smart drug

Nootropics, 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 1964 by the Romanian Dr. Corneliu E. Giurgea, derived from the Greek words noos, or "mind," and tropein 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.

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.^[3] The most commonly used class of drug are the stimulants.^[4]

These drugs are used primarily to treat people with cognitive difficulties: Alzheimer's disease, Parkinson's disease, ADHD. However, more widespread use is being recommended by some researchers. 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.

In academia, modafinil has been used to increase productivity, although its long-term effects have not been assessed in healthy individuals.^[3] Stimulants such as methylphenidate and atomoxetine are being used on college campuses, and by an increasingly younger group.^[3] 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%.^[4]

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.^[3]

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;^[5] 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.^[6] (This mainly applies to the USA, but may not apply in the EU or elsewhere.)

Some dangers of nootropics include, but are not limited to:

• Downregulation of neurological activity upon stimulation, resulting in a permanent or temporary hypoactive system and/or addictive properties (applies to dopamine, choline, and many other neurotransmitter systems)
• Serotonin syndrome from serotonergic agents
• Excessive acetylcholine receptor activation - see acetylcholinesterase inhibitor
• Heart failure, such as that from stimulants or any substance which alters heart rate
• Organ failure such as liver failure and kidney failure

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.

Nootropics and racetams

The word nootropic was coined upon discovery of the effects of piracetam, developed in the 1960s.^[7] Although piracetam is the most commonly taken nootropic,^[7] 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.^[8] Although aniracetam and nebracetam show affinity for muscarinic receptors, only nefiracetam shows it at the nanomolar range. Racetams have been called "pharmacologically safe" drugs.^[5]

Other substances sometimes classified as nootropics include hydergine, vinpocetine, bifemelane, huperzine A (cholinergic activator below), and dimethylaminoethanol.^[5]

Stimulants

Stimulants are often seen as smart drugs, but are actually just productivity enhancers. 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.^[4][9]

• Amphetamines
  • Amphetamine (Adderall, Dexedrine) - adrenergic, dopaminergic
  • Lisdexamfetamine (Vyvanse) - adrenergic, dopaminergic
  • Methamphetamine (Desoxyn) - adrenergic, dopaminergic
  • Methylphenidate (Ritalin) - adrenergic, dopaminergic
• 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 - purported cognitive improvement
• Reuptake inhibitors - stabilize/improve levels
  • Amineptine - mild stimulant
• MAO-B inhibitors - prevent breakdown
  • Selegiline - mild stimulant
• Others
  • cocaine and the relatives - multiple mechanisms that amplify dopamine release
  • amphetamine and relatives
  • Yohimbe - purported dopaminergic activity

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
  • Meclofenoxate - probable precursor of acetylcholine, approved for Dementia and Alzheimer's
• 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
  • 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 with significant memory improvements and possible alertness enhancement when agonized. The drug class for AMPA system modulation is called Ampakines. Although there are many in-research ones, the main ones mentioned will be the ones possibly coming to market or are significantly notable.

Some racetams have shown this activity

• 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 - Drug. shows alertness enhancement, long term memory improvement and neuroprotection
• Mesembrine - PDE4-inhibitor with possible serotonergic activity

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
• SSRIs - Class of antidepressants that increase active serotonin levels by inhibiting its reuptake. Have also been shown to promote Neurogenesis in the hippocampus.
• Tianeptine - paradoxical antidepressant, improves mood and reduces anxiety
• Methamphetamine - some serotonin activity

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
• Kava kava - mild euphoric depressant used in relaxation
• Lemon Balm - Displays adaptogen properties
• Passion Flower - possible MAOI and neurotransmitter reuptake activity
• Rhodiola Rosea - possible MAOI activity
• St John's Wort - herbal MAOI 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 anti-anxiety effect
• Valerian - possible anti-anxiety effect
• Butea frondosa - possible anti-anxiety effect^[10]
• Gotu Kola - adaptogen and anxiolytic

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 - 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
• Vinpocetine - increases blood circulation (vasodilator) and metabolism in the brain
• Picamilon - GABA activity and blood flow improver
• Ginkgo biloba - vasodilator

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
• Inositol - implicated in memory function, deficit linked to some psychiatric illnesses
• dopamine enhancers - dopamine is an antioxidant and can enhance dendrite extension
• Anticonvulsants inhibit seizure related brain malfunction if a person has seizures
• Phosphatidylserine - possible membrane stabilizer

Recreational drugs

Many recreational substances that are currently illegal or heavily controlled have effects on the brain or long-term functions that are typically considered secondary to their effects on perception. Note that this list is not intended to be exhaustive. This list include substances which are illegal, or not completely illegal, but are controlled or exempt under a Drug schedule.

• Tetrahydrocannabinol - Anxiolytic and analgesic found in cannabis. Neuroprotectant, possible Alzheimer's prevention and possible neurogenesis inducer
• Amphetamine-type stimulants are described above
• 4-methylaminorex - similar to Modafinil but significantly more abuse potential
• Most Entheogens, including hallucinogens - drugs or substances which have shown value in psychotherapy, like mescaline, MDMA, and LSD.
• MDPV - designer drug, 4x as potent as methylphenidate, greater abuse potential
• Tobacco - Contains nicotine and also has significant MAOI activity

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.

Some regular food items contain substances with alleged nootropic benefits:

• Hemp or Flax - seeds as source of omega-3 fatty acids (see essential fatty acid)
• Fish - sources of omega-3 fatty acids (see essential fatty acid)
• Berries - may contain high levels of antioxidants

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 - enhances memory and concentration.^[11] Folk use in Ayurvedic medicine purports "enhancement of curiosity".
• Brahmi rasayana - improved learning and memory in mice.^[12]
• Ergoloid mesylates - Drug. Similar to LSD. Used against Dementia and Alzheimers
• 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.^{[13][14][15][16][17][18]}

See also

The length of this "see also" section may adversely affect readability. Please ensure that the "see also" links are not mentioned elsewhere in the article, are not red links, are as few in number and as relevant as possible.

Brain and neurology

Thought and thinking (what nootropics are used for)

Health

References

External links

• 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