Adrafinil was a wakefulness drug developed back in the late 1970s. It worked reasonably well in animals and humans1, and interestingly enough, in a different way from most stimulants.2 Inside the body, adrafinil is metabolized by the liver into modafinil. So using adrafinil is inferior to using a straight dose of modafinil both because it [stresses the liver] and because reportedly you need about 3 times more adrafinil to be metabolized into an equivalent dose of modafinil. Its chief advantages are that all patents on it expired long ago, and it’s very rarely proscribed - so it is relatively cheap & easy to get.

Modafinil is better, but the problem is that a number of forms are patented, and in addition, it’s a proscribed drug in the US & Canada3. So you can either try to convince a doctor to give you a prescription or deal with dubious online pharmacies or suppliers in countries where modafinil is available over-the-counter. The former way is annoying and you pay full price, and the latter way is unreliable and still expensive - you may be buying at a lower price, but the risks of seizure at the border, shipping, possibly paying for laboratory assays etc. can more than make up for that.

Modafinil costs about $24–12 a day5; non-prescription sources are too unpredictable to say.6

Usage

“Modafinil can be reliably determined in plasma and urine (Schwertner and Kong, 2005; Tseng et al, 2005), and is readily absorbed (40–65%, as measured by urinary recovery) after single (Wong et al, 1999a) or multiple oral doses (Wong et al, 1999b), reaching peak plasma concentrations 2–4 h after administration (Wong et al, 1999a). The presence of food in the gastrointestinal tract can slow the rate but does not affect the total extent of absorption. Steady-state plasma concentrations are achieved between 2 and 4 days with repeated dosing. It is highly lipophilic, and approximately 60% bound to plasma proteins, primarily albumin. Major pharmacokinetic parameters are independent of doses in the range of 200–600 mg/day (Robertson and Hellriegel, 2003). The major circulating metabolites modafinil acid and modafinil sulfone do not appear to exert any significant activity in the brain or periphery (Robertson and Hellriegel, 2003). The elimination half-life is approximately 12–15 h (Wong et al, 1999a), and single daily dosing is adequate and common in clinical practice.”7

Effects

Modafinil has a couple different but closely related benefits. You can sum them up as pretty much it cuts your sleep need by about 2/3s8:, or it allows you to go without sleep for a day with little mental penalty9 with increasing penalties thereafter. (If you aren’t sleep-deprived, it seems to just increase your alertness and energy levels, with mixed effects on other things.) It is overall a better stimulant than caffeine or the amphetamines10, and targets different receptors than the amphetamines.11 The picture is good enough that some bioethicists are daring enough to go off their usual script (‘the long-term effects are unclear; more study is required’) and abandon the Precautionary Principle and suggest that maybe healthy people using modafinil might be a good thing12.

Besides compensating for sleep-related mental deficits in general13, it may make you smarter14 - even if you’re healthy:

“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.”15

Interestingly, there seem to be some groups for which modafinil does little or nothing, and this ineffectiveness may not be due to counterfeit product or poor self-monitoring, but genetics:

“…Two-time 100 mg modafinil potently improved vigor and well-being, and maintained baseline performance with respect to executive functioning and vigilant attention throughout sleep deprivation in Val/Val genotype subjects but was hardly effective in subjects with the Met/Met genotype.”16

The genotype variation specifically refers to the Rs4680 SNP, which is one of the SNPs that services like 23andMe test for. So someone could sign up for 23andMe testing and only start buying modafinil if the results are favorable; considering that 23andMe sometimes holds sales at $100 or $200 and that one could easily spend this much on a single order of modafinil, testing first is not a bad idea at all.

On the other hand, the 100mg dose may be the problem; “Modafinil affects mood, but not cognitive function, in healthy young volunteers” (PDF; Randall et al 2003) noted no benefits on the CANTAB test suite that

“There was a significant post-treatment change in the factor measuring ‘somatic anxiety’ and in individual ratings of ‘shaking’, ‘palpitations’, ‘dizziness’, ‘restlessness’, ‘muscular tension’, ‘physical tiredness’ and ‘irritability’, which was mainly due to significantly higher ratings of somatic anxiety in the 100 mg group compared with the other two groups [placebo & 200mg]. Further changes in mood were revealed after the stress of cognitive testing, with the 100 mg group showing greater increases in the ‘psychological anxiety’ and the ‘aggressive mood’ factors.”17

The effect of modafinil on mood is cloudy18 (part of the problem being, I suspect, varying doses and populations); “A Randomized, Double-Blind, Crossover Trial of Modafinil on Mood” (Taneja et al 2007) used doses of 400mg, finding:

Normal healthy volunteers (n = 12, 10 men and 2 women; 30–44 years) underwent a 3-day, counterbalanced, randomized, crossover, inpatient trial of modafinil (400 mg daily) versus placebo with 4-day washout period between 2 treatments. Mood was assessed daily using both the Positive and Negative Affect Schedule and a general mood scale, which consisted of 10 bipolar adjective ratings based on a severity scale ranging from 1 to 10. Modafinil increased general mood and Negative Affect scales relative to placebo and had a significant effect on Positive Affect scales. These results suggest that modafinil may have general mood-elevating effects accompanied by increased negative affect (anxiety). The findings may have implications for clinical practice, in particular for the adjunctive use of modafinil in treatment-resistant depression19.

Side effects

Modafinil has a few side-effects. (I omit adrafinil’s possible liver damage since it doesn’t apply to modafinil.)

  • Hormonal birth control may be less effective, as well as methadone20
  • Bad-smelling urine is very commonly reported21. Apparently is related to sulfur breakdown products22.
  • General symptoms of over-stimulation: confusion, nervousness, tremors, irritability, etc.23
  • Weight loss24

From the abstract of a journal review of modafinil:

“Furthermore, modafinil appears to be well-tolerated, with a low rate of adverse events and a low liability to abuse.”25

But a low rate of adverse events is still a rate. (And - this is a truism that applies to every single drug or substance which I should not have to point out - everyone is unique in that some substance will be horrible for them while great for others and vice versa; this is as true for modafinil26 as it is for much more dangerous drugs like aspirin27.) What are those adverse events?

