Modafinil (Rx-only reference)

BACKGROUND: A systematic review was conducted following PRISMA guidelines to identify human studies investigating pharmacological interventions and reported sleep outcomes among individuals with CUD or MUD. METHODS: PubMed and APA PsycInfo were searched from inception to January 2025 and risk of bias was assessed. Articles were included if they included human participants with either cocaine or methamphetamine dependence, administered a pharmacological treatment, and reported night-time sleep as an outcome using at least one rigorous measurement tool. Articles were excluded if they included animals, did not include pharmacological intervention (e.g., supplements or behavioral treatments), or only assessed baseline sleep or if sleep was only reported as a side effect rather than as a formal outcome. RESULTS: Eighteen studies (N = 678) met inclusion criteria, eleven in CUD and seven in MUD. The results of the risk-of-bias assessment indicated good-to-excellent interrater reliability (ICC range=0.85-0.90), and overall methodological quality across studies was moderate to high. For CUD, modafinil, buprenorphine, and suvorexant were preliminarily associated with improvements in sleep parameters, with modafinil linked to higher abstinence rates. Results for mirtazapine, lisuride, lorazepam, tiagabine, and cannabidiol were mixed. For MUD, mirtazapine and modafinil demonstrated modest initial benefits, while quetiapine and suvorexant showed preliminary promise in smaller studies. CONCLUSIONS: Overall, pharmacological interventions targeting sleep disturbances showed emerging but inconsistent benefits in CUD and MUD, which could be due to small sample sizes, short treatment durations, side effects, or comorbidities. Addressing sleep dysregulation may represent a novel and clinically meaningful pathway to improve recovery outcomes in stimulant use disorders.

INTRODUCTION: Cognitive impairment is a core feature of bipolar disorder (BD) that impacts functioning and quality of life. This review systematically summarizes the evidence on pharmacological and nutraceutical interventions for cognitive deficits in BD. METHODS: A systematic search of MEDLINE, Embase, and PsycInfo was conducted to identify studies examining the efficacy of pharmacological or nutraceutical interventions on cognition in individuals aged 18-65 years with euthymic or partially remitted BD from inception to December 29, 2024. This review was registered with PROSPERO (Reference No. CRD42024618397). Risk of bias assessment was conducted using the National Institutes of Health (NIH) quality assessment tools. The extracted data were summarized using a narrative synthesis approach. RESULTS: Sixteen studies were included, evaluating 13 different agents. Working memory, verbal learning and memory, executive functioning, social cognition, and attention/vigilance were improved by multiple agents. Galantamine showed replicated pro-cognitive effects on verbal learning and memory. Lithium, tianeptine, Withania somnifera (ashwagandha), insulin, and lurasidone each demonstrated cognitive benefits in single studies. Erythropoietin and pramipexole showed mixed results across two studies. Methylene blue, JNJ-18038683, docosahexaenoic acid, modafinil, and quetiapine revealed no significant effects. The quality of the studies ranged from good to poor, and the safety and tolerability profiles of the agents were favorable. CONCLUSION: These results suggest possible approaches for improving cognitive functioning in individuals with BD. Nevertheless, the inconsistency in outcomes and differences in study methodologies highlight the need for larger, rigorously controlled trials with uniform cognitive evaluations to confirm these findings and to assess their clinical relevance. © 2026 S. Karger AG, Basel.

Update of doi: 10.1002/14651858.CD006448. RATIONALE: Despite the high prevalence and medico-social significance of fatigue in post-traumatic brain injury (post-TBI) populations, there are no validated management strategies to control this condition. It is timely to provide clinicians and patients with the best available evidence of the efficacy of current pharmacological and non-pharmacological fatigue management practices. OBJECTIVES: To assess the effectiveness of pharmacological and non-pharmacological interventions for fatigue in people who have experienced a TBI. SEARCH METHODS: For this review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO. We also searched relevant conference proceedings, and we searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for ongoing trials. The most recent searches were conducted on 12 February 2025. ELIGIBILITY CRITERIA: Eligible study designs were randomised controlled trials (RCTs) and randomised cross-over trials (for pharmacological interventions only). Studies with participants of all ages (children and adults) with a TBI (of any severity) were included, where at least 75% of participants had a TBI. Any type of treatment for fatigue was considered. Four categories of interventions were prioritised: pharmacological, cognitive, stimulation/biofeedback, and psychoeducational. These interventions were compared to placebo groups, no treatment, or groups receiving other interventions. OUTCOMES: The critical outcome was fatigue. Important outcomes include fatigue-related outcomes of psychological functioning (depression and anxiety), cognitive functioning (processing speed), general quality of life, and daytime sleepiness. RISK OF BIAS: We assessed risk of bias using the original Cochrane risk of bias tool for RCTs (RoB 1). SYNTHESIS METHODS: We synthesised the results for each outcome by meta-analysis where possible using mean differences (MDs) and standardised mean differences (SMDs) and a fixed-effect model. Where meta-analysis was not possible due to the nature of the data, we narratively reported the results. We used GRADE t

