Methylphenidate In Adolescents Research Articles

What are the benefits and harms of methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder? A Cochrane Review summary with commentary.

What are the benefits and harms of methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder? A Cochrane Review summary with commentary.

Methylphenidate and Sleep Difficulties in Children and Adolescents With ADHD: Results From the 2-Year Naturalistic Pharmacovigilance ADDUCE Study

Objective: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. Methods: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children’s-Sleep-Habits-Questionnaire (CSHQ). Results: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. Conclusion: Our findings support that sleep-problems are common in ADHD, but don’t suggest significant negative long-term effects of MPH on sleep.

Effects of adolescent methylphenidate administration on methamphetamine conditioned place preference in an animal model of attention-deficit/hyperactivity disorder: Examination of potential sex differences

BackgroundIndividuals with attention-deficit/hyperactivity disorder (ADHD) are more likely to be diagnosed with a substance use disorder; however, the effects of long-term psychostimulant treatment on addiction are mixed. Preclinical studies are useful for further elucidating the relationship between ADHD and addiction-like behaviors, but these studies have focused on male subjects only. The goal of the current study was to determine if early-life administration of methylphenidate (MPH) augments methamphetamine (METH) conditioned place preference (CPP) and/or potentiates reinstatement of CPP in both male and female rats. MethodsMale and female spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) received either MPH (1.5mg/kg; p.o.) or vehicle (1.0ml/kg) during adolescence (postnatal day [PND] ~29–57). Two weeks after cessation of MPH treatment, rats were tested for METH CPP (1.0mg/kg or 2.0mg/kg; s.c.). Rats were then given extinction sessions. Once rats met extinction criteria, they were tested for reinstatement of CPP following a priming injection of METH (0.25mg/kg; s.c.). ResultsAll groups developed METH CPP, except vehicle-treated SHR males and vehicle-treated WKY females conditioned with the higher dose of METH (2.0mg/kg). Female SHRs treated with MPH showed greater reinstatement of METH CPP compared to female SHRs treated with vehicle. Adolescent MPH treatment did not augment the locomotor-stimulant effects of METH in adulthood. ConclusionsThese results demonstrate the importance of considering biological sex when prescribing psychostimulant medications for ADHD as long-term MPH administration may increase the risk of continued drug use in females with ADHD following a period of abstinence.

The long-term use of methylphenidate in children and adolescents

The long-term use of methylphenidate in children and adolescents

What are the benefits and harms of methylphenidate in children and adolescents with attention deficit hyperactivity disorder (ADHD)?

What are the benefits and harms of methylphenidate in children and adolescents with attention deficit hyperactivity disorder (ADHD)?

Long-term safety of methylphenidate in children and adolescents with ADHD: 2-year outcomes of the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study

