Summary

BACKGROUND

Modafinil is a drug developed for the treatment of extreme lethargy. Despite being
proven effective in the intervention of sleep disorders, there is still controversy
about whether it can improve the subject’s performance in higher cognitive processes such as
memory and executive functions.

METHODS
This randomized, crossover, double-blind, placebo-controlled clinical trial; was designed
to evaluate the effect of modafinil compared to a placebo, on the cognitive functions of
healthy college students. 162 volunteers were recruited, randomly assigned to a
modafinil consumption group or a placebo consumption group. Both groups were evaluated using
the Stroop Test, the Cognitive Estimation Biber Test and the Digit Span Test
. After 15 days, they were assigned to the other intervention

RESULTS
A significant difference was found in favor of modafinil compared to placebo in the proportion of correct responses of the Stroop Test in the congruent situation. A lower response latency was also found among subjects who consumed modafinil in the incongruous situation of the same test. No differences were found in the Digit Span or the Cognitive Estimation Biber Test.

CONCLUSIONS
This study demonstrates that modafinil does not improve the overall cognitive performance of healthy students without sleep deprivation, except for non-demanding tasks. In particular, this drug does not seem to have positive effects on the mental processes that sustain study activities in the university population under normal conditions. These findings are expected to demystify the use of this neurostimulant and contribute to public drug policy decision-making.

Introduction

Modafinil (-2 – [(diphenyl) methylsulfinil] acetamide) is a psychostimulant with wake-promoting properties, which was already available for commercial use in France in the 1990s  . It has shown particular effectiveness for the treatment of lethargy and sleep disorders .

Some authors state that modafinil increases performance in tasks associated with cognitive functions such as working memory, visuospatial attention and executive functions . For others, modafinil improves cognitive performance in healthy sleep-deprived adults, but only with regard to attentional and alert functions.

Its primary mechanism of action is unknown, although its effects on different neurotransmitter systems have been demonstrated .

The use of stimulants to improve academic performance has increased in the young population in the United States  . More than 7 million Americans use bedside stimulants, and approximately 1.6 million of these people are students . An online survey of more than 1400 people from sixty countries, showed that 20% of the respondents had used a psychoactive drug to improve their concentration or memory at some time and 44% of them had used modafinil. The population most frequently associated with the use of stimulants to improve attention and memory are students between the ages of 18 and 25 .

There are no formal studies that report the use of modafinil among students in Chile. However, some media surveys report an increase in the consumption of stimulants in students between 19 and 25 years old, concentrating the highest levels of consumption during the final exam periods of the courses .

Effect of Modafinil on Attention
Most of the research carried out in healthy adults to evaluate whether stimulants improve cognitive performance has produced conflicting or inconclusive results . Although modafinil plays a key role in certain cognitive functions such as attention and tasks that demand a certain level of performance, it seems to have little effect when a higher demand is added .

Trials evaluating attention on adults demonstrate advantages among those who use modafinil compared to those who consumed placebo, with regard to the care using the task Stop-Signal Task (task detention signal)  , but this result seems be highly associated with the subject’s IQ.

A study in young volunteers also found evidence of a positive effect on the Attention Shift Task , after taking Modafinil. This appears to facilitate rapid switching of attention under demanding conditions, although it offers minimal benefit when an unpredictable and infrequent disengagement of attention is required to respond to an alternative stimulus in a concurrent task .

A clinical trial with 45 participants without sleep deprivation found no conclusive results regarding attentional performance, possibly due to the small sample size. This finding demonstrates that the evidence in favor of modafinil as an attentional optimizer is ambiguous.

This is why it is relevant to investigate the role that this substance plays in relation to certain attentional phenomena. In particular regarding selective attention (inhibition of a response to irrelevant information), which is a key process in learning . This dimension of attention has been selected in the present research, due to the fact that it has been shown that impairments in selective attention among students at secondary and tertiary levels are usually accompanied by low information processing and learning capacity. and therefore, poor academic performance.

Executive functions and memory
Studies that have aimed to prove that modafinil can improve performance in higher cognitive processes such as memory and executive function in healthy participants have yielded contradictory results. So far there are no systematic reviews on its impact.

