2021-payette.pdf: “An anti-narcolepsy drug reveals behavioral and fitness costs of extreme activity cycles in arctic-breeding songbirds”, (2021-04-15):
Sleep loss impairs cognitive function, immunological responses and general well-being in humans. However, sleep requirements in mammals and birds vary dramatically. In circumpolar regions with continuous summer light, daily sleep duration is reduced, particularly in breeding birds. The effect of an anti-narcolepsy drug (modafinil) to putatively extend wakefulness was examined in two species of closely related arctic-breeding passerine birds: Lapland longspurs (Calcarius lapponicus) and snow buntings (Plectrophenax nivalis). Free-living adult males were implanted during the nestling phase on day 4 (D4; 4 days post-hatching) with osmotic pumps containing either vehicle or modafinil to extend the active period for 72 h. Nestlings were weighed on D2 and D7 to measure growth rates. Additionally, focal observations were conducted on D6. Male longspurs receiving modafinil made fewer feeding visits and spent less time at the nest but tended to spend more time near the nest than controls. We observed no change in longspur nestling growth rates, but fledging occurred significantly later when males received modafinil, suggesting a fitness cost. In contrast, modafinil had no measurable impact on male or female snow bunting behavior, nestling growth rates or time to fledging. We suggest male longspurs compromise and maintain vigilance at their nests in lieu of sleeping because of the increased predation risk that is characteristic of their tundra nesting habitat. Snow buntings are cavity nesters, and their nests do not require the same vigilance, allowing males to presumably rest following provisioning. These life-history differences between species highlight the role of predation risk in mediating behavioral modifications to prolonged wakefulness in arctic-breeding songbirds.
2021-inoue.pdf: “Efficacy and safety of modafinil in patients with idiopathic hypersomnia without long sleep time: a multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison study”, (2021-04):
- The efficacy and safety of modafinil was assessed for idiopathic hypersomnia.
- Excessive daytime sleepiness was evaluated both objectively and subjectively.
- Mean sleep latency was prolonged in patients treated with modafinil vs. placebo.
- No clinically-significant adverse events occurred with modafinil or placebo.
- Modafinil was safe and effective in Japanese patients with idiopathic hypersomnia.
Background: Few treatments are available for patients with idiopathic hypersomnia (IH). Modafinil, an established treatment for narcolepsy, was tested for efficacy and safety in Japanese patients with IH without long sleep time.
Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison study was conducted at 20 institutions in Japan. Patients who met the diagnostic criteria of IH in the International Classification of Sleep Disorders (second edition) were included. The study comprised a ≥17-day observation period and a 3-week treatment period during which modafinil (200 mg) or placebo was administered orally once daily (in the morning). The primary efficacy endpoint was change in mean sleep latency on the Maintenance of Wakefulness Test (MWT). Adverse events (AEs) were also recorded to evaluate safety.
Results: In total, 123 patients were screened and 71 were randomized to receive modafinil (n = 34) or placebo (n = 37). Patients treated with modafinil experienced a statistically-significantly prolonged mean sleep latency on the MWT at the end of the study compared with placebo (5.02 min, 95% confidence interval: 3.26–6.77 min; p < 0.001). AEs occurred in 58.8% (20⁄34) and 27.0% (10⁄37) of patients in the modafinil and placebo groups, respectively. Frequent AEs in the modafinil group were headache (n = 6), dry mouth (n = 3), and nausea (n = 3); no clinically-significant AEs occurred.
Conclusion: Modafinil was shown to be an effective and safe treatment for excessive daytime sleepiness in patients with IH without long sleep time.
Clinical Trial Registration: JapicCTI; 142539.
[Keywords: modafinil, idiopathic hypersomnia without long sleep time, randomized controlled trial, maintenance of wakefulness test, Japanese version of the Epworth Sleepiness Scale]
2021-haney.pdf: “Modafinil reduces smoked cocaine self-administration in humans: effects vary as a function of cocaine ‘priming’ and cost”, (2021-04; backlinks):
- Modafinil has had mixed efficacy for treating cocaine use disorder.
- This study tested modafinil’s effects on cocaine self-administration under a range of conditions.
- Modafinil robustly reduced self-administration when cocaine was costly and no cocaine was ‘on board.’
- Modafinil had little effect if cocaine was recently used or could be self-administered at low cost.
- Modafinil may be most effective for preventing relapse rather than initiating abstinence.
Background: The absence of an FDA-approved medication for the treatment of cocaine use disorder (CUD) may, in part, reflect the varying conditions present when the decision to use cocaine is made, with one medication unlikely to work under all conditions. The objective of this double-blind, placebo-controlled, human laboratory study was to test the effects of modafinil, a medication with mixed efficacy for the treatment of CUD, using a novel self-administration procedure designed to model distinct clinical scenarios.
Methods: During modafinil maintenance (0, 300 mg/day), participants chose to self-administer up to 7 doses of smoked cocaine (25 mg) under 9 conditions: immediately after exposure to: (a) cues associated with cocaine and a non-contingent cocaine administration, ie. ‘prime’ (25 mg), (b) only cocaine cues, and (c) neither cues nor cocaine. Each condition was tested when self-administered cocaine cost $5, $10 and $15/dose.
