See the 1999_25ya Milgram review, “Adrafinil: A Novel Vigilance Promoting Agent”↩︎

See Minzenberg et al:

It is currently approved by the United States Food and Drug Administration as a schedule IV agent to treat excessive daytime sleepiness in narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hypopnea syndrome. It has been popularly categorized as a psychostimulant due to its wake-promoting properties. However, it has shown a number of effects on physiology and behavior in both animal models and in humans, which suggest a divergent mechanism of action compared to amphetamine (described in detail below). This includes a lower liability to abuse, and a lower risk of adverse effects on organ systems such as the cardiovascular system.

There’s some question whether the dismissal of adrafinil may be overblown. In his 2014 SSC nootropics survey, Scott Alexander comments:

There is some theoretical concern about liver-related side effects from adrafinil, but some pharmacologists say these are overblown and that its liver profile is similar to Tylenol—ie don’t take a massive overdose on it or use it every day for years and you’ll be fine. None of my respondents reported ever having any liver problems with adrafinil—not even asymptomatic elevation of liver enzymes—but n = only 17 so the results don’t rule out even moderately common adverse reactions.

Admittedly, Schedule IV drugs like modafinil are not one of the scheduled drugs which send people to federal pound-you-in-the-butt prison, but it still is troublesome.↩︎

One American prescription user said ~2011 that his prescription was for 200mg pills; each box cost around $50 copay for 30 pills, or about $1.70 (120 mg/USD). He took one a day. In 2013, another American gave the same price, but a third listed a $5 copay; a person claiming to work in a pharmacy said “the wholesale price for modafinil 200mg is 15 bucks per pill.”↩︎

from Businessweek’s “The 10Q Detective: Losing Sleep Over Cephalon”, 2009:

Supplementing the coupon efforts: discounted pricing. The prescription cost to the patient for a 30-day supply of daily recommended dosages of Provigil (200 mg) and Nuvigil (150 mg) is $361 and $295, respectively, a savings to cash-paying patients and health-care payers of 23%, according to pharmaceutical information site Destination Rx.

$\frac{361}{30}=12.03$; although it’s unclear what of this is the actual price to the consumer.↩︎

This is just conventional wisdom, echoed by many websites. An example:

When you buy modafinil online, make sure the company you are buying it from has a good track record and delivers orders promptly and securely. Modafinil is available in 100-mg and 200-mg doses and in packets of 30 tablets to 100 tablets. Prices may vary depending on where you are in the world. But in the United States, prices may range from $50 to more than $300. Make sure that you compare online modafinil prices to get a better deal.

Minzenberg again.↩︎

I hedge and say 2⁄3s rather than 100%, as most people use it, because any such claim ought to take into account the total cost of use—such as sleep rebound/recovery sleep’. (If a drug lets you skip a night of sleep and then you sleep 16 hours the next day, would it be honest or dishonest to claim it cuts your sleep need by 100%?) How much of a penalty is unclear. From Bonnet et al 2005_19ya:

In 1 study,⁹¹ modafinil reduced total sleep time (sum of stages 2, slow-wave, and REM sleep; 9.78 hours) relative to placebo (11.43 hours) on the first night of recovery sleep but not on the second night. Another study showed a reduction in total sleep time and sleep efficiency when modafinil 200 mg but not 100 mg was administered 30 minutes prior to bedtime (no sleep deprivation).⁸⁹ Modafinil also impairs recovery sleep, as recorded subjectively via sleep logs; and it delays rebound recovery sleep. Lagarde et al¹²⁶ reported that sleep duration increased on the first recovery sleep night for the placebo group but not for the modafinil group (10.0 hours vs 8.5 hours, respectively), compared with baseline. On the second night, the reverse was found-placebo subjects reported 8.1 hours of sleep, whereas modafinil subjects reported sleeping 10 hours. These results suggest that modafinil delays recovery sleep but, like all other stimulants, does not reduce sleep need.

The extent to which poor sleep following modafinil administration could impair performance has received little attention. In those studies in which performance after recovery sleep was measured,^{27,82,119,126,132} statistical results were not provided. However, the results appear to indicate that performance after recovery sleep did not differ between modafinil and placebo, and that, for both groups, performance was restored to pre-sleep-deprivation levels. A recent study²⁷ showed that performance was restored to pre-sleep-deprivation levels; however, in that study, 400 mg of modafinil did not impair sleep during a 12-hour recovery period following 85 hours of total sleep deprivation (also, recovery sleep commenced 20 hours after the dose was given).

Wesensten et al 2005_19ya discusses recovery sleep after testing caffeine vs modafinil vs amphetamines:

Sleep periods commencing closer to drug administration might reveal drug-induced effects on recovery sleep. For example, in the same study as Pigeau et al 1995, Buguet et al 1995_29ya evaluated the effect of modafinil 200 mg versus amphetamine 20 mg or placebo on recovery sleep. The first recovery sleep session commenced at 22:00 hours—after 64 h of total sleep deprivation and 6.5 h after the third drug administration. Buguet et al 1995_29ya reported significantly decreased total recuperative sleep time (sum of stages 2; SWS, stages 3 and 4; and REM) in both the modafinil and amphetamine groups (9.78 h and 9.37 h respectively, compared with 11.43 h for placebo). In a study by Lagarde et al 1995, volunteers maintained sleep logs for 5 days following participation in a study involving sleep deprivation and modafinil or placebo. Lagarde et al 1995_29ya reported that sleep duration increased on the first recovery sleep night for the placebo group but not for the modafinil group (10 versus 8.5 h, respectively), compared with baseline sleep. However, on the second night, the situation was reversed—placebo subjects reported 8.1 h of sleep whereas modafinil subjects reported sleeping for 10 h. It has been suggested that modafinil actually reduces the extra ‘sleep need’ driven by sleep deprivation (Buguet et al 1995_29ya, in which amphetamine- induced decreased recovery sleep time was ascribed to a deleterious effect of drug whereas modafinil-induced decreased recovery sleep time was ascribed to a reduced need for recovery sleep). However, these same results (Buguet et al 1995_29ya), those of Lagarde et al 1995_29ya, and results from the present study suggest a more parsimonious explanation, i.e. that drug half-life and dosage determine whether a given stimulant will likely interfere with recovery sleep.

…In the present study, postrecovery sleep performance did not differ among drug groups—and for all groups, performance appeared to be restored to presleep deprivation levels. These results correspond to those reported by Pigeau et al 1995_29ya in which postrecovery sleep performance in both the modafinil and dextroamphetamine groups was restored to baseline levels (despite the decreased recovery sleep time relative to placebo). The recovery sleep period in this study was relatively long (12 h) as was that in the Pigeau et al 1995_29ya and Buguet et al 1995_29ya study. Rosenthal et al 1991_33ya found that when an enforced recovery sleep period of 24 h was imposed following a 0, 24, or 48-h sleep deprivation period, volunteers sleep deprived for 48 h accumulated significantly more TST [sum of sleep stages 2, SWS, and REM] than nonsleep-deprived volunteers for up to 16 h. Thereafter, however, the effects were reversed, suggesting little or no additional benefit to extending recovery sleep beyond 16 h.

Estrada et al 2012_12ya:

Results showed significant differences between the sleep periods of the placebo and modafinil groups. Of the 8 h (480 min) allowed for sleep, the placebo group recorded longer inactivity (recovery sleep) than the modafinil group (453.91 min versus 438.91 min, respectively). Significant differences were detected for mean sleep efficiency (the percentage of time actually sleeping), with the placebo group recording significantly greater sleep efficiency than the modafinil group (94.58% versus 91.55%). These significant differences may suggest one of two hypotheses: 1. that subjects required a longer period of rest to recover from the placebo condition and also slept more efficiently than in the recovery from the modafinil condition; or 2. that modafinil interferes with the time it takes to go to sleep. This second hypothesis is supported by the level of estimated serum concentration that remained at bedtime. This suggests that modafinil differentially impacted the need for recovery rest. A review of the mood and performance assessment results showed that the sleep effects identified had no detectable impact on recovery session performance, with nearly all measures returning to general baseline levels following recovery sleep.