Methylphenidate is the most frequently prescribed medication for the treatment of ADHD in children and adolescents in many countries. Although many randomised controlled trials support short-term efficacy, tolerability, and safety, data on long-term safety and tolerability are scarce. The aim of this study was to investigate the safety of methylphenidate over a 2-year period in relation to growth and development, psychiatric health, neurological health, and cardiovascular function in children and adolescents. We conducted a naturalistic, longitudinal, controlled study as part of the ADDUCE research programme in 27 European child and adolescent mental health centres in the UK, Germany, Switzerland, Italy, and Hungary. Participants aged 6-17 years were recruited into three cohorts: medication-naive ADHD patients who intended to start methylphenidate treatment (methylphenidate group), medication-naive ADHD patients who did not intend to start any ADHD medication (no-methylphenidate group), and a control group without ADHD. Children with ADHD diagnosed by a qualified clinician according to the DSM-IV criteria and, in the control group, children who scored less than 1·5 on average on the Swanson, Nolan, and Pelham IV rating scale for ADHD items, and whose hyperactivity score on the parent-rated Strengths and Difficulties Questionnaire was within the normal range (<6) were eligible for inclusion. Participants were excluded if they had previously taken any ADHD medications but remained eligible if they had previously taken or were currently taking other psychotropic drugs. The primary outcome was height velocity (height velocity SD score; estimated from at least two consecutive height measurements, and normalised with reference to the mean and SD of a population of the same age and sex). Between Feb 01, 2012, and Jan 31, 2016, 1410 participants were enrolled (756 in methylphenidate group, 391 in no-methylphenidate group, and 263 in control group). 1070 (76·3%) participants were male, 332 (23·7%) were female, and for eight gender was unknown. The average age for the cohort was 9·28 years (SD 2·78; IQR 7-11). 1312 (93·0%) of 1410 participants were White. The methylphenidate and no-methylphenidate groups differed in ADHD symptom severity and other characteristics. After controlling for the effects of these variables using propensity scores, there was little evidence of an effect on growth (24 months height velocity SD score difference -0·07 (95% CI -0·18 to 0·04; p=0·20) or increased risk of psychiatric or neurological adverse events in the methylphenidate group compared with the no-methylphenidate group. Pulse rate and systolic and diastolic blood pressure were higher in the methylphenidate group compared with the no-methylphenidate group after 24 months of treatment. No serious adverse events were reported during the study. Our results suggest that long-term treatment with methylphenidate for 2 years is safe. There was no evidence to support the hypothesis that methylphenidate treatment leads to reductions in growth. Methylphenidate-related pulse and blood pressure changes, although relatively small, require regular monitoring. EU Seventh Framework Programme.

Observing the behavioural effects of methylphenidate in children and adolescents with ASD-ADHD dual diagnosis: A mini review

Research aimThe aim of this study is to focus on the main neurophysiological aspects of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) and the current pharmacological treatment used for the management of hyperactivity and attention deficits in children aged 6-20 years with a diagnosis of ASD, not associated with other genetic or epileptic disorders, such as Fragile X Syndrome (FXS), Tuberous Sclerosis, Kleefstra Syndrome or Angelman Syndrome.MethodsThis mini review was conducted according to the P.I.C.O. model and according to the PRISMA guidelines. The keywords used were: autism spectrum disorder; attention deficit hyperactivity disorder; attention deficit disorder; methylphenidate; ritalin; ADHD; youth autism; childhood autism; childhood autism spectrum disorder; adolescent autism. The strings produced were compared and selected by a third independent clinician. The PubMed and PsycArticles search yielded a total of 3,200 articles. For their inclusion, the 3,200 articles were examined by two clinicians who ultimately selected 28 (15 clinical trials and 13 reviews/meta-analyses) articles analysed according to their consistency with the inclusion and exclusion criteria.ConclusionsThree main aspects emerged from the review: (1) According to the existing literature, new randomized controlled trials are needed to ensure a better understanding of the most effective drug treatments for dual-diagnosed ASD-ADHD patients and of the related behavioural effects. Currently, the use of drugs varies depending on psychiatric comorbidity, symptoms, age and gender and there is no univocal reference therapy; (2) Methylphenidate (MPH) has currently been shown to be the most suitable drug for the treatment of hyperactivity and inattention in individuals diagnosed with ASD and ADHD; (3) There is a need to create and evaluate appropriate tests to analyse more specific patterns of behaviour presented in the two conditions.

Dose titration of osmotic release oral system methylphenidate in children and adolescents with attention-deficit hyperactivity disorder: a retrospective cohort study

BackgroundOsmotic release oral system methylphenidate (OROS-MPH) is one of the most commonly used medication for attention-deficit hyperactivity disorder (ADHD), however, real-world knowledge on OROS-MPH dose titration has been limited. This study aims to summarize and visualise the OROS-MPH titration patterns in children and adolescents with ADHD in the United States (US) and Japan.MethodsThis retrospective cohort study used the US IBM® MarketScan® Commercial Claims and Encounters database from 2000 to 2019 and the Japan Medical Data Centre database from 2008 to 2019. New OROS-MPH users with ADHD were identified and split into child (6 to < 13 years) and adolescent (13 to < 18 years) groups according to age at OROS-MPH initiation/reinitiation. Patient characteristics and OROS-MPH treatment patterns were described. OROS-MPH dose titration pathways were visualised by Sankey diagrams.ResultsWe included 98,973 children and 62,002 adolescents in the US cohort, and 4595 children and 1508 adolescents in the Japanese cohort. In Japanese cohort, 91.9% of children and 77.9% of adolescents initiated OROS-MPH at the lowest dose (18 mg/day), whereas US patients had a broader distribution of initial doses (e.g., 18–54 mg/day). The US patients had higher daily dose of OROS-MPH than Japanese patients. Overall, a minority (< 40%) of the OROS-MPH users underwent dose titration, and different titration patterns were observed between the US and Japanese patients.ConclusionsDifferent treatment and titration patterns of OROS-MPH were observed in the two countries. Additional real-world studies about clinical reasoning underlying dose selection are needed to support clinical decision-making.

