Nootropic is a non-prescribed compound that enhances cognitive function and/or protects or repair the brain with no tolerance and few to no side effects. The compound is made up of different “stacks” or combination of amino acids, natural/synthetic compounds, herbs, vitamins, minerals and/or other supplements together to leverage synergistic effects.
History of Nootropics
In 1950, the discovery of the ability of gamma amino butyric acid (GABA) to act as a major inhibitory neurotransmitter in the brain caused a lot of interest in gamma amino butyric acid related pharmacology. Being one of the researchers interested in gamma amino butyric acid, Dr. Guirgea, a Romanian psychologist, and chemist, created a cyclic derivative called “2-oxo-I-pyrrolidine acetamide”, in 1964. Although the molecule properties were chemically similar to gamma amino butyric acid, it appeared to have properties that were almost opposite of what they were trying to develop which was a calming agent and sleep inducer. Under the careful guidance of Dr. Giurgea, he turned what could have been written off as a failure to a major medicinal discovery. The compound called Piracetam led Dr. Giurgea to coin the term “Nootropic” in 1972. This compound success led to an ever expanding family of compounds called Racetams.
However, the first Nootropic invented was not Piracetam, rather it was a different compound called “Pyritinol”. Merck Laboratories created Pyritinol in 1961 by bonding two vitamin B6 compounds (pyridoxine) together with a disulfide bridge. However, the term “nootropic” did not exist in 1961 when Merck Laboratories created Pyritinol. It was developed for the purpose of improving cognition and learning disorders. The compound eventually grew to include Sulbutiamine, where two vitamin B1 molecules bound together instead of Vitamin B6, making it less polar, and easier to cross the blood brain barrier. The class of modified Vitamin B derivatives eventually expanded to more compounds such as benfotiamine, nicotinamide riboside, pirisudanol, and pyridoxamine. Overall, Pyritinol is technically the first Nootropic, yet most people still think of Piracetam when they hear the term.
Difference between Smart Drugs and Nootropics
All Nootropics are cognitive enhancers, but not all cognitive enhancers are Nootropics. For example, Adderall is a cognitive enhancer but it is not a Nootropic. This is because Adderall is a smart drug.
Smart Drugs are supplements that enable the user to have greater processing speed for acquiring knowledge and understanding through thought, experience, and the senses. It is different compared to Nootropics, as it can only be legally obtained through a prescription from the doctor to treat a specific kind of mental or cognitive disorder. Additionally, there is no current information stating it will make the brain healthier.
The smart drugs are designed to temporarily enhance memory, energy, learning ability, attention, and focus. However, it has little to no concern about the long-term side effects. This makes the use of smart drugs very dangerous due to the serious side effects that can happen when taken for a duration of time.
Adderall is the most common smart drug that is prescribed to patients to treat narcolepsy and attention deficit hyperactivity disorder. It enhances the user’s ability to stay focused, pay attention, control behavior problems, and improve listening skills. The ingredients found in Adderall contain a combination of amphetamine and dextroamphetamine, which are central nervous stimulants that affect the chemicals in the nerves and brain that correlates to hyperactivity and impulse control. However, the long-term use of Adderall leads to tolerance and reliance. This can be extremely dangerous because the ingredient amphetamine leads to mental health problems, irregular heartbeat, physical collapse, and death if used for a duration of time. There have been 20 reports of sudden death by Adderall since the drug has been introduced in 1994, which resulted in Canada banning Adderall in 2005.
Similarly, Ritalin is another smart drug used to treat narcolepsy, attention deficit disorder, and attention deficit hyperactivity disorder. This cognitive enhancer is a central nervous stimulant and the side effects include numbness, irregular heartbeat, seizure, and death. Just like Adderall, it contains amphetamines which increase short-term alertness and mental clarity, however, long term use can be potentially fatal.
Modafinil is an ingredient found in various smart drugs and it has the ability to increase the user’s alertness and energy levels. In Canada, it is sold under the brand name Alertec and can only be obtained through a prescription. The possession of Modafinil is legal, however, if non-prescribed Modafinil is imported into Canada the supplement can be seized at the border. Conversely, it is not recommended to import Modafinil due to possible legal issues. Modafinil works by restraining the actions of the dopamine transporter, leading to the increase in extracellular and synaptic concentrations of dopamine. This promotes a natural sense of wakefulness in the user by raising the hypothalamic histamine levels. Additionally, Modafinil restrains the GABAergic neurotransmission and activates the glutamatergic circuits in the brain. As a result, the user is able to concentrate, learn and perform various mental tasks at ease. On the other hand, the short-term side effects of Modafinil include a headache, anxiety, and a decrease in appetite, nausea, and insomnia.