The most serious reported side-effect I know of is Stevens–Johnson syndrome (SJS); but the FDA report specifies that there was only 1 ‘possible’ syndrome during the clinical trials of around 1,585 people. Presumably if modafinil really did cause SJS at a rate of 1 in 1500, then the hundreds of thousands or millions of users since would have caused ~667 or more cases of SJS. Page 2 of Cephalon’s physician guide goes into all the details:

“In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil. Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide post-marketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years.”

In the previous adult trial, with ~3x as many patients, no rashes were reported and no SJS. With a background incidence rate of 1 to 2 cases per million-person-years, to be distinguishable, the rate would only have to rise a little. Too bad they don’t tell us exactly how many but given the reporting biases at play (both for and against reporting), perhaps the FDA doesn’t permit more details; for example, I‘d especially want to know whether those ’adults and children’ is really just ‘children’. As it stands, it looks like the problem is primarily in juveniles, and they are not the ones considering whether to experiment with modafinil. For adults, adverse side-effects are generally in the 0–4% range of the population (see table 3, page 4 of the guide).

Few long-term studies have been done of modafinil’s safety outside of the drug approval trials. The LD50 is so high that it is currently not known for humans28; one troubled woman attempted suicide with 4.5 grams of modafinil but failed29; no deaths are known to be attributable to modafinil (which curiously makes it safer, acute dose-wise, than caffeine). Of course, one cannot rule out that there might be drastic consequences which manifest only decades later, but given that modafinil could be called a pseudo-life-extension drug due to its famous wakefulness effects, there’re arguments that modafinil is a net gain even with any (a priori unlikely) long-term backfiring.

Tolerance

Indeed, modafinil’s relative lack of side-effects has led to it being called the most perfect nootropic around, in the etymological sense of a drug which has no bad aspects and only improves the mind. But there is no free lunch, after all. (There may be bargain lunches which we are thrilled to buy, but they aren’t free. If they were, why didn’t Evolution grab them already? For discussion of how drugs can be bargain lunches, see Drug heuristics.)

Anecdotally, the real troll under the bridge for modafinil seems to be that one can develop tolerance, where it no longer has the stimulant or anti-sleep effects that made it so awesome. For example, poker player Paul Phillips took 2–300mg daily for a long period and said the effects “have attenuated over time. The body is an amazing adjusting machine, and there’s no upside that I’ve been able to see to just taking more.”

There are two pieces of good news in the anecdotes, though. It seems that it is only tolerance, and not addiction/dependence. Caffeine tolerance builds up rapidly, and worse, there is dependence: one declines to below baseline mental performance when one stops using the caffeine; but there seems only to be tolerance to modafinil - I have seen no anecdotes reported performance declines after tolerance and ceasing use. (But one’s baseline productivity may be so low compared to productivity while using modafinil that one feels like there is dependence.) Secondly, some anecdotes report that modafinil can be used indefinitely on a weekly or more frequent basis without developing tolerance. So even this downside isn’t very large. There’s no evidence that modafinil tolerance is linked to medium-term changes in the brain (like use of irreversible MAO inhibitors, which affect MAO levels for weeks), so I’ll ignore it in the following cost-benefit analysis. A drug which offers a high return on investment but can only be used once a week is still offering a high return on one’s investment.

But what does medicine say? It seems to report no euphoria30, tolerance or dependency.3132333435363738

There has been speculation39 and reports of subjects acting as if there were tolerance40. One study that garnered a tremendous amount of media attention, relatively speaking, was “Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications” (Volkow et al 2009) which, somewhat against earlier non-human research41, found some dopamine upregulation; while a feature commonly found in addictive drugs, that’s a long way from actual addiction, especially given the real-world data.

Analysis

So what’s the cost benefit analysis here? We need to take into account the financial expense of modafinil, the biological side-effects, and the benefit of less sleep.

Benefits

As in Melatonin, we’ll assume the value of our time is measured by the minimum wage. We’ll also assume modafinil costs $3 a day (this adds 50% to be conservative). Finally, we’ll assume the average sleep savings per day is 4 hours - roughly half one’s sleep; this seems reasonable since sometimes people will use modafinil to skip that day’s sleep and sometimes they’ll sleep normally and will take it for greater performance while they are awake.

So, our very first calculation goes minimum wage×hours saved, or 6.55×4, or $26.2. $26.2 > $3, so off-hand modafinil seems worthwhile: the return is 873%.

Costs

But what of the other costs? There’s the stinky pee, for example. I don’t think this is even worth including, but let’s assign it 5¢ (how long are you going to be in the bathroom anyway?). Then there are the unknown health effects. Sure, the skeptic says, the studies have turned up little to nothing, but what about the long-term effects?

Well, alright. We’ll add it in. Let’s consider the worst-case: modafinil is fatal. One human life is usually valued at around 10 million dollars. I personally can expect another 50 years of life. So per day, the expense of a fatal-modafinil habit (we assume the death could any day) would be $, or $548. Ouch. That is noticeably larger than the $26.2 we expected to gain. But this is the worst case; there’s no way modafinil is actually 100% lethal.

So the expected value of modafinil is approximately 21 times less than it needs to be. Or, to put it another way, if modafinil had a less than 121 chance of killing you, it could be worth while. Do you think modafinil has a less than $ kill rate? I do.

(We could complicate the analysis by incorporating a discount rate and reduce the value of modafinil by assuming that one only uses it occasionally to avoid building up tolerance, but the basic point is made: there needs to be an improbably high risk to modafinil to neutralize its benefits.)

Suppliers & Prices

Fine, but how are we going to get any modafinil? (We’ll ignore getting a legitimate prescription or having a friend buy you some in India.) Buying modafinil is very much a grey-market. And it’s a black-market if one wants genuine Cephalon-manufactured Provigil/Nuvigil42.

So Indian generics it is. (India ignores any pharmaceutical patents before a certain year, which includes those on modafinil.)

