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“Cognitive Enhancement: Effects of Methylphenidate, Modafinil and Caffeine on Latent Memory and Resting State Functional Connectivity in Healthy Adults”, Becker et al 2022

“Cognitive enhancement: Effects of methylphenidate, modafinil and caffeine on latent memory and resting state functional connectivity in healthy adults”⁠, Maxi Becker, Dimitris Repantis, Martin Dresler, Simone Kühn (2022-04-21; similar):

Stimulants like methylphenidate, modafinil and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebo-controlled study of methylphenidate, modafinil and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the fronto-parietal (FPN) and default mode (DMN) network is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine’’s role in attention and memory as well as its ability to modulate FC between large-scale neural networks (eg. FPN and DMN) as a potential cognitive enhancement mechanism.

“Beliefs About Medicines Predict Side-Effects of Placebo Modafinil”, Heller et al 2022

2022-heller.pdf: “Beliefs About Medicines Predict Side-Effects of Placebo Modafinil”⁠, Monika K. Heller, Sarah C. E. Chapman, Rob Horne (2022-02-22; ; similar):

Background: Patients receiving placebo in clinical trials often report side-effects (nocebo effects), but contributing factors are still poorly understood.

Purpose: Using a sham trial of the cognition-enhancing “smart pill” Modafinil we tested whether medication beliefs and other psychological factors predicted detection and attribution of symptoms as side-effects to placebo.

Methods: Healthy students (n = 201) completed measures assessing beliefs about medication, perceived sensitivity to medicines, negative affectivity, somatization, and body awareness; 66 were then randomized to receive Deceptive Placebo (told Modafinil–given placebo, 67 to Open Placebo (told placebo–given placebo, and 68 to No Placebo. Memory and attention tasks assessed cognitive enhancement. Nocebo effects were assessed by symptom checklist.

Results: More symptoms were reported in the Deceptive Placebo condition (M = 2.65; SD = 2.27) than Open Placebo (M = 1.92; SD = 2.24; Mann–Whitney U = 1,654, z = 2.30, p = 0.022) or No Placebo (M = 1.68; SD = 1.75, Mann–Whitney U = 1,640, z = 2.74, p = 0.006). Participants were more likely to attribute symptoms to Modafinil side-effects if they believed pharmaceuticals to be generally harmful (incidence rate ratio [IRR] = 1.70, p = 0.019), had higher perceived sensitivity to medicines (IRR = 1.68, p = 0.011), stronger concerns about Modafinil (IRR = 2.10, p < 0.001), and higher negative affectivity (IRR = 2.37, p < 0.001).

Conclusions: Beliefs about medication are potentially modifiable predictors of the nocebo effect. These findings provide insight into side-effect reports to placebo and, potentially, active treatment.

“A Multi-pronged Investigation of Option Generation Using Depression, PET and Modafinil”, Ang et al 2022

2022-ang.pdf: “A multi-pronged investigation of option generation using depression, PET and modafinil”⁠, Yuen-Siang Ang, Cristina Cusin, Yoann Petibon, Daniel G. Dillon, Micah Breiger, Emily L. Belleau, Marc Normandin et al (2022-02-12; ; similar):

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood.

Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals.

We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2⁠/​D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind⁠, placebo-controlled, 3-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug.

The first study revealed that patients with major depressive disorder produced statistically-significantly fewer options [t(96) = 2.68, p = 0.009, Cohen’s d = 0.54], albeit with greater uniqueness [t(96) = −2.54, p = 0.01, Cohen’s d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = −0.69, p = 0.001) but positively associated with uniqueness (r = 0.59, p = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/​D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/​D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, p = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, p = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, p = 0.058, partial η2 = 0.19].

Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced.

[Keywords: depression, option generation, dopamine, modafinil, raclopride PET, positron-emission tomography⁠, dopamine, creativity, decision making, depressive disorders, putamen, raclopride, major depressive disorder, speech fluency, enhancer of transcription]

“Modafinil Reduces Neuronal Pyroptosis and Cognitive Decline After Sleep Deprivation”, Xiong et al 2022

“Modafinil Reduces Neuronal Pyroptosis and Cognitive Decline After Sleep Deprivation”⁠, Xiangyang Xiong, Yan Zuo, Lu Cheng, Zhenyu Yin, Tianpeng Hu, Mengtian Guo, Zhaoli Han, Xintong Ge, Wenzhu Li et al (2022; ; similar):

Sleep deprivation (SD) induces systemic inflammation that promotes neuronal pyroptosis.

The purpose of this study was to investigate the effect of an antioxidant modafinil on neuronal pyroptosis and cognitive decline following SD.

Using a mouse model of SD, we found that modafinil improved learning and memory, reduced proinflammatory factor (IL-1β, TNF-α, and IL-6) production, and increased the expression of anti-inflammatory factors (IL-10). Modafinil treatment attenuated inflammasome activity and reduced neuronal pyroptosis involving the NLRP3/​NLRP1/​NLRC4-caspase-1-IL-1β pathway. In addition, modafinil induced an upregulation of brain-derived neurotrophic factor (BDNF) and synaptic activity.

These results suggest that modafinil reduces neuronal pyroptosis and cognitive decline following SD. These effects should be further investigated in future studies to benefit patients with sleep disorders.

“Memory Enhancement With Stimulants: Differential Neural Effects of Methylphenidate, Modafinil, and Caffeine. A Pilot Study”, Adam et al 2021

2021-adam.pdf: “Memory enhancement with stimulants: Differential neural effects of methylphenidate, modafinil, and caffeine. A pilot study”⁠, Lucas C. Adam, Dimitris Repantis, Boris N. Konrad, Martin Dresler, Simone Kühn (2021-11-01; similar):

  • 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]

“Regression To The Mean Fallacies”, Branwen 2021

Regression: “Regression To The Mean Fallacies”⁠, Gwern Branwen (2021-05-20; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks):

Regression to the mean is a general statistical phenomenon which leads to several widespread fallacies in analyzing & interpreting statistical results, such as residual confounding and Lord’s paradox.

