Nootropic

Nootropics (pronounced /noʊ.ɵˈtrɒpɨks/), also referred to as smart drugs, memory enhancers, and cognitive enhancers, are drugs, supplements, nutraceuticals, and functional foods that are purported to improve mental functions such as cognition, memory, intelligence, motivation, attention, and concentration.^[1][2] The word nootropic was coined in 1972^[3][4] by the Romanian Dr. Corneliu E. Giurgea, derived from the Greek words νους nous, or "mind," and τρέπειν trepein meaning "to bend/turn". Nootropics are thought 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 nootropic substances, in most cases, has not been conclusively determined. This is complicated by the difficulty of defining and quantifying cognition and intelligence.

Nootropic vs. cognitive enhancer

A nootropic is a cognitive enhancer that is neuroprotective or extremely nontoxic.

The term cognitive enhancer is not to be confused with the word "nootropic". Nootropics are by definition cognitive enhancers, but a cognitive enhancer is not necessarily a nootropic.

A cognitive enhancer is a substance that enhances concentration and memory. The first synthetic cognition enhancers to see widespread use were the amphetamines. The word "nootropic" has been abused by researchers who wish to promote a certain drug as side-effect free. The word was first coined by Corneliu E. Giurgea in 1972. He stated that nootropic drugs should have the following characteristics:^[4]

1. They should enhance learning and memory.
2. They should enhance the resistance of learned behaviors/memories to conditions which tend to disrupt them (e.g. electroconvulsive shock, hypoxia).
3. They should protect the brain against various physical or chemical injuries (e.g. barbiturates, scopalamine).
4. They should increase the efficacy of the tonic cortical/subcortical control mechanisms.
5. They should lack the usual pharmacology of other psychotropic drugs (e.g. sedation, motor stimulation) and possess very few side effects and extremely low toxicity.

Note: section 5. of Giurgea's original definition has been gradually dropped by most researchers.

Availability and prevalence

At present, there are several drugs on the market that improve memory, concentration, planning, and reduce impulsive behavior. Many more are in different stages of development.^[5] The most commonly used class of drug is stimulants.^[6]

These drugs are used primarily to treat people with cognitive difficulties such as Alzheimer's disease, Parkinson's disease, and ADHD. However, more widespread use is being recommended by some researchers^[7]. These drugs have a variety of human enhancement applications as well, and are marketed heavily on the internet. 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.

In academia, modafinil has been used to increase productivity, although its long-term effects have not been assessed in healthy individuals.^[5] Stimulants such as methylphenidate are being used on college campuses, and by an increasingly younger group.^[5] One survey found that 7% of students had used stimulants for a cognitive edge in the past year, and on some campuses the number is as high as 25%.^[6]

Hazards

The main concern with pharmaceutical drugs is adverse effects, and these concerns apply to cognitive-enhancing drugs as well. Cognitive enhancers are often taken for the long-term when little data is available.^[5]

Dr. Corneliu E. Giurgea originally coined the word nootropics for brain-enhancing drugs with very few side effects. Racetams are sometimes cited as an example of a nootropic with few effects and wide therapeutic window;^[8] however, any substance ingested could produce harmful effects. An unapproved drug or dietary supplement does not have to have safety or efficacy approval before being sold.^[9] (This mainly applies to the USA, but may not apply in the EU or elsewhere.)

Examples

The term "drug" here is used as a legal designation. Although some of the effects of these substances may be similar to others, only those substances that have shown cognitive effects are included.

Dietary sources and supplements

Cognitive function is largely impacted by one’s diet. The nutrients in food can influence our memory, learning, concentration, and decision-making; therefore the lack of them has a negative effect on the brain. So far, the studies have been able to link brain function to vitamin B₁ and B₁₂, omega-3, caffeine, antioxidants, protein, and iron. In addition, there is research on certain supplements and whether or not they have any benefit, and how blood glucose levels play an effect on concentration and recall.

B Vitamins are vital in cognitive function, but not all B vitamins play a role in brain function. Some aid in the synthesis of chemicals, but two in particular have a significant influence in brain function. Vitamin B₁, thiamin, aids nerve cell function and helps the body convert food, specifically carbohydrates, into glucose. Glucose is what the brain uses as an energy source, making it a very critical need for the brain. Foods containing vitamin B₁ include whole grains, rice, wheat germ, bran and organ meats. Vitamin B₁₂, cyanocobalamin, is used to make neurotransmitters. One of their primary functions is the formation of blood cells. They also maintain the nervous system by helping to metabolize fatty acids, which are essential for the maintenance of myelin that surrounds nerves. B₁₂ is originally synthesized by bacteria only. There are no dietary plant sources for it. In addition to including vitamin B in one’s diet, there are factors that can play a role in the uptake and use of vitamin B.^[10]

Homocysteine and folate each affect how various B vitamins are metabolized. Homocysteine is a byproduct of the body’s metabolism of methionine, one of the essential amino acids, although not one used to build protein that is converted back to methionine or cysteine, through reactions with certain B vitamins. Methionine is used to breakdown fats, which is crucial, since the brain needs certain fats to function properly. Cysteine helps to detoxify harmful substances in the body and can also help to increase levels of the antioxidant glutathione, a substance which helps to stop compounds in the body that alter cell membranes, tamper with DNA, or cause cell death. In one of the studies young mice genetically predisposed to atherosclerosis were fed one of four diets for 8 weeks, which differed in B vitamin and methionine contents. Psychomotor, memory, spatial and learning tests were done, and researchers reported brain dysfunction in those with low vitamin B intake. Low amounts of vitamin B₁₂ with normal folate have been shown to cause cognitive impairment and anemia, while normal vitamin B₁₂ and high amounts of folate have been shown to improve cognitive function. While vitamin B₁ and B₁₂ improve cognitive function, it is not enough; other dietary factors come into play as well (Bliss, 2007).