The general feeling, which my own reading agrees with, is that the generics in descending order of desirability go:

  1. Modapro
  2. Modalert
  3. Alertec

Vendor notes:

  • VisaPharmacy.com is on drugbuyers.com’s blacklist as well as that of Pharmacy Reviewer; I am considering removing them entirely
  • EDAndMore.com has a great deal of negative feedback, few or no other vendors sell the same SpierX modafinil, and one commenter has pointed out that the EDAndMore.com domain is registered to the same Malaysian registrar as SpierX.com, suggesting a close relationship behind-the-scenes. (Pharmacy reviewer likes them.) Even online acquaintances I consider sensible and trustworthy can come to diametric appraisals of the quality of SpierX. My working hypothesis is that EDAndMore has an unreliable supply chain or SpierX has poor quality control (which makes them a good candidate for some of the later statistics discussion).
  • Nubrain4344 seems to have a reputation for honesty

It’s worth noting that shipping can make a major difference. For example, now-defunct Airsealed’s $22 modafinil seemed like an excellent deal - but the price was almost doubled by their $15 shipping. The above table assumes that one orders only one unit of whatever it is; if one had been ordering several hundred dollars of modafinil from Airsealed, say, then Airsealed might look much better, and so for that purpose S&H is listed.

With all that in mind, my research into online vendors produced the follow table (last updated 19 December 2011):

mg/$45 mg Amt $ S&H Provider
238 200 100 84 0 4NRX Pharmacy46
215 200 100 85 8 United Pharmacies.co.uk4748
202 200 200 198 0 EDAndMore.com49
192 200 200 192 15 ThePharmacyExpress50
167 200 500 600 0 Pharmland
167 100 100 60 0 4NRX Pharmacy5152
164 200 60 58 15 VisaPharmacy.com
162 200 400 482 10 Good Health Pharmacy
158 200 360 445 10 Good Health Pharmacy
157 200 180 215 15 ThePharmacyExpress
156 100 400 246 10 Good Health Pharmacy
152 200 100 132 0 EDAndMore.com
150 200 200 256 10 Good Health Pharmacy
147 200 300 408 0 Pharmland
147 100 100 60 8 United Pharmacies.co.uk53
142 200 270 380 0 DesiredMeds
142 200 240 339 0 Pharmland
140 200 120 171 0 Pharmland
138 200 120 159 15 Controlled Pills
129 200 90 125 15 Controlled Pills
129 200 500 775 0 OneMedStore54
128 200 180 267 15 TabsMarket
127 200 360 566 0 OneMedStore
127 200 200 316 0 EDAndMore.com
126 200 90 128 15 Pharmland
126 200 240 382 0 OneMedStore
125 200 120 170 22 RxShop.md
124 200 120 194 0 OneMedStore
120 200 60 100 0 EDAndMore.com
120 200 180 299 0 DesiredMeds
119 200 60 86 15 Pharmland
118 200 90 131 22 RxShop.md
116 200 90 140 15 TabsMarket
115 200 60 89 15 Controlled Pills
112 200 100 178 0 EDAndMore.com
109 200 90 147 18 OneMedStore
109 200 30 40 15 Pharmland
108 200 60 89 22 RxShop.md
103 200 60 99 18 OneMedStore
101 200 90 179 0 DesiredMeds
100 200 60 120 0 EDAndMore.com
98 200 60 107 15 TabsMarket
96 100 100 94 10 Good Health Pharmacy
91 100 300 329 0 Pharmland
86 100 240 279 0 Pharmland
86 100 120 140 0 Pharmland
83 200 30 50 22 RxShop.md
82 200 30 55 18 OneMedStore
82 100 270 330 0 DesiredMeds
81 200 30 59 15 TabsMarket
78 100 500 645 0 OneMedStore
76 100 360 472 0 OneMedStore
75 100 240 320 0 OneMedStore
74 100 90 106 15 Pharmland
74 100 120 162 0 OneMedStore
73 100 180 231 15 TabsMarket
70 100 60 71 15 Pharmland
69 100 50 65 7 Nubrain
69 100 180 259 0 DesiredMeds
66 100 90 122 15 TabsMarket
63 100 90 124 18 OneMedStore
62 200 50 155 7 Nubrain
59 200 90 306 0 Super Drug Saver
58 100 60 85 18 OneMedStore
56 100 90 160 0 DesiredMeds
56 100 60 93 15 TabsMarket
56 100 30 39 15 Pharmland
53 200 30 105 7 Nubrain
49 200 30 108 15 Super Drug Saver
46 100 30 47 18 OneMedStore
45 100 30 52 15 TabsMarket
41 100 90 222 0 Super Drug Saver
34 100 30 81 8 United Pharmacies.co.uk
31 100 30 82 15 Super Drug Saver
22 100 30 125 10 AuraPharm
17 100 30 160 15 SomatropinOnline.com
16 100 30 178 15 Biogenesis AntiAging
16 100 30 168 15 Biogenesis AntiAging

Alternative price charts:

  1. Pharmacy Reviewer
  2. Ben on Imminst.org

There are other sources; the Silk Road black market usually has generic modafinil, and sporadically armodafinil55, at reasonable prices; but given the anonymizing measures, use of Bitcoin rather than dollars, and the inherent flux of an online marketplace, I cannot possibly incorporate it into the chart.

Another fascinating possibility for obtaining modafinil is to not order pills, but order power or one’s own synthesis of modafinil. A Korean company offered in 2006 to synthesize modafinil at $550/kg; an old Chinese supplier offers it for an unknown price, “Drugs Power Store”, a Chinese-Thai producer, offers 1kg for ~$3,000 (~$0.6 per 200mg, competitive with the ~$0.9 of the cheapest online stores). I have never heard of anyone actually doing this. If you have or know of a write-up, please contact me.

Examples

Counterfeits seem to be responsible for many negative experiences with modafinil; in the absence of effective assaying, this section is an experiment with providing data on what believed genuine product looks like, inasmuch as the counterfeits sometimes not do a good job of replicating the packaging & appearance of genuine products.

Modalert

Below is data given to me by an acquaintance about 2 strips of 200mg Modalert which he obtained through 2 separate sources.

