People can also take l-theanine supplements. A review reported that l-theanine may increase alpha waves in the brain. Alpha waves may contribute to a relaxed yet alert mental state. L-theanine may work well when paired with caffeine.

Some evidence suggests that this combination helps boost cognitive performance and alertness. There are no dosage guidelines for l-theanine, but many supplements recommend taking — mg per day.

Omega-3 fatty acids are among the most well-known and well-studied mental enhancers. These polyunsaturated fats are found in fatty fish and fish oil supplements. This type of fat is important for brain health, and a person must get it from their diet. These fats are important for repairing and renewing brain cells.

A review found that omega-3 fatty acids protect against brain aging. Other research has concluded that omega-3s are important for brain and nervous system function. A person can get omega-3 supplements in various forms, including fish oil, krill oil, and algal oil. These supplements carry a low risk of side effects when a person takes them as directed, but they may interact with medications that affect blood clotting.

Ask a doctor before taking them. Racetams are synthetic compounds that can affect neurotransmitters in the brain. Some nootropic racetams include:.

A study conducted in rats suggests that piracetam may have neuroprotective effects. There is no set dosage for racetams, so a person should follow instructions and consult a healthcare provider.

Overall, studies have no found adverse effects of taking racetams as directed. Ginkgo biloba is a tree native to China, Japan, and Korea. Its leaves are available as an herbal supplement.

Ginkgo biloba may help with dementia symptoms, according to one review , which reported the effects occurring in people who took more than mg per day for at least 5 months. Also, with prescription nootropics available, ginkgo biloba may not be the most safe or effective option. Panax ginseng is a perennial shrub that grows in China and parts of Siberia.

People use its roots for medicinal purposes. People should not confuse Panax ginseng with other types of ginseng , such as Siberian or American varieties. These are different plants with different uses.

It also may help with brain recovery after a stroke. Panax ginseng interacts with many medications, so consult a doctor before taking it. A typical dosage for mental function is — mg once or twice a day. Some evidence suggests that Rhodiola rosea L. One review reported that rhodiola may have neuroprotective effects and may help treat neurodegenerative diseases.

Another review found that rhodiola helped regulate neurotransmitters in the brain, having a positive effect on mood. Creatine is an amino acid, which is a building block of protein.

This supplement is popular among athletes because it may help improve exercise performance. It may also have some effects on mental ability. A review found that taking creatine appears to help with short term memory and reasoning.

Whether it helps the brain in other ways is unclear. The International Society of Sports Nutrition report that creatine supplementation of up to 30 grams per day is safe for healthy people to take for 5 years.

Another review notes that there has been limited research into whether this supplement is safe and effective for adolescent athletes. Some small studies show that some nootropic supplements can affect the brain. But there is a lack of evidence from large, controlled studies to show that some of these supplements consistently work and are completely safe.

Because of the lack of research, experts cannot say with certainty that over-the-counter nootropics improve thinking or brain function — or that everyone can safely use them. For example, one report on cognitive enhancers found that there is not enough evidence to indicate that they are safe and effective for healthy people.

The researchers also point to ethical concerns. However, there is evidence that omega-3 fatty acids can benefit the brain and overall health. Recent research papers mostly focus on the misuse of specific and well-known CEs such as methylphenidate analogs 36 , 37 , designer benzodiazepines, phenmetrazine, modafinil, novel synthetic opioids 37 , and MPH More literature is available on CEs which are potentially able to address cognitive deficits in specific patient groups.

Froestl and Maitre 39 have classified these molecules into 19 categories based on their pharmacodynamics. Some of these molecules could not be classified based on their pharmacodynamics and hence were classified based on their chemical structure or their origin i.

as natural products or endogenous molecules Many of these drugs were clinically tested for their potential to improve cognitive function. Although they all might have a potential for being misused by the general public looking to enhance their cognitive abilities, the vast majority of these molecules have never reached the market as most of them have been discontinued in Phase II or III clinical trials 7 — 9.

