**3. Depressant drugs**

**2.2. Methamphetamine (MA)**

62 Health and Academic Achievement

withdrawal syndrome [20].

MA abuse represents a serious public health issue associated with a high likelihood of relapse. By 2008, nearly 25 million people worldwide were estimated to have used MA, with abuse being among younger age groups [18]. MA used is mainly for recreational purposes and it is known to induce a variety of desirable effects, including increased energy levels, positive mood, euphoria, reduced appetite, weight loss, enhanced mental acuity and social and sexual disinhibition [19]. In addition, MA-dependent individuals often claimed enhancement of cognitive function and ability to focus following drug administration. However, this drug induces long-term changes in the brain structure and function, changes in synaptic plasticity, cell death via apoptosis and neurotoxicity, and consequently, it causes dependence and

Anatomically, MA has a preferential neurotoxic effect on the frontostriatal systems that contributes to both emotion dysregulation and neurocognitive impairment [21]. For instance, MA addicts showed impaired performance on tests of cognitive flexibility, which measures the ability to modify behavior when presented with new information or changing outcomes. These deficits may impair MA addicts from altering their habitual drug abuse behavior, leading to an inability to initiate abstinence or resist relapse [22]. Cellular mechanism of this MA impairment has been associated with long-term downregulation of dopamine transporters, suggesting that there are structural changes in some of the dopamine nerve terminals [23]. Other findings suggest that MA use causes changes in the metabolism of the insula and striatum [24]. In a study in humans, MA-dependent participants had significantly lower results than control participants on memory tasks, including prospective memory and visual memory [25]. Accordingly, studies in young adult MA abusers have shown impaired verbal ability, deficits in psychomotor processing [26], reasoning deficits reflecting problematic decision-

The evidences pointed that acute administration of MA improves cognitive functions, while

Cocaine has long been one of the most common recreational stimulants, especially for adolescents. A recent estimate indicates that half a million of United States habitants use this drug weekly; in this sense, cocaine addiction represents a substantial burden for societies worldwide, linked to adverse outcomes such as violence, suicide and disability, as well as high rates of chronic relapse [28]. In the brain, crack cocaine use has been shown to cause toxic effects, particularly in the prefrontal cortex. These abnormalities are associated with neuropsychological impairments. Abundant evidence has shown that cocaine withdrawal induces memory decline after its chronic use. It has been reported that chronic cocaine users showed significant harm on verbal memory and fluency as well as deficits in cognitive flexibility, but not in spatial memory, after acute withdrawal. Further, Briand and colleagues observed that object recognition was disturbed after withdrawal from chronic exposure to cocaine by an object recognition task in 2-week abstinent rats [29]. Several reports have shown that the insular and prefrontal cortices, involved in cognitive control, show reduced activity on selective attention and inhibitory

making abilities as well as retrospective memory task impairment [27].

chronic consumption of MA deteriorates them.

**2.3. Cocaine**

Adolescence is the critical period for initiation of alcoholic beverage consumption. Epidemiologic studies reveal that alcohol use is remarkably common among teenagers, with increasing rates of alcohol abuse in the US including heavy episodic drinking [33]. After alcohol and tobacco, marijuana is the social drug most frequently consumed by this cohort. Additionally, a high percentage of alcohol abusers also consume marijuana [34]. Several studies have shown that both alcohol and marijuana tend to alter the structure and function of the brain and are associated with impaired decision-making, memory and impulsivity in young adults and adolescents (**Table 1**).

## **3.1. Ethanol**

Evidence shows a direct correlation between early onset of alcohol intake and alcohol-related problems in adulthood, suggesting that adolescent exposure to the reinforcing properties of this drug increases the probability of its abuse later [35]. However, as for other addictive substances, the effect of exposure to alcohol depends to a great extent on how much and for how long it is consumed.

Acute alcohol intake has a biphasic effect on brain activity, causing excitation and euphoria at low blood concentration and depression as it increases [36]. However, regarding cognitive functions, experimental data have been inconsistent using a variety of cognitive tests. Thus, low or moderate doses of alcohol, relative to placebo, produced facilitation [37, 38], deficits [39] or no change [40] in memory performance at subtoxic amounts (<65 mg/dl). Moreover, it apparently does not produce adverse effects and may even slightly improve working memory in nonproblem drinkers, regardless of sex [41]. However, as the dose of alcohol increases, confusion, loss of awareness and selective attention begin to occur, significantly diminishing the execution of working memory and its long-term consolidation. The effect of alcohol on long-term memory formation is much greater than its impact on the capacity to remember previously consolidated memories or to retrieve short-term memory. It is well known that if subjects are asked to repeat newly acquired information following short delays (seconds) after its presentation while intoxicated, they often do fine [42]. Likewise, they are able to retrieve information acquired before acute intoxication. On the contrary, subjects perform very poorly using delays longer than 20 min, particularly if they are distracted between the stimulus presentation and testing [43].

