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Nootropics, popularly referred to as "smart drugs", "smart nutrients", "cognitive enhancers" and "brain enhancers", are a class of drugs that improve impaired human cognitive abilities (the functions and capacities of the brain).[1]

The word nootropic was coined in 1964 by the Romanian Dr. Corneliu E. Giurgea, derived from the Greek words noos, or "mind," and tropein meaning "to bend/turn". Typically, nootropics are alleged to work by altering the availability of the brain's supply of neurochemicals (neurotransmitters, enzymes, and hormones), by improving the brain's oxygen supply, or by stimulating nerve growth. However the efficacy of alleged nootropic substances in most cases has not been conclusively determined. This is complicated by the difficulty of defining and quantifying cognition and intelligence.

Availability

Nootropic drugs are generally only available by prescription or through personal importation. The other nootropic substances listed below are either nutritional supplements or plant components (herbs, roots, beans, bark, etc.), and are generally available over the counter at health food and grocery stores, and are used as nutritional supplements.

The drugs are used to treat people with cognitive learning difficulties, neural degradation (Alzheimer's disease or Parkinson's disease), and for cases of oxygen deficit to prevent hypoxia. These drugs have a variety of human enhancement applications as well and are marketed heavily on the World Wide Web. Nevertheless, intense marketing may not correlate with efficacy; while scientific studies support some of the claimed benefits, it is worth noting that many of the claims attributed to most nootropics have not been formally tested.

Therapy or enhancement

Nootropic drugs are primarily for therapeutic use, in the sense that they normalize an inhibited mental performance by various causes. In fact, some nootropic substances are ineffective unless there is a malfunction in the first place[How to reference and link to summary or text]; replenishing neurotransmitters for instance, is only positively effective when there is a lack of the neurotransmitters in the first place.

On the other hand, many nootropics may theoretically be used as human enhancement, boosting mental function in otherwise normal healthy people. This is physically problematic, however, e.g. since compensatory mechanisms of the brain prevents long-term enhancements[How to reference and link to summary or text]. For instance, a short period of increased concentration and alertness of taking stimulants[How to reference and link to summary or text], e.g. caffeine, is compensated for by a period at least as long with decreased alertness etc. in order to avail for recovery. Furthermore, there is much controversy over such applications. This may contribute to the lacking research on such effects.

Nevertheless, colostrinin may enhance long-term memory retention even in young, already healthy, individuals[2].

Examples

The term "drug" here is used as a legal designation, and does not indicate greater efficacy. With nootropics, the effects, effectiveness, and potency differ from substance to substance and from individual to individual. See the substance descriptions below for more detail.

Replenishing and increasing neurotransmitters

As the brain ages, its ability to produce and maintain youthful levels of neurotransmitters declines.[3] There are various reasons for such an insufficiency. For instance, there might be a lack of enzymes involved in the neurotransmitter synthesis. Nevertheless, in many cases, providing the brain with ample raw materials necessary to make neurotransmitters can restore them to more youthful levels and thus help maintain cognitive function at vigorous youthful levels.[How to reference and link to summary or text] Furthermore, there are declines in immune and endocrine functioning. [4] Certain nootropics enhance immune and endocrine functioning.

Cholinergics

Cholinergics are substances that affect the neurotransmitter acetylcholine or the components of the nervous system that use acetylcholine. Acetylcholine facilitates memory, concentration, focus, and high-order thought processes (abstract thought, calculation, innovation, etc.).[How to reference and link to summary or text] Increasing the availability of this neurotransmitter in the brain may improve these functions and increase the duration in which they may be engaged without slowing down or stopping. Oversupplying the brain with acetylcholine may have the opposite effect, temporarily reducing rather than improving mental performance.[How to reference and link to summary or text] Cholinergic nootropics include acetylcholine precursors and cofactors, and acetylcholinesterase inhibitors:

Piracetam
Main article: Piracetam

Piracetam (Nootropil) - Prescription drug (in Europe). The original (first),[5] and most commonly taken[6][5] nootropic drug. It is a cholinergic agent, synergistic with DMAE, Centrophenoxine, choline, and Hydergine. Increases brain cell metabolism and energy levels,[7][5] and speeds up interhemispheric flow of information (left-right brain hemisphere communication).[8] Increases alertness,[9] improves concentration, and enhances memory. Protects neurons from hypoxia,[5] and stimulates growth of acetylcholine receptors. May also cause nerves to regenerate. Piracetam markedly decreases the formation of neuronal lipofuscin.[10] It improves posture in elderly people.[11] It is not regulated in the US. It is a pyrrolidone derivative.

