History of Nootropics

An accidental discovery...

In the early 1960s, scientists were working to develop a form of the neurotransmitter GABA, that would be able to cross the blood-brain barrier and potentially work as a sleep aid.^[5]How To Deal With An Unusual Pharmacological Pattern: The Nootropic Case, C Giurgea, P197, 1976.

While they succeeded in developing a molecule with the ability to enter the brain, they failed at creating a sleep aid. What they discovered instead, however, was a molecule that would later prove to be much more profound.

Like a sculptor removing parts of the stone to reveal the beauty within,^[6]"Within the marble itself, Michelangelo thought lies the beauty, it is not created by the sculptor. He only takes out the excess of stone and so makes beauty available to our eyes. Scientific … Continue reading Corneliu Giurgea, the lead scientist at the lab, and his team would work diligently to chip away at the unknowns of piracetam, to reveal the properties within it.

After 9 years of research, Giurgea had determined that this molecule (piracetam) acted in such a unique way on the higher-level, integrative activities of the brain, that in order to classify it, the creation of an entirely new classification was required: " the nootropic approach to integrative activity of the mind."

A Challenging Compound

"Lack of Usual Activity"

On over 30 pharmacological tests, Piracetam was found to have no activity, including being neither a sedative nor a stimulant. It also had no toxicity and few side effects, even when given in extremely high doses, such as grams per kilogram of body weight, to mice, rats, cats, dogs, and monkeys with single or multiple doses, even over long-term administration.

In fact, because of those properties, piracetam seemed to be inactive. Had it not been for a test on nystagmus (involuntary eye movements), where they found it immediately active, piracetam likely would have been passed over. This discovery was especially intriguing to the researchers because all of the then-known agents active against nystagmus were either antihistamines or anticholinergics.

It was clear that piracetam did not fit into either of those classes, so the researchers set out to understand which class it did fit into. As they would eventually discover, no existing class embodied the properties of this "unusual" molecule.^[7]"Piracetam was such a challenge to our laboratory until we accumulated an important body of knowledge, which made it possible to attempt a relatively comprehensive interpretation of the particular … Continue reading ^[8]"Piracetam: Nootropic Pharmacology of the Neurointegrative Activity, P229

Unexpected Results

"Memory Seemed Somehow Improved"

The first human trials began in 1965 and showed that piracetam was able to significantly inhibit nystagmus.^[9]Giurgea et al 1976 Because there was extremely low toxicity and seemingly few side-effects, they began to test piracetam in other populations. Further data reported internally^[10]at their lab, UCB Pharma in Belgium then claimed "fairly good efficacy against motion sickness and vertigo" in humans. These findings lead them to search for a "more comprehensive picture of piracetam from the neurophysiological point of view."^[11]Fundamentals to a Pharmacology of the Mind, Giugea 1981

As they were carrying out these follow up studies over 1966-1967, a series of surprising results were reported. First, results came in from a study done at a hospital in Finland on post-concussion patients. The scientists running the study wrote to Giurgea^[12]Personal Communications between Giurgea and Prof. Hilboom and Dr. Jahro to let him know that the "patients memory seemed somehow improved, that they declared to 'think' better."^[13]How To Deal With An Unusual Pharmacological Pattern ; The Nootropic Case, C Giurgea, P198, 1976.

Then came word from a trial in Brusseles^[14]Personal Communications between Giurgea and Prof. Sorel on epileptic children administered piracetam. The parents of the children in the study "claimed a kind of improvement in the overall mental efficiency." And then another researcher^[15]Personal Communications between Giurgea and Prof. Ectors in Bruxelles reported to him that his Parkinsonian patients under Piracetam were "somehow more aware of their sickness."

Since Giurgea and his team had previously demonstrated piracetam selectively enhanced interhemispheric communication (see associated image), he had suspected that the compound might facilitate other cortically integrated mental functions, but at that time, he had no idea the extent.

This new information changed the course of their clinical work and they began to focus on "studies related to a potential beneficial effect of Piracetam on mental activity."^[16]How to Deal With an Unusual Pharmacological Pattern: The Nootropic Case, Giurgea 1976, P198

”"Man's brain is remarkable among mammals because of the greatly increased volume of the cerebral cortex...Unlike the cortex of the rat, which is completely motor or sensory except for a small undefined area, most of the human cortex is neither sensory in function nor motor... Man is different from lower mammals...[he is] part of an evolving society. He has in his brain, extensive areas of undefined and uncommitted cerebral cortex... The brain of man is molded by his mind."

Wilder Penfield (1966)

Towards the Mind

Integrative Activity of the Brain

Giurgea defined integrative activity as: "the body of operations through which the brain accomplishes its most specific function, i.e., enables us to acquire new experiences, to retrieve past ones, and by a constant interaction between them, interfere with our own past and future."^[19]Piracetam: Nootropic Pharmacology of Neurointegrative Activity, Giurgea 1976, P224

Through our sensory abilities, we create a "phantom-like" image of the real world. And then from complex, "integrating activity" in the telencephalon, we then derive our "capacities [of] perception, conscience, and other features of the inner life of a human being."