If the supplement gets the user high, wired, sedated, or altered it considered a smart drug, not a Nootropic. This is because Nootropic does not seem to have adverse body side effects, impaired brain function, deplete neurotransmission, or build tolerance/habit-forming potential. Nootropic is/should be sustainable and focuses on mild metabolic and nutritive for long term gains and protection.
The first researcher to classify the term “Nootropic” was Dr. Guirgea. The series of criteria the substance had to meet to be classed as a Nootropic include:
- The substance must possess few or no side effects, be nearly non-toxic, and not have the pharmacology of other psychotropic drugs, such as motor stimulation and sedation.
- The substance must protect the brain against physical and chemical injuries, such as scopolamine, barbiturates, and anticholinergic drugs.
- The substance must aid the brain function under disruptive conditions, such as electroconvulsive shock and hypoxia (low oxygen).
- The substance must enhance memory and the ability to learn.
- The substance must increase the efficacy of neuronal firing control mechanisms in cortical and sub-cortical regions of the brain.
Likewise, Dr. Skondia was the second researcher to classify the term “Nootropic”. His criteria were based on a Nootropic metabolic approach compared to Dr. Giurega’s criteria. Specifically,
- The substance possesses no direct vasoactivity (vasodilation or vasoconstriction).
- The substance shouldn’t change basic EEG rhythm.
- The substance must cross the blood-brain barrier.
- The substance must possess metabolic activity in the human brain.
- The substance must have little-no side effects.
- The substance must undergo clinical trials which reveal metabolic cerebral improvement.
The biggest difference between the two researcher’s criteria is that Dr. Giurgea thought the substance should enhance learning and memory while Dr. Skonida thought a substance has to enhance brain metabolism through glucose or oxygen update. Racetams are one of the many Nootropics that meet the true definition of Nootropic.
Synthetic Nootropics and Natural Nootropics
Racetam is a synthetic Nootropic used to enhance cognitive abilities. It was initially developed to treat motion sickness, however, it proved successful in enhancing mental performance, information processing, and memory consolidation. The four common types of Racetams are Piracetam, Aniracetam, Oxiracetam, and Pramiracetam. Some are stimulatory, some give a soothing feeling, some enhance concentration, and some are suited for creative thought. Therefore, each Racetam has similar, yet distinct benefits. It is important to note each person’s biochemistry is different, hence not all of the effects will be the same.
Racetam improves the communication between the two hemispheres of the brain. This results in a higher level of idea formation, a higher degree of thinking and enhanced memory temporarily. Other benefits include enhanced alertness, IQ in elderly patients, reading speed and accuracy, writing, spelling, and overall mental performance.
Another benefit of Racetam is that it improves the Cyclic Adenosine Monophosphate (cAMP) levels and Adenosine Triphosphate (ATP) turnover. This results in the body and brain working more efficient with the greater amount of energy levels. It also influences the cerebral neurons and enhances the protein synthesis in the brain and brain metabolism through stimulation of oxidative catabolism. However, compared to Natural Nootropics, specifically Gingko Biloba, Racetam barely act on the hippocampal portion of the brain; which is involved in long-term memory potentiation and release of dopamine and acetylcholine.
Types of Racetam
Piracetam is an odorless, partially bitter white powder that is a cyclic derivative of GABA but does not act like GABA in the body. It is a positive allosteric modulator (PAM), a molecule that increases the activity of the GABAa receptor protein in the vertebrate central nervous system, of the N-methyl-D-aspartate receptor (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The NMDA and AMPA receptors are the body’s excitatory receptors that are normally bound by glutamate, however, since Piracetam is an allosteric modulator it can modulate the function of the receptor by binding to a second site instead of the main site of a receptor. This enables Piracetam to modulate, both up and down, the signaling of the NMDA and AMPA receptors, but still, allows them to be bound to by agonists/antagonists. In other words, Piracetam increases the excitability of the when they are bound to by glutamate, which enhances neuronal transmission.
Piracetam improves ATP metabolism and usage, cell membrane permeability, and mitochondrial electron transport chain, which facilitates the citric acid cycle. The citric acid cycle is responsible for the release of stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins into energy in the form of adenosine triphosphate (ATP). Piracetam also affects multiple neurotransmitter systems such as acetylcholine, glutamate, and kainite, in so doing increasing blood flow and oxygen to modify cognitive, neuronal, and vascular functions. This improves the long-term brain health, as well as short term enhanced cognition. Studies show Piracetam improves mental cognition when supplemented by people in a state of cognitive decline. It enhances the cellular membrane fluidity which explains why Piracetam enhances cognition, specifically in the elderly.