Omega-3, alpha linolenic acid, has a strong influence on the brain. It influences both communication between cells and cell function. It appears to make receptors on the cell membranes that are more sensitive to serotonin, a neurotransmitter, which helps give people a “happy” feeling. Omega-3 has also been linked to helping retain brain function . A study done in Norway, according to Chillot, proved how omega-3 eaten during pregnancy helped to produce a more intelligent child^[11]. Increasing omega-3 in the diet has been shown to lower risk of depression, even better than depression medication. Omega-3’s can be found in cold-water fish, such as salmon, as well as almonds, avocadoes, walnuts and flaxseed. Fish oils in particular, are components of nerve cell membranes and myelin, which help to keep blood vessels in the brain healthy. A study on cats demonstrated that fish oil reduced the degree of brain damage experienced in cerebral stroke. Unfortunately today, it is harder to find regular sources of omega-3.^[12]

Interestingly enough, diets of prehistoric families included sufficient amounts of omega-3 due to cooking methods and agricultural practices, yet in today’s world such practices are no longer the norm. Traditional sources of omega-3 could be found richly in cattle, since they used to graze on grass, which contains omega-3, but today they are mostly fed grain, which does not contain omega-3’s. Today’s society gets too much omega-6, and less of omega-3, both of which are polyunsaturated fats (Chillot, 2004).

While unsaturated fats, such as omega-3 fat, are known to be beneficial to the brain, saturated fats, are not. According to the Sukitt-Hale, saturated fat, which is a triglyceride, is strongly linked to causing depression, manic depression and schizoaffective disorder, in addition to hostility and aggression. Studies on patients have showed that lowering levels of triglycerides help to alleviate depression and improve scores on dementia screening tests in the elderly.^[13] One cause for this is due to the fact that high levels of triglycerides increase blood sluggishness, so it becomes harder for the blood to transport sufficient amounts of oxygen to brain cells. Without oxygen in the brain, mini brain lesions and blood clots can form. Memory tests have also been done on rats that were fed high saturated fat diets and found those with the least amount of saturated and total fat to have performed better in the memory tests. A study done on infant rhesus monkeys lead by William Connor, M.D, also concurred with these results when they fed each monkey diets with adequate amounts of fat, but differed in the types of fats.^[14] The ones with more saturated fats grew well, but their visual development was impaired and they kept pacing and forth, as if they had a neurological defect, while the ones with unsaturated fats grew normally. Although not all omega-3’s are made the same. Long-chain omega-3’s appear to be more favorable in the brain, compared to the medium lengths, which are found in plants (Gómez-Pinilla, 2008), however the human body is able to make its own long-chain omega-3's when plants containing medium length omega-3's are consumed, therefore you do not need to eat meat to obtain long-chain omega-3's. In fact, despite common myths involving fish oil, plant based medium length ALA is the only essential omega-3 fatty acid.^[15]

There are many mixed opinions about caffeine and the effects that it has on the brain. Some say that it helps cognitive function, while others find its benefits to be equivalent to its negative effects. Caffeine reaches its highest concentration in the blood and brain within 30–40 minutes after consumption and has an elimination half-life of 4 to 6 hours. The half-life of caffeine may be shorter for smokers and longer for pregnant women. It has been shown to increase alertness, performance and in some studies memory.^[16]

Children and adults who consume low doses of caffeine showed increase alertness, yet a higher dose was needed to improve performance.^[17] Kiefer (2007) found caffeinated beverages to help improve short-term concentration and facilitate learning, as well as memory. Caffeine dilates the blood vessels in the brain, if consumed in small amounts. Kiefer (2007) compared the benefits and effects of coffee versus tea. Coffee took effect within 20 minutes and lasted for 2–3 hours, while tea, had a weaker effect, yet lasted longer, since it was released more slowly, although, Rogers (2007) emphasized moderation, since studies suggested that too much caffeine would decrease concentration. One underlining factor, is also the liquid in caffeinated beverages, which helps to stabilize circulation and nutrient transport (Rogers, 2007). Negative effects of caffeine are not seen if it is consumed 6 hours or more apart and in appropriate doses. Such regular consumption may also enhance the neuro-protective actions of adenosine. Adenosine is a nucleoside that contains adenine as its base. Adenosine dilates the coronary arteries and is employed in the adenosine thallium scan of heart. Caffeine has also been shown to have more of an effect on improving cognitive performance and sustaining attention in older adults. Chronic pretreatment of caffeine in animals has shown to reduce ischaemic brain damage, in addition to reducing the risk of Parkinson’s disease (Rogers, 2007). Although caffeine may help brain function, it may not necessarily be recommended for those who do not already consume it.