Strips:

  • Weight: 4.62 +/- 0.05g
  • Size: 4.8x12.0cm
  • Texture: Dimpled, with dimples approx 0.5mm apart
  • Material: Two layers of aluminum, with two thin layers of glue in between them (one on each side of the pouch). The glue is a clear, thin, stretchy plastic; it is not sticky unless heated.
  • Texture: Solid silver, dimpled except in the rounded-rectangle pouches that contain the pills. The dimples are approximately 0.5mm apart. The spacing between the pill-pouches is 6–7 dimples in size
  • The front has purple printed text and a red stripe down the left. The red stripe is 2 dimples wide.

2 strips, front & back The front of 1 10x100mg strip, and rotated The back of said strip, also with rotated view

Pills:

  • Weight: 320mg
  • Color: White, slightly shiny, and made of the same material throughout with no coating
  • Shape: 1cm in diameter, 3mm thick. The bottom has a 1mm bevel around the circumference. The top has a similar bevel, plus a diameter about 1mm thick and 0.5mm deep. Sometimes the bevel is offset slightly (<.02mm) so that there’s a 90 degree corner in front of the bevel.
  • In water, breaks into small particles producing a milky liquid, but settles to the bottom if left still for several hours

3 pills, one broken in half One pill, top & bottom

In October 2011, Paul Newcomb ordered from Nubrain & EDandMore, providing photographs:

10x100 Modalert, ordered from Nubrain 10x200 Modalert, ordered from Nubrain

Modapro

Paul Newcomb:

10x200 Modapro, ordered from Nubrain

10x200 Modapro, ordered from Nubrain

Margins

One way to evaluate whether something is ‘too good to be true’ is to figure out what the cost to the seller is. Obviously it is impossible for them to sell it for less in the long run - they would lose money on each purchase. And they have overhead, too, so their price to you must be greater than cost. There are exceptions where you can buy for less than cost and not be scammed, but every exception has some exceptional reason driving it. If you can’t figure the reason out, you should be suspicious.

So what’s the raw cost of modafinil to these online pharmacies? They are almost all sourcing their modafinil (if it’s actual modafinil) from Indian sources. We can get a first estimate by looking at affiliate commissions. Commissions are part of the cost structure, so we can subtract the commission from the price and get an upper bound on how much the modafinil cost. (A company might be willing to pay a commission so high it makes a sale unprofitable if it generates a lot of return business, but this seems unlikely in an online pharmacy scenario.)

I have signed up for 3 affiliate programs. In order, by price per mg as given in the above chart (cheapest first):

  1. EDAndMore: 20%56
  2. ThePharmacyExpress: 15%
  3. Good Health Pharmacy: 15%
  4. OneMedStore: 30%

Interestingly, there is only a weak pattern of commissions shrinking with prices, which suggests we may be seeing price discrimination at work57; if EDAndMore can offer both the cheapest prices and higher commissions, that suggests there is considerable margin to cut. Further, EDAndMore offers shipping ‘for free’, but of course, there is no such thing as a free lunch so what that actually means is that the shipping is built into the price. If we assume that shipping costs them $10 a package of 200x200 and exclude it from their modafinil cost, and we cut 20% for commission, that suggests a price of 200×200180-(180×0.2)-10, or ~300 mg/$ - substantially higher than the 222 mg/$ available to the consumer. More directly, there are scattered reports online about pricing in places like Russia or, most relevant, India:

"the modalert from india, which is sold through both european and indian online pharmacies, costs about 12$ / 10 pills - 200mg

now the same stuff in an indian pharmacy costs only $3 / 10 pills - 200mg"58

Such a pharmacy price would be 10×2003 or 667 mg/$. So this sets another bound - it’s highly unlikely any online pharmacy would be able to beat an Indian pharmacy. Modalert packaging (see above) comes with retail prices in rupees stamped on it, presumably for tax purposes; at 81 rupees for 10 pills, and ~50 rupees to the dollar, that’s ~$2 per 10 or 20 cents per 100mg pill. The 200mg pills are stamped 129 rupees, or ~$2.5 or 25 cents per 200mg pill. (There is another, more pessimistic bound - the cost of fake medicines, which aren’t as cheap as one might guess, one example being a $59.95 product costing $2.5059)

Ordering behavior

Internet suppliers are not known for their transparency or reliability, and on top of the technical difficulties it is well-known that suppliers can be untrustworthy and actively deceptive; and the few retailers online of modafinil which are trustworthy tend to be more expensive (as a look at the above chart shows) or they require prescriptions for US buyers (like the Canadian online pharmacies). So we are faced with a classic problem of risk: given that any supplier may shaft us, how should we rationally order products to reduce our risk?

For modafinil we can come up with a few distinct ordering scenarios:

  1. a one-shot order
  2. multiple orders, with oneself as an oracle (perhaps one has used genuine Provigil in the past and is sufficiently rational to avoid mistakes caused by things like the placebo effect)
  3. multiple orders, with laboratory assays as the oracle

One-shot ordering

For #1, the simple answer is best. You decide roughly how much you trust each supplier based on factors like how their website looks, what descriptions of them you found online, whether they seem ‘too good to be true’, etc - what is the percentage that they will pay? An obvious scam is 0%, a totally trusted source is 100% and everyone else is a shade of gray. Then you multiply their trustworthiness against their modafinil/mg price. Whomever comes out on top, you order from.

So, if I thought EDAndMore had only a 60% chance of delivering real modafinil rather than caffeine pills, I would multiply their unit-price 222 against the trust-penalty of 0.6 and get 133.2 (222×0.6). And then I might decide United Pharmacies smells a bit better and give them a 70% chance, for a total of 145.6 (208×0.7); and perhaps Airsealed gets a whopping 95% trust from me, for a total of 71.25 (75×0.95). In this scenario, Airsealed is highly trustworthy compared to the other two, but because Airsealed costs nearly 3 times its competitors, it comes out poorly against United Pharmacies; UP is only a little more expensive than EDAndMore, but has a noticeable edge over EDAndMore in trust and so wins. For Airsealed to win, I would have to trust both EDAndMore and United Pharmacies somewhere less than 33%.

