2021-adam.pdf: “Memory enhancement with stimulants: Differential neural effects of methylphenidate, modafinil, and caffeine. A pilot study”,
Methylphenidate deactivated BOLD signal in
fronto-parietal and temporal regions during recognition of previously learned words.
- Methylphenidate enhanced performance in late recall in a declarative memory task.
- Caffeine led to deactivations in the precentral gyrus during encoding.
- Modafinil did not show any BOLD signal alterations in a declarative memory task.
Human memory is susceptible to manipulation in many respects. While consolidation is well known to be prone to disruption, there is also growing evidence for
the enhancement of memory function. Beside cognitive strategies and mnemonic training, the use of stimulants may improve memory processing in healthy adults.
In this single-dose, double-blind, within-subject, randomized, placebo-controlled pilot study, 20 mg methylphenidate (n = 13) or 200 mg modafinil
(n = 12) or 200 mg caffeine (n = 14) were
administered to 39 healthy participants while performing a declarative memory task. Each participant received only one substance and functional magnetic
resonance imaging (fMRI) was used to assess drug-dependent memory effects of the substance for encoding and recognition
compared to task-related activation under placebo.
While methylphenidate showed some behavioral effect regarding memory recall performance, on the neural level, methylphenidate-dependent deactivations were found
in fronto-parietal and temporal regions during recognition of previously learned words. No BOLD alterations were
seen during encoding. Caffeine led to deactivations in the precentral gyrus during encoding whereas modafinil did not show
any BOLD signal alterations at all.
These results should be interpreted with caution since this a pilot study with several limitations, most importantly the small number of participants per group.
However, our main finding of task-related deactivations may point to a drug-dependent increase of efficiency in physiological response to memory processing.
[Keywords: declarative memory, neuroenhancement, memory enhancement, methylphenidate, modafinil, caffeine, fMRI, imaging]
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
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
2021-haney.pdf: “Modafinil reduces smoked cocaine self-administration in humans: effects vary as a function of cocaine ‘priming’ and cost”,
- 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”,
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
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]
“Spontaneously Generated Online Patient Experience of Modafinil: A Qualitative and NLP Analysis”, (2021-02-17):
Objective: To compare the findings from a qualitative and a natural language processing (NLP) based
analysis of online patient experience posts on patient experience of the effectiveness and impact of the drug Modafinil.
Methods: Posts (n = 260) from 5 online social media platforms where posts were publicly available formed the dataset/corpus. 3
platforms asked posters to give a numerical rating of Modafinil. Thematic analysis: data was coded and themes generated. Data were categorized into Pre-Modafinil,
Acquisition, Dosage, and Post-Modafinil and compared to identify each poster’s own view of whether taking Modafinil was linked to an identifiable outcome. We
classified this as positive, mixed, negative, or neutral and compared this with numerical ratings. NLP: Corpus text was
speech tagged and keywords and key terms extracted. We identified the following entities: drug names, condition names, symptoms, actions, and side-effects.
We searched for simple relationships, collocations, and co-occurrences of entities. To identify causal text, we split the corpus into Pre-Modafinil and
Post-Modafinil and used n-gram analysis. To evaluate sentiment, we calculated the polarity of each post between −1 (negative) and +1 (positive).
NLP results were mapped to qualitative results.
Results: Posters had used Modafinil for 33 different primary conditions. 8 themes were identified: the reason for taking (condition or
symptom), impact of symptoms, acquisition, dosage, side effects, other interventions tried or compared to, effectiveness of Modafinil, and quality of life
outcomes. Posters reported perceived effectiveness as follows: 68% positive, 12% mixed, 18% negative. Our classification was consistent with poster ratings. Of the
most frequent 100 keywords/keyterms identified by term extraction 88⁄100 keywords and 84⁄100 keyterms mapped directly to the 8 themes. 7 keyterms indicated
negation and temporal states. Sentiment was as follows 72% positive sentiment 4% neutral 24% negative. Matching of sentiment between the qualitative and
NLP methods was accurate in 64.2% of posts. If we allow for one category difference matching was accurate in 85% of
Conclusions: User generated patient experience is a rich resource for evaluating real world effectiveness, understanding patient perspectives,
and identifying research gaps. Both methods successfully identified the entities and topics contained in the posts. In contrast to current evidence, posters with a
wide range of other conditions found Modafinil effective. Perceived causality and effectiveness were identified by both methods demonstrating the potential to
augment existing knowledge.