Those opposed to caffeine find there to be little to no acute benefit from regular caffeine consumption due to withdrawal lowering alertness and mood. After consumption, it is rapidly distributed throughout the body and blocks actions of endogenous adenosine at adenosine A1 and A2 receptors resulting in different physiological effects. The blockage is how caffeine can affect alertness and performance, since adenosine is closely involved in sleep regulation. For example, the extra cellular adenosine concentration increases during waking and decreases during sleep. Withdrawal from caffeine tends to cause headaches, with its increase in cerebral blood flow. It is worse for those who typically consume caffeine and then try to abstain from it for a long term. There was no shown effect on performance in non-consumers and long-term withdrawn consumers, even when sleep deprived. Still, such findings may be due to the fact that those who were studied who did not consume caffeine were different in that they already functioned well without caffeine, so they had no need or were not missing any gap to begin with. Another problem with caffeine is that it causes an anxiety and jitteriness effect, although some heath surveys have found caffeine to improve mood in both young and old adults. It is thought that depression, stress, and anxiety may be lessened with caffeine (Rogers, 2007). Beverages that contain caffeine typically have antioxidants as well, which have show to have a strong association with improving brain cognition.

Antioxidants have been found to be very beneficial to brain functioning in many ways. The more commonly known aspect of antioxidants on the brain would be their protection from oxidative damage. A study which lasted 3–6 years, showed how vegetables, most likely due to their vitamin E, folate and antioxidant content, helped people to retain their mental abilities longer, keeping their brain younger. Those vegetables emphasized were leafy green or cruciferous vegetables. Both polyphenolics and isoflavones are two types of antioxidants that have been studied.^[18]

Polyphenolics (also known as phenols) in fruits and vegetables may help brain functioning. The darker colored fruits and vegetables tend to be high in phenolics, therefore possessing large antioxidant and anti-inflammatory activity. At high levels, it has been shown that these effects can retard and reverse elements of brain aging, such as dopamine decrease and other cognitive deficits. The polyphenolics increased antioxidant and anti-inflammatory levels. Such effects are particularly effective with dietary intake of berry fruit. A study was done on rats, where a 2% blackberry supplemented diet was shown effective in reversing age related deficits and neural function. This diet helped improve motor performance based on three tasks. Polyphenolics positively affect brain signaling to enhance neural communication. In addition to polyphenolics, flavonoids and other antioxidants also help to get rid of free radicals.^[19]

Other antioxidants include flavonoids, tannins, phenolic acids and stilbenoids. Berries are a great antioxidant food source, and happen to be high in flavonoids, condensed and hydrolysable tannins, phenolic acids, stilbenoids, and cyanidin-3-O-glucoside, which has the highest oxygen radial absorbance capacity among anthocyanins. Blackberries are high in antiproliferative, antioxidant and anti-inflammatory activities, making them a great food for the brain. In one study showing the benefits of blackberries, rats were fed a 2% blackberry diet, and they were able to perform much better on behavioral tests than the control rats. According to Nutritional Neuroscience, blackberry juice and its main anthocyanin component, cyanidin-3-O-glucoside had been seen to the protective effect against free radical-mediated endothelial dysfunction and vascular failure. Blackberries, like blueberries, may exert their protective effects directly through alterations in cell signaling to improve or increase neuronal communication, calcium buffering ability, neuroprotective stress shock proteins, and plasticity on stress signaling pathways. The study had found that the blueberry diet improved spatial working memory in older rats, and changes were regulated by the camp response element binding (CREB) and brain-dervied neurotrophic factor (BDNF) pathway in the hippocampus. Anthocyanins, which are found in blueberries and blackberries, enter the brain and improve cognitive function. Isoflavonoes have been found to help the cognitive process, but in a different way (Shukitt-Hale, 2009).

Wong et al. (2008) found that consumption of isoflavones of 50 mg of soy dietary supplements twice a day for three weeks, decreased a biomarker of DNA oxidation damage. Isoflavones are a plant derived class of phytoestrogens. They are richest in soy products, but can also be found in foods such as legumes. There is some evidence suggesting that isoflavones may protect the brain from cognitive decline. Wong et al. reported that the UK the Joint Health believed that soy protein helps to reduce cholesterol, which may impact how the brain works (2008). Another study that looked mainly at the effects of soy on females during their cycle.^[20] This was done because the estrogen levels constantly change throughout the female cycle. The results suggested that, dietary phytoestrogens may have an effect on cognitive function in females and that soy appeared to affect some cognitive processes. While soy products do contain isoflavones, which has shown benefit they also contain many essential amino acids, which may partially explain the benefits of soy other than isoflavones (Shukitt-Hale, 2009).

Adult brains use amino acids, which are typically found in protein rich food, for the production of enzymes that transport molecules, structural material and neurotransmitters, along with other essential molecules. Some of the amino acids include tyrosine and phenylalanine, which help to produce the catecholamines dopamine, norepinephrine, and epinephrine. These catecholamines help create alertness. Nutrition scientist Karina Fischer and her colleagues suggest eating high protein but low calorie meals to increases alertness and attentiveness, although too much protein can have a negative effect as well (Kiefer, 2007). Protein, especially protein found in dairy products, contains tryptophan, another important amino acid. Tryptophan helps to stabilize mood and may also influence the cognitive process, specifically learning and memory ( Kiefer, 2007). According to Blaun, there have been both human and rat studies which have indicated a deficit in long term memory and information processing due to tryptophan depletion and other studies show how tryptophan helps to improve decision making (1996). Foods high in carbohydrates, which do not contain tryptophan, help to push tryptophan into the brain by triggering the release of insulin. Insulin stimulates muscles to take up competing amino acids. Even calcium, which typically comes in many protein-rich foods, helps regulate nerve impulse transmission (Kiefer, 2007). Two other important neurotransmitters are acetylcholine and serotonin. Acetylcholine is essential in memory formation and maintenance. It is found in egg yolks and organ meats. Creation and utilization of acetylcholine is crucial to memory. Serotonin helps with sleep regulation and anxiety reduction. It is manufactured from tryptophan (Blaun, 1996). In addition to amino acids, iron is also necessary for a fully functioning brain.