Modafinil is approved for excessive daytime sleepiness in narcolepsy, obstructive sleep apnoea (OSA), and shift work sleep disorder (SWSD), but its widespread off-label use raises safety concerns. We evaluated the risk of adverse events (AEs) associated with both labelled and off-label use of modafinil. A systematic search of PubMed, Embase, and Cochrane identified 54 studies that met the inclusion criteria. In labelled uses, narcolepsy patients had significantly elevated risks of diarrhoea (risk ratio [RR]: 2.16, 95% confidence interval [CI]: 1.06-4.41) and nausea compared to those with placebo (RR: 2.44, 95% CI: 1.05-5.72). OSA/hypopnea syndrome patients had higher risks of insomnia (RR: 5.82), anxiety/nervousness (RR: 3.26), and headache (RR: 1.92). SWSD patients had elevated risks of insomnia (RR: 4.09), anxiety/nervousness (RR: 3.85), and nausea (RR: 2.93). Among off-label users, patients with attention deficit hyperactivity disorder had higher risks of insomnia (RR: 4.97) and decreased appetite (RR: 4.21). Patients with major depressive disorder showed higher risks of anxiety/nervousness (RR: 1.95). While modafinil users share common AEs, specific risks vary across patient groups. Our findings on condition-specific AE profiles would support cautious prescribing of modafinil and careful consideration of alternative treatments. Plain Language Summary: Modafinil is a medication used to help people stay awake, especially those with sleep disorders. However, it is also widely used for other conditions, such as ADHD or depression, where it is not officially approved. We reviewed data from 54 research papers to understand the adverse events of modafinil. We found that while users share some common adverse events, specific risks vary depending on why the drug is being used. These findings suggest that doctors should consider the patient's specific condition when prescribing modafinil. © 2025 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

BACKGROUND: As a rare sleep disorder, narcolepsy is treated with various therapeutic options. This article systematically analyzes the efficacy and safety of novel approved wake-promoting drugs. METHODS: Randomized controlled trials (RCTs) for patients with narcolepsy and treated with approved interventions were searched. Outcome measures included Epworth sleepiness scale (ESS) score, mean latency in the maintenance of wakefulness test (MWT), cataplexy frequency, number of subjects with ESS scores < 10, standard deviation of lane position (SDLP) score, and adverse events (including anxiety, dizziness). This paper was registered in INPLASY (INPLASY2024120052). RESULTS: The final analysis included 13 RCTs with four drugs involved: modafinil/armodafinil, sodium oxybate (SXB), pitolisant, and solriamfetol, at different dosages or combinations. All drugs were effective in treating narcolepsy compared to placebo. Solriamfetol 300 mg was more effective than other treatments in reducing ESS scores (MD = -4.74, 95%CI: -6.51,-2.97) and prolonging sleep latency (MD = 10.82 min, 95%CI: 6.99, 14.31). Several novel wake-promoting drugs did not show significant differences in improving cataplexy frequency, the number of people with ESS scores < 10, and SDLP scores. The novel wake-promoting drugs compared in this article could improve adverse effects, but some drugs showed an elevated likelihood of some adverse effects compared to controls or other drugs. Compared to placebo, SXB yielded the highest risk of gastrointestinal adverse effects such as diarrhea [8.53, (1.14,263)] and vomiting [29.5, (2.46,1.46e+03)], pitolisant induced the highest risk of nausea [4.22e+08, (4.09,1.26e+32)], and SXB+modafinil had the highest risk of dizziness [7.67, (1.01,58.7)]. There were no considerable differences among drugs in other adverse effects. CONCLUSION: All of the approved new wake-promoting drugs are effective in controlling narcolepsy symptoms with acceptable adverse effects. Trial Registration The study was prospectively registered in the INPLASY database (INPLASY2024120052). © 2025. The Author(s).

OBJECTIVES: To compare the effects of various pharmacological treatments on partial test results and adverse effects in patients with cognitive dysfunction (CD) induced by multiple sclerosis (MS) through a network meta-analysis. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were systematically retrieved for randomized controlled trials (RCTs) evaluating the influence of different pharmacological treatments on CD in MS patients. The search was updated until October 8, 2024. The Risk of Bias tool was used to assess the quality of eligible studies, and R was employed for data analysis. RESULTS: Twenrt six studies involving 23,839 MS patients were included for our analysis. Network meta-analysis results indicated that compared to placebo, L-amphetamine may improve memory in MS-induced CD. Memantine may enhance performance on the Paced Auditory Serial Addition Test (PASAT). Compared to memantine, fampridine-SR, ginkgo biloba, and melatonin showed inferior effects. Atomoxetine may improve Symbol Digit Modalities Test (SDMT) scores, outperforming donepezil, ginkgo biloba, L-amphetamine, modafinil, and rivastigmine. Additionally, atomoxetine may improve California Verbal Learning Test (CVLT) performance, compared to ginkgo biloba, L-amphetamine, and memantine. In terms of adverse effects, rivastigmine was less likely to cause dyspepsia. CONCLUSION: Based on current evidence, L-amphetamine may improve memory in MS-induced CD. Melatonin may enhance PASAT performance, and atomoxetine may improve both SDMT and CVLT scores in these patients. However, rivastigmine was found to have a lower likelihood of causing dyspepsia among the treatments assessed. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024623642.

PURPOSE: During pregnancy, it is unclear whether women with attention deficit hyperactivity disorder (ADHD) should stop prescribed medication - risking relapse - or continue - risking harm to themselves and their baby. We aimed to conduct a systematic review to examine whether ADHD medications should be continued during pregnancy. METHODS: We searched MEDLINE, Embase, PsycINFO, PubMed, CINAHL, AMED, CENTRAL, Cochrane Library, NHS Knowledge and Library Hub from 1st July 2019 to 1st July 2024, without any restrictions on language, setting, or study type. We supplemented this with relevant studies identified from the references of retrieved studies. Two authors used the Newcastle-Ottawa Scale (NOS) to independently rate the quality of included studies. RESULTS: Twelve cohort studies were included in the qualitative review. All were deemed high quality (NOS ≥ 7). Seven studies found ADHD medication use during pregnancy had no significant negative effect on maternal or offspring outcomes. One study found continuing ADHD medication reduced the risk of various negative outcomes, and another found stopping ADHD medication may increase the risk of threatened abortion. Three studies concluded that ADHD medication use was associated with negative outcomes: pre-eclampsia, gastroschisis, omphalocele, and transverse limb deficiency. Modafinil was identified as significantly increasing the risk of congenital malformations. CONCLUSION: Women taking modafinil should consider stopping it prior to pregnancy. Clinicians should discuss the risks, benefits, and uncertainties of other ADHD medications with women who are pregnant, or considering pregnancy, keeping in mind that the benefits of continuing ADHD medications- where it is effective for an individual- are likely to outweigh the risks. © 2025. Crown.