The ambiguity of these previous findings motivated this investigation. The objective was to evaluate the effects of modafinil on the cognitive performance of university students, particularly with regard to short-term memory, executive functions and attention.

Method

Design
This randomized, double-blind, placebo-controlled, crossover design trial was designed to evaluate the effect of modafinil on the cognitive functions of healthy students. It was held at the University of Valparaíso, Chile. The protocol was approved by the Ethics Committee of the Faculty of Medicine of the University of Valparaíso, under the authorization code 04/2010 CEFM and was registered on the Clinical Trials website (http://clinicaltrials.gov/) under NCT code 01365897.

Participants
Eligible participants included health students between the ages of 18 and 29. They were summoned using open notices on a website. Thus, medical and psychology students (n = 180) of both sexes were contacted, recruiting those who met the inclusion criteria (n = 162). The minimum sample size was 155 subjects considering the level of significance p = 0.05, power of 0.80 (1-beta), expected difference from 19 to 19.15 and a possible loss of 20%.

1. Significance level of p = 0.05.
2. Power (1-β) of = 0.80.
3. Expected difference from 19 (SD = 0.7) to 19.25 (SD = 0.7) and a possible loss of 20%.  

The inclusion criteria were:

a) Age between 18 and 29 years: this age range was chosen because there is a cognitive impairment of 1% of the total IQ between 25 and 29 years. The purpose of this criterion was to work with a sample without cognitive impairment, as this could modify the performance of the volunteers.

b) Be a student of health careers at the University of Valparaíso.

c) Have a healthy weight. The reason behind this criterion is based on the fact that all volunteers received the same dose of Modafinil. Therefore, subjects outside this range could have generated different plasma levels.

The exclusion criteria were:

a) Mental disorders. Assessed based on the subject’s medical history or by obtaining a pathologic significance score on the Primary Care Evaluation of Mental Disorders ( Prime-MD ) questionnaire.

b) Current use of psychotropic substances of any kind.

c) Alcohol consumption up to three days before the experiment.

d) History or symptoms of current chronic physical illness.

e) Being pregnant or breastfeeding.

f) Being deprived of sleep.

Outcome measures
The main result was the attention score, expressed according to the proportion of correct answers of the Stroop Test . Additional analyzes were conducted comparing the percentage of correct responses and the latency of responses in this test, in the digit width task and in the Biber Cognitive Estimation Test (BCET Test) between both groups.

Procedure
The participants were recruited from various cohorts of the aforementioned careers, without receiving financial compensation. They signed the corresponding informed consent and answered the Primary Care Evaluation of Mental Disorders , a self-administered questionnaire used to evaluate possible psychiatric conditions. Subsequently, they were briefly interviewed to inquire about the presence of any other exclusionary condition related to sleep deprivation and substance use (psychotropic drugs or alcohol use). Those who did not meet any exclusion criteria were considered eligible to participate in the research.

Once the definitive sample was defined, the volunteers were summoned in randomly formed groups in shifts of twenty people to take the tests simultaneously. This with the intention of ensuring that the tests were applied appropriately, according to the conditions and the capacity of the computer room of the School of Psychology of the University of Valparaíso, and to achieve the adequate plasma levels of modafinil during the administration of the evidence.

The allocation of participants to each arm (group that received one of the two substances) was done randomly using a computer program and the sequence was concealed by the principal investigator. On the first day, the participants received substance A or substance B, which corresponded to 200 mg of modafinil or placebo (placebo tablets that were manufactured in the Faculty of Chemistry and Pharmacy of the university with the same shape and color of the modafinil lozenge used in the experiment).

Volunteers were tested with the instruments 120 minutes after dragee administration to achieve the highest possible plasma level. The first experimental phase evaluated attention and executive functions using the Stroop Test and the Biber Test of Cognitive Estimation, respectively. Short-term memory was then assessed using the Digit Span test . These tests were administered on computers using the MediaLab © program ( New York , United States). After a seven-day wash out period to allow for plasma modafinil clearance, the participants returned and were assigned to the other group. Thus, each person received both modafinil and placebo during the trial. 