As studies indicate that the extent of alcohol-induced memory deficits increases with the dose but maintains the same pattern (i.e., greater difficulty at forming new long-term memories than recalling the existing ones), it appears that this drug mostly affects memory consolidation.

and prevailing memory deficits. We will further discuss the present state of knowledge on such questions as how is it that cannabis consumption can affect memory? Is memory homogenously affected or are there certain types of memory more impaired? Also, if cannabis intake during

Influence of Drugs on Cognitive Functions http://dx.doi.org/10.5772/intechopen.71842 65

First, as for the acute effects of marijuana consumption, impaired working memory during the acute phase of cannabis intoxication has been observed in several studies [55, 56]. For instance, randomized clinical trials with dronabinol, a synthetic derivate of THC, revealed impaired verbal fluency, working memory and executive functions in healthy subjects during and in the hours following intoxication [57]. On the other hand, other works on healthy subjects found that performance on verbal working memory was left unaffected but that the tasks elicited a higher activation of parahippocampal areas, which may indicate either "neurophysiological inefficiency" or alternate/compensatory neural mechanisms in these subjects [58]. This is consistent with another fMRI study that was conducted on otherwise healthy adults that were current marijuana users and that showed hyperactivation during a verbal working memory challenge, which the authors suggest may be related to suboptimal efficiency during cognitive challenge in this group [59]. Finally, another study by the same group showed that the frequency of cannabis use is positively correlated to blood oxygenation level–dependent signal in the left parahippocampal gyrus during a visual associative memory task, regardless

But beyond the acute intoxication phase, one obvious question is whether cannabis consumption produces long-term sequelae on cognition. Working memory performance appears to be especially sensitive to cannabis consumption in the early teenage years (before the age of 16–17). Testing 122 long-term heavy cannabis users on a corroborated 28-day abstinence period and 87 control subjects, Pope and collaborators showed that although adult-onset cannabis users hardly differed from controls, those that started before the age of 17 were impaired in a series of cognitive tests, most especially in verbal memory [61]. Further research has shown that the observed cannabis-induced deficits may prevail even after 6 weeks of discontinuation; although after 3 months of complete discontinuation, no difference was observed between previous heavy users and controls [62]. However, a more recent study in adolescents 18–20 years old with a history of chronic, heavy cannabis use, while performance in a verbal memory test was comparable to that of age-matched controls, a significant bilateral atrophy was observed, even after 6 months of supervised drug abstinence [63]. The putative detrimental effects of cannabis use appear to be dose-dependent. For example, performance in the Rey Auditory Verbal

Learning Test correlated negatively with the number of years of cannabis misuse [64].

therefore made them less prone to develop these cognitive skills through adulthood.

However, these results did not allow to determine whether cannabis had long-term detrimental effects on the cognitive abilities and brain functioning of these youths once they reached adulthood or whether a preexisting set of slight cognitive deficiencies such as lower verbal memory somewhat predisposed these youths to maladaptive behaviors including earlyonset cannabis consumption. More to the point, as the authors pointed out, even if the toxic effects of cannabis were the culprit, it was impossible to determine in the light of these results, whether the observed differences were due to long-term effects of cannabis on these subjects or more short-term effects during adolescence that made them perform poorly at school and

adolescence affects brain function in the long-term, are such sequelae reversible?

of the age of onset (early vs. late adolescence) [60].

Unfortunately, during adolescent life, repeated intoxication with high doses of alcohol becomes more frequent and memory impairments are more profound, commonly resulting in blackouts, that is, a complete incapability to remember all or part of a drinking event [44]. Heavy alcohol drinking associated with blackouts [45] does not necessarily involve loss of consciousness, but rather a failure to transfer information from short- to long-term memory [46]. Individuals with a history of blackouts show episodic memory impairments while intoxicated [47], particularly at retrieving the spatiotemporal context of events [48]. Moreover, longterm (3 years) heavy alcohol intake in adolescents between 15 and 19 years of age induced memory deficits [49] as well as volume reduction in subcortical and temporal regions [50].