Aniracetam is an odorless, mildly bitter, fluffy white powder synthesized by Hoffmann-La Roche in 1970. It is more potent and lipid soluble than Piracetam, meaning more of it passes the blood brain barrier. It is an ampakine nootropic, which acts primarily on the AMPA receptors, and decreases the rate of receptor desensitization. Since AMPA receptors are different in terms of structure in the brain, different AMPA modulators impact the brain in different ways. This can greatly improve perceptions of sounds and colors, increase focus and concentration levels, and increase the blood flow to the brain.
Aniracetam is also a fat soluble, however, it does not need fat to be bioavailable since it is completely absorbed in the gastrointestinal tract on an empty stomach. Using fat will lower bioavailability due to higher amounts of fat-soluble compounds being excreted in feces. The effects are short-lived, typically no more than 2 to 4 hours, because it is rapidly and completely metabolized in the liver after absorption. Although Aniracetam is a fat soluble, it does not build up in the body because it has very little binding to plasma proteins and the fat-soluble compound buildup has more to do with its protein binding rather than lipid solubility.
Approximately, 70% of Aniracetam is metabolized into N-anisoyl-GABA and the remaining 30% metabolizes into P-Anisic Acid and 2-pyrrolidinone. N-anisoyl-GABA is considered to be an active metabolite due to it having similar cognitive effects as Aniracetam when injected into the brain. Although Aniracetam is biological half-life is short, N-anisoyl-GABA continues to act on the body and brain for a bit longer.
Aniracetam has shown to have anxiolytic effects, meaning it has anti-anxiety properties. This is most likely due to its major metabolite, N-anisoyl-GABA, and enhanced effects of cortical GABA. Aniracetam has been shown to increase dopamine and serotonin levels through cholinergic mechanisms in the prefrontal cortex, basolateral amygdala, and dorsal hippocampus of the mesocorticolimbic system. It also reduces cognitive impairment with cerebrovascular insufficiency and reduces scopolamine induce amnesia in young healthy human. Like piracetam, it is a positive allosteric modulator and increases the uptake and usage of acetylcholine in the brain.
Oxiracetam is an odorless, sweet and slightly bitter white powder. The only difference between Oxiracetam and Racetam is the addition of a hydroxyl group. The hydroxyl group lowers lipid solubility, making it slightly less likely to pass a lipid membrane-like the blood brain barrier. It modulates AMPA receptors and increases acetylcholine usage making it similar to Piracetam and Aniracetam. However, oxiracetam affects D-aspartic acid (D-AA) which can lead to increased metabolic activity in neuronal cells, which may be the reason it provides the stimulating effect.
Oxiracetam is a positive allosteric modulator of the AMPA receptors that binds to a different AMPAR binding site than that of piracetam and aniracetam. Therefore, by taking Oxiracetam together with Piracetam and Aniracetam, this leads to synergistic effects, without competitive inhibition of each other’s action. Oxiracetam is also a choline uptake, increases the utilization of acetylcholine, prevents scopolamine-induced amnesia in humans, clinically used to prevent cognitive decline in dementia, increase memory formation in young and healthy individuals, enhance the release of excitatory neurotransmitters, and modulate cholinergic transmission.
Pramiracetam is an odorless, bitter, and white to beige powder. It is structurally different than Piracetam due to the addition of a 2-(diisopropyl amino)ethyl group. This extra functional grouping alters the potency and effects of the compound. It acts as a central nervous system stimulant and is a high-affinity choline uptake enhancer. The memory consolidation effects of Pramiracetam can be abolished by an organ removal surgery that removes one or both of your adrenal glands called adrenalectomy. This shows that the adrenal function is crucial to getting the benefits. Additionally, it is both water and fat-soluble making it ideal for both absorption and blood-brain permeability. Compared to Piracetam, Aniracetam, and Oxiracetam, Pramiracetam is more water soluble than them all. Some benefits include memory enhancement in people with cerebral injury, increase in mental energy levels and concentration, increase cerebral flow, improve long-term memory and spatial learning, and improve neuroplasticity. It works by binding the acetylcholine receptors and modulating them to augment the effectiveness and efficiency of acetylcholine transmission, which is vital in the formation of new memories. With greater amounts of acetylcholine in the brain, this increases the stimulation of the cholinergic system can increase the memory capacity of the brain. As the synaptic plasticity and computational power of the cerebrum increases, there is an improvement in problem-solving and information processing.