Results: Nontreatment-seeking cocaine smokers (3 F,13 M), spending $388 ± $218/week on cocaine and with no history of alcohol use disorder, completed the study. Relative to placebo, modafinil robustly attenuated self-administration when cocaine was expensive ($10 or $15/dose) and when there was no ‘prime.’ Modafinil had no effect on self-administration when cocaine was inexpensive ($5/dose) or when participants received a ‘prime.’
Conclusions: Modafinil’s effects on cocaine-taking varied substantially as a function of recent cocaine exposure and cost, which may help explain the mixed clinical findings. Modafinil may be most effective for preventing relapse in abstinent patients, particularly under conditions in which cocaine is costly, rather than initiating abstinence for those continuing to use cocaine.
[Keywords: cocaine use disorder, smoked cocaine, modafinil self-administration, relapse prevention, medications development]
2021-garg.pdf: “Recovery from refractory chronic fatigue syndrome with CBT and modafinil”, (2021-03-22):
Many patients with chronic fatigue syndrome (CFS) fail to derive benefit from evidence-based treatments such as cognitive–behavioural therapy (CBT) and graded exercise therapy leading to permanent disability. To discover whether a repeat prescription of modafinil might potentiate the benefits of CBT leading to social recovery as defined by 2 or more point improvement in energy and muscular pain/concentration and return to work or full-time training. Three patients with treatment-resistant CFS (mean duration 17.66 years) treated with modafinil and CBT in a Liaison Psychiatry clinic were retrospectively reviewed. Progress was reviewed at baseline, 4–6 months and 10–24 months. Patients rated their fatigue, pain and concentration using 10-point Likert scales. 2⁄3 achieved clinically meaningful improvements in energy and pain/concentration and 3/3 achieved social recovery. Modafinil, when prescribed over the medium term, would appear to be a potentially useful potentiating agent when added to CBT.
2021-robble.pdf: “Concordant neurophysiological signatures of cognitive control in humans and rats”, (2021-03-21):
Progress towards understanding neural mechanisms in humans relevant to psychiatric conditions has been hindered by a lack of translationally-relevant cognitive tasks for laboratory animals. Accordingly, there is a critical need to develop parallel neurophysiological assessments of domains of cognition, such as cognitive control, in humans and laboratory animals.
To address this, we developed a touchscreen-based cognitive (Eriksen Flanker) task in rats and used its key characteristics to construct a novel human version, with similar testing parameters and endpoints across species. We obtained continuous electroencephalogram (EEG) recordings, including local field potentials in rats, and compared electrophysiological signatures locked to stimulus onset and responses across species. We also assessed whether behavioral or physiological task effects were modulated by modafinil, which enhances aspects of cognitive function in humans. In both species, the task elicited expected flanker interference effects (reduced accuracy) during high-conflict trials.
Across homologous neuroanatomical loci, stimulus-locked increases in theta power during high-conflict trials as well as error-related negative potentials were observed. These endpoints were not affected by modafinil in either species. Despite some species-specific patterns, our findings demonstrate the feasibility of a rat Flanker task as well as cross-species behavioral and neurophysiological similarities, which may enable novel insights into the neural correlates of healthy and aberrant behavior and provide mechanistic insights relevant to treatment.
2021-anderson.pdf: “Cognitive boosting interventions for impulsivity in addiction: a systematic review and meta-analysis of cognitive training, remediation and pharmacological enhancement”, (2021-03-10):
Aims: To evaluate and compare the effects of 3 cognitive boosting intervention approaches (computerised cognitive training, cognitive remediation and pharmacological cognitive enhancers) on measures of impulsive action and impulsive choice.
Design: Systematic review and meta-analysis of publications that reported original controlled trials of cognitive boosting interventions.
Setting: Studies conducted anywhere in the world. No language restrictions were applied.
Participants: Treatment-seeking adults with substance use disorder or gambling disorder.
Measurements: Our primary outcome was a reduction in impulsive action or choice on a validated cognitive measure post-intervention. We assessed risk of bias using the Cochrane Collaboration tool and determined pooled estimates from published reports. We performed random-effects analyses for impulsive action and impulsive choice outcomes and planned moderator analyses.
Findings: Of 2204 unique studies identified, 60 were included in the full-text review. 23 articles were considered eligible for inclusion in the qualitative synthesis and 16 articles were included in our meta-analysis. Articles eligible for pooled analyses included 5 working memory training (computerised cognitive training) studies with 236 participants, 3 goal management training (cognitive remediation) studies with 99 participants, 4 modafinil (cognitive enhancer) studies with 160 participants and 4 galantamine (cognitive enhancer) studies with 131 participants. Study duration ranged from 5 days to 13 weeks, with immediate follow-up assessments. There were no studies identified that specifically targeted gambling disorder. We only found evidence for a benefit on impulsive choice of goal management training, although only in 2 studies involving 66 participants (standardised mean difference (SMD) = 0.86; 95% CI = 0.49–1.23; p = 0.02; I2 = 0%, p = 0.95).
