The age-old dream to increase human performance seems to become true for mental performance due to recent pharmacological developments. Mental performance enhancement is described with various terms such as “Pharmacological Neuroenhancement” (PN), “Brain Doping,” or “Academic Performance Enhancement” (1–3). The corresponding substances are often referred to as “smart drugs” (1, 4). Except from technically elaborated experimental approaches such as (magnetic) brain stimulation via huge laboratory “machines,” the pragmatic and easier way to increase mental performance is delivered via the use of substances (5–7). Some of these substances are well-known to be drugs of abuse and addiction.

Klaus Lieb and Andreas G. Franke and the many other scientists belonging to the research field of PN define the latter as the use of specific substances by healthy individuals to increase mental performance without any medical need and therefore without any medical indication (5–8). Specific aims of this use are to increase cognitive domains such as vigilance, attention, concentration and memory. However, even the attempt to increase motivation and mood, or attempts to appear more intelligent to others or even to “be smart” falls under the definition of PN. The latter is sometimes also referred to as mood enhancement (3).

The motivation for the use of PN substances usually originates in the desire for a more intensive use of one's leisure time, which is aimed to be achieved by attempting to reduce or condense working hours and achieving (professional) goals in a shorter time (9) being underlined by divergent studies (6, 10–13). Therefore, PN is often considered to be a coping strategy that has been underlined in national (Germany) and international studies (13–21)—a coping strategy by the use of drugs that can lead to abuse and/or addiction.

Multiple studies underline the character of PN to be a coping strategy. A representative survey in Germany examined the professional situation of workers (14). It showed that participants felt psychological stress from the “circumstances” of their work (e.g., workload, multitasking, pressure to perform, etc.). Furthermore, data was collected on recovery strategies showing an increasing demand both in a professional and private environment (15). Eight percent of the surveyed 2,000 participants reported using prescription drugs to “unwind” and 12% to cope with the needs mentioned above.

Already in 2009, one of the largest German health insurance companies introduced this topic with a focus report on “Doping at work” (22, 23): According to the report of 2009, 5% and in 2015 even 6.7% of the surveyed employed persons between 20 and 50 years of age admitted to use prescription drugs to enhance cognitive performance or mental wellbeing without indication. In addition, many of the surveyed participants stated that PN was justifiable for occupational needs. The authors of the study estimated the number of unreported cases at 12.1%.

Studies using survey techniques to increase anonymity (internet-based, anonymization techniques) show prevalence rates of up to 20% use of prescription and illicit drugs among students, surgeons, “white collar workers” and readers of Nature magazine (6, 12, 24, 25). In addition, several studies showed that PN substance use is a coping strategy for perceived stress (12, 26, 27).

Interestingly, an older study demonstrated clearly that legal aspects such as punishment are crucial for the decision whether or not to use prescription and/or illegal PN medicines (28). However, the legal situation in Germany has not been analyzed systematically so far.

Therefore, aim of the paper was to (1) review potential and frequently used drugs for PN, (2) demonstrate their clinical and especially pro-cognitive effects and side effects and (3) integrate these drugs in legal categories based on the German legal system. Thus, an integration of PN substance use in legal categories was the predominant aim of this review. To achieve this aim systematically, the manuscript is designed according to the PRISMA guidelines.

To examine the three above mentioned goals, an intensive study of the literature was performed.

Two of the authors (raters) performed a literature search with the search terms “neuroenhancement,” “cognitive enhancement,” “academic performance enhancement” and “smart drugs” in the natural science data base “pubmed.”

For filtering and to reduce the number of hits, quotation marks were used. Then, only hits were used having an abstract and a full text. For further specification, only studies were included that were published later then 2007. To answer aspect (a) (types of substances) specifically and to address only the above mentioned definition by Lieb and Franke as well as many other scientists investigating PN, all studies about drugs affecting mood and/or moral were excluded. Furthermore, as well as regarding the second aim (b) (pro-cognitive effectiveness), only studies were included that demonstrate pro-cognitive effects and side effects; to explain effects on the molecular level, references were chosen voluntary. In a second step all abstracts were screened by two raters and publications which did not meet the subject (a, b, or c) sufficiently were excluded.