Fronto-Cerebellar Neurometabolite Alterations After Methylphenidate in Children and Adolescents With ADHD: A Proton Magnetic Resonance Spectroscopy Study

Objective: The fronto-cerebellar circuit is involved in ADHD pathophysiology. Methylphenidate, as a first-line medication for ADHD, affects different brain regions, however, its effect on the fronto-cerebellar circuit is not investigated sufficiently. We aimed to investigate the effect of 8-week treatment with methylphenidate on neurometabolite ratios in the fronto-cerebellar circuit in ADHD participants using magnetic resonance spectroscopy (MRS). Methods: Fifteen drug-naïve ADHD children and adolescents were enrolled in the present study. Two single-voxel MR spectra were acquired from the right dorsolateral prefrontal cortex (DLPFC) and left Crus 1, before and after the medication. Also, neuropsychological and behavioral assessments were administered. Results: After medication, the glutamate/creatine in the DLPFC and the choline/creatine in the Crus 1 decreased in the ADHD participants. Conclusion: These findings propose that methylphenidate-induced metabolite changes in the fronto-cerebellar circuit could be associated with improvement in cognitive/behavioral characteristics in ADHD. Also, results highlighted cerebellar engagement in ADHD pathophysiology.

Methylphenidate cross-sensitization with amphetamine is dose dependent but not age dependent

Psychostimulants such as methylphenidate (MPD) and amphetamine (AMP) are often prescribed to young children and adolescents to treat behavioral disorders, or used to improve their intellectual performance in our competitive society. This is concerning as the temporal effects of how MPD exposure at a young age influences the response to MPD and AMP administration later in adulthood remains unclear. The objective of this study was to test whether MPD has the characteristics of substances that elicit behavioral symptoms of dependence and whether those effects are influenced by the initial age of MPD exposure. Three control and nine experimental groups of male rats were used. They were exposed to repetitive (chronic) 0.6, 2.5, or 10.0 mg/kg MPD in adolescence only, adulthood only, or adolescence and adulthood respectively. Then all groups were subsequently re-challenged with a single AMP dose in adulthood to test whether cross-sensitization between MPD and AMP was expressed, potentially as a result of prior MPD consumption. Exposure to 2.5 mg/kg and 10.0 mg/kg MPD in adolescence and adulthood or in adulthood alone led to cross-sensitization with AMP while exposure to 0.6 mg/kg MPD in adolescence and adulthood or in adulthood alone did not lead to cross-sensitization with AMP. Thus, these results indicate that MPD cross-sensitization with AMP is dose dependent.

A Study of Safety and Efficacy of Methylphenidate in Children and Adolescents: An Observational Clinical Study

A Study of Safety and Efficacy of Methylphenidate in Children and Adolescents: An Observational Clinical Study

A Study of Safety and Efficacy of Methylphenidate in Children and Adolescents: An Observational Clinical Study

A Study of Safety and Efficacy of Methylphenidate in Children and Adolescents: An Observational Clinical Study

The effect of environment on cross-sensitization between methylphenidate and amphetamine in female rats