Aniracetam
Main article: Aniracetam

Aniracetam is a pyrrolidone derivative drug, analogous of piracetam, and considered more potent[How to reference and link to summary or text]. Like piracetam, aniracetam protects against some memory impairing chemicals, such as diethyldithiocarbamate and clonidine.[12] Also like piracetam, aniracetam may enhance memory in aging adults by increasing levels of brain biogenic monoamines, which are beneficial to learning and memory.[3] Both racetams have possible therapeutic use in treating fetal alcohol syndrome.[13] Aniracetam increases vigilance[9]. Aniracetam has shown to positively potentiate AMPA receptors.

Other cholinergic
  • Acetyl-L-carnitine (ALCAR) - Amino acid. Precursor of acetylcholine (donating the acetyl portion to the acetylcholine molecule). It is synergistic with lipoic acid.[14]
  • Choline - precursor to acetylcholine (an essential component of the acetylcholine molecule).
  • DMAE - approved treatment for ADD/ADHD[How to reference and link to summary or text], precursor of acetylcholine, cholinergic agent, removes lipofuscin from the brain, anti-depressant.
  • Galantamine - acetylcholinesterase inhibitor made from chemical synthesis or extract from plants such as Red Spider Lily (Lycoris radiata).
  • Huperzine A - potent acetylcholinesterase inhibitor derived from Chinese club-moss.
  • Lecithin - contains phosphatidylcholine, precursor of acetylcholine.
  • Other pyrrolidone derivatives:
    • Etiracetam - It increases vigilance.[9]
    • Nefiracetam - Drug. Analog of piracetam, and facilitates hippocampal neurotransmission.[15]
    • Oxiracetam - Drug. Analog of piracetam, and 2 to 4 times stronger. Improves memory, concentration, and vigilance. When fed to pregnant rats, the offspring of those rats were more intelligent than the offspring of rats fed a saline solution placebo.
    • Pramiracetam - Drug. Analog of piracetam.
    • In animal studies, nootropics such as piracetam, oxiracetam and aniracetam are known to facilitate the formation of long term memory traces and to restore object recognition in aging rats. [16] There is evidence that the beneficial effect of racetams may result from an interaction with the central glutamatergic receptor function. [16]
  • Vitamin B5 - cofactor in the conversion of choline into acetylcholine, cholinergic agent, increases stamina (including mental stamina).

Excess acetylcholine is considered by many to be potentially harmful; see cholinesterase inhibitor.

Dopaminergics

Dopaminergics are substances that affect the neurotransmitter dopamine or the components of the nervous system that use dopamine. Dopamine is produced in the synthesis of all catecholamine neurotransmitters, and is the rate limiting step for this synthesis. Dopaminergic nootropics include dopamine precursors and cofactors, and dopamine reuptake inhibitors:

  • Mucuna pruriens - Seed powder contains high concentrations of levodopa (L-dopa),[17] a direct precursor of the neurotransmitter dopamine.
  • Lazabemide is a MAO-B inhibitor and has potent membrane lipid antioxidant activity. The antioxidant effects of lazabemide are attributed to its chemical structure and direct physicochemical interactions with the membrane lipid bilayer. It is a potent antioxidant, even more powerful than selegiline (deprenyl) or vitamin E, and is used to treat Alzheimer’s disease.[18]
  • L-dopa - Prescription drug and dietary supplement. Precursor to the neurotransmitter dopamine, anti-depressant.
  • Phenylalanine (requires Vitamin B6 and Vitamin C) - Essential amino acid. Precursor to dopamine, anti-depressant, sleep reducer.
  • Theanine - Found in tea. Increases serotonin and dopamine levels in the brain. Increases alpha-wave based alert relaxation.
  • Tyrosine (requires Vitamin B6 and Vitamin C) - Amino acid. Precursor to dopamine, anti-depressant, sleep reducer.
  • Vitamin C- improves cardiovascular elasticity and integrity, membrane stabilizer and major anti-oxidant (protects brain cells and prevents brain cell death), cofactor in the production of the neurotransmitters dopamine and serotonin.
  • Vitamin B6 - co-factor used by the body to produce dopamine.
  • Yohimbe - Bark. Boosts dopamine levels, though how it does this is not yet understood. Aphrodisiac. Yohimbe poses some health risks through its side-effects: it is a neuro-paralytic which slows down breathing and induces acidosis, some symptoms of which are malaise, nausea, and vomiting. Contraindicated for users of megadoses of acidic vitamins or nutrients.
  • Deprenyl - (selegiline) L-Deprenyl is an irreversible MAO-B inhibitor, an enzyme that breaks down dopamine. Thus, it is used to treat Parkinson's disease, and to delay the progression of Alzheimer's disease. It protects against the genotoxin AraC, provides neuroprotection against growth factor withdrawal in PC12 cells, protects against oxidative stress in mesencephalatic neurons, and delays neuronal cell death in the hippocampus after global ischemia.[19]
  • Tolcapone - Inhibits COMT (an enzyme that breaks down the neurotransmitters dopamine, epinephrine, and norepinephrine) and increases performance in tasks depending on working memory in individuals with the val/val and val/met genotype of the val158Met polymorphism of the catechol-O-methyltransferase gene, while decreasing it in presence of the met/met version. Tolcapone presents the risk of deadly side effects.