Because a plethora of studies from the field of natural sciences was found and to explain the subject to the reader in a reasonable and comfortable way, only a convenience sample characterizing and demonstrating PN drugs robustly, was cited in this article.

For studying the third aim (c) to integrate and characterize use of PN drugs with respect to legal categories, the German legal databases “juris” and “beck-online” were used and only studies were included which were published after 2008. Therefore, two authors performed a literature search using the search terms “neuroenhancement,” “Selbstdoping,” and “mentale Selbstbestimmung.” Because of different legal systems all over the world, the German situation is not comparable to others. To characterize the latter, only German speaking databases have been searched for legal sources.

Subsequently to the literature search, search results of the two authors were compared and discussed.

When performing the initial search in “pubmed” in sum, n = 56,595 hits/papers were identified using the specific search terms (neuroenhancement, cognitive enhancement, academic performance enhancement, smart drugs). Using filters (quotation marks, only papers containing an abstract as well as the full text, papers between 2008 and today) hits were reduced to n = 746 publications. After having screened the respective abstracts by two raters for the question of being relevant for the subject, n = 322 publications remained. For further details see Figures 1, 2.

The “everyday” substances and OTC drugs taken for PN are mostly “harmless” and do not significantly improve brain function (59). From the legislator's point of view, prescription substances that are not subject to criminal law do not have the required degree of danger. Therefore, these substances have to be excluded from further consideration.

Further substances, however, have to be considered even if their clinical effects by influencing mood states and indirectly cognitive functions, are low. The effects of narcotics go beyond this; they increase attention and promote sustained concentration. However, even this is not sufficient to derive punishability from it. It remains that the consumption of substances—outside the scope of the German Anti-Doping Act (AntiDopG)—is exempt from punishment.

This result may displease the interested reader. On the one hand, almost all acts surrounding and leading up to consumption are punishable, merely the consumption itself is not. This appears to be a legal subtlety. However, this is not the case: acts outside of consumption regularly endanger third parties. For example, the trafficking of narcotics endangers the health of third parties. As the state is also tasked with the protection of “public health,” according to Article 2 (2) of the German Basic Law (GG), the application of criminal law is legitimate. If the consumer only harms himself, there is no legitimizing reference to third parties.

This means to the German population that the “only” offense is the ownership of narcotics without having a respective prescription. Of course, using PN drugs may lead to the fact of changes regarding mental states and/or mood. Furthermore, it may lead to aspects of self-harm; however, this is not prohibited by any German law and therefore cannot be punished. Beyond that, it has to be stated that using PN drugs without affecting others, the use seem to be legally “unproblematic.”

This use becomes problematic, when others could be or even are threatened. Therefore, you have to ask what would the criminal law assessment look like if performance-enhancing substances were taken in situations with a third party reference? If a physician took substances after a tiring shift in order to be able to perform an operation with the required attention? Superficially, he is harming his own health. However, performance-enhancing narcotics such as prescription and illegal stimulants are known to cause deficits in judgment, perceptual changes, mental health changes etc. that has to be considered as side effects in the medical understanding given in the respective information (Arzneimittelfachinformation) (92). If a physician operates in this state, a danger to patients can no longer be objectively ruled out. However, if the physician overestimates his abilities, it can usually be assumed that he firmly trusts that he can treat the patient better because of the consumption. With regard to the Hippocratic Oath, it is to be assumed that he acts in the patient's best interest and does not intend to harm the patient's health beyond the necessary invasive measures. According to the current legal situation, he should remain unpunished. However, it should be noted that the circumstances of the “individual case” are always decisive (93). What is meant by individual case? The individual case depends i.a., on the drug (drug characteristics), the amount (dose) and the state of the use [tired, sleep-deprived, etc.; e.g., (44, 47, 58)]. These are the most important aspects determining the “individual case” leading to a more or less significant cognitive and mood change. The consequence as a more or less significant change of behavior and a more or less significant risk of damage for a patient or another person interacting with someone influenced by the use of a PN drug.