I took a closer look at Lagarde et al 1995_29ya since it was an unusually long 60 hour sleep deprivation experiment (2 nights skipped, as opposed to my usual 1) with unusually high modafinil doses (200mg every 8 hours or 600mg a day); they write:

The sleep log maintained by the subjects during the five days following sleep deprivation revealed a sleep rebound during the first recovery night (p < 0.05) in the placebo condition. A comparison with the pre-treatment night shows that the same phenomenon occurred with the modafinil condition but on the second night (p < 0.01). Sleep duration increased from the first to the fifth night in the modafinil condition (p < 0.05) and persisted after the sixth night in the placebo condition (p < 0.05) (table I). Two subjects had to take a diurnal nap on the second and third day after sleep deprivation in both situations. A detailed behavior analysis showed significant differences when using the placebo between responses on the first morning of sleep deprivation, used as reference, and responses obtained on the second day of sleep deprivation: [placebo] Subjects reported having less energy (p < 0.05), being less relaxed (p < 0.05) and in worse condition (p < 0.05). They were also sleepier after 24 hours of sleep deprivation (p < 0.05) and were more tired (p < 0.05). Recovery was rapid, on the very first day following termination of sleep deprivation.

…Analysis of the sleep logs has shown that modafinil did not increase the recovery time of the subjects, in fact, it may have shortened it since the quantitative aspect of sleep was restored on the 5th night post-treatment, whereas, it remained high at the same point in time in subjects given the placebo. However, the sleep rebound observed after sleep deprivation only occurred on the second night post-treatment, perhaps due to the persistent effect of the modafinil molecule which may have accumulated in the body after several administration.

I am interested in total sleep rebound, however, since that is what matters from the economic perspective. The table reports that pre-treatment sleep for placebo was 6.53±1 hours & modafinil 7.03±0.36. If I sum the 6 nights of sleep means and then pool variance, I get these results: control slept 51.88±1.53 hours during the 6 recovery nights while experimental: 51.24±1.43. Multiplying the original pre-treatment sleep estimate of 7 hours gives 42.2 hours expected sleep, so both groups incurred the same penalty of ~9.7 hours for skipping 2 nights (~14 hours) of sleep, for a net savings of just 4-5 hours.↩︎

But modafinil doesn’t erase the cost completely nor can you simply keep using it. “The Use of Stimulants to Modify Performance During Sleep Loss: A Review by the Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine”, Bonnet et al 2005_19ya:

…In some studies, a return to baseline (pre-sleep-deprivation) performance was noted, but, in other studies, performance did not appear to be restored to baseline levels. The effects of different doses of modafinil were not directly compared in these studies, and it is therefore difficult to determine whether failures to find statistically significant differences were dose related. In 1 study, modafinil appeared to impair performance on a map-reading/reconstruction task; however, the relevance of this finding to other aspects of operational performance is unclear…As the duration of continuous wakefulness is extended, the effectiveness and/or duration of the effect of modafinil on performance appears to be reduced. For example, 1 study⁸² found that both modafinil (300 mg) and d-amphetamine (20 mg) significantly improved performance on 4-choice serial reaction time for 9 hours when administered at 17.5 hours of sleep deprivation, but the performance-enhancing effects of modafinil were significant (compared with placebo) for only 6 hours after a subsequent administration at 47.5 hours of sleep deprivation. A similar effect was reported for the group administered 20 mg of d-amphetamine. Statistically significant effectiveness was maintained for only 8 hours when administered at 47.5 hours of sleep deprivation…. Results from some studies suggest that modafinil at doses of 200 mg or greater restore performance to pre-sleep-deprivation levels,^98,123 although this does not appear to be the case in all studies, or for all performance measures (for example, see results reported in)^82,83. In some studies, it was difficult to determine whether modafinil restored performance to baseline levels because of the statistical techniques reported.

From the 2010_14ya review “Modafinil and methylphenidate for neuroenhancement in healthy individuals: A systematic review”, Repantis et al:

For methylphenidate an improvement of memory was found, but no consistent evidence for other enhancing effects was uncovered. Modafinil on the other hand, was found to improve attention for well-rested individuals, while maintaining wakefulness, memory and executive functions to a significantly higher degree in sleep deprived individuals than did a placebo. However, repeated doses of modafinil were unable to prevent deterioration of cognitive performance over a longer period of sleep deprivation though maintaining wakefulness and possibly even inducing overconfidence in a person’s own cognitive performance.

Similar results were reached by the review Bagot & Kaminer2013. Gill et al 2006:

…This was a randomized, double-blind, placebo-controlled crossover study that followed CONSORT guidelines. Participants were assigned to one of two study groups, with study sessions occurring at least seven weeks apart, and received either modafinil or placebo depending on their random allocation. Testing after night shifts included a coding task and an AX version of the Continuous Performance Task, both of which test cognitive function. Participants also completed visual analog scales for three subjective outcomes, and symptoms were elicited.

Results: Modafinil facilitated performance on long interstimulus-interval AX trials (F [1, 23] = 6.65, p = 0.1) and marginally reduced errors on AY trials in the Continuous Performance Task (F [1, 23] = 3.59, p = 0.07), suggesting facilitation of sustained attention, cognitive control, and working memory. Additionally, modafinil, compared with placebo, facilitated performance on the coding task at the first session. Subjective data from visual analog scales confirmed that modafinil increased perceived alertness during the simulated patient care sessions but worsened sleep onset when opportunities for sleep arose.

Another study using sleep-deprived doctors (Sugden et al 2012_12ya) found:

Modafinil improved performance on tests of higher cognitive function; participants in the modafinil group worked more efficiently when solving working memory (F1,38 = 5.24, P = 0.028) and planning (F1,38 = 4.34, P = 0.04) problems, were less-impulsive decision makers (F1,37 = 6.76, P = 0.01), and were more able to flexibly redirect their attention (F1,38 = 4.64, P = 0.038). In contrast, no improvement was seen in tests of clinical psychomotor performance.

A battery of tests from “Effects of modafinil on cognitive and meta-cognitive performance” (Baranski et al 2004_20ya):

The design involved a double-blind, placebo controlled, fully within-subjects manipulation of placebo and modafinil (4 mg/kg: approximately 300 mg, on average) over three 50-min cognitive testing sessions (ie. before drug ingestion, and at 90 and 180 min after drug ingestion). The cognitive task battery included subjective assessments of mood, fatigue, affect, vigor and motivation, and cognitive assessments of serial reaction time, logical reasoning, visual comparison, mental addition and vigilance. In addition, trial-by-trial confidence judgements were obtained for two of the cognitive tasks and more global, task level assessments of performance were obtained for four of the cognitive tasks. Relative to placebo, modafinil improved fatigue levels, motivation, reaction time and vigilance. In terms of self-assessments of cognitive performance, both the placebo and modafinil conditions were ‘well calibrated’ on trial-by-trial confidence judgements, showing neither marked over- nor under-confidence. Of note, the modafinil condition displayed a non-statistically-significant tendency towards ‘overconfidence’ for task-level assessments of performance.

