# Modafinil

Effects, health concerns, suppliers, prices & rational ordering (biology, psychology, nootropics, politics, statistics, predictions, law, Bayes)
created: 20 Feb 2009; modified: 06 Jan 2019; status: finished; confidence: highly likely;

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

Modafinil is a wakefulness drug developed in the 1980s. It is prescribed for narcolepsy but is widely used off-label for its stimulating effects and to deal with sleep deficits. As such, many believe it helps their cognitive performance & productivity. (However, comparing it to the fictional drug NZT in the 2011 movie Limitless is a gross exaggeration.) I would describe its advantages over other common stimulants as: more powerful and less addictive & tolerating than caffeine or khat; much longer-lasting than nicotine; less likely to alter mood or produce tweaking behavior than Adderall or Vyvanse; and much more legal & with almost no side-effects compared to methamphetamine or cocaine. On any specific aspect, there may be a stimulant superior to modafinil, but few stimulants come close to modafinil’s overall package of being a long-lasting, safe, effective, non-mood-altering, quasi-legal stimulant, and that is why it has become so popular.

Its development stems from adrafinil, 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 (which apparently caused its discontinuation by the usual manufacturer3) and because reportedly you need about 3 times more adrafinil to be metabolized into an equivalent dose of modafinil. Its chief advantages were that all patents on it expired long ago, and it’s very rarely proscribed - so it was 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 & Canada4. 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.

So, our very first calculation goes $\text{minimum wage} \times \text{hours saved}$, or $6.55 \times 4$, 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. We could look at it this way: what if modafinil had an average fatality rate of 1 over those 50 years, and I value the overall 50 years at$10m (and 25 years at $5m, and 5 years at$1m etc.), and each day has the same chance of killing you, so you could die the first day at $\frac{1}{50 \times 365.25}$ probability. Applying the usual expected gain/loss formula, each day we incur an expected loss of $10,000,000 \times \frac{1}{50 \times 365.25}$, or $548. Ouch. That is noticeably larger than the$26.2 we expected to gain. 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 $\frac{1}{21}$ chance of killing you, it could be worth while. Do you think modafinil has a less than $\frac{1}{21}$ 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

## Brands

Generally, armodafinil > modafinil > adrafinil, brand-name > generic, but how do the generics go? The general scuttlebutt seems to be that the generics in descending order of desirability go:

1. Modapro
4. SpierX

## Vendors

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/Nuvigil. (The real deal in pharmacies runs upwards of $10 per pill; so we won’t even bother to include it in the price table. Generic competition as of 2016 has reportedly driven it down to a more reasonable$1/pill.)

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

Vendor notes:

• 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); one primitive test reported that there’s some sort of sulfur content, indicative of modafinil.
• Nubrain3738 seems to have a reputation for honesty
• Additional review sources include Longecity & SafeOrScam

It’s worth noting that shipping can make a major difference. For example, the now-defunct Airsealed’s $22 modafinil seemed like an excellent deal - but the price was almost doubled by their$15 shipping, but if one bought a lot the price also looked a lot better. 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.

A final note: reputations are not a perfect defense as one often hears of sellers that start off good but degenerate. There are many compelling economic or statistical reasons for this to happen:

• regression to the mean of any relevant factors

• eg. regression to the mean of the owner: what happens when the passionate founder sells or leaves?
• charging a inverse risk premium once a reputation is established (people who are risk-averse will rationally pay extra for an established trustworthy service than a newcomer)
• lack of competition (possible, but doesn’t seem like an issue of late; this may be an exacerbating factor in the previous - there may be no other trusted sellers really competing)
• lack of investment into lowering prices or using new technology, treating the service as a cash cow (possibly irrationally, or rationally if it’s powering another, more lucrative, investment)
• burning a reputation/consuming reputational capital; the service becomes more profitable exploiting customers temporarily even though this destroys the long-term value - the most extreme example is cut and run, simply never delivering on a batch of orders, this can be very profitable if a vendor is very trusted, as Silk Road 1 proved (The bigger a modafinil site, the more temptation because the more orders that will naturally come in before the news gets out.)

The riskier an investment is, the less each future dollar it might earn is worth; risk encourages ripping and running. Being quasi-legal or illegal is risky, quite on top of the usual small-business risks.