Serotonergics

Serotonergics are substances that affect the neurotransmitter serotonin or the components of the nervous system that use serotonin. Serotonergic nootropics include serotonin precursors and cofactors, and serotonin reuptake inhibitors:
  • Griffonia simplicifolia a natural source of 5-HTP (an alternative in countries where 5-HTP not legal, freely available.)
  • Tryptophan (requires Vitamin B6 and Vitamin C) - Essential amino acid. Precursor to serotonin, found in high concentration in bananas and poultry (especially turkey), also in milk, promotes relaxed poise and sound sleep. 5-HTP is a form of Tryptophan.
  • 5HT2A agonists such as LSD and 2C-T-7 have been shown to produce nootropic effects when used at a dose much lower than a hallucinogenic dose. (e.g. 10 μg for LSD and 1 mg 2C-T-7, 1/25 of a normal recreational dose )[How to reference and link to summary or text]
  • SSRIs - Class of antidepressants that increase serotonin levels in the brain by inhibiting its reuptake. Have also been shown to promote Neurogenesis in the hippocampus.

Anti-depression, adaptogenic (antistress), and mood stabilization

Depression and depressed mood negatively affect cognitive performance. Feelings of sadness, guilt, helplessness, hopelessness, anxiety, and fear caused by depression detract from productive thought, while apathy (which is also induced by depression) is the lack of motivation and driving moods (like curiosity, interest, determination, etc.) Other symptoms include disturbed sleep patterns, mental fatigue and loss of energy, trouble concentrating or making decisions, and a generalized slowing and obtunding of cognition, including memory. Obviously, removing these effects improves intelligence and mental performance, and therefore, counteracting and preventing depression are effective nootropic strategies. There is a high correlation between depression and a reduction or depletion of neurotransmitters (dopamine, acetylcholine, and serotonin) in the brain, therefore it is no surprise that increasing the brain's supply of neurotransmitters alleviates (or at least reduces the symptoms of) most depressions. Stress is another major factor in neurotransmitter depletion, being both a cause and effect of it (creating a vicious downward spiral), therefore stress management and anti-stress substances are also very useful nootropic strategies.

All of the "nergics" listed above have been found to increase stress tolerance and alleviate depression (by replenishing or increasing the brain's supply of specific neurotransmitters)[How to reference and link to summary or text], especially when used in precursor/co-factor combinations[How to reference and link to summary or text].

Below are additional nootropics which affect mood and stress:[How to reference and link to summary or text]