2021-eggink.pdf: “Prescription medication use by emergency department doctors to improve work and academic performance, and to manage stress and
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.
“Cognitive enhancement effects of stimulants: a randomized controlled trial testing methylphenidate, modafinil, and caffeine”,
Rationale: 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 3 arms in which male participants received placebo and one of 3 stimulants (caffeine, methylphenidate, modafinil) and assessed cognitive performance with a test battery that captures various cognitive
Results: Our study showed some moderate effects of the 3 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
statistically-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 statistically-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.
2020-bajorek.pdf: “Exploring the Economic Benefits of Modafinil for Post-Stroke Fatigue in Australia: A Cost-Effectiveness Evaluation”,
- 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 AUD$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
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]
leads to meth charges for Rome woman”, (2020-10-23; backlinks):
Police conducting a road check outside Rolater Park in Cave Spring Thursday arrested a Rome woman on multiple drug charges.
According to Floyd County Jail reports:
Heather Leighann McLemore, 44, was charged with felonies for possession of methamphetamine with the intent to distribute, possession of methamphetamine,
possession of a Schedule IV controlled substance and a felony probation violation after a K-9 unit alerted to a vehicle which resulted in a search and recovery of
three bags of methamphetamine and numerous modafinil pills scattered about her purse.
McLemore was also charged with misdemeanors for having drugs not in an original container and possession of drug-related objects. She remained in jail Friday
morning on a $10,100 bond.
2020-sholtes.pdf: “Optimising sleep and performance during night float: A systematic review of evidence and implications for graduate medical education
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
“Differential effects of modafinil on performance of low-performing and high-performing individuals during total sleep deprivation”,
- Some people are more vulnerable to the effects of sleep loss than others.
- Modafinil (200mg) administered to 22 men over 36 hours of continuous wakefulness.
- Modafinil did not help the best performers compared to their performance with placebo.
- The worst performers statistically-significantly improved after receiving modafinil compared to placebo.
Background: Individual responses to the effects of inadequate sleep have been well documented; some people are more vulnerable to the effects
of sleep loss than others. Fatigue-vulnerable individuals generally require access to effective fatigue countermeasures; however, the question arises as to whether
these fatigue-vulnerable individuals receive the same benefits shown in group efficacy data. The present study administered modafinil to individuals to determine
its differential effects on performance of best and worst performers during sleep deprivation.
Methods: A sample of 22 men, age 21–40 yrs., was tested on 2 separate occasions during which they were kept awake for 36 h. During one period
they received 200 mg modafinil; during the other they received placebo. Participants were tested on a variety of tasks while rested and at 5-hr intervals across
the continuous wakefulness period. Performance for each cognitive task and subjective measure of fatigue from the placebo period was used to group individuals into
high (HP) or low performance (LP) groups to indicate fatigue vulnerability for each task.
Results: Results indicated that on the MTS task, the HP group performed the same throughout
the testing period, regardless of whether they received modafinil or not. However, the LP group statistically-significantly improved after receiving modafinil
compared to placebo. Performance on the PVT showed the HP group had a small decrease in the number of lapses after
receiving modafinil compared to placebo, whereas the LP group had a large decrease in lapses after receiving modafinil compared to placebo. Performance on
the RDM showed no difference between groups, regardless of drug condition. Groups did not differ after receiving
modafinil on subjective fatigue measured by the POMS.
Conclusions: Depending on the task, HP individuals did not benefit substantially when administered modafinil compared to placebo. However, the
LP individuals improved after receiving modafinil compared to placebo.
[Keywords: Individual differences, Modafinil, Sleep deprivation]
“On-spot quantification of modafinil in generic medicines purchased from the Internet using handheld Fourier transform-infrared,
near-infrared and Raman spectroscopy”, (2020-08-13; backlinks):
Poor quality medicines represent an expanding global public health threat facilitated by the Internet. A recent survey showed that one in five students have
used modafinil to enhance learning ability mainly purchased from Internet sources. The aim of this work was to develop on-the-spot and simple methods for the
quantification of modafinil in generic medicines using Fourier transform-infrared (FTIR), near-infrared
(NIR) and Raman spectroscopy along with partial least square regression (PLSR). Modafinil tablets were measured in intact form using NIR and Raman and in powdered
form using FTIR, NIR and Raman. Additionally, powder mixtures of crushed modafinil
tablets and excipient(s) were prepared either by diluting the crushed tablets with excipient(s), or sequentially adding excipient(s) to the crushed tablets.