Instruments

Stroop test: it was usedthe Iowa Stroop Test, in a computerized adaptation through the Medialab program. This test requires participants to read names of colors (blue, green, red, and yellow) that are displayed in different colors (blue, green, red, and yellow). Your task is to identify the color of the word while ignoring its meaning. There are two conditions: a congruent one, in which the name of the color and the color of the letters coincide; and an incongruous one, in which the name of the color and the color of the letters are different. The variables recorded were response precision (correct color identification) and response latency (in milliseconds). This registration method yielded two types of measurements: precision and latency, for both the congruent and the incongruous conditions.

The Stroop Test primarily assesses selective attention, since the subject must ignore the distracting stimulus in the incongruous situation. According to a systematic review, the Stroop Test has been the most widely used instrument to assess this cognitive function.

Digit Span in normal and reversed order:This test consists of a series of digits presented to the volunteer and measures the breadth of short-term memory, attention, and the ability to form sequences. The test is made up of two sections: normal and inverted. In the normal section, the stimulus must be repeated in sequence. In the inverted section, the stimulus must be repeated in reverse order. The maximum evaluation of the first section is 8 points and the maximum of the second is 7, which yields a maximum total score of 15. This measure has a high reliability split-hal f (r = 0.89)  and an acceptable test-retest reliability (r = 0.80).

The Biber Cognitive Estimation Test (BCET): consists of twenty items, five from each of the following categories: time / duration, quantity, weight and distance / length. The test demands that the participants give values ​​to questions for which they do not have ready answers. For example, the question “What is the length of the average man’s spinal cord?” it requires the participant to select an appropriate response and estimate its plausibility, but does not require a complex calculation. Each answer that falls within a preset range receives one point. The maximum score for this test is 20 points.

Design and data analysis
A randomized crossover design was chosen , which is based on the advantage that each participant acts as their own control. The allocation sequence was concealed by the principal investigator from the volunteers, the implementers, and the data analysts.

Based on the methodological design used, the Student’s t test was used to compare means of paired samples. Specifically, the analysis compared the means obtained for each item in the experimental condition and in the placebo condition. Statistical analyzes were performed with the Stata 12.0 program ( Statacorp, College Station , Texas, United States). The level of significance considered was p <0.05.

Results

Prior to exclusion, the original sample consisted of 180 medical and psychology students, aged between 18 and 29 years. As shown in the flow chart (Figure 1), 18 participants were not included due to a history of mental disorders and / or an abnormal score on the Primary Care Evaluation of Mental Disorders . The 162 selected participants were randomly assigned to the groups, however 34 people did not complete the study. The final sample that completed the study consisted of 128 volunteers, of which 76 were women.

Figure 1. CONSORT flow diagram that graphically shows the design and conduct of the clinical trial.

Table 1. Characteristics of the subjects recruited for the modafinil trial expressed in means (and standard deviation).

1. Stroop test : a significant difference was found between the experimental and control groups in the correct proportion of responses in the congruent condition (p = 0.01). However, no difference was found for the incongruous condition (p = 0.81). As shown in Table 2, there is a significantly lower latency for the modafinil group in the incongruous condition (p <0.05), but there is no latency difference in the congruent condition (p = 0.15).
2. Biber Cognitive Estimation Test: no significant differences were found between the modafinil and placebo groups with respect to this test (items 0-20; p = 0.26; Table 2).
3. Digit Span : the total mean score of correct answers in the Digit Span test did not reveal significant global differences between groups (p = 0.26), nor were there differences for the normal (p = 0.85) or inverted (p = 0.93) (Table 2).

Table 2. Comparison of scores from the Stroop Test, the Cognitive Estimation Biber Test and the Digit Span between placebo and modafinil conditions, with measurements (SD) and p-values ​​(paired t-test).

Discussion

This study showed a positive effect of modafinil on the cognitive performance of healthy, non-sleep-deprived young university students, only with respect to the greater precision of the participants under the effects of modafinil in the congruent condition and its lower response latencies in the congruent condition. incongruous situation the Stroop Test. The modafinil group showed no advantages over the placebo group when it came to short-term memory or executive function. 

Considering that the greatest strength of this work is methodological, because the design crossover pharmacological evaluations – to the extent that the plasma clearance of the drug is ensured, this research provides evidence about a highly relevant phenomenon for university students. Health and education policies should consider the possible abuse of this drug, given the belief that it optimizes study performance. 

