Background
Methamphetamine (MA) is a potent psychoactive substance which produces acute stimulating effects and can be consumed via oral ingestion, insufflation, smoking, or intravenous and intramuscular injection [
1]. While some individuals use MA in a recreational manner, a large proportion of chronic users develops a stimulant use disorder – methamphetamine type (MUD). For example, in 2012, 1.2 million adults in the U.S.A used MA, of which 44% (535.000) fulfilled the criteria for a MUD [
2]. The chronic use of MA, as seen in patients with MUD, is associated with numerous psychological side effects, such as insomnia, agitation, paranoia, acute psychosis, anxiety, and depressive states [
3‐
5]. Furthermore, regular adult MA use was demonstrated to induce mild cognitive impairment [
6] and the presence of a MUD seems to be associated with impaired impulsivity, social cognition, verbal learning, and working memory [
7].
While a large number of MA users are adults, adolescent use is widespread as well. In Europe, the prevalence of MA use in high school students (15–16 years) is highest in Poland and Cyprus, with 2.4 and 2.5% respectively, while in Germany prevalence of MA use is estimated to be around 0.7% [
8]. Like adult users, adolescent MA users show high rates of psychiatric symptoms [
4,
9], especially depressive states [
10], anti-social behaviour [
11], and seem to retain psychiatric problems after prolonged abstinence [
12].
In addition to comorbid psychiatric problems, a MUD in adolescence is associated with changes in brain structure and functioning. Specifically, adolescent MA users show reduced levels of n-acetylaspartic acid (NAA) in the prefrontal cortex (PFC), which indicates reduced neuronal integrity [
13] and metabolic functioning of the PFC [
14]. These brain changes might specifically influence cognitive performance, since lower levels of NAA in the frontal cortex have been shown to be related to reduced attention [
15], executive functioning [
16], and memory [
17]. Additionally, the influence of MA use on the PFC could be particularly damaging in adolescence, since the PFC is still developing [
18]. By interfering with this maturation process, MA use might disrupt the normal increase in inhibitory control or memory performance seen during adolescent development [
19,
20].
Even though various lines of evidence point towards adolescent MA use being associated with cognitive impairments, few studies directly investigated cognitive functioning among adolescents with MUD [
14,
21‐
23]. King et al. [
22] found adolescents with a MUD show reduced performance in tasks related to inhibitory control, task-switching, spatial organization and fine motor speed [
22]. Similarly, Cuzen et al. [
21] found significant impairments in the domain of self-monitoring related to adolescent MA use [
21]. On the other hand, Lyoo et al. [
23] failed to detect significant differences in cognitive performance between MA and non-MA using adolescents. However, Kim et al. [
14] used the same dataset and found MA-using adolescents to perform worse than non-using adolescents specifically in the Stroop task.
In conclusion, in adolescent MA users with MUD, only executive functions like inhibition and self-monitoring were consistently found to be impaired compared to non-MA using adolescents. However, these findings are in stark contrast to research with adults with MUD, who consistently show impairments in verbal learning, verbal memory, and short-term memory in addition to executive functions [
6,
7,
24]. To further investigate what specific cognitive impairments are associated with MA use and MUD in adolescence we conducted the present study. Building upon previous studies [
14,
21‐
23] we matched one sample of adolescents with a MUD, with one sample of adolescents with other SUDs, and one sample of adolescents without SUDs on age, gender, and depressivity. Those with MUD or SUD were additionally matched regarding their use of substances other than MA, i.e. cannabis, alcohol, and other stimulants (amphetamine or 3,4-methylendioxymethamphetamine (MDMA)). Additionally, we aimed to investigate how MA use frequency is associated with cognitive performance.
Discussion
In this cross-sectional study, we compared a group of adolescents with MUD with a group without MUD matched for depressivity, age, gender, and other substance use. Additionally, we compared both groups with adolescents without past-year substance use or SUDs, matched for depressivity, age and gender. We could show that adolescents with a MUD showed a reduced performance in trial 5 of the VLMT, indicating lower verbal learning ability. Additionally, a larger number of MA use days per month was associated with reduced performance in VLMT trials 1 and 5, indicating a negative association with short-term memory and verbal learning ability respectively. The negative relationship between performance in trial 5 and MA use was confirmed by the significant negative correlation, as well as medium to large differences between the MA and noMA group as well as the MA group and noSUD group.