A comprehensive literature review completed by Froestl et al. Many CEs were described as groups or families i. beta-amyloid aggregation inhibitors. These CEs were not identified by either the EDND, EWA, or NPSfinder ® as this is not part of the remit of any of the NPS early identification systems.

In particular, many categories of CEs described by Froestl et al. Apart from the known families of CEs historically derivatives of MPH, modafinil, and racetams , psychonauts subjects who experience intentionally drug-induced altered states of consciousness 40 have been experimenting with a variety of commonly prescribed drugs as well as illicit substances, often finding subjective evidence of cognitive enhancement and sharing their knowledge within the dark web sites and surface internet fora.

At present, a comprehensive, up-to-date list of currently available CEs does not exist. Finally, some of these substances are not illegal i. prescribed medication, food supplements, natural remedies etc. For these reasons, it is difficult to create an early identification system which is able to keep professionals up-to-date with the CEs which are currently available to the general public via the online market.

At present, NPSfinder ® is a password protected proprietary software, which allows registered researchers only to screen and classify the substances that are identified by the software. An open access part, which will allow the general public to have free access to the substances, is under development.

Every time a new website is identified, all its items are scanned and compared with the online existing ones. When a novel substance is found, this is added to the growing NPSfinder ® database.

NPSfinder ® screening process is tailored to each website, and no specific keywords are used by the software. This list is continuously growing the current, full list of these sites is available upon request.

NPSfinder ® has been already successfully used to identify other types of NPS, including synthetic cathinones 41 , novel psychedelics 42 , and novel opioids In each paper, the comparison with international or European NPS databases has shown that NPSfinder ® is able to identify substances which were not previously described by the existent early detection systems.

Raising awareness of novel substances has important implications from both a legislative and a clinical perspective. Although the language most typically used in these websites was English, further languages analyzed by NPSfinder ® included: Dutch, French, German, Italian, Russian, Spanish, Swedish, and Turkish.

FN, DA, CZ, and LG. In this way, a full assessment and editing of each NPSfinder ® data item were conducted, and the range of unique CEs presented here was identified. The collection of further information was completed by consulting a range of open libraries and chemistry databases referring to the index item, if existing.

Data were then screened for relevance and possible duplications. Therefore, it is to be noted that these identified CEs are thought by psychonauts as having cognitive enhancing properties according to their subjective and anecdotical experience rather than due to any pharmacological analysis.

When a substance that was identified by NPSfinder ® was not explicitly described as able to enhance cognitive abilities but was listed as a known CE within the comprehensive review by Froestl et al.

Using chemical structure identification and other published information i. published research papers and official databases , researchers assigned each molecule to its drug class, using the classification described by Schifano et al.

After about 18 months of operation, the number of substances identified by the web crawler activities was 5, By the time of writing January , 4, unique NPS substances were included in the database, and 1, out of 5, A total of unique CEs was identified by NPSfinder ® Table A1.

Of these, 35 were explicitly described as having nootropic properties by psychonauts; the remaining molecules were classified as CEs as also present in the comprehensive review on CEs written by Froestl et al.

Table 1 CEs identified by NPSfinder ® using Schifano et al. Current NPSfinder ® results were compared with the EMCDDA and the UNODC databases in order to ascertain which molecules were also detected and listed by the official European and United Nation early identification systems.

Only one CE was uniquely identified by the EDND MIQ, also called meta-IQ ; no CE was uniquely identified by the EWA database. Figure 1 shows the number of CEs identified by each source including NPSfinder ® , EDND and EWA database as well as the ones identified by more than one source. A full list of the CEs is available upon request.

In this paper, we aimed to evaluate whether the innovative crawling software NPSfinder ® can be employed as a helpful tool in the early identification and prediction of CEs. To the best of our knowledge, this is an unprecedented list of drugs which are described as CEs and, therefore, with a potential for recreational misuse by healthy individuals.

NPSfinder ® identified 35 molecules out of the total of 4, that were described by psychonauts as having cognitive enhancing effects, such as improved memory, alertness, attention, and concentration. A further molecules were previously described as CE 7 — 9 , although psychonauts did not explicitly describe them as CE.

