We need to talk about the use of methylphenidate by medical students – review of the literature

Introduction: Studies methylphenidate (MPH) has been used by medical students to increase their mental activity and improve the performance required during undergraduate school, generating concern regarding the risks to their physical and mental health. This scenario indicates the need for specifically aimed measures in medical schools. Objective: To review the literature about the use of MPH without medical indication amongst medical students. Method: A thorough review of the literature published in English, Spanish, and Portuguese, between 2013 and 2019, based on data made available by P ubmed and S cielo , utilizing keywords in the three above languages, along the four stages of the selection process. Results and Discussion: Altogether, 224 articles were found, of which 25 were selected after reading, dealing with the use of MPH or ‘cognition enhancer’ by undergraduate medical students without a doctor’s prescription. The research indicated significant variability in the frequency of consumption, related to the investigated pattern of use, use with or without indication, before or after entering University and country where the study was carried out. The most frequent justification for the use without medical indication was to attain improvement in academic performance. A lack of research with a fair appraisal of the cognition, behavioral and psychic risks involved, among them addiction and the approach of the topic in medical schools, was noted. Conclusion: The high rates of usage of MPH by medical students aiming at cognitive enhancement strengthens the importance of preventative actions in medical schools. The strategies must consider information concerning the risks of use (of MPH) without medical indication; non-pharmacological interventions for performance improvement; sleep hygiene measures organization for adequate study activities; broad discussions about ethical aspects and curricular structure.


INTRODUCTION
In the last decade, there has been a growing concern in the academic world regarding the continuous use of psychostimulants to improve school performance amongst undergraduate students 1 . These substances are characterized by their capacity to stimulate the Central Nervous System (CNS) 2 , enhancing attention and concentration. Among these substances, 'energy beverages' (drinks based on caffeine, guaranine, cola, and taurine), medications used for weight loss, and the drugs indicated for the treatment of attention deficit and hyperactivity disorder (ADHD) and narcolepsy stand out 2, 3 . The medications more frequently utilized to improve cognitive performance are those indicated for the treatment of ADHD, which is characterized by loss of attention, mental organization, and hyperactivity/impulsivity, starting at childhood and being able to persist up to adult life, which can harm an individual's social, academic, and professional life 4 . The ADHD pharmacological treatment includes using Methylphenidate (MPH) 5 , a stimulant drug sold in Brazil under the commercial names Concerta ® , Ritalina ® , and Ritalina LA ®6 , as first-class medications for therapeutic intervention 2,5,7,8,9 . This drug promotes an increase in attention and the control of behavioral impulses; however, it has the potential for the development of drug dependence when inadequately used 6 . Therefore, the recommendation for its use should follow strict criteria, after a medical and psychological evaluation taking into account family history, development during childhood, school performance, an analysis of the use of other psychoactive substances, as well as the level of intelligence of the personality 10 . The use of stimulants to enhance mental activity has been described as an option to deal with the demands that undergraduate school requires and to improve academic performance 2 , generating concerns about the risks to the individuals' health and quality of life. Recent investigations carried out at the University of Rhode Island, Brown University, and at the Rhode Island Memorial Hospital studied the consequences of the unprescribed use , of Adderall® (a mixture of amphetamine salts, also used to treat ADHD) by undergraduate students. The authors verified that the attention capacity improves, albeit to the detriment of the working memory functions, which, in turn, could compromise the performance of daily tasks, solving problems, and social relations as well 1 . Amongst the university courses, a degree in Medical Science is considered one of the most demanding in respect to the performance of its students 2,11 . Their journeys begin the moment they choose the profession, going through pre-college preparatory courses, competing with others to get into a university, and after that having to keep up the high performance during the entire graduation 11 . Most of the students arrive at the University hoping that the level of continued dedication demand will slack down and gets frustrated when they realize that, quite to the contrary, the rhythm of studies will continue at a very high rate of demand 11 . Besides this, other factors such as sleep and leisure deprivation contribute to stress and low academic performance 2 .
Committed to a strenuous routine, the students may resort to means to attain efficiency in the course activities, amongst them the use of brain stimulants such as the MPH 2 . This subject is essential to all Higher Medical Education institutions and those that render student support. This essay aims to make a literature revision concerning the usage of MPH among medical students without a doctor's prescription, seeking a better understanding of the aspects of using psychostimulants and promoting preventive actions to offer medical students better learning conditions and quality of life.

