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Sources & Further Reading

1. UK army tested ‘stay awake’ pills

      A controversial drug which can keep people awake for days has been tested by the UK military, MPs have been told.
      Modafinil pills – known on the drugs scene as “zombies” – are used to treat the rare sleeping disorder narcolepsy.
      The Ministry of Defence reportedly stockpiled thousands of pills ahead of the Iraq war but they have never been given to combat personnel.
      Defence contractor Qinetiq told the commons’ science committee the drug had recently been tested for military use.
      Qinetiq scientist Dr Anna Casey told the Science and Technology Committee the MoD funded research into stimulant and performance-enhancing drugs and dietary supplements.
      “One is always looking for something that would give military personnel an extra edge,” she told the committee which is investigating the use of such drugs in sport.

 

2. MoD’s secret pep pill to keep forces awake

      Soldiers and aircrews will be dosed up with “pep pills” to help them stay alert for longer under controversial plans being developed by the Ministry of Defence, confidential papers have revealed.
      A secret MoD report obtained by Scotland on Sunday has laid bare the project to test whether the drug modafinil could be used to reduce the amount of sleep needed by servicemen and women on active duty.
      The covert supply of stimulants to fighting forces has become a controversial subject in recent years, particularly after it emerged that two United States F-16 pilots – Major Harry Schmidt and Major William Umbach – who killed four Canadians in a “friendly fire” incident in Afghanistan in April 2003, had taken an amphetamine issued by their superiors.
      Defence chiefs have spent more than 50,000 on modafinil allegedly to treat conditions including the sleep disorder narcolepsy.
      However, the secret report, obtained by Scotland on Sunday under the Freedom of Information Act, shows that the MoD has ploughed hundreds of thousands of pounds into researching whether they should follow the lead of forces including the French Foreign Legion and start using the drug to keep military personnel vigilant for up to 60 hours at a time.
      A 300,000 investigation completed last year has effectively given the green light to start using the drug, marketed as ‘Provigil’, after it found a single dose helped people stay alert for more than 18 hours with limited side-effects.
      Following problems with the amphetamine Dexedrine, attention has switched to modafinil, which has vastly improved alertness in patients with narcolepsy, shift-work sleep disorder and sleep apnoea, and with few apparent side-effects.

 

3. Pilot Pill Project

 

4. MoD bought thousands of stay awake pills in advance of war in Iraq

      MoD bought thousands of stay awake pills in advance of war in Iraq
      The MoD has admitted to buying more than 24,000 Provigil pills, which are licensed in Britain only to help people with rare sleeping disorders shrug off daytime sleepiness. Experts say the drug could be used “off license” to keep pilots and special forces troops awake on little sleep.

 

5. Air Force Special Operations Command Instructions 48-101

      Combat Controllers, Combat Weathermen and AFSOC assigned TAC-Ps) are authorized to use Modafinil as a “Go Pill” during ground operations requiring extended wakefulness after all other fatigue countermeasures have been implemented. Approval of distribution and use of fatigue management medication is contingent on compliance with all procedures contained within this instruction.

 

6. The Effects of Modafinil on Aviator Performance During 40 Hours of Continuous Wakefulness: A UH-60 Helicopter Simulator Study

      The results of this study, in which six helicopter pilots flew a flight simulator and completed other tests throughout 40-hour periods of continuous wakefulness, showed that modafinil was moderately effective for sustaining both performance and alertness. On four of the six “instrument maneuvers” in the UH-60 flight simulator, modafinil significantly attenuated the sleep-deprivation problems which were observed under placebo. Similar modafinil related benefits were seen in the cognitive performance data. Both EEG activity and self-reports indicated that alertness was better under modafinil than placebo. The greatest drug-related effects occurred between 0330 and 1200 when the impact of fatigue was most profound. Recovery sleep following the period of sustained wakefulness in which modafinil was used did not evidence disrupted sleep architecture. Therefore, modafinil would not be expected to prolong recovery time when used to maintain performance in sustained operations.