Three PLSR models were constructed in MATLAB 2014a from powder mixtures and
two from intact and powdered tablets. For FTIR and Raman spectroscopy, PLSR
models based on tablets gave linear calibration curve with correlation coefficient (r2) values above 0.94 and a root mean square error of
calibration (RMSEC) below 0.96% m/m. Conversely, the PLSR model based on
powder sequential addition gave the highest accuracy using the NIR spectra (r2 = 0.99,
RMSEC = 1.15% m/m). The latter model showed accuracy in predicting the concentration of the active pharmaceutical
ingredient in modafinil generic medicines proving their authenticity. The overall results showed that the combination of the three spectroscopic methods with
PLSR offered a rapid technique for authenticating generic modafinil medicines.
2020-flavell.pdf: “Modafinil-induced psychosis in a patient with attention deficit hyperactivity disorder”,
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”,
- 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.
“Former Area Physician Charged with Forging
Prescriptions Sent to ARD”, (2019-12-11; backlinks):
A former area physician charged with forging prescriptions was placed into a special program Monday. John Sylvester O’Shea, 69, of Washington, D.C. was charged
by the attorney general’s office with procuring for self/other drug by fraud, identity theft and forgery, all misdemeanors, in July after a tip from a DuBois
pharmacist led to an investigation into his prescriptions. According to the affidavit of probable cause, O’Shea was receiving prescriptions for Modafinil and
Armodafinil from doctors in DuBois, Washington, D.C., and Raleigh, N.C., as well as others.
…In his interview with police, O’Shea explained he was taking the drugs because of his shift work. He stated he knew the maximum dosage for the drugs was 200 mg
for the Modafinil and 250 mg for the Armodafinil per day. O’Shea admitted he was taking approximately 800 mg per day or three to four pills per shift since he had
built up a tolerance to the drugs. He reportedly admitted he was “doctor shopping” and the other doctors did not know about his other prescriptions. He said his
need for the drug “got out of hand.”
On Monday President Judge Fredric J. Ammerman placed O’Shea into the accelerated rehabilitative disposition program, which is for first-time offenders. He
must serve two years ARD probation and was ordered to complete drug and alcohol counseling. He will not be able to
prescribe any drugs for this time period and he is not to be practicing medicine for one year. O’Shea’s attorney noted that O’Shea’s medical license has been
suspended and he is on a drug monitoring program already in his home area.
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
[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
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
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]
“Developing expertise, customizing sleep, enhancing study practices: exploring the legitimization of modafinil use within the accounts
of UK undergraduate students”, (2019-01-16):
Introduction and aim: Increasing numbers of students are reportedly using prescription medications to enhance cognition. This study aimed to
generate qualitative data on UK students’ understandings and perspectives of the risks and benefits surrounding so-called ‘study drugs’ (particularly, modafinil).
Design & methods: 15 undergraduate students studying biomedical science subjects were interviewed about their perspectives on study drugs.
Interviews were recorded and transcribed for thematic analysis. Users and non-users were included in the sample.
Results: The prescription status and comparisons to other legal and illicit stimulants informed accounts of the (lack of) risks associated with
study drugs, legitimizing use. The customization of sleep(iness) and wakefulness was described as a key benefit of study drug use. Drivers of use related to
university pressures and desires to increase productivity. In periods of heightened stress, such as examinations, students reported altered practices and
perspectives on risk.
Discussion and conclusions: We noted the contextual nature of students’ use and risk appraisals, with fluctuating social contexts and pressures
over time being capable of altering prior assessments and current practices (including the legitimization of study drug consumption). Further, we highlighted the
degree to which students leveraged their biomedical and experiential expertise to account for drug consumption.
[Keywords: modafinil, enhancement, students, UK, cognitive enhancers, pharmaceuticalisation]
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.
“Stevens-Johnson Syndrome After Armodafinil Use”, (2018-05-15; backlinks):
We present the case of a 21-year-old woman in whom Stevens-Johnson
syndrome (SJS) developed after initiation of armodafinil. Although this rare and life-threatening reaction is
listed on armodafinil’s label, no cases have been reported in the literature. This case, in addition to an update of the drug’s label after post-marketing
research, both support the link between armodafinil and SJS. Providers should maintain a high clinical suspicion for
SJS when starting therapy to minimize associated morbidity and mortality by discontinuing armodafinil at the onset of
“A rare case of modafinil dependence”, (2015-01; backlinks):
Modafinil, a non-amphetamine psychostimulant, is indicated for narcolepsy, shift work sleep disorder and severe obstructive sleep apnea syndrome. Modafinil is
prescribed at the dose of 100 mg once in a day or as two doses, 12 h apart in a day. It has also been found that it reduces cocaine dependence and withdrawal
phenomenon. Modafinil is claimed to have very low liability for abuse and dependence. Here we report a rare case of modafinil dependence.
