Long-term use of stimulants in children with attention deficit hyperactivity disorder: safety, efficacy, and long-term outcome

The purpose of this review is to summarize existing data on the long-term safety and efficacy of stimulant treatment, and how long-term stimulant treatment of children with attention deficit hyperactivity disorder (ADHD) affects their outcome. Existing controlled studies of children with ADHD treated and untreated with stimulants, as well as long-term prospective follow-up studies, are reviewed. Children with ADHD treated with stimulants for as long as 2 years continue to benefit from the treatment, with improvements observed in ADHD symptoms, comorbid oppositional defiant disorder, and academic and social functioning, with no significant problems of tolerance or adverse effects. Long-term, prospective follow-up studies into adulthood show that stimulant treatment in childhood has slight benefits regarding social skills and self-esteem. Long-term adverse effects from stimulant treatment in childhood regarding adult height or future substance abuse have not been supported by existing studies.     

Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults

Compared to children, adults with ADHD are at greater risk for developing adverse cardiovascular related outcomes and, if treated, may be likely to carry a greater burden of exposure to stimulant medications. The goal of this report is to critically review the available literature relevant to the cardiovascular safety of CNS stimulants for adult ADHD (aADHD). Twenty potential clinical trials of a CNS stimulant for aADHD have been published between 1979 and 2012. Of these, ten presented sufficient data to estimate the relative change in various cardiovascular parameters associated with ADHD treatment modalities. These trials were predominantly focused on long-acting stimulant preparations for acute symptom reduction (median duration=6 weeks, range: 4–24 weeks) and enrolled relatively young subjects (median age=36 years, range: 22–40). Using random effects meta-analysis, we found that subjects randomized to CNS stimulant treatment demonstrated a statistically significant increased resting heart rate [+5.7 bpm (3.6, 7.8), p<0.001] and systolic blood pressure findings [+2.0 mmHg (0.8, 3.2), p=0.005] compared with subjects randomized to placebo. There was a statistically significant increased risk for a resting heart rate >90 bpm [4.2% (n=50) vs. 1.7% (n=8), OR=2.75 (1.3, 6.7), p=0.006] associated with CNS stimulant treatment. In light of prognostic value of resting heart rate with regard to cardiovascular morbidity in epidemiological studies, future research of adults with ADHD should focus on the potential clinical impact of the increase in heart rate observed in this meta-analysis.     

Stimulants and the developing brain

For almost 70 years, children have received stimulants for the treatment of attention deficit hyperactivity disorder [ADHD (initially called hyperkinetic syndrome)], with little understanding of the long-term effects of these drugs on brain development. The maturation and refinement of the brain during childhood and adolescence, including the overproduction and selective elimination of synapses, is based on genetic programming and experience. The effects of stimulant drugs during different stages of this process have unique short-term, acute effects that also influence their long-term effects. Chronic, pre-pubertal exposure alters the expected developmental trajectory of brain structure and function and results in a different topography in adulthood. The timing of exposure (childhood versus adolescence), the age of examination after drug exposure (immediately or delayed into adulthood) and sex influence the observable effects. Preclinical studies of the effects of stimulant exposure provide increased understanding about the impact of stimulant drugs on brain development and provide insight into new treatment options for ADHD and other disorders of childhood.     

Efficacy and tolerability of pharmacotherapies for attention-deficit hyperactivity disorder in adults

This review examines the evidence regarding the efficacy and tolerability of long- and short-acting stimulant medications, as well as the non-stimulant medications atomoxetine and bupropion in the treatment of adult attention-deficit hyperactivity disorder (ADHD). Effect sizes in adults appear to be of almost the same magnitude as in school-age children when robust doses are used. There are adequate data demonstrating short-term efficacy and safety of medication in ADHD during adulthood but long-term studies are lacking, particularly in view of concerns regarding cardiovascular adverse events. There is some evidence that stimulant medication can improve driving performance in adults with ADHD. The extent to which medication may improve academic, occupational and social functioning in adults with ADHD is unclear, and future research should investigate these outcomes. Medication treatment of adults with ADHD in sports is controversial. Both stimulant and non-stimulant medications seem to be well tolerated. Monitoring of pulse and blood pressure is recommended with these drugs because of their cardiovascular effects. There have been extremely rare case reports of sudden death in adults and children treated with stimulants and atomoxetine, but it is difficult to clearly establish causality. In view of reports of treatment-related suicide-related behaviour with atomoxetine, it is recommended that adults should be observed for agitation, irritability, suicidal thinking, self-harming or unusual behaviour, particularly in the first months of treatment, or after a change of dose. ADHD in adults continues to remain an under-recognized disorder in many parts of the world and there is a lack of specialist clinics for assessment and treatment of adult ADHD. Studies to date have failed to show efficacy of medications in the treatment of ADHD in the substance misuse population. There is little evidence so far to suggest an increased misuse of stimulants or diversion amongst substance misusers; however, data are insufficient to draw firm conclusions. Further work is necessary to evaluate effective treatments in subgroups such as the substance misuse population, those with multiple co-morbidities and different ADHD subtypes.     