Iron is also important for staying mentally sharp. It helps create hemoglobin, an iron containing protein in red blood cells, which transports oxygen to the brain. Oxygen in the brain is vital, since it helps to metabolize glucose. If a child does not receive enough iron, it can impair brain development and lead to deficits in speech, math, and reading. Women of reproductive age need the most iron, and therefore may be more likely to end up with a deficiency. Those with sufficient iron in their blood have been proven to perform better on cognitive tests than those who were iron-deficient. It is sometimes hard to get all these nutrients from one's diet, so supplementation can often be beneficial in supporting brain function (Kiefer, 2007).

Typical diets do not contain all our required amounts of nutrients, therefore it is recommended to take supplements and/or daily multi-vitamins. Although we would like for the multivitamin to fill in where we are missing nutrients from the diet, that is not always the case. Some nutrients are absorbed better than others and we do not always receive the same benefit from supplements as we would from the nutrient in real food. Research has examined a few of the supplements for nutrients that have been found to improve cognitive function and have found some to be beneficial, while others showed to have little to no effect.

Some studies found certain supplements to be beneficial only in certain situations. Supplemental tyrosine, was found only to be beneficial in stressful conditions. In one study, soldiers were exposed to high altitudes or prolonged cold, which would normally deplete the body of tyrosine due to environmental stress. The soldiers who took the supplemental tyrosine did not suffer the loss of memory or any other side effects such as headache and lightheadedness. The one thing to consider in taking amino acid supplements is that they will tend to compete with one another for absorption. If too many amino acids are obtained from supplements, it will inhibit the absorption of amino acids from other sources.

There is little evidence of a benefit in terms of cognitive function from taking B vitamins or antioxidant supplements. Jia et al. (2008) gathered data from a wide variety of trials and found there to be no changes in cognitive function from taking vitamin B supplements in either healthy or cognitively impaired individuals. Yet, such results could be due to insufficient duration of supplementation. It may also be that the trials were done on older adults and vitamin B supplementation effect could be more beneficial at a younger age, when the brain is still developing.^[21] Cognitive decline may be very difficult to reverse in older adults. While taking supplements is one alternative to increasing brain function, watching glycemic index is another.

In addition to what you eat, when and how you eat also plays a role in how the brain operates. This is primarily due to the need of constant supply of glucose for the brain. Optimal brainpower is reached when blood glucose is stable. This is where diets, such as trying to eat a low glycemic index, can be beneficial. Simple sugars can spike blood glucose and their glucose supply does not last long, so they should be avoided. Too high blood glucose can also inhibit mental function, according to Cox, who ran cognitive tests on diabetics (Kiefer, 2007). Their verbal and math skills were much slower and less accurate when their glucose levels rose too high. It is best to replace simple sugars with complex carbohydrates found in fiber rich food, starchy whole grains, protein, legumes or vegetables, which take longer to be broken down and therefore, do not spike blood glucose. Eating regularly and snacking can help maintain glucose supply to the brain. Unfortunately, the brain cannot store carbohydrates, which is why it is in need of a constant supply of glucose. Without it, we lose the ability to concentrate. If one is low on glucose supply due to fasting, the brain is forced to get its energy from metabolizing ketones, which come from the breakdown of body fat, and cognitive function worsens, since it requires synthesis of special enzymes which take longer to metabolize. The saying, “eating breakfast helps one do better in school,” is not an old wives' tale, but truly does help one stay alert, focused and have a better retention rate. Some suggestions for breakfast food are fruit, yogurt, whole grain bread and low fat cheese. Surprisingly, even something as little as chewing gum could help improve memory (Kiefer, 2007). When picking foods, its is recommended to try to choose foods lower in saturated fats and cholesterol as well as simple sugars.

Choosing a diet with appropriate levels of cholesterol has been shown to be beneficial in terms of brain function, although the specifics are controversial. Diets too low in cholesterol, which some people strive for thinking it helps out their heart, have been linked to increased risk of suicide. Too little cholesterol makes the brain unstable, which tells people that it is missing something in cholesterol that is vital to our brains function. High cholesterol levels are also bad for the brain, especially when they are due to saturated fat (Blaun, 1996). So keeping in mind saturated fat and cholesterol when eating, really does help more than the heart.

