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Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue. In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed. Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0–53·6) at baseline, 40·6 (38·2–43·1) with placebo, 41·3 (38·8–43·7) with amantadine, 39·0 (36·6–41·4) with modafinil, and 38·6 (36·2–41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil). Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis. Patient-Centered Outcomes Research Institute.

An increasing number of healthy people use methylphenidate, a psychostimulant that increases dopamine and noradrenaline transmission in the brain, to help them focus over extended periods of time. While methylphenidate has been shown to facilitate some cognitive functions, like focus and distractor-resistance, the same drug might also contribute to cognitive impairment, for example, in creativity. In this study, we investigated whether acute administration of a low oral dose (20 mg) of methylphenidate affected convergent and divergent creative processes in a sample of young healthy participants. Also, we explored whether such effects depended on individual differences in ADHD symptoms and working memory capacity. Contrary to our expectations, methylphenidate did not affect participants’ creative performance on any of the tasks. Also, methylphenidate effects did not depend on individual differences in trait hyperactivity–impulsivity or baseline working memory capacity. Thus, although the effects of methylphenidate on creativity might be underestimated in our study due to several methodological factors, our findings do not suggest that methylphenidate impairs people’s ability to be creative. •Methylphenidate effects on convergent and divergent creativity were studied.•Methylphenidate did not affect performance on any of the creativity tasks.•Effects did not depend on individual differences in hyperactivity–impulsivity.•Effects did not depend on individual differences in working memory capacity.•Findings do not suggest that methylphenidate impairs people’s creative ability.

Intellectual drug doping in athletics by using stimulants that affect central nervous system functions has been diversified. Stimulants are regulated by the World Anti-Doping Agency according to their levels of urinary concentration. Positron emission tomography could evaluate how stimulants affect central nervous system functions. We aimed to evaluate the effect of stimulants on brain function by examining the difference in brain dopamine transporter occupancy by PET after administration of dl -methylephedrine or pseudoephedrine at the clinical maximum daily dose. Four PET scans without and with drug administration (placebo, dl -methylephedrine 150 mg and pseudoephedrine 240 mg) were performed. The concentrations of dl -methylephedrine and pseudoephedrine in plasma and urine were measured. DAT occupancies in the striatum with placebo, dl -methylephedrine and pseudoephedrine were calculated by PET images. The urinary concentration of dl -methylephedrine (12.7 µg/mL) exceeded the prohibited concentration (10 µg/mL), but the DAT occupancy with dl -methylephedrine (6.1%) did not differ (p = 0.92) from that with placebo (6.2%). By contrast, although the urinary concentration of pseudoephedrine (144.8 µg/mL) was below the prohibited concentration (150 μg/mL), DAT occupancy with pseudoephedrine was 18.4%, which was higher than that with placebo (p = 0.009). At the maximum clinical dose, dl -methylephedrine was shown to have weaker effects on brain function than pseudoephedrine.