Pharmacotherapy of adolescent attention deficit hyperactivity disorder: challenges, choices and caveats

A recent increase in stimulant treatment of adolescents with attention deficit hyperactivity disorder (ADHD) has been documented. Challenges in treating adolescent ADHD with methylphenidate or dextroamphetamine include compliance with frequent dosing, abuse potential and wear-off or rebound effects. Co-morbid anxiety, occurring in at least 30 percent of ADHD youths, is associated with lower rate of response to stimulants. The effective alternatives, tricyclic antidepressants or pemoline, are each associated with rare but serious toxicity. Bupropion has recently proven effective in controlled trials. Other noradrenergic or dopamine-enhancing agents such as venlafaxine and nicotine show some benefit in open trials. The need for more options in pharmacotherapy of ADHD is evidenced by rapid adoption in clinical practice of alternative and adjunctive medication despite lack of controlled research on efficacy and safety. The indications for long-term stimulant treatment of ADHD present some controversy, and highlight a need for more research on safety and efficacy through the lifespan. Thresholds for diagnosis are much lower with DSM than with ICD, and thresholds for treatment are contentious, given the performance-enhancing effects of stimulants in normal students. The endpoint for treatment is unclear, as stimulants are also effective in adult ADHD. Based on short- and intermediate-term studies to date, stimulant medication is clearly more efficacious than cognitive and behavioral strategies for the symptoms of ADHD. Longer term research is needed to determine whether sustained stimulant therapy will reduce the adverse emotional, behavioral and academic consequences of inattention and impulsivity in adolescents and adults.     

Aripiprazole augmentation strategy in clomipramine-resistant depressive patients: An open preliminary study

Recent evidence supports the use of second generation antipsychotics in drug resistant depression. The aim of the present open-label study was to evaluate the effect of aripiprazole as an add-on medication in drug-resistant depressed patients who had not responded to clomipramine. Thirty-five patients with major depressive disorder (MDD) were included in the study. All patients had not responded to a previous adequate treatment with an SSRI and had been receiving clomipramine (daily doses ranging from 100 to 300 mg) for 113.9 ± 18.9 days without getting significant clinical improvement. Aripiprazole was added at the fixed dose of 5 mg/day and clinical status as well as clomipramine plasma levels were monitored before and after 4, 8, and 24 weeks of combined treatment. Hamilton depression rating scale scores significantly decreased over the follow-up period with 91.4% and 34.3% of patients getting a response or a remission, respectively, after 24 weeks of combined treatment. No worsening of clomipramine-related side effects nor new side effects were observed. The clinical improvement was accompanied by a progressive and significant increase in clomipramine plasma levels. With the limitation of an open-label design, these data suggest for the first time the putative efficacy and safety of aripiprazole in combination with a tricyclic medication in drug resistant depressed patients. The role of the observed pharmacokinetic interaction in the mechanism of aripiprazole antidepressant activity remains to be proved.     

Evaluation of risks associated with short- and long-term psychostimulant therapy for treatment of ADHD in children

Attention-deficit hyperactivity disorder (ADHD) is a common condition during childhood that is associated with significant psychosocial dysfunction. Psychostimulants are the compounds that have been most extensively studied for the treatment of ADHD in children. There is substantial scientific evidence that several methylphenidate- and amphetamine-based preparations have acute efficacy in the treatment of this condition in children. The short-term safety and tolerability of these compounds has been reasonably well-studied and the risks associated with psychostimulant therapy in the short-term are generally acceptable. However, the amount of long-term effectiveness and safety data relating to these compounds is relatively small. Data that do exist suggest that long-term treatment with psychostimulants in appropriately diagnosed patients may be associated with salutary effects as well as relatively modest risks. Until more extensive, methodologically rigorous data are available, it appears that judicious psychostimulant pharmacotherapy of ADHD in children may be justified.     

