The Psychonauts’ World of Cognitive Enhancers

Background There is growing availability of novel psychoactive substances (NPS), including cognitive enhancers (CEs) which can be used in the treatment of certain mental health disorders. While treating cognitive deficit symptoms in neuropsychiatric or neurodegenerative disorders using CEs might have significant benefits for patients, the increasing recreational use of these substances by healthy individuals raises many clinical, medico-legal, and ethical issues. Moreover, it has become very challenging for clinicians to keep up-to-date with CEs currently available as comprehensive official lists do not exist. Methods Using a web crawler (NPSfinder®), the present study aimed at assessing psychonaut fora/platforms to better understand the online situation regarding CEs. We compared NPSfinder® entries with those from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and from the United Nations Office on Drugs and Crime (UNODC) NPS databases up to spring 2019. Any substance that was identified by NPSfinder® was considered a CE if it was either described as having nootropic abilities by psychonauts or if it was listed among the known CEs by Froestl and colleagues. Results A total of 142 unique CEs were identified by NPSfinder®. They were divided into 10 categories, including plants/herbs/products (29%), prescribed drugs (17%), image and performance enhancing drugs (IPEDs) (15%), psychostimulants (15%), miscellaneous (8%), Phenethylamines (6%), GABAergic drugs (5%), cannabimimetic (4%), tryptamines derivatives (0.5%), and piperazine derivatives (0.5%). A total of 105 chemically different substances were uniquely identified by NPSfinder®. Only one CE was uniquely identified by the EMCDDA; no CE was uniquely identified by the UNODC. Conclusions These results show that NPSfinder® is helpful as part of an Early Warning System, which could update clinicians with the growing numbers and types of nootropics in the increasingly difficult-to-follow internet world. Improving clinicians’ knowledge of NPS could promote more effective prevention and harm reduction measures in clinical settings.


INTRODUCTION
Cognitive enhancement may be defined as "the amplification or extension of core capacities of the mind through improvement or augmentation of internal or external information processing systems" (1). Both non-pharmacological and pharmacological enhancers are sought by the general public in order to improve performance during studying and at work by increasing concentration, motivation and accuracy, via physical, behavioral and biochemical activities (2).
Cognitive enhancer drugs (CEs) are also known as "nootropics" (from the Greek 'nous' meaning 'mind' and 'trepein' meaning 'turning/bending'), a term initially penned by Corneliu Giurgea when piracetam was found to exhibit memoryenhancing properties in clinical trials (3,4). Cognitive enhancer drugs such as modafinil improve cognition in very specific ways such that it enhances "pattern recognition memory, digit span recall, and mental digit manipulation" (5).

Cognitive Enhancers, Historical Perspective and State of the Art
Historically, CEs have been used to treat conditions related to cognition deficits such as Alzheimer's disease, psychiatric disorders such as schizophrenia (6), stroke or attention deficit hyperactivity disorder (ADHD) (7)(8)(9). These phenomena commonly occur with aging (7)(8)(9). It was found that some CEs also improve cognitive functions in healthy subjects, such as memory, executive functions, creativity, and motivation (10). Their use has become more and more prevalent among college, high school, and university students as well as in the military (11)(12)(13).
The world of CEs is multifaceted and complex, with different molecules acting with different modes of actions and on different (and often multiple) receptors in the central nervous system (CNS). "Natural" enhancers such as nicotine (14)(15)(16)(17) and caffeine (18) are generally accepted as substances that help us by improving focus, alertness, and productivity. Food-based antioxidants, herbal, and other food-derived nootropic agents have become increasingly popular in recent times after there have been suggestions of associations between cognition and diet (19). Prescription drugs, such as modafinil, amphetamine, and methylphenidate are used off-label by healthy people who do not have specific deficits but want to improve their standards of intellectual and cognitive performance (20). Cognitive enhancers also include many drugs which have never reached the market as they have been discontinued in Phase II or III clinical trials (7)(8)(9). The many dimensions of cognitive enhancement are described and disentangled in a recent review (2). Dresler and colleagues (2) pointed out how cognitive enhancement is not a monolithic phenomenon and how there are a great variety of interventions that can be classified and clustered into biochemical, physical, and behavioural enhancement strategies.