Postural orthostatic tachycardia syndrome (POTS) is defined as the presence of chronic symptoms of orthostatic intolerance accompanied by an increase in heart rate greater than 30 beats per minute within 10 min of assuming an upright posture in the absences of orthostatic hypotension. It is a condition which lacks a definitive treatment strategy, with weak evidence and clinical expertise to support the available guidelines from the Heart Rhythm Society in 2015 and the Canadian Cardiovascular Society in 2020. The limited systematic reviews evaluating the treatment for POTS only reported three or fewer trials when many more trials have been published. In this systematic review, we evaluate the evidence for different treatments for POTS from 21 randomized clinical trials with 750 patients that took place between 2000 and 2023. This review summarizes the available evidence from trials on propranolol, midodrine, pyridostigmine and ivabradine as well as less commonly used medications such as desmopressin, melatonin, atomoxetine, modafinil, sertraline and intravenous immunoglobulins. Moreover, the trial evidence for non-pharmacological treatments is described including increase intake of dietary sodium, exercise training, compression and devices. We conclude that many small trials have evaluated different treatments for POTS. Large randomized trials are needed to determine if mainstay treatments beta-blockers, midodrine, and pyridostigmine should be used as first line treatment(s).

BACKGROUND: Narcolepsy is a rare neurological cause of chronic sleepiness. This study aimed to better understand global narcolepsy through bibliometric analysis. METHODS: Articles and reviews on narcolepsy were sourced from the Web of Science Core Collection. A bibliometric analysis was performed using Microsoft Excel, Python, CiteSpace, VOSviewer, R (bibliometrix), and the Online Analysis Platform of Literature Metrology to assess publication outputs, countries, institutions, authors, journals, co-cited references, and keywords. RESULTS: The analysis included 5,215 publications, with citations significantly increasing from 1996 to 2024. The USA led in publications, while the top institutions were Stanford University, INSERM, and Université de Montpellier. Key authors like Professors Plazzi G, Mignot E, and Dauvilliers Y greatly contributed to the field through numerous publications and high citation rates. Sleep published the most articles, followed by Sleep Medicine. Keyword analysis indicated a shift toward molecular mechanisms, comorbidities, and diagnosis. Recent interest has surged in medications for excessive daytime sleepiness, such as "Pitolisant", "Modafinil" and "Sodium Oxybate" along with the relationship between narcolepsy and COVID-19. CONCLUSION: "Pitolisant," "Modafinil," and "Sodium Oxybate" have gained prominence in narcolepsy treatment. This study also highlights common comorbidities linked to narcolepsy, including "obstructive sleep apnea", "epilepsy" and "atrial fibrillation" driving researchers to explore these conditions to improve the quality of life for affected individuals. However, the interactions between key neurotransmitters in narcolepsy are still unclear, and challenges remain regarding factors that complicate drug therapy efficacy, necessitating further investigation.

OBJECTIVES: Previous studies investigated pharmacological options for reducing excessive daytime sleepiness (EDS) after traumatic brain injury (TBI), with mixed results. This meta-analysis aimed to assess the efficacy and safety of modafinil or armodafinil in post-TBI persons experiencing EDS. METHODS: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov and identified studies comparing modafinil/armodafinil versus placebo for treating EDS after TBI. We computed pooled risk ratios (RR) or mean differences (MD) for binary and continuous outcomes, respectively. EDS was assessed using the Epworth Sleepiness Scale (ESS). RESULTS: We included data from 158 individuals (mean age 34.28 years; 62.64% male) from three randomized controlled trials. In those treated with modafinil (dose range: 100-400 mg) or armodafinil (dose range: 150-250 mg), the mean ESS score was decreased in comparison with placebo (MD -1.65; 95% CI -3.26 to -0.04; p = 0.04). The risk of insomnia was higher in the modafinil/armodafinil group compared with the placebo group (RR 3.73; 95% CI 1.11 to 12.54; p = 0.03). There was no significant difference between groups in the risk of other adverse events (e.g., nausea, headache, dizziness, and nasopharyngitis). CONCLUSION: Modafinil/armodafinil effectively improved EDS after TBI, as compared with placebo, albeit with an increased risk of insomnia.

BACKGROUND: There is limited research on the course of drug craving in treatment trials of stimulant use disorders. This study examined trajectories of cocaine craving and use and their associations with other outcomes of cocaine use disorder in pharmacotherapy trials of cocaine use disorder. METHODS: In 1070 participants from 6 randomized controlled trials testing selegiline, baclofen, cabergoline, modafinil, reserpine, and tiagabine, we used multi-trajectory modeling to identify joint trajectories of weekly-measured cocaine craving and use. Association of these trajectories with Addiction Severity Index (ASI) health and social outcomes was assessed. RESULTS: A 3-trajectory model with High craving/High use (40.0 %), Decreasing craving/High use (36.8 %), and Decreasing craving/Decreasing use (23.2 %) groups was the most parsimonious. Compared to the High craving/High use group, the Decreasing craving/Decreasing use group experienced significantly greater improvement on ASI domains of drug use (change score = -13.7 vs. -3.3), alcohol use (-7.3 vs. -4.4), psychiatric status (-5.6 vs. 0.7) and relationships status (-7.0 vs. -2.8) (all p < 0.05). Compared to placebo, those on modafinil 200mg/day were more likely to be in the Decreasing craving/Decreasing use group (Relative Risk Ratio [RRR]=4.84, 95 % CI=1.38-17.00) or Decreasing craving/High use group (RRR=5.55, 2.04-14.08) than in the High craving/High use group. CONCLUSIONS: Trajectories of craving/drug use in clinical trials for cocaine use disorder are heterogeneous. Participants experiencing the greatest reduction in cocaine craving/use experienced the greatest improvement in other measures of drug use and psychosocial functioning, supporting the utility of reduced craving/use as a clinically relevant outcome in pharmacotherapy trials of people with cocaine use disorder.