Methylphenidate (MPD) and amphetamine (AMP) are both psychostimulants that are often used to treat behavioral disorders. More recently, it has also been increasingly used illicitly for recreation as well as to improve intellectual performance. Many factors such as age, gender, genetic background, and environment govern the development of behavioral sensitization to MPD and cross-sensitization with other drugs, which are experimental behavioral markers indicating potential of substance dependence and abuse. This study examines the effects of the environment and age when MPD was exposed in adulthood alone as well as in adolescence into adulthood on cross-sensitization with AMP in female SD rats by randomizing animals to either receive the drug in a home cage or a test cage during adolescence, adulthood, or both. In a 34 day experiment, 16 groups of animals starting in adolescence were treated with saline on experimental day one (ED1), followed by a 6 day (ED2-ED7) treatment with either saline, 0.6 mg/kg AMP, 0.6, 2.5, or 10.0 mg/kg MPD. Experimental groups were then subject to a 3-day washout period (ED8-ED10) and then a retreatment with the respective drug on ED11 in adolescence (P-38 to P-49). Experiments continued in the same animal groups now in adulthood (P-60) with a saline treatment (ED1), followed by the same sequence of treatments in adolescence (ED2-ED11;P-61 to P-69). A rechallenge with the same AMP or MPD dose was performed on ED11 (P-70) followed by a single exposure to 0.6 mg/kg AMP on ED12 (P-71) to assess for cross sensitization between MPD and AMP. Animals treated with MPD in both adolescence and adulthood and in the last experimental day of AMP (ED12) showed higher intensity of cross-sensitivity between MPD and AMP as compared to animals treated with MPD only in adulthood. AMP and MPD treatment in adolescence and into adulthood in the home or test cage resulted in significantly higher responses to the drug as compared to those treated only in adulthood. Overall, we conclude that environmental alteration and adolescent exposure to MPD appeared to increase the risk of cross-sensitization to AMP in female SD rats i.e, using MPD in adolescence may increase the probability of becoming dependent on drugs of abuse. This further indicates that age, sex, and environment all influence the response to MPD and AMP, and further work is needed to elucidate the risks associated with MPD and AMP use.

Acute Hyperkinetic Movement Disorders as a Multifactorial Pharmacodynamic Drug Interaction Between Methylphenidate and Risperidone in Children and Adolescents.

Acute hyperkinetic movement disorders have been reported with the concomitant use of attention-deficit/hyperactivity disorder (ADHD) stimulants and antipsychotics in children and adolescents. We analyzed postmarketing reports of suspected acute hyperkinetic movement disorder associated with concomitant use of ADHD stimulants and antipsychotics. We searched for postmarketing reports of acute hyperkinetic movement disorders associated with concomitant use of ADHD stimulants-antipsychotics in the US Food and Drug Administration Adverse Event Reporting System through December 6, 2019. PubMed and EMBASE were also searched for acute hyperkinetic movement reports with the concomitant use of ADHD stimulants-antipsychotics through January 13, 2020. We identified 36 cases resulting in acute hyperkinetic movement disorder associated with the concomitant use of ADHD stimulants-antipsychotics, 19 of which were also identified in the medical literature. From an ADHD stimulant perspective, methylphenidate products accounted for the largest number of cases (n = 23 [64%]), followed by amphetamine products (n = 9 [25%]) and atomoxetine (n = 4 [11%]). From an antipsychotic perspective, all 36 cases were reported with second-generation antipsychotics, particularly risperidone (n = 20 [56%]). Most of the cases were reported in boys (n = 31 [86%]) aged 6 to 12 years (n = 27 [75%]). Approximately 53% of the cases reported a time to onset within 24 hours of the drug change. Acute dystonic reactions (n = 27 [75%]) were the most frequently reported movement disorder. As outlined in changes to the US prescribing information for all methylphenidate and risperidone products, health care professionals should be aware that changes to this combination may be associated with a pharmacodynamic drug-drug interaction resulting in acute hyperkinetic movement disorder.