Misuse of Cognitive Enhancers
The most prevalent CEs that are currently abused/misused include diverted prescription medicines such as those used for the treatment of attention deficit hyperactivity disorder (ADHD) i.e. methylphenidate (MPH) and amphetamine/dextroamphetamine (Adderall-most common brand); "wakefulness-promoting agents" with psychostimulant effects such as modafinil (21-23); illicit psychostimulants such as amphetamine, and drugs that act on the glutamatergic AMPA receptors, the so-called ampakines or "glutamate activators" (24). While the benefits of medications, such as MPH or modafinil, in patients suffering from specific diagnosed conditions (such as ADHD or narcolepsy) have been studied and evaluated, the potential benefits of these substances in heathy individuals remain unclear. The use of CEs in healthy individuals poses significant concerns due to the lack of clinical evidence regarding their safety, effectiveness, and social consequences, especially with long-term use.
Urban and Gao (24) emphasized that these newly misused drugs, i.e. MPH, may in fact improve cognition by acting on the memory and learning circuits, thus exciting the dopamine/ glutamate/noradrenergic neurons. The modulation of these neurotransmitters in healthy individuals seeks to enhance their cognitive functions beyond baseline levels, but may also lead to paradoxical effects, particularly in children's and adolescent's growing brains (25). In these cases, glutamate modulation may impair behavior flexibility, which may facilitate addictive behaviors. Conversely, dopamine and norepinephrine reuptake inhibition may lead to a hyperdopamin-/hypernoradrenalin-ergic state, which may induce a cognition decline because the relationship between the prefrontal cortex cognition enhancement and the levels of both dopamine and noradrenaline is non-linear and actually an inverted U-curve (25-27). Urban et al. (28) have also emphasized that the use of CEs such as MPH and modafinil can have short-and long-term impacts on plasticity in the pre-frontal cortex that may affect the potential for plastic learning especially in children and adolescents.
Like many other NPS, nootropics have become increasingly easily available on the internet over the last 20 years. According to the United Nations Office on Drugs and Crime (UNODC) Early Warning Advisory (EWA) on new psychoactive substances (NPS), NPS have been reported from over 100 countries and territories from all regions of the world (29-32). In addition, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has been monitoring more than 700 NPS that have appeared on Europe's drug market in the last 20 years, of which almost 90% have appeared in the last decade (33, 34). The European Database on New Drugs (EDND) of the EMCDDA records the notifications of new substances and the detection of NPS in Europe (35). Although many of these identified NPS might be used by healthy people as CEs, there are limited data on how many or which substance is, nor are CEs classified as a specific category. Despite being a challenging task in view of the pharmacological differences of CEs, producing a formal classification of these substances is crucial in order to further develop scientific research on the topic as well as regulate and monitor their use and effects.

NPSfinder ® , a Tool for the Early Recognition of NPS
NPSfinder ® is a crawling/navigating software which was designed to facilitate the early recognition of the continuously growing amount of NPS that are available on the internet. 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.
NPSfinder ® automatically scans the web for new/novel/ emerging NPS, including CEs, via the identification of psychonauts' websites/fora. 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 proprietary method, which was created by trained software engineers, allows to map, on a 24/7 basis, the large variety of psychoactive molecules mentioned/discussed within a range of representative online psychonauts' web sites/fora. This list is continuously growing (the current, full list of these sites is available upon request).
NPSfinder ® was designed to extract a range of information regarding NPS, including: chemical and street names; chemical formulae; three-dimensional images and anecdotally reported clinical/psychoactive effects.

Identification of Cognitive Enhancers by NPSfinder ®
NPSfinder ® has been already successfully used to identify other types of NPS, including synthetic cathinones (41), novel psychedelics (42), and novel opioids (43). 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.
Between 26 November 2017 and 31 May 2019, NPSfinder ® carried out a range of open web crawling identification activities focusing on a large range of psychonaut-based, specialized, multilingual sources with a specific focus on new/traditional psychoactive substances of likely recreational interest. 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. With the help of an ad hoc check control panel, all data were manually examined by four medically/psychiatrically-trained professionals (i.e. 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. These data were then stored in an online, restricted access/password-controlled database located within firewall protected, highly secure, and consistently performing servers.
When any new item was detected during the automated web scan, the system sent an e-mail notification/alert to the core researchers' mailing list. Data were then screened for relevance and possible duplications.
The identified psychoactive substances were classified as CEs when a cognitive enhancing ability of any kind (such as improved attention, concentration, alertness, and memory) was mentioned in the description and/or among the effects of the psychoactive substance. The used terms for the search were "nootropic", "cognitive enhancers", "cognition enhancement", "smart drugs", "memory enhancers", "concentration enhancers", "attention enhancers", "neuro enhancers", and "intelligence enhancers". 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. (7)(8)(9), it was still included among the list of NPSfinder ® CEs.