“An Anti-narcolepsy Drug Reveals Behavioral and Fitness Costs of Extreme Activity Cycles in Arctic-breeding Songbirds”, Payette et al 2021

2021-payette.pdf: “An anti-narcolepsy drug reveals behavioral and fitness costs of extreme activity cycles in arctic-breeding songbirds”⁠, Wesley I. Payette, Brett L. Hodinka, Keelee B. Pullum, Melanie M. Richter, Noah T. Ashley (2021-04-15; ; similar):

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.

“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”, Inoue et al 2021

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”⁠, Yuichi Inoue, Toshiyuki Tabata, Naoji Tsukimori (2021-04; similar):

  • 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]

“Modafinil Reduces Smoked Cocaine Self-administration in Humans: Effects Vary As a Function of Cocaine ‘priming’ and Cost”, Haney et al 2021

2021-haney.pdf: “Modafinil reduces smoked cocaine self-administration in humans: effects vary as a function of cocaine ‘priming’ and cost”⁠, Margaret Haney, Eric Rubin, Rebecca K. Denson, Richard W. Foltin (2021-04; backlinks; similar):

  • 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]

“Recovery from Refractory Chronic Fatigue Syndrome With CBT and Modafinil”, Garg et al 2021

2021-garg.pdf: “Recovery from refractory chronic fatigue syndrome with CBT and modafinil”⁠, Himanshu Garg, Maggie Douglas, Gordon Douglas Turkington, Douglas Turkington (2021-03-22; similar):

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.

“Concordant Neurophysiological Signatures of Cognitive Control in Humans and Rats”, Robble 2021

2021-robble.pdf: “Concordant neurophysiological signatures of cognitive control in humans and rats”⁠, Mykel A. Robble (2021-03-21; similar):

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.

“Cognitive Boosting Interventions for Impulsivity in Addiction: a Systematic Review and Meta-analysis of Cognitive Training, Remediation and Pharmacological Enhancement”, Anderson et al 2021

2021-anderson.pdf: “Cognitive boosting interventions for impulsivity in addiction: a systematic review and meta-analysis of cognitive training, remediation and pharmacological enhancement”⁠, Alexandra C. Anderson, George J. Youssef, Alex H. Robinson, Dan I. Lubman, Antonio Verdejo-Garcia (2021-03-10; similar):

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”, Walsh et al 2021

“Spontaneously Generated Online Patient Experience of Modafinil: A Qualitative and NLP Analysis”⁠, Julia Walsh, Jonathan Cave, Frances Griffiths (2021-02-17; similar):

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 posts.

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.

“Prescription Medication Use by Emergency Department Doctors to Improve Work and Academic Performance, and to Manage Stress and Anxiety”, Eggink et al 2021

2021-eggink.pdf: “Prescription medication use by emergency department doctors to improve work and academic performance, and to manage stress and anxiety”⁠, Karin M. Eggink, Simone E. Taylor, Simon Judkins, David McD. Taylor (2021-02-02; similar):

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.

“A Rare Case of Modafinil Dependence Presenting As Sleep Disorder”, Samudra et al 2021

2021-samudra.pdf: “A rare case of modafinil dependence presenting as sleep disorder”⁠, Madhura Samudra, Nishtha Gupta, Sana Dhamija, Suprakash Chaudhury, Daniel Saldanha (2021-01-01)

“Modafinil Induced Spontaneous Ejaculation Without Orgasm: A Case Report”, Aras 2020

2020-aras.pdf: “Modafinil Induced Spontaneous Ejaculation Without Orgasm: A Case Report”⁠, Neriman Aras (2020-11-27; similar):

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”, Repantis et al 2020

“Cognitive enhancement effects of stimulants: a randomized controlled trial testing methylphenidate, modafinil, and caffeine”⁠, Dimitris Repantis, Leonore Bovy, Kathrin Ohla, Simone Kühn, Martin Dresler (2020-11-17; similar):

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 domains.

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.

“Exploring the Economic Benefits of Modafinil for Post-Stroke Fatigue in Australia: A Cost-Effectiveness Evaluation”, Bajorek et al 2020

2020-bajorek.pdf: “Exploring the Economic Benefits of Modafinil for Post-Stroke Fatigue in Australia: A Cost-Effectiveness Evaluation”⁠, Beata Bajorek, Lan Gao, Tom Lillicrap, Andrew Bivard, Carlos Garcia-Esperon, Mark Parsons, Neil Spratt et al (2020-11-01; similar):

Highlights:

  • 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 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]

“Road Check Leads to Meth Charges for Rome Woman”, Walker 2020

“Road check leads to meth charges for Rome woman”⁠, Doug Walker (2020-10-23; backlinks; similar):

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.

“Optimising Sleep and Performance during Night Float: A Systematic Review of Evidence and Implications for Graduate Medical Education Trainees”, Sholtes et al 2020

2020-sholtes.pdf: “Optimising sleep and performance during night float: A systematic review of evidence and implications for graduate medical education trainees”⁠, David Sholtes, Howard M. Kravitz, Aniruddha Deka, Jennifer Westrick, Louis F. Fogg (2020-10-15; similar):

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.