With all that in mind, my research into online vendors produced the follow tables (began February 2009; last updated 15 November 2013; previous versions: October 2010, March 2011, December 2011, May 2012, March 2013):

### Grey markets

#### Modafinil table

To make updates easier, entries are batched by domain; click to sort columns

mg/$39 mg Amt$ S&H Brand Provider
87 100 500 575 0 Modalert OneMedStore
87 100 360 414 0 Modalert OneMedStore
88 100 240 274 0 Modalert OneMedStore
85 100 120 142 0 Modalert OneMedStore
70 100 90 110 18 Modalert OneMedStore
61 100 60 81 18 Modalert OneMedStore
47 100 30 46 18 Modalert OneMedStore
196 200 500 510 0 Modalert OneMedStore
177 200 360 407 0 Modalert OneMedStore
156 200 240 308 0 Modalert OneMedStore
148 200 120 162 0 Modalert OneMedStore
126 200 90 125 18 Modalert OneMedStore
106 200 60 95 18 Modalert OneMedStore
82 200 30 55 18 Modalert OneMedStore
270 200 400 281 15 Modvigil The Pharmacy Express40
209 200 200 176 15 Modvigil The Pharmacy Express
172 200 100 101 15 Modvigil The Pharmacy Express
106 100 100 79 15 Modalert The Pharmacy Express
168 200 100 104 15 Modalert The Pharmacy Express
122 100 200 149 15 Modalert The Pharmacy Express
209 200 200 176 15 Modalert The Pharmacy Express
133 200 100 135 15 Modafil The Pharmacy Express
196 200 200 189 15 Modafil The Pharmacy Express
200 200 300 285 15 Modafil The Pharmacy Express
208 200 540 520 0 Modalert DesiredMeds
161 200 270 335 0 Modalert DesiredMeds
151 200 180 238 0 Modalert DesiredMeds
144 200 90 125 0 Modalert DesiredMeds
126 200 60 95 0 Modalert DesiredMeds
105 200 30 57 0 Modalert DesiredMeds
88 100 180 205 0 Modalert DesiredMeds
87 100 270 310 0 Modalert DesiredMeds
82 100 90 110 0 Modalert DesiredMeds
74 100 60 81 0 Modalert DesiredMeds
62 200 10 32 0 Modalert DesiredMeds
61 100 30 49 0 Modalert DesiredMeds
32 100 10 31 0 Modalert DesiredMeds
120 200 300 499 0 Modalert EDAndMore.com
115 200 200 347 0 Modalert EDAndMore.com
103 200 100 195 0 Modalert EDAndMore.com
200 200 300 300 0 Alertec EDAndMore.com
202 200 200 218 0 Alertec EDAndMore.com
152 200 100 145 0 Alertec EDAndMore.com
149 200 180 226 16.1 Modvigil MODafinil UK
143 200 150 194 16.1 Modvigil MODafinil UK
130 200 120 169 16.1 Modvigil MODafinil UK
124 200 90 129 16.1 Modvigil MODafinil UK
114 200 60 89 16.1 Modvigil MODafinil UK
94 200 30 48 16.1 Modvigil MODafinil UK
136 200 180 265 0 Modalert RxShop.md
126 200 120 169 22.1 Modalert RxShop.md
124 200 150 220 22.1 Modalert RxShop.md
110 200 90 141 22.1 Modalert RxShop.md
99 200 60 99 22.1 Modalert RxShop.md
73 200 30 60 22.1 Modalert RxShop.md
75 200 30 58 22.1 ModaFresh RxShop.md
102 200 60 96 22.1 ModaFresh RxShop.md
111 200 90 140 22.1 ModaFresh RxShop.md
128 200 120 166 22.1 ModaFresh RxShop.md
137 200 150 219 0 ModaFresh RxShop.md
141 200 180 256 0 ModaFresh RxShop.md
67 200 90 269 0 Super Drug Saver
55 200 30 95 15 Super Drug Saver
43 100 90 195 15 Super Drug Saver
34 100 30 72 15 Super Drug Saver
57 200 180 610 25 Controlled Pills
56 200 150 515 25 Controlled Pills
53 200 120 425 25 Controlled Pills
49 200 90 339 25 Controlled Pills
45 200 60 240 25 Controlled Pills
40 200 30 125 25 Controlled Pills
114 200 40 70 0 Modalert Rx_rex
119 200 80 135 0 Modalert Rx_rex
120 200 120 200 0 Modalert Rx_rex
47 100 50 99 7 Modalert Nubrain
48 150 20 55 7 Modalert Nubrain
62 200 50 155 7 Nubrain
238 200 100 84 0 Modalert 4NRX Pharmacy41
167 100 100 60 0 Modalert 4NRX Pharmacy
37 100 30 81 0 Modvigil 4NRX Pharmacy
215 200 100 85 8 Modalert United Pharmacies42
147 100 100 60 8 Modalert United Pharmacies43
31 100 30 90 8 Modvigil United Pharmacies
23 100 30 130 0 Modiodal Modafinil Store
15 100 30 180 15 Modiodal Biogenesis AntiAging44
22 100 30 125 10 Modiodal AuraPharm