 

7. Modafinil as a replacement for dextroamphetamine for sustaining alertness in military helicopter pilots.

      RESULTS: Statistical results showed that modafinil, like dextroamphetamine, maintained alertness, feelings of well-being, cognitive function, judgment, risk perception, and situation awareness of sleep-deprived aviators consistently better than placebo and without side effects of aeromedical concern.
      DISCUSSION: Like previous research, this study strongly suggests that both drugs can maintain acceptable levels of mood and performance during sleep deprivation. The results also confirm that modafinil is well tolerated and appears to be a good alternative to dextroamphetamine for countering the debilitating mood and cognitive effects of sleep loss during sustained operations.

 

8. The Efficacy of Modafinil for Sustaining Alertness and Simulator Flight Performance in F-117 Pilots During 37 Hours of Continuous Wakefulness

      Modafinil improved vigilance and tracking performance in a divided-attention task, CNS activation, oculomotor performance, and aspects of subjective mood. Flight performance decrements were mitigated on six of eight maneuvers. Benefits were most noticeable after 24 to 32 hours of continuous wakefulness. Although modafinil did not sustain performance at pre-deprivation levels, its numerous positive effects make it a useful adjunct to the currently-approved fatigue countermeasure dextroamphetamine.

 

9. A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study

      Results: Modafinil attenuated sleep deprivation effects on four of six flight maneuvers, reduced slow-wave EEG activity, and lessened self-reported problems with mood and alertness in comparison to placebo. The most noticeable benefits occurred between 0330 and 1130 hours, when the combined impact of sleep loss and the circadian trough was most severe. The most frequently observed drug side effects were vertigo, nausea, and dizziness. These could have been related to: 1) the motion-based testing, 2) the use of a simulator rather than an actual aircraft (i.e., “simulator sickness”), and/or 3) the administration of more than 400 mg modafinil. Conclusions: Modafinil is a promising countermeasure for sleep loss in normals.

 

10. The Maryland Medical Protocols for Emergency Medical Services Providers

      OPTIONAL SUPPLEMENTAL PROGRAM TACTICAL EMERGENCY MEDICAL SERVICES
      MODAFINIL (Provigil)
      AVAILABILITY…………………………200mg Tablet
      ACTION…………………………….…. Enhances alertness / concentration
      INDICATIONS…………………….……To facilitate functioning with limited rest periods
      CONTRAINDICATIONS………..…….Known hypersensitivity
      PRECAUTIONS………………………..aL CC ª?
      OPERATIONAL STATUS?……..……. Operational
      SIDE EFFECTS……………………….Insomnia, mild blood pressure elevation
      INTERACTIONS………………….……
      DOSAGE……………………………….200mg once daily

 

11. The space-flight environment: the International Space Station and beyond

 

      Modafinil is a drug that is prescribed for narcolepsy and other disorders that involve excessive daytime exhaustion. It has been approved in various military situations and for astronauts thanks to its ability to stave off fatigue. It is unclear whether astronauts sometimes use the drug because they are sleep-deprived – it might only be used on spacewalks and in other high-risk situations.

12. Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers

            RESULTS: Improvements under modafinil were seen on spatial working memory, planning and decision making at the most difficult levels, as well as visual pattern recognition memory following delay. Subjective ratings of enjoyment of task performance were significantly greater under modafinil compared with placebo, but mood ratings overall were not affected. The effects of modafinil on creativity were inconsistent and did not reach statistical significance.
      CONCLUSIONS: Modafinil reliably enhanced task enjoyment and performance on several cognitive tests of planning and working memory, but did not improve paired associates learning. The findings confirm that modafinil can enhance aspects of highly demanding cognitive performance in non-sleep deprived individuals. This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

 

13. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature.