I order and I get… something. This is where the one-shot strategy ends. You calculated, did your best, and either won or lost.

If you plan to order again (and modafinil is such a useful drug that it is hard to see why one would not plan to use it indefinitely as side-effects, tolerance, and finances permit), you have a chance to update based on how the first order went.

Presumably one has learned from one’s own experiences whether the product was modafinil or not. Modafinil is fairly distinct from caffeine; one gains tolerance to caffeine very quickly, and caffeine will not keep one going overnight with little mental penalty. So we’ll assume one knows.

If it was modafinil, then great. You’ve found an honest supplier. You might want to order a few years’ supply while you can. If you really want an optimally cheap supply, you can try some of the other suppliers. Naturally you will not try any supplier whose per-unit price is more expensive, because you trust your current supplier 100% and must distrust the others at least a little, so the list of possible suppliers has been cut down.

Ordering with learning

If it was not, then you have a problem. Are you the vengeful sort who assumes that suppliers are all-rotten? Then you blacklist them and order from the next cheapest supplier (by unit-price adjusted for perceived risk). If you’re not vengeful, if you believe the suppliers who say that they don’t have control of their supply chain and sometimes bad products slip in, then you have to do more work.

If we interpret our distrust probability as instead ‘what percentage of delivered product is genuine’, then to continue the previous example, my trust probability would drop only a little if EDAndMore sent me caffeine/fake modafinil. Why? Because I estimated a 60% chance of them sending me modafinil, and 60% is another way of saying there’s a 40% chance they’ll send me not-modafinil. 40% chances happen quite often and I wouldn’t be very surprised if one happened when I ordered. On the other hand, I expected mostly pure product out of Airsealed (95% of their shipments being good), so if Airsealed sent fakes to me, then I would be quite shocked - 5% chances don’t happen all that often (it’s like rolling a 20 in D&D). How much do I knock down my estimate of Airsealed? By more than EDAndMore, obviously. But how much more? Well, you have to apply Bayes’ theorem. (One basic property of Bayes’ theorem is that extreme probabilities are hugely damaged by opposed observations, while equivocal probabilities like 51% take a lot of data to knock down. For a good explanation, see “An Intuitive Explanation of Bayes’ Theorem” or “Visualizing Bayes’ Theorem”.)

P(ab)=P(ba)×P(a)P(b)

The former is a little complex, so we’ll simplify down again. Here’s our scenario: 95% of the orders delivered by a ‘good’ supplier will be real (all modafinil); but bad suppliers have only 5% of the orders be real. (Apparently this isn’t all that unrealistic; whether it’s because supply chains are unreliable or deliberate profit-maximizing behavior, often neither good or bad suppliers ship all fakes or all genuine modafinil.)

Now, supplier A, whom you had calculated was probably good with 90% probability, sent you a fake. Keeping in mind that you might just be one of the unlucky 5%, now how much do you think that A is good?

A rearrangement of Bayes’ theorem from the end of Eliezer Yudkowsky’s “Intuitive Explanation of Bayes’ Theorem” (he explains its derivation if you don’t trust me):

P(ab)=P(ba)×P(a)(P(ba)×P(a))+(P(b¬a)×P(¬a))

How confusing and intimidating! Where does one start, with all the differing entries?

Let’s break it down step by step. If you didn’t read either Wikipedia or Yudkowsky, you should have, but remember the pipe is read backwards: P(foobar) means ‘how likely is foo now that I have observed bar’ (you could mentally rewrite it to something like P(barfoo)). b represents our observation, whatever it is. In this case, it’s the not-modafinil, the fake pills. a represents our new, reduced, belief that A is a good place to order from. So at the beginning we can make a few definitions:

  • a = being a good supplier
  • b = receiving fakes

If you look, the right-hand side of that equation has exactly 4 pieces in its puzzle:

  1. P(a)

    This is something we already know, ‘probability of being a good supplier’. Well, we specified a few paragraphs above that we had somehow concluded that A was a good supplier with 90% odds.
  2. P(¬a)

    This is the opposite of the previous. Now logically, if something has a 90% chance of being true, then obviously it has a 10% chance of not being true. Either one or the other. So this is simply equal to 10%.
  3. P(ba)

    Remember, we read the pipe notation backwards, so this is ‘the probability that a good supplier (a) will send us fakes (b)’. We also said that good suppliers send 95% good orders; by the same logic as above, that’s another way of saying they send 5% fakes. So this is simply 5%.
  4. P(b¬a)

    Finally, we have ‘the probability that a bad supplier will send us fakes’. We said bad suppliers send 5% good orders, so again, subtracting from 100 and we know they must send 95% fakes. So this is simply 95%.

To put all these definitions in a list:

  1. a = good supplier
  2. b = fakes
  3. P(a) = probability of being a good supplier = 90% = 0.90
  4. P(¬a) = probability of being a bad supplier = 10% = 0.10
  5. P(ba) = probability a good supplier will send fakes = 5% = 0.05
  6. P(b¬a) = probability a bad supplier will send fakes = 95% = 0.95

We substitute in to the original equation:

P(ab)=P(ba)×P(a)(P(ba)×P(a))+(P(b¬a)×P(¬a))=0.05×0.9((0.05×0.9)+(0.95×0.1))=0.045((0.05×0.9)+(0.95×0.1))=0.045(0.045+0.095)=0.0450.14=0.32

32% seems like a reasonable answer. Intuitively, I’d expect my trust to drop considerably below 50%, but still noticeably above 5%, and 32% is well within that range.

Phew! So, now we have a full system for situation #2. First, go through the expected utility calculation for all the prices you’ve gathered in which you trade off risk versus price. Then order, test for modafinil or not-modafinil, and do a Bayesian update on the supplier. Rinse, and repeat. This procedure terminates if there are any good suppliers (suppose you luck out and the second supplier you test, #4 on the per-unit list, is honest; now you only need to test 3 more suppliers since they are the only ones cheaper - why would you care about a equally reliable but more expensive supplier?).