Due to severe problems with payment processors, online pharmacies (including modafinil sellers) have been exploring Bitcoin as a solution. Bitcoin, being relatively new, has a volatile exchange rate, and pricing can be confusing. This table breaks out Bitcoin-denominated modafinil products separately. Generally, the sellers seem to automatically peg their Bitcoin prices to dollar-equivalents so the prices remain constant in dollars whatever the most recent Bitcoin price may be. (Conversions were made with the Bitstamp price of $415/฿ & £270/฿ on 10:30PM 14 November 2013.) mg/$ mg Amt ฿ $S&H Brand Provider 94 200 30 0.0990041 48 16 Modvigil MODafinil UK 115 200 60 0.16091261 88 16 Modvigil MODafinil UK 125 200 90 0.22282113 128 16 Modvigil MODafinil UK 130 200 120 0.28472964 169 16 Modvigil MODafinil UK 144 200 150 0.32256156 193 16 Modvigil MODafinil UK 149 200 180 0.37219406 225 16 Modvigil MODafinil UK ? 200 200 ? ? 0 Modalert MedsForBitcoin.com45 ? 200 100 ? ? 0 Modalert MedsForBitcoin.com ? 200 40 ? ? 0 Modalert MedsForBitcoin.com 114 200 40 0.1684 70 0 Modalert Rx_rex 119 200 80 0.3248 135 0 Modalert Rx_rex 120 200 120 0.4811 200 0 Modalert Rx_rex 178 200 40 0.1085 45 0 Modalert Modadeals46 222 200 100 0.2169 90 0 Modalert Modadeals 267 200 200 0.3614 150 0 Modalert Modadeals #### Armodafinil table mg/$47 mg Amt $S&H Brand Provider 104 150 270 388 0 Waklert SunModalert.ru 94 150 90 143 0 Waklert SunModalert.ru 91 150 180 297 0 Waklert SunModalert.ru 86 150 60 105 0 Waklert SunModalert.ru 82 150 30 55 0 Waklert SunModalert.ru 44 50 90 102 0 Waklert SunModalert.ru 35 50 60 85 0 Waklert SunModalert.ru 34 150 10 44 0 Waklert SunModalert.ru 31 50 30 49 0 Waklert SunModalert.ru 16 50 10 32 0 Waklert SunModalert.ru 59 50 279 235 0 Waklert SunModalert.ru 53 50 180 170 0 Waklert SunModalert.ru 91 150 120 198 0 Waklert myModafinil.net 76 150 80 157 0 Waklert myModafinil.net 52 150 30 87 0 Waklert myModafinil.net 162 150 200 185 0 Waklert MedsForBitcoin.com48 143 150 100 105 0 Waklert MedsForBitcoin.com 100 150 40 60 0 Waklert MedsForBitcoin.com 50 150 10 30 0 Waklert ArmodafinilNow 69 150 40 87 0 Waklert ArmodafinilNow 76 150 90 177 0 Waklert ArmodafinilNow 150 150 100 92 8 Waklert United Pharmacies49 81 50 100 54 8 Waklert United Pharmacies50 163 150 100 92 0 Waklert 4NRX Pharmacy51 Bitcoin: mg/$ mg Amt ฿ $S&H Brand Provider 91 1 50 1 20 0.477 198 0 Waklert myModafinil.net 76 1 50 8 0 0.3783 157 0 Waklert myModafinil.net 52 1 50 3 0 0.2096 87 0 Waklert myModafinil.net 50 1 50 1 0 0.07228 30 0 Waklert ArmodafinilNow 69 1 50 4 0 0.2096 87 0 Waklert ArmodafinilNow 76 1 50 9 0 0.4265 177 0 Waklert ArmodafinilNow ? ? ? ? ? 0 Waklert MedsForBitcoin.com ? ? ? ? ? 0 Waklert MedsForBitcoin.com ? ? ? ? ? 0 Waklert MedsForBitcoin.com Alternative price charts: 1. Pharmacy Reviewer (covers only EDAndMore & Medstore Online) 2. Ben on Imminst.org (February 2011) #### Bulk synthesis/purchases Another fascinating possibility for obtaining modafinil is to not order pills, but order powder or one’s own synthesis of modafinil: 1. A Korean company Chemland21 offered in 2006 to synthesize modafinil at$550/kg
2. a possibly-defunct Chinese supplier pharm-marketing.com offers it for an unknown price
3. a Chinese-Thai producer Drugs Power Store offers 1kg for ~$3,000 (~$0.6 per 200mg, competitive with the ~$0.9 of the cheapest online stores) 4. the Chinese supplier Sun Nootropic formerly advertised 1kg for >$1,057 or 0.2kg for $200; they received positive reviews but one Longecity poster said Paypal no longer allows anything to do with Modafinil but they can still sell it, at the same prices, through paypal, only if Modafinil isn’t mentioned at all reportedly took it down due to Chinese regulations in March 2013 (they currently advertise 100g adrafinil for$133)