Evaluation of risks associated with short- and long-term psychostimulant therapy for treatment of ADHD in children

Attention-deficit hyperactivity disorder (ADHD) is a common condition during childhood that is associated with significant psychosocial dysfunction. Psychostimulants are the compounds that have been most extensively studied for the treatment of ADHD in children. There is substantial scientific evidence that several methylphenidate- and amphetamine-based preparations have acute efficacy in the treatment of this condition in children. The short-term safety and tolerability of these compounds has been reasonably well-studied and the risks associated with psychostimulant therapy in the short-term are generally acceptable. However, the amount of long-term effectiveness and safety data relating to these compounds is relatively small. Data that do exist suggest that long-term treatment with psychostimulants in appropriately diagnosed patients may be associated with salutary effects as well as relatively modest risks. Until more extensive, methodologically rigorous data are available, it appears that judicious psychostimulant pharmacotherapy of ADHD in children may be justified.     

盐酸哌甲酯控释片治疗注意缺陷多动障碍研究进展

注意缺陷多动障碍是一种儿童期常见的精神障碍，中枢兴奋剂如盐酸哌甲酯片是临床治疗此类障碍的一线药物。然而，由于盐酸哌甲酯片疗效持续时间较短，需要每天多次服药使治疗依从性不佳。盐酸哌甲酯控释片（专注达）是每天1次服用的渗透型控释片剂，成为治疗注意缺陷多动障碍的有价值药物。现综述其药动学、药理作用、剂型特点、临床疗效和安全性研究进展。     

A Prospective Examination of the Association of Stimulant Medication History and Drug Use Outcomes among Community Samples of ADHD Youths

A continuing debate in the child psychopathology literature is the extent to which pharmacotherapy for children with attention-deficit/hyperactivity disorder (ADHD), in particular stimulant treatment, confers a risk of subsequent drug abuse. If stimulant treatment for ADHD contributes to drug abuse, then the risk versus therapeutic benefits of such treatment is greatly affected. We have prospectively followed an ADHD sample (N = 149; 81% males) for approximately 15 years, beginning at childhood (ages 8 to 10 years) and continuing until the sample has reached young adulthood (ages 22 to 24 years). The sample was originally recruited via an epidemiologically derived community procedure, and all youths were diagnosed with ADHD during childhood. We report on the association of childhood psychostimulant medication and subsequent substance use disorders and tobacco use. The substance use outcomes were based on data collected at three time points when the sample was in late adolescence and young adulthood (age range approximately 18 to 22 years old). We did not find evidence to support that childhood treatment with stimulant medication, including the course of stimulant medication, was associated with any change in risk for adolescent or young adulthood substance use disorders and tobacco use. These results from a community-based sample extend the growing body of literature based on clinically derived samples indicating that stimulant treatment does not create a significant risk for subsequent substance use disorders.     

A Prospective Examination of the Association of Stimulant Medication History and Drug Use Outcomes among Community Samples of ADHD Youths

A continuing debate in the child psychopathology literature is the extent to which pharmacotherapy for children with attention-deficit/hyperactivity disorder (ADHD), in particular stimulant treatment, confers a risk of subsequent drug abuse. If stimulant treatment for ADHD contributes to drug abuse, then the risk versus therapeutic benefits of such treatment is greatly affected. We have prospectively followed an ADHD sample (N = 149; 81% males) for approximately 15 years, beginning at childhood (ages 8 to 10 years) and continuing until the sample has reached young adulthood (ages 22 to 24 years). The sample was originally recruited via an epidemiologically derived community procedure, and all youths were diagnosed with ADHD during childhood. We report on the association of childhood psychostimulant medication and subsequent substance use disorders and tobacco use. The substance use outcomes were based on data collected at three time points when the sample was in late adolescence and young adulthood (age range approximately 18 to 22 years old). We did not find evidence to support that childhood treatment with stimulant medication, including the course of stimulant medication, was associated with any change in risk for adolescent or young adulthood substance use disorders and tobacco use. These results from a community-based sample extend the growing body of literature based on clinically derived samples indicating that stimulant treatment does not create a significant risk for subsequent substance use disorders.     