(The 2009_15ya Navy study of armodafinil “A Single Dose of Armodafinil Significantly Promotes Vigilance 11 Hours Post-Dose” didn’t agree with the finding of calibration.) If reviews aren’t your thing and you’d like specifics, here are some citations on the general topic of modafinil counteracting cognitive impairments from sleep loss in healthy adults:

• Bensimon G, Benoit D, Lacomblez L, Weiller E, Warot D, Weil JS, et al. “Antagonism by modafinil of the psychomotor and cognitive impairment induced by sleep-deprivation in 12 healthy volunteers”. Eur Psychiatry 1991_33ya;6:93–7

• Hart, Margaret Haney, Suzanne K Vosburg, Sandra D Comer, Erik Gunderson and Richard W Foltin. “Modafinil Attenuates Disruptions in Cognitive Performance During Simulated Night-Shift Work”. Neuropsychopharmacology (2005_19ya), 1-11

• Lagarde D, Batéjat. “Disrupted sleep-wake rhythm and performance: advantages of modafinil”. Mil Psychol 1995_29ya;7:165–91

• Pigeau R, Naitoh P, Buguet A, McCann C, Baranski J, Taylor M, et al. “Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work: Effects on mood, fatigue, cognitive performance and body temperature”. J Sleep Res 1995_29ya;4:212–28

• Stivalet P, Esquivie D, Barraud P-A, Leifflen D, Raphel C. “Effects of modafinil on attentional processes during 60 hours of sleep deprivation”. Hum Psychopharmacol 1998_26ya;13:501–7

• Wesensten NJ, Belenky G, Kautz MA, Thorne DR, Reichardt RM, Balkin TJ. “Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine”. Psychopharmacology 2002_22ya;159:238–47 (Heavy caffeine users were screened out, and subjects went through 48h withdrawal as well.)

• Wesensten et al 2004_20ya, “Modafinil vs. caffeine: effects on fatigue during sleep deprivation”

• Wesensten et al. “Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation”. J. Sleep Res. (2005_19ya) 14, 255-266

• Wesnes KA, Macher J-P. “Modafinil reverses the marked attentional deficits produced by sleep deprivation in healthy volunteers”. Eur Neuropsychopharmacol 2004_20ya;14:S380

Caffeine is pretty ineffective because tolerance develops. One amusing comparison of modafinil versus caffeine, dextroamphetamine, and placebo: “The effects of caffeine, dextroamphetamine, and modafinil on humor appreciation during sleep deprivation”. But the Air Force study on helicopter pilots (“The Effects of Modafinil on Aviator Performance During 40 Hours of Continuous Wakefulness: A UH-60 Helicopter Simulator Study”; journal version, “A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study”, Psychopharmacology 2000_24ya;150:272–82) disagrees, commenting that while they knew of no direct comparisons, modafinil was probably less effective at compensating for sleep deprivation than dextroamphetamine. Estrada et al 2012 directly compared modafinil & dextroamphetamine in helicopter tasks, and found them similar.↩︎

See the 1996_28ya study checking neuroreceptor activation: “Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat”. Their wakefulness effects also differ in fundamental respects like circadian rhythms. For more on modafinil vs amphetamines, see the tolerance/addiction section.↩︎

“The Ethical Consequences of Modafinil Use” (Cahill 2005_19ya) summarizes the general vein of thinking:

In informed conversations about modafinil, people are always astonished to learn that there are no apparent side-effects to this drug. They insist that there must be a catch, and more than half decide that there is little chance that there are no side-effects, instead opting to believe that disastrous consequences will be discovered down the road. There is a deep-rooted understanding in our culture that supernaturally enhanced ability does not come without a price. Modafinil seems to offer many benefits with minimal physical cost, but the hidden cost of modafinil’s conferring superhuman powers could lie in unanticipated ethical side effects. Although discussion surrounding the public policy issues that neurocognitive enhancers like modafinil raise is interesting, the more difficult issues that sleep-preventing drugs such as modafinil raise concern what has been called “personhood and intangible values” (Farah et al, 2004_20ya). These issues will mainly be faced by ordinary people in the course of daily life. For example, in a culture where sleep deprivation is a “serious public health problem” (National Center on Sleep Disorders Research, 2003_21ya) what effect will a drug that ameliorates the negative consequences of sleep deprivation have on personal autonomy? Modafinil also highlights conflicts between cultural values concerning success and effort that will have to be resolved for modafinil to assume a role in society.

…Americans are wary of the amount of meaning that can come from work done on modafinil because of another cultural concept called pharmacological Calvinism. Peter Kramer defined this concept as “a general distrust of drugs used for non-therapeutic purposes and a conviction that if a drug makes you feel good it must be morally bad” (Listening to Prozac, Kramer 1993_31ya). According to pharmacological Calvinism, drugs should only be used for the purpose of curing or treating illness and disease. Neurocognitive enhancers are particularly subject to scrutiny by this cultural value because they raise questions about what constitutes an illness or disease. For instance, Cephalon’s website sells modafinil as treatment for “excessive sleepiness”, despite the fact that this is not commonly considered a specific medical condition and is not a condition that modafinil is FDA approved to treat. On one hand, excessive sleepiness is an unpleasant condition that many Americans may wish there were more help for. If excessive sleepiness were ever recognized as a condition in and of itself deserving of medical treatment, our culture might come to embrace use of modafinil for this purpose. On the other hand, pharmacological Calvinists fear that this could pathologize what is seen as normal sleeping time and daytime energy, and this raises difficult questions surrounding how much sleep and daytime energy is “normal”.

“The Ethics of Designer Brains”, Big Think, quoting “Dr. Paul Root Wolpe, senior Bioethicist at NASA”:

Up until now, it’s been a bit of a moot question because the drugs that we had had side effects that made them undesirable. So if you take amphetamines to try to increase your attention, you’re going to have jitters, sleep disturbances and other things like that. Now you have something like Modafinil, a much more benign drug that can, in many people, enhance attention without any of those systemic side effects. And now we really have to begin to ask ourselves some interesting questions. They did some studies, for example, with pilots. Gave some of them, not Modafinil, but a similar type drug and some they didn’t and then they threw emergencies at them in flight simulators. And what they discovered is that the pilots that were on attention enhancing drugs responded faster and more accurately to those emergencies. So now we’re not just talking about, should I take it when I want to pay attention, maybe we should make people take it who have—surgeons and pilots and other people—who have other people’s lives in their hands. Maybe my surgeon on Modafinil will be much more able to focus on what he’s doing than my surgeon off of Modafinil.

From Bonnet et al 2005_19ya:

Reaction time from several different types of tasks has been frequently reported. Reaction time or response time was significantly improved after modafinil administration (50 to 400 mg per 24 hours) during sleep-deprivation periods of 36 to 88 hours, compared with placebo, in 9 of 10 studies.^{25,27,117-124} Short-term memory has been examined with tasks, including the DSST and memory search. During sleep loss, significant beneficial effects of modafinil relative to placebo have been found in 3 studies^119,120,122 but not in a fourth.¹¹⁷ Mathematic ability, usually measured by numbers of correct addition or subtraction problems completed in a given period of time, was significantly improved during sleep loss after administration of modafinil compared with placebo in 3 studies^83,117,119 but not in a fourth.²⁵ Two studies both found improved grammatical reasoning ability during sleep loss after administration of modafinil compared with placebo.^118,123…Although, as reviewed above, modafinil has been shown to improve performance on simple psychomotor tasks, its effect on executive functions during sleep deprivation has received less attention. One study¹²² found improved performance after modafinil, compared with placebo, on creative-thinking and sentence-completion tasks during a night-shift paradigm. Another study showed decreased errors in complex estimation during sleep loss after modafinil, 400 mg, compared with placebo.²⁷

Some relevant citations (omitting a mouse study):

• “Modafinil effects on cognitive function in HIV+ patients treated for fatigue: a placebo controlled study” (McElhiney 2010_14ya): ambiguous because the HIV+ patients improved on a “global change score”, which might be due solely to the stimulant effect

• “Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived?” (Randall et al 2004_20ya): Unlike Randall 2003_21ya, 100mg doses helped and had no listed negatives:

  Modafinil was without effect in several tests of reaction time and attention, but the 200-mg group was faster at simple color naming of dots and performed better than placebo in the Rapid Visual Information Processing test of sustained attention. Modafinil was without effect on spatial working memory, but the 100-mg group performed better in the backward part of the digit span test. Modafinil was without effect on verbal short-term memory (story recall), but 100 mg improved digit span forward, and both doses improved pattern recognition, although this was accompanied by a slowing of response latency in the 200-mg group. There were no significant effects of modafinil compared with placebo in tests of long-term memory, executive function, visuospatial and constructional ability, or category fluency…

• “Effects of modafinil on working memory processes in humans” (Mueller et al) tested healthy non-sleep-deprived volunteers on 200mg doses:

  Two 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….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.