      Modafinil is an alerting substance that is considered safer than amphetamine with fewer side effects. Although modafinil has been used successfully to treat narcolepsy, relatively little is known about its ability to ameliorate fatigue and declines in mental performance due to sleep deprivation (SD) in a normal population. Forty-one military subjects received either 300 mg of modafinil, 20 mg of d-amphetamine, or placebo on 3 separate occasions during 64 hours of continuous cognitive work and sleep loss. Three drug treatments were given: at 23.30 hours and 05.30 hours during the first and second SD nights, respectively, and once at 15.30 hours during the third day of continuous work. Subjective estimates of mood, fatigue and sleepiness, as well as objective measures of reaction time, logical reasoning and short-term memory clearly showed better performance with both modafinil and amphetamine relative to placebo. Both modafinil and amphetamine maintained or increased body temperature compared to the natural circadian cycle observed in the placebo group. Also, from subject debriefs at the end of the study, modafinil elicited fewer side-effects than amphetamine, although more than the placebo group. Modafinil appears to be a good alternative to amphetamine for counteracting the debilitating mood and cognitive effects of sleep loss during sustained operations.

 

14. Impact of armodafinil on cognition in multiple sclerosis: a randomized, double-blind crossover pilot study.

          RESULTS: After correcting for multiple comparisons of the 8 neuropsychological dependent measures, we found that the patients had significantly improved delayed memory on a list-learning task after they took armodafinil (P = 0.0005), but no improvement on measures of executive function, visual memory, processing speed, or self-reported fatigue. CONCLUSIONS: Results provide preliminary evidence that

armodafinil

         may improve delayed verbal recall in patients with MS. A larger trial showing enhanced memory among patients taking long-term armodafinil could serve as a foundation for its possible clinical use as a memory enhancer in patients with MS.

 

15. Association of a deficit of arousal with fatigue in multiple sclerosis: effect of modafinil.

      Modafinil displayed alerting and sympathomimetic effects in all three groups of subjects. As fatigue in MS is associated with reduced levels of alertness and sympathetic activity, modafinil may exert its anti-fatigue effect in MS by correcting these deficiencies. The anti-fatigue effect of modafinil may reflect the activation of the noradrenergic locus coeruleus (LC), since there is evidence that this wakefulness-promoting nucleus is damaged in MS, and that modafinil, probably via the dopaminergic system, can stimulate the LC. This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

 

16. Modafinil administration improves working memory in methamphetamine-dependent individuals who demonstrate baseline impairment.

      Modafinil improves working memory in healthy subjects and individuals diagnosed with schizophrenia and Attention Deficit/Hyperactivity Disorder, though the effects of modafinil have not been evaluated on working memory in methamphetamine-dependent subjects. This double-blind, placebo-controlled study evaluated whether a daily dose of 400 mg of modafinil, administered over three consecutive days, would enhance performance on a measure of working memory relative to test performance at baseline and following 3 days of placebo administration in 11 methamphetamine addiction, nontreatment-seeking volunteers. The results revealed that participants demonstrating relatively poor performance on the third day of a 3-day washout period (ie, at baseline), showed significant improvement on measures of working memory, but not on measures of episodic memory or information processing speed. In contrast, for participants demonstrating relatively high performance at baseline, modafinil administration did not affect test scores. The findings provide an initial indication that modafinil can reverse methamphetamine-associated impairments in working memory.

 

17. Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humans.

      RESULTS: Across subjects, modafinil improved performance on a test of sustained attention, with no significant improvement on any other cognitive tests. However, within the methamphetamine-dependent group only, participants with a high baseline frequency of methamphetamine use demonstrated a greater effect of modafinil on tests of inhibitory control and processing speed than those participants with low baseline use of methamphetamine. CONCLUSIONS: Although modafinil produced limited effects across all participants, methamphetamine-dependent participants with a high baseline use of methamphetamine demonstrated significant cognitive improvement on modafinil relative to those with low baseline methamphetamine use. These results add to the findings from a clinical trial that suggested that modafinil may be particularly useful in methamphetamine-dependent subjects who use the drug frequently.