“Incidence of Malformations After Early Pregnancy Exposure to Modafinil in Sweden and Norway”, Cesta et al 2020

2020-cesta.pdf: “Incidence of Malformations After Early Pregnancy Exposure to Modafinil in Sweden and Norway”⁠, Carolyn E. Cesta, Anders Engeland, Pär Karlsson, Helle Kieler, Johan Reutfors, Kari Furu (2020-09-01; similar):

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”, Caldwell et al 2020

“Differential effects of modafinil on performance of low-performing and high-performing individuals during total sleep deprivation”⁠, J. Lynn Caldwell, Valarie M. Schroeder, Christina L. Kunkle, Henry G. Stephenson (2020-09; backlinks; similar):

Highlights:

  • 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”, Assi et al 2020

“On-spot quantification of modafinil in generic medicines purchased from the Internet using handheld Fourier transform-infrared, near-infrared and Raman spectroscopy”⁠, Sulaf Assi, Iftikhar Khan, Aaron Edwards, David Osselton, Hisham Al-Obaidi (2020-08-13; backlinks; similar):

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.

“Modafinil-induced Psychosis in a Patient With Attention Deficit Hyperactivity Disorder”, Flavell 2020

2020-flavell.pdf: “Modafinil-induced psychosis in a patient with attention deficit hyperactivity disorder”⁠, Joshua Flavell (2020-07-26; similar):

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.

“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”, Roberts et al 2020

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”⁠, Carl A. Roberts, Andrew Jones, Harry Sumnall, Suzanne H. Gage, Catharine Montgomery (2020-07-21; backlinks; similar):

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 an user perception that these drugs are effective cognitive enhancers, but this is not supported by the evidence so far.

“Procognitive Effects of Antidepressants and Other Therapeutic Agents in Major Depressive Disorder: A Systematic Review”, Blumberg et al 2020

2020-blumberg.pdf: “Procognitive Effects of Antidepressants and Other Therapeutic Agents in Major Depressive Disorder: A Systematic Review”⁠, Michelle J. Blumberg, Sophie R. Vaccarino, Shane J. McInerney (2020-07-21; similar):

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.

“Hyponatraemia and Cerebral Oedema due to a Modafinil Overdose”, Kandasamy & Kaminskaite 2020

2020-kandasamy.pdf: “Hyponatraemia and cerebral oedema due to a modafinil overdose”⁠, Rohan Oliver Kandasamy, Viktorija Kaminskaite (2020-07-05; backlinks; similar):

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.

“The Use of Stimulants in Depression: Results from a Self-controlled Register Study”, Rohde et al 2020

2020-rohde.pdf: “The use of stimulants in depression: Results from a self-controlled register study”⁠, Christopher Rohde, Philip Brink, Søren D. Østergaard, Jimmi Nielsen (2020-05-23; similar):

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]

“Modafinil Potentiates Cocaine Self-administration by a Dopamine-independent Mechanism: Possible Involvement of Gap Junctions”, Mereu et al 2020

2020-mereu.pdf: “Modafinil potentiates cocaine self-administration by a dopamine-independent mechanism: possible involvement of gap junctions”⁠, Maddalena Mereu, Takato Hiranita, Chloe J. Jordan, Lauren E. Chun, Jessica P. Lopez, Mark A. Coggiano et al (2020-04-27; ; backlinks; similar):

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 an 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.

“Modulating the Immune Response With the Wake-promoting Drug Modafinil: A Potential Therapeutic Approach for Inflammatory Disorders”, Zager 2020

2020-zager.pdf: “Modulating the immune response with the wake-promoting drug modafinil: A potential therapeutic approach for inflammatory disorders”⁠, Adriano Zager (2020-04-18; similar):

Highlights:

  • Modafinil is a psychostimulant drug approved for the treatment of sleep disorders.
  • Recent preclinical findings point to an 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]

“Cognitive Enhancement Drug Use among Resident Physicians: Prevalence and Motivations for Use—results from a Survey”, Rubin-Kahana et al 2020

2020-rubinkahana.pdf: “Cognitive enhancement drug use among resident physicians: Prevalence and motivations for use—results from a survey”⁠, Dafna Sara Rubin-Kahana, Ziv Rubin-Kahana, Maya Kuperberg, Rafael Stryjer, Dorit Yodashkin-Porat (2020-04-16; similar):

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”, Teodorini et al 2019

“The off-prescription use of modafinil: An online survey of perceived risks and benefits”⁠, Rachel D. Teodorini, Nicola Rycroft, James H. Smith-Spark, Kenji Hashimoto, Kenji Hashimoto, Kenji Hashimoto et al (2019-12-30; backlinks; similar):

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”, Rickard 2019

“Former Area Physician Charged with Forging Prescriptions Sent to ARD”⁠, Julie Rae Rickard (2019-12-11; backlinks; similar):

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 ~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.

“Excessive Sleepiness in Shift Work Disorder: a Narrative Review of the Last 5 Years”, Savarese & Perri 2019

2019-savarese.pdf: “Excessive sleepiness in shift work disorder: a narrative review of the last 5 years”⁠, Mariantonietta Savarese, Maria Caterina Di Perri (2019-08-30; similar):

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]

“The Availability of Modafinil and Methylphenidate Purchased from the Internet in the United Kingdom Without a Prescription”, Joanna et al 2019

2019-hockenhull.pdf: “The Availability of Modafinil and Methylphenidate Purchased from the Internet in the United Kingdom Without a Prescription”⁠, Hockenhull Joanna, Wood David M., Dargan Paul I. (2019-08-20)

“The Efficacy of Modafinil As a Cognitive Enhancer: A Systematic Review and Meta-Analysis”, Kredlow et al 2019

2019-kredlow.pdf: “The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis”⁠, M. Alexandra Kredlow, Ani Keshishian, Sarah Oppenheimer, Michael W. Otto (2019-08-19; backlinks; similar):

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.