Since psychonauts experiment with novel substances in order to intentionally experience altered states of consciousness, it is to be expected that their interest also extends to the world of CEs.

Among the CEs that they have been discussing online, there are mostly molecules that are known to have nootropic properties, are not illegal, and are likely to be easily available on the market such as racetam compounds, modafinil and its derivatives, methylphenidate and its derivatives and food supplements.

Our results showed that NPSfinder ® could be employed as an Early Warning System tool to help clinicians with keeping their knowledge up-to-date with the growing numbers and types of nootropics in the increasingly difficult-to-follow online market.

It is not surprising that the included sources i. NPSfinder ® , EDND, and EWA have identified mis-matching numbers and types of CEs, as they differ in their methodology and purposes of CE identification. In fact, the EDND was created in order to allow the European Union to rapidly detect, assess, and respond to health and social threats caused by NPS The UNODC EWA on NPS provides access to basic information on new psychoactive substances, including trend data, chemical details on individual substances, supporting documentation on laboratory analysis and legislative responses Specifically, the EDND and EWA focus on illegal drugs and do not look at websites that contain patented medications, while NPSfinder ® looks at websites whose contributors might have accessed sources containing patent medications.

The large number of molecules that are both identified by NPSfinder ® and described by Froestl et al. Among the CEs that have been subjectively identified by psychonauts as able to improve certain aspects of their cognition, there are molecules whose objective cognitive enhancing properties have not been established by research studies, such as the selective serotonin re-uptake inhibitors SSRIs , melatonin and many others.

The large number of unique molecules that were uniquely identified by NPSfinder ® can be explained with the innovative methodology that NPSfinder ® used for the early identification of all NPS, including CEs 41 — Flavonoids such as quercetin and naringin, as well as vitamins A, B, and D are also part of this group.

Perry and Howes 51 completed an informative review on medicinal plants in dementia, pointing out the potential cognitive benefits of a significant variety of plants and herbs.

A recent systematic review has found that tyrosine and caffeine could enhance cognitive performance when healthy young adults are sleep-deprived in a military context The non-medical use of methylphenidate as a CE, which involves an attempt to improve memory, increase mental concentration, control anxiety, and stimulate motivation and creativity, is rising worldwide 38 , Research studies have often failed to demonstrate that SSRIs can have cognitive enhancing properties 54 , It was also suggested that any cognitive benefits of SSRIs were likely to be secondary to their effect on mood or behavioral disturbances.

Interestingly, both fluoxetine and methylphenidate potentiate gene regulation in the striatum, and their combination seems to mimic cocaine effects, with related increased risk for substance use disorder It is possible that many prescribed drugs are currently being misused by the general public but not picked up by the regulatory bodies because the vast majority of them are not classified as illegal.

It is important that more studies and cross-sectional surveys are conducted as well as that the current pharmacovigilance systems focus on determining current patterns and quantifying current usage of these drugs by healthy people.

Racetam compounds, which are classically one of the major CE family 58 , are identified by NPSfinder ® and listed within the IPEDs sub-group Table 4. Piracetam enhances cognitive function without causing sedation or stimulation 3. This drug is also being used in clinical practice for the treatment of several diseases 59 — 62 although its mechanism of action remains not fully understood.

NPSfinder ® identified aniracetam, coluracetam, fasoracetam, nefiracetam, oxiracetam, phenylpiracetam, piracetam, and pramiracetam. For example, recent studies failed in showing that aniracetam improves working memory in pigeons 63 , learning and memory in rats 64 , or cognitive and affective behavior in mice Moreover, nefiracetam did not prove to be more efficacious than placebo in ameliorating apathy in stroke 66 despite some positive pre-clinical results 67 , There are no available studies on coluracetam, fasoracetam , and phenylpiracetam.

Among the psychostimulant CEs are described many derivatives of methylphenidate and modafinil Table 5. These have been listed in this group when not licensed as prescribed drugs. Methylphenidate is a prescription drug with medical restrictions in several countries, therefore, many illegal analogues have emerged on the internet and darknet drug markets during the last few years The derivatives of methylphenidate that have been identified by NPSfinder ® include: 3,4-dichloromethylphenidate, 4-fluoromethylphenidate, 4-methylmethylphenidate, dexmethylphenidate, ethylphenidate, methylmorphenate , and methylnaphthidate.