 

18. Cognitive enhancing effects of modafinil in healthy volunteers.

      RESULTS: Modafinil significantly enhanced performance on tests of digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time. These performance improvements were complemented by a slowing in latency on three tests: delayed matching to sample, a decision-making task and the spatial planning task. Subjects reported feeling more alert, attentive and energetic on drug. The effects were not clearly dose dependent, except for those seen with the stop-signal paradigm. In contrast to previous findings with methylphenidate, there were no significant effects of drug on spatial memory span, spatial working memory, rapid visual information processing or attentional set-shifting. Additionally, no effects on paired associates learning were identified.
      CONCLUSIONS: These data indicate that modafinil selectively improves neuropsychological task performance. This improvement may be attributable to an enhanced ability to inhibit pre-potent responses. This effect appears to reduce impulsive responding, suggesting that modafinil may be of benefit in the treatment of attention deficit hyperactivity disorder.

 

19. Effects of modafinil on working memory processes in humans.

      RESULTS: Modafinil 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.

20. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature.

      Modafinil is an alerting substance that is considered safer than amphetamine with fewer side effects. Although modafinil has been used successfully to treat narcolepsy, relatively little is known about its ability to ameliorate fatigue and declines in mental performance due to sleep deprivation (SD) in a normal population. Forty-one military subjects received either 300 mg of modafinil, 20 mg of d-amphetamine, or placebo on 3 separate occasions during 64 hours of continuous cognitive work and sleep loss. Three drug treatments were given: at 23.30 hours and 05.30 hours during the first and second SD nights, respectively, and once at 15.30 hours during the third day of continuous work. Subjective estimates of mood, fatigue and sleepiness, as well as objective measures of reaction time, logical reasoning and short-term memory clearly showed better performance with both modafinil and amphetamine relative to placebo. Both modafinil and amphetamine maintained or increased body temperature compared to the natural circadian cycle observed in the placebo group. Also, from subject debriefs at the end of the study, modafinil elicited fewer side-effects than amphetamine, although more than the placebo group. Modafinil appears to be a good alternative to amphetamine for counteracting the debilitating mood and cognitive effects of sleep loss during sustained operations.

 

21. The space-flight environment: the International Space Station and beyond.

          Modafinil is a drug that is prescribed for narcolepsy and other disorders that involve excessive daytime exhaustion. It has been approved in various military situations and for astronauts thanks to its ability to stave off fatigue. It is unclear whether astronauts sometimes use the drug because they are sleep-deprived – it might only be used on spacewalks and in other high-risk situations.

 

 

22. Safety profile of modafinil across a range of prescribing indications, including off-label use, in a primary care setting in England: results of a modified prescription-event monitoring study.

      CONCLUSIONS:
      This study provides important additional safety data on the use of modafinil in patients in ‘real-world’ use, including those for whom the prescribing indication is outside the terms of licence, as per recent changes to the licensed indications for treatment. In addition to safety data, our study provides useful utilization data. Results from this study indicate that a significant number of women of child-bearing potential had not been commenced on appropriate contraceptive programmes prior to starting modafinil. There were three pregnancies that occurred whilst taking contraception, highlighting the necessity of ensuring effective contraceptive cover for women during and after stopping treatment with modafinil. Analysis of the data showed that the majority of events reported as ADRs or reasons for stopping and ranked events during the first month of treatment had been previously documented with the use of modafinil. Stratification of events according to dose revealed a number of events that occurred at the higher dose only, including serious events such as psychosis. The targeted events for which causality assessments were undertaken confirmed the potential of modafinil to induce certain types of events in individual patients, including cardiac and psychiatric events.