BACKGROUND: Previous meta-analyses suggested methylphenidate may be effective for cancer-related fatigue. TRIAL DESIGN: Phase III, parallel-group, randomised, double-blind, placebo-controlled trial. METHODS: Participants were adults with advanced cancer with cancer-related fatigue receiving palliative care at 17 palliative care services in England between June 2018 and April 2023. PRINCIPAL EXCLUSIONS: Pregnancy; glaucoma; pheochromocytoma; planned general anaesthesia; hyperthyroidism; severe psychiatric disorders; hypertension; severe cardiovascular disorders; cerebrovascular disorders; anaemia; thrombocytopenia; leucopenia; infection; renal or liver impairment; concomitant clonidine, warfarin, monoamine oxidase inhibitors or modafinil; alcohol or drug dependency; epilepsy. INTERVENTIONS: Methylphenidate 5 mg tablets or matching placebo. Starting at 1 tablet twice daily, titrated over 6 weeks to a maximum of 12 tablets/day. OBJECTIVE: To estimate clinical effectiveness of methylphenidate versus placebo for cancer-related fatigue in patients receiving palliative care. PRIMARY OUTCOME: Fatigue at 6 (± 2) weeks measured using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale score. Secondary outcomes were fatigue at other time points; quality of life, adverse events, activities of daily living; appetite; anxiety; depression; patient satisfaction; survival and need for other medication. RANDOMISATION: Computer-generated 1 : 1 randomisation, stratified by centre, concomitant treatment, depression and initial fatigue score. BLINDING: Participants and outcome assessors were blinded to group assignment. RESULTS: Eighty-four were allocated to methylphenidate and 78 to placebo. RECRUITMENT: : Study completed. NUMBERS ANALYSED: Seventy-five in methylphenidate group and 72 in placebo group were included in analysis of primary outcome. OUTCOME: There was no statistically or clinically significant difference in primary outcome between groups. Functional Assessment of Chronic Illness Therapy - Fatigue Scale scores were 1.97 points (95% confidence interval -0.95 to 4.90; p = 0.186) higher (better) on methylphenidate than placebo. Functional Assessment of Chr

Modafinil promotes wakefulness and enhances cognitive function through mechanisms and neural effects that are still partially unknown. Several studies have shown that the compound alters the functional cortical architecture. In contrast, its influence on subcortical regions and thalamocortical connections, which are crucial for modulating neocortical connectivity, remains unexplored. The acute modulation of thalamo-cortical connectivity was assessed in two groups of participants who received either a single 100 mg dose of modafinil (N = 25) or a placebo (N = 25). Magnetic Resonance Imaging (MRI) was used to parcel the thalamus into its constituent nuclei, which served as seeds for voxel-wise resting state functional connectivity analyses. Additionally, maps of nuclei-specific functional reorganization were compared to those of receptor/transporter expression to assess their spatial overlaps. Modafinil, but not placebo, altered the connectivity of three thalamic nuclei. Specifically, the medial pulvinar nuclei showed increased connectivity with cortical regions of the Sensorimotor and Salience/Ventral Attention (SVAN) Networks. These functional changes spatially overlapped with the distribution of the norepinephrine transporter (NET). Additionally, the anterior and inferior pulvinar complex exhibited enhanced connectivity with the insular and supramarginal regions of the SVAN and superior frontal area of the Default Mode Network (DMN). However, unlike the medial pulvinar, these effects were not spatially linked to the expression of any specific receptor or transporter. Finally, the ventro-lateral anterior complex exhibited increased connectivity with the posterior region of the DMN and the Fronto-Parietal Control Network, along with decreased connectivity to the premotor cortex. The topography of these functional modifications mainly overlaps with the distribution of glutamatergic and serotonergic receptors. In summary, our findings highlight modafinil's influence on thalamocortical circuits, emphasizing the role of higher-order pulvinar nuclei and ventro-lateral anterior complex.

It is debated whether seasonal variation in outside temperature contributes to MS fatigue, one of the disease's most common symptoms. We analyzed the effect of the season on the baseline fatigue levels in our randomized, placebo-controlled, crossover, double-blind trial, Treatment of Fatigue with Methylphenidate, Modafinil, and Amantadine in MS (TRIUMPHANT-MS) conducted in two sites with very different climates. Fatigue was measured using two validated instruments (Modified Fatigue Impact Scale (MFIS) and Neuro-QoL fatigue score). MFIS scores varied with season and study site, while Neuro-QoL fatigue scores did not. The impact of temperature on multiple sclerosis fatigue depends on the specific patient-reported outcome measure employed.