RESULTS
In total, 224 articles were found, of which 09 were from the Scielo database, and 215 from Pubmed. The repeated articles or the ones that did not address MPH use by medical students without clinical orientation were excluded, as shown in Figure 1.

DISCUSSION
The study indicated significant variability in the frequency of consumption, related to the pattern of use investigated, use with or without indication, before or after entering University and country where the study was performed. Among the assessed articles, the students from Latin American countries were the ones who showed a higher prevalence of MPH use. A Puerto Rican survey showed the highest prevalence (47.4 %) 12 , followed by 45% of the students interviewed in a Paraguayan school, of which 33% used the drug without adequate clinical indication 13 . Then comes a total of 34.2% of the students from a medical school in the Rio Grande do Sul, Brazil, of which 23% used it without adequate indication 14 . The other two studies carried out in Brazil 2,7 indicated higher rates of use when compared to other countries such as the USA, with 18% 15 , Israel 8 and Africa with 17% 16 , North of Iran with 11% 17 and a study in Pakistan with 9% 18 .  The use of psychostimulants was higher by doctors' supervisors and medical students than in the pharmacy course. Those three mentioned groups had a two-fold higher stress level than the general population Jain R, Chang C, Koto M, Geldenhuys A, Nichol R, Joubert G. 2017.
To investigate the persistence of MPH misuse and the knowledge regarding this drug Cross-sectional study (n=541) Persistence of use by 9.9%, the majority use it to improve academic performance, and it is used the most by third-year students.
To discuss the prescription of agents that improve cognition in healthy adults

Opinion article
Questions the risks and benefits of the use of cognitive enhancers in healthy adults and their prescription.

Chart 1.
Highlights of the review on the use of psychostimulants by medical students.

Topic Description
Epidemiological data Significant variability in use rates (3% to 47%), depending on the location of the study and methodological differences in data collection (use throughout life or after entering University; prescribed or self-recommended use; frequent use or experimentation).
Indications of an average rate of use in life are around 10%.
Conflicting data regarding gender distribution: some studies point to greater use by men, and others have found no differences.
Data are inconclusive regarding the course period most associated with the use.
Most studies suggest a preponderance of use after entering University.

Motivations for use
Unlike medical students' usual consumption pattern of other psychoactive substances (recreational use and in social contexts), psychostimulants, particularly MPH, are mostly related to the search for increased waking time and improved concentration, attention, memory, and academic performance.

Use of other substances
Some studies indicate higher consumption rates among students who use other icit and illicit substances -particularly alcohol -however, there are little data on the risks of interaction and abuse or dependence rates.