Identification and Classification of Cognitive Enhancers
The NPSfinder ® CE results (updated to May 2019) were compared with those reported by the UNODC's EWA on NPS (updated by April 2019) and the EMCDDA's EDND (updated by April 2019).
Using chemical structure identification and other published information (i.e. published research papers and official databases), researchers assigned each molecule to its drug class, using the classification described by Schifano et al. (44,45) for NPS. This classification includes the following families: synthetic cannabimimetics, synthetic cathinones, novel psychostimulants, novel derivatives of classic psychedelics phenethylamines/ MDMA-like drugs, synthetic opioids, synthetic cocaine substitutes, novel tryptamines derivatives, GABAergic drugs, phencyclidine-like dissociative drugs, piperazine derivatives, herbs/plants, prescribed drugs, and image and performance enhancing drugs (IPEDs).

Identification and Classification of CEs
After about 18 months of operation, the number of substances identified by the web crawler activities was 5,922. By the time of writing (January 2020), 4,204 unique NPS substances were included in the database, and 1,718 out of 5,922 (29.0%) remaining substances were found to be false positives or duplicates. The most common NPS mentioned in psychonauts' fora included: psychedelic phenethylamines (30.1%); synthetic cannabimimetics (29.8%); and opioids (10.1%).
A total of 142 unique CEs was identified by NPSfinder ® ( Table A1). Of these, 35 were explicitly described as having nootropic properties by psychonauts; the remaining 107 molecules were classified as CEs as also present in the comprehensive review on CEs written by Froestl et al. (7)(8)(9).

Comparison of NPSfinder ® Findings With EU and UN NPS-Related Databases
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.
Out of the 142 molecules identified as CEs by NPSfinder ® , a total of 105 chemically different substances were uniquely identified by NPSfinder ® ; of the remaining 37 molecules, 22 were also listed in both the EDND and EWA databases, 15 of which were reported in both the NPSfinder ® and in either the EMCDDA (n = 11) or the UN databases (n = 4) ( Table A1).
Only one CE was uniquely identified by the EDND (MIQ-001, also called meta-IQ); no CE was uniquely identified by the EWA database. CEs Identified According to Their Identification Source 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.

DISCUSSION
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. In order to achieve this goal, findings from NPSfinder ® were cross-checked with two official sources (EMCDDA's EDND and UNODC's EWA). 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 4,204) that were described by psychonauts as having cognitive enhancing effects, such as improved memory, alertness, attention, and concentration. A further 107 molecules were previously described as CE (7)(8)(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.e. 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 (35). 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 (30). 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.

NPSfinder ® Findings
The large number of molecules that are both identified by NPSfinder ® and described by Froestl et al. (7)(8)(9) leads us to believe that nowadays psychonauts are discussing (and likely using) substances that have been considered or used for the treatment of the Alzheimer's disease over seven years ago, and they are doing so in order to improve their cognitive performances in the absence of clinical reasons.
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.

Comparison of NPSfinder ® Findings With EDND or EWA Databases
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 (41-43). Being a dynamic software, NPSfinder ® is able to automatically scan the web for new/novel/emerging NPS on a 24/7 basis. This is indeed an effective mechanism for the early identification of (potential) NPS, which are being discussed on the psychonauts' websites and fora.

Description and Classification of CEs Identified by NPSfinder ®
The CEs identified by NPSfinder ® (n = 142) were divided into 10 categories as shown in Table 1.