Conclusion: Cognitive remediation, and specifically goal management training, may be an effective treatment for addressing impulsive choice in addiction. Preliminary evidence does not support the use of computerised cognitive training or pharmacological enhancers to boost impulse control in addiction.
[Keywords: cognitive remediation, cognitive training, gambling disorder, impulsivity, meta-analysis, pharmacological enhancers, substance use disorder, systematic review treatment]
2021-eggink.pdf: “Prescription medication use by emergency department doctors to improve work and academic performance, and to manage stress and anxiety”, (2021-02-02):
Objective: To determine medications used by ED doctors to improve work and academic performance, and to manage stress and anxiety.
Methods: We undertook an online, voluntary, anonymous survey of ACEM fellows and trainees.
Results: 139 (46.5%) respondents used a medication under examination. Sleep aids included melatonin (19.1% of respondents) and benzodiazepines (8.7%). Medications to improve performance included modafinil (4.7%), pseudoephedrine (2.0%), melatonin (2.0%) and beta blockers (1.3%). Some medications were taken prior to shifts. Medications to manage stress and anxiety included benzodiazepines (3.0%) and beta blockers (2.0%).
Conclusion: Medication use is common and support for some doctors may be required.
2020-aras.pdf: “Modafinil Induced Spontaneous Ejaculation Without Orgasm: A Case Report”, (2020-11-27):
Modafinil is used for the treatment of narcolepsy and obstructive sleep apnea syndrome, and as add-on therapy for psychiatric diseases such as attention-deficit/hyperactivity disorder, schizophrenia, depression, cocaine addiction. The exact mechanism of action is unknown. Modafinil may be helpful for the treatment of erectile dysfunction and premature ejaculation. The addition of modafinil to antidepressant treatment may provide positive effects on sexual dysfunction. However, side effects such as hypersexuality and unwanted orgasm have been reported with modafinil treatment. In this article, a patient who had developed spontaneous ejaculations after the addition of modafinil for the treatment of depression with venlafaxine is discussed. Although venlafaxine treatment continued after the discontinuation of modafinil, spontaneous ejaculation did not continue. It should be kept in mind that agents with dopaminergic and noradrenergic effects, such as modafinil, can cause undesirable sexual side effects.
2020-bajorek.pdf: “Exploring the Economic Benefits of Modafinil for Post-Stroke Fatigue in Australia: A Cost-Effectiveness Evaluation”, (2020-11-01):
- Modafinil is cost-effective, costing AUD$0.20/day per unit change in fatigue score.
- Treatment to increase stroke-survivors’ productivity saves AUD$467 million annually.
- Treating post-stroke fatigue to reduce unemployment saves $383 billion over 10 years.
- Modafinil use post-stroke derives large cost-savings to health-systems and society.
Background: In stroke survivors, post-stroke fatigue predicts dependency in daily living and failure to return to work. Modafinil shows promise as a pharmacotherapy to reduce post-stroke fatigue and related sequelae, eg., poorer functional and clinical outcomes.
Aims This study explored the cost-effectiveness of modafinil in treating post-stroke fatigue in the Australian context, by determining its incremental cost-effectiveness ratio (ICER) and by simulating the potential cost-savings on a national scale, through a re-analysis of MIDAS trial data.
Methods: A post hoc cost-effectiveness analysis was undertaken. Part A: patient-level cost and health effect data (Multidimensional Fatigue Inventory (MFI) scores) were derived from the MIDAS trial and analysis undertaken from a health-system perspective. Part B: a secondary analysis simulated the societal impact of modafinil therapy in terms of national productivity costs.
Results: Part A: Mean cost of modafinil treatment was AUD$3.60/day/patient for a minimally clinically important change (10 points) in total MFI fatigue score, ie., AUD$0.36/day/unit change in fatigue score per patient. For the base case scenario, the ICER of using modafinil (versus placebo) was AUD$131.73 ($90.17—248.15, for minimum and maximum costs, respectively). Part B: The potential productivity cost-savings to society were calculated as nearly AUD$467 million over 1 year, and up to AUD$383,471,991,248 over 10 years, from the widespread use of modafinil treatment in the Australian population of working-age stroke-survivors, representing a substantial societal benefit.
Conclusions: Modafinil is a highly cost-effective treatment for post-stroke fatigue, offering substantial productivity gains and potential cost-savings to society from the widespread use of modafinil treatment in the Australian population of working-age stroke-survivors.