“Sleep-Promoting and Wake-Promoting Drugs: Where Are They Being Sourced, and What Is Their Impact?”, Ogeil et al 2019

2019-ogeil.pdf: “Sleep-Promoting and Wake-Promoting Drugs: Where Are They Being Sourced, and What Is Their Impact?”⁠, Rowan P. Ogeil, James G. Phillips, Michael Savic, Daniel I. Lubman (2019-07-08; similar):

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”, Steward & Pickersgill 2019

“Developing expertise, customizing sleep, enhancing study practices: exploring the legitimization of modafinil use within the accounts of UK undergraduate students”⁠, Alice Steward, Martyn Pickersgill (2019-01-16; similar):

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]

“Moral Decision Making under Modafinil: a Randomized Placebo-controlled Double-blind Crossover FMRI Study”, Ngo et al 2019

2019-ngo.pdf: “Moral decision making under modafinil: a randomized placebo-controlled double-blind crossover fMRI study”⁠, Thao Ngo, Marta Ghio, Lars Kuchinke, Patrik Roser, Christian Bellebaum (2019-01-01)

“The Availability and Acquisition of Modafinil on the Internet”, Dursun et al 2019

2019-dursun.pdf: “The availability and acquisition of modafinil on the internet”⁠, Suat Dursun, Matthew Dunn, Fiona H. McKay (2019-01-01)

“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”, Billiard & Broughton 2018

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”⁠, Michel Billiard, Roger Broughton (2018-09-01; similar):

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”, Holfinger et al 2018

“Stevens-Johnson Syndrome After Armodafinil Use”⁠, Steven Holfinger, Asim Roy, Markus Schmidt (2018-05-15; backlinks; similar):

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 first symptoms.

“Pharmacological Cognitive Enhancement among Non-ADHD Individuals—A Cross-sectional Study in 15 Countries”, Maier et al 2018

2018-maier.pdf: “Pharmacological cognitive enhancement among non-ADHD individuals—A cross-sectional study in 15 countries”⁠, Larissa J. Maier, Jason A. Ferris, Adam R. Winstock (2018-01-01; backlinks)

“Modafinil and the Risk of Cardiovascular Events: Findings from Three US Claims Databases”, Kaplan et al 2018

2018-kaplan.pdf: “Modafinil and the risk of cardiovascular events: Findings from three US claims databases”⁠, Sigal Kaplan, Earl L. Goehring, Sigal Melamed-Gal, Bao-Anh Nguyen-Khoa, Helena Knebel, Judith K. Jones et al (2018-01-01)

“Modafinil and Armodafinil”, Šonka et al 2015

2015-sonka.pdf: “Modafinil and Armodafinil”⁠, Karel Šonka, Peter Šoš, Marek Susta (2015-01-01)

“Compulsive Modafinil Use in a Patient With a History of Alcohol Use Disorder”, Mete et al 2015

2015-mete.pdf: “Compulsive modafinil use in a patient with a history of alcohol use disorder”⁠, Melek Cengiz Mete, Ömer Şenormancı, Özge Saraçlı, Nuray Atasoy, Levent Atik (2015-01-01; backlinks)

“A Rare Case of Modafinil Dependence”, Krishnan & Chary 2015

“A rare case of modafinil dependence”⁠, Raman Krishnan, Krishnan Vengadaragava Chary (2015-01; backlinks; similar):

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.

“Modafinil Combined With Cognitive Training Is Associated With Improved Learning in Healthy Volunteers—A Randomised Controlled Trial”, Gilleen et al 2014

2014-gilleen.pdf: “Modafinil combined with cognitive training is associated with improved learning in healthy volunteers—A randomised controlled trial”⁠, J. Gilleen, P. G. Michalopoulou, A. Reichenberg, R. Drake, T. Wykes, S. W Lewis, S. Kapur (2014-01-01)

“Catechol-O-methyltransferase, Dopamine, and Sleep-wake Regulation”, Dauvilliers et al 2014

2014-dauvilliers.pdf: “Catechol-O-methyltransferase, dopamine, and sleep-wake regulation”⁠, Yves Dauvilliers, Mehdi Tafti, Hans Peter Landolt (2014-01-01)

“Acute Effects of Modafinil on Brain Resting State Networks in Young Healthy Subjects”, Esposito et al 2013

“Acute Effects of Modafinil on Brain Resting State Networks in Young Healthy Subjects”⁠, Roberto Esposito, Franco Cilli, Valentina Pieramico, Antonio Ferretti, Antonella Macchia, Marco Tommasi et al (2013-06-05; ; backlinks; similar):

Background :

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.

Methodology :

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; http://clinicaltrials.gov/ct2/show/NCT01684306⁠.

Principal Findings :

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 effects.

Trial Registration :

ClinicalTrials.gov NCT01684306 http://clinicaltrials.gov/ct2/show/NCT01684306⁠.

“Modafinil Effects on Cognition and Emotion in Schizophrenia and Its Neurochemical Modulation in the Brain”, Scoriels et al 2013

2013-scoriels.pdf: “Modafinil effects on cognition and emotion in schizophrenia and its neurochemical modulation in the brain”⁠, Linda Scoriels, Peter B. Jones, Barbara J. Sahakian (2013-01-01; backlinks)

“Effects of Modafinil on Neural Correlates of Response Inhibition in Alcohol-Dependent Patients”, Schmaal et al 2013

2013-schmaal.pdf: “Effects of Modafinil on Neural Correlates of Response Inhibition in Alcohol-Dependent Patients”⁠, Lianne Schmaal, Leen Joos, Marte Koeleman, Dick J. Veltman, Wim van den Brink, Anna E. Goudriaan (2013-01-01; backlinks)

“A Preclinical Evaluation of the Discriminative and Reinforcing Properties of Lisdexamfetamine in Comparison to D-amfetamine, Methylphenidate and Modafinil”, Heal et al 2013