Plants/herbs/product:
The NPSfinder ® family of "Plants/herbs/product" contains a list of plant-based substances with a variety of psychoactive ingredients ( Table 2).
In this group, there are many well-known substances such as: caffeine, nicotine, cinnamon, ginger root extracts, curcumin, ginseng, coumarins, menthol, St John's wort, Yerba mate, Bacopa monnieri, Areca nut (and its main active ingredient arecoline), Lemon balm, Mucuna pruriens, Peganum harmala, harmaline, harmalol, and lobeline, some of which are commonly used by ayurvedic traditional medicine or in other branches of alternative medicine to improve memory and/or to treat various diseases. Flavonoids such as quercetin and naringin, as well as vitamins A, B, and D are also part of this group.
There are studies on the cognitive enhancing properties of caffeine (18), nicotine (14)(15)(16)(17), curcumin (46-48), St John's wort (Hypericum perforatum) (49), Bacopa monnieri (50), and many others. 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 (52).

Prescribed drugs:
Methylphenidate is undoubtedly the most prescribed CE, and being indicated for the treatment of ADHD in many countries, it is described, in this paper, within the "prescribed drugs" group. 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, 53). Many other prescribed drugs are being talked about in psychonauts' blogs and fora ( Table 3).
Among the "prescribed drugs" family described by NPSfinder ® the SSRIs are also listed as a class. Research studies have often failed to demonstrate that SSRIs can have cognitive enhancing properties (54, 55). For example, neither sertraline (54) nor citalopram (55) appeared to be superior to placebo in improving cognition in patients with Alzheimer's disease and comorbid depression. It was also suggested that any cognitive benefits of SSRIs were likely to be secondary to their effect on mood or behavioral disturbances. However, a more recent review on the topic concluded that the lack of evidence for SSRIs as CEs or disease modifiers in Alzheimer's disease is more the result of omissions in clinical trial design, as opposed to reports of negative evidence (56). 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 (57).
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.  7  Galantamine  8  Hydergine  9  Lisdexamfetamine  10  Melatonin  11  Memantine  12  Memantine extended release  13  Methylphenidate  14  Modafinil  15  Modafinil suphone  16  NSI-189  17  Quetiapine  18  S-adenosyl-methionine  19  Selegiline  20  Sildenafil  21  Stablon  22  Tadalafil  23  Tropicamide  24 Vasopressin Image and Performance Enhancing Drugs (IPEDs): 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)(60)(61)(62) although its mechanism of action remains not fully understood.
NPSfinder ® identified aniracetam, coluracetam, fasoracetam, nefiracetam, oxiracetam, phenylpiracetam, piracetam, and pramiracetam. Although all these substances have been mentioned in the psychonauts' fora as having nootropic properties, research studies have not always succeeded in demonstrating their cognitive enhancing qualities. 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 (65). Moreover, nefiracetam did not prove to be more efficacious than placebo in ameliorating apathy in stroke (66) despite some positive pre-clinical results (67,68). One old study on pramiracetam has failed to demonstrate any cognitive benefit from its administration to patients suffering from Alzheimer's disease (69). There are no available studies on coluracetam, fasoracetam, and phenylpiracetam.

Psychostimulant drugs:
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 (53). The derivatives of methylphenidate that have been identified by NPSfinder ® include: 3,4-dichloromethylphenidate, 4-fluoromethylphenidate, 4-methylmethylphenidate, dexmethylphenidate, ethylphenidate, methylmorphenate, and methylnaphthidate.

Miscellaneous:
The categories "miscellaneous" include amino-acids such as tryptophan and L-tryptophan, 5-hydroxytryptophan, phenylalanine, and theanine, as well as man-made chemicals such as vinpocetine and sulbutiamine and other various molecules such as beta-asarone, PRE-084, and RO-4491533. No research studies are available regarding the misuse of these molecules by healthy subjects in order to ameliorate their cognitive function ( Table 6).

Phenethylamines:
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 (70).
Phenethylamines are known to enhance mood and empathy in healthy subjects. Substituted phenethylamines also include substituted amphetamines, which have been used as CEs to

GABAergic drugs:
GABAergic drugs are chemicals that produce their effects via interactions with the GABA system, such as by stimulating or blocking neurotransmission (71). Among these, GABA, tolibut, picamilon, phenibut, and fphenibut were discussed in the psychonauts' fora as having tranquillizing as well as nootropic properties ( Table 8). There is increasing evidence suggesting that phenibut, a potent psychoactive substance with GABA-B agonist properties which is often sold as a "dietary supplement", can induce withdrawal and physical dependence which makes its use dangerous (72)(73)(74)(75)(76). 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 g-aminobutyric acid (GABA). Picamilon was developed in the Soviet Union in 1969 (78) and further studied in both Russia (79) and Japan (80) as a prodrug of GABA.