BACKGROUND: Traumatic Brain Injury (TBI) is a leading cause of hospitalization and disability in young and middle-aged adults. This study aims to survey the efficacy of oral modafinil, a low-side-effect central nervous system stimulant, in the enhancement of consciousness recovery in moderate to severe TBI patients in the ICUs of a referral trauma center. MATERIALS AND METHODS: All ICU patients meeting inclusion criteria between April 2021 and April 2023 were screened. Eligible patients had a motor Glasgow Coma Score(GCS) of 4 or 5 and did not receive continuous intravenous sedatives within 24 h before screening. They were randomly assigned to receive 200mg of enteral modafinil or placebo daily for 7 days. Motor GCS and total GCS scores, ICU/hospital stay duration, mechanical ventilation requirement, tracheal tube removal time, and tracheostomy needs were recorded. RESULTS: Among the included 85 eligible patients, there was no significant difference between the modafinil and placebo groups in the median days between the intervention and the time of a 2-unit increase in total GCS (P = 0.25) or a 1-unit increase in motor GCS (P-value = 0.31). The group assignment also had no impact on the mean GCS (P-value = 0.533) and mean motor GCS (P-value = 0.167) over time. The only significant difference was in the proportion of patients with an increase in total GCS by 2 units, which was 54% for the modafinil vs. 32% for the placebo group (P-value = 0.04), and an increase in motor GCS by 1 unit, with 56% in the modafinil vs. 34% in the placebo group (P-value = 0.04). CONCLUSION: The administration of modafinil appears to be safe and beneficial for patients with severe TBI during their stay in the ICU. © 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

BACKGROUND: Modafinil is primarily used to treat narcolepsy but is also used as an off-label cognitive enhancer. Functional magnetic resonance imaging studies indicate that modafinil modulates the connectivity of neocortical networks primarily involved in attention and executive functions. However, much less is known about the drug's effects on subcortical structures. Following preliminary findings, we evaluated modafinil's activity on the connectivity of distinct cerebellar regions with the neocortex. We assessed the spatial relationship of these effects with the expression of neurotransmitter receptors/transporters. METHODS: Patterns of resting-state functional magnetic resonance imaging connectivity were estimated in 50 participants from scans acquired pre- and postadministration of a single (100 mg) dose of modafinil (n = 25) or placebo (n = 25). Using specific cerebellar regions as seeds for voxelwise analyses, we examined modafinil's modulation of cerebellar-neocortical connectivity. Next, we conducted a quantitative evaluation of the spatial overlap between the modulation of cerebellar-neocortical connectivity and the expression of neurotransmitter receptors/transporters obtained by publicly available databases. RESULTS: Modafinil increased the connectivity of crus I and vermis IX with prefrontal regions. Crus I connectivity changes were associated with the expression of dopaminergic D2 receptors. The vermis I-II showed enhanced coupling with the dorsal anterior cingulate cortex and matched the expression of histaminergic H3 receptors. The vermis VII-VIII displayed increased connectivity with the visual cortex, an activity associated with dopaminergic and histaminergic neurotransmission. CONCLUSIONS: Our study reveals modafinil's modulatory effects on cerebellar-neocortical connectivity. The modulation mainly involves crus I and the vermis and spatially overlaps the distribution of dopaminergic and histaminergic receptors.

BACKGROUND: Fatigue is one of the most disabling symptoms reported by people with multiple sclerosis. Although behavioural and pharmacological interventions might be partly beneficial, their combined effects have not been evaluated for multiple sclerosis fatigue, or examined with sufficient consideration of characteristics that might affect treatment response. In this comparative effectiveness research trial, we compared the effectiveness of cognitive behavioural therapy (CBT), modafinil, and their combination for treating multiple sclerosis fatigue. METHODS: This randomised, analyst-blinded, parallel-arm, comparative effectiveness trial was done at two universities in the USA. Adults (aged ≥18 years) with multiple sclerosis and problematic fatigue (Fatigue Severity Scale [FSS] score ≥4) were randomly assigned (1:1:1), using a web-based treatment assignment system with minimisation, to receive CBT, modafinil, or both for 12 weeks. Statisticians were masked to group assignment, but participants, study neurologists, CBT interventionalists, and coordinators were not masked to treatment assignment. The primary outcome was the change in Modified Fatigue Impact Scale (MFIS) from baseline to 12 weeks, assessed using multiple linear regression, adjusted for age, sex, study site, anxiety, pain, baselines MFIS score, and physical activity. Analyses were done by intent to treat. The trial was registered with clinicaltrials.gov, NCT03621761, and is completed. FINDINGS: Between Nov 15, 2018, and June 2, 2021, 336 participants were randomly assigned treatment (114 assigned to CBT, 114 assigned to modafinil, and 108 assigned to combination therapy). At 12 weeks, CBT (n=103), modafinil (n=107), and combination therapy (n=102) were associated with clinically meaningful within-group MFIS reductions of 15·20 (SD 11·90), 16·90 (15·90), and 17·30 (16·20) points, respectively. Change in MFIS scores from baseline to 12 weeks did not differ between groups: relative to combination therapy, the adjusted total mean difference in MFIS change score was 1·88 (95% CI -2·21 to 5·96) for CBT and 1·20 (-2·83 to 5·23) for modafinil. Most common adverse events for modafinil-containing treatment gr

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. . © 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

BACKGROUND: Studies have found that the use of clinically approved caffeine and modafinil can alleviate cognitive impairment due to sleep deprivation (SD) to some extent. However, the neural mechanisms by which these two cognitive enhancers work to counteract the effects of SD on cognitive impairment remain unclear. METHODS: A double-blind within-subjects experiment using resting-state functional magnetic resonance imaging (rs-fMRI) was designed. Participants underwent three 36-h SD trials, each of which involved taking 200 mg of caffeine, modafinil, or placebo at the 28th and 32 nd h of SD. Sixteen subregions of the thalamus were selected as the regions of interest and changes in functional connectivity (FC) between the thalamus and the other brain regions were explored after the participants took caffeine or modafinil. RESULTS: The subjective sleepiness of the participants increased with the duration of SD. compared with placebo, modafinil and caffeine had insignificant effects on wakefulness or sleepiness. However, in terms of neural FC, we found varying degrees of attenuation or enhancement of the FC between the thalamus and other regions. Taking caffeine during SD weakened the FC between the right rostral temporal thalamus (rTtha) subregion and the left lingual gyrus compared with placebo. Caffeine enhanced the FC between three subregions of the thalamus, namely the left sensory thalamus, the left rTtha, and the right lateral pre-frontal thalamus, and the right inferior temporal, left orbitofrontal, and right superior occipital gyris. Modafinil weakened the FC between the right posterior parietal thalamus and left middle temporal gyrus, and enhanced the FC between the left medial pre-frontal thalamus, left rTtha, and right occipital thalamus and left middle frontal gyrus. CONCLUSIONS: After 36 h of total SD, modafinil and caffeine administration enhanced or attenuated the time-domain correlations between various subregions of the thalamus and brain regions of the frontal and temporal lobes in healthy adults, compared with placebo. These results provide valuable evidence for further unraveling the neuropharmacological mechanisms of caffeine and modafinil, as