Nootropics and racetams

The word nootropic was coined upon discovery of the effects of piracetam, developed in the 1960s.^[22] Although piracetam is the most commonly taken nootropic,^[22] there are many relatives in the family that have different potencies and side effects. Other common racetams include pramiracetam, oxiracetam, and aniracetam. There is no generally-accepted mechanism for racetams. In general, they show no affinity for the most important receptors, although modulation of most important central neurotransmitters, including acetylcholine and glutamate, have been reported.^[23] Although aniracetam and nebracetam show affinity for muscarinic receptors, only nefiracetam shows it at the nanomolar range. Racetams have been called "pharmacologically safe" drugs.^[8]

Other substances sometimes classified as nootropics include hydergine, vinpocetine, bifemelane, huperzine A (cholinergic activator below), and dimethylaminoethanol (DMAE).^[8]

Stimulants

Stimulants are often seen as smart drugs, but may be more accurately termed productivity enhancers. Some stimulants can enhance cognition and memory in some people, but cause psychosis in others. They generally have a very substantial side-effect profile and are not considered classical "nootropic" drugs. These typically improve concentration and a few areas of cognitive performance, but only while the drug is still in the blood. Some scientists recommend widespread use of stimulants such as methylphenidate and amphetamines by the general population to increase brain power.^[6][24]

• Amphetamines
  • Amphetamine (Adderall, Dexedrine) - adrenergic, dopaminergic
  • Lisdexamfetamine (Vyvanse) - adrenergic, dopaminergic

(It must be noted, however, that amphetamines also act as potent neurotoxins to dopaminergic and serotonergic neurons, particularly after chronic usage. Therefore, their effectiveness as nootropics are highly limited.)

• Adrenergics
  • Atomoxetine - Norepinephrine reuptake inhibitor; approved for ADHD
  • Reboxetine - Norepinephrine reuptake inhibitor; approved in Europe for clinical depression but may also be used off-label to treat ADHD
• Cholinergics
  • Arecoline
  • Nicotine
• Eugeroics ("Wakefulness Enhancers") - unproven primary mechanisms but proven efficacy
  • Adrafinil
  • Armodafinil
  • Modafinil
• Xanthines - reduces fatigue perception
  • Caffeine
  • Paraxanthine
  • Theobromine
  • Theophylline

Dopaminergics

Dopaminergics are substances that affect the neurotransmitter dopamine or the components of the nervous system that use dopamine. Attributable effects of dopamine are enhancement of attention, alertness, and antioxidant activity. Dopamine is the primary activity of stimulants like methylphenidate (Ritalin) or amphetamine. Dopaminergic nootropics include dopamine synthesis precursors, dopamine reuptake inhibitors, monoamine oxidase inhibitors, and other compounds:

• Metabolic precursors - raise levels
  • L-Phenylalanine - purported cognitive improvement
  • L-Tyrosine (or N-Acetyl-L-Tyrosine, more bioavailable form) - purported cognitive improvement
  • L-DOPA (L-3,4-dihydroxyphenylalanine) - precursor to catecholamines (dopamine)
  • Biopterin - A rare vitamin (coenzyme) that is synthesized in the pineal gland^[25] & crucial to the biosynthesis of dopamine
• Reuptake inhibitors - stabilize/improve levels
  • Amineptine - mild stimulant
  • Methylphenidate - stimulant approved for ADHD; strong DAT inhibition
  • Bupropion - atypical antidepressant; moderate inhibition of DAT
• MAO-B inhibitors - prevent breakdown
  • Selegiline - Mild stimulant; irreversible
  • Rasagiline - Mild stimulant; irreversible
  • Rhodiola Rosea - Adaptogenic herb; reversible (Also shown to inhibit Monoamine Oxidase A)
• Dopamine agonists
  • Ropinirole - Agonist at D2, D3, and D4 receptors
  • Pramipexole - Agonist at D2, D3 and D4 receptors
• Others
  • Mucuna pruriens (Velvet Bean) - Natural source for L-DOPA
  • Modafinil - purported dopaminergic activity
  • Yohimbe - purported dopaminergic activity; however, it has an inhibitory effect on D2 receptor signalling

Memory enhancement

Memory can come from many different processes, but is dependent on the ability to store and recall information.

Cholinergics

Cholinergics are substances that affect the neurotransmitter acetylcholine or the components of the nervous system that use acetylcholine. Acetylcholine is a facilitator of memory formation. Increasing the availability of this neurotransmitter in the brain may improve these functions. Cholinergic nootropics include acetylcholine precursors and cofactors, and acetylcholinesterase inhibitors:

• Precursors
  • Choline - precursor of acetylcholine and phosphatidylcholine
  • DMAE - precursor of acetylcholine
  • Meclofenoxate - probable precursor of acetylcholine, approved for Dementia and Alzheimer's
  • Alpha-GPC - delivers choline to the brain across the Blood-brain barrier, it is sold under its chemical name or in Neurostin
• Cofactors
  • Acetylcarnitine - amino acid that functions in acetylcholine production by donating the acetyl portion to the acetylcholine molecule
  • Vitamin B₅ - cofactor in the conversion of choline into acetylcholine
• Acetylcholinesterase inhibitors
  • Galantamine
  • Huperzine A - also shown to act as an NMDA antagonist
  • Donepezil
  • Rosemary
  • Sage
• Reuptake inhibitors and enchancers
  • Coluracetam - choline uptake enhancer
• Agonists
  • Ispronicline
  • Nicotine
  • Arecoline

GABA blockers

The GABA_A α5 receptor site has recently displayed memory improvements when inverse agonized.

• α5IA - α5 inverse agonist
• Suritozole - α5 partial inverse agonist

Glutamate activators

The AMPA transmitter and the AMPA receptors are currently being researched, and there are signs that significant memory improvement and possible alertness enhancement may occur when agonized. The drug class for AMPA system modulation is called Ampakines. Although there are many Ampakines currently in-research, those mentioned here are significantly notable, and/or show reasonable signs of coming to market.