Acetyl-L-Carnitine (ALCAR) is an amino acid that is essential for muscle movement, brain and heart function, and other body processes. It is considered a Natural Nootropic due to its ability to cross the blood-brain barrier to get from the bloodstream into the brain. In terms of cognitive enhancement, ALCAR produces acetylcholine, which is an essential neurotransmitter required for memory function and learning. Other benefits include improved processing speed, focus, memory, mood, alertness, clarity, and has a fast acting antidepressant properties.
Acetyl-L-Tyrosine is an amino acid used to treat phenylketonuria, which is a problem for people who can’t process phenylalanine properly. It is considered a precursor for dopamine, which is the neurotransmitter that allows one to maintain motivated and focused. Acetyl-L-Tyrosine will benefit users who suffer from procrastination or lack focus and drive.
Artichoke Extract is the leaf of the Cynara Scolymus plant. It is one of the most effective and safest PD4E inhibitors. PD4E is an enzyme that breaks down cyclic adenosine monophosphate (cAMP) molecules and blocks the breakdown of cAMP which increases the levels of cAMP in the brain. This can result in an overall increase in cognition, improved memory, and alertness. The leaves are also rich in luteolin flavonoids and caffeoylquinic acids are known to possess great amounts of antioxidant, lipid lowering properties, and hepatoprotective. In terms of Nootropics, the luteolin flavonoids from the artichoke extract show potent anti-inflammatory response by inhibiting NFkB signaling in the brain cells. This reduction of inflammation in the brain protects the brain from toxins, minimizes the effects of brain aging, and contributes to the stimulation of new neuron cells. The new neuron cells improve memory, increase neuroprotection, cognition, wakefulness and neuroplasticity.
Bacopa Monnieri is an extract from the Brahmi plant and has been used as a cognitive enhancer for thousand years. It works by balancing serotonin, GABA, and dopamine while reducing the stress hormone cortisol. The benefits include improved concentration, memory, and reduces stress. On the other hand, to experience maximum benefits of Bacopa Monnieri, long duration of use is necessary, of at least two to three months. Therefore, Bacopa Monnieri will not enhance the cognitive abilities instantly but rather it will gradually. Studies have been shown that there is a link between Bacopa Monnieri and the improvement on hand-eye coordination and memory. It’s also known for reducing and relieving anxiety, negative effects of stress, depression, and insomnia.
Coleus Forskolin is from the root of the Coleus Forkohlii plant. It increases the cAMP and cAMP-mediated functions through the activation of the enzyme adenylate cyclase. The cAMP is the messenger system that relay signals in the brain, increase in cAMP, improve cognitive function, restrain cell degranulation, lowers blood pressure, intraocular pressure, and stimulates lipolysis in fat cells. Additionally, due to the interference with platelet activation factor (PAF), Forskolin restrains the binding of PAF, independently of the cAMP formation.
Fish Oil is rich in Omega 3 fatty acids which contain eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The fatty acids reduce inflammation, enhance neurotransmission, and increase activity in the prefrontal cortex. Studies also show that it protects the brain from Alzheimer’s and Parkinson’s disease.
Ginkgo Biloba is leaves from the Ginkgo Biloba tree and it acts as an antioxidant and improves circulation of blood flow to the brain. Many people take it to ward off dementia, stay mentally sharp, and improve memory. It is an inhibitor of the platelet activating factor (PAF) receptor which may underlie some neuroprotective effects. Additionally, oral ingestion of Ginkgo Biloba subchronically appears to increase dopamine concentrations in the prefrontal cortex, which seems to be related to the flavonoids rather than terpenoids. However, even though Ginkgo Biloba can boost cognition, its effect is not very reliable.
Huperzine A is Natural Nootropic ingredient purified and extracted from the Chinese club moss (Huperziceae family). It is known as an acetylcholinesterase inhibitor, which means that it stops an enzyme from breaking down acetylcholine which results in increases in acetylcholine. Additionally, it is beneficial for problems with loss of mental abilities (dementia) and memory.
Lion’s Mane is an edible mushroom that is linked to nerve growth factor. Nerve growth factor is a neurotrophin, a small secreted protein that is crucial for the survival and growth of neurons. It is one of the essential building blocks of neuroplasticity and brain health. The nerve growth factor advocates the growth of axons, nerve cells extension where impulses are conducted. Therefore, the more axons that exist, the better the overall function of the brain. Studies have shown that the mushroom incorporated in the daily diets of the elderly improved their cognitive abilities. Additionally, Lion’s Mane is rich in numerous polysaccharides that could provide anti-cancer, antioxidant effects, reduce blood glucose, regulate blood lipid levels, neuroprotective, and wound healing benefits.