### India

These pharmacies are almost all sourcing their modafinil (if it’s actual modafinil) from Indian sources. 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 (http://www.longecity.org/forum/topic/44117-modafinil-sources/page__st__20__p__454877#entry454877)

Such a pharmacy price would be $\frac{10 \times 200}{3}$ 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. Another reader reports similar Indian prices in January 2012: 85 rupees for 10x100 and 130 rupees for 10x200. A reader setting up a business told me in January 2012 that he had arranged with a UK-India importer for modafinil at$0.35-45 per pill in bulk, which is consistent with the stamp prices plus overhead & profit for the importer. A similar reader said, when I asked in February 2012, that the going price was 131 rupees for 10x200 and my February 200mg Modalert arrived with stamps for 131 rupees per 10 pills. My armodafinil (Waklert generic brand) bought on Silk Road are stamped 150 rupees (per 10x150mg) or ~$3, which is less of a premium than I would have guessed. An Indian redditor claims February 2013 Sun Waklert/Modalert at$0.28 per pill, and the Indian drug database HealthKartPlus prices Sun 150mg Waklert at 150 rupees per 10 and 200mg Modalert at 131 per 10. In September 2015, another redditor reported 40x200mg at $9.6. (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 $2.50 sometime before 2003.57) ### Estimates So to review: • your standard blister-pack of 200mg Sun modafinil will run one around$4 in an Indian pharmacy. Since real fake medicine costs about as much and the cost of the modafinil is one of the smallest costs involved, we can assume that it is probably real and the Indian pharmacy prices apply.
• The India Post shipping from India to USA will cost ~$14. • On the clearnet end, the costs are domain name, hosting, customer support, and processing bitcoins; • cashing out bitcoins to pay the India drop-shipper might cost 5% of that in various fees • a domain name shouldn’t cost more than$20/year even for a Russian registrar
• hosting an ecommerce site is also maybe $20/month which totals to~$300 (the modafinil business can be rough so probably a seller will actually be paying more for security than I include here)
• support might be something like minimum wage at a 40-hour year-round job or $8 \cdot 365 = 2920$ handling all the orders; domain, hosting, and support are amortized over all orders, which for a top modafinil seller should easily be thousands of orders per year, so let’s say 2000 orders