The perception of taking a generic, relative to brand, medication has been demonstrated to exacerbate the nocebo effect. Conversely, positive attribute framing has been shown to attenuate the nocebo effect. However, little is known about the longevity of positive attribute framing nor how it interacts with generic versus brand treatment cues. Healthy participants (N = 205) were randomised to receive either sham-modafinil capsules with a brand or generic appearance, in conjunction with standard negative side effect framing (brand-negative: N = 42; generic-negative: N = 41) or positive side effect framing (brand-positive: N = 40; generic-positive: N = 40). The remainder were randomised to a no-treatment control (N = 42). Participants were informed that modafinil could enhance alertness and cognitive performance and reduce fatigue. Critically, modafinil was described as having several potential side effects. Treatment-related side effects, alertness, fatigue and cognitive performance were measured at baseline, 30-min post-treatment and 24 h later. Nocebo and placebo effects were observed across modafinil-treated participants relative to control. Positive framing significantly reduced warned side effects for 24 h. Perceived side effect likelihood, severity, and worry mediated the nocebo, but not framing, effect. Results have important implications for the presentation of side effect information, providing a potential route to reduce unwanted negative effects of generic medication. © 2024 The Author(s). Applied Psychology: Health and Well‐Being published by John Wiley & Sons Ltd on behalf of International Association of Applied Psychology.

PURPOSE: The dispense of methylphenidate (MPH) for attention-deficit hyperactivity disorder (ADHD) treatment often raises concerns about overdiagnosis, over-, mis-, and abuse. However, in-depth temporal analyses on dispensing and reimbursement data are lacking in Belgium and globally. METHODS: Longitudinal trends in the dispensing of MPH and its alternatives, including atomoxetine (ATO), modafinil (MOD), and guanfacine (GUA), were analyzed from 2011 to 2022 in Belgium using data from IFSTAT and IQVIA databanks. The dataset uniquely separates MPH and MOD into reimbursed and non-reimbursed categories across age groups (6-17 and > 17 years). These trends were further examined in the context of international literature to provide a comprehensive framework for comparison. RESULTS: MPH is the most prescribed ADHD medication. Over the 12-year study period, all included drugs showed an increasing trend. For MPH and MOD, this rise is driven by non-reimbursed dispensing, while reimbursed dispensing remained stable. During summer months, a seasonal drop in MPH dispensing for the 6-17Y age group suggests an annual 'MPH drug holiday' to evaluate the necessity of continued use. While comprehensive pharmacovigilance is currently limited by insufficient demographic data and specific prescription indications, addressing these gaps presents an opportunity to better understand the underlying causes of observed dispensing trends. CONCLUSION: Differentiating between reimbursed and non-reimbursed dispensing is crucial to accurately describe the increasing use of this group of ADHD medication. More granular data is needed to assess whether changes to prescribing practices are necessary and to inform future development of guidelines. Plain Language Summary: The dispensing of methylphenidate for ADHD treatment raises concerns about overdiagnosis, misuse, and abuse. However, comprehensive temporal analyses of dispensing and reimbursement data remain limited in Belgium and internationally. The dataset uniquely separates MPH and MOD into reimbursed and non‐reimbursed categories across age groups (6–17 and > 17 years). Over the 12‐year study period, all included drugs showed an increasing

Modafinil is a well-established wake-promoting agent with emerging applications as a cognitive enhancer; however, its clinical potential is constrained by poor aqueous solubility and suboptimal systemic absorption, limiting effective brain delivery. This study presents transethosomes as a hitherto unexplored nanocarrier for modafinil and combines design-driven formulation with nuclear imaging-based biodistribution. Transethosomal vesicles were prepared using the ethanol injection method and systematically optimized through a 23 factorial design employing Design-Expert® software. Key formulation variables were investigated for their impact on EE%, PS, PDI, and ZP. Additionally, an in-vivo biodistribution and pharmacokinetic studies were conducted after labeling MOD with Technetium-99 m using sodium dithionite as a reducing agent. The optimized formulation achieved a high desirability value (0.919), superior EE% (85.87%), nanoscale PS (180.30 nm), and a negative ZP (- 42.60 mV), indicative of excellent vesicular stability. Morphological and FTIR analyses confirmed spherical vesicles, drug-excipient compatibility, and preservation of Modafinil's structure. In-vitro studies demonstrated a controlled biphasic release, supporting sustained drug availability, while stability assessments revealed no significant changes in vesicular characteristics over time. Ex-vivo studies highlighted markedly enhanced permeability, due to improved membrane fluidity and vesicle deformability from ethanol and the edge activator. The radiolabeling efficiency was high (92.18%), and it was stable for two hours. Biodistribution and pharmacokinetic studies confirmed significantly higher brain drug accumulation, elevated brain Cmax (5.4%ID/g) and AUC, reduced Tmax (10 min) and high relative bioavailability (424.3 ± 4.5%). Importantly, histopathological examination of nasal mucosa revealed normal architecture. Collectively, these findings establish transethosomes as a promising and safe nano-platform for advanced brain targeting. HIGHLIGHTS: Modafinil-loaded transethosomes were designed as nanovesicles for brain targeting. The optimized formulation showed spherical morphology, uniform size dis