Some racetams have shown this activity, such as aniracetam

• CX-717 - Going through FDA approval for memory-impairing illnesses
• IDRA-21 - believed to improve memory by significantly enhancing long-term potentiation but used only in animals - incredibly potent
• LY-503,430 - Being developed for Parkinson's but showing increase in BDNF, specifically in areas of memory and higher cognitive skills

cAMP

Cyclic adenosine monophosphate is a secondary messenger that, if increased, has shown memory improvements. One common method is by decreasing the activity of phosphodiesterase-4, an enzyme that breaks down cAMP. Typical effects include wakefulness and memory enhancement.

• Propentofylline - nonselective phosphodiesterase inhibitor with some neuroenhancement
• Rolipram - PDE4 inhibitor, shows alertness enhancement, long term memory improvement and neuroprotection
• Mesembrine - PDE4-inhibitor with possible serotonergic activity

Other

α_2A receptors are concentrated heavily in the prefrontal cortex and the locus coeruleus, with the potential to improve attention abilities via modulating post-synaptic α_2A receptors in the prefrontal cortex.^[26]

• Guanfacine is an α_2A receptor agonist, FDA approved for and frequently used to treat ADHD symptoms.[2][3] Studies have shown guanfacine to strengthen working memory, reduce distractibility, improve response inhibition, increase regional cerebral blood flow, reduce locomotor hyperactivity, and improve attentional control in animal models, as well as enhance memory function in humans.^[27]

Serotonergics

Serotonin is a neurotransmitter with various effects on mood and possible effects on neurogenesis. 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:

• 5-HTP - precursor
• Tryptophan - Essential amino acid precursor
• SSRIs - Class of antidepressants that increase active serotonin levels by inhibiting its reuptake. Have also been shown to promote Neurogenesis in the hippocampus.
• Kanna - herb with antidepressant properties; shown to act as a potent SSRI
• Tianeptine - paradoxical antidepressant, improves mood and reduces anxiety

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

Stress, depression, and depressed mood negatively affect cognitive performance. It is reasoned that counteracting and preventing depression and stress may be an effective nootropic strategy. The term adaptogen applies to most herbal anti-stress claims.

The substances below may not have been mentioned earlier on the page:

• Beta blockers - anxiolytic
• Lemon Balm - Displays adaptogen properties. Has also shown to possess GABA transaminase inhibitor properties
• Passion Flower - possible MAOI and neurotransmitter reuptake activity
• Rhodiola Rosea - adaptogen; possible MAOI activity
• St John's Wort - herbal SSRI that has been approved (in Europe) to treat mild depression
• Ginseng (including Siberian ginseng) - adaptogenic effects shown
• Sutherlandia frutescens - possible anti-inflammatory reducing pain from those illnesses
• Tea - contains many different adaptogens
• Theanine - GABAergic activity producing relaxation, also increases brain serotonin and dopamine levels
• Grape seed extract - has shown some efficacy in reducing bodily stress
• Adafenoxate - possible anxiolytic effect
• Valerian - possible anxiolytic effect through agonism at GABA-A receptors
• Butea frondosa - possible anxiolytic effect^[28]
• Gotu Kola - adaptogen and anxiolytic
• Foti - adaptogen; possible MAOI activity
• Berberine - alkaloid, found in various herbs, with powerful antidepressant properties; acts as a sigma receptor agonist

Blood flow and metabolic function

Brain function is dependent on many basic processes such as the usage of ATP, removal of waste, and intake of new materials. Improving blood flow or altering these processes can benefit brain function. Vasodilators mentioned are only those which have shown, at minimum, probable mental enhancement.

• Blessed Thistle - increases blood circulation, improving memory.
• Coenzyme q-10 - antioxidant; increases oxygen usage by mitochondria.
• Creatine - protects ATP during transport.
• Lipoic acid - improves oxygen usage and antioxidant recycling, possibly improving memory.
• Pyritinol - Drug. Similar to B vitamin Pyridoxine.
• Picamilon - GABA activity and blood flow improver.
• Ginkgo biloba - vasodilator; it has also been shown to act as a negative allosteric modulator of GABA-A receptors, and as an antagonist at GABAA-rho receptors (formerly known as GABA-C receptors)
• Vinpocetine - increases blood circulation (vasodilator) and metabolism in the brain; also shown to inhibit voltage-sensitive Na+ channels. However, through a similar mechanism to reserpine, Vinpocetine may induce the temporary depletion of the monoamines serotonin, dopamine and norepinephrine by inhibiting VMAT, thus causing or aggravating depression as an adverse effect.

Nerve growth stimulation and brain cell protection

Nerves are necessary to the foundation of brain communication and their degeneracy, underperformance, or lacking can have disastrous results on brain functions. Antioxidants are frequently used to prevent oxidative stress, but do not improve brain function if that is their only activity.