Risks related to use
Few studies address the topic, but they mainly point out increased anxiety and problems with sleep.
There is no confirmation of benefits in cognitive functions, only increased waking time.
The role of the medical school Articles point to concern about how university disciplines present the substances to the students, as there are indications of greater use after its mention in the initial years of the course.
Other studies indicate the need to discuss the topic with students, mainly because they describe behavior facilitated by peers.
Additionally, they highlight the importance of addressing the risks of use, self-prescription, and the ethical aspects involved.
Few articles discuss, although they point out, the need for studies on issues related to medical education, content, forms of teaching/learning, competitiveness, and mental health of future doctors. Seven studies were carried out on the difference in use between the genders, without significant differences.
Five, however, indicated a higher rate of consumption of psychostimulants (including MPH) by the male gender 3,9,15,17,20 , while one of these specified the use of MPH 9 . Only one article described a higher prevalence of use by the female gender 21 .
Some studies suggest that the majority of the medical students that use MPH started using it after entering the a background of use claimed they started using this substance during the medical course 2 . In a North American study performed with students of Osteopathic Medicine, the authors found that the frequency of students that admitted the use of psychostimulants without medical indication was higher than the diagnosis rate in the population 22 .
In a study carried in a University in the Brazilian state of Minas Gerais, half of the students who used psychostimulants did it before the exams 21 . Another study in Puerto Rico found a rate of 60.3% 12 . These findings emphasize that the stimulants seem to be considered a facilitator for "good" results in the exams 21 . Other studies also pointed out that the motivation leading to the use of MPH without a medical indication aimed at better academic performance 23 , increasing waking hours, improving concentration, attention capacities, and extended memory 2,3,7,8,9,12,13,14,15,17,18,21,24,25 . In addition, research in Iran revealed the role of social groups in the indication of brain stimulants 17 , also considered a motivator for consumption without medical indication.
A Belgium study of 2019, set to investigate what would be "behind" the need of the students seeking cognitive enhancement, questioned 3,159 students that used nontherapeutic stimulant medications 26 . The authors pointed out that the clearer the perception that the medical school is a competitive environment, the more significant the levels of stress and the higher the probability for inadequate stimulant use. The research reveals that, contrary to expectations, the association of competition with stress was significantly stronger in those students who wanted to become general practitioners, with the consequent use of stimulants, compared to those aiming to have a medical specialization 24 . In another study, medical supervisors and medical students reported greater use of psychostimulants, without medical indication, than the Pharmacy course students.
These three groups showed stress rates roughly two times higher than the adult population in general 27 .
A study carried out in the state of Rio Grande do Sul, Brazil, determined that 14.3% 14 of the users of stimulants were associated with alcohol consumption, and 5.7% admitted using MPH in parties as well 14 . These findings suggest that the most frequent use was not related to social activities or parties, such as the other psychoactive substances, but was probably associated with academic performance improvement. This research also realized that MPH users who used it together with alcohol, with or without a medical prescription, showed alcohol consumption patterns that were considered a health risk 14 .
The MPH, when associated with alcohol, produces a euphoric effect decreases the sensation of inebriation or drunkenness 14 .
However, this combination produces a toxic metabolite, and its effect on the organism remain little known 14 .  14 . Some references deal with the dependence on this medication as something more theoretical than practical 3 ; however, the increase in consumption by the young people seeking cognitive enhancement deserves attention and care, for its use without therapeutic indication can raise the potential of dependence. According to Dafny 5 , sensitization can increase the experienced effects when compared to those experienced at the first use of the same dose, which can be considered an additional warning signal for the need to evaluate groups regarding the chemical dependence.
An US article published in 2013 measured the consumption pattern of stimulants, with a predominance of amphetamine salts and MPH 15 . Among the users, an average frequency of drug use ranged from 10 to 12 occasions during a 30 day period, which consisted in most cases in oral administration (92%), with a smaller percentage (18%) of inhaled administration, associated or not with oral administration 13 . In 2018, an Iranian study demonstrated that most interviewed individuals consumed these substances through an oral route (79.6%). However, 6.1% said they consumed it by an intravenous route and 2% by the inhaled route 17 . Thus, although the selected studies indicate the use of MPH primarily by oral administration, it is essential to follow a possible increase in the other means of administration of these substances, keeping in mind that the use of intravenous or intranasal drugs implies more severe damage and potential risks such as of overdose.
Addressing the possible consequences of MPH use,

AUTHORS' CONTRIBUTION
Natália Aparecida Amaral ontributed with the study design, research, data analysis and the writing of the manuscript; Eliza Maria Tamashiro contributed with the writing of the manuscript and data analysis; Eloisa Helena Rubello Valler Celeri, Amilton dos Santos Júnior and Paulo Dalgalarrondo were responsible for the overall review and final approval of the manuscript and Renata Cruz Soares de Azevedo was the advisor, study supervisor and contributed with the study performance, data analysis, drafting and final approval of the manuscript.