Our results are in line with research in adult MUD patients in which medium sized negative effects are found for verbal learning and verbal memory [
7]
. Specifically, previous studies in adults also associated MA use with learning impairments in an auditory verbal learning task (AVLT) [
37‐
40]. Further, Hoffman et al. [
37] found a significant negative association between MA use and performance on the first trial of an AVLT as well, which supports the finding of our correlational analysis. Two biological processes related to MA use might explain the effects of MA use on verbal memory performance. First, regular use of MA seems to diminish functionality of n-methyl-d-aspartate (NMDA) and quisqualate (AMPA) receptors in the striatum and frontal cortex through an MA-induced increase of glutamate flow [
41]. These effects [
41,
42], in addition to the MA-induced dysfunction of NAA in the PFC [
13,
14], might play a role in the observed verbal learning deficits, since normal PFC development is related to increases in memory performance [
17,
18]. Additionally, high doses of MA have been shown to lead to neuronal damage in the mouse hippocampus [
43], which is a region strongly involved in memory processing [
44].
Second, MA use is associated with reduced density of the dopamine transporter [
45], which is directly related to memory impairments, specifically in an AVLT [
39]. Volkow et al. [
39] used PET scanning to show that the presence of a MUD is related to decreased dopamine transporter availability in the striatum, which was directly related to verbal learning impairment. Whereas the loss of dopamine transporters seems to recover with MA abstinence, verbal learning ability has shown no such recovery in adults [
46].
While consistent with findings in adult MA users, our results oppose previous studies in adolescents [
21‐
23]. All three studies also used an AVLT to assess memory performance but detected no significant differences between MA using and non-using groups [
21‐
23]. However, we detected a medium-sized negative effect for verbal learning performance and significant negative associations between MA use and short-term memory as well as verbal learning. A possible explanation for this difference in results might be the selection of outcome variables. We used three specific variables from the VLMT on which to compare participants and in doing so focused on specific aspects of verbal memory (short-term memory, learning ability, cued recall). In contrast, Lyoo et al. [
23], and Cuzen et al. [
21], calculated new variables across several tests to compare groups on global domain scores. If they had included comparisons between singular variables, focusing on specific aspects of verbal memory instead of the global domain, similar differences as we found might have emerged. Additionally, King et al. [
22] sampled adolescent with a MUD that were abstinent for several months at the time of testing. While abstinence-related recovery of memory performance has not been shown for adults [
46,
47], no investigations in adolescent users have been conducted. It is possible, that the abstinent adolescent MA users had already recovered memory performance at the time of testing. However, we cannot be sure if the difference in memory outcomes is due to a possible recovery effect or that King et al. [
22] did not control for use of other stimulant-type drugs (e.g., amphetamine or MDMA). Especially the second aspect is important, since use of other stimulant-type drugs has also been shown to be related to impairments in verbal memory [
48].
Another discrepancy to previous research relates to inhibitory performance. Four previous investigations with adolescents [
14,
21‐
23] found a negative effect of MA use on inhibitory control and self-monitoring, while we did not. One explanation for the discrepancy could be test selection. All studies with adolescents [
14,
21‐
23] as well as the majority of adult studies [
24] assessed inhibition with the Stroop task, while we used a go/noGo task. Even though both tests load on an factor related to inhibition [
49], the Stroop task is mainly a measure of taking control over an interference effect, while the go/noGo task measures the inhibition of an activated motor response [
50]. Thus, the combination of previous research in adolescents and our results indicates that MA use in adolescents might be uniquely related to impairments in interference control, rather than pure response inhibition.
Limitations
First, we recruited a small sample, which constrains the generalizability of our results. Nonetheless, sample sizes of this magnitude are common in studies dealing with MUD patients, e.g. 9 of the 17 studies investigating cognitive functioning in MA users included in the review by Scott et al. [
24] had groups of MA users with
n < 20. Furthermore, we took great care to control for various confounding factors by applying an extensive matching procedure.
Second, our sample consisted of adolescents with MUD that consumed other psychoactive substances on a regular basis. On one hand, this is an accurate representation of the reality of adolescent MA users and we took great effort to match the groups on their substance use. On the other hand, combining MA use with other substances might have additive detrimental effects on cognitive performance over and above MA use on its own. For example, Cuzen et al. [
21] showed that users of MA and cannabis showed stronger cognitive deficits, than exclusive MA users. Third, we did not record the time of abstinence since last MA use. Since, it might be possible that cognitive effects recuperate after MA abstinence (see [
22,
51]), future longitudinal studies need to control for this variable.
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