  • Ashwagandha (Withania somnifera) - Root. Also known as Indian ginseng. Adaptogen used as a tonic to normalize body processes and reduce stress and anxiety.
  • Inositol - Is a B-vitamin like substance with anti-anxiety effects. It is believed to produce its anti-anxiety effects by improving the binding of gabaergics to GABAA receptors. Inositol is a sugar, and is therefore an alternative energy source for brain and muscle tissues. It produces a sugar high without a sugar low, making it especially suited for sweetening tea (instead of sugar). It is also a membrane stabilizer which can strengthen (and therefore help protect) neurons.
  • Kava-kava - The roots of the Kava-Kava plant contain Kavalactones which have GABAergic properties and are used to combat anxiety.[20]
  • Lemon Balm (Melissa officinalis) - Herb. Anti-depressant.
  • Passion Flower is used to treat depression. It is commonly combined with St. John’s Wort and Valerian, which work synergistically to reestablish the patients emotional balance without causing tachyphylaxia, hangovers, or addiction. [20]
  • Rhodiola Rosea - Herb. Adaptogen; elevates mood, alleviates depression. Promotes mental energy and stamina, reduces fatigue.
  • St John's Wort - Herb. The active components: hypericin and hyperforin, are clinically indicated to be effective in cases of mild to moderate depression, on par with synthetic drugs. However, St John's Wort is not suitable for the treatment of severe depression or suicidal tendencies. Side effects include gastrointestinal complaints and allergic reactions such as pruritus and phototoxicity. [20]
  • Ginseng, Siberian (Eleutherococcus senticosus) - Root. Anti-anxiety adaptogen that normalizes physical stress and mental consequences.
  • Selegiline (Deprenyl) - Along with Piracetam and Meclofenoxate, Deprenyl decreases the amount of lipofuscin pigment and ceroid pigment accumulations in the brain by improving cellular recycling activities.[21] Therefore, these nootropics may slow age-related diseases in the brain. Selegiline, an MAO-B inhibitor, is used as an antioxidant for the treatment of Alzheimer’s disease. [18]
  • Sutherlandia frutescens - Herb. Adaptogen, blood detoxifier.
  • Tea - Herb. Contains theophylline and theanine. Increases alpha-wave based alert relaxation (relieves stress).
  • Theanine - Amino acid. Found in tea. Increases serotonin and dopamine levels in the brain. Increases alpha-wave based alert relaxation.
  • Tianeptine - Anxiolytic anti-depressant. It enhances working and reference memory in rats.[22]
  • Vasopressin - Drug. Memory hormone produced by the pituitary gland which improves both memory encoding and recall. Rapidly counters chronic apathy syndrome and drug-induced vasopressin depletion.
  • Nicotinic acid (vitamin B3) - Essential nutrient. Mild enhancer of concentration and memory. Vasodilator - Mood stabilizer, with a powerful anti-anxiety effect — perhaps the best and most immediate stress reliever available (note that other forms of vitamin B do not have this effect). Side effects: gastric upset (which is easily prevented and relieved with antacids), reduced blood pressure and flushing of the skin (caused by vasodilation), and itchy sensation in the skin caused by histamine release.
  • Vitis vinifera (Grape Seed) Grape seed has antistress (adaptogenic) activity, protects against memory loss induced by scopolamine, is an antioxidant, has nootropic activities, and supports the traditional claims for the use of grape fruits and seeds in stress induced disorders. [23]

Brain energy and improved oxygen supply

  • Acetyl-L-carnitine (ALCAR) - Amino acid. Transports fatty acids through cellular membranes and cytosol into cells' mitochondria, where the fats undergo oxidation to produce ATP, the universal energy molecule. Synergistic with lipoic acid.
  • Chromium- stabilises blood sugar levels promoting concentration.
  • Coenzyme q-10 syn. Ubiquinone - increases oxygen transport through the mitochondria of the cells.
  • Creatine - increases brain energy levels via ATP production.
  • Inositol -
  • Lipoic acid - synergistic with Acetyl-L-carnitine.
  • Piracetam - improves alertness, blood flow, oxygen supply, and stroke recovery.
  • Pyritinol (Enerbol) - Drug. Enhances oxygen and glucose uptake in the brain, and allows glucose to pass more easily through the blood-brain barrier. It is also a powerful anti-oxidant which scavenges hydroxyl radicals created in the very processes it is involved in.
  • Vinpocetine - Vinpocetine increases blood circulation and metabolism in the brain. Animal studies have shown that vinpocetine can reduce the loss of neurons due to decreased blood flow. [5]

Mental agility, concentration, stamina, and focus

  • Adrafinil (Olmifon) - Drug.
  • Caffeine - Drug. improves concentration, idea production, but hinders memory encoding. Also produces the jitters. Caffeine is the most widely used psychoactive substance in the world, and may be susceptible to strong levels of tolerance.
  • Coffee - Bean. Contains caffeine; brewed coffee is high in antioxidants.
  • Nicergoline - Drug. Nicergoline is an ergoloid mesylate derivative used to treat senile dementia. It has also been found to increase mental agility and enhance clarity and perception. It increases vigilance.[9] Increases arterial flow and use of oxygen and glucose in the brain.
  • Nicotine - stimulus barrier (aids in concentration). Stimulus barrier rebound effect (an unpleasant side effect).
  • Cocaine - Drug.
  • Methylphenidate (Ritalin) - Drug
  • Dextroamphetamine - (Adderall, Dexedrine) - Drug.
  • Modafinil - (Provigil) - Drug.
  • Piracetam - improves alertness, socialization, and co-operation in the brain impaired from age, dementia, and reduced blood flow.
  • Phenibut -
  • Theophylline -
  • Amphetamine - aids in concentration, focus and stamina. Prescribed for ADD/ADHD
  • Carphedon (Phenotropil) -

Purported memory enhancement and learning improvement

All of the "nergics" listed above are purported to improve memory (encoding and recall), As do all nootropics which improve general brain performance in categories such as the brain energy and oxygen supply, and nerve growth stimulation and protection. Other agents purported to have these specific benefits are mentioned in their own sections.