Cannabimimetic:
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 (81,82). dexanabinol, drinabant, Dronabinol, JZL-184, rimonabant, and URB-597 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)(84)(85)(86)(87)(88). However, recent pre-clinical studies have found that delta-9-THC can improve cognitive performances in rats (89) and mice (90). THC, in fact, appears to promote hippocampal neurogenesis to prevent neurodegenerative processes occurring in animal models of Alzheimer's disease, to protect from inflammation-induced cognitive damage, and to restore memory and cognitive function in old mice (91).

Tryptamines derivatives:
5-Methoxytryptamine (5-MT, also called mexamine) ( Table 10) was the only tryptamine derivative identified by NPSfinder ® (as well as by the EWA). This is a tryptamine derivative closely related to both the serotonin and melatonin neurotransmitters (92). 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. (93) reviewed the efficacy of melatonin in addressing cognitive impairment in dementia but found the evidence for this to be inconclusive.

Piperazine derivatives:
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 1983 (94) and used as a CE in Italy and France for the treatment of dementia (95). Fipexide is no longer in use due to the occurrence of rare side-effects (96,97). On psychonauts' fora it is described as a molecule able to improve short term memory, attention, learning, and cognition.

Ethical, Clinical and Legal Issues
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 (99). While CEs hold significant benefits in improving cognitive impairments in several neuropsychiatric disorders such as Alzheimer's disease (7)(8)(9) and schizophrenia (100), the use of nootropics by healthy individuals clearly poses ethical, clinical,   and legal issues, as well as the need to develop a practical policy framework. Mohamed and Sahakian (101) pointed out that CEs' use in healthy people might have some advantages, such as: helping reduce disparity in society by mitigating the adverse environmental effects (like poverty) on the brain; improving the performances of people who need to perform at the best of their abilities in every situation (such as surgeons or pilots); finally CEs might also be used by people with undiagnosed disorders (such as ADHD) who might be therefore selfmedicating with stimulant medications.
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. Furthermore, CEs' effects (if present at all) seem to be temporary, lasting until their metabolism and elimination (102). 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 (103).
The limited evidence of effectiveness as well as the potential side-effects should be cautiously considered by relevant legislative and regulatory bodies. In 2015, the US Presidential Commission for the Study of Bioethical Issues (104) released a report on CE, reporting up-to-date findings and providing recommendations for clinicians (104). 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 (105).
While further research is needed on the topic, the early identification of CEs that are most commonly discussed on the internet will increase clinicians' awareness of this phenomenon and potentially help them make clinical decisions for patients presenting with psychiatric symptoms or physical health problems related to these substances. NPSfinder ® could also be an important tool for analytical toxicologists to focus their efforts on the detection of the most recently misused substances (106,107).

LIMITATIONS
In the online world, a significant variety of molecules/substances are described as CEs by anecdotal report or unofficial sources; it is important to note that the list of CEs is constantly evolving and changing. 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.
In addition, there is a lack of an official classification of CEs in families/categories. We based our classification on the one described by Schifano et al. (44). We noted that another type of classification, such as the one described by Froestl et al. (7)(8)(9) which is based on substances' pharmacodynamics properties, is also relevant and useful and could be used when further data on NPS pharmacological properties will be available.
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.e. might target several different receptors), and they could therefore belong to more than one category; for example, one CE might belong both to the "prescription drugs" and the "GABAergic drugs" groups. Some of the categories can themselves be very broad and have different types of molecules belonging to it, for example "IPEDs".
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.

CONCLUSIONS
In this paper, three different databases, including the innovative crawling software (NPSfinder ® ) and two official sources (EMCDDA's EDND, UNODC's EWA) were cross-checked.
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. Due to its innovative methodology, NPSfinder ® has demonstrated its ability to identify a higher number of CEs than the official EMCDDA's EDND and UNODC's EWA (108). 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 176 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.
Improving clinicians' knowledge of CEs is of paramount importance, and further research in order to clarify mechanism of actions, as well as short-and long-term effects of many CEs is also needed. 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.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
The current study involving human participants were reviewed and approved by the University of Hertfordshire Ethics' Committee; protocol number: aLMS/SF/UH/02951(3). Written informed consent from the patients/participants OR patients'/ participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