Hence, if you order a 40x200mg Sun Modalert, it will generally run you something like $80 from a seller; then the bare minimum that modafinil seller could manage is a cost of $(4+14)\cdot 1.05 + (\frac{300}{2000})+(\frac{8 \cdot 365}{2000}) = ~20$ for a maximum possible margin of <74%. Being more conservative and assuming a 50% profit margin, this is consistent with (ie, greater than) both the affiliate percentages from past modafinil sellers and with the general affiliate percentages quoted by spam researchers, so it seems safe to assume that once a modafinil seller is up and running with a secure bugfree ecommerce website, a reliable dropshipper & modafinil source, and a good reputation, then it is profitable. # 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). It’s hard to get any hard numbers on how likely a particular supplier is to be a scam, or how many customers of a particular site are happy. A BBC online poll58 (for what that’s worth) about cognitive-enhancing drugs (eg. modafinil, Adderall, and Ritalin) got 761 responses, of which 38% were users at any point (~289), of which nearly 40% said they had bought the drug online, and 92% said they would try it again. In the worst case scenario that the 8% who wouldn’t try it again were all online buyers, that’d implies be a $\frac{8}{39}=0.2051$ or 21% unsatisfied rate or 79% satisfaction rate. 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 a extended example of how one might calculate an order, see a Silk Road example 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? A known scam is 0%, a totally trusted source is 100% and everyone else is a shade of gray. Then you multiply their trustworthiness against their unit price (milligrams per dollar) 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 ($222 \times 0.6$). And then I might decide United Pharmacies smells a bit better and give them a 70% chance, for a total of 145.6 ($208 \times 0.7$); and perhaps Airsealed gets a whopping 95% trust from me, for a total of 71.25 ($75 \times 0.95$). 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. 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.) $P(a|b) = \frac{P(b|a) \times P(a)}{P(b)}$ 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): $P(a|b) = \frac{P(b|a) \times P(a)}{(P(b|a) \times P(a)) + (P(b|\lnot a) \times P(\lnot a))}$ How confusing and intimidating! Where does one start, with all the different symbols? 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: $P(foo|bar)$ means how likely is foo now that I have observed bar (you could mentally rewrite it to something like $P(bar \rightarrow foo)$). 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. $P(\lnot a)$ This is the opposite of the previous. Now logically, if something has a 90% chance of being true, then it has a 10% chance of not being true. Either one or the other. So this is simply equal to 10%. 3. $P(b|a)$ 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. $P(b|\lnot a)$ 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. $P(\lnot a)$ = probability of being a bad supplier = 10% = 0.10 5. $P(b|a)$ = probability a good supplier will send fakes = 5% = 0.05 6. $P(b|\lnot a)$ = probability a bad supplier will send fakes = 95% = 0.95 We substitute in to the original equation: $P(a|b) = \frac{P(b|a) \times P(a)}{(P(b|a) \times P(a)) + (P(b|\lnot a) \times P(\lnot a))} = \frac{0.05 \times 0.9}{((0.05 \times 0.9) + (0.95 \times 0.1))} = \frac{0.045}{((0.05 \times 0.9) + (0.95 \times 0.1))} = \frac{0.045}{(0.045 + (0.95 \times 0.1))} = \frac{0.045}{(0.045 + 0.095)} = \frac{0.045}{0.14} = 0.32$ 32% seems like a reasonable answer. Intuitively, I’d expect my trust to drop considerably below 50%, but still well 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 less than $\frac{3}{n}$. 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 $\frac{3}{10} = 0.3 = 30\%$ of the time. The weaker generalization is Laplace’s Rule of succession, which says the odds of a fake in the next order, given $s$ failures and $n$ total orders, is $\frac{s+1}{n+2}$ - 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 an additional fake. In the previous example, that works out to $\frac{0+1}{9+2} = \frac{1}{11} = 0.09 = 9\%$. (We can apply Laplace to all sorts of instances; one cute example is estimating whether a cop will pull you over for driving faster than him - if we assume that you were pulled over once, and you saw 4/5 others try & fail, then the odds you will be pulled over the next time is $\frac{4+1}{5+2} = \frac{5}{7} = 0.71 = 71\%$.) We could also try applying the rule of three and Laplace’s rule of succession to estimating seizures by customs: I personally have ordered modafinil perhaps 7 times, one of which was not seized by customs but unusual circumstances meant I dastn’t get it; so I would obtain $\frac{3+1}{7} = 0.57 = 57\%$ by the rule of three or $\frac{1+1}{6+2} = 0.25 = 25\%$. And the real rates? One supplier told me of 20-30 shipments without seizure, which would be $\frac{3}{20} = 15\%$ or $\frac{0+1}{20+2} = 4.5\%$, and specifically claims a 3% rate; another supplier claims in their FAQ a 3% rate for all packages which are stolen, returned, delayed till deadline. Levchenko et al 2011 reports that of 120 purchase attempts, 56 purchases went through and only 3 were not delivered for any reason, for a failure rate of ~5%.59 Darknet market sellers seem to enjoy similar success rates, I infer from the general tenor of forum posts. In general, these low rates seem plausible given how rarely I hear of actual seizures. (People ask what the odds of seizure are far more often than seizures actually happen, it seems.) ## Ordering when learning isn’t free See also the discussion as applied to evaluating sleep experiments and nootropics experiments. 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 of money. 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 $62 \times 1000$, 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? If we’re saying $1000 on every order, then we do want to spend it, and if we’re saving 1 penny on each order, but can you say instantly and with confidence that saving$50 is worth it? Or $55? Our intuitions are not that precise, and in cases like this, we ought to look for a more rigorous and precise way of expressing this trade-off. As it happens, there’s a nifty formula for our dilemma. 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 loans or saving bonds or annuities: is the small expense or payoff each year worth the large upfront payment or investment? In economics terminology, the question is whether the net present value of that payoff stream is larger than our present potential 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: $\text{NPV} = \frac{\text{annualPayoff}}{\ln(\text{discountRate}+1)}$ 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, where the$7 feels a little too little. So let’s say my discount rate is 7%.