[Keywords: Drug dependence, modafinil, psychostimulant]
…During follow-up, the patient complained of episodes of depressed mood, anxiety and sleep disturbance, lethargy and sleepiness that affected his shift work,
for which he was prescribed modafinil 200 mg, along with the antipsychotics Risperidone 4 mg and Amisulpride 400 mg. The patient himself gradually increased the
dose to overcome the drowsiness that interrupted his shift work. He started with 100 mg every 3–4 h over a shift work of 12 h. For the last 6 months he was unable
to overcome his sleepiness during work without modafinil 100 mg/h thus making a total of 1200 mg/day of modafinil which he used to obtain over the counter. He
claimed to have symptoms of worsening of lethargy, tremors of hands, anxiety and erratic sleep hours when he skipped modafinil, patient reported a sense of
well-being only with the drug and with the above dose…The dose was tapered slowly over a period of 1 month with 100 mg every 2–3 days and started on bupropion. He
reported sleep disturbance, increased sense of body warmth, lethargy and low mood during the process of tapering the drug. Low dose of clonazepam was added to
reduce the withdrawal symptoms. Patient reported substantial improvement in his sleep pattern. His dysphoric mood and lethargy improved and his level of anhedonia
and amotivation decreased.
“Acute Effects of Modafinil on Brain Resting State Networks in Young Healthy Subjects”, (2013-06-05;
There is growing debate on the use of drugs that promote cognitive enhancement. Amphetamine-like drugs have been employed as cognitive enhancers, but they show
important side effects and induce addiction. In this study, we investigated the use of modafinil which appears to have less side effects compared to other
amphetamine-like drugs. We analyzed effects on cognitive performances and brain resting state network activity of 26 healthy young subjects.
A single dose (100 mg) of modafinil was administered in a double-blind and placebo-controlled study. Both groups were tested for neuropsychological performances
with the Raven’s Advanced Progressive Matrices II set (APM) before and three hours after administration of
drug or placebo. Resting state functional magnetic resonance (rs-FMRI) was also used, before and after three
hours, to investigate changes in the activity of resting state brain networks. Diffusion Tensor Imaging (DTI) was
employed to evaluate differences in structural connectivity between the two groups. Protocol ID: Modrest_2011; NCT01684306; https: / / www.clinicaltrials.gov / ct2 / show / NCT01684306.
Results indicate that a single dose of modafinil improves cognitive performance as assessed by APM. Rs-fMRI showed that the drug produces a statistically-significant increased activation of Frontal
Parietal Control (FPC; p < 0.04) and Dorsal Attention (DAN; p < 0.04) networks. No modifications in structural connectivity were observed.
Conclusions and Significance:
Overall, our findings support the notion that modafinil has cognitive enhancing properties and provide functional connectivity data to support these
ClinicalTrials.gov NCT01684306 https: / / www.clinicaltrials.gov / ct2 / show / NCT01684306.
“Most reported genetic associations with general intelligence are probably false positives”, (2012; ; backlinks):
General intelligence (g) and virtually all other behavioral traits are heritable. Associations between g and specific single-nucleotide polymorphisms
(SNPs) in several candidate genes involved in brain function have been reported. We sought to replicate published
associations between g and 12 specific genetic variants (in the genes DTNBP1, CTSD,
DRD2, ANKK1, CHRM2, SSADH, COMT, BDNF, CHRNA4,
DISC1, APOE, and SNAP25) using data sets
from three independent, well-characterized longitudinal studies with samples of 5,571, 1,759, and 2,441 individuals. Of 32 independent tests across all
three data sets, only 1 was nominally statistically-significant. By contrast, power analyses showed that we should have
expected 10 to 15 statistically-significant associations, given reasonable assumptions for genotype effect sizes. For
positive controls, we confirmed accepted genetic associations for Alzheimer’s disease and body mass index, and we used SNP-based
calculations of genetic relatedness to replicate previous estimates that about half of the variance in g is accounted for by common genetic variation among individuals. We conclude that the molecular genetics
of psychology and social science requires approaches that go beyond the examination of candidate genes.