AUTHOR CONTRIBUTIONS
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.
Phenyltropane isotope used for as a solution to inject into living test subjects for neuroimaging in the diagnosis of Parkinson's Disease.
Atomoxetine is a selective norepinephrine reuptake inhibitor (SNRI) approved as a less stimulating treatment for ADHD in 2002 (U.S.). The precise mechanism by which it produces its therapeutic effects is unknown, but is thought to be related to its SNRI action. It appears to have minimal affinity for noradrenergic receptors or other neurotransmitter transporters or receptors.      Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone. DHEA also has a variety of potential biological effects in its own right, binding to an array of nuclear and cell surface receptors, and acting as a neurosteroid and neurotrophin. In addition to its role as a natural hormone, DHEA is used as an over-the-counter supplement and medication; for information on DHEA as a supplement or medication    It is often used to prevent low blood pressure during spinal anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in nasal congestion. As a phenethylamine, ephedrine has a similar chemical structure to amphetamines and is a methamphetamine analogue having the methamphetamine structure with a hydroxyl group at the b position. 44 Ethylphenidate EPH Ethyl 2-phenyl-2-(piperidin-2-yl)acetate Y Y N Ethylphenidate is a synthetic molecule of the substituted phenethylamine class. It contains a phenethylamine core featuring a phenyl ring bound to an amino -NH2 group through an ethyl chain. It is structurally similar to amphetamine, featuring a substitution at Ra which is incorporated into a piperdine ring ending at the terminal amine of the phenethylamine chain. Additionally, it contains an ethyl acetate bound to R2 or its structure. Ethylphenidate is structurally differed to methylphenidate by elongation of the carbon chain. Ethyl-regards the side chain of two carbon atoms, phen-indicates the phenyl ring, id-is contracted from a piperidine ring, and -ate indicates the acetate group containing the oxygens. Ethylphenidate is a chiral compound, presumably produced as a racemic mixture. It has an almost identical chemical structure to baclofen (only replacing a chlorine with a fluorine atom in the para-position of the phenyl group). [5] Additionally, the widely prescribed gabapentinoid pregabalin also possesses a similar structure as phenibut, except that the phenyl group is instead replaced with an isobutyl group.       It is a nootropic drug invented in 1996 by a team working for Merck, Sharp and Dohme, that was the first compound developed which acts as a subtype-selective inverse agonist at the a5 subtype of the benzodiazepine binding site on the GABAA receptor. It acts as an inverse agonist at the a1, a2, a3 and a5 subtypes, but with much higher affinity for a5, and unlike newer a5 inverse agonists such as a5IA, L-655,708 exerts its subtype selectivity purely via higher binding affinity for this receptor subtype, with its efficacy as an inverse agonist being around the same at all the subtypes it binds to.A radiolabelled form of L-655,708 was used to map the distribution of the GABAA a5 subtype in the brain, and it was found to be expressed predominantly in the hippocampus, an area of the brain involved with learning and memory. Activation of this subtype is thought to be largely responsible for producing the cognitive side effects displayed by many benzodiazepine and nonbenzodiazepine drugs, such as amnesia and difficulties with learning and memory, and so this led researchers to conclude that a drug acting as an inverse agonist at this subtype should have the opposite effect and enhance learning and memory. 70 L-Tryptophan L-TRP (2S)-2-amino-3-(1H-indol-3-yl)propanoic acid N N Y Tryptophan (symbol Trp or W) is an a-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an a-amino group, an a-carboxylic acid group, and a side chain indole, making it a non-polar aromatic amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Tryptophan is also a precursor to the neurotransmitter serotonin, the hormone melatonin and vitamin B3. It is encoded by the codon UGG. 71 Lemon Balm N/A N N Y Lemon Balm is a perennial (its root survives the winter) herb usually growing 1-2 feet (50 cm) tall. The leaves are ovate to heart-shaped and mint-like. Its flowers are white to yellowish in loose, small bunches and have a lemony-minty smell and flavor. Lemon Balm is used in foods and teas, as an insect repellant, and there is evidence that it has anxiolytic, sedative, mood improving, and nootropic effects. Some people report distinct psychoactive effects taking it as a tea, snorting, or smoking it, sometimes in combination with other plants or drugs, though reports are inconsistent.
