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Psychopharmacology Feb 2021At all times humans have made attempts to improve their cognitive abilities by different means, among others, with the use of stimulants. Widely available stimulants... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONAL
At all times humans have made attempts to improve their cognitive abilities by different means, among others, with the use of stimulants. Widely available stimulants such as caffeine, but also prescription substances such as methylphenidate and modafinil, are being used by healthy individuals to enhance cognitive performance.
OBJECTIVES
There is a lack of knowledge on the effects of prescription stimulants when taken by healthy individuals (as compared with patients) and especially on the effects of different substances across different cognitive domains.
METHODS
We conducted a pilot study with three arms in which male participants received placebo and one of three stimulants (caffeine, methylphenidate, modafinil) and assessed cognitive performance with a test battery that captures various cognitive domains.
RESULTS
Our study showed some moderate effects of the three stimulants tested. Methylphenidate had positive effects on self-reported fatigue as well as on declarative memory 24 hours after learning; caffeine had a positive effect on sustained attention; there was no significant effect of modafinil in any of the instruments of our test battery. All stimulants were well tolerated, and no trade-off negative effects on other cognitive domains were found.
CONCLUSIONS
The few observed significant positive effects of the tested stimulants were domain-specific and of rather low magnitude. The results can inform the use of stimulants for cognitive enhancement purposes as well as direct further research to investigate the effects of stimulants on specific cognitive domains that seem most promising, possibly by using tasks that are more demanding.
Topics: Adult; Attention; Caffeine; Central Nervous System Stimulants; Cognition; Double-Blind Method; Fatigue; Humans; Male; Methylphenidate; Modafinil; Nootropic Agents; Pilot Projects; Treatment Outcome; Young Adult
PubMed: 33201262
DOI: 10.1007/s00213-020-05691-w -
British Journal of Pharmacology May 2019Sleep deprivation compromises learning and memory in both humans and animals, and can be reversed by administration of modafinil, a drug promoting wakefulness....
BACKGROUND AND PURPOSE
Sleep deprivation compromises learning and memory in both humans and animals, and can be reversed by administration of modafinil, a drug promoting wakefulness. Dysfunctional autophagy increases activation of apoptotic cascades, ultimately leading to increased neuronal death, which can be alleviated by autophagy inhibitors. This study aimed to investigate the alleviative effect and mechanism of modafinil on the excessive autophagy occurring in the hippocampus of mice with deficiency of learning and memory induced by sleep deprivation.
EXPERIMENTAL APPROACH
The Morris water maze was used to assess the effects of modafinil on male C57BL/6Slac mice after 48-hr sleep deprivation. The HT-22 hippocampal neuronal cell line was also used. Nissl staining, transmission electron microscope, immunofluorescence, Western blot, transient transfection, and autophagy inducer were used to study the effect and mechanism of modafinil on hippocampal neurons with excessive autophagy and apoptosis.
KEY RESULTS
Modafinil improved learning and memory in sleep-deprived mice, associated with the inhibition of excessive autophage and apoptosis and an enhanced activation of the PI3K/Akt/mTOR/P70S6K signalling pathway in hippocampal neurons. These effects of modafinil were abolished by rapamycin. In addition, modafinil suppressed the aberrant autophagy and apoptosis induced by rapamycin and reactivated PI3K/Akt/mTOR/P70S6K signals in HT-22 cells.
CONCLUSIONS AND IMPLICATIONS
These results suggested that modafinil alleviated impaired learning and memory of sleep-deprived mice potentially by suppressing excessive autophagy and apoptosis of hippocampal neurons. This novel mechanism may add to our knowledge of modafinil in the clinical treatment of impaired memory caused by sleep loss.
Topics: Animals; Apoptosis; Autophagy; Central Nervous System Stimulants; Hippocampus; Male; Mice; Mice, Inbred C57BL; Modafinil; Neurons; Protective Agents; Sleep Deprivation
PubMed: 30767208
DOI: 10.1111/bph.14626 -
The Lancet. Neurology Jan 2021Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their...