• Idebenone - antioxidant
• Melatonin - antioxidant
• Glutathione - chief antioxidant
• Inositol - implicated in memory function, deficit linked to some psychiatric illnesses; it possesses an antidepressant effect primarily through actions on 5-HT2 receptors; has also been shown to increase dopamine D2 receptor density in the striatum
• Anticonvulsants inhibit seizure related brain malfunction if a person has seizures
• Phosphatidylserine - possible membrane stabilizer
• Lion's Mane Mushroom - Stimulated myelination in an in vitro experiment^[29] and stimulated nerve growth factor in an in vitro experiment with human astrocytoma cells.^[30] Also improved cognitive ability, in a double-blind, parallel-group, placebo-controlled trial.^[31]
• SAM-e (S-Adenosyl methionine) - crucial for cellular regeneration, also involved with the biosynthesis of dopamine & serotonin.
• (Dopamine enhancers) - dopamine is an antioxidant and can enhance dendrite extension

Dietary nootropics

Diet can have the greatest effect on cognition and the brain, as there are many necessary things that must be consumed. However, other substances have been linked to certain benefits, and may be predominant in certain foods. Studies have been able to link vitamin B₁, vitamin B₁₂, omega-3, caffeine, antioxidants, protein and iron to brain function. It is crucial to obtain the nutrients that increase cognitive function directly, as well as those that effect how those nutrients are absorbed and used in the body.

Vitamin B₁, thiamin, aids nerve cell function and helps the body convert food, specifically carbohydrates, into fuel, known as glucose. Glucose is what the brain runs off of, making it crucial for the brain. Foods containing vitamin B₁, include whole grains, rice, wheat germ, bran and organ meats. B₁₂, cobalamin, is used to make neurotransmitters. They also maintain the nervous system by helping to metabolize fatty acids, which are essential for the maintenance of myelin, which surrounds nerves. Vitamin B₁₂ is found primarily in animal products, but it may also be found in soy products, eggs, seaweeds and algae. Low amounts of vitamin B₁₂ with normal folate have been shown to cognitive impairment and anemia, while High amounts of folate and normal vitamin B 12 have been shown to improve cognitive function.^[10]

Traditional sources of omega-3, an unsaturated fat, could be found richly in cattle, since they used to graze on grass, which contains omega-3, but today they are mostly fed grain, which does not contain omega 3’s. Today’s diet is thought to be too high in omega-6, and too low in omega-3. Omega-3, alpha linolenic acid, has a strong influence on the brain. They influence both communication between cells and cell function. It appears to make receptors on the cell membranes who are more sensitive to serotonin, a neurotransmitter, which helps give us a “happy” feeling. Omega-3 has also been linked to helping retain brain function. A study done in Norway proved how omega 3 eaten during pregnancy helped to produce a more intelligent child. Higher omega-3 has been shown to lower risk of depression, even better than depression medication. Omega-3’s are what build cell membranes. Omega-3’s can be found in cold water fish, such as salmon, as well as hemp seeds, almonds, avocadoes, walnuts and flaxseed. Fish oils in particular, are components of nerve cell membranes and myelin, which help to keep blood vessels in the brain healthy (Chillot, 2004) (myelin applies only to nervous tissue not cardiovascular). On a side note, in terms of fats in general, high saturated fat diets have been linked to worsen memory.

Caffeine effects on the brain are quite controversial. Some admit to their effect on the brain, while others deny any benefits, due to its addictive effects. Caffeine has been shown to help improve short-term concentration and facilitate learning, as well as memory. Caffeine dilates the blood vessels in the brain, if consumed in small amounts. In low doses it increases alertness, but a high dose is needed to show improved performance. After consumption, it is rapidly distributed throughout the body and blocks actions of endogenous adenosine at adenosine A1 and A2 receptors resulting in different physiological effects. The blockage is how caffeine can affect alertness and performance, since adenosine is closely involved in sleep regulation.

Antioxidants have been found to be very beneficial to brain functioning in many ways. The more commonly known aspect of antioxidant on the brain, would be their protection for oxidative damage. A recent study which lasted three – six years, showed how vegetables, most likely due to their vitamin E, folate and antioxidant content, helped people to retain their mental abilities longer, keeping their brain younger (Environmental Nutrition, 2009). Those vegetables emphasized were leafy green or cruciferous vegetables (Environmental Nutrition, 2009). It was also found that consumption of isoflavonoes of 50 mg of soy dietary supplements twice a day for three weeks, decreased a biomarker of DNA oxidation damage. Isoflavones are a plant derived class of phytoestrogens. Isoflavones are richest in soy products, but can also be found in foods such as legumes. It is not overwhelming, but there is some evidence suggesting that isoflavones may protect the brain from cognitive decline. M.C.Y. Wong et al. found that the UK the Joint Health believed that soy protein helps to reduce cholesterol, which may impact how the brain works. Another study that looked mainly at the effects of soy on females during their cycle, since their estrogen levels constantly changed, suggested that dietary phytoestrogesn may have effects on cognitive function in females and that soy appeared to affect some cognitive processes. (Nutritional Nerosicence, 2008). Polyphenolics in fruits and vegetables help brain functioning. The darker colored fruits and vegetables tend to be high in phenolics, therefore possessing large antioxidant and inflammatory activity. At such levels, it has been shown that these effects can retard and reverse bits of brain aging, such as dopamine release and other cognitive deficits. The polyphenols increased antioxidant and anti-inflammatory levels. Such effects are particularly effective with dietary intake of berry fruit. A study was done on rats, where a 2% blackberry supplemented diet was proven effective in reversing age related deficits and neural function. This diet helped improve motor performance based on three tasks. Polyphenolics positively effect brain signaling to enhance neural communication. Berries are also high in flavonoices, condensed and hydrolysable tannins, phenolic acids and stillbenoids, amongst other properties, such as Cyanidin-3-O-glucoside, which has the highest oxygen radial absorbance capacity among anthocyanins. Blackberries are so high in antiproliferative, antioxidant and anti-inflammatory activities, making them a great food for the brain. In one study proving the benefits of blackberries, rats were fed a 2% blackberry diet, and they were able to perform much better on behavioral tests than the control rats. According to Nutritional Neuroscience, blackberry juice and its main anthocyanin component, cyaniding-3-O-glucoside had been seen to the protective effect against free radical-medicated endothelial dysfunction and vascular failure Blackberries, like blueberries, may exert their protective effects directly through alterations in cell signaling to improve or increase neuronal communication, calcium buffering ability, neuroprotective stress shock proteins, plasticity an stress signaling pathways (Barbara, 2009). The study had found that the blueberry diet improved spatial working memory in older rats, and changes were regulated by the CREB and BDNF pathway in the hippocampus. Anthocyanins, which are found in blueberries and blackberries, enter the brain and improve cognitive function.