While other classifications include molecules that can have an effect on higher mental function, it is usually through an indirect pathway and is typically accompanied by side effects (especially in high doses). No other class includes agents that act directly on higher-level integrative activity or met the other properties and so it became clear that piracetam was the forerunner of an entirely new class.

Based on the evidence of a direct, selective activity of piracetam on the higher integrative mechanisms of the brain, in 1972, Giugea proposed the formation of an entirely new class of agents that would be known as nootropics, meaning "towards the mind."

Pharmacology of Higher Brain Integrative Activity

Nootropic Classification

The prototypical nootropic agent:

(a) Facilitates learning acquisition and enhances resistance to learning impairments
(b) Facilitates interhemispheric transfer of information
(c) Enhances cerebral resistance to aggressions
(d) Strengthens control on subcortical CNS activity
(e) Virtually free of side effects and non-toxic even in very high doses

Nootropics are practically nontoxic and bear a direct impact on noetic, telencephalic, higher integrative mechanisms.

And like Michalenago, Giurgea had removed enough of the "excess of misunderstanding" to reveal the true beauty of the nootropic approach towards the integrative activity of the mind.^[20]"Within the marble itself, Michelangelo thought lies the beauty, it is not created by the sculptor. He only takes out the excess of stone and so makes beauty available to our eyes. Scientific … Continue reading)

Increase In Interhemispherical Transmission

"Superconnection of the Brain"

Now that scientists had a framework for understanding the action of piracetam, they began devising new studies to explore how increases in efficiency of high-level activity could be demonstrated in healthy humans. In 1975 a study was devised to test the transfer of information across the corpus callosum in healthy college students.

Researchers administered a dichotic listening test, where words are played simultaneously on stereo headphones (with one message in the right ear and another message in the left ear), and subjects would be asked to write down as many words as they could remember from each ear.

Because words that come in the left ear are processed in the right side of the brain, then sent to the language area on the left side, they must cross the corpus callosum. This study showed remarkable results, the students on piracetam showed a 15% increase in their verbal capacity.

The scientists referred to this as a "superconnection of the brain," and stated: "what does seem to be established...is that there is an increase in the capacity for learning and the registration of verbal information is increased...It is tempting, however, to believe that superconnection not only leads to increased registration but also plays a part in integrating different brain areas and thus lead to a greater capacity for learning."

Enhancing the Healthy

"Increase In the Power of Human Memory"

As a follow up to the "superconnection" study, the researchers^[21]Dimond and Brouwers set up another placebo-controlled, double-blind study on healthy college students. Instead of verbal learning though, they decided to test recall with written words.

In the study, subjects were shown two-syllable long words and were asked to recall them after varying lengths of time. After 14 days of treatment with piracetam, they found that both direct and delayed recall was significantly increased.

The researchers concluded that "piracetam promotes verbal learning and in this, it would appear to be a substance which in a specific respect is capable of extending the intellectual functions of man."

The researchers concluded that even though verbal learning is only one aspect of the intellect, this study demonstrated that "human brain power can be selectively increased." ^[22]"Increase in the power of human memory...", Dimond and Brouwers 1976

Synergistic Effects

Profound Effects Combining Piracetam Choline

Researchers studying deficient brains in older populations are constantly working to activate the cholinergic system, as the neurotransmitter acetylcholine is directly implicated in memory. Normally, administering choline alone can increase cholinergic transmission and raise the levels of acetylcholine in the brain.

However, in some older patients, their cholinergic systems are so deteriorated, that they are unable to turn the choline into acetylcholine. The scientists theorized that if they could administer choline, while simultaneously administering a compound that could correct for the critical age-related neuronal deficiencies, it might enable the choline to be properly metabolized.

When they learned that piracetam enables the central nervous system to function more effectively, the researchers^[23]Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats.
Bartus RT, Dean RL 3rd, Sherman KA, Friedman E, Beer B. decided to run an experiment on aged rats. They administered choline, piracetam, alone as well as the combination of the two.

Both choline and piracetam alone seemed to have a somewhat positive, albeit limited effect. However, when they combined piracetam and choline, the results were considered "profound." See the dramatic difference the combination makes in the gold bar labeled "C+P" in the accompanying graph.

Our Gold & Silver stacks are based on the principles behind this synergistic combination of ingredients.

Quo Vadis

What is Next?

Having firmly established the nootropic concept, by the early 1980s Giurgea began to imagine the development of more advanced nootropic molecules.

He wrote, "I do consider piracetam merely as the first"^[24]Fundamentals to a Pharmacology of the Mind, Chapter 9 of the nootropics and that "new nootropics should be made available, these should be more active than piracetam in terms of dosage, delay of therapeutic effect, duration of activity, etc."^[25]Piracetam: Nootropic Pharamcology of Neurointegrative Activity, P264 He also thought that there should be versions that have a more specific effect on a given aspect of the nootropic concept.

Giurgea was not sure exactly what would come next though, which is which is why he left a "?" after Piracetam on the accompanying image showing where the nootropics classification fits.

That question mark now has an answer, because more advanced versions of piracetam have been successfully developed.