Other nootropics with specific effects on memory encoding and recall include:

  • Bacopa monniera (Brahmi) - Herb. Elevates curiosity, enhances memory and concentration.[24] Brahmi also protects against amnesia inducing chemicals such as scopolamine or loss of memory due to electro convulsive shocks.[24] It is a traditional ayurvedic medicine.
  • Piracetam - improves memory. Used to treat Alzheimer's, dementia, dyslexia and Down's syndrome
  • Rosemary - Herb. Rosemary has a very old, albeit unverified, reputation for improving memory.
  • Vasopressin - Hormone, prescription drug.
  • Dextroamphetamine- Adderall, Dexedrine.[25]
  • Nicotine - Improves working memory and learning[26]

Nerve growth stimulation and brain cell protection

  • Acetyl-L-carnitine (ALCAR) - Amino acid. Inhibits lipofuscin formation.
  • Bacopa monnieri (Brahmi) - Herb. Improves protein synthesis in brain cell repair and new dendritic growth.
  • Selegiline (Deprenyl) - Drug. Brain cell protectant, delays senescence of brain cells, proven to increase maximum life span in laboratory rats.
  • Ergoloid mesylates (Hydergine) - Drug. Mimics nerve growth factor (NGF), and is a powerful anti-oxidant capable of delaying brain death in cases of heart failure and stroke by several minutes with regular use. It increases vigilance.[9]
  • Idebenone - stimulates nerve growth, and has same effects as Coenzyme q-10.
  • Inositol - Membrane stabilizer. Strengthens neurons, making them less susceptible to damage.
  • Pyritinol (Enerbol) - Drug. Powerful anti-oxidant which scavenges hydroxyl radicals.
  • Rasagiline (Azilect) - Drug. Treats Parkinson’s disease either as monotherapy (by itself) or in addition to levodopa therapy. Promotes increased and sustained levels of dopamine by selectively inhibiting an enzyme, monoamine oxidase-B.
  • Vitamin C - Membrane stabilizer, involved in collagen synthesis. Vitamin C is also a co-factor in the brain's production of dopamine.

Recreational drugs with purported nootropic effects

  • Amphetamine-type stimulants (such as Adderall, Dexedrine, Desoxyn, etc.) are Schedule II controlled substances in the United States, and Class B drugs in the United Kingdom, with comparable legal controls in effect in most countries throughout the world. They are prescribed for attention-deficit disorders, narcolepsy, and certain cases of obesity; and are issued to counteract fatigue and to enhance performance for pilots in the armed forces of the United States of America.[27][28] These also heighten alertness, mental focus, vigilance, stamina, and sex drive. They tend to be habit-forming, and exhibit side effects with prolonged or heavy use. Personal importation of amphetamine-class drugs is prohibited in many countries, and their use for recreation or for performance enhancement without a medical prescription is likewise illegal in most countries.
  • Cannabis is reported to heighten the ability of the senses, as well as heighten alpha wave activity in the brain associated with creativity.
  • LSD - Schedule I / Class A drug. At higher doses, the impact of the senses on one's mind are expanded to such an overwhelming degree that what is being sensed seems qualitatively different. Many psychedelic drugs are known to produce this overwhelming effect on the mind. Aldous Huxley called this state of mind "Mind at Large". Activity in the Raphe Nuclei and Locus ceruleus increases dramatically following administration of LSD to produce extremely heightened creativity in many users. This effect on the creative process is a phenomenon that may be due to ascending traffic in the reticular activation system, which can result in stimulus overload. The longest single research project with LSD, at Spring Grove Hospital, Maryland, showed an average 10% increase in linear IQ alone.[29] Also produces hallucinogenic and entheogenic effects at doses as low as 30–40 μg (micrograms), with the likelihood of having a bad trip increasing as dose is increased if these effects are undesired. May also cause cognitive shifts, synesthesia, and flashbacks. The drug sometimes spurs long-term or even permanent changes in a user's personality and life perspective. (For more details, see Albert Hofmann: LSD - My Problem Child.)
  • 4-methylaminorex
  • Pemoline
  • Psilocybin and Psilocin
  • MDPV
  • Mescaline

Dietary Nootropics

Some regular food items are rich sources of substances with alleged nootropic benefits:

Other nootropics

See also

Brain and neurology

Thought and thinking (what nootropics are used for)

Health

References

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