No research studies are available regarding the misuse of these molecules by healthy subjects in order to ameliorate their cognitive function Table 6.

The phenethylamines-related compounds that have been identified by NPSfinder ® are listed in Table 7. These are stimulant, entactogenic, and hallucinogenic substances that share similar chemical structures with amphetamine, catecholamines, synthetic cathinones, and other molecules Phenethylamines are known to enhance mood and empathy in healthy subjects.

Substituted phenethylamines also include substituted amphetamines, which have been used as CEs to promote learning and memory but can ultimately lead to addiction Dolder et al. To the best of our knowledge, there are no research studies or case reports focusing on the misuse of specific phenethylamines as CEs by healthy subjects.

GABAergic drugs are chemicals that produce their effects via interactions with the GABA system, such as by stimulating or blocking neurotransmission f-phenibut , which is closely related to phenibut , is a central nervous system depressant 72 ; tolibut is a GABA analog that was developed in Russia 77 , similarly to picamilon , which is formed by a synthetic combination of niacin and γ -aminobutyric acid GABA.

Picamilon was developed in the Soviet Union in 78 and further studied in both Russia 79 and Japan 80 as a prodrug of GABA. Among Cannabimimetic drugs there are the synthetic cannabimimetics that are designer drugs that target the same receptors to which cannabinoids in cannabis plants, tetrahydrocannabinol THC and cannabidiol CBD bind 81 , dexanabinol , drinabant , Dronabinol , JZL , rimonabant , and URB were the six CEs belonging to this group that were identified by the NPSfinder ® Table 9.

The use of cannabimimetics as CEs seems counter-intuitive as both pre-clinical and human studies have found a link between consumption of cannabinoids and long-term deficits of cognitive functions, especially high-order cognitive functions 83 — However, recent pre-clinical studies have found that deltaTHC can improve cognitive performances in rats 89 and mice This is a tryptamine derivative closely related to both the serotonin and melatonin neurotransmitters To the best of our knowledge, there are no studies, surveys, or case reports that identified 5-MT as a drug used by healthy people in order to improve their cognitive abilities.

Jansen et al. Fipexide also known as attentil and vigilor Table 11 is the only substitute piperazine that has been identified by NPSfinder ® as a CE.

This was initially developed in Italy in 94 and used as a CE in Italy and France for the treatment of dementia Fipexide is no longer in use due to the occurrence of rare side-effects 96 , Ethical issues raised by cognitive enhancement have been debated for over a decade 98 , and many experts have identified multiple ethical concerns including risks to mental and health safety On the other hand, it is of concern that the safety and efficacy of these drugs in healthy individuals in the long-term are still unclear.

While some CEs have been studied and research data on their mechanism of action and potential benefit are available, the action, the beneficial effects, and the potential side-effects of the majority of them have yet to be fully described and understood.

Some of these drugs can cause dependence and have a significant range of harmful effects; they can be particularly dangerous to young people as their brains are not fully developed. Studies producing null results and some evidence of task-specific impairments should be also noted The limited evidence of effectiveness as well as the potential side-effects should be cautiously considered by relevant legislative and regulatory bodies.

In , the US Presidential Commission for the Study of Bioethical Issues released a report on CE, reporting up-to-date findings and providing recommendations for clinicians The Australian Alcohol and Drug Foundation has recently raised doubts about the actual cognitive benefits of most CEs, indicating that scientific studies showed only little to no benefits for cognitive enhancement in healthy individuals, while the associated side-effects do pose significant risks to health and safety of the general public NPSfinder ® could also be an important tool for analytical toxicologists to focus their efforts on the detection of the most recently misused substances , An official, up-to-date, comprehensive list of CEs is not currently available in the literature.

The Early Warning Systems fail in the early detection of these substances as they are mostly legal products such as food supplements or prescribed medication, which are misused by healthy individuals to improve their cognitive abilities.