• “Effects of modafinil on cognitive performance and alertness during sleep deprivation” (Wesensten 2006_18ya) is a review of then-available modafinil studies:

  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. [That is, you sleep less than normal but this seems to translate to normal wakefulness.] 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.

  • “A Match Made by Modafinil: Probability Matching in Choice Decisions and Spatial Attention”, Geng et al 2012_12ya: “Modafinil also enhanced learning of the probability distribution, evidenced by earlier learning of the probability distribution.”

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

• Some unfortunate results for the bright young nerds interested in modafinil:

  1. “Cognitive effects of modafinil in student volunteers may depend on IQ”, Randall et al 2005_19ya:

     The results of two previous studies on the effects of modafinil, a selective wakefulness-promoting agent, in healthy university students were combined in a retrospective analysis. This allowed determination of whether the effects of modafinil were dependent on IQ and whether the larger sample size (n=89) would reveal more cognitive benefits. A battery of cognitive tests was completed 2-3 h after dosing. In the whole sample, modafinil (200 mg) significantly reduced the number of missed targets in a test of sustained attention (RVIP). However, interestingly, several interactions between modafinil and IQ emerged. Modafinil (100 and 200 mg) significantly improved target sensitivity in the RVIP test, but only in the group of ‘lower’ IQ (mean+/-sem=106+/-0.6), not in the ‘higher’ IQ group (mean+/-sem=115.5+/-0.5). Furthermore, there were significant modafinil x IQ interactions in two further tests. Modafinil significantly reduced speed of responding in a colour naming of dots, and in clock drawing, but only in the ‘lower’ IQ group. Thus, the cognitive benefits of modafinil seem particularly marked in tests of vigilance and speed, in which sleepiness would be an important factor. Furthermore, the results indicate that high IQ may limit detection of modafinil’s positive effects.

  2. “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_13ya:

     …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 methylphenidate and on a measure of processing speed in favor of modafinil. 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.

  3. “Acute Effects of Modafinil on Brain Resting State Networks in Young Healthy Subjects”, Esposito et al 2013_11ya:

     …As far as modafinil Gf effects, regression analysis of APM results indicates that in the treated group, but not in the placebo cohort, there is an improvement in subject that are low performing at baseline when these individuals are challenged with items of medium levels of difficulty. This finding is in line with the idea that the drug can work better in individuals performing at submaximal levels

  (One odd result is Killgore et al 2006_18ya, “The Effects of Caffeine, Dextroamphetamine, and Modafinil on Humor Appreciation During Sleep Deprivation”: “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.”)

• Mueller et al 2012

  A double-blind placebo-controlled parallel design study evaluated the effect of 200 mg of Modafinil (n = 32) or placebo (n = 32) in non-sleep deprived healthy volunteers. Non-verbal tests of divergent and convergent thinking were used to measure creativity. A new measure of task motivation was used, together with more levels of difficulty on neuropsychological tests from the CANTAB battery. 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….Participants on modafinil felt considerably more pleasurable after performing individual tasks assessing ‘cold’ cognition and on all but one of the creativity tasks (the Group Embedded Task). This finding is reminiscent of the reinforcing effects of modafinil in humans described by Stoops et al 2005_19ya which were only evident when there were additional cognitive task demands, suggesting that any motivational effects of the drug derived mainly from its perceived effects on task performance and were thus not similar to those of ‘recreational’ drugs of abuse such as cocaine and amphetamine. The interesting question is whether modafinil enhances motivation through an hypothesised perception by the subject of its ability to enhance performance, or alternatively whether the drug enhances motivational factors which directly impact cognition (and both of these may obtain). It should be noted, however, that modafinil did not produce obvious subjective effects, for example, on arousal, as indicated by visual analogue rating scales or cardiovascular measures.

• Caldwell et al 2020

• Randall’s review of the mixed literature on modafinil improvements:

In a group of high IQ (mean 115) university students, Randall et al 2003_21ya failed to detect any positive effects on cognitive performance of modafinil (100 and 200 mg) Liepert et al 2004_20ya found no effects of modafinil (200 mg) on the performance of a small battery of tests (reaction time, nine-hole-peg and letter cancellation tasks) in healthy male subjects (mean age 27 years, IQ not specified). In a group of high IQ (mean 118) middle-aged volunteers, modafinil (200 mg) improved performance in a simple speed test (colour naming of dots) and in a clock-drawing test (Randall et al 2004_20ya). Using a somewhat different range of tests, and combining the data for the 100 and 200 mg doses, Turner et al 2003 found that modafinil improved performance of a high IQ (mean 115) group of young men (mean age 25 years) in the Digit Span, Pattern Recognition Memory (PRM), Stop-Signal Reaction Time [cf. healthy controls in Schmaal et al 2013) and spatial planning (New Tower of London) tests. Finally, Randall et al 2005_19ya found that modafinil improved performance in a group of students (mean IQ 109) in Digit Span (100 mg), PRM (100 and 200 mg), colour naming of dots (200 mg) and in a test of sustained attention (Rapid Visual Information Processing, RVIP; 200 mg). Mueller et al 2004 found that the positive effects of modafinil (200 mg) in students (IQ not specified) were limited to two relatively difficult and monotonous computerised working memory tests. Improved performance in the RVIP test of sustained attention had been previously found by Randall et al 2005_19ya in a sample of 60 students with a mean IQ of 109. No effects had been found in a smaller sample of 30 students with a mean IQ of 115 (Randall et al 2003_21ya), which may have resulted from a combination of a small sample and a higher IQ group. A faster speed in naming coloured dots had previously been found by Randall et al (2004_20ya, 2005_19ya), using sample sizes of 45 and 60, respectively. Improved performance in clock drawing had previously been found in the group of middle-aged volunteers (Randall et al 2004_20ya), but not in the student studies, where the level of performance in this task was higher (Randall et al 2003_21ya, 2005_19ya). However, this meta-analysis did not reveal any more effects of modafinil on cognitive performance than those previously reported with smaller sample sizes and even with our larger sample size we were unable to find any improvement in spatial planning, as had been reported by Turner et al 2003_21ya. As the Digit Span and PRM tasks were used only in our second student study (Randall et al 2005_19ya), these tasks could not be included in the meta-analysis, but improvements by modafinil have been reported in more than one study (Turner et al 2003_21ya, 2004_20yaa, 2004_20yab; Randall et al 2005_19ya)

The 2012 meta-analysis “Cognition Enhancement by Modafinil: A Meta-Analysis” wound up drawing on only 3 studies, and is not very informative. The 2015 review, “Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: a systematic review”, likewise found only a few studies. The 2019 meta-analysis “The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis”, Kredlow et al 2019, manages to pull together 19 usable studies on cognition in healthy non-sleep-deprived subjects, and finds a small overall average effect of g = 0.10, much like the Roberts et al 2020 meta-analysis.↩︎

See Repantis et al 2010_14ya.↩︎

On the other hand, Randall et al 2004_20ya, ibid, didn’t measure mood but did find benefits to working memory (WM) on the forwards and backwards digit span with the 100mg dose.↩︎

Taneja et al 2007_17ya, describing previous research:

Becker and colleagues used the Profile of Mood States to assess the impact of modafinil for 6 weeks on tension-anxiety and anger-hostility (components of high NA) and depression-dejection (akin to low PA) in patients with narcolepsy. They found non-statistically-significant improvements in the NA and depression subscales and concluded that there were no adverse effects of modafinil on mood.⁴ However, another study using the Profile of Mood States in patients with myotonic dystrophy concluded that modafinil significantly increased the tension-anxiety factor while improving other aspects of mood.³ Clouding the picture further, Randall et al 2003_21ya concluded that, compared with placebo, modafinil increased physiological symptoms of anxiety, but subjective negative affective states were not impacted except under challenge conditions. Thus, the specific impact of modafinil on PA and NA is unclear.