2013-heal.pdf: “A preclinical evaluation of the discriminative and reinforcing properties of lisdexamfetamine in comparison to D-amfetamine, methylphenidate and modafinil”⁠, David J. Heal, Niki W. Buckley, Jane Gosden, Nigel Slater, Charles P. France, David Hackett (2013-01-01; backlinks)

“Efficacy of Stimulants for Cognitive Enhancement in Non-attention Deficit Hyperactivity Disorder Youth: a Systematic Review”

2013-bagot.pdf: “Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review” (2013-01-01; backlinks)

“Modafinil Alone and in Combination With Low Dose Amphetamine Does Not Establish Conditioned Place Preference in Male Sprague-Dawley Rats”, Quisenberry & al 2013

2013-quisenberry.pdf: “Modafinil Alone and in Combination With Low Dose Amphetamine Does Not Establish Conditioned Place Preference in Male Sprague-Dawley Rats”⁠, Quisenberry, et al (2013; backlinks)

“DNM-related Arrests, 2011–2015”, Branwen 2012

DNM-arrests: “DNM-related arrests, 2011–2015”⁠, Gwern Branwen (2012-07-14; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar):

A census database of all publicly-reported arrests and prosecutions connected to the Tor-Bitcoin drug darknet markets 2011-2015, and analysis of mistakes.

I compile a table and discussion of all known arrests and prosecutions related to English-language Tor-Bitcoin darknet markets (DNMs) such as Silk Road 1, primarily 2011–2015, along with discussion of how they came to be arrested.

“SLA202494.dvi”

2012-sugden.pdf: “SLA202494.dvi” (2012-01-01; backlinks)

“Interactions between Modafinil and Cocaine during the Induction of Conditioned Place Preference and Locomotor Sensitization in Mice: Implications for Addiction”, Shuman et al 2012

2012-shuman.pdf: “Interactions between modafinil and cocaine during the induction of conditioned place preference and locomotor sensitization in mice: Implications for addiction”⁠, Tristan Shuman, Denise J. Cai, Jennifer R. Sage, Stephan G. Anagnostaras (2012-01-01; backlinks)

“Effects of Modafinil on Non-verbal Cognition, Task Enjoyment and Creative Thinking in Healthy Volunteers”, MUller et al 2012

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 et al (2012-01-01; backlinks)

“Asem3212.indd”

2012-kelley.pdf: “asem3212.indd” (2012-01-01; backlinks)

“Asem3129.indd”

2012-estrada.pdf: “asem3129.indd” (2012-01-01; backlinks)

“A Randomized Trial on the Efficacy of Methylphenidate and Modafinil for Improving Cognitive Functioning and Symptoms in Patients With a Primary Brain Tumor”, Gehring et al 2011

2011-gehring.pdf: “A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor”⁠, K. Gehring, S. Y. Patwardhan, R. Collins, M. D. Groves, C. J. Etzel, C. A. Meyers, J. S. Wefel (2011-10-02; ; backlinks; similar):

Limited research is available regarding the efficacy of psychostimulants in treating cognitive function in primary brain tumor patients.

An open-label, randomized, pilot trial examined both the general and differential efficacy of 4 weeks of methylphenidate (MPH) and modafinil (MOD) in 24 brain tumor patients. Participants completed cognitive tests and self-report measures of fatigue, sleep disturbance, mood and quality of life at baseline and after 4 weeks.

Following stimulant treatment, there was evidence of a beneficial effect on test performance in speed of processing and executive function requiring divided attention. Patients with the greatest deficit in executive function at baseline appeared to derive the greatest benefit following stimulant therapy. Inconsistent, differential effects were found on a measure of attention in favor of MPH and on a measure of processing speed in favor of MOD. There was also evidence of a general beneficial effect on patient-reported measures of fatigue, mood, and quality of life, with no statistically-significant differences between treatment arms in these measures over time.

The results from this small pilot study should be interpreted with caution, but appear to warrant additional research, in larger study samples, targeting fatigue, processing speed and executive function, and exploring different doses of stimulants. Future studies may also wish to explore the specific patient factors that may be associated with responsiveness to psychostimulant treatment.

[Keywords: cognitive deficit, brain tumor, psychostimulant, stimulant treatment]

“The Atypical Stimulant and Nootropic Modafinil Interacts With the Dopamine Transporter in a Different Manner Than Classical Cocaine-Like Inhibitors”, Schmitt & Reith 2011

“The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors”⁠, Kyle C. Schmitt, Maarten E. A. Reith (2011-09-11; backlinks; similar):

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 state.

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.

“The False-positive to False-negative Ratio in Epidemiologic Studies”

2011-ioannidis.pdf: “The False-positive to False-negative Ratio in Epidemiologic Studies” (2011-01-01; ; backlinks)

“Click Trajectories: End-to-End Analysis of the Spam Value Chain”, Levchenko & al 2011

http://www.icir.org/christian/publications/2011-oakland-trajectory.pdf: “Click Trajectories: End-to-End Analysis of the Spam Value Chain”⁠, Levchenko, et al (2011; backlinks)

“Provigil: A Case Study Of Anticompetitive Behavior”, Carrier 2011

http://hstlj.org/articles/provigil-a-case-study-of-anticompetitive-behavior/: “Provigil: A Case Study Of Anticompetitive Behavior”⁠, Carrier (2011; backlinks)

“Experimental ‘Jet Lag’ Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters”, Gibson et al 2010

“Experimental ‘Jet Lag’ Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters”⁠, Erin M. Gibson, Connie Wang, Stephanie Tjho, Neera Khattar, Lance J. Kriegsfeld (2010-11-03; backlinks; similar):

Background :

Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined.

Methodology/​Principal Findings :

In the present study, we investigated whether experimental ‘jet lag’ (ie. phase advances of the light∶dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/​memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function.

Conclusions/​Significance :

Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learning and memory.