Beyond that, it could be argued about the possibility of impairment of the user. However, PN drugs are not known to decrease the users' level of functioning. Therefore, this aspect does not have to be considered.

Except from the above mentioned physician, easier and less complicated cases are imaginable e.g., nurses, taxi, bus or truck drivers, pilots or other people (in a professional or non-professional context) demonstrating the possibility to harm others influenced by the use of PN drugs.

From a legal perspective, it must be stated that the consumption of any PN substances is exempt from punishment. Based on the known clinical effects, there seem to be no need for further regulation based on a lack of cases of accidents, deaths, malpractice or even violence in the context of PN. If there are no such cases or the context could not be drawn cannot be evaluated yet.

It is conceivable, however, that research into more effective substances will necessitate a different assessment under criminal law in the future. The jurisprudence is obliged to take medical progress into consideration.

Apart from the clinical effects of PN drug use, there are already weighty reasons in favor of criminal law regulation. Because of the more or less rare side effects (e.g., mania, psychosis, overconfidence, euphoria, etc.) physicians and others (nurses, truck drivers, etc.) can endanger the physical integrity of their patients or others. It is hardly predictable when side effects such as mania, psychosis, overconfidence, euphoria, etc. will set in. The users decisions (speed of driving, using specific surgical instruments, landing a plane, etc.) can be negatively influenced by this. Through PN, users may set others on risk; e.g., the physician exposes his patients to the risk of wrong decisions and treatment errors. He thereby impairs the trust in the physician-patient relationship. The protection of life and limb and the reliability of health care services could legitimize regulation under criminal law.

Bringing together medical and legal aspects of the PN phenomenon systematically for the first time, the manuscript allows a legal approach based on medical and especially pharmacological aspects. However, there are some aspects that are limiting the meaningfulness of this article that have to be considered.

Main problem of this article is the fact that there are more or less different legal systems all over the world. This means that the German legal perspective regarding PN is not transferrable to other countries' legal systems. However, it has to be stated, that there are some fundamental legal principles being equal in many countries' legal systems. Therefore, this review allows a slight approach to an international consideration how to deal with PN drug use. Comparing the legal situation of PN drug use internationally or at least multinationally should be investigated in further studies.

Beyond this major weakness of the paper, the legal consideration is based on a systematic search of the literature in one search engine (pubmed). This search engine is the most well-known and used data base of the field of natural sciences including medicine and pharmacy. However, there are further but smaller and less important data bases. This may have led to the possibility that some studies deriving from the field of psychology are not included in this review. However, the substances that are included in this review are designated in the vast majority of the studies found. The used studies show an enormous unity in designating substances. Only very few studies suggested to add further substances such as beta blockers or benzodiazepines (6). However, the respective studies argued that benzodiazepines and beta blockers are used to get “calm” e.g., in case of stage fright of musicians or to counteract a high arousal during daytime (29, 94). These properties do not meet the definition of PN by Franke and Lieb (3, 8) the review is based on. Therefore, substances such as benzodiazepines and beta blockers are not included in this review.

Beyond that, studies measuring the clinical effects of PN drugs are based on a plethora of assessment instruments. These psychological assessment instruments cannot be compared to each other. Therefore, the review is unable to compare the studies and putative effective sizes directly to each other. However, to gain insight being as objective as possible (primarily), studies have been chosen using a RCT design (randomized, double-blind, placebo-controlled trials) to characterize clinical effects of the PN substances. This RCT study design offers an objective analysis of (clinical) effects avowing any subjective bias. Therefore, the evaluation of clinical effects is based (primarily) on this type of studies.

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

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

The 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.

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