BACKGROUND
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.
METHODS
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.
FINDINGS
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).
INTERPRETATION
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.
FUNDING
Patient-Centered Outcomes Research Institute.
Topics: Adult; Amantadine; Central Nervous System Stimulants; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Fatigue; Female; Humans; Male; Methylphenidate; Middle Aged; Modafinil; Multiple Sclerosis; Outcome Assessment, Health Care; Severity of Illness Index
PubMed: 33242419
DOI: 10.1016/S1474-4422(20)30354-9 -
Human Brain Mapping Oct 2022Stimulants like methylphenidate, modafinil, and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional... (Randomized Controlled Trial)
Randomized Controlled Trial
Stimulants like methylphenidate, modafinil, and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebocontrolled study of methylphenidate, modafinil, and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the frontoparietal network (FPN) and default mode network (DMN) is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine's role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g., FPN and DMN) as a potential cognitive enhancement mechanism.
Topics: Adult; Brain; Brain Mapping; Caffeine; Central Nervous System Stimulants; Cognition; Double-Blind Method; Humans; Magnetic Resonance Imaging; Male; Methylphenidate; Modafinil; Neural Pathways
PubMed: 35670369
DOI: 10.1002/hbm.25949 -
Frontiers in Bioscience (Landmark... Jan 2019Modafinil (Mo) is increasingly being used as an enhancement drug rather than for its therapeutic effects. The effects of this drug have been examined in attention... (Review)
Review
Modafinil (Mo) is increasingly being used as an enhancement drug rather than for its therapeutic effects. The effects of this drug have been examined in attention deficit disorders, depression, mental fatigue, and in enhancing concentration. The drug possesses wakefulness-promoting properties which are mediated through the interaction of orexinergic system with the activated sympathetic nervous system. Mo exerts a synergistic effect on the orexin system, controls energy expenditure and strengthens the ability of the individual to exercise. Some view Mo as a drug that enhances sports performance, since it induces a prolonged wakefulness and decreasing the sense of fatigue. These characteristics being similar to conventional stimulants have allowed Mo to emerge as a novel stimulant requiring medico-legal considerations. However, more studies are needed to better understand the mid and long-term effects of the drug on user/abuser.
Topics: Animals; Attention; Central Nervous System; Cognition; Humans; Modafinil; Neurons; Orexins; Wakefulness; Wakefulness-Promoting Agents
PubMed: 30468674
DOI: 10.2741/4736 -
Substance Use & Misuse Aug 2017Currently, there is none FDA-approved medication to treat cocaine dependency. Studies conducted with various medications, including antipsychotics, antidepressants,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Currently, there is none FDA-approved medication to treat cocaine dependency. Studies conducted with various medications, including antipsychotics, antidepressants, anticonvulsants, and others, revealed inconsistent results.
OBJECTIVES
To meta-analytically investigate the efficacy and safety of modafinil in the treatment of cocaine-dependent patients.
METHODS
Randomized controlled trials with ≥20 subjects comparing the numerical therapeutic outcomes of modafinil with placebo were identified in databases, such as PUBMED, psycINFO, EMBASE, and Clinicaltrials.gov. Relevant data on efficacy and safety were extracted. Relative risk (RR) and standardized mean difference were applied for reporting dichotomous and continuous outcomes respectively. Random effects, subgroup, and meta-regression analyses were conducted to further explore the results and evaluate for any moderators.
RESULTS
In total, 11 studies (participants = 896, duration = 6.7 ± 1.9 weeks) comparing modafinil with placebo were systematically analyzed, which indicated that modafinil was not superior to placebo in improving the treatment retention rate (studies = 11, participants = 891, RR = 1.030, 95% CI = 0.918-1.156, p = .613). Similarly, data from 7/11 studies did not evidence superiority of modafinil in achieving cocaine abstinence (participants = 696, RR = 1.259, 95% CI = 0.813-1.949, p = .302). However, subgroup analysis of six studies conducted in the United States demonstrated superiority of modafinil in cocaine abstinence rate (studies = 6, participants = 669, 95% CI = 1.027-2.020, p = 0.035). In addition, no evidence suggested modafinil-related discontinuation or specific adverse events than placebo.