Persistent behavioral impairment caused by embryonic methylphenidate exposure in zebrafish

As more adults take the stimulant medication methylphenidate to treat attention deficit hyperactivity disorder (ADHD) residual type, the risk arises with regard to exposure during early development if people taking the medication become pregnant. We studied the neurobehavioral effects of methylphenidate in zebrafish. Zebrafish offer cellular reporter systems, continuous visual access and molecular interventions such as morpholinos to help determine critical mechanisms underlying neurobehavioral teratogenicity. Previously, we had seen that persisting neurobehavioral impairment in zebrafish with developmental chlorpyrifos exposure was associated with disturbed dopamine systems. Because methylphenidate is an indirect dopamine agonist, it was thought that it might also cause persistent behavioral impairment after developmental exposure. Zebrafish embryos were exposed to the ADHD stimulant medication methylphenidate 0-5 days post fertilization (12.5-50 mg/l). They were tested for long-term behavioral effects as adults. Methylphenidate exposure (50 mg/l) caused significant increases in dopamine, norepinepherine and serotonin on day 6 but not day 30 after fertilization. In the novel tank diving test of predatory avoidance developmental methylphenidate (50 mg/l) caused a significant reduction in the normal diving response. In the three-chamber spatial learning task early developmental methylphenidate (50 mg/l) caused a significant impairment in choice accuracy. These data show that early developmental exposure of zebrafish to methylphenidate causes a long-term impairment in neurobehavioral plasticity. The identification of these functional deficits in zebrafish enables further studies with this model to determine how molecular and cellular mechanisms are disturbed to arrive at this compromised state.     

Economic implications of attention-deficit hyperactivity disorder for healthcare systems

Attention-deficit hyperactivity disorder (ADHD) is one of the most common chronic conditions of childhood, with adverse consequences that persist through adolescence into adulthood. Thus, the burden of illness associated with ADHD is high for affected individuals, their families, and society at large. This article reviews available information about ADHD-associated utilisation of healthcare resources, direct medical costs, and the costs or cost effectiveness of pharmacological interventions. Published estimates suggest that direct medical costs for youth with ADHD are approximately double those for youth without ADHD. Cross-sectional studies suggest that ADHD-associated incremental costs are highest for mental health services and pharmaceutical costs, and are greatest for youth with comorbid psychiatric conditions and for those being treated with stimulant medication. To guide relevant clinical and health policy, additional research is warranted on the following: source of increased costs observed among persons with ADHD; patient characteristics of those accruing high medical costs; and the long-term effect of ADHD treatment on direct and indirect costs.     

Current issues around the pharmacotherapy of ADHD in children and adults

Background New drugs and new formulations enter the growing market for ADHD medication. The growing awareness of possible persistence of ADHD impairment beyond childhood and adolescence resulting in increased pharmacotherapy of ADHD in adults, is also a good reason for making an inventory of the what is generally known about pharmacotherapy in ADHD. Aim To discuss current issues in the possible pharmacotherapy treatment of ADHD in children, adolescents and adults with respect to the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used. Methods A search of the literature with an emphasis on the position of pharmacotherapy in ADHD treatment guidelines, the pharmacoepidemiological trends, and current concerns about the drugs used in pharmacotherapy. Results According to the guidelines, the treatment of ADHD in children consists of psychosocial interventions in combination with pharmacotherapy when needed. Stimulants are the first-choice drugs in the pharmacological treatment of ADHD in children despite a number of well known and frequently reported side effects like sleep disorders and loss of appetite. With regard to the treatment of adults, stimulant treatment was recommended as the first-choice pharmacotherapy in the single guideline available. Both in children and adults, there appears to be an additional though limited role for the nonadrenergic drug atomoxetine. The increase of ADHD medication use, in children, adolescents and in adults, can not only be interpreted as a sign of overdiagnosis of ADHD. Despite the frequent use of stimulants, there is still a lack of clarity on the effects of long-term use on growth and nutritional status of children. Cardiovascular effects of both stimulants and atomoxetine are rare but can be severe. The literature suggests that atomoxetine may be associated with suicidal ideation in children. Conclusion Although pharmacotherapy is increasing common in the treatment of ADHD in both children and adults, there are still a lot of questions about side effects and how best to counter them. This suggests an important role for close monitoring of children and adults treated with stimulants or atomoxetine.     

Treatment of attention deficit hyperactivity disorder in children and adolescents: safety considerations.