See also “Modafinil for Atypical Depression: Effects of Open-label and Double-blind Discontinuation Treatment”, Vaishnavi et al 2006↩︎

“Advisory Panel Endorses More Uses for Stimulant”, by Andrew Pollack with Alicia Ault, New York Times 2003_21ya:

Cephalon said it had not seen much evidence of such use. It said Provigil should not be used to fight sleepiness in just any night shift worker, only those with a clinical condition called shift work sleep disorder. People with that condition never quite adjust to night work…F.D.A. officials suggested during the meeting that they were not overly concerned with use of the drug by healthy people because the drug was generally safe. Robert Temple, an F.D.A. official, said it was “not completely obvious” that use of the drug just to keep healthy people alert would be a bad thing, because sleepy people could endanger others. “If they’re driving next to me, I think I’d prefer they be on it”, he said.

Erowid covers both in its interaction page:

The [anti birth-control] mechanism is that Modafinil upregulates (increases effectiveness of) the enzyme CYP3A4/5, which is involved in the metabolism of the contraceptive hormones and thus breaks them down more quickly. We have only been able to find a single paper that looked at the issue in humans and it showed that daily 400 mg doses of Modafinil for a month [statistically] significantly reduced the levels of the hormone estradiol and norgestimate in the 16 women studied. There is no direct research showing actual increases in impregnation rates and it is unclear whether less frequent or lower doses of Modafinil would have clinically significant effects on hormonal birth control…Methadone is metabolized by several liver enzymes in the CYP2* cluster, with CYP3A4 being an important metabolizer. Because modafinil up-regulates CYP1A2, CYP2B6, and CYP3A4/5, the action of methadone may be substantially shortened [Wang & DeVane2003]. Erowid also received one experience report from a reported methadone user who found that they had to redose with methadone every few hours to avoid opiate-withdrawal after taking large doses (> 1000_1,024ya mg) of modafinil.

It’s unfortunate that the real endpoint of getting pregnant couldn’t be tested; otherwise, the methodology looks pretty good (except for the issue of 400mg dosage for many days). Eyeballing the table on pg3 & graphs on pg6, the decrease in birth-control hormone (ethinyl estradiol) looks like it’s “statistically significant” but the effect size only medium. Specifically, the 400mg modafinil group saw their total ethinyl estradiol level fall 18% (d = 0.53). Since few dose 400mg but rather 200mg, I wonder if the real effect is more like 9% and this in turn is small enough that I wonder if modafinil would actually increase the birth control’s failure rates. (I should mention that the effect size on triazolam, the “commonly prescribed sedative hypnotic and anxiolytic agent”, looks quite serious, so the CYP metabolism is an issue.) ↩︎

Bonnet et al 2005_19ya covers some side-effects listed in studies & trials; for a comprehensive list, one could consult the FDA’s prescribing information:

In the above-reviewed studies, however, no serious adverse events were reported. For modafinil, the LD-50 (ie. the dose that is fatal for 50% of animals administered the drug) is 1250_774ya mg/kg in mice and rats and 200 mg/kg in dogs. Assuming identical dosing, the LD-50 for dogs would be comparable to 14 grams in a 70-kg human. In humans, there have been 2 cases of reported high-dose ingestion of modafinil. In 1 case, 4.0 gm of modafinil was ingested, and, in the second case, 4.5 gm of modafinil was ingested. Both cases resulted in excitation/agitation, insomnia, and “slight or moderate elevations in hemodynamic parameters” (modafinil package insert). Both patients fully recovered within 24 hours. In clinical studies, effects observed at elevated doses included confusion, nervousness, tremor, palpitations, anxiety, irritability, aggressiveness, sleep disturbances, nausea, diarrhea, and decreased prothrombin time. In comparison to placebo-treated patients, the most commonly observed adverse events associated with modafinil include headache, infection, nausea, nervousness, anxiety, and insomnia. In 2 multicenter studies, 5% of patients (19 of 369) discontinued modafinil due to an adverse event. Reasons for discontinuation included headache (most common), cataplexy, nausea, depression, and nervousness. Since few studies exist in which different doses of modafinil have been compared within the same study, it is unclear whether side effects are dose related. Results indicate a dose-response relationship for incidence of adverse events;133 however, in that study, data for specific adverse events were not provided, and, of the doses tested (200 mg, 400 mg, 600 mg, and 800 mg administered as a single dose), the 600-mg and 800-mg doses exceeded those administered in normal, healthy adults in the above-reviewed sleep-deprivation studies. Side effects similar to those reported by sleep-deprived volunteers (eg. shaking, palpitations, dizziness, restlessness, irritability) were reported by non-sleep-deprived volunteers receiving comparable modafinil doses,129 and this suggests that the side effects of modafinil are a direct effect and not due to an interaction with sleep deprivation.

Example feedback, from Makris 2004_20ya:

Based on participant written statements, two males and three females reported side effects following administration of modafinil but not following administration of amphetamine. Unusual feelings or significant occurrences reported following administration of modafinil were ‘headache,’ ‘hyped up/could run a marathon,’ ‘restless,’ ‘could not sleep, ’extreme anxiety and sleeplessness,’ and ‘sick in my stomach.’ These effects occurred only after the high dose [<630mg? “7.0 mg/kg”] of modafinil and during the late afternoon and/or evening hours while participants were away from the laboratory.

“Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity” (Makris et al 2004_20ya), Appetite 42 (2004_20ya) 185-195:

…This study compared the effects of amphetamine and modafinil on food intake and cardiovascular activity in healthy men and women. Participants (n = 11) completed 11 sessions. In random order, participants received placebo on five separate sessions and single oral doses of modafinil (1.75, 3.5, or 7.0 mg/kg) and amphetamine (0.035, 0.07, 0.14 mg/kg). Free time between hourly performance testing intervals gave participants the opportunity to eat. Like amphetamine, modafinil reduced the amount of food consumed and decreased energy intake, without altering the proportion of macronutrients consumed. Although both medications significantly increase heart rate and blood pressure at higher doses, the dose of modafinil that was efficacious in decreasing food intake did not significantly increase heart rate. Modafinil may be well suited for the treatment of obesity, although further studies with repeated dosing in overweight populations are warranted. Modafinil may have less adverse health consequences than some anorectic agents and greater treatment efficacy….A limited number of studies have examined the effects of modafinil on food intake in nonhumans and humans. Nonhuman studies suggest that modafinil decreases appetite and food intake and reduces frequency of eating (Nicolaidis & Saint Hilaire, 1993_31ya; Shelton, Nishino, Vaught, Dement, & Mignot, 1995_29ya). Two human studies evaluating the efficacy of modafinil for the treatment of attention deficit hyperactivity disorder (ADHD) in adults reported reductions in energy intake or appetite suppression following acute administration of modafinil, while no changes in appetite were observed in another study evaluating the effects of modafinil in children with ADHD (Jasinski & Kovacevic-Ristanovic, 2000_24ya; Taylor & Russo, 2000_24ya; Rugino & Copley, 2001_23ya)….The high doses of modafinil and amphetamine increased heart rate and blood pressure, but the magnitude of effects was relatively small. For example, compared to baseline measurements, heart rate increased by approximately 8 beat/min, reaching an apex of 78 beats/min, following the high dose of modafinil. A similar pattern was observed with blood pressure. The moderate dose of modafinil, which significantly reduced energy intake, increased cardiovascular measures to a lesser degree suggesting that it may have a safer profile of effects compared to amphetamine. These findings are comparable to the findings of previous studies, which report that modafinil produces fewer, if any, cardiovascular changes than stimulant drugs, is well tolerated, and produces a more desirable safety profile than stimulants. Significant increases in cardiovascular parameters generally occur following administration of doses greater than 400 mg (Jasinski & Kovacevic-Ristanovic, 2000_24ya; Rush et al 2002_22ya; Caldwell, Caldwell, Smythe, & Hall, 2000_24ya; PDR, 2002_22ya).