The mechanisms underlying alcohol-induced memory disruption are still elusive. Throughout several decades, it was supposed that alcohol produces a nonspecific general depression of brain activity. Later, research led to assumption that alcohol depressed the activity of neurons by altering the fluidity of the neuronal membrane and consequently the activity of proteins, including ion channels that might, in turn, produce synaptic dysfunctions [51].

It was not until recently that new pharmacological information regarding the effects of alcohol on neural cells revealed that this drug has actually very selective effects on various neurotransmitter systems, both excitatory, e.g., glutamatergic and cholinergic, and inhibitory, such as GABAergic, glycinergic and serotonergic among others. Alcohol could alter the activity of specific receptor subtypes as well [52]. All these neurotransmission mechanisms have a deep impact on cognitive functions. Paradoxically, repeated alcohol exposure might promote the formation of a particular drug-reward–associated implicit memory that could underlay its addiction [53].

The main risk of alcohol ingestion early in life is that the adolescent brain is still in a maturation period and drug intoxication greatly affects its development and the individual's future life.

#### **3.2. Cannabis**

Recently, endocannabinoids, endogenous ligands that bind to and activate the same receptors as 9-delta-tetrahydrocannabinol (THC), the psychoactive component of cannabis, were found to play an important role in the diminution of gray matter [3]. Cannabis is the third most prevalent drug of abuse among teenagers, behind alcohol and tobacco [54]. Many studies in humans have shown that chronic cannabis consumption, especially when initiated early in life, correlates with a range of cognitive impairments in adulthood, including learning and memory deficits. Meanwhile, the evidence remained equivocal, partly due to the myriad of confounding factors, characteristic of human studies, as well as different methodology employed by the distinct studies, some unveiling clear effects, while others finding marginal or no effects [55]. However, in recent years, a clearer picture is emerging, which seems to suggest that teenage cannabis consumption may indeed have long-term detrimental effects on cognitive processes, including memory. The present section surveys the evidence linking adolescent cannabis consumption and prevailing memory deficits. We will further discuss the present state of knowledge on such questions as how is it that cannabis consumption can affect memory? Is memory homogenously affected or are there certain types of memory more impaired? Also, if cannabis intake during adolescence affects brain function in the long-term, are such sequelae reversible?

As studies indicate that the extent of alcohol-induced memory deficits increases with the dose but maintains the same pattern (i.e., greater difficulty at forming new long-term memories than recalling the existing ones), it appears that this drug mostly affects memory consolidation.

Unfortunately, during adolescent life, repeated intoxication with high doses of alcohol becomes more frequent and memory impairments are more profound, commonly resulting in blackouts, that is, a complete incapability to remember all or part of a drinking event [44]. Heavy alcohol drinking associated with blackouts [45] does not necessarily involve loss of consciousness, but rather a failure to transfer information from short- to long-term memory [46]. Individuals with a history of blackouts show episodic memory impairments while intoxicated [47], particularly at retrieving the spatiotemporal context of events [48]. Moreover, longterm (3 years) heavy alcohol intake in adolescents between 15 and 19 years of age induced memory deficits [49] as well as volume reduction in subcortical and temporal regions [50].

The mechanisms underlying alcohol-induced memory disruption are still elusive. Throughout several decades, it was supposed that alcohol produces a nonspecific general depression of brain activity. Later, research led to assumption that alcohol depressed the activity of neurons by altering the fluidity of the neuronal membrane and consequently the activity of proteins,

It was not until recently that new pharmacological information regarding the effects of alcohol on neural cells revealed that this drug has actually very selective effects on various neurotransmitter systems, both excitatory, e.g., glutamatergic and cholinergic, and inhibitory, such as GABAergic, glycinergic and serotonergic among others. Alcohol could alter the activity of specific receptor subtypes as well [52]. All these neurotransmission mechanisms have a deep impact on cognitive functions. Paradoxically, repeated alcohol exposure might promote the formation of a particular drug-reward–associated implicit memory that could underlay

The main risk of alcohol ingestion early in life is that the adolescent brain is still in a maturation period and drug intoxication greatly affects its development and the individual's future life.

