**5. Cognition-enhancing drugs**

The search for drugs that improve cognitive functions to treat several diseases, including Alzheimer disease (AD), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), has derived a wide number of synthetic drugs that, in turn, increase learning, executive functions, or creativity in healthy people. These drugs, also named "smart drugs" or "nootropics," have different chemical origins and mechanisms and in general have showed little or no effect in improving learning and memory tasks. There is a growth in the consumption of these drugs by adolescents [91, 92], mainly due to academic demands and competitiveness [93]. According to the Federal Substance Abuse and Mental Health Services Administration, every year around 137,000 college students in the US begin to use psychostimulants. Furthermore, consumption of stimulant drugs of abuse increases in key academic dates (**Table 2**) [94].

Nootropics have focused their targets on modulation of neurotransmission, hormones, transduction systems and neuron metabolism. However, we will focus on legal stimulants commonly used by students to improve academic performance: acetylcholinesterase inhibitors, memantine, modafinil and methylphenidate.

#### **5.1. Antidementia drugs**

#### *5.1.1. Acetylcholinesterase inhibitors (AChEIs)*

Most of the drugs that are used to enhance cognitive functions, both in patients and in healthy volunteers, work through acetylcholine (ACh) neurotransmission. ACh is a neurotransmitter closely involved in synaptic transmission and also in the formation of memories and performing tasks. Donepezil, rivastigmine or galantamine had good results enhancing cognitive performance in patients with mild to moderate AD, when compared with placebo [95]. However, diverse studies conducted in healthy volunteers have showed that AChEIs lightly improve verbal memory after semantic processing of words, attention memory, information processing, executive function and memory mood [96].

Several studies have reported that MPH treatment during childhood produces "permanent" changes in behavioral responses to other psychostimulants [110]. Moreover, a recent study made on rats has showed that acute and long-term exposure of adolescents to MHP has

Influence of Drugs on Cognitive Functions http://dx.doi.org/10.5772/intechopen.71842 71

There are some difficulties evaluating the efficacy of smart drugs, mainly due to the heterogeneity of subjects and the differences in the cognitive evaluation methods. Besides, the disparities in the design of the studies have been challenging the evaluation of smart drugs in healthy subjects. However, there are some studies that have used systematic methodology to analyze the literature published on healthy volunteers [96, 97]. According to these reviews, antidementia drugs, AChEIs and memantine enhance cognitive functions in patients with AD; nevertheless, their effects on healthy volunteers appear to be very poor [107]. Another aspect to consider is the interindividual variability of volunteers, because it could be an important

There are also several ethical considerations about the use of psychostimulants in healthy people. Currently, caffeine is the stimulant most commonly used to get alertness. However, the misuse of MPH and modafinil is growing among students, since these drugs are cheap and

Drug abuse and addiction to legal and illegal substances have become a major challenge in western developed and developing societies. Growing evidence has shown that the onset age of drug consumption is around 15 years. At this age, the central nervous system is still under maturation. Childhood and adolescence are critical stages for neural and social development. Therefore, worldwide increasing prevalence of drug abuse among teenagers will certainly have an effect on scholar performance. All the evidence described in the present review suggests that teenagers that consume drugs risk deleterious consequences in their academic growth, since the neural mechanisms targeted by these drugs may have long-term impacts on cognitive functions. Therefore, prevention initiatives and public health programs must be implemented in schools to protect children and teenagers from escalating drug use.

In summary, the evidence regarding the possible long-term detrimental effects of teenage drug consumption on learning and memory adds to the increased risk of developing mental disorders, and therefore it should be included in public health information campaigns that seek to encourage delaying and/or reducing drug consumption at this stage of life. The scientific information obtained from studies such as those described above will be of little use

without adequate public policies aimed at alleviating this serious problem.

important effects on reward-dependent learning and decision [111].

reason that masks the cognitive effect of these drugs.

easy to obtain illegally.