The efficacy and safety of modified-release methylphenidate (MPH-MR) in the treatment of attention-deficit/hyperactivity disorder (ADHD) have been shown in both pediatric and adult Caucasian patients. The objective of this study was to assess the efficacy and safety of MPH-MR in Chinese children and adolescents with ADHD. MICCA was a randomized, double-blind, placebo-controlled trial conducted at 19 sites in China from September 2018 to July 2021. The study enrolled children and adolescents aged 6 to < 18 years with a primary diagnosis of ADHD according to the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5). Patients were randomized 1:1 to once-daily MPH-MR (10-60 mg) or placebo. The study included an up-titration phase of up to 5 weeks and a dose maintenance phase of 4 weeks. The primary efficacy endpoint was the change in the ADHD Rating Scale-IV (ADHD-RS-IV) total score from baseline to the end of the maintenance phase (EoM). Secondary endpoints included the change from baseline to EoM in Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) total score, and Clinical Global Impression-Improvement (CGI-I) scores at EoM. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. A total of 221 patients were randomized (MPH-MR: n = 110; placebo: n = 111). The change in the ADHD-RS-IV total score from baseline to EoM was significantly greater for MPH-MR versus placebo, with a least squares (LS) mean (95% confidence interval [CI]) treatment difference of - 4.6 (- 6.92, - 2.30) (p < 0.001). The mean (95% CI) treatment difference for the WFIRS-P total score change from baseline to EoM also significantly favored MPH-MR over placebo (- 6.46 [- 10.57, - 2.34]; p = 0.002). The CGI-I score at EoM was significantly lower in the MPH-MR group compared to the placebo group (2.2 vs 2.5; p = 0.002). Treatment-emergent adverse events were reported for 74 (67.3%) patients in the MPH-MR group and 55 (49.1%) patients in the placebo group. Most TEAEs were mild to moderate in severity. The most common TEAEs for MPH-MR were decreased appetite, nausea and upper respiratory tract infection. Treatment-emergent adverse events leading to study drug discontinuation/study withdrawal were reported in 4 (3.6%) patients in the MPH-MR group and 1 (0.9%) patient in the placebo group. No clinically relevant changes in vital signs were observed during the study. Modified-release methylphenidate was superior to placebo in improving ADHD symptoms and functioning in Chinese pediatric patients with ADHD. Modified-release methylphenidate had a good safety and tolerability profile. Trial Registration http://www.chinadrugtrials.org.cn/ Identifier: CTR20180056 (registered on 21 May 2018).

Stimulants used to treat attention-deficit/hyperactivity disorder (ADHD) have been well researched, but comparisons among stimulants are hindered by the absence of direct comparative trials. The goal of this work was to compare the efficacy of methylphenidate and amfetamine formulations through a meta-analysis of double-blind placebo-controlled trials. We analyzed recent published literature on the stimulant therapy of ADHD to describe the variability of drug–placebo effect sizes. A literature search was conducted to identify double-blind, placebo-controlled studies of ADHD in children and adolescents published after 1979. Meta-analysis regression assessed the influence of medication type and study design features on medication effects. Twenty-three trials met criteria and were included in this meta-analysis. These trials studied 11 drugs using 19 different outcome measures of hyperactive, inattentive, or impulsive behavior. We found significant differences between amfetamine and methylphenidate products, even after correcting for study design features that might have confounded the results. Our analyses indicate that effect sizes for amfetamine products are significantly, albeit moderately, greater than those for methylphenidate. We found that most measures of effect from all studies were statistically significant. Our findings suggest that amfetamine products may be moderately more efficacious than methylphenidate products, even after controlling for potentially confounding study design features. This difference in effect size may be due to differences between amfetamine and methylphenidate in the molecular mechanisms involved in facilitating the dopaminergic neurotransmission.