The side-effects of other weight-loss drugs are pretty heart-stopping:

Medications have been successful in supporting weight loss but many of them have been withdrawn from the market or are not recommended for weight loss due to adverse effects such as hemorrhagic stroke (phenylpropanolamine), heart valve disease and pulmonary hypertension (fenfluramine, dexfenfluramine), and abuse liability (amphetamine).

See, eg. https://ask.metafilter.com/47324/How-well-does-Modafinil-work#720855, https://ask.metafilter.com/47324/How-well-does-Modafinil-work#1072382; but for reports to the contrary (poster sure they used genuine modafinil but no smells), see Reddit.↩︎

“Urine smells of sulfur”↩︎

Mike Darwin, a dialysis technician, on aspirin (“Interventive Gerontology 101.01: The Basics”):

It is almost axiomatic in medicine that any increase in bleeding time (anticoagulation) is associated with an increased incidence of clinically significant gastrointestinal (GI) and intracranial bleeding. For vitamin E to show benefit, it would be necessary for any increase in adverse effects to be offset by the benefits it conferred. For vitamin E, this was not the case, whereas for aspirin, which also increases bleeding time and causes an increased incidence of GI and intracranial bleeding, shows such strong benefit in the reduction of myocardial infarction that it is worth the associated risk in the appropriate patient population (ie. those 50 or over and those with known cardiovascular disease).

…For instance, take Vioxx. Poor Merck! Vioxx probably causes no more heart attacks than ibuprofen and it certainly didn’t kill as many people as aspirin does each year in the US. Consider that there were 7,600 deaths and 76,000 hospitalizations in the US last year due to NSAIDs (NSAIDs include aspirin, ibuprofen, naproxen, diclofenac, ketoprofen, and tiaprofenic acid.)! You have to be pretty sick to be hospitalized. The Phase I–III clinical trial size is simply too small to show that a drug causes 1 in 1,000, let alone 1 in 5,000 or 1 in 10,000 people to drop over dead and to do so with no prior toxicity, or signs of toxicity (abnormal labs, etc.)…My point was that other NSAID drugs wreak more death and mayhem than Vioxx did every year, and yet thy are sold OTC and no one gives the truly incredibly morbidity and mortality a second thought. Any GP or ED doc will regurgitate countless stories of serious GI bleeding due to NSAIDS (and especially aspirin) on cue. Of course, they don’t mention all the hemorrhagic strokes caused by aspirin’s anti-platelet activity because they have no way to distinguish those from “regular strokes” and with so much of the population on aspirin that wouldn’t be easy.

Aspirin causes a truly gruesome and often fatal condition in children called Reye’s syndrome, and if it were any other drug than aspirin, it would have been pulled from the market, Instead, a massive educational campaign was launched to teach parents not to give sick children aspirin—the rational thing to do! However, meanwhile (until the population was educated), children continued to be neurologically maimed and killed by Reye’s. I’ve dialyzed youngsters with multi-system organ failure from Reye’s and it is a wretched and heartbreaking illness with a poor outcome.

Beyond the COX-inhibiting NSAIDS, there is “Tylenol”, or more properly, acetaminophen (APAP) (paracetamol in the rest of the world). Johnson&Johnson/MacNeil are apparently getting tired of paying for liver transplants and paying out judgments for people who die of liver failure because this hepatotoxic drug has spread into almost every product on the market for pain or discomfort, ranging from nostrums for menstrual cramps to sleep aids. APAP toxicity is the most common cause of hepatic failure requiring liver transplantation in Great Britain. In the United States, APAP toxicity has replaced viral hepatitis as the most common cause of acute liver failure, and it is the second most common cause of liver failure requiring transplantation in the US.The percentage of cases of acute liver failure caused by an overdose of acetaminophen increased considerably 1998^–₅2003_21ya, with unintentional overdose accounting for at least half of these case. Acetaminophen (APAP) is now the drug of choice for suicide in the US & UK and the number of deaths and hospitalizations from APAP has risen steadily since its widespread introduction in the 1960s (it was initially introduced in the 1950s). I can’t find the numbers for the US, but in England and Whales there are ~700 successful suicides/yr using APAP. The drug interacts unpredictably with alcohol in many individuals to cause serious liver toxicity and the economic costs of APAP toxicity are estimated to be in the hundred of millions of dollars/yr. I note that few, if any other PRESCRIPTION, let alone OTC drug, with a decades long history of steadily escalating injury and death to the population. By contrast, Vioxx was a dream drug! So it is the hypocrisy and unfairness of the treatment of Vioxx that I find objectionable.

Wikipedia, citing no sources unfortunately, reports that:

Modafinil toxicity levels vary widely among species. In mice and rats, the median lethal dose (LD50) of modafinil is approximately or slightly greater than 1250_774ya mg/kg. Oral LD50 values reported for rats range from 1000_1,024ya mg/kg to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. In clinical trials on humans, taking up to 1200_824ya mg/day for 7 to 21 days or one-time doses up to 4500 mg did not appear to cause life-threatening effects, although a number of adverse experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, and diarrhea.

“Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil”, Bastuji & Jouvet 1988_36ya.↩︎

Here is an interesting pseudonymous anecdote (emphasis added) on the risks of skipping multiple nights:

You need to know (and monitor) your own body, and not ignore physiological imbalance, even if it seems trivial. Drink a lot of water, eat lots of nutritious food while taking it, and for the love of god, do not stay up more than 2 or 3 nights in a row without sleep. It’s not worth it….make no mistake—modafinil is an effective medication, and like all effective medications, it has side effects, (light) mental habituation, and potentially life threatening side effects if used improperly. At the end of one particularly rough 9 days or so of straight usage during a major release for a contract, averaging 3 hours of sleep once every two to three nights (and the rest solidly awake), I settled with the team at a 24-hour diner right before release, and had an all-potato breakfast. My stomach had been steadily gaining in acidity over the week, but I had ignored it. A couple of hours later, I threw up and accidentally inhaled a small amount of the most corrosive stomach acid I’ve ever felt. When I coughed it out I tasted blood, and shortly after found it harder to breath. The bleeding was so profuse that I found it necessary to handstand over a hotel bathroom sink to let it all drain out without choking me. Luckily the person who had dropped me off was nearby—I phoned him and he took me straight to the hospital. I never had experienced that level of lung trauma before, and I’ve had a lot of hospitalization events related to some pretty severe asthma in my life, and it was this moment more than any other in my life that I seriously considered that I might die. In the end, I made it out with a light lung infection, and was treated at the hospital for an allergic reaction. I’ve never been able to eat potatoes since without experiencing an allergic reaction.

A 2005 case study discussed a 17-year-old boy who had a manic episode on methylphenidate and then on modafinil (“…this may be the first report of a patient experiencing mania while undergoing treatment with modafinil in therapeutic doses”). An extremely pleasurable experience would certainly be worrisome from an addiction point of view, but users often note the ‘subtlety’ of being on modafinil and general lack of altered states that would make modafinil more of a ‘recreational’ than ‘study’ drug. (As well, 3 doctors in 2006_18ya pointed out in a letter to The American Journal of Psychiatry that the cocaine addicts in their study—who ought to know—were not hoarding the prescribed modafinil and assert that “Postmarketing surveillance and animal studies suggest modafinil has little potential for abuse.”)