L-Theanine is an amino acid found naturally in green tea. It enables the user to reach an optimal state of relaxed concentration without feeling drowsy. The brainwave patterns get altered into the same brainwave state experienced during meditation. When consumed as a supplement it is believed to reduce the symptoms of anxiety and neurodegeneration. L-Theanine increases the levels of dopamine, GABA, and neurotransmitters serotonin which improves mood, recall, learning, calm focus, and speed and accuracy of performance.
Although caffeine is not a Natural Nootropic and considered a stimulant, it is known for providing the user a feeling of energy, concentration, and alertness. It pairs perfectly with L-Theanine and it works by suppressing the production of adenosine in our body and increasing the production of the neurotransmitter dopamine. Studies have shown that caffeine helps ward off Alzheimer’s and may protect against Parkinson’s disease. The only side effects of caffeine are that it leads to headaches and jitteriness if high quantities are consumed.
Panax Ginseng appears to be effective for cognition, immunity, and mood. It contains many substances affecting many different systems of the body. Specifically, ginsenosides and panaxosides are found almost exclusively in the plant genus Panax (ginseng). When Ginseng is paired up with Gingko Biloba it results in greater accuracy and reduces errors in cognitive tests. Studies also have shown Ginseng to be somewhat effective at reducing the rate of cognitive decline from aging and toxins.
Rhodiola Rosea is a traditional Chinese perennial flowering plant in the family Crassulaceae and is used to promote physical/cognitive vitality. It acts as a neuroprotective and promotes longevity in preliminary evidence and reduces fatigue and exhaustion in prolonged stressful situations.
Vitamin B12 plays a vital role in the function of the brain, health of the nervous system and energy. Specifically, it is required for neurological function, DNA synthesis, and proper red blood cell formation. However, due to it being a water soluble, meaning it is not capable being stored in the body for long periods of time, it must be constantly replenished to keep up with one’s cognitive performance.
Nootropics Benefits to the Brain
The human cortex is composed of billions of independent neurons, each with numerous axons (nerve cell extensions). The axons form synapses (electrical connections) between the neurons which enable them to connect to over thousands of others neurons. The synapses communicate through the use of acetylcholine (a neurotransmitter) to send signals. Some Nootropics increase the levels of neurotransmitters, such as acetylcholine, which improves the magnitude of neurotransmissions to the cortex. While other Nootropics form and/or strengthen synapses which open more bridges for communication, through a process called Long-Term Potentiation. With new neuron cells and the improved synaptic communication, this enhances the proliferation (rapid reproduction of a cell) and growth of dendrites – the branched nerve cell extensions where neural impulses travel – boosting neural signaling. The brain activity increases which improves neural impulse transmission, enhances memory and thinking abilities, thus increasing neuroplasticity.
Certain Nootropics ingredients inhibit (restraints or stop) the platelet-activating factor receptor. The platelet activating factor (PAF) transmit signals between cells, however, it can trigger serious inflammation. This can cause sepsis, shock, traumatic injury, and pathological inflammation. With the inhibition of platelet activating factor, less inflammation will occur, resulting in the efficient flow of blood and other nutrients to the body and brain. Likewise, certain Nootropics initiate the dilation (widening) of blood vessels and decrease blood pressure, through a process called “vasodilation”. The vasodilation process improves the cerebral circulation of blood, nutrient, oxygen, and glucose throughout the body and brain resulting in energy generation and absorption efficiency.
Nootropic benefits the brain by acting as an antioxidant to regulate or remove harmful substances from the brain. It reduces the inflammation occurrence in the brain and repairs the neuron cells damaged by damaged by beta-amyloids, glutamate, peroxides, and platelet activating factors. In the maintenance process, the Nootropics increase the amount of Nerve Growth Factor in the brain which protects the brain from toxins, minimizes the effects of brain aging, and contributes to the stimulation of new neuron cells. Specifically, Nerve Growth Factor is a neurotrophin which is a small secreted protein that is crucial for the survival, maintenance, proliferation and growth of neurons. It is one of the essential building blocks of neuroplasticity and brain health. The nerve growth factor advocates the growth of axons, nerve cells extension where impulses are conducted. Therefore, the more axons that exist, the greater the overall function of the brain. The increase of nerve growth factor also enhances cognition by promoting myelination, the growth of the lipid and protein sheath that covers and protects the axons. The myelin increases the speed at which impulses travel along the axon by increasing the resistance of the neural cell walls and preventing the impulses from dispersing or leaving the axon. To repair and regrow the damaged axon, the myelination lays the foundation to aid the process. This is vital for protecting the brain from aging or diseases such as Alzheimer’s because it potentially slows or even prevents the cognitive diseases connected with advanced age.
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