 

23. A retrospective review of supratherapeutic modafinil exposures.

      Modafinil is a non-amphetamine wakefulness-promoting agent used for the treatment of various sleep disorders characterized by excessive daytime sleepiness. There is little information in the medical literature with respect to supratherapeutic doses of this medication. We performed a retrospective review of the California Poison Control System database for all cases of single-substance ingestion of modafinil with follow-up to a known outcome for the time period 1998-2008. Data collected included age, gender, dose ingested, clinical effects, and medical outcome. There were a total of 87 patients, 53 (61%) of which were female. Patient ages ranged from 1.25 to 72 years with a mean of 30 years; 17 (20%) patients were aged 6 years or less. Thirty-three (38%) were intentional overdoses. Most commonly reported effects were tachycardia (n=23), agitation (n=14), anxiety (n=11), headache (n=8), hypertension (n=6), dystonia/tremor (n=6), and dizziness (n=5). Forty-nine patients (56%) were managed at home, and 38 (44%) were managed in a healthcare setting. Therapies administered included activated charcoal (n=8), benzodiazepines (n=7), antihistamines (n=2), intravenous fluids (n=2), haloperidol (n=2), and beta-blockers (n=1). Effects were classified as none (n=22), minor (n=54), and moderate (n=11). No major effects and no deaths occurred. Effects of modafinil overdose appear to be mild in most cases, with tachycardia and CNS symptoms predominating. Clinically significant effects requiring treatment occurred in a small number of patients.

 

24. Poised to challenge need for sleep, “wakefulness enhancer” rouses concerns.

      …In case of Modafinil, estimates are that 90% of prescriptions is off-label…
      …It is noteworthy that this substance is considered to be relatively safe to use by some researchers (Turner and Sahakian 2006) and that there is already a striking percentage of off-label prescriptions (90%; Vastag 2004) as well as a considerable amount of illegal sales on the internet (Wilford et al. 2005)…
      …Cephalon, the company behind Provigil, already proposed a completely novel taxonomy of sleeping disorders, including ‘‘long sleeper’’ and ‘‘subwakefulness syndrome’’, with the aim of increasing the number of indications for its drug (Vastag 2004)…
      …Experiments using modafinil have shown that it can keep people alert and engaged in mental activities despite long periods of sleep deprivation…
      …The wakefulness-promoting agent modafinil, approved in the US for treatment of certain sleep disorders, is prescribed off label for a panoply of other conditions and is said to be favored by some ambitious professionals as a way of packing more work into a day…

 

25. Modafinil – Examine.com

      Studies show that Modafinil’s side effects did not differ from those of a placebo control (sugar pill)
      There appear to be no known cases of death attributed to modafinil

 

26. Modafinil: a review of neurochemical actions and effects on cognition.

      Modafinil (2-[(Diphenylmethyl) sulfinyl] acetamide, Provigil) is an FDA-approved medication with wake-promoting properties. Pre-clinical studies of modafinil suggest a complex profile of neurochemical and behavioral effects, distinct from those of amphetamine. In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia. Cognitive dysfunction may be a particularly important emerging treatment target for modafinil, across these and other neuropsychiatric disorders. We aimed to comprehensively review the empirical literature on neurochemical actions of modafinil, and effects on cognition in animal models, healthy adult humans, and clinical populations. We searched PubMed with the search term ‘modafinil’ and reviewed all English-language articles for neurochemical, neurophysiological, cognitive, or information-processing experimental measures. We additionally summarized the pharmacokinetic profile of modafinil and clinical efficacy in psychiatric patients. Modafinil exhibits robust effects on catecholamines, serotonin, glutamate, gamma amino-butyric acid, orexin, and histamine systems in the brain. Many of these effects may be secondary to catecholamine effects, with some selectivity for cortical over subcortical sites of action. In addition, modafinil (at well-tolerated doses) improves function in several cognitive domains, including working memory and episodic memory, and other processes dependent on prefrontal cortex and cognitive control. These effects are observed in rodents, healthy adults, and across several psychiatric disorders. Furthermore, modafinil appears to be well-tolerated, with a low rate of adverse events and a low liability to abuse. Modafinil has a number of neurochemical actions in the brain, which may be related to primary effects on catecholaminergic systems. These effects are in general advantageous for cognitive processes. Overall, modafinil is an excellent candidate agent for remediation of cognitive dysfunction in neuropsychiatric disorders.