Mueller et al 2012_12ya tested healthy naive adults:

It is also important to gauge some of the psychological mechanisms by which modafinil may exert its beneficial effects on cognition, both in terms of clinical and shift-work related use. An important finding of this study is that there was a striking increase in task motivation. Participants on modafinil felt considerably more pleasurable after performing individual tasks assessing ‘cold’ cognition and on all but one of the creativity tasks (the Group Embedded Task). This finding is reminiscent of the reinforcing effects of modafinil in humans described by Stoops et al 2005_19ya which were only evident when there were additional cognitive task demands, suggesting that any motivational effects of the drug derived mainly from its perceived effects on task performance and were thus not similar to those of ‘recreational’ drugs of abuse such as cocaine and amphetamine. The interesting question is whether modafinil enhances motivation through an hypothesised perception by the subject of its ability to enhance performance, or alternatively whether the drug enhances motivational factors which directly impact cognition (and both of these may obtain). It should be noted, however, that modafinil did not produce obvious subjective effects, for example, on arousal, as indicated by visual analogue rating scales or cardiovascular measures.

This finding of motivation enhancing effects of modafinil lends empirical validity to anecdotal evidence from lifestyle use of modafinil that the drug improves concentration and enhances the ability to work for longer periods (Sahakian and Morein-Zamir, 2011_13ya). On the other hand, cognitive enhancing effects as described by recreational users of modafinil have to be carefully differentiated from placebo effects. So far, no study has demonstrated cognitive enhancing effects of modafinil in real life situations outside of laboratory settings.

From a Cephalon-funded study, “An evaluation of the abuse potential of modafinil using methylphenidate as a reference”, Jasinski 2000_24ya:

Preclinical studies indicate a mechanism of action which is distinct from that of amphetamine or methylphenidate. To compare the pharmacodynamic profiles of modafinil, methylphenidate [Ritalin], 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, behavioral, and physiological responses were evaluated at fixed intervals during 72 h 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 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.

Why compare these two? From the Discussion section:

One method of assessing the abuse potential of a new drug is to determine if the drug is pharmacologically equivalent to a prototypic drug of abuse. In a series of prior studies, it was shown that methamphetamine, ephedrine, phenmetrazine, methylphenidate, diethylproprion and phentermine produced a grossly similar profile of subjective and physiologic effects to amphetamine (Martin et al 1971_53ya; Chait et al 1987_37ya). For the most part, the relative potencies of these agents, calculated from parallel line bioassays, were similar across pressor response, decreases in caloric intake, and subjective measures, indicating a lack of pharmacological selectivity among these agents. For these reasons, it was judged that all of these phenylethylamines possessed the same potential for producing reinforcing effects and adverse effects as amphetamine. Consequently, all were judged to have similar potential for abuse.

…The subjective findings from our study are consistent with those from a study by Warot and colleagues (1993_31ya) in which they compared the effects of amphetamine 15 mg, modafinil 300 mg, and caffeine 300 mg in healthy volunteers. Their results showed that modafinil was clearly differentiated from amphetamine on the Amphetamine Scale of the ARCI. Furthermore, subjects indicated that if they had to take the drug on another occasion, they would chose amphetamine rather than modafinil or caffeine…If pharmacological equivalence to a drug with known abuse potential is not shown, a second method of assessing the abuse potential of a new drug is to determine if the drug produces reinforcing or toxic effects that could lead to abuse. At the doses tested in our study, modafinil was ‘liked’ by the subjects and raised mean blood pressure; however, it is our opinion that these qualities alone do not indicate that the drug will be abused. Other drugs with adrenergic ‘stimulant’ activity, such as phenylpropanolamine and caffeine, raise blood pressure and promote wakefulness, but do not represent significant public health or safety concerns as drugs of abuse (Chait et al 1988; Warot, 1993_31ya). In a prior study, Warot et al 1993_31ya determined that the subjective effects of modafinil 300 mg were very similar to those produced by caffeine 300 mg; however, further study may be required to compare the effects of higher doses of modafinil to those produced by these agents…However, it should be noted that non-pharmacological factors that are part of the social response to its availability will also determine whether this drug will be abused or misused. Because of the unique pharmacologic profile and low toxicity, there is likelihood for off-label use in which physicians prescribe modafinil to promote wakefulness in situations other than patients with narcolepsy.

The mechanisms of modafinil are poorly understood, but the wakefulness at least seems to involve different mechanisms than the amphetamines; from “Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG” (Chapotot et al 2003_21ya):

Results: One hour following ingestion, both psychostimulants increased alertness during 10-12 h, independently of the time of administration. At the level of the waking EEG, d-amphetamine attenuated the natural circadian rhythm of the different frequency bands and suppressed the sleep deprivation-related increase in low frequency (0.5-7 Hz) powers. In contrast, modafinil, which exhibited a transient amphetamine-like effect, had slight effect on circadian rhythms. Its selective action was characterized by maintenance of the a1 (8.5-11.5 Hz) EEG power, which under placebo exhibited a homeostatic decrease paralleling that of alertness with a circadian trough at night. Conclusions: These findings demonstrate that the alertness-promoting effects of modafinil and d-amphetamine involve distinct EEG activities and do not reside on the same vigilance regulatory processes. While d-amphetamine inhibits the expression of a sleep-related process, probably through a direct cortical activation masking EEG circadian rhythms, modafinil, through a synchronic effect, preferentially disrupts the homeostatic down-regulation of a waking drive.

See the Wisor 2013_11ya review, “Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions”.↩︎

The poorer response of multiple sclerosis patients to 400mg than 200mg was due to a U-shaped response curve—or perhaps tolerance, speculates “Efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study” Rammohan et al 2002_22ya. On the positive side, this study represents another citation for the thesis that modafinil has few and minor side-effects.↩︎

One study mentions that the subjects were taking “drug holidays” from modafinil; see “Efficacy and safety of modafinil for improving daytime wakefulness in patients treated previously with psychostimulants”, Schwartz 2002_22ya.↩︎

Jasinski2000’s summary:

Modafinil does not bind with high affinity to dopamine uptake carrier sites (Mignot et al 1994) or stimulate release of dopamine in vitro (Simon et al 1995), increase extracellular catecholamine levels (De Séréville et al 1994), alter the electrophysiology of dopaminergic (nigrostriatal) or noradrenergic (locus coeruleus) neurons; and is not anxiogenic (Simon et al 1994). Dopamine antagonists attenuate only the wakefulness and hyperlocomotion promoted by amphetamine, not modafinil (Duteil et al 1990; Lin et al 1992).

“Sniffing out the internet drug barons”, Guardian:

The MHRA collaborates with a number of organisations to target illegal websites, from the Metropolitan police e-crimes unit to US homeland security and specialised organisations that identify suspect online activity…Not long after the officers made their way up the stairs, Lee-Frost, on the pavement outside, got a call on his mobile. He looked glum. “It’s a one-room bedsit,” he said. “He claims he has closed down the website and it all comes from China. He rents a mailbox in the City and says that’s where his laptop is.” There were no pills and just a small amount of paperwork. They would try to persuade the suspect to hand over his laptop, but this raid was unlikely to lead to a spectacular court case, although they do happen. In April, the MHRA got a confiscation order in Southwark crown court for £14.4m against a fake medicines dealer after tracking down his assets across Europe, which a judge decided were all the proceeds of crime. ModafinilUK, the website registered to the man in north-west London, was closed down on the day of the raid, just one of nearly 9,000 illegal pharmacy websites shut down. Like twigs on the branches of a tree, their URL addresses lead to a few “anchor sites” run, said the MHRA’s head of enforcement, Nimo Ahmed, by organised crime networks, often based in Russia…Unable to stamp out the anchor sites, the MHRA is still managing to choke off a lot of their trade, closing down linked sites, confiscating and testing suspect packages entering the country and working with Visa, MasterCard, PayPal and other payment organisations to stop the money getting through to the dealers.

