neither are eugeroics (wakefulness agents) like Modafinil/Provigil. While they may have traits that enhance aspects of cognition, they clearly do not meet the defintion of a nootropic.

Nootropics are not new, there are decades of research on them from many high level sources, including double-blind, placebo controlled, studies from high quality journals and respected researchers. The number of research papers indexed by PubMed mentioning the term nootropics is steadily increasing.

In researching the use of Piracetam in alcoholics 4)Weckroth and Mikkonen, 1972, researchers noted increases in the coordination of the individual’s behavior and improvements in learning and memory. 5)Stegnick 1972

This lead the authors to question “whether it is possible to improve different parts of the mental makeup of normal man” with Piracetam.

In 1976 they tested healthy college-aged students and found that treatment with Piracetam was able to significantly increase the power of human memory after 7-14 days of use. This set off a whirlwind of research activity and interest in the use of nootropics in healthy individuals that continues to this day.

While researchers continued to experiment on different groups from all age groups including kids with dyslexia, to pregnant mothers experiencing birth delays (to protect that brains of the babies from lack of oxygen), to patients with dementia, to post neurosurgery patients, they started to hone in on the mechanisms of action of this novel molecule, Piracetam, and find ways to optimize and increase its efficacy.

Development of more powerful nootropic agents

Targeted Enhancement

As mentioned, piracetam was discovered accidentally, so as scientists began to learn the beneficial properties of the molecule and the methods of action, they set out to design more powerful and targeted versions.

Advanced Versions

Two of the most promising versions of piracetam developed over the ensuing decades of research were phenylpiracetam and noopept. Phenylpiracetam retained the cognitive enhancement aspects of piracetam, while enhancing psychomotorstimulation. Noopept was designed as a peptide version of piracetam that would target nootropic effects deeper in the brain and has additonal calming properties. These are the nootropics selected for use in Nootroo Gold Formula (Noopept) and Silver Formula (Phenylpiracetam).

Profound effects combining nootropics and choline source

Synergy

Nootroo's formulas are based on the "profound effects" found when combining a nootropic agent (Noopept/Phenylpiracetam) along with a choline source (Citicoline). There is a synergistic effect that is profoundly better than either alone. Long-term administration of piracetam and choline, along with short-term dosing, have been demonstrated to have the greatest effect increase memory and learning retention in aged humans.

Boosting neurotransmitters

One mechanism of action of nootropics is to increase the ability of the brain to increase its usage of the neurotransmitter acetylcholine, which regulations memory formation and synapse firing 6)Bartus, R. T., R. L. Dean, J. A. Goas and A. S. Lippa. Age-
related changes in passive avoidance retention: Modulation with
dietary choline. Science 209: 301-303, 1980.
. By supplementing the building blocks of acetylcholine, the brain will then create more of that neurotransmitter in the brain, which the main nootropics then bring into the hippocampus (where memory is formed).

Piracetam, while revolutionary and the impetus for the creation of the word “nootropic,” it was actually discovered accidentally. This meant it had some drawbacks, mostly that the effective dose could be pretty high, in the levels of 10-20 grams for some treatments (which translates to approx. 15-30 capsules).  In addition to the limitations of Piracetam, the success of the molecule inspired other research groups around the world to try and improve upon it. This led to the creation of an entire class of “piracetam-like” molecules.

Some Selected Research on Effects, Mechanisms of Actions, General Research and Other Information on Nootropics

Nootropics Basics:

Nootropics are substances that enhance learning and memory, with being safe and neuroprotective of the brain.

Nootropics comes from the greek words “noos” meaning “mind” and “tropein” meaning “towards.”

The first nootropic, piracetam, which at the time was known as UCB 6215 and was discovered while in pursuit of a sleep aid related to GABA. Piracetam was an amazing substance with properties unlike any other molecule or class of molecules known at the time. The effect that tipped them off was Piracetam’s prevention of disruption of memory from rats that were suffocated (hypoxia).