“The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical
Cocaine-Like Inhibitors”, (2011-09-11; backlinks):
Modafinil is a mild psychostimulant with pro-cognitive and antidepressant effects. Unlike many conventional stimulants, modafinil has little appreciable
potential for abuse, making it a promising therapeutic agent for cocaine addiction. The chief molecular target of modafinil is the dopamine transporter (DAT); however, the mechanistic details underlying modafinil’s
unique effects remain unknown. Recent studies suggest that the conformational effects of a given DAT ligand
influence the magnitude of the ligand’s reinforcing properties. For example, the atypical DAT inhibitors benztropine and
GBR12909 do not share cocaine’s notorious addictive liability, despite having greater binding affinity.
Here, we show that the binding mechanism of modafinil is different than cocaine and similar to other atypical inhibitors. We previously established two
mutations (W84L and D313N) that increase the likelihood that the DAT will adopt an outward-facing conformational
state—these mutations increase the affinity of cocaine-like inhibitors considerably, but have little or opposite effect on atypical inhibitor binding. Thus, a
compound’s WT/mutant affinity ratio can indicate whether the compound preferentially interacts with a more outward-facing or inward-facing conformational
Modafinil displayed affinity ratios similar to those of benztropine, GBR12909 and bupropion (which lack cocaine-like
effects in humans), but far different than those of cocaine, β-CFT or methylphenidate. Whereas treatment
with zinc (known to stabilize an outward-facing transporter state) increased the affinity of cocaine and methylphenidate two-fold, it had little or no effect on
the binding of modafinil, benztropine, bupropion or GBR12909. Additionally, computational modeling of
inhibitor binding indicated that while β-CFT and methylphenidate stabilize an “open-to-out” conformation, binding of
either modafinil or bupropion gives rise to a more closed conformation.
Our findings highlight a mechanistic difference between modafinil and cocaine-like stimulants and further demonstrate that the conformational effects of a
given DAT inhibitor influence its phenomenological effects.
“Modulatory effects of modafinil on neural circuits regulating emotion and cognition”, (2010):
Modafinil differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavioral effects. Most functional neuroimaging studies
to date examined the effect of modafinil only on information processing underlying executive cognition, but cognitive enhancers in general have been shown to have
pronounced effects on emotional behavior, too. We examined the effect of modafinil on neural circuits underlying affective processing and cognitive functions.
Healthy volunteers were enrolled in this double-blinded placebo-controlled trial (100 mg/day for 7 days). They
underwent BOLD fMRI while performing an emotion information-processing task
that activates the amygdala and two prefrontally dependent cognitive tasks-a working memory (WM) task and a variable attentional control (VAC) task. A clinical assessment that included measurement of blood pressure, heart rate, the Hamilton anxiety scale, and the
profile of mood state (POMS) questionnaire was also performed on each test day. BOLD fMRI revealed significantly decreased amygdala reactivity to fearful stimuli on modafinil
compared with the placebo condition. During executive cognition tasks, a WM task and a VAC task, modafinil reduced BOLD signal in the prefrontal cortex and anterior
cingulate. Although not statistically-significant, there were trends for reduced anxiety, for decreased fatigue-inertia and
increased vigor-activity, as well as decreased anger-hostility on modafinil. Modafinil in low doses has a unique physiologic profile compared with stimulant drugs:
it enhances the efficiency of prefrontal cortical cognitive information processing, while dampening reactivity to threatening stimuli in the amygdala, a brain
region implicated in anxiety.
“Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT”, (2010; backlinks):
Study Objectives: Modafinil may promote wakefulness by increasing cerebral dopaminergic neurotransmission, which importantly depends on
activity of catechol-O-methyltransferase (COMT) in prefrontal cortex. The effects of modafinil on sleep
homeostasis in humans are unknown. Employing a novel sleep-pharmacogenetic approach, we investigated the interaction of modafinil with sleep deprivation to study
dopaminergic mechanisms of sleep homeostasis.
Design: Placebo-controlled, double-blind, randomized crossover study.
Setting: Sleep laboratory in temporal isolation unit.
Participants: 22 healthy young men (23.4 ± 0.5 years) prospectively enrolled based on genotype of the functional Val158Met polymorphism
of COMT(10 Val/Val and 12 Met/Met homozygotes).