[Keywords: modafinil, stroke, fatigue, cost analysis, cost-effectiveness]
2020-sholtes.pdf: “Optimising sleep and performance during night float: A systematic review of evidence and implications for graduate medical education trainees”, (2020-10-15):
Graduate medical education (GME) training commonly requires residents and fellows to engage in night float shift work. This review aims to assess the effectiveness of interventions for trainees when preparing for, completing, and recovering from working night float shifts. We reviewed all available studies published prior to September 2019 using PubMed, Scopus, CINAHL, the Cochrane library, PsycINFO, and Google Scholar databases. We included all original, primary research articles assessing either non-pharmacological or pharmacological interventions on the chronobiological and physiological effects of night float shift work among GME trainees. Five studies (n = 179 patients) met inclusion criteria. Interventions included melatonin in the morning before sleep after night float shifts, napping during night float shifts, modafinil after a night of sleep deprivation, and caffeinated energy drinks after 6 consecutive night float shifts. Melatonin improved one measure of attention. A 2-hr nap was associated with improved speed related to task switching. Modafinil improved performance in tests of cognition. Caffeinated energy drinks led to improvement in select driving performance variables and reaction time. Effect sizes for outcome variables were calculated. Heterogeneity among the studies precluded combining the data in a meta-analysis. According to GRADE criteria, the quality of the evidence in these studies was low or very low. Our findings suggest GME trainees may benefit from utilising a limited number of interventions when preparing for or recovering from night float shift work. More investigation is needed to identify interventions that could help GME trainees adapt to and recover from working night float shifts.
2020-cesta.pdf: “Incidence of Malformations After Early Pregnancy Exposure to Modafinil in Sweden and Norway”, (2020-09-01):
Modafinil is used to improve wakefulness in adults with excessive sleepiness due to narcolepsy, for fatigue related to multiple sclerosis, and for the treatment of attention-deficit/hyperactivity disorder. In 2018, an interim report from a manufacturer-established pregnancy registry reported a prevalence of 15% for major malformation in infants exposed to modafinil during pregnancy, spurring regulatory bodies to amend product information.1–3 Recently, a Danish study reported a major malformation rate of 12% (n = 6) among 49 infants exposed to modafinil during early pregnancy compared with 3.9% (n = 32 466) among 828 644 unexposed to modafinil (adjusted odd ratio, 2.7; 95% CI, 1.1–6.9).4 To add to the emerging evidence, we investigated if modafinil use during early pregnancy was associated with major malformations in Norway and Sweden.
…Compared with pregnant women who had not taken modafinil, pregnant women who had taken modafinil were more often overweight or obese and had higher rates of smoking and diagnoses of narcolepsy, multiple sclerosis, and attention-deficit/hyperactivity disorder (Table).
Overall, the rate of major malformations in the unexposed group was 2.1% (n = 40 697). There were 3 modafinil-exposed infants diagnosed as having a major malformation, resulting in a prevalence rate of 2.6% and a crude risk ratio of 1.06 (95% CI, 0.35–3.26). When restricted to only filled prescriptions during the first trimester, 75 pregnancies were exposed and 1 modafinil-exposed infant was diagnosed as having a major malformation(risk ratio, 0.44; 95% CI, 0.06–3.10).
Discussion: In this study, modafinil use during early pregnancy was not statistically-significantly associated with increased risk of major malformations. The combined Norwegian and Swed-ish study population had a similar proportion of modafinil-exposed pregnancies compared with the Danish study, allowing for more than double the number of exposed infants to be followed up. However, the 95% CIs estimated in this study overlap with those from the Danish study and allow for the possibility of a greater than 3-fold risk as previously reported.4
2020-flavell.pdf: “Modafinil-induced psychosis in a patient with attention deficit hyperactivity disorder”, (2020-07-26):
Modafinil is a wakefulness-promoting agent that is known to be used off-label as a cognitive enhancer and for the treatment of attention deficit hyperactivity disorder (ADHD).1 There are increasing case reports of Modafinil-induced psychosis; however, this is the first to report a patient with ADHD to develop psychosis from Modafinil use.
2020-roberts.pdf: “How effective are pharmaceuticals for cognitive enhancement in healthy adults? A series of meta-analyses of cognitive performance during acute administration of modafinil, methylphenidate and D-amphetamine”, (2020-07-21; backlinks):
Modafinil, methylphenidate (MPH) and d-amphetamine (d-amph) are putative cognitive enhancers. However, efficacy of cognitive enhancement has yet to be fully established. We examined cognitive performance in healthy non-sleep-deprived adults following modafinil, MPH, or d-amph vs placebo in 3 meta-analyses, using subgroup analysis by cognitive domain; executive functions (updating, switching, inhibitory control, access to semantic/long term memory), spatial working memory, recall, selective attention, and sustained attention. We adhered to PRISMA. We identified k = 47 studies for analysis; k = 14 studies (64 effect sizes) for modafinil, k = 24 studies (47 effect sizes) for Methylphenidate, and k = 10 (27 effect sizes) for d-amph. There was an overall effect of modafinil (SMD = 0.12, p = 0.01). Modafinil improved memory updating (SMD = 0.28, p = 0.03). There was an overall effect of MPH (SMD = 0.21, p = 0.0004) driven by improvements in recall (SMD = 0.43, p = 0.0002), sustained attention (SMD = 0.42, p = 0.0004), and inhibitory control (SMD = 0.27, p = 0.03). There were no effects for d-amph. MPH and modafinil show enhancing effects in specific sub-domains of cognition. However, data with these stimulants is far from positive if we consider that effects are small, in experiments that do not accurately reflect their actual use in the wider population. There is a user perception that these drugs are effective cognitive enhancers, but this is not supported by the evidence so far.