Despite a large body of evidence for both the validity of the diagnosis of attention deficit hyperactivity disorder (ADHD) and the efficacy of its treatment with medication, there is an equally long history of controversy. This article focuses on presenting safety information for medications approved by the US FDA for the treatment of individuals with ADHD. Stimulant medications are generally safe and effective. The common adverse effects of stimulant medications, including appetite suppression and insomnia, are usually of mild severity and manageable without stopping the medication. The more severe adverse effects such as tics or bizarre behaviours occur with low frequency and usually resolve when the medication is stopped. The possible impact on growth requires careful monitoring. Several rare but potentially severe adverse effects including sudden cardiac death and cancer following long-term treatment have been reported; however, these effects have not been adequately demonstrated to be of significant concern at this time. Atomoxetine also has a mild adverse effect profile in terms of severity and frequency although the numbers of studies and years of clinical experience is considerably less with this drug than for the stimulant medications. When the risks are juxtaposed to the clear efficacy in significantly reducing dysfunctional symptoms of ADHD, benefit-risk analyses support the continued use of these pharmacological treatments for patients with ADHD.     

A systematic review and meta-analysis of oxaceprol in the management of osteoarthritis: An evidence from randomized parallel-group controlled trials

Oxaceprol, a derivative of l-proline, is an established drug for managing osteoarthritis (OA) with better safety profile than non-steroidal anti-inflammatory drugs (NSAIDs). This systematic review and meta-analysis, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, evaluated the efficacy, safety and tolerability of oxaceprol in OA. Electronic databases for published and grey (unpublished) literature were searched to identify parallel-group randomized controlled trials (RCTs) evaluating the impact of oxaceprol in patients with OA. Risk of bias was assessed using the Cochrane collaboration's tool. A total of seven parallel-group RCTs involving 1087 participants were included in the systematic review. Meta-analysis, in Review Manager, demonstrated numerically greater/significant improvements compared to active control [diclofenac/ibuprofen]/placebo in pain and function of joint; similar improvement vs. active control in global treatment efficacy; no difference/significant difference vs. active control/placebo in NSAIDs as rescue medication. Treatment with oxaceprol showed numerically less adverse events (AEs) than active control (diclofenac: risk ratio [RR], 0.71; 95% confidence interval [CI], 0.45 to 1.11; p = 0.14: ibuprofen: RR, 0.73; 95% CI, 0.30 to 1.78; p = 0.49) and significantly fewer AEs compared to placebo (RR, 0.76; 95% CI, 0.63 to 0.92; p = 0.004). Given the nature of small-to-moderate sample size and short duration of eligible studies, the available clinical evidence of oxaceprol in the management of OA is modest – though looks promising. New and better RCTs with larger sample size and longer follow-up are warranted to strengthen the use of oxaceprol in clinical setting for managing OA.     

Defining the phenotype of young adults with family histories of alcohol and other substance use disorders: Studies from the family health patterns project

Individuals with a family history of alcohol and other drug use disorders (FH +) are at increased risk for developing substance use disorders themselves relative to those with no such histories (FH −). Here we sought to identify key characteristics associated with FH + status and alcohol and other drug use disorder status in a large cohort of FH + and FH − young adults.We conducted principal component analyses on demographic, temperament, and cognitive measures differentiating 506 FH + and 528 FH − young adults. Three principal components were identified, and these component scores were then used to predict the odds of being FH + and the odds of having an alcohol or other drug use disorder. Component 1 consisted of measures indexing internalizing traits, with higher component scores indicating greater depressive, anxious, and emotional instability tendencies. Component 2 consisted of measures of externalizing traits as well as exposure to early life adversity (ELA), with higher scores indicating less impulse control, more antisocial behavior, and greater ELA exposure. Component 3 consisted of estimated intelligence, delay discounting, and demographic characteristics, with higher scores indicating lower estimated intelligence, greater discounting of delayed rewards, less education, and lower childhood socioeconomic status. For each 1-point increase in the Component 1, 2, and 3 scores, the odds of being classified FH + increased by 2%, 8%, and 4%, respectively. Similar findings were observed when individuals with alcohol or other drug use disorders were removed from the analyses. Finally, greater Component 2 scores were also associated with increased odds of having an alcohol or other drug use disorder. Collectively, these findings provide a more comprehensive understanding of the FH + phenotype in young adults and help form a basis for further studies on biological mechanisms underlying risk for substance use disorders. The present findings also provide further support for a prominent role of ELA in promoting risk for problem alcohol and other drug use.     