Effect of Methylphenidate on Resting-State Connectivity in Adolescents With a Disruptive Behavior Disorder: A Double-Blind Randomized Placebo-Controlled fMRI Study

Some studies suggest that methylphenidate (MPH) might be an effective treatment for antisocial and aggressive behavior in adolescence. However, little is known about the mechanism of action of MPH in adolescents with this kind of psychopathology. MPH is a dopamine and norepinephrine reuptake inhibitor and thus it is likely to affect dopaminergic mesocorticolimbic pathways. This is the first study to investigate the effect of MPH on resting-state connectivity of three mesolimbic seed regions with the rest of the brain in clinical referred male adolescents with a disruptive behavior disorder (DBD). Thirty-six male DBD adolescents and 31 male healthy controls (HCs) were included. DBD subjects were randomly allocated to a single dose of MPH (DBD-MPH, n = 20) or placebo (DBD-PCB, n = 16). Seed-based resting-state functional connectivity of the nucleus accumbens (NAcc), amygdala, and ventral tegmental area (VTA) with the rest of the brain was compared between groups. The NAcc seed showed increased connectivity in DBD-PCB compared to HC with the occipital cortex, posterior cingulate cortex (PCC), precuneus, and inferior parietal lobule (IPL) and increased connectivity in DBD-PCB compared to DBD-MPH with occipital cortex, IPL, and medial frontal gyrus. The amygdala seed showed increased connectivity in DBD-PCB compared to HC with the precuneus and PCC. The VTA seed showed increased connectivity in the DBD-MPH compared to the DBD-PCB group with a cluster in the postcentral gyrus and a cluster in the supplementary motor cortex/superior frontal gyrus. Both NAcc and amygdala seeds showed no connectivity differences in the DBD-MPH compared to the HC group, indicating that MPH normalizes the increased functional connectivity of mesolimbic seed regions with areas involved in moral decision making, visual processing, and attention.

A review of Cochrane reviews on pharmacological treatment for attention deficit hyperactivity disorder.

ABSTRACT.Attention deficit hyperactivity disorder (ADHD) is one of the most frequent childhood psychiatric problems.Objective:The objective of this study was to identify, synthesize the results, and critically evaluate all Cochrane systematic reviews (SRs) on the pharmacological interventions for children and adolescents (up to age 18) diagnosed with ADHD.Methods:The search was performed in the Cochrane Database of Systematic Reviews (via Wiley) in July 2020.Results:The search strategy resulted in four SRs of high methodological quality, analyzing 51 randomized clinical trials (9,013 participants). Compared to placebo, treatment with tricyclic antidepressants (TCAs) (desipramine), amphetamine, and methylphenidate showed improvement in symptoms such as difficulty concentrating, impulsivity, and hyperactivity in the short term (up to 6 months). There was an increase in the occurrence of adverse events, such as reduced appetite, difficulty sleeping, and abdominal pain. Insufficient evidence was found to support the effects of supplementation with polyunsaturated fatty acids.Conclusions:The use of TCAs, amphetamine, and methylphenidate in children and adolescents with ADHD seems to present positive effects and higher rates of minor adverse events when compared to placebo.

P.046 Expression of the adult ADHD-associated gene ADGRL3 is dysregulated by genetic risk variants and environmental risk factors

Attention-deficit/hyperactivity disorder (ADHD) is often comorbid with cocaine abuse. Controversy exists regarding long-term consequences of ADHD medications on cocaine abuse liability. Whereas childhood methylphenidate treatment may be preventative, methylphenidate in teens appears to further increase later cocaine abuse risk. In rodents, adolescent methylphenidate treatment further increases adult cocaine self-administration in the Spontaneously Hypertensive Rat (SHR) model of ADHD, whereas adolescent atomoxetine treatment does not. Effects of ADHD medications on cocaine cue reactivity, a critical component of addiction, are unknown.To investigate this, SHR, Wistar–Kyoto (inbred control) and Wistar (outbred control) rats received therapeutically relevant doses of methylphenidate (1.5 mg/kg, oral) and atomoxetine (0.3 mg/kg, intraperitoneal), or respective vehicles from post-natal day 28–55. Cocaine seeking, reflecting cue reactivity, was measured in adulthood during self-administration maintenance and cue-induced reinstatement tests conducted under a second-order schedule.Compared to control strains, SHR earned more cocaine infusions, emitted more cocaine-seeking responses during maintenance and reinstatement testing, and required more sessions to reach the extinction criterion. Compared to vehicle, adolescent methylphenidate, but not atomoxetine, further increased cocaine intake during maintenance testing in SHR. Adolescent atomoxetine, but not methylphenidate, decreased cocaine seeking during reinstatement testing in SHR. Neither medication had effects on cocaine intake or cue reactivity in control strains.The SHR successfully model ADHD and cocaine abuse comorbidity and show differential effects of adolescent ADHD medications on cocaine intake and cue reactivity during adulthood. Thus, SHR have heuristic value for assessing neurobiology underlying the ADHD phenotype and for evaluating pharmacotherapeutics for ADHD.