Of course, this does require you to already have beliefs about the reliability of a supplier. If one is willing to order blind, there’s a cute frequentist trick for rough estimation when you have a bunch of independent binary experiments: the rule of three, which goes simply that if you haven’t observed x despite looking n times, then 95% of the time x has a probability of n3. So if we had ordered 10 times from a seller and we assume the seller isn’t doing anything tricky like ‘send a new customer 11 real orders and then sell him only fakes’ but is randomly sending reals and fakes, we can calculate the seller sends fakes less than 103=3.3 of the time. (Related is Laplace’s Rule of succession, which says the odds of a fake in the next order, given n real orders, is just 1n - the idea being that we should assume the worse, that we get a fake in the next order; then, if one looked at one of our orders randomly, there’d be only 1 fake and n real orders and so the odds of a fake are that 1n.)

Ordering when learning isn’t free

How do we extend this procedure to handle situation #3, where we no longer trust ourselves to test the supposed modafinil (for free)? This is a question on the value of information (4 examples).

Let’s assume it costs $1000 to assay some pills and like in #2, we’ll assume the assay is infallible. Then we just repeat the #2 procedure except with the assay replacing our own subjective testing. Fair enough, right?

But a wrinkle comes to mind. $1000 is a lot. Quite a lot, really. You could buy a lot of modafinil with $1000; even if we played it safe and bought from Nubrain, $1000 would get us 62×1000, or 62,000 mg, or at 200mg a day, 310 days’ worth60.

Are we sure we want to spend that? I mean, what if the price difference between the last 2 suppliers is just a few pennies - would we still want to spend $1000 just to be sure? Even if we plan to buy for years, decades, or the rest of our life, that $1000 might not be worth spending to optimize and save a few pennies. We could ask ourselves - is the possible penalty of a few pennies every order over our lifetime worth the $1000 right now? As it happens, there’s a nifty formula for this.

We want to compare an infinite stream of small savings against a single large expenditure. The savings would make us slightly wealthier each time period. In fact, you could imagine that we were actually discussing savings bonds or annuities: is the small payoff each year worth the large upfront investment? In economics terminology, the question is whether the ‘net present value’ of that payoff stream is larger than our investment.

Net present value can be approximated based on knowing one’s discount rate (which is a percentage) and then plugging in the numbers to the following formula:

NPV=annualPayoffln(discountRate+1)

What is my discount rate? If I introspect and ask myself, would I prefer $150 in a year to $100 right now; I say yes, so I know my discount rate is less than 0.5/50%; would I prefer $125 to $100 now? Yes, so it’s less than 0.25/25%; and so on down to around $107 versus $100. So let’s say 7% for me.

What do our two suppliers look like? Maybe one charges me $220 for a year’s supply and the other, the one I haven’t yet tested, supplies it for $200. So $20 a year is at stake. Let’s plug it in:

NPV=annualPayoffln(discountRate+1)=20ln(1+0.07)=20ln(1.07)=200.06765=295.6

But it would cost us $1000 to assay and find out whether there was a savings or not! Clearly it’s not a good idea to spend the money for the assay. $20 a year is just not enough.

As it happens, at a discount rate of 7%, we would have to potentially save about $68 before the assay became a good idea. (For $20 a year to be worthwhile, your discount rate has to fall down to around 2%, and very few people are that patient and self-sacrificing!) If you look back at the supplier chart, it runs the gamut from 222 mg per dollar to 16 mg; so for the first few purchases the assay might well be worthwhile.

Thus we solve situation #3. You apply the #1 method to decide at any point which supplier to order from next by their risk-adjusted unit-price; then you update the risk-adjusted unit-price through #2’s idea of using Bayes’ theorem; then if testing is not free, you decide to stop testing and stop searching suppliers when, as given by #3’s present value formula, the testing (assays) start costing more than one can hope to gain.

A final thought about modafinil:

“I am not interested in talking about my ideas. I am interested in your application of them to your life.”61

It goes without saying that #1–3 are all simplified models which may not apply to every situation; but at some point, the would-be user of nootropics must start thinking for himself.

Discount rate applications: swapping time for time

Here is a thought experiment for you: a genie offers to tinker with your lifespan in the following manner, he will take away your scheduled year as an 85-year-old but give you an additional year as a 25-year-old. I think many people would take such a deal - more youth is good; even if you don’t get any more life, you are getting better life. Slightly stickier would be if the genie changed the deal slightly: you lose the same year as a sickly old man, but you only get 11 months in the prime of your life. I would still take this deal, and I think so would many people. It’s a hard problem to decide where I would finally decide I would prefer to live the year as a sickly old man than a virile young self with no health problems at all, but I’d trade off quite a bit of time; I think I would definitely accept anywhere down to 6 months or 50%. (I haven’t been impressed by the quality of old folk’s lives, and I’ve been told that it is overall like having a permanent cold in terms of energy and capability - which is pretty miserable!) Deciding the exact QALY is a much-debated problem. But whether you like it or not, you are making this sort of tradeoff every time you decide not to exercise or eat right, and it is a tradeoff many make at the end of their lives by avoiding heroically painful and expensive medical interventions, or simply face the prospect of living with diminished capacities62.

All this is to say that I do not value life as an old man as much as life as a young man. This leads to the interesting observation: suppose modafinil use resulted in hideous crippling disease which manifests decades down the line, which is why the existing studies and large populations of users have not reported anything but rare and relatively minor side-effects; and suppose further that the risk was proportional to usage or something along those lines such that every modafinil dose that granted 8 hours of productivity cost one 8 hours of life in half a century - given all this, I would still regard modafinil as a blessing! From my perspective, if I lost a year to the disease, I gained the equivalent of 1.5 old years, which is quite a bargain.