2020-blumberg.pdf: “Procognitive Effects of Antidepressants and Other Therapeutic Agents in Major Depressive Disorder: A Systematic Review”, (2020-07-21):
Objective: To review the efficacy of antidepressants and other therapeutic agents for the treatment of cognitive impairment in adults with major depressive disorder (MDD).
Data Sources: We conducted a database search of MEDLINE, PsycINFO, and Embase through Ovid on May 7, 2019. The year of publication was not restricted. The search terms “Major Depressive Disorder”, “depress*”, “cognit*”, and “therapeutics” were used.
Study Selection: The studies included in this review were clinical trials of antidepressants and other therapeutic agents in MDD populations. Participants were aged between 18 and 65 years and had a DSM-III, -IV, or -5 diagnosis of MDD. In total, 2,045 research papers were screened, 53 full-text articles were assessed, and 26 articles were eligible to be included in this systematic review.
Data Extraction: The data and quality of research papers were assessed and screened by 2 independent reviewers. Discrepancies were resolved through a third reviewer.
Results: Overall, studies demonstrated that tricyclic antidepressants do not have procognitive effects, while vortioxetine and bupropion have demonstrated procognitive effects in MDD populations relative to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Several non-antidepressant agents, such as modafinil, amphetamines, and erythropoietin, have also demonstrated statistically-significant positive effects on cognition in depression.
Conclusions: Present-day antidepressants and other agents have demonstrated procognitive effects in MDD, but the findings between various agents are mixed. Further research looking at objective measures of cognitive performance would be helpful to obtain more definitive results regarding the efficacy of therapeutics for cognitive impairment in MDD.
2020-kandasamy.pdf: “Hyponatraemia and cerebral oedema due to a modafinil overdose”, (2020-07-05; backlinks):
Modafinil is a non-amphetamine stimulant that is prescribed for narcolepsy-associated sleepiness as well as reported off-licence uses among university students looking to improve wakefulness and focus. There is limited information in the medical literature about supratherapeutic modafinil dosage, symptomatology and management of overdose. We report a case of a healthy 32-year-old man who was found unconscious, having vomited, with an empty modafinil blister strip. At the emergency department, he presented with reduced Glasgow Coma Scale and prolonged episodes of vomiting. This acute presentation was conservatively managed in the intensive care unit. Antibiotics were also given for a suspected aspiration pneumonia. CT of the head showed cerebral oedema and biochemistry investigations revealed hyponatraemia. Result aetiology was unclear, however, it has been theorised to be secondary to a sizeable modafinil overdose.
2020-rohde.pdf: “The use of stimulants in depression: Results from a self-controlled register study”, (2020-05-23):
Objective: To investigate the effectiveness of stimulants in patients with depression, by using naturalistic outcome measures, such as psychiatric admissions, psychiatric bed-days and incidents of intentional self-harm or suicide attempts.
Methods: Via linkage of the Danish nationwide health registers, we identified all patients with a diagnosis of depression initiating stimulants, including methylphenidate, modafinil, amphetamine, dexamphetamine or lisdexamphetamine, from 1995 to 2012. We used a mirror-image model to test whether redemption of a stimulant prescription was associated with a reduction in psychiatric admissions, inpatient days and incidents of intentional self-harm or suicide attempts. Specifically, the number of these outcomes in the 2 years leading up to redemption of a stimulant prescription was compared to the two subsequent years. Similar outcomes were used in a reverse mirror-image model to investigate the effect of stimulant termination.
Results: A total of 3354, 935 and 105 patients diagnosed with depression redeemed prescriptions for methylphenidate, modafinil or amphetamine/dexamphetamine/lisdexamphetamine, respectively. Initiation of methylphenidate was not associated with a statistically-significant change in psychiatric admissions (mean: −0.02 admissions, p = 0.11) or inpatient days (mean: 0.13 days, p = 0.74). Similar findings were made for modafinil and the amphetamines. In addition, no clinically relevant change in psychiatric admissions or inpatient days was found after termination of a stimulant. After initiation of methylphenidate, the incidents of self-harm or suicide attempts were reduced by 54%, from 68 to 31 events (p = 0.004). No statistically-significant change in incidents of self-harm or suicide attempts were found for modafinil or the amphetamines.
Conclusion: This nationwide study, using naturalistic outcomes, does not support the use of stimulants in patients with depression. However, the use of methylphenidate was associated with a 54% reduction in incidents of self-harm or suicide attempts, indicating that methylphenidate may potentially be useful in patients with depression with suicidal or self-harming behaviour. However, further studies are needed, before any firm conclusions can be made.
[Keywords: Depression, methylphenidate, modafinil, amphetamines, self-injurious behaviour]
2020-mereu.pdf: “Modafinil potentiates cocaine self-administration by a dopamine-independent mechanism: possible involvement of gap junctions”, (2020-04-27; backlinks):
Modafinil and methylphenidate are medications that inhibit the neuronal reuptake of dopamine, a mechanism shared with cocaine. Their use as “smart drugs” by healthy subjects poses health concerns and requires investigation. We show that methylphenidate, but not modafinil, maintained intravenous self-administration in Sprague-Dawley rats similar to cocaine. Both modafinil and methylphenidate pretreatments potentiated cocaine self-administration. Cocaine, at self-administered doses, stimulated mesolimbic dopamine levels. This effect was potentiated by methylphenidate, but not by modafinil pretreatments, indicating dopamine-dependent actions for methylphenidate, but not modafinil. Modafinil is known to facilitate electrotonic neuronal coupling by actions on gap junctions. Carbenoxolone, a gap junction inhibitor, antagonized modafinil, but not methylphenidate potentiation of cocaine self-administration. Our results indicate that modafinil shares mechanisms with cocaine and methylphenidate but has a unique pharmacological profile that includes facilitation of electrotonic coupling and lower abuse liability, which may be exploited in future therapeutic drug design for cocaine use disorder.