Methodological advantages and disadvantages of parallel and crossover randomised clinical trials on methylphenidate for attention deficit hyperactivity disorder: a systematic review and meta-analyses

ObjectiveTo assess the methodological advantages and disadvantages of parallel and crossover designs in randomised clinical trials on methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).DesignSecondary analyses of...

A cross sectional survey of adherence, perceived efficacy and side effects of methylphenidate among children at a teaching hospital in Sri Lanka

Introduction Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric condition in childhood, which if untreated may have a negative effect on education, peer relationships and family disharmony. Methylphenidate is an effective treatment for ADHD, although its use is limited by poor compliance and side effects. Studies on effects of side effects on efficacy, and adherence of methylphenidate in developing countries are scarce. Methods We assessed the adherence, efficacy, and side effects of methylphenidate in children and adolescents treated at a child and adolescent psychiatry clinic of North Colombo Teaching Hospital, Ragama. We gathered information from guardians of the children treated with methylphenidate for at least 2 months, using an interviewer administered questionnaire. Results Among the 149 participants, a majority were males and the mean age of the population was 10.4 years. More than 52% participants reported 100% compliance with methylphenidate, but only 12% complied with non-pharmacological therapies. While 75% believed the medication to be effective, only 17% perceived psychosocial strategies to be useful. Poor appetite (44%) was the most common side effect of methylphenidate and 43% did not report any side effect. There was a negative correlation between compliance with methylphenidate and the occurrence of poor appetite, as well as with not increasing the initial dose. Discussion The results of this study suggest that methylphenidate is an effective and well-tolerated treatment for children in Sri Lanka with ADHD.

Exposure to methylphenidate in adolescence and adulthood modulates cross-sensitization to amphetamine in adulthood in three genetically variant female rat strains

Attention Deficit Hyperactivity Disorder (ADHD) is a developmental, behavioral disorder that is characterized by patterns of impulsivity and limited attention. Stimulants, such as methylphenidate (MPD) and amphetamine (Amph), are utilized as first-line agents in the treatment of ADHD. While Amph is known to elicit dependence, MPD is not. Interdependence between MPD and Amph is a growing concern. Therefore, it is important to explore this interaction in animal models to gain insight on its mechanisms. In experimental studies, drugs that elicit behavioral sensitization and cross-sensitization in animals are considered to have the potential to elicit dependence. This study evaluated whether chronic repetitive MPD exposure in adolescence and/or adulthood in various genetic strains of female rats elicits behavioral sensitization as well as cross-sensitization with Amph. We used three strains: SHR (ADHD model), WKY, and SD rats. The three rat strains were exposed to chronic MPD in their adolescence and adulthood or exposed to chronic MPD only in adulthood. When the female rats were treated with MPD only in adulthood, the SHR strain exhibited cross-sensitization to Amph but the WKY and SD strains did not. Whereas, when the female rats were pretreated with MPD in adolescence and adulthood, the SHR and WKY strains exhibited cross-sensitization response to Amph, but the SD strain did not. This study showed that the genetic strain and age of exposure to MPD plays a crucial role in cross-sensitization to Amph in female rodents. Furthermore, we showed that genetics associated with ADHD pre-dispose animals to dependence between drugs even if the exposure starts in adulthood compared to control strains that did not show dependence with adult only MPD exposures. Genetic variability, age of initial drug exposure, and sex of the subject are key variables that should be accounted in studies that explore effects of psychostimulants.