Long-term Nootropic Use Produces Neuroplastic Response Identical to that Obatined by Complex  Environment Rearing7)Chronic Exposure of Rats to Cognition Enhancing Drugs
Produces a Neuroplastic Response Identical to that Obtained
by Complex Environment Rearing https://www.nature.com/articles/1300810

One way nootropics work is by stimulating the cells in the hippocampus as the brain does when it is exploring and remember physical locations. When a rat is exposed to a complex environment that is considered “enriched” new neurons are created in order to store the information. There is a stark difference that can be seen when one evaluates the levels of a type of neuron found in the hippocampus (polysialyalated hippocampal infragranular) in rats that have complex environments. What is interesting, is that they found the long term treatment with a nootropic molecule “resulted in an increase in polysialylated cell frequency that was indistinguishable from that obtained with rearing in a complex environment.” See the image above, where (A) is the placebo mouse (saline water), (B) is the nootropic, and (C) is the complex environment.

 

Nootropics Long Term Use Timeline

Long-term nootropic use has thus far demonstrated the principals put forward in the nootropic concept, that they must be neuroprotective. A one-year-long, placebo-controlled, double-blind study on pre-dementia adults taking piracetam compared to those those taking a placebo, measured measured 14 different psychometric tests found that those who were on the placeba went down on 9 out of 14 tests, those on piracetam went down on just 1 metric. Nootropics also work in a way typically different in mechanism that other substances. Chronic (long-term) of treatment of animals with noopept found “treatment with Noopept was not followed by the development of tolerance, but even potentiated the neurotrophic effect.

 

Piracetam increased the levels of polyribosomes (responsible for biosynthesis of proteins) to a level beyond untreated young rats.

Polyribosomes are cytoplasmic structures responsible for the biosynthesis of proteins and the amount pressed in cells is directly related to the protein synthesis in the cell. In the present study, the polyribosomes were chosen as indicators of cell ageing because the polyribosome content of the post-mitochondrial supernatant was defined by a mild treatment with ribonuclease, an enzyme which in very low concentrations selectively destroys the mRNA strand and transforms the polyribosomes into ribosomes.

The influence of the ageing process on the polyribosome:ribosome content was checked in four groups of rats of increasing age and a significant and progressive decrease of the polyribosome : ribosome ratio was observed in aged animals. Secondly, rats were treated with Piracetam and the same parameter examined. A significant increase in the polyribosome:ribosome ratio was observed in the treated animals. The measured values were even higher than those observed in young animals.

Moreover, a comparison of the sedimentation profiles of the polyribosomes ex-tracted from Piracetam-treated and untreated animals indicated that a significantly larger amount of polyribosomes occurred in the treated rats. It is well established today that the storage of long term memory is dependent on the synthesis of one or several proteins in the brain cells.’ Moreover, an increase in the polyribosome:ribosome ratio was also observed during the training of old rats.2 The Piracetam-induced stimulation of the protein synthesis machinery thus gives support to the neuropharmacological experiments which show an increase in many cereberal performancs and protection against posthypoxic amnesia in rats.3-5

From the Paper:”PIRACETAM (2-PYRROLIDINONE ACETAMIDE) INDUCED MODIFICATIONS OF THE BRAIN POLYRIBOSOME PATTERN IN AGEING RATS”

 

Indeed, animals treated with piracetam during withdrawal, although also displaying a smaller number of synapses than control, pair-fed control, and control + piracetam-treated animals, have more synaptic contacts than non-treated withdrawn animals and even more synapses than age-matched, alcohol-treated rats

References   [ + ]

1. Giurgea, C., Mouravieff-Lesuisse, F., and Leemans, R.: Correlations electropharmacologiques au cours de l’anoxie oxyprive chez le lapin en respiration libre ou artificielle. Rev. Neurol. (Paris), 122:484-486, 1970.
2. Giurgea, C., Moyersoons, F., and Evraerd, A. C.: A GABA related hypothesis on the mechanism of action of the antimotion sickness drugs. Arch. Int. Pharmacodyn. Ther. 166:238-251, 1967.
3. The “Nootropic” Approach to the Pharmacology of the Integrative Activity of the Brain C. GIUIRGEA, M.D. 1972
4. Weckroth and Mikkonen, 1972
5. Stegnick 1972
6. Bartus, R. T., R. L. Dean, J. A. Goas and A. S. Lippa. Age-
related changes in passive avoidance retention: Modulation with
dietary choline. Science 209: 301-303, 1980.
7. Chronic Exposure of Rats to Cognition Enhancing Drugs
Produces a Neuroplastic Response Identical to that Obtained
by Complex Environment Rearing https://www.nature.com/articles/1300810