Background The effects of stimulant treatment on sleep in adults with attention-deficit/hyperactivity disorder (ADHD) are complex and varied, with some individuals experiencing worsening of sleep but others experiencing improvement. Methods Data from previously reported trials of the clinical efficacy and safety of the long-acting methylphenidate formulation PRC-063 (Adhansia XR ® in the USA; Foquest ® in Canada) in adults with ADHD were used to evaluate patient-reported sleep outcomes, as captured using the Pittsburgh Sleep Quality Index (PSQI) and adverse events of insomnia. The trials comprised 4 weeks of randomized, forced-dose PRC-063 treatment at a dose of 0 (placebo), 25, 45, 70, or 100 mg/day followed by an optional 6 months of open-label PRC-063 treatment at an individually optimized dose of 25–100 mg/day. Results At the end of double-blind treatment, PRC-063 (all doses combined; N  = 297) showed no significant difference versus placebo ( N  = 78) in least squares mean change in global PSQI score from baseline (− 0.7 vs. − 1.3; P  = 0.0972) or in scores for each of the seven subscales of the PSQI. For patients enrolled in the open-label extension ( N  = 184), mean ± standard deviation global PSQI score improved from 7.8 ± 3.55 at the end of double-blind treatment to 5.8 ± 3.11 at 1 month and 5.4 ± 3.21 at 6 months ( P  < 0.0001). A greater proportion of patients were good sleepers (global PSQI score ≤ 5) at the end of the open-label extension (57.3%) than at baseline (20.9%) or at the end of double-blind treatment (26.0%). In a logistic regression analysis, baseline global PSQI score (odds ratio 1.491; P  < 0.0001), but not randomized study treatment ( P  = 0.1428), was a significant predictor of poor sleep (global PSQI score > 5) at the end of double-blind treatment. Adverse event rates for insomnia (15.8 vs. 3.8%) and initial insomnia (6.1 vs. 1.3%) during double-blind treatment were higher for PRC-063 (all doses combined) than for placebo. Two patients receiving PRC-063 in the double-blind study and one patient in the open-label study were withdrawn because of insomnia adverse events. Conclusions Our findings indicate that, on average, PRC-063 had no significant impact on overall sleep quality in adults with ADHD. Although insomnia was observed as an adverse event, when sleep was measured over time as an outcome in its own right for patients receiving dose-optimized PRC-063 open-label, more patients showed improvement in sleep than deterioration. ClinicalTrials.gov Identifer NCT02139124 and NCT02168127.

Background and Objective Although there are several treatments for narcolepsy type 2 and idiopathic hypersomnia, studies that assess amphetamines, symptoms beyond sleepiness, and comparative effectiveness are needed. We performed a randomized, fully blinded, noninferiority trial of modafinil versus amphetamine–dextroamphetamine in these disorders. Methods Forty-four adults were randomized to modafinil or amphetamine–dextroamphetamine, individually titrated to a maximum of modafinil 200 mg twice daily or amphetamine–dextroamphetamine 20 mg twice daily, for 12 weeks. Primary outcome was change in Epworth from baseline to week 12, with a noninferiority threshold of 2 points. Secondary outcomes were (1) patient global impression of change measures of disease severity, sleepiness, sleep inertia, and cognition; (2) change from baseline in Hypersomnia Severity Index; and (3) change from baseline in Sleep Inertia Questionnaire. Adverse events were compared between groups. Results Epworth improved 5.0 [± standard deviation (SD) 2.7] points with modafinil and 4.4 (± SD 4.7) with amphetamine–dextroamphetamine; noninferiority of amphetamine–dextroamphetamine was not demonstrated ( P = 0.11). Noninferiority of amphetamine-dextroamphetamine was demonstrated for change scores of severity, sleepiness, sleep inertia, Hypersomnia Severity Index, and Sleep Inertia Questionnaire. Dropouts due to adverse events were 31.8% for modafinil (including two severe events) and 9.1% for amphetamine–dextroamphetamine, P = 0.13. Anxiety was more common with modafinil and appetite suppression with amphetamine-dextroamphetamine. Conclusion Noninferiority of amphetamine–dextroamphetamine to modafinil was not demonstrated for the primary outcome. However, amphetamine–dextroamphetamine was noninferior on multiple secondary measures of disease severity and symptomatology. These data may inform shared decision-making regarding treatment for idiopathic hypersomnia and narcolepsy type 2. Registration Clinicaltrials.gov Registration (NCT03772314) 12/10/18. .