CONCLUSIONS
Overall, there is no evidence to conclude superiority of modafinil in increasing cocaine abstinence and treatment retention rate. However, promising result in subgroup analysis of cocaine abstinence, secondary outcomes, and good safety profile urged the need of larger studies to derive more conclusive results.
Topics: Benzhydryl Compounds; Cocaine-Related Disorders; Humans; Modafinil
PubMed: 28350194
DOI: 10.1080/10826084.2016.1276597 -
Advances in Pharmacology (San Diego,... 2024Modafinil is a central nervous system stimulant approved for the treatment of narcolepsy and sleep disorders. Due to its wide range of biochemical actions, modafinil has...
Modafinil is a central nervous system stimulant approved for the treatment of narcolepsy and sleep disorders. Due to its wide range of biochemical actions, modafinil has been explored for other potential therapeutic uses. Indeed, it has shown promise as a therapy for cognitive disfunction resulting from neurologic disorders like ADHD, and as a smart drug in non-medical settings. The mechanism(s) of actions underlying the therapeutic efficacy of this agent remains largely elusive. Modafinil is known to inhibit the dopamine transporter, thus decreasing dopamine reuptake following neuronal release, an effect shared by addictive psychostimulants. However, modafinil is unique in that only a few cases of dependence on this drug have been reported, as compared to other psychostimulants. Moreover, modafinil has been tested, with some success, as a potential therapeutic agent to combat psychostimulant and other substance use disorders. Modafinil has additional, but less understood, actions on other neurotransmitter systems (GABA, glutamate, serotonin, norepinephrine, etc.). These interactions, together with its ability to activate selected brain regions, are likely one of the keys to understand its unique pharmacology and therapeutic activity as a CNS stimulant. In this chapter, we outline the pharmacokinetics and pharmacodynamics of modafinil that suggest it has an "atypical" CNS stimulant profile. We also highlight the current approved and off label uses of modafinil, including its beneficial effects as a treatment for sleep disorders, cognitive functions, and substance use disorders.
Topics: Humans; Modafinil; Central Nervous System Stimulants; Benzhydryl Compounds; Dopamine; Substance-Related Disorders
PubMed: 38467484
DOI: 10.1016/bs.apha.2023.10.006 -
Current Opinion in Pharmacology Feb 2021Pharmacotherapeutics for treatment of psychostimulant use disorder are still an unmet medical goal. Recently, off label use of modafinil (MOD), an approved medication... (Review)
Review
Pharmacotherapeutics for treatment of psychostimulant use disorder are still an unmet medical goal. Recently, off label use of modafinil (MOD), an approved medication for treatment of sleep disturbances, has been tested as a therapeutic for cocaine and methamphetamine use disorder. Positive results have been found in subjects dependent on psychostimulants without concurrent abuse of other substances. Novel structural analogs of MOD have been synthesized in the search for compounds with potentially broader therapeutic efficacy than the parent drug. In the present report we review their potential efficacy as treatments for psychostimulant abuse and dependence assessed in preclinical tests. Results from these preclinical proof of concept studies reveal that some modafinil analogs do not possess typical cocaine-like neurochemical and behavioral effects. Further, they might blunt the reinforcing effects of psychostimulants in animal models, suggesting their potential efficacy as pharmacotherapeutics for treatment of psychostimulant use disorders.