Recently, endocannabinoids, endogenous ligands that bind to and activate the same receptors as 9-delta-tetrahydrocannabinol (THC), the psychoactive component of cannabis, were found to play an important role in the diminution of gray matter [3]. Cannabis is the third most prevalent drug of abuse among teenagers, behind alcohol and tobacco [54]. Many studies in humans have shown that chronic cannabis consumption, especially when initiated early in life, correlates with a range of cognitive impairments in adulthood, including learning and memory deficits. Meanwhile, the evidence remained equivocal, partly due to the myriad of confounding factors, characteristic of human studies, as well as different methodology employed by the distinct studies, some unveiling clear effects, while others finding marginal or no effects [55]. However, in recent years, a clearer picture is emerging, which seems to suggest that teenage cannabis consumption may indeed have long-term detrimental effects on cognitive processes, including memory. The present section surveys the evidence linking adolescent cannabis consumption

including ion channels that might, in turn, produce synaptic dysfunctions [51].

its addiction [53].

64 Health and Academic Achievement

**3.2. Cannabis**

First, as for the acute effects of marijuana consumption, impaired working memory during the acute phase of cannabis intoxication has been observed in several studies [55, 56]. For instance, randomized clinical trials with dronabinol, a synthetic derivate of THC, revealed impaired verbal fluency, working memory and executive functions in healthy subjects during and in the hours following intoxication [57]. On the other hand, other works on healthy subjects found that performance on verbal working memory was left unaffected but that the tasks elicited a higher activation of parahippocampal areas, which may indicate either "neurophysiological inefficiency" or alternate/compensatory neural mechanisms in these subjects [58]. This is consistent with another fMRI study that was conducted on otherwise healthy adults that were current marijuana users and that showed hyperactivation during a verbal working memory challenge, which the authors suggest may be related to suboptimal efficiency during cognitive challenge in this group [59]. Finally, another study by the same group showed that the frequency of cannabis use is positively correlated to blood oxygenation level–dependent signal in the left parahippocampal gyrus during a visual associative memory task, regardless of the age of onset (early vs. late adolescence) [60].

But beyond the acute intoxication phase, one obvious question is whether cannabis consumption produces long-term sequelae on cognition. Working memory performance appears to be especially sensitive to cannabis consumption in the early teenage years (before the age of 16–17). Testing 122 long-term heavy cannabis users on a corroborated 28-day abstinence period and 87 control subjects, Pope and collaborators showed that although adult-onset cannabis users hardly differed from controls, those that started before the age of 17 were impaired in a series of cognitive tests, most especially in verbal memory [61]. Further research has shown that the observed cannabis-induced deficits may prevail even after 6 weeks of discontinuation; although after 3 months of complete discontinuation, no difference was observed between previous heavy users and controls [62]. However, a more recent study in adolescents 18–20 years old with a history of chronic, heavy cannabis use, while performance in a verbal memory test was comparable to that of age-matched controls, a significant bilateral atrophy was observed, even after 6 months of supervised drug abstinence [63]. The putative detrimental effects of cannabis use appear to be dose-dependent. For example, performance in the Rey Auditory Verbal Learning Test correlated negatively with the number of years of cannabis misuse [64].

However, these results did not allow to determine whether cannabis had long-term detrimental effects on the cognitive abilities and brain functioning of these youths once they reached adulthood or whether a preexisting set of slight cognitive deficiencies such as lower verbal memory somewhat predisposed these youths to maladaptive behaviors including earlyonset cannabis consumption. More to the point, as the authors pointed out, even if the toxic effects of cannabis were the culprit, it was impossible to determine in the light of these results, whether the observed differences were due to long-term effects of cannabis on these subjects or more short-term effects during adolescence that made them perform poorly at school and therefore made them less prone to develop these cognitive skills through adulthood.

In this regard, a recent widely reaching analysis from the Cannabis Cohorts Research Consortium using data from three distinct longitudinal studies started to shed light on this issue [57]. The study found that young adults that were cannabis users as teenagers were more likely to experience adverse outcomes as diverse as cannabis addiction, suicide attempt and highschool dropout. Importantly, the authors report that controlling for the potential confounding factors present, both before and during adolescence and spanning individual, parental and peer factors, failed to abolish most of the associations observed. Along with the fact that they also observed a dose-response relation, heavy users having the poorest outcomes as adults, the findings support the hypothesis that teenage marijuana consumption has long-term detrimental effects on cognition, memory and general well-being. Finally, preclinical research brought further support for a causal relationship between teenage cannabis consumption and adult cognitive impairments; chronic consumption of cannabis in rats during adolescence, but not adulthood, impaired spatial working memory when tested as adults [65, 66].