2020-zager.pdf: “Modulating the immune response with the wake-promoting drug modafinil: A potential therapeutic approach for inflammatory disorders”, (2020-04-18):
- Modafinil is a psychostimulant drug approved for the treatment of sleep disorders.
- Recent preclinical findings point to a immunomodulatory property of modafinil.
- Modafinil impairs immune cells infiltration and glial activation during neuroinflammation.
- Modafinil decreases neuroinflammation in models of neurodegenerative diseases.
- Modafinil may be useful as adjuvant treatment for neurodegenerative diseases.
Modafinil is a psychostimulant drug approved by the FDA primarily for the treatment of sleep disorders such as narcolepsy, excessive daytime sleepiness and sleep apnea. Several documented but not yet approved uses for modafinil have been described over the last 30 years, including alleviating fatigue in neurological and neurodegenerative disorders. Recent evidence has suggested that modafinil may have an immunomodulatory effect. Here, we review the different effects of modafinil treatment in animal models of brain inflammation and peripheral immune function. We conclude that there is unequivocal evidence of an anti-inflammatory effect of modafinil in experimental animal models of brain inflammation and neurodegenerative disorders, including systemic inflammation and methamphetamine-induced neuroinflammation, Parkinson’s disease, brain ischemia, and multiple sclerosis. Modafinil acts on resident glial cells and infiltrating immune cells, negatively affecting both innate and adaptive immune responses in the brain. We also review the outcomes of modafinil treatment on peripheral immune function. The results of studies on this subject are still controversial and far from conclusive, but point to a new avenue of research in relation to peripheral inflammation. The data reviewed here raise the possibility of modafinil being used as adjuvant treatment for neurological disorders in which inflammation plays an important role.
[Keywords: modafinil, immunity, inflammation, dopamine, microglia, T cells, macrophages]
2020-rubinkahana.pdf: “Cognitive enhancement drug use among resident physicians: Prevalence and motivations for use—results from a survey”, (2020-04-16):
Background: Non-medical use of prescription drugs for the enhancement of cognitive functioning has gained popularity in recent years, especially among young educated adults. To our knowledge, no previous study investigated this phenomenon among resident physicians.
Objective: To analyze cognitive enhancement drugs use motivations and patterns among resident physicians.
Methods: A survey and statistical analysis regarding the use of drugs traditionally prescribed for the treatment of Attention Deficit Hyperactivity Disorder: stimulants, amphetamines and modafinil.
Participants: 1,453 residents who took their written residency exam in the summer of 2017. The response rate was 32.3%.
Results: 28.1% of responders reported past use, with 73.67% of them reporting use without a related medical diagnosis. Almost half of the users (47.1%) acquired the drug with a prescription, but without a diagnosis of a related medical disorder. The first use was predominantly during residency (54.3%), with 45% reporting it as related to the residency exam.
Factors found to positively impact non-medical use include: declaring undiagnosed Attention Deficit Hyperactivity Disorder, fear of failing the exam, a belief that more than 30% of other examinees take cognitive enhancements drugs, and a learning disability diagnosis. Self-reports of being a competitive person and being a parent, were negatively correlated with non-medical use.
Conclusions: The use of drugs that are taken traditionally for the treatment of Attention Deficit Hyperactivity Disorder is common among resident physicians, both with and without related medical indication. Interestingly, factors associated with the fear of being “left behind” increase non-medical use and not the desire to succeed.
[Keywords: substance misuse, cognitive enhancement, physicians, prescription stimulants, residents]
“The off-prescription use of modafinil: An online survey of perceived risks and benefits”, (2019-12-30; backlinks):
Cognitive enhancing drugs are claimed to improve cognitive functions such as learning and attention. However, little is known presently about the characteristics of off-prescription cognitive enhancing drug users or their perceived everyday experience with these drugs. As modafinil is the most commonly used off-prescription cognitive enhancing drug, the current study aimed to provide a detailed profile of modafinil users and their experiences and perceptions of this drug. To this end, an online survey, targeting cognitive enhancing drug users and students, was advertised on forum sites. Information was obtained regarding demographic data, illicit drug use, psychiatric diagnosis and experience of modafinil. Of the 404 respondents, 219 reported taking modafinil. Of these the majority were male, American or British, university-educated and currently employed, with a mean age of 27. Overall, modafinil was perceived by users as being safe. Modafinil users reported higher levels of illicit drug use and psychiatric diagnosis than would be expected from population-based data. More frequent reported modafinil use was associated with higher numbers of perceived benefits whilst reported frequency of use was not associated with the number of perceived risks. There was also a tentative link between the reported use of modafinil and the reported presence of psychiatric disorders, largely depression and anxiety. Respondents who had reported a psychiatric diagnosis declared higher subjective benefits of modafinil. This may suggest further beneficial effects of modafinil or it may reflect insufficient medical treatment for psychiatric disorders in some people. Overall, the findings of the current study should be beneficial in informing clinicians and legislative bodies about the modafinil user profile and how modafinil is perceived.