We based our classification on the one described by Schifano et al. We noted that another type of classification, such as the one described by Froestl et al. In fact, many CEs do not have a fully understood mechanism of action, which makes it difficult to link them to a specific category; other CEs have multiple mechanisms of actions i.

Furthermore, it is important to note that a limited number of languages were used for the screening of molecules on the web, and although many substances were first identified in seizures in Asia, only European languages are used. For all these reasons, forming a comprehensive and definite classification of CEs remains a complex challenge.

CEs are a wide and diverse group of molecules, constantly growing in terms of numbers as well as availability among the general public and especially via online platforms. CEs differ for pharmacological activity, time, and mode of action, targeted cognitive domain, pharmacodynamic and pharmacokinetic properties, as well as possible short- and long-term side-effects.

The popularity of chemicals that are potentially able to augment brain functions is not surprising in a society which constantly demands for increasingly high cognitive performances. For the current official Early Warning Systems, it is challenging to identify and monitor the use of CEs as they are often sold as legal food supplements or as prescribed medication for a number of medical conditions.

For this reason, NPSfinder ® can be considered as a helpful systematic tool which could update clinicians with the growing numbers and types of nootropics in the increasingly difficult-to-follow internet world. Previously, Arillotta and colleagues 43 have identified novel opioids which were not listed in either international or European NPS databases, such as EMCDDA or UNODC.

This information is useful to stakeholders such as enforcement agents, emergency department, scientific community, prevention program setters, and other regulatory agencies.

The same applies to CEs; in particular, the early identification of substances that are misused as CEs and the discovery of novel CEs that were never reported or identified before are crucial to raise the awareness of regulatory bodies.

The identification of a drug is key to the treatment of its potential physical and psychiatric effects; if the drug is novel, its description may shed some light on its pharmacokinetics and toxicodynamics, which would in turn inform treatment decision-making in clinical settings.

The early identification and better understanding of the distribution and effects of CEs could promote both more effective prevention and harm reduction measures in clinical settings, including emergency departments, mental health and general practice clinics.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. FS and AV have conceived the idea of the manuscript and have coordinated the whole project.

FN, CZ, DA, and LG have actually carried out the process of both data collection and systematization. FN performed the literature searching, the analysis of data and drafted the manuscript. FS, JC, and AG supervised the manuscript and contributed to the final version of the manuscript.

FS approved the final content of the manuscript. JC provided data from the EMCDDA and UNODC databases for the purposes of this research. FS, JC, and AG have provided relevant epidemiological data and have contributed as well to the drafting and checking of the paper itself.

None of the authors of this paper was directly involved with the website development. AV has conceived the idea of a new early detention software for NPS, which was developed by the professionals at Damicom srl, a small enterprise from Rome Italy.

FS and AV have coordinated the testing of the web crawler. FN, CZ, and DA have suggested minor changes to the software which have made the screening process more precise and efficient. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer, SC, declared a shared affiliation, though no collaboration, with several of the authors, FN, FS, JMC, AG, DA, CZ, and AV to the handling editor. The authors are grateful to Damicom srl, a small enterprise from Rome Italy , whose professionals have developed the NPSfinder ® web crawler and so generously have allowed here the testing of its potential.

The authors are also grateful to the EMCDDA and UNODC for being able to use their databases for the purposes of this research. ADHD, attention deficit hyperactivity disorder; CEs, cognitive enhancers; EDND, European Database on New Drugs; EMCDDA, European Monitoring Centre for Drugs and Drug Addiction; EWA, Early Warning Advisory; GABA, gamma-aminobutyric acid; IPEDs, imaging and performance enhancing drugs; MPH, methylphenidate; NPS, novel psychoactive substances; SSRIs, Selective Serotonin Re-uptake Inhibitors; UNODC, United Nations Office on Drugs and Crime.

Bostrom N, Sandberg A. Cognitive enhancement: methods, ethics, regulatory challenges. Sci Eng Ethics — doi: PubMed Abstract CrossRef Full Text Google Scholar. Dresler M, Sandberg A, Bublitz C, Ohla K, Trenado C, Mroczko-Wąsowicz A, et al. Hacking the Brain: Dimensions of Cognitive Enhancement.