To determine whether the ergogenic effects of caffeine ingestion on neuromuscular performance are similar when ingestion takes place in the morning and in the afternoon. Double blind, cross-over, randomized, placebo controlled design. Thirteen resistance-trained males carried out bench press and full squat exercises against four incremental loads (25%, 50%, 75% and 90% 1RM), at maximal velocity. Trials took place 60min after ingesting either 6mgkg−1 of caffeine or placebo. Two trials took place in the morning (AMPLAC and AMCAFF) and two in the afternoon (PMPLAC and PMCAFF), all separated by 36–48h. Tympanic temperature, plasma caffeine concentration and side-effects were measured. Plasma caffeine increased similarly during AMCAFF and PMCAFF. Tympanic temperature was lower in the mornings without caffeine effects (36.7±0.4 vs. 37.0±0.5°C for AM vs. PM; p<0.05). AMCAFF increased propulsive velocity above AMPLAC to levels similar to those found in the PM trials for the 25%, 50%, 75% 1RM loads in the SQ exercise (5.4–8.1%; p<0.05). However, in the PM trials, caffeine ingestion did not improve propulsive velocity at any load during BP or SQ. The negative side effects of caffeine were more prevalent in the afternoon trials (13 vs. 26%). The ingestion of a moderate dose of caffeine counteracts the muscle contraction velocity declines observed in the morning against a wide range of loads. Caffeine effects are more evident in the lower body musculature. Evening caffeine ingestion not only has little effect on neuromuscular performance, but increases the rate of negative side-effects reported.

Abstract Study Objectives To investigate the effect of a typical dose of caffeine and a high dose of caffeine consumed in the morning, afternoon, and evening on subsequent sleep. Methods Using a placebo-controlled, double-blind, randomized crossover design, 23 males (25.3 ± 5.0 years) with a moderate habitual caffeine intake (<300 mg∙day−1) completed seven conditions: placebo, and 100 and 400 mg of caffeine consumed 12, 8, and 4 hours prior to bedtime, with a 48-hour washout. In-home partial polysomnography and sleep diaries were used to assess sleep. Linear mixed models estimated the effect of each condition. Results No significant effect on objective or subjective sleep occurred with the 100 mg dose of caffeine compared with the placebo (p > .05), but significant effects occurred with the 400 mg dose (p < .05). Significant delays in sleep initiation and alterations to sleep architecture were observed when 400 mg was consumed within 12 hours of bedtime (p < .05), and significantly greater sleep fragmentation occurred when 400 mg was consumed within 8 hours of bedtime (p < .05). Additionally, perceived sleep quality was significantly reduced when 400 mg was consumed 4 hours prior to bedtime (−34.02%, p = .006) but not at 8 or 12 hours. Conclusions A 100 mg dose of caffeine can be consumed up to 4 hours prior to bedtime, but 400 mg may negatively impact sleep when consumed as one dose within 12 hours of bedtime, with the adverse influence on sleep increasing the closer consumption occurs to bedtime. The discrepancy between objective and subjective sleep quality suggests that individuals may have difficulty accurately perceiving the influence of caffeine on sleep quality. Clinical trial registration Australian and New Zealand Clinical Trials Registry, registration number: ACTRN12621001625864, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12621001625864. Graphical Abstract Graphical Abstract

Stimulants that act on the central nervous system have been used since antiquity for ritual and other uses. Organic chemistry techniques, especially those developed in Germany in the late 1800s, resulted in the isolation and structural determination of several important stimulants. Synthetic pathways for amphetamine and related stimulants were developed in the first half of the 19th century, and these new drugs were widely marketed. Awareness of abuse potential emerged soon after but was contested. Stimulants have been used to counteract fatigue and promote wakefulness during military operations, as well as to treat sleep disorders, since the 1930s. Methylphenidate was approved to treat children with behavioral problems in 1962, predating the recognition of attention deficit hyperactivity disorder (ADHD). Stimulant abuse became a political concern in the post-war period, initially with the use of “pep-pills” by long-haul truck drivers and later as drug dealing became common in night clubs, with new laws limiting availability passed in the early 1960s. They have also been used to increase athletic and cognitive performance. Stimulants are still first-line therapies for ADHD and some sleep disorders; however, newer-generation drugs have been developed with better safety profiles and lower abuse potential. Illicit stimulant use continues to be common in many countries.