2019-savarese.pdf: “Excessive sleepiness in shift work disorder: a narrative review of the last 5 years”, (2019-08-30):
Introduction: Shift work sleep disorder (SWSD), also known as shift work disorder (SWD), is a circadian rhythm sleep disorder characterized by insomnia and/or excessive sleepiness, associated with a recurring work schedule that overlaps the usual time designated for sleeping.
Purpose: This article aims to provide a narrative review of the pharmacological trials conducted on SWD in the last 5 years, to better address safety and health issues inherent to this disorder.
Methods: An electronic literature search was conducted using PubMed. All eligible randomized controlled trials (RCTs) and cross-over RCTs with employees undertaking shift work (including night shifts) were considered, yielding three articles.
Results: All three studies showed the efficacy of armodafinil in improving subjective and objective sleepiness, clinical conditions, and global functioning regardless of shift duration. Both performance and driving simulator performance tests administered during the night shift bore better results following armodafinil administration than after placebo. However, armodafinil only reduced subjective disability in individuals working more than 9 h; furthermore, even after armodafinil, alertness was reduced but not normalized.
Conclusion: These studies underscore the importance of preventing and/or minimizing disturbances due to shift work. This may be achieved through various strategies, such as the employer’s commitment to adopt ergonomic criteria in shift design and to implement work-environment interventions like controlled bright light. Health personnel is of pivotal importance to detect potential factors of intolerance to shift work or early symptoms of SWD. Additional and improved studies are needed to further evaluate the effectiveness and safety of both pharmacological and non-pharmacological interventions.
[Keywords: shift work disorder, excessive sleepiness, insomnia, performance, alertness, stimulants, armodafinil]
2019-kredlow.pdf: “The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis”, (2019-08-19; backlinks):
Background: Animal models and human studies have identified the potential of modafinil as a cognitive enhancing agent, independent of its effects on promoting wakefulness in sleep-deprived samples. Given that single-dose applications of other putative memory enhancers (eg, D-cycloserine, yohimbine, and methylene blue) have shown success in enhancing clinical outcomes for anxiety-related disorders, we conducted a meta-analytic review examining the potential for single-dose effects for modafinil on cognitive functioning in non-sleep-deprived adults.
Methods: A total of 19 placebo-controlled trials that examined the effects of single-dose modafinil versus placebo on the cognitive domains of attention, executive functioning, memory, or processing speed were identified, allowing for the calculation of 67 cognitive domain-specific effect sizes.
Results: The overall positive effect of modafinil over placebo across all cognitive domains was small and statistically-significant (g = 0.10; 95% confidence interval, 0.05–0.15; p < 0.001). No statistically-significant differences between cognitive domains were found. Likewise, no statistically-significant moderation was found for modafinil dose (100 mg vs 200 mg) or for the populations studied (psychiatric vs nonpsychiatric).
Conclusions: In conclusion, the available evidence indicates only limited potential for modafinil to act as a cognitive enhancer outside sleep-deprived populations.
2019-ogeil.pdf: “Sleep-Promoting and Wake-Promoting Drugs: Where Are They Being Sourced, and What Is Their Impact?”, (2019-07-08):
Background: Recent decades have seen both an increased number of shift workers in order to deliver services 24/7, and increased potential for social interactions at all hours of the day. People have sought to engage in strategies, which either promote vigilance or facilitate sleep, with the use of sleep-promoting and wake-promoting drugs representing one strategy.
Methods: We investigated use of sleep-promoting and wake-promoting drugs in participants (n = 377) who completed a survey investigating the type and source of sleep-promoting and wake-promoting drugs, and their impact on sleep and performance outcomes.
Results: The most commonly reported wake-promoting drugs were amphetamine and dextroamphetamine salts, modafinil, and illicit substances including methamphetamine and cocaine, while the most commonly reported sleep-promoting drugs were benzodiazepines and antihistamines. Use of a sleep-promoting drug in the past month was associated with higher odds of having poorer sleep quality (OR = 3.15) and moderate-high insomnia (OR = 3.30), while use of a wake-promoting drug was associated with poor sleep quality (OR = 3.76), or making a fatigue-related error (OR = 2.65).
Conclusions: These findings represent novel data on the use and source of sleep-promoting and wake-promoting drugs, and suggest that despite their use, poor sleep and performance outcomes persist, likely representing individuals struggling to keep up with the 24/7 world.