So the anti-modafinil argument starts off at a disadvantage if it wants to appeal to long-delayed consequences. Above we already saw how to use discount rates; discounting is applicable here, except our unit would be ‘years’ rather than ‘dollars’. It would be enlightening to ask, what is the net present value of one year of life 50 years in the future? We can’t use the exact formula from above because a year isn’t an income stream; the formula we want is the inverse of the interest rate formula:

presentValue=futureValue(1+discountRate)years

We say a year is worth 100 and will interpret the answer as a percentage; while real people have discount rates much higher63, we will generously assume the improbably low discount rate of 2%; and then ask how much a year is worth 50 years from now:

presentValue=100(1+0.02)50=1002.692=~37

Which is interesting as it suggests, on a pure discount-rate basis, that we will benefit from any activity which has a less than 3:1 penalty between then and now; if modafinil gains us 1 hour today and costs us 2 hours in that distant future, we are better off. I earlier said I was willing to trade, based purely on qualitative considerations, future and present at a 2:1 rate, so between that (~2:1) and the discount rate (>3:1), an hour of modafinil use would have to cost me at least 6 hours in the future! A single 8-hour session on modafinil would need to cost me more than a day to be a bad idea.

It’s quite a poisonous drug that comes with such a penalty; I don’t believe even smoking has that kind of penalty (I cite one calculation in Nicotine that one cigarette costs 11 minutes). So the reader could ask themselves: with everything they know and have heard about modafinil (and have not heard), how likely is it that modafinil is even worse than smoking?

Coordination problems: assaying

“On the one hand, information wants to be expensive because it’s so valuable. The right information in the right place just changes your life. On the other hand, information wants to be free, because the cost of getting it out is lower and lower all the time. So you have these 2 things fighting against each other.”64

The obvious response to the price of laboratory assays is to somehow distribute the cost among interested persons.

Any user-based service would founder, I think. Look at my footnote about EDAndMore - there is a link to user feedback about EDAndMore, but it is littered with what smells like fake reviews. But how could I possibly prove that? If people really began to use the service, then the sellers have great incentive to corrupt it. One of the best user-generated sources was DrugBuyers.com, and even there, if you looked through threads, you would find endless comments by users banned for being shills.

Now, it’s easy to avoid this problem and create a reliable rating system for modafinil sellers. All one has to do is order every few months, and send the product to a lab for assays. (This would be the Consumer Reports model for drugs.)

But this requires a spare couple thousand dollars, and is a public good susceptible to the free rider problem. I certainly don’t have $2000 to buy $100 of product (plus S&H) from 10 retailers and then pay for 10 lab assays. So really, the best I can do is catalogue what they advertise.

It’s a public good, because while rationally, modafinil buyers should be willing to pay a few dozen or even hundred dollars to obtain access to the results of dozens of assays of purchases (avoiding, in the long run, spending thousands on counterfeits), and there are many thousands of buyers, plenty to collectively pay the vendor enough to cover the purchases & assays and provide a profit, it would be even more rational for one buyer to find the result and resell the summarized info for less, or just release it for free - ‘X.com is the best’ - and thereby ruining the vendor.

Knowing how vulnerable they are, no vendor will go into the business to begin with - keeping everyone ignorant and making everyone worse off than if they could just have agreed not to share that result. (Consumer Reports gets away with it because it covers so much, there’s a lot of detail, and they seem to be largely funded by their automobile division.)

One of the canonical solutions to a public good problem like this is called the assurance contract: participants legally bind themselves to contribute a sum of money if there are enough other such promises that the necessary threshold is passed. One of the most successful facilitators of assurance contracts is the online site Kickstarter; but of course, it is illegal to order modafinil without a prescription, and it is highly unlikely Kickstarter would permit an assurance contract for modafinil assaying to be created or completed.

Assaying

But suppose one has resolved this problem. There are a few options:

  1. Erowid’s EcstasyData.org will, for $120, test for the presence or absence of modafinil (but not the concentration; see their FAQs)
  2. There are a few laboratories which have been suggested:


  1. See the 1999 Milgram review, “Adrafinil: A Novel Vigilance Promoting Agent”

  2. 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.”

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

  4. One American prescription user I spoke with said that his prescription was for 200mg pills; each box cost around $50 for 30 pills. He took one in a day, or about $1.70 (120 mg/USD).

  5. from Businessweek’s “The 10Q Detective: Losing Sleep Over Cephalon”:

    “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 pharma information site Destination Rx.”

    36130=12.03; although it’s unclear what of this is the actual price to the consumer.

  6. 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.”

  7. Minzenberg again.

  8. I hedge and say 2/3s rather than 1/1, as most people use it, because any such claim ought to take into account the total cost of use - such as ‘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%?) Modafinil may have some recovery sleep, but the studies and my personal experience suggest that it’s not more than 2 hours. From Bonnet et al 2005:

    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 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) 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) 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) 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, 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), those of Lagarde et al. (1995), 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) 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) and Buguet et al. (1995) study. Rosenthal et al. (1991) 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.

  9. 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:

    “…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 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.”

    A 2011 study using sleep-deprived doctors 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):

    “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 (i.e. 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-significant tendency towards ‘overconfidence’ for task-level assessments of performance.”

    (The 2009 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:

  10. Caffeine is pretty ineffective because tolerance develops. One amusing comparison of modafinil versus caffeine, dextroamphetamine, and placebo: http://www.ncbi.nlm.nih.gov/pubmed/16796223. 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;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.

  11. See the 1996 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.

  12. “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.”

  13. From Bonnet et al 2005:

    “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 studies119,120,122 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 studies83,117,119 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

  14. Some relevant citations (omitting a mice study):

    • “Modafinil effects on cognitive function in HIV+ patients treated for fatigue: a placebo controlled study” (McElhiney 2010): 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): Unlike Randall 2003, 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” (Müller 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) 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 (e.g., abstract thought, critical reasoning, planning, decision-making, situational awareness, and effective judgment) which are critical in most modern operational settings.”

    • One unfortunate result for the bright young nerds interested in modafinil: “Cognitive effects of modafinil in student volunteers may depend on IQ” (PDF), Randall et al 2005:

      “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.”