This drug is a CNS stimulant often prescribed for ADHD, narcolepsy and obesity. It is also a pro-drug for dextroamphetamine, and functions as a method for providing extended-release stimulation. It is sometimes prescribed alongside an SSRI for depression. Lisdexamfetamine (contracted from L-lysinedextroamphetamine) is a prodrug of the central nervous system (CNS) stimulant dextroamphetamine, a phenethylamine of the amphetamine class that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and binge eating disorder. Its chemical structure consists of dextroamphetamine coupled with the essential amino acid L-lysine. Lisdexamfetamine itself is inactive prior to its absorption and the subsequent ratelimited enzymatic cleavage of the molecule's L-lysine portion, which produces the active metabolite (dextroamphetamine). 73 Lobeline derived from lobelia inflata Native Americans used lobelia to treat respiratory and muscle disorders, and as a purgative. The species used most commonly in modern herbalism is Lobelia inflata (Indian tobacco). However, there are adverse effects that limit the use of lobelia. Lobelia has been used as "asthmador" in Appalachian folk medicine. Two species, L. siphilitica and L. cardinalis, were once considered a cure for syphilis.
Cannabis is an annual herbaceous flowering plant indigenous to eastern Asia but now of cosmopolitan distribution due to widespread cultivation. It has been cultivated throughout recorded history, used as a source of industrial fibre, seed oil, food, recreation, religious and spiritual moods and medicine. Each part of the plant is harvested differently, depending on the purpose of its use. The species was first classified by Carl Linnaeus in Melatonin is comprised of a monoamine chain attached to an indole ring at the third carbon. A monoamine chain is made up of an amine group attached to an ethane chain. This monoamine chain can be found in many neurotransmitters, including histamine, dopamine, adrenaline, and noradrenaline. It is also found in many psychoactive substances such as members of the tryptamine and phenethylamine chemical classes. 78 Memantine Axura, Ebixa, Namenda, Memary 3,5-Dimethyladamantan-1-amine Y Y N Memantine or 3,5-dimethyladamantan-1-amine is a synthetic molecule classified as a substituted adamantane derivative. Its core structure is adamantane, a diamondoid of four interlocked cyclohexane rings in a stable 3-dimensional lattice conformation. Memantine is substituted with a methyl carbon at both R3 and R5; it contains an amine substitution at R1. Its name is derived from its structure, 3,5-dimethyladamantan-1-amine. Memantine is an arycyclohexylamine, belonging to the same category as ketamine and is a derivative of amantadine (adamantan-1-amine). It was originally synthesized in the late 1960s and like amantadine it is an adamantan-amine based uncompetitive NMDAR antagonists, used in the treatment of Alzheimer's disease and other dementias and is considered to be 'well-tolerated'.  Methylphenidate's mechanism of action involves the inhibition of catecholamine reuptake, primarily as a dopamine reuptake inhibitor. Methylphenidate acts by blocking the dopamine transporter and norepinephrine transporter, leading to increased concentrations of dopamine and norepinephrine within the synaptic cleft. This effect in turn leads to increased neurotransmission of dopamine and norepinephrine. [10] Methylphenidate is also a weak 5HT1A receptor agonist.   Modafinil sulphone is structurally related to the previously notified modafiendz which is the bis-fluoro-Nmethyl analogue of modafinil.The properties of modafinil sulphone have not been described extensively in the literature. It has been reported that this substance has anticonvulsant activity and therefore may find use in the "treatment of preclinical subconvulsive manifestations", further studies are required in this area. In other research, it has been stated that modafinil sulphone is pharmacologically active with a half-life of approximately 12 hours but it has been reported that it may also not exert any significant activity in the brain or periphery.