[Keywords: sleep-promoting drug, wake-promoting drug, sleep quality, performance, insomnia, daytime dysfunction]
2018-billiard.pdf: “Modafinil: its discovery, the early European and North American experience in the treatment of narcolepsy and idiopathic hypersomnia, and its subsequent use in other medical conditions”, (2018-09-01):
Adrafinil, a new molecule identified by a French drug company, L. Lafon Ltd, in 1974, was found to cause a statistically-significant dose-dependent increase in motor activity in mice, without exerting peripheral sympathomimetic effects.
As early as 1977–78, Michel Jouvet prescribed adrafinil to narcoleptic patients, but without consistent results. Meanwhile the kinetics of adrafinil led to the identification of an active metabolite, modafinil.
In 1983, Jouvet and Bastuji prescribed modafinil to narcoleptic and idiopathic hypersomnia patients and obtained a statistically-significant decrease of excessive daytime sleepiness and sleep attacks in a majority of patients.
L. Lafon Ltd was initially not interested in developing this molecule for market however, thanks to Jouvet’s insistence, it decided to start clinical trials in both healthy volunteers and narcoleptic patients as well as conduct animal studies. Results were excellent and led to the use of modafinil by the French army during the Gulf War in January–February 1991, as well as to the official registration of the drug in France in 1992.
Subsequent multicenter controlled clinical trials in North America confirmed the findings in Europe. Modafinil was later used to treat sleepiness, somnolence and fatigue in a large number of medical conditions.
2012-mueller.pdf: “Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers”, U. MUller, J. B. Rowe, T. Rittman, C. Lewis, T. W. Robbins, B. J. Sahakian, J. B. Rowe, T. Rittman, C. Lewis, T. W. Robbins, B. J. Sahakian (backlinks)
2006-wesensten.pdf: “Effects of Modafinil on Cognitive Performance and Alertness During Sleep Deprivation”, (2006-07-01; backlinks):
The performance-sustaining and alertness-sustaining/restoring effects of modafinil during sleep deprivation in normal, healthy adults were reviewed.
Results: indicate that modafinil is efficacious for sustaining/restoring objective performance and alertness during sleep deprivation with few adverse effects. At appropriate dosages, modafinil restores performance and alertness to non-sleep deprived levels. Modafinil also impairs post-sleep deprivation recovery sleep, but from the few studies available addressing this issue, it is unclear whether these sleep impairments translate into post-sleep performance impairments.
Further research is needed to determine whether modafinil restores performance on simple cognitive tasks only or whether modafinil additionally restores executive functions (e.g., abstract thought, critical reasoning, planning, decision-making, situational awareness, and effective judgment) which are critical in most modern operational settings. In addition, studies are needed to determine whether modafinil use during sleep deprivation is preferable to that of other available controlled stimulants (such as dextroamphetamine) or non-controlled stimulants (such as caffeine).
Such studies would be comprised of direct, head-to-head comparisons among various stimulants across a range of dosages.
[Keywords: stimulants, alertness, executive function, modafinil, reaction time, sleep deprivation]
2000-jasinski.pdf: “An evaluation of the abuse potential of modafinil using methylphenidate as a reference”, (2000-01-01; backlinks):
Modafinil is a unique wake-promoting agent. Preclinical studies indicate a mechanism of action which is distinct from that of amphetamine or methylphenidate. To compare the pharmacodynamic profiles of modafinil, methylphenidate, and placebo in humans, a double-blind Latin square crossover study was conducted in 24 male volunteers with a history of polysubstance abuse that included the stimulant cocaine. Each subject was given single oral doses of methylphenidate (45 mg or 90 mg), modafinil (200 mg, 400 mg or 800 mg) and placebo. Measures of subjective, behavioural, and physiological responses were evaluated at fixed intervals during 72h after each dosing occasion. Subjects discriminated both modafinil and methylphenidate from placebo. Subjects liked the effects of both drugs. However, modafinil differed from methylphenidate in its lack of a statistically-significant response on the Amphetamine Scale of the Addiction Research Center Inventory. The profile of physiological effects for modafinil differed from methylphenidate in that it showed greater inhibition of observed and reported sleep, less facilitation of orthostatic tachycardia and less reduction of caloric intake. These findings are consistent with preclinical pharmacological data suggesting that modafinil is not an amphetamine-like agent.
1999-batejat.pdf: “Naps and modafinil as countermeasures for the effects of sleep deprivation on cognitive performance”, (1999-05-01; backlinks):
Disruptions in wake-sleep rhythms, particularly induced by sleep deprivation are limiting factors for military personnel in operations. The role of sleep and naps in the recovery of performance is generally accepted. Pharmacological aids, for example hypnotic or stimulant substances can also be effective countermeasures.
Recently, a new stimulant compound, modafinil (MODIODAL) has also proven effective. Considering the excellent results obtained with napping and modafinil, we have studied the combined effect of these 2 countermeasures on psychomotor performance under conditions simulating an operational situation. Beneficial effects of a few hours’ nap on performance were confirmed. Consequently naps should be encouraged, even if limited and diurnal. Modafinil, which combines wakening and stimulating properties without any known side effects, was useful for longer periods of sleep deprivation and when there was no real possibility of sleep recovery. Modafinil did not prevent sleep if sleep opportunities were available.
The combination of naps and modafinil demonstrated the best cognitive performance during sleep deprivation.