Adult brains used amino acids, which are typically found in protein rich food, for the production of enzymes that transport molecules, structural material and neurotransmitters, along with other essential molecules. Some of the amino acids include tyrosine and phenylalanine, which help to produce the hormone epinephrine and neurotransmitter dopamine. These two hormones help create alertness. Therefore it is suggested to eat low calorie, but high protein meals, so people are more alert and attentive. Although too much protein can have a negative effect as well. In addition to toxicity which too high protein levels can cause, foods high in protein have less tryptophan, a precursor to the neurotransmitter serotonin.[?] Tryptophan helps to stabilize mood and may also influence the cognitive process, specifically learning and memory. There have been both human and rat studies which have indicated a deficit in long term memory and information processing due to tryptophan depletion and other studies show how tryptophan helps to improve decision making. Although, carbohydrates, which don’t contain tryptophan, help to push it into the brain, by triggering the release of insulin. Insulin stimulates muscles to take up competing amino acids. Even, calcium, which typically comes in many foods with protein, helps regulate nerve impulse transmittion (Kiefer, 2007). Two other important neurotransmitters are acetycholine and serotonin. Acetycholine is essential in memory formation and maintenance. It is found in egg yolks and organ meats. Creation and utilization of acetylcholine is crutial to memory. Serotonin helps with sleep regulation and anxiety reduction. It is manufactured from tryptophan (Blaun, 1996).

Iron is also important for staying mentally sharp. Iron helps create hemoglobin, an iron containing protein in red blood cells, which transport oxygen to the brain. Oxygen in the brain is vital, since it helps to metabolize glucose. If a child does not receive enough iron, it can impair brain development and lead to deficits in speech, math and reading. Women of reproductive age need the most iron, and therefore may be more likely to end up with a deficiency. Those with sufficient iron int heir blood have been proven to perform better cognitive tests than those who were iron-deficient.

Direct hormones

These are hormones that have activity not necessarily attributable to another specific chemical interaction, but have shown effectiveness. Only specific nootropic effects are stated.

• Vasopressin - memory hormone that improves both memory encoding and recall
• Pregnenolone - increases neurogenesis
• Orexin - Significant wakefulness promoter

Secondary enhancers

These are substances which by themselves may not improve brain function, but may have benefits for those lacking them (in the case of hormones) or may alter the balance of neurotransmitters.

• DHEA - Precursor to Estrogen and Testosterone

Unknown enhancement

Other agents purported to have nootropic effects but which do not (yet) have attributable mechanisms or clinically significant effects (but may upon refinement of administration) are mentioned here.

Nootropics with proven or purported benefits:

• Bacopa monniera - shown to possess adaptogenic properties; enhances memory and concentration.^[32] Folk use in Ayurvedic medicine purports "enhancement of curiosity".
• Brahmi rasayana - improved learning and memory in mice.^[33]
• Fipexide - drug for Dementia
• Gerovital H3 - famous anti-aging mixture, most effects disproven, but some mind enhancement shown
• Sulbutiamine - fat soluble vitamin B₁ derivative . Some shown memory improvement
• Royal Jelly - Increases brain cell growth and diversity, only proven in-vitro, improbable in-vivo
• Curcumin - Significant in-vitro activity, but in-vivo activity is limited by low bioavailability

Other nootropics

These substances have been linked to better cognitive function, but may not be the cause. See correlation does not imply causation

• Moderate use of alcohol - Moderate drinkers tend to have better cognitive function than both abstainers and heavy drinkers.^{[34][35][36][37][38][39]}

See also

Brain and neurology

Thought and thinking (what nootropics are used for)

Health

References

External links

• "A Pandora's box full of smart drugs" by Ann Robinson (The Guardian: February 23, 2010)
• Greely H, Sahakian B, Harris J, et al. (December 2008). "Towards responsible use of cognitive-enhancing drugs by the healthy". Nature 456 (7223): 702–5. doi:10.1038/456702a. PMID 19060880. http://www.nature.com/nature/journal/vaop/ncurrent/full/456702a.html. 
• "Brain Gain: The underground world of “neuroenhancing” drugs" by Margaret Talbot (The New Yorker: April 27, 2009)
• Business Week Online - "I Can't Remember" September 1, 2003 at Business Week
• List of Nootropic drugs at Erowid