“Stimulants in Bipolar Disorder: beyond Common Beliefs”, Hensch et al 2010

2010-hensch.pdf: “Stimulants in bipolar disorder: beyond common beliefs”⁠, Tilman Hensch, Hubertus Himmerich, Ulrich Hegerl (2010-07-01; backlinks)

“Modafinil Use in Patients With a Primary Psychiatric Illness”, Black et al 2010

2010-black.pdf: “Modafinil Use in patients with a Primary Psychiatric Illness”⁠, Warwick Black, Peter Hoey, Thomas Mayze (2010-05-20; ; similar):

We report 4 individuals with a variety of psychiatric diagnoses whose symptoms of fatigue, sleepiness or hypoarousal were treated successfully with modafinil⁠. In each case the patient remains on modafinil therapy, with no important adverse events reported to date.

…The first patient had a 30 year history of bipolar disorder type 1…The second patient had experienced massive cerebral trauma requiring a long period of rehabilitation…The third patient is a 70 year old male with treatment-resistant depression characterized by severe fatigue and a possible obsessive-compulsive spectrum disorder…Finally, a 32 year old female patient presented with severe uncontrolled trichotillomania, and depressive symptoms.

“The Algernon Argument”, Branwen 2010

Drug-heuristics: “The Algernon Argument”⁠, Gwern Branwen (2010-03-23; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks):

Why most supplements fail: IQ improvement skepticism, Yudkowsky & Bostrom’s heuristics, nootropics

“Nootropics”, Branwen 2010

Nootropics: “Nootropics”⁠, Gwern Branwen (2010-01-02; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar):

Notes on nootropics I tried, and my experiments

Bacopa is a supplement herb often used for memory or stress adaptation. Its chronic effects reportedly take many weeks to manifest, with no important acute effects. Out of curiosity, I bought 2 bottles of Bacognize Bacopa pills and ran a non-randomized non-blinded ABABA quasi-self-experiment from June 2014 to September 2015, measuring effects on my memory performance, sleep, and daily self-ratings of mood/​productivity. Because of the very slow onset, small effective sample size, definite temporal trends probably unrelated to Bacopa, and noise in the variables, the results were as expected, ambiguous, and do not strongly support any correlation between Bacopa and memory/​sleep/​self-rating (+/​-/​- respectively).

“Modulatory Effects of Modafinil on Neural Circuits Regulating Emotion and Cognition”, Rasetti et al 2010

“Modulatory effects of modafinil on neural circuits regulating emotion and cognition”⁠, Roberta Rasetti, Venkata S. Mattay, Beth Stankevich, Kelsey Skjei, Giuseppe Blasi, Fabio Sambataro, Isabel C. Arrillaga-Romany et al (2010; similar):

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 an 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”, Bodenmann & Landolt 2010

“Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT”⁠, Sereina Bodenmann, Hans-Peter Landolt (2010; ; backlinks; similar):

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 of COMT.

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”, McElhiney et al 2010

“Modafinil effects on cognitive function in HIV+ patients treated for fatigue: a placebo controlled study”⁠, Martin McElhiney, Judith Rabkin, Wilfred Van Gorp, Richard Rabkin (2010; backlinks; similar):

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 domain.

“Modafinil”, Branwen 2009

Modafinil: “Modafinil”⁠, Gwern Branwen (2009-02-20; ⁠, ; backlinks; similar):

Effects, health concerns, suppliers, prices & rational ordering.

Modafinil is a prescription stimulant drug. I discuss informally, from a cost-benefit-informed perspective, the research up to 2015 on modafinil’s cognitive effects, the risks of side-effects and addiction/​tolerance and law enforcement, and give a table of current grey-market suppliers and discuss how to order from them.

“Samosseiko-VB2009.indd”, HelenMartin 2009

2009-samosseiko.pdf: “Samosseiko-VB2009.indd”⁠, HelenMartin (2009-01-01; backlinks)

“Modafinil and Memory: Effects of Modafinil on Morris Water Maze Learning and Pavlovian Fear Conditioning”, Shuman et al 2009

“Modafinil and memory: effects of modafinil on Morris water maze learning and Pavlovian fear conditioning”⁠, Tristan Shuman, Suzanne C. Wood, Stephan G. Anagnostaras (2009; backlinks; similar):

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.

“Effects of Modafinil on Cognitive Performance and Alertness During Sleep Deprivation”, Wesensten 2006

2006-wesensten.pdf: “Effects of Modafinil on Cognitive Performance and Alertness During Sleep Deprivation”⁠, Nancy J. Wesensten (2006-07-01; backlinks; similar):

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 (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]

“The Effects of Caffeine, Dextroamphetamine, and Modafinil on Humor Appreciation During Sleep Deprivation”, Killgore et al 2006

2006-killgore.pdf: “The Effects of Caffeine, Dextroamphetamine, and Modafinil on Humor Appreciation During Sleep Deprivation”⁠, William D. S. Killgore, Sharon A. McBride, Desiree B. Killgore, Thomas J. Balkin (2006-06-01; ; backlinks; similar):

Study Objectives: Sleep loss consistently impairs performance on measures of alertness, vigilance, and response speed, but its effects on higher-order executive functions are not well delineated. Similarly, whereas deficits in arousal and vigilance can be temporarily countered by the use of several different stimulant medications, it is not clear how these compounds affect complex cognitive processes in sleep-deprived individuals.

Design: We evaluated the effects of double-blind administration of 3 stimulant medications or placebo on the ability to appreciate humor in visual (cartoons) or verbal (headlines) stimuli presented on a computer screen following 49.5 hours of sleep deprivation.

Setting: In-residence sleep-laboratory facility at the Walter Reed Army Institute of Research⁠.

Participants: 54 healthy adults (29 men, 24 women), ranging in age from 18 to 36 years.