Interventions: 2 x 100 mg modafinil and placebo administered at 11 and 23 hours during 40 hours prolonged wakefulness.
Measurements and Results: Subjective sleepiness and EEG markers of sleep homeostasis in
wakefulness and sleep were equally affected by sleep deprivation in Val/Val and Met/Met allele carriers (placebo condition). Modafinil attenuated the
evolution of sleepiness and EEG 5–8 Hz activity during sleep deprivation in both genotypes. In contrast to caffeine, modafinil did not reduce EEG slow wave activity (0.75–4.5 Hz) in recovery
sleep, yet specifically increased 3.0–6.75 Hz and > 16.75 Hz activity in NREM sleep in the Val/Val genotype
Conclusions: The Val158Met polymorphism of COMT modulates the effects of modafinil on
the NREM sleep EEG in recovery sleep after prolonged wakefulness. The sleep
EEG changes induced by modafinil markedly differ from those of caffeine, showing
that pharmacological interference with dopaminergic and adenosinergic neurotransmission during sleep deprivation differently affects sleep homeostasis.
“Modafinil effects on cognitive function in HIV+ patients treated for fatigue: a placebo controlled study”, (2010; backlinks):
Both mild cognitive impairment and fatigue are common among people with HIV/AIDS. This study examined the efficacy
of modafinil for HIV+ patients who sought treatment for fatigue in a placebo-controlled double-blind 4-week trial. A
battery of standard neuropsychological tests was administered at study entry and Week 4, and change in performance was compared for 59 patients receiving modafinil
versus 44 patients receiving placebo. A statistically-significant effect on fatigue was observed. In addition, cognitive
performance, as measured by a global change score, improved more in the modafinil than in the placebo group although the effect was not specific to any cognitive
“Modafinil and memory: effects of modafinil on Morris water maze learning and Pavlovian fear conditioning”, (2009; backlinks):
Modafinil has been shown to promote wakefulness and some studies suggest the drug can improve cognitive function. Because of many similarities, the mechanism of
action may be comparable to classical psychostimulants, although the exact mechanisms of modafinil’s actions in wakefulness and cognitive enhancement are unknown.
The current study aims to further examine the effects of modafinil as a cognitive enhancer on hippocampus-dependent memory in mice. A high dose of modafinil (75
mg/kg ip) given before training improved acquisition on a Morris water maze. When given only before testing, modafinil did not affect water maze performance. We
also examined modafinil (0.075 to 75 mg/kg) on Pavlovian fear conditioning. A low dose of pretraining modafinil (0.75 mg/kg) enhanced memory of contextual fear
conditioning (tested off-drug 1 week later) whereas a high dose (75 mg/kg) disrupted memory. Pretraining modafinil did not affect cued conditioning at any dose
tested, and immediate posttraining modafinil had no effect on either cued or contextual fear. These results suggest that modafinil’s effects of memory are more
selective than amphetamine or cocaine and specific to hippocampus-dependent memory.
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
Further research is needed to determine whether modafinil restores performance on simple cognitive tasks only or whether modafinil additionally restores
executive functions (eg. 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]
2003-wang.pdf: “Involvement Of CYP3A4, CYP2C8, And CYP2D6 In The Metabolism Of (R)- And (S)-Methadone In Vitro”, (2003-06-01; ; backlinks):
To clarify the oxidative metabolism of methadone (R)- and (S)-enantiomers, the depletion of parent (R)- and (S)-methadone
and the formation of racemic 2-ethylidene-1,5-dimethyl-3,3-diphe-nylpyrolidine were studied using human liver microsomes and recombinant cytochrome P450 enzymes.
Based on studies with isoform-selective chemical inhibitors and expressed enzymes, CYP3A4 was the predominant enzyme
involved in the metabolism of (R)-methadone. However, it has different stereoselectivity toward (R)- and (S)-methadone. In
recombinant CYP3A4, the metabolic clearance of (R)-methadone was about 4-fold higher than that of
(S)-methadone. CYP2C8 is also involved in the metabolism of methadone, but its contribution to the
metabolism of (R)-methadone was smaller than that of CYP3A4. But for the metabolism of
(S)-methadone, the roles of CYP2C8 and CYP3A4 appeared equal.