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: $\text{NPV} = \frac{\text{annualPayoff}}{\ln(\text{discountRate}+1)} = \frac{20}{\ln(1+0.07)} = \frac{20}{\ln(1.07)} = \frac{20}{0.06765} = 295.6$ 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 200+ 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. As it happens,$1000 is a gross exaggeration of how much assaying would cost; Erowid will do a kind of testing for $120, and we can run 2 simple chemistry tests to learn if there’s a sulfur group (which is a good proxy for modafinil) in a pill at an amortized cost of <$1 a pill or <$50 to start. It goes without saying that #1-3 are all simplified models which may not apply to every situation; but at some point, the would-be user of nootropics must start thinking for himself. ### Extended present-value example So let’s step through a problem using expected value and net present value. Starting with the price-chart, our top contenders per unit cost (mg/$) are (as of December 2011):

1. 238, 4NRX Pharmacy
2. 215, United Pharmacies.co.uk
3. 202, EDAndMore.com
4. 192, ThePharmacyExpress

If we trust them all implicitly, we should order 4NRX. Let’s imagine our trust differs and come up with some hopefully non-random percentages about whether a supplier is honest:

1. 238, 4NRX Pharmacy, 65%
2. 215, United Pharmacies.co.uk, 90%
3. 202, EDAndMore.com, 50%
4. 192, ThePharmacyExpress, 90%

We apply expected value to get our expected unit cost, as it were, and we get new rankings:

1. 215, United Pharmacies.co.uk, 90% = 194
2. 192, ThePharmacyExpress, 90% = 173
3. 238, 4NRX Pharmacy, 65% = 155
4. 202, EDAndMore.com, 50% = 101

One can change the ranking arbitrarily, of course, with extreme enough confidences. In this case, it wouldn’t be too hard to swap the first and second or restore 4NRX to the top of the heap. We’ve finished applying expected value.

Let’s ask about net present value. We can ask: is it worth our while to assay, based on the difference of 194 expected mg/$versus 173 expected mg/$? Maybe we should just order forever from UP.co.uk and forget about TPE.