ACS Chem Neurosci — Giurgea C. Pharmacology of integrative activity of the brain. Attempt at nootropic concept in psychopharmacology. Actual Pharmacol Paris — PubMed Abstract Google Scholar. Cond Reflex — Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ.

Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacol Berl —9. CrossRef Full Text Google Scholar. Millan MJ, Agid Y, Brune M, Bullmore ET, Carter CS, Clayton NS, et al. Cognitive dysfunction in psychiatric disorders: Characteristics, causes and the quest for improved therapy.

Nat Rev Drug Discovery — Froestl W, Muhs A, Pfeifer A. Cognitive enhancers nootropics. Caffeine is a natural stimulant most commonly found in tea, coffee and dark chocolate.

It works by stimulating the brain and central nervous system, making you feel less tired and more alert In fact, studies have shown that caffeine can make you feel more energized and improve your memory, reaction times and general brain function 29 , 30 , For most people, single doses of around — mg per day are generally considered safe and are enough to benefit health 32 , 33 , However, taking too much caffeine can be counterproductive and has been linked with side effects such as anxiety, nausea and trouble sleeping.

Caffeine is a natural stimulant that can improve your brain function and make you feel more energized and alert. Phosphatidylserine is a type of fat compound called a phospholipid, which can be found in your brain 35 , You can easily buy these supplements online.

Studies have shown that taking mg of phosphatidylserine three times per day could help reduce age-related decline in brain function 38 , 39 , 40 , Additionally, healthy people who take phosphatidylserine supplements of up to mg per day have been shown to have improved thinking skills and memory 42 , However, larger studies need to be carried out before its effects on brain function can be fully understood.

Phosphatidylserine supplements could improve your thinking skills and memory. They could also help combat the decline in brain function as you age. However, further study is needed. Acetyl-L-carnitine is an amino acid produced naturally in your body. It plays an important role in your metabolism, particularly in energy production.

Taking acetyl-L-carnitine supplements has been claimed to make you feel more alert, improve memory and slow down age-related memory loss These supplements can be found in vitamin stores or online.

Some animal studies have shown that acetyl-L-carnitine supplements can prevent age-related decline in brain function and increase learning capacity 45 , In humans, studies have found that it may be a useful supplement for slowing the decline in brain function due to age.

Its effects in healthy people are unknown. Ginkgo biloba is an herbal supplement derived from the Ginkgo biloba tree. Despite the widespread use of ginkgo biloba, results from studies investigating its effects have been mixed. Some studies have found that taking ginkgo biloba supplements can help reduce age-related decline in brain function 54 , 55 , One study in healthy middle-aged people found that taking ginkgo biloba supplements helped improve memory and thinking skills 57 , However, not all studies have found these benefits 59 , Ginkgo biloba may help improve your short-term memory and thinking skills.

It may also protect you from age-related decline in brain function. However, results are inconsistent. Bacopa monnieri is a medicine made from the herb Bacopa monnieri. People generally take about mg per day and it may take around four to six weeks for you to notice any results.

Studies of Bacopa monnieri also show that it may occasionally cause diarrhea and an upset stomach. Because of this, many people recommend taking this supplement with food Bacopa monnieri has been shown to improve memory and thinking skills in healthy people and in those with a decline in brain function.

Rhodiola rosea is a supplement derived from the herb Rhodiola rosea , which is often used in Chinese medicine to promote well-being and healthy brain function. People taking Rhodiola rosea have been shown to benefit from a decrease in fatigue and improvement in their brain function 72 , 73 , However, results have been mixed A recent review by the European Food Safety Authority EFSA concluded that more research is required before scientists can know if Rhodiola rosea can reduce tiredness and boost brain function Rhodiola rosea may help improve thinking skills by reducing fatigue.

However, more research is needed before scientists can be certain of its effects. S-Adenosyl methionine SAMe is a substance that occurs naturally in your body. It may be useful for enhancing the effects of some antidepressants and reducing the decline in brain function seen in people who have depression 77 , 78 ,