But Nubrain itself is a cautionary anecdote; it may have a very good reputation, but it’s still not hard to find bad reviews. This is a point that should not need to be made, but I still will anyway: everything in this page deals with risky & uncertain probabilities. If you want guarantees and certainty, go read a logic textbook.↩︎

Caveat: Nubrain can process and ship orders very slowly; and as of 2011_13ya, their adrafinil seems to be fake or in some wise deficient even while people (including personal acquaintances of the author) continue to report their modafinil copacetic. There are negative reports for Nubrain though, eg. unsleepable saw no benefit and anxiety from Modalert bought from Nubrain.↩︎

Prices in pounds are converted to dollars. Milligrams per dollar is calculated: $\text{round}\left(\frac{\text{mg}\cdot \text{Amount}}{\text{\$}+\text{S\&H}}\right)$↩︎

If ordering from TPE, I recommend avoiding the MoneyGram payment option. The discount seems to barely cover the MoneyGram fees and MoneyGram is strict about what they will allow.↩︎

Calculated in bulk: 10x10x200mg units, £5.39 each. Note that 4NRX appears to be denying access to US-based IPs; the price information may be out of date.↩︎

Like 4NRX, appears to be filtering accesses by geography. UP used to sell 10 pill units, but as mentioned above, this would massively penalize UP and who orders 10 pills at a time? So this row calculates an order of 10 units of 10 pills each, at the volume price of £5.49 each. ↩︎

See previous UP note; this is calculated at 10x10, £3.99 each.↩︎

Biogenesis AntiAging says their modafinil “can NOT be shipped to South Africa, European Union, United Kingdom, Canada, the United States of America and Japan.”↩︎

The owner announced 2013-11-10 that he was temporarily backlogged and took down price information.↩︎

Modadeals is very new & informal; I do not recommend using them.↩︎

Prices in pounds are converted to dollars. Milligrams per dollar is calculated: $\text{round}\left(\frac{\text{mg}\cdot \text{Amount}}{\text{\$}+\text{S\&H}}\right)$↩︎

Not accepting new orders as of 2013-11-15.↩︎

UP may no longer be offering Waklert. Calculated as 10x10 at £6.39↩︎

10x10 at £3.59↩︎

4NRX may no longer be offering Waklert. Calculated at 10x10 with free S&H.↩︎

I once ordered armodafinil off Silk Road.↩︎

For example, Sun apparently used to confirm or disconfirm batch numbers via email or telephone, but I have been told that they have stopped doing this because of worries over the exporting of their modafinil and a desire to discourage it. It may be possible to call them via Skype or hire an Indian to check.↩︎

I dropped them when I checked into my accounts and discovered I had been credited with $0 after that time-span. Why bother?↩︎

They seem to do ~20% commission; for the cheapest modafinil, as of 2011-04-28:

1. 200x200 sells for $197.95, commission of $39.59

2. 100x200 sells for $131.95, commission of $26.39

For example, if multiple sites/‘businesses’ were set up, each with different prices, then the true owners may be able to engage in price discrimination and capture more of the consumer surplus. It’s impossible to know for sure how many online pharmacies are just independent-looking fronts for one real business; it has been asserted that this is the case, eg. dontj:

thepharmacyexpress.com is actually the same source as usadiscreetmeds and a whole bunch of other sites (see my first post in this thread). Monarchpharm just uses different sites (that also look really similar) to sell the same meds at sometimes different prices. I think when I ordered from usadiscreetmeds.com the [SSL] certificate was also expired—but NP [no problem]. I’d say go for it!

S. Cobb: The Economics of Spam. ePrivacy Group, February 2003_21ya. Cited in “‘Proof-of-Work’ Proves Not to Work”, Laurie, Ben; Clayton, Richard (May 2004_20ya)↩︎

Note, incidentally, that the BBC writer took a modafinil and a placebo blinded—and guessed wrong which day was modafinil, but saw some computer test scores improve.↩︎

Due to the problems in processing credit card payments & the researchers’ mailbox expiring, it’s a little more complicated than that, but I believe 53⁄56 is the most relevant proportion here:

We attempted 120 purchases, of which 76 authorized and 56 settled.¹⁰ Of those that settled, all but seven products were delivered. We confirmed via tracking information that two undelivered packages were sent several weeks after our mailbox lease had ended, two additional transactions received no follow-up email, another two sent a follow-up email stating that the order was re-sent after the mailbox lease had ended, and one sent a follow-up email stating that our money had been refunded (this refund, however, had not been processed three months after the fact).

Which is more than a year’s supply because taking it every single day is asking for tolerance to build up.↩︎

Miyamoto Musashi, “Book of Water”, Book of Five Rings↩︎

John Dryden, Act IV of Aureng-zebe (1675_349ya)↩︎

When Hal Finney announced he had developed ALS in “Dying Outside”, he wrote something that surprised me (but later struck a cryonics chord in me, especially given heart attack research):

Although ALS is generally described as a fatal disease, this is not quite true. It is only mostly fatal. When breathing begins to fail, ALS patients must make a choice. They have the option to either go onto invasive mechanical respiration, which involves a tracheotomy and breathing machine, or they can die in comfort. I was very surprised to learn that over 90% of ALS patients choose to die. And even among those who choose life, for the great majority this is an emergency decision made in the hospital during a medical respiratory crisis. In a few cases the patient will have made his wishes known in advance, but most of the time the procedure is done as part of the medical management of the situation, and then the ALS patient either lives with it or asks to have the machine disconnected so he can die. Probably fewer than 1% of ALS patients arrange to go onto ventilation when they are still in relatively good health, even though this provides the best odds for a successful transition.

US Army personnel, considering various large bonus offers, manifested annual discount rates as high as 57.2%.↩︎

I say improbably low because at a discount rate of 2%, a person ought to exhibit behaviors like never spending a single penny as they shovel all their money into bonds and stocks, to be spent when they are ancient and about to die—they are extreme misers. Most people discount too much rather than too little, but nevertheless, one can damage one’s quality of life with too low a discount rate.↩︎

Commenter Spike questions the terminology here:

Is modafinil a “sulpha drug”? Sulpha drugs contain a single sulphanomide functional group, eg. SO₂NH₂ or SO₂NHR. modafinil does not contain a sulphanomide functional group, it does, however, contain discrete, separate sulphonyl (SO₂) and carboxamide (CONH₂) groups. Modafinil is also deficient an aromatic amino group, which are common in “sulpha” compounds (the haptens formed by the reaction of the aromatic amino group with proteins in the body is thought to be the cause of allergic reactions in people using “sulpha” drugs). Alas, modafinil is a “sulphonyl amide”, not a sulphanomide. I don’t why that is important, but I just thought I’d let you know.

For example, all the test could tell us is the ‘presence of sulfur’. But this is not the same thing as the ‘presence of modafinil’. Spike again:

There are obviously a number of possible reasons why the quality of Modalert (and other generics of modafinil) is so variable. There is one other explanation; the process by which the generics are produced. The original US Patent for modafinil contains a number of methods of synthesis. The simplest and most cost effective (fair to say that this is what the generic manufacturers are using) results in a problem of over-oxidation of the sulphide to sulphone, a phenomenon that is particularly difficult to reverse and may sterically hinder the compound. A closely related method (perhaps the second most likely synthesis procedure used by the generic manufacturers) involves a sequence of inert intermediates being produced in relatively large proportions; these compounds are also very difficult to separate from the modafinil. Personally, I think that this may be a primary reason behind the variable quality of generic modafinil products.