**6. Perspectives**

**7. Conclusion**

**5.4. Considerations about use and misuse of cognition-enhancing drugs**

#### *5.1.2. Memantine*

Memantine is a psychostimulant used to treat moderate to severe AD. It acts on the glutamatergic system by antagonizing N-methyl-d-aspartate (NMDA) receptors. This drug has been showed to slightly improve cognitive functions as monotherapy of AD [97]. There are few studies about the cognitive-enhancing capacity of memantine on healthy volunteers. The studies published were tested with acute single dose of memantine, finding that this drug does not increase mental performance significantly [96].

#### **5.2. Modafinil**

Modafinil is a psychostimulant indicated in the treatment of narcolepsy, shift work sleep disorder and excessive daytime sleepiness [98]. Since approval by FDA, in 1998, modafinil has been widely used not only to treat wakefulness disorders, but also to increase alertness and enhance cognition. Modafinil exhibits advantages among other psychostimulants, including the lack of unwanted side effects (e.g., tolerance, abuse potential, sleep rebound and locomotor excitability) [99], and, in most countries, it is not a controlled substance; therefore, it can be easily purchased online. Modafinil exerts its actions through an unknown mechanism. Still, it is recognized that modafinil inhibits dopamine and noradrenaline uptake, elevates catecholamine's levels, therefore raises extracellular serotonin, glutamate, histamine and orexin and reduces GABA's concentration [100]. Although the effects of modafinil as a wakefulness promoter have been proven [101], its properties as cognitive enhancer are still controversial. In sleep-deprived individuals, modafinil improves attention, memory and executive function [102], while the effects of modafinil in non–sleep-deprived adolescents are limited [103]. Other reports have found that modafinil actually improves several cognitive functions [104]. Interestingly, modafinil has showed to enhance mental performance of subjects with low baseline performance or IQ on several tasks evaluated [105].

#### **5.3. Methylphenidate (MPH)**

MPH (Ritalin©) is a psychostimulant approved for the treatment of attention deficit/hyperactivity disorder (ADD/ADHD) [106]. Additionally, MPH is one of the most effective cognitive enhancers used by healthy people [107], because it acts through a mechanism analogous to that of cocaine: increases the levels of the catecholamines, dopamine, norepinephrine and serotonin, by blocking their transport [108]. This drug improves working memory, speed of processing, verbal learning and memory and attention [102]. Nevertheless, MPH effects are not restricted to spatial problems, since it also improves digit span test score [109]. Although MPH has demonstrated to be effective and safe in most of the patients when used in the short term, several side effects have been reported: decrease of appetite, insomnia, headache, irritability, weight loss, sadness, abdominal pain, nausea, somnolence, dizziness, among others. Several studies have reported that MPH treatment during childhood produces "permanent" changes in behavioral responses to other psychostimulants [110]. Moreover, a recent study made on rats has showed that acute and long-term exposure of adolescents to MHP has important effects on reward-dependent learning and decision [111].

#### **5.4. Considerations about use and misuse of cognition-enhancing drugs**

There are some difficulties evaluating the efficacy of smart drugs, mainly due to the heterogeneity of subjects and the differences in the cognitive evaluation methods. Besides, the disparities in the design of the studies have been challenging the evaluation of smart drugs in healthy subjects. However, there are some studies that have used systematic methodology to analyze the literature published on healthy volunteers [96, 97]. According to these reviews, antidementia drugs, AChEIs and memantine enhance cognitive functions in patients with AD; nevertheless, their effects on healthy volunteers appear to be very poor [107]. Another aspect to consider is the interindividual variability of volunteers, because it could be an important reason that masks the cognitive effect of these drugs.

There are also several ethical considerations about the use of psychostimulants in healthy people. Currently, caffeine is the stimulant most commonly used to get alertness. However, the misuse of MPH and modafinil is growing among students, since these drugs are cheap and easy to obtain illegally.