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

      “In a group of high IQ (mean 115) university students, Randall et al. (2003) failed to detect any positive effects on cognitive performance of modafinil (100 and 200 mg) Liepert et al. (2004) 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). 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 and spatial planning (New Tower of London) tests. Finally, Randall et al. (2005) 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). Muller 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) 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), 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, 2005), 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), but not in the student studies, where the level of performance in this task was higher (Randall et al., 2003, 2005). 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). As the Digit Span and PRM tasks were used only in our second student study (Randall et al., 2005), 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, 2004a,b; Randall et al., 2005)”

  15. See Repantis et al 2010.

  16. Quote from the abstract of “Pharmacogenetics of modafinil after sleep loss: catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep”, March 2009

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

  18. Taneja et al 2007, 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 nonsignificant 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 al6 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.”

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

  20. 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 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 & DeVane 2003]. 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 mg) of modafinil.”

  21. See, eg. http://ask.metafilter.com/47324/How-well-does-Modafinil-work#720855, http://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.

  22. “Urine smells of suplhur”

  23. Bonnet et al 2005 covers some side-effects listed in studies & trials; obviously for a truly 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 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:

    “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.”

  24. “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), Appetite 42 (2004) 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; Shelton, Nishino, Vaught, Dement, & Mignot, 1995). 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; Taylor & Russo, 2000; Rugino & Copley, 2001)….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; Rush et al., 2002; Caldwell, Caldwell, Smythe, & Hall, 2000; PDR, 2002).”

    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).”

  25. “Modafinil: A Review of Neurochemical Actions and Effects on Cognition”; Michael J Minzenberg, and Cameron S Carter. Neuropsychopharmacology (2008) 33, 1477–1502; PDF

  26. For example, one person I know experienced ‘serious muscle pain’ which he described as proportional to the dose.

  27. 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 (i.e., 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 from 1998 to 2003, 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."

  28. 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 mg/kg. Oral LD50 values reported for rats range from 1000 mg/kg to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. In clinical trials on humans, taking up to 1200 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.”

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

  30. 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 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.”)

  31. “Modafinil, used for at least 3 years in some patients, produces, in most cases, no peripheric sides effects, does not disturb night sleep and is never responsible of tolerance of drug dependence.” Bastuji & Jouvet 1988, “Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil”.

  32. “Off-label uses of modafinil”, Teitelman E. Am J Psychiatry 2001.

  33. “There was also no significant difference in final modafinil dosage between patients who had a positive history of chemical abuse/dependence (290 mg/day) and those who did not (258 mg/day).”, from “Absence of mood switch with and tolerance to modafinil: a replication study from a large private practice”, Nasr et al 2006

  34. “Efficacy and safety profiles of Provigil (modafinil) maintained during long term (40 and 88 weeks) treatment of excessive daytime sleepiness associated with narcolepsy”, Emsellem HA. Neurology 2000, 54 (Suppl 3): A29

  35. “Modafinil is well tolerated, with no evidence of tolerance developing during 40 weeks of treatment.” from “Long-term efficacy and safety of modafinil (PROVIGIL®) for the treatment of excessive daytime sleepiness associated with narcolepsy”, Mitler 2000.

  36. Deroche-Gamonet et al 2002 experimented on rats with modafinil and cocaine: “Modafinil did not produce reinforcing or rewarding effects and did not modify the effects of cocaine…However, as shown previously in nonhuman primates and in humans, modafinil could possibly have reinforcing effects in cocaine-experienced individuals.” One such study, using rhesus monkeys, was “Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil” where: “The reinforcing and discriminative stimulus effects of modafinil-required very high doses: modafinil was over 200 times less potent than d-amphetamine and was also less potent than l-ephedrine.”

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

    “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, behavioural, 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; Chait et al., 1987). 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) 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). In a prior study, Warot et al. (1993) 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):

    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.”

  38. From the abstract of “Discriminative-stimulus effects of modafinil in cocaine-trained humans”, Rush et al 2002: “Cocaine and methylphenidate, but neither modafinil nor triazolam, produced cocaine-like discriminative-stimulus, subject-rated, and cardiovascular effects.”

  39. 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. On the positive side, this study represents another citation for the thesis that modafinil has few and minor side-effects.

  40. 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.

  41. Jasinski 2000’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 (DeSereville 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).”

  42. The real deal runs upwards of $10 per pill; so we won’t even bother to include it in the price table

  43. 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.

  44. Caveat: Nubrain can process and ship orders very slowly; and as of 2011, 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.

  45. Prices in pounds are converted to dollars. Milligrams per dollar is calculated the obvious way: $\text{round} \frac{\text{mg} \times \text{Amount}}{\text{$} + }$

  46. Likewise calculated, 10x10 units, £5.39 each.

  47. Apparently not to be confused with UnitedPharmacies.com; the .com will ship to the US, but the .co.uk will not ship to the US. So UP is useless for American buyers.

  48. UP actually sells 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.

  49. As something of an experiment, I have signed up as an affiliate with OneMedStore; it will be interesting to find out how many sales were thanks to this article and what sort of profit margin that implies. It’d also be nice if I could cover hosting costs for gwern.net.

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

  51. 4NRX redirects US customers to a US site which does not offer modafinil; one probably cannot order modafinil from them. Unusually, they offer armodafinil.

  52. As with UP, 4NRX sells 10-pill units; this is calculated against 10 units, £3.89 each.

  53. See previous UP note; this is calculated at 10x10, £3.74 each.

  54. Affiliate.

  55. I once ordered armodafinil off Silk Road.

  56. They seem to do ~20% commission; for the cheapest modafinil, as of 28 April 2011:

    1. 200x200 sells for $197.95, commission of $39.59
    2. 100x200 sells for $131.95, commission of $26.39
  57. For example, if multiple sites/‘businesses’ were set up, each with different prices, then the true owners may be able to 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 certificate was also expired - but NP. I’d say go for it!”

  58. http://www.longecity.org/forum/topic/44117-modafinil-sources/page__st__20__p__454877#entry454877

  59. S. Cobb: The Economics of Spam. ePrivacy Group, Feb 2003. Cited in ““Proof-of-Work” Proves Not to Work", Laurie, Ben; Clayton, Richard (May 2004)

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

  61. Miyamoto Musashi, “Book of Water”, _Book of Five Rings

  62. 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.”

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

  64. Stewart Brand to Steve Wozniak (1984; First Hacker’s Conference)

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