Significant differences were found between the groups in the performance of the Stroop Test in the congruent condition, but not in the incongruous condition. These results are inconsistent with previous findings. This discrepancy could be explained by methodological differences, such as sample size, age range, sleep deprivation, and experimental protocols; that make it difficult to compare these results with those of other studies. 

Given that the congruent condition demands fewer cognitive resources than the incongruous condition, this result confirms that modafinil optimizes the performance of selective attention when the task has a low cognitive demand. Said result conflicts with those reported by Marchant, who indicates that participants who consumed modafinil achieved better specific performance in the attentional change task, both for the constant condition and for the alternating condition, the latter being of greater difficulty. However, this task is not directly comparable to the Stroop Test. Marchant states that the attentional shift task is linked to a prospective memory based on an event, which requires a person to interrupt a concurrent activity to retrieve and act on a previously formed intention . In a standard prospective memory task, participants exhibit different responses when they recognize new goals that are associated with a previously formed intention. These objectives appear relatively infrequently and require attentional resources. Since modafinil increases arousal and elevated arousal has been shown to improve sustained attention, change, and prospective memory, this drug may improve performance on prospective memory-like tasks such as the task of attentional change, but not in those that rely on selective attention. 

In contrast to this result, several studies have shown a lack of physiological or subjective effects of modafinil on arousal. However, they have observed an increase in cognitive functions . In principle, attentional change requires resources similar to those of prospective memory. In fact, the literature tends to assume that prospective memory and task-changing abilities are governed by the same brain regions, that is, the prefrontal cortex. However, while one requires continuous and rapid shifts of attention, the others require disengagement from an attentively demanding task to successfully detect and respond to an infrequent target at the appropriate time. 

This observation is not surprising and parallels Randall’s inconclusive results, possibly because the best effect of modafinil occurs when it is used in disadvantageous conditions (for example in illness or sleep deprivation) and to restore a healthy life. baseline cognitive level. This means that it allows the nervous system to function and reach full arousal levels , but there is no evidence of cognitive improvement in an already fully awake individual. 

An unexpected finding from this trial was that the latency of the Stroop Test in the incongruous condition was significantly lower in the modafinil group compared to the control group. So Modafinil does not improve accuracy, but rather reduces reaction time in the incongruous condition.

There were no significant differences between groups in terms of short-term memory or executive functions. Although these results diverge with those of Turner and Randall, they do agree with those of Baranski et al. and Müller. This result may be because the effects of modafinil are mediated by a plethora of variables that have not been fully studied, particularly IQ.

The benefits of modafinil on memory and executive functions for people with sleep disorders or pathologies involving attentional impairment appear to be irrefutable. However, the goal of making these results more generalizable to healthy populations remains ambiguous and requires further research.

A potential limitation of the study is that sleep quality was not assessed, except by the recruitment protocol. Even though the participants were told to come forward rested, they may have given an erroneous report or they may have had an undiagnosed sleep disorder. 

It should be considered that this design and the large sample size allowed the detection of highly significant statistical differences in the Stroop Test. Whether these statistical differences are clinically relevant, that is up for debate. 

Regarding the ecological validity of this work, it should be noted that modafinil is consumed by students to improve their academic performance. For this reason studies like this trial, which measure the effectiveness of this drug using tasks that assess study skills, are relevant. However, it is advisable to complement this work with research directed towards other aspects of memory and executive functions. 

Conclusions

Modafinil does not improve the overall cognitive performance of healthy students without sleep deprivation, except for non-demanding tasks. In particular, this drug does not appear to have positive effects on the basic mental processes that support study tasks in the university population under normal conditions. These findings are expected to demystify the use of this drug and aid in decision-making on public drug policy.

Grades

Declaration of conflicts of interest
The authors have completed the ICMJE conflict of interest form, and declare that they have no conflicts of interest associated with the subject of the study. The forms can be requested from the responsible author or the editorial direction of the Journal .

Ethical aspects
The participants signed an informed consent document. The Institutional Ethics Committee of the Faculty of Medicine of the University of Valparaíso approved this research protocol with the authorization code: 04/2010 CEFM. The project was registered on the international website of the Clinical Trials Registry (http://clinicaltrials.gov/) and received the identifier NCT01365897.