Atomoxetine, a novel treatment for attention-deficit-hyperactivity disorder

Atomoxetine is the first nonstimulant drug approved by the United States Food and Drug Administration (FDA) for the treatment of attention-deficit-hyperactivity disorder (ADHD), and the only agent approved by the FDA for the treatment of ADHD in adults. Atomoxetine is a norepinephrine transport inhibitor that acts almost exclusively on the noradrenergic pathway. Its mechanism of action in the control and maintenance of ADHD symptoms is thought to be through the highly specific presynaptic inhibition of norepinephrine. Clinical trials to evaluate the short-term effects of atomoxetine in children and adults have shown that atomoxetine is effective in maintaining control of ADHD. Likewise, long-term trials have determined that atomoxetine is effective in preventing relapse of ADHD symptoms without an increase in adverse effects. A comparative trial of atomoxetine with methylphenidate in school-aged children indicated similar safety and efficacy without the abuse liability associated with some psychostimulants. The most commonly reported adverse effects in children and adolescents are dyspepsia, nausea, vomiting, decreased appetite, and weight loss. The rates of adverse events in the trials were similar for both the once- and twice-daily dosing regimens. The discontinuation rate was 3.5% in patients treated with atomoxetine versus 1.4% for placebo and appeared to be dose dependent, wit a higher percentage of discontinuation at dosages greater than 1.5 mg/kg/day. In clinical trials involving adults, the emergence of clinically significant or intolerable adverse events was low. The most common adverse events in adults were dry mouth, insomnia, nausea, decreased appetite, constipation, urinary retention or difficulties with micturition, erectile disturbance, dysmenorrhea, dizziness, and decreased libido. Sexual dysfunction occurred in approximately 2% of patients treated with atomoxetine. Atomoxetine should be used with caution in patients who have hypertension or any significant cardiovascular disorder. Overall, atomoxetine therapy in patient with ADHD appears to be effective in controlling symptoms and maintaining remission, with the advantages being comparable efficacy with that of methylphenidate, a favorable safety profile, and non-controlled substance status. Additional long-term studies are needed to determine its continued efficacy for those who require lifelong treatment, and comparative trials against other stimulant and nonstimulant agents.     

ADHD,stimulant treatment in childhood and subsequent substance abuse in adulthood — A naturalistic long-term follow-up study

The purpose of the study was to estimate the risk of substance use disorder (SUD) and alcohol abuse in adulthood among children and adolescents with attention-deficit hyperactivity disorder (ADHD) compared to the background population. Furthermore, to examine whether the age at initiation and duration of stimulant treatment in childhood predicts SUD and alcohol abuse in adulthood. 208 youths with ADHD (183 boys; 25 girls) were followed prospectively. Diagnoses of SUD and alcohol abuse were obtained from The Danish Psychiatric Central Register. The relative risk (RR) of SUD and alcohol abuse for cases with ADHD, compared to the background population was 7.7 (4.3–13.9) and 5.2 (2.9–9.4), respectively. Female gender, conduct disorder in childhood and older age at initiation of stimulant treatment increased the risk of later SUD and alcohol abuse. Our results warrant increased focus on the possibly increased risk of substance abuse in females with ADHD compared to males with ADHD.     

Safety of therapeutic methylphenidate in adults: a systematic review of the evidence

Attention deficit hyperactivity disorder (ADHD) often persists into adulthood. Stimulant drugs, including methylphenidate, have showed efficacy in trials for ADHD in adults. Adult psychiatrists are likely to encounter increasing numbers of adult patients who may benefit from methylphenidate. A systematic review of the literature was made to examine the evidence on the safety of methylphenidate, when used therapeutically in adults. Twenty-six placebo-controlled trials were found, in which 811 adults received methylphenidate for ADHD and other conditions. In the short term, methylphenidate was well tolerated and no serious side effects were observed. There is little information on the long-term safety of methylphenidate in adults, although the number of serious adverse effects reported to regulatory authorities has, so far, been low. Methylphenidate is associated with a modest rise in blood pressure and heart rate. Surveys of stimulant use in US universities show that misuse of prescribed medication, for recreation or to enhance study, is fairly common although the level of harm that arises from this practice is unclear.