Psychostimulants act on monoamine systems including the dopamine transporter (DAT), a key regulator of dopamine reuptake following synaptic release. While these compounds can enhance energy, cognition, and sociability, their clinical utility is often limited by their abuse potential and peripheral side effects. Research has traditionally focused more on their addictive properties rather than their therapeutic potential. However, certain psychostimulants, such as R-modafinil, enhance cognitive performance without inducing significant euphoria or addiction, making them promising lead candidates for clinical application. In this study, we hypothesized that R-modafinil analogs with extended residence time at DAT (i.e., slow koff) would enhance cognitive function more effectively. To test this, we evaluated a series of R-modafinil analogs using in vitro equilibrium and non-equilibrium measurements, in vivo fast-scan cyclic voltammetry, and highly translational cognitive assays in both healthy and scopolamine-treated rats modelling cognitive impairment. Our findings show that prolonging DAT occupancy improves dopamine signalling and leads to more robust enhancements in cognitive flexibility. Compounds with longer DAT resident time-such as S-MK-26 and (S,S)-CE-158-produced the strongest cognitive effects. These results highlight the importance of DAT binding kinetics in shaping the behavioural actions of psychostimulants and support the development of safer and more effective dopamine-based cognitive enhancers.

Concerns exist that psychostimulants may increase the risk of psychosis, particularly in individuals with a history of psychosis. This study assessed whether psychosis risk increases after initiating psychostimulant or atomoxetine treatment in individuals with prior psychotic events. In this cohort study, we used Swedish population-based register data that contain data on all Swedish residents. We identified adults aged 18-64, who had a history of psychosis and initiated psychostimulant or atomoxetine treatment between 2008 and 2021. A within-individual design compared the rate of psychotic events in two 6-month periods before and after treatment initiation. Rate ratios (RR) with 95% confidence intervals (CI) were estimated. Sensitivity analyses were stratified by sex, age groups, and medication classes and also investigated substance-related psychosis as alternative outcome. We identified 3,770 individuals with a history of psychosis that received psychostimulant or atomoxetine prescriptions during the study period. Compared to the period before treatment initiation, the RR for psychotic events in the six months following treatment initiation was 0.95 (95% CI 0.84-1.08). Sensitivity analyses, considering only substance-induced psychotic events, or eight-week intervals and subgroup analyses by sex, age groups and separately for individuals receiving either (dex-)methyphenidate or (lis-)dexamphetamine or atomoxetine or (ar-)modafinil showed consistent results. Contrary to concerns, psychostimulant or atomoxetine treatment was not associated with an increased risk of psychotic events in adults with a history of psychosis. These findings may inform clinicians considering psychostimulant prescriptions in this population. © 2026. The Author(s).

We review the literature regarding repurposed medications for major depressive disorder (MDD). Preclinical and clinical research on repurposed medications for MDD was reviewed, including agents that modulate the dopaminergic, glutamatergic, and GABAergic systems; enhance neurotrophic signalling; and reduce neuroinflammation, as well as nutraceuticals. Telmisartan, statins, celecoxib, valproic acid, pregabalin, metformin, pioglitazone, ketamine, dextromethorphan-bupropion, aripiprazole, and modafinil show effectiveness in the treatment of MDD, as do nutritional supplements such as vitamin D, zinc, selenium, and spermidine. Mechanisms include neurotransmission modulation, neuroplasticity promotion, and neuroinflammatory cascade suppression. However, the current evidence is limited by a lack of large-scale randomised controlled trials and insufficient mechanistic characterisation. Drug repurposing leverages proven safety profiles while reducing development costs and time. Nonetheless, clinical studies are needed to confirm effectiveness, elucidate mechanisms, and specify their incorporation into clinical practice.

BACKGROUND: In our clinical practice, we encountered a patient with autism spectrum disorder (ASD) and comorbid narcolepsy who developed dyskinesia following the administration of modafinil for excessive daytime sleepiness. Modafinil is widely prescribed as a wakefulness-promoting agent for the treatment of narcolepsy. Although dyskinesia has been reported as a potential adverse effect of modafinil, to our knowledge, no cases have been described in individuals with ASD. We hypothesized that modafinil contributed to the development of dyskinesia in this patient and conducted a literature review to explore the possible underlying mechanisms. CASE PRESENTATION: A 24-year-old Japanese woman with ASD was diagnosed with narcolepsy type 2. She had previously been treated with aripiprazole for ASD-related symptoms, but it had been discontinued more than two weeks before the sleep study. Modafinil was initiated at 100 mg/day and increased to 200 mg/day after three weeks because of insufficient efficacy. Two weeks after the dose increase, dyskinesia developed. A literature review was performed to identify potential mechanisms. Dyskinesia may have resulted from dysregulated striatal dopamine release associated with ASD and residual dopamine D2 receptor blockade from prior aripiprazole use, triggered by modafinil. CONCLUSION: Dopaminergic agents in individuals with ASD may induce dyskinesia, particularly following dose escalation, underscoring the need for clinical vigilance. © 2026. The Author(s).