Intervention: Each participant was randomly assigned to 1 of 3 stimulant medication groups, including caffeine⁠, 600 mg, n = 12; modafinil⁠, 400 mg, n = 11; dextroamphetamine⁠, 20 mg, n = 16; or placebo⁠, n = 14.

Measurements and Results: Humor appreciation for cartoon stimuli was enhanced by modafinil relative to both placebo and caffeine, but there was no effect of any stimulant medication on the appreciation of verbal humor during sleep loss. In contrast, all 3 stimulants improved psychomotor response speed, whereas only caffeine and dextroamphetamine improved ratings of subjective sleepiness.

Conclusions: Findings suggest that, despite similar alerting and vigilance-promoting effects, these 3 compounds have statistically-significantly different effects on those highly complex cognitive abilities mediated by the prefrontal cortex⁠.

[Keywords: sleep deprivation, modafinil, performance, caffeine, dextroamphetamine, cognitive function, humor appreciation]

“Template”, Mike 2005

2005-cahill.pdf: “template”⁠, Mike (2005-01-01; backlinks)

“Effects of Modafinil on Working Memory Processes in Humans”, Müller et al 2004

2004-muller.pdf: “Effects of modafinil on working memory processes in humans”⁠, Ulrich Müller, Nikolai Steffenhagen, Ralf Regenthal, Peter Bublak (2004-06-24; backlinks; similar):

Rationale: modafinil is a well-tolerated psychostimulant drug with low addictive potential that is used to treat patients with narcolepsy or attention deficit disorders and to enhance vigilance in sleep-deprived military personal. So far, understanding of the cognitive enhancing effects of modafinil and the relevant neurobiological mechanisms are incomplete.

Objectives: The aim of this study was to investigate the effects of modafinil on working memory processes in humans and how they are related to noradrenergic stimulation of the prefrontal cortex⁠.

Methods: Sixteen healthy volunteers (aged 20–29 years) received either modafinil 200 mg or placebo using a double blind crossover design. 2 computerized working memory tasks were administered, a numeric manipulation task that requires short-term maintenance of digit-sequences and different degrees of manipulation as well as delayed matching task that assesses maintenance of visuo-spatial information over varying delay lengths. The battery was supplemented by standardized paper pencil tasks of attentional functions.

Results: Modafinil statistically-significantly reduced error rates in the long delay condition of the visuo-spatial task and in the manipulation conditions, but not in the maintenance condition of the numeric task. Analyses of reaction times showed no speed-accuracy trade-off. Attentional control tasks (letter cancellation, trail-making, catch trials) were not affected by modafinil.

Conclusions: In healthy volunteers without sleep deprivation modafinil has subtle stimulating effects on maintenance and manipulation processes in relatively difficult and monotonous working memory tasks, especially in lower performing subjects. Overlapping attentional and working memory processes have to be considered when studying the noradrenergic modulation of the prefrontal cortex.

[Keywords: human, modafinil, noradrenaline, prefrontal, working memory]

“Effects of Modafinil on Working Memory Processes in Humans”

2004-mueller.pdf: “Effects of modafinil on working memory processes in humans” (2004-01-01; backlinks)

“Poised to Challenge Need for Sleep, 'Wakefulness Enhancer' Rouses Concerns”, Vastag 2004

2004-jama.pdf: “Poised to Challenge Need for Sleep, 'Wakefulness Enhancer' Rouses Concerns”⁠, Vastag (2004-01-01; backlinks)

“Effect of Modafinil on Fatigue, Mood, and Health-related Quality of Life in Patients With Narcolepsy”, Becker & al 2004

2004-becker.pdf: “Effect of modafinil on fatigue, mood, and health-related quality of life in patients with narcolepsy”⁠, Becker, et al (2004; backlinks)

“Involvement Of CYP3A4, CYP2C8, And CYP2D6 In The Metabolism Of (R)- And (S)-Methadone In Vitro”, Wang & DeVane 2003

2003-wang.pdf: “Involvement Of CYP3A4, CYP2C8, And CYP2D6 In The Metabolism Of (R)- And (S)-Methadone In Vitro”⁠, Jun-Sheng Wang, C. Lindsay DeVane (2003-06-01; ; backlinks; similar):

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× 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.

“Distinctive Effects of Modafinil and D-amphetamine on the Homeostatic and Circadian Modulation of the Human Waking EEG”, Chapotot & al 2003

2003-chapotot.pdf: “Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG”⁠, Chapotot, et al (2003; backlinks)

“Modafinil Reduces Excessive Somnolence and Enhances Mood in Patients With Myotonic Dystrophy”, MacDonald & al 2002

2002-macdonald.pdf: “Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy”⁠, MacDonald, et al (2002-01-01; backlinks)

“Study of the Addictive Potential of Modafinil in Naive and Cocaine-experienced Rats”, Deroche-Gamonet & al 2002

2002-deroche-gamonet.pdf: “Study of the addictive potential of modafinil in naive and cocaine-experienced rats”⁠, Deroche-Gamonet, et al (2002-01-01; backlinks)

“An Evaluation of the Abuse Potential of Modafinil Using Methylphenidate As a Reference”, Jasinski 2000

2000-jasinski.pdf: “An evaluation of the abuse potential of modafinil using methylphenidate as a reference”⁠, Donald R. Jasinski (2000; backlinks; similar):

Modafinil is an 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.

“Naps and Modafinil As Countermeasures for the Effects of Sleep Deprivation on Cognitive Performance”, Batéjat & Lagarde 1999

1999-batejat.pdf: “Naps and modafinil as countermeasures for the effects of sleep deprivation on cognitive performance”⁠, Denise M. Batéjat, Didier P. Lagarde (1999-05-01; backlinks; similar):

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.