 

27 .The increasing lifestyle use of modafinil by healthy people: safety and ethical issues

      No withdrawal symptoms were observed when modafinil was abruptly discontinued at the beginning of the two week observation period. Modafinil was generally well tolerated. Insomnia, headache and decreased appetite were the most commonly reported adverse events.

 

28. Brain Gain: The underground world of “neuroenhancing” drugs.

      “This age of cosmetic neurology is coming……the use of Provigil (Branded Modafinil) and its progeny will be mainstream and mainlined in just a few years” – Professor Anjan Chatterjee, M.D. – Centre for Cognitive Neuroscience”

29. Why You Are Suffering from a Modafinil Deficiency

      “For the first time in my life I felt like I was awake; I got stuff done that I had put off, and I felt optimistic and energetic.” – Jonathan Reilly – Los Angeles bioengineer.

 

30. Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies.

      CONCLUSIONS: Despite similar half-lives, plasma concentrations following armodafinil administration are higher late in the day than those following modafinil administration on a milligram-to-milligram basis. The different pharmacokinetic profile of armodafinil may result in improved wakefulness throughout the day in patients with ES compared with modafinil.

 

31.My Experiment With Smart Drugs

      “My mood wasn’t any different; I wasn’t high. My heart wasn’t beating any faster. I was just able to glide into a state of concentration – deep, cool, effortless concentration.” – Johann Harry – British Journalist.

 

32. Use of illicit and prescription drugs for cognitive or mood enhancement among surgeons.

      “increasing numbers of healthy physicians on-call, students, and academic professionals are using modafinil with the aim of enhancing their cognitive abilities.”

 

33. Neuroethics: Defining the issues in theory, practice, and policy

      The term ‘neuroethics’ has been given several kinds of meanings. One use of neuroethics describes ethical problems arising directly from research in neuroscience; for example, what should researchers doing brain imaging tell research subjects about unusual findings of no known clinical significance? The term is also used to describe neuroscience (usually imaging) research into how humans resolve ethical or moral issues; for example, what parts of the brain are activated when subjects are wrestling with moral dilemmas? This chapter discusses a third area of neuroethics: the implications of new discoveries in, and capabilities of, neuroscience for our society and their consequences for the legal system. It looks specifically at three different ways in which neuroscience seems likely to change society and law. The discussion focuses on the society and the legal system of the United States, but the same basic issues will be found in all technologically advanced societies.

 

34. One in five students have taken the study drug modafinil

      One in five students at UK universities have used the study drug modafinil to study and stay awake, according to a survey.
      The study, carried out by student website the Tab, asked almost 2000 students at 41 different universities about their use of study drugs.
      It found that one in five had taken modafinil, a drug which is used to prevent sleepiness and increase concentration, to help them with their academic work.

 

35. Narcolepsy medication modafinil is world’s first safe ‘smart drug’

      Modafinil is the world’s first safe “smart drug”, researchers at Harvard and Oxford universities have said, after performing a comprehensive review of the drug. They concluded that the drug, which is prescribed for narcolepsy but is increasingly taken without prescription by healthy people, can improve decision- making, problem-solving and possibly even make people think more creatively.

 

36. Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: a systematic review’

      In contrast, when more complex assessments are used, modafinil appears to consistently engender enhancement of attention, executive functions, and learning. Importantly, we did not observe any preponderances for side effects or mood changes. Finally, in light of the methodological discrepancies encountered within this literature, we conclude with a series of recommendations on how to optimally detect valid, robust, and consistent effects in healthy populations that should aid future assessment of neuroenhancement.