The present experiments determined the role of the α1-adrenergic receptor in mediating the behavioral actions of caffeine in rats utilizing two different paradigms: drug discrimination (DD) and conditioned taste avoidance (CTA). After rats achieved response proficiency (80% caffeine-appropriate responding) with caffeine (30 mg/kg) during DD training, rats underwent stimulus generalization tests in which rats were administered vehicle (0.5% gum Arabic) or modafinil (5, 10 or 20 mg/kg) 30 min prior to the session, as determined by a Latin-Square design. In the CTA experiment, two conditioning sessions occurred 48-h apart in which rats received 15 min access to salt water (0.6%) followed immediately by an injection of vehicle (distilled water) or prazosin (0.5, 1.0, or 2.0 mg/kg) and then 5 min later a second injection of vehicle (physiological saline) or caffeine (30 mg/kg). The test session occurred 96 h after the last conditioning session. The α1-adrenergic agonist, modafinil, dose-dependently generalized to caffeine. The selective α1-adrenergic antagonist, prazosin, dose-dependently potentiated caffeine-induced CTA. Taken together, these results suggest that the α1-adrenergic receptor system contributes to the behavioral actions of a moderate caffeine dose.

Disorders of consciousness pose major therapeutic challenges owing to the complexity of underlying brain dysfunctions. Current pharmacological interventions explored in disorders of consciousness target distinct molecular systems, including dopaminergic modulators (amantadine, levodopa, apomorphine, bromocriptine, selegiline, methylphenidate, and modafinil), GABAergic agents (zolpidem and baclofen), and other neuromodulatory compounds acting on glutamatergic, opioid, or serotonergic receptors (ketamine, remifentanil, and psilocin). These treatments aim to modulate disrupted neural circuits, including the mesocircuit, a thalamocortical-striatal network critically involved in consciousness and motor control. This review explores the pathophysiological mechanisms underlying disorders of consciousness and the pharmacological profile of these agents. It summarizes reported clinical improvements and discusses determinants of therapeutic response, highlighting the role of biomarkers derived from neurophysiological and neuroimaging assessments. Safety profiles associated with these treatments are also critically evaluated to guide clinical decision making. By integrating current knowledge on pharmacological modulation of key neural systems, including dopaminergic and GABAergic pathways, this article provides a comprehensive framework for understanding treatment strategies in disorders of consciousness. © 2026. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

BACKGROUND: Comorbid attention-deficit/hyperactivity disorder (ADHD) increases the burden in bipolar disorder (BD). Concerns about the risk/benefit balance of ADHD treatment have been raised. OBJECTIVE: This study aimed to investigate the association between hospital admissions and add-on ADHD medications to antipsychotics and/or mood-stabilisers (APs/MSs) compared with AP/MS alone in BD. METHODS: Individuals with BD prescribed ADHD medications in Sweden during 2006-2021 were identified from national registers of inpatient care, specialised outpatient care, sickness absence and disability pension. ADHD treatment was defined as stimulants (mostly methylphenidate and lisdexamfetamine, rarely amphetamine, dexamphetamine) and non-stimulants (atomoxetine, modafinil). Add-on ADHD treatment to concomitant AP/MS was compared with treatment periods with AP/MS without ADHD treatment, using within-individual models where individuals acted as their own control. Adjusted HRs (aHRs) and CIs (95% CIs) were calculated for the primary outcome of psychiatric hospitalisation, and for the secondary outcomes: substance-use-related, somatic or mania-related hospitalisations, and all-cause hospitalisation/mortality. RESULTS: Altogether, 17 971 individuals (mean age=32.0±11.6 years, males=37.6%, ADHD=88.9%, follow-up=8.9±4.4 years) with BD who used any ADHD treatment were included. compared with the use of AP/MS alone, add-on stimulant use was related to a lower risk of psychiatric hospitalisations (aHR=0.89, 95% CI 0.85 to 0.93), substance-related hospitalisations (aHR=0.75, 95% CI 0.70 to 0.81) and all-cause hospitalisations/mortality (aHR=0.90, 95% CI 0.87 to 0.93), but was not associated with increased risk for somatic (aHR=1.00, 95% CI 0.90 to 1.12) or mania-related hospitalisations (aHR=0.93, 95% CI 0.72 to 1.20). Of commonly used specific ADHD medications, add-on lisdexamfetamine (aHR=0.81, 95% CI 0.75 to 0.87) and methylphenidate (aHR=0.92, 95% CI 0.88 to 0.97) were associated with decreased risk of psychiatric hospitalisations while add-on atomoxetine was not. Findings on substance-use-related hospitalisations were significant only for stimulants, specifically lisdexamfetamine

CLINICAL CHARACTERISTICS: Prader-Willi syndrome (PWS) is characterized by severe hypotonia, poor appetite, and feeding difficulties in early infancy, followed in early childhood by excessive eating and gradual development of morbid obesity (unless food intake is strictly controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone). A distinctive behavioral phenotype (temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Characteristic facial features, strabismus, and scoliosis are often present. DIAGNOSIS/TESTING: PWS is a contiguous gene syndrome due to abnormal DNA methylation within the Prader-Willi critical region (PWCR) at 15q11.2-q13. The diagnosis and molecular cause can be identified in a proband by simultaneous DNA methylation analysis and oligo-SNP combination array (OSA). DNA methylation analysis identifies maternal-only imprinting within the PWCR. OSA can identify the molecular cause in those with a 15q11.2-q13 deletion, imprinting center deletion, and uniparental isodisomy and segmental isodisomy. In individuals with maternal-only imprinting identified on DNA methylation analysis and a normal OSA, DNA polymorphism analysis can be used to distinguish uniparental heterodisomy from an imprinting defect by epimutation. MANAGEMENT: Targeted therapy: Diazoxide choline for hyperphagia. Supportive care: In infancy, special nipples or nasogastric tube feeding to assure adequate nutrition. In childhood, strict supervision of daily food intake based on height, weight, and body mass index (BMI) to provide energy requirements while limiting excessive weight gain (maintain BMI z score <2); encourage physical activity. Developmental services and educational support; hormonal and surgical treatments can be considered for cryptorchidism; growth hormone therapy to normalize height, increase lean body mass and mobility, and decrease fat mass; endoc