“Potential Brain Neuronal Targets for Amphetamine-induced, Methylphenidate-induced, and Modafinil-induced Wakefulness, Evidenced by C-fos Immunocytochemistry in the Cat”, Lin et al 1996

“Potential brain neuronal targets for amphetamine-induced, methylphenidate-induced, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat”⁠, Lin, J. S Hou, Y. Jouvet, M (1996; backlinks; similar):

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]

“Sleepless Pill”, Journal 1989

1989-bmj-sleeplesspill.pdf: “Sleepless Pill”⁠, British Medical Journal (1989-06-10)

“The Global Threat of Counterfeit Drugs: Why Industry and Governments Must Communicate the Dangers”, Cockburn et al 2022

“The Global Threat of Counterfeit Drugs: Why Industry and Governments Must Communicate the Dangers”⁠, Robert Cockburn, Paul N. Newton, E. Kyeremateng Agyarko, Dora Akunyili, Nicholas J. White (; backlinks; similar):

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.

“薬物密輸:容疑で理研実習生逮捕 兵庫県警”

https://archive.ph/9dFGL: “薬物密輸:容疑で理研実習生逮捕 兵庫県警” (backlinks)

“Letter to the Editor: Modafinil for Narcolepsy”

https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.158.6.970-a: “Letter to the Editor: Modafinil for Narcolepsy” (backlinks)

“Controlled Mental Health Drug Seized in South China”

http://www.xinhuanet.com/english/2019-08/13/c_138306693.htm: “Controlled mental health drug seized in south China” (backlinks)

“Uses of Modafinil and Its D/L Enantiomers”

http://www.ptodirect.com/Results/Patents?query=PN/6465519: “Uses of modafinil and its D / L enantiomers” (backlinks)

“Cognitive Performance Following Modafinil versus Placebo in Sleep-deprived Emergency Physicians: A Double-blind Randomized Crossover Study”

http://prdupl02.ynet.co.il/ForumFiles_2/15246312.pdf: “Cognitive Performance Following Modafinil versus Placebo in Sleep-deprived Emergency Physicians: A Double-blind Randomized Crossover Study” (backlinks)

“Modafinil Augmentation Therapy in Unipolar and Bipolar Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials”

2013-goss.pdf: “Modafinil Augmentation Therapy in Unipolar and Bipolar Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials” (backlinks)

“Effects of Modafinil on Cognitive Functions in First Episode Psychosis”

2011-scoriels.pdf: “Effects of modafinil on cognitive functions in first episode psychosis” (backlinks)

“Adjunctive Armodafinil in Schizophrenia”

2009-kane.pdf: “Adjunctive Armodafinil in Schizophrenia” (backlinks)

“Neuroenhancement: Status Quo and Perspectives”

2008-norman.pdf: “Neuroenhancement: status quo and perspectives” (backlinks)

“Modafinil: A Review of Neurochemical Actions and Effects on Cognition”

2008-minzenberg.pdf: “Modafinil: A Review of Neurochemical Actions and Effects on Cognition” (backlinks)

“Approved and Investigational Uses of Modafinil: An Evidence-based Review”

2008-kumar.pdf: “Approved and Investigational Uses of Modafinil: An Evidence-based Review” (backlinks)

“Benefits of Adjunct Modafinil in an Open-label, Pilot Study in Patients With Schizophrenia”

2004-rosenthal.pdf: “Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia” (backlinks)

“Effects of Modafinil on Cognitive and Meta-cognitive Performance”

2004-baranski.pdf: “Effects of modafinil on cognitive and meta-cognitive performance” (backlinks)

“Cognitive Enhancing Effects of Modafinil in Healthy Volunteers”

2003-turner.pdf: “Cognitive enhancing effects of modafinil in healthy volunteers” (backlinks)

“Non-amphetaminic Mechanism of Stimulant Locomotor Effect of Modafinil in Mice”

1995-simon.pdf: “Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice” (backlinks)

“Modafinil, D-amphetamine and Placebo during 64 Hours of Sustained Mental Work. I. Effects on Mood, Fatigue, Cognitive Performance and Body Temperature”

1995-pigeau.pdf: “Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature” (backlinks)

“Interest of Modafinil, a New Psychostimulant, during a Sixty-hour Sleep Deprivation Experiment”

1995-lagarde.pdf: “Interest of modafinil, a new psychostimulant, during a sixty-hour sleep deprivation experiment” (backlinks)

“The Stimulant Effect of Modafinil on Wakefulness Is Not Associated With an Increase in Anxiety in Mice. A Comparison With Dexamphetamine”

1994-simon.pdf: “The stimulant effect of modafinil on wakefulness is not associated with an increase in anxiety in mice. A comparison with dexamphetamine” (backlinks)

“Modafinil Binds to the Dopamine Uptake Carrier Site With Low Affinity”

1994-mignot.pdf: “Modafinil binds to the dopamine uptake carrier site with low affinity” (backlinks)

“Lack of Pre-synaptic Dopaminergic Involvement in Modafinil Activity in Anaesthetized Mice: in Vivo Voltammetry Studies”

1994-desereville.pdf: “Lack of pre-synaptic dopaminergic involvement in modafinil activity in anaesthetized mice: in vivo voltammetry studies” (backlinks)

“Subjective Effects of Modafinil, a New Central Adrenergic Stimulant in Healthy Volunteers: a Comparison With Amphetamine, Caffeine and Placebo”

1993-warot.pdf: “Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo” (backlinks)

“Central Alpha 1-adrenergic Stimulation in Relation to the Behaviour Stimulating Effect of Modafinil; Studies With Experimental Animals”

1990-duteil.pdf: “Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals” (backlinks)

“Phenylpropanolamine: Reinforcing and Subjective Effects in Normal Human Volunteers”

1988-chait.pdf: “Phenylpropanolamine: reinforcing and subjective effects in normal human volunteers” (backlinks)

Miscellaneous