Although CYP2D6 is involved in the metabolism of (R)- and (S)-methadone, its role was
smaller compared with CYP3A4 and CYP2C8. Using clinically relevant concentrations of
ketoconazole (1 μM, selective CYP3A4 inhibitor), trimethoprim (100 μM, selective CYP2C8 inhibitor), and paroxetine (5 μM, potent CYP2D6 inhibitor), these inhibitors
decreased the hepatic metabolism of (R)-[(S)-]methadone by 69% (47%), 22% (51%), and 41% (77%), respectively. However, inhibition of the
metabolism of (R)-methadone and (S)-methadone by paroxetine was due to inhibition not only of CYP2D6,
but also CYP3A4 and, to a minor extent, CYP2C8. The present in vitro findings
indicated that CYP3A4, CYP2C8, and CYP2D6 are
all involved in the stereoselective metabolism of methadone (R)- and (S)-enantiomers. These data suggest that coadministration of
inhibitors of CYP3A4 and CYP2C8 may produce clinically-significant drug-drug
interactions with methadone.
2001-warner.pdf: “The Personal Discount
Rate: Evidence from Military Downsizing Programs”, (2001-03; ; backlinks):
The military drawdown program of the early 1990’s provides an opportunity to obtain estimates of personal discount rates based on large numbers of people making
real choices involving large sums. The program offered over 65,000 separatees the choice between an annuity and a lump-sum payment. Despite break-even discount
rates exceeding 17%, most of the separatees selected the lump sum—saving taxpayers $2.87$1.702001 billion in separation costs. Estimates of discount rates range from 0 to over 30% and vary with education,
age, race, sex, number of dependents, ability test score, and the size of payment.
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
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.
“Potential brain neuronal targets for amphetamine-induced, methylphenidate-induced, and modafinil-induced wakefulness, evidenced by
c-fos immunocytochemistry in the cat”, (1996; backlinks):
Much experimental and clinical data suggest that the pharmacological profile of modafinil, a newly discovered waking substance, differs from those of
amphetamine and methylphenidate, two classical psychostimulants. The brain targets on which modafinil acts to induce wakefulness, however, remain unknown.
A double-blind study using the protooncogene c-fos as experimental marker in the cat was, therefore, carried out to identify the potential target neurons of modafinil and compare them with those for
amphetamine and methylphenidate. Cats were sacrificed after a single oral administration of amphetamine, methylphenidate, or
modafinil at equivalent doses for wake induction (1, 2.5, or 5 mg/kg, respectively) and brain sections examined for Fos by immunocytochemistry.
Administration of either amphetamine or methylphenidate evoked Fos-like immunoreactivity in a large number of neurons in the striatum and whole cortex,
especially in the caudate nucleus and mediofrontal cortex, which are known to be dopaminergic targets. In contrast, administration of modafinil resulted in the
labeling of few cells in these structures, but did induce marked Fos labeling in neurons of the anterior hypothalamic nucleus and adjacent areas.
These results provide evidence for the potential brain targets of modafinil, which differ from those of amphetamine or methylphenidate, and suggest that
modafinil induces wakefulness by mechanisms distinct from those of the two stimulants.
[Keywords: immediate-early gene, protooncogene, anterior hypothalamic nucleus, striatum, dopaminergic system]
1989-bmj-sleeplesspill.pdf: “Sleepless Pill”, British Medical Journal (1989-06-10)
Global Threat of Counterfeit Drugs: Why Industry and Governments Must Communicate the Dangers”, (; backlinks):
The production of substandard and fake drugs is a vast and under-reported problem, particularly affecting poorer countries. It is an important cause of
unnecessary morbidity, mortality, and loss of public confidence in medicines and health structures. The prevalence of counterfeit drugs appears to be rising (see
“The Scale of the Problem”) and has not been opposed by close cooperation between drug companies, governments, or international organizations concerned with trade,
health, customs and excise, and counterfeiting.
In this article we suggest that many pharmaceutical companies and governments are reluctant to publicize the problem to health staff and the public, apparently
motivated by the belief that the publicity will harm the sales of brand-name products in a fiercely competitive business. Publicly, at least, several industry
sources say the justification for secrecy is to avoid any alarm that could prevent patients taking their genuine medicines. We argue that this secrecy, and the
subsequent lack of public health warnings, is harming patients and that it is also not in the long-term interests of the legitimate pharmaceutical industry. We
urge a change to mandatory reporting to governmental authorities, which should also have a legal duty to investigate, issue appropriate public warnings, and share
information across borders. This is not a role for the pharmaceutical industry, which has a serious conflict of interest.