Topics: Animals; Benzhydryl Compounds; Central Nervous System Stimulants; Cocaine; Dopamine Uptake Inhibitors; Humans; Modafinil
PubMed: 32927246
DOI: 10.1016/j.coph.2020.07.007 -
European Neuropsychopharmacology : the... Nov 2015Modafinil is an FDA-approved eugeroic that directly increases cortical catecholamine levels, indirectly upregulates cerebral serotonin, glutamate, orexin, and histamine... (Review)
Review
Modafinil is an FDA-approved eugeroic that directly increases cortical catecholamine levels, indirectly upregulates cerebral serotonin, glutamate, orexin, and histamine levels, and indirectly decreases cerebral gamma-amino-butrytic acid levels. In addition to its approved use treating excessive somnolence, modafinil is thought to be used widely off-prescription for cognitive enhancement. However, despite this popularity, there has been little consensus on the extent and nature of the cognitive effects of modafinil in healthy, non-sleep-deprived humans. This problem is compounded by methodological discrepancies within the literature, and reliance on psychometric tests designed to detect cognitive effects in ill rather than healthy populations. In order to provide an up-to-date systematic evaluation that addresses these concerns, we searched MEDLINE with the terms "modafinil" and "cognitive", and reviewed all resultant primary studies in English from January 1990 until December 2014 investigating the cognitive actions of modafinil in healthy non-sleep-deprived humans. We found that whilst most studies employing basic testing paradigms show that modafinil intake enhances executive function, only half show improvements in attention and learning and memory, and a few even report impairments in divergent creative thinking. In contrast, when more complex assessments are used, modafinil appears to consistently engender enhancement of attention, executive functions, and learning. Importantly, we did not observe any preponderances for side effects or mood changes. Finally, in light of the methodological discrepancies encountered within this literature, we conclude with a series of recommendations on how to optimally detect valid, robust, and consistent effects in healthy populations that should aid future assessment of neuroenhancement.
Topics: Benzhydryl Compounds; Cognition; Humans; Modafinil; Nootropic Agents
PubMed: 26381811
DOI: 10.1016/j.euroneuro.2015.07.028 -
Neuropsychopharmacology : Official... Jun 2008Modafinil (2-[(Diphenylmethyl) sulfinyl] acetamide, Provigil) is an FDA-approved medication with wake-promoting properties. Pre-clinical studies of modafinil suggest a... (Review)
Review
Modafinil (2-[(Diphenylmethyl) sulfinyl] acetamide, Provigil) is an FDA-approved medication with wake-promoting properties. Pre-clinical studies of modafinil suggest a complex profile of neurochemical and behavioral effects, distinct from those of amphetamine. In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia. Cognitive dysfunction may be a particularly important emerging treatment target for modafinil, across these and other neuropsychiatric disorders. We aimed to comprehensively review the empirical literature on neurochemical actions of modafinil, and effects on cognition in animal models, healthy adult humans, and clinical populations. We searched PubMed with the search term 'modafinil' and reviewed all English-language articles for neurochemical, neurophysiological, cognitive, or information-processing experimental measures. We additionally summarized the pharmacokinetic profile of modafinil and clinical efficacy in psychiatric patients. Modafinil exhibits robust effects on catecholamines, serotonin, glutamate, gamma amino-butyric acid, orexin, and histamine systems in the brain. Many of these effects may be secondary to catecholamine effects, with some selectivity for cortical over subcortical sites of action. In addition, modafinil (at well-tolerated doses) improves function in several cognitive domains, including working memory and episodic memory, and other processes dependent on prefrontal cortex and cognitive control. These effects are observed in rodents, healthy adults, and across several psychiatric disorders. Furthermore, modafinil appears to be well-tolerated, with a low rate of adverse events and a low liability to abuse. Modafinil has a number of neurochemical actions in the brain, which may be related to primary effects on catecholaminergic systems. These effects are in general advantageous for cognitive processes. Overall, modafinil is an excellent candidate agent for remediation of cognitive dysfunction in neuropsychiatric disorders.
Topics: Animals; Benzhydryl Compounds; Brain Chemistry; Cognition; Humans; Mental Disorders; Modafinil; Neuroprotective Agents
PubMed: 17712350
DOI: 10.1038/sj.npp.1301534