is a naturally occurring bicyclic compound comprised of a pyridine ring attached to the second carbon of a pyrrolidine ring that has a methyl substituent on the nitrogen. Pyridine is an unsaturated six-membered ring structurally related to benzene but with a nitrogen member. Nicotine additionally contains a substituted pyrrolidine ring, which is a saturated five-membered ring with one nitrogen member. These rings are bridged from the R3 position of the pyridine ring to the R2 position of the pyrrolidine ring. Tobacco is an annual or bi-annual growing 1-3 meters tall with large sticky leaves that contain nicotine. Native to the Americas, tobacco has a long history of use as a shamanic inebriant and stimulant. It is extremely popular and well-known for its addictive potential.  Octopamine is an organic chemical closely related to norepinephrine. In many types of invertebrates it functions as an important neurotransmitter and hormone, but in the human body it normally exists only at trace levels and has no known function. Because it shares some of the actions of norepinephrine, octopamine has been sold under trade names such as Epirenor, Norden, and Norfen for use as a sympathomimetic drug, available by prescription. In mammals, octopamine may mobilize the release of fat from adipocytes (fat cells), which has led to its promotion on the internet as a slimming aid. However, the released fat is likely to be promptly taken up into other cells, and there is no evidence that octopamine facilitates weight loss. It is also used to treat hypotension and as a cardiotonic.
(Continued)  4-Amino-3-phenylbutanoic acid N Y N Phenibut is a derivative of GABA with a phenyl group in the b-position. It is a chiral molecule and thus has two potential configurations, as (R)-and (S)-enantiomers. It has almost the same structure of baclofen (lacking only a chlorine atom in the para-position of the phenyl group) and contains phenethylamine in its structure.Pregabalin has the same structure as phenibut, except that the phenyl group is instead an isobutyl group. 101 Phenylalanine (S)-2-Amino-3-phenylpropanoic acid N N Y Phenylalanine is found naturally in the breast milk of mammals. It is used in the manufacture of food and drink products and sold as a nutritional supplement for its reputed analgesic and antidepressant effects. It is a direct precursor to the neuromodulator phenethylamine, a commonly used dietary supplement. As an essential amino acid, phenylalanine is not synthesized de novo in humans and other animals, who must ingest phenylalanine or phenylalanine-containing proteins.       [1,4] benzodiazepine-3-carboxylate N N Y SH-053-R-CH3-2′F is a drug used in scientific research which is a benzodiazepine derivative. It produces some of the same effects as other benzodiazepines, but is much more subtype-selective than most other drugs of this class, having high selectivity, binding affinity and efficacy at the a5 subtype of the GABAA receptor. This gives much tighter control of the effects produced, and so while SH-053-R-CH3-2′F retains sedative and anxiolytic effects, it does not cause ataxia at moderate doses. [1] SH-053-R-CH3-2′F also blocks the nootropic effects of the a5-selective inverse agonist PWZ-029, so amnesia is also a likely side effect.  Dissolve it in hot water, tea, hot milk, coffee or in any another type of drink. Best is to first take one drink. Then you can experience the effect on your body. If the effect is pleasant, you can always try another drink. 128 Theanine Theanine, L-Theanine, L-gglutamylethylamide and N5ethyl-L-glutamine; Theanine; L-Theanine; L-gglutamylethylamide and N5ethyl-L-glutamine N-ethyl-L-glutamine; (2S)-2-ammonio-5-(ethylamino)-5-oxopentanoate N N Y Theanine, or N-ethyl-L-glutamine, is an amino acid analogue of L-glutamine. Its structure is comprised of a five carbon straight chain carboxylic acid called pentanoic acid, which is bonded to an amino group at R2, and an additional ketone group at R5. Also substituted at R5 of the pentanoic group is an ethylamino chain connected at its amino constituent. Theanine is understood to refer to the levorotary enantiomer, which is well documented, rather than the relatively unresearched dextrorotary enantiomer.    [2] is an a-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an a-amino group, an a-carboxylic acid group, and a side chain indole, making it a non-polar aromatic amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Tryptophan is also a precursor to the neurotransmitter serotonin, the hormone melatonin and vitamin B3. [3] It is encoded by the codon UGG. 132 Tyrosine L-Tyrosine or 4hydroxyphenylalanine; Tyrosine; L-Tyrosine or 4hydroxyphenylalanine L-Tyrosine N N Y Tyrosine is a non-essential phenylalanine-derived amino acid. Tyrosine's structure is made a para-hydroxylated phenyl ring connected to a pentanoic acid group, which is a five member carbon chain with a carboxyl (C(=O) OH) group on the terminal carbon. This pentanoic acid chain is substituted at R2 with an amino group in levorotary orientation. 133 URB-597 KDS-4103; Cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester    Is an Adaptogen. It is commonly used for its ability to prevent anxiety. It also is helpful in relieving insomnia. It's name means "Smell of Horse" due to its smell and the traditional belief that ingesting the this herb will give you the strength and virility of a horse.