Well, let’s make the assumption that we will order 100 doses of 200mg of modafinil every year indefinitely,

That is $\frac{100 \times 200}{194} = 103$ dollars with UP.co.uk and $\frac{100 \times 200}{173} = 116$ dollars with TPE, a difference of $13 per year. For the cost of our assay, we’ll go with the$50 amateur assay-test, and we’ll use my own personal discount-rate of around 5%:

$\text{NPV} \gt \text{testCost} = \frac{\text{annualPayoff}}{\ln(\text{discountRate}+1)} \gt \text{testCost} = \frac{13}{\ln(1+0.05)} \gt 50 = \frac{13}{\ln(1.05)} \gt 50 = \frac{13}{0.048790} \gt 50 = 266.4 \gt 50$

#### 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 and have done so (but they do not test the concentration; see their FAQs) 2. There are a few laboratories which have been suggested: ##### Amateur Modafinil is not that water-soluble while most pill binders are or at least have different densities, so it should be possibly to extract purer modafinil by crushing & dissolving pills in water. Trajork writes: Modafinil is a sulfa drug, containing a certain chemical group called a sulfonamide group67. And lo and behold I stumbled across a simple pair of chemical tests for sulfonamides. I took about a third of a pill and placed it in a test tube, adding a few ml of dilute NaOH. I then mixed it up and heated it over an alcohol burner. This should produce ammonia, which has a really characteristic odor. I got a whiff of my tube and, indeed, it was ammonia! I also tested the fumes with a piece of litmus paper - it turned blue, as expected [litmus turns red for acids & blue for bases; ammonia is a base]. Then I put another third of a pill in another test tube and added dilute HCl. Upon heating it, sulfur dioxide should be produced - another gas with a characteristic, pungent odor. So I sniffed my tube - it smelled awful! Further, my litmus paper turned red, which is what I’d expect because SO2 is acidic. Finally, one other test - I wanted to make sure this isn’t a characteristic of pill binder substances or anything. So I took half a caffeine pill and did the NaOH -> NH3 test on it. No ammonia whatsoever. I am not a chemist & cannot vouch for this procedure; at best, such a test would be crude and likely produces many false positives and negatives68, but may still be worth using. At least it should be cheap - checking, 50+ strips of pH/litmus paper is ~$5; hydrochloric acid is harder to find, but seems to be obtainable at $10-20 online; and sodium hydroxide similarly (and no doubt purchasable cheaper locally), for a worst-case cost of$45. This is roughly a third of EcstasyData.org’s price, and enough to test 50+ samples at a worst-case cost of ~$1 per sample. Another possibility is to attempt to rule out possible substitutes like amphetamines using a standard reagent test like the Mecke or Marquis tests; this has been tried before, apparently successfully. # Appendix ## Schizophrenia ### Epidemiology General observations: modafinil does not seem to be suspected as a cause of schizophrenia in any of the usual documentation, suggesting that even agencies like the FDA with incentive to find fault with modafinil see nothing suspicious. (Cephalon’s legal woes demonstrate, I think, that it has little corrupting influence over government agencies.) Similarly, while schizophrenia is a mysterious disorder or cluster of disorders, modafinil does not seem to have any chemical connections. Between these two, my expectation is that there is no causal link, or the link is from schizophrenia to modafinil use. Schizophrenia famously strikes young people, so we might expect some low correlation if we do not correct for age - young people also being famously adventurous and drug-using. But how to estimate? One of the main causal links to problems for modafinil are SJS and rashes, based on a patient population of roughly a million. The FDA estimated a rough tripling of that risk: given a case count of 4 (excluding the clinical trial case) and a projected total patient exposure of 704,167.7 patient years in the U.S., the calculated reporting rate for modafinil associated SJS/TEN in all ages in the U.S. is 5.7 per 1,000,000 patients as compared to the background rate of 1-2 million per patient. The important thing is the patient-years estimate of 704k. More germane is the FDA summary for mental issues: Dr. Mosholder [22] analyzed three clinical trials, two double blind and one open label. There were no completed suicides across trials. Although the exposure to modafinil was greater, there were more events of psychosis/mania, suicidality, and aggression among the modafinil treated patients as compared to placebo. Coinciding with Dr. Mosholder’s review was another DDRE review [23] performed by Dr. Kate Gelperin and Ms. Kate Phelan, RPh that analyzed the same psychiatric events from postmarketing sponsor submitted and AERS data. These data were presented at the March 2006 Advisory Committee Meeting. The most important finding of this review is that signs and symptoms of psychosis or mania, particularly hallucinations, can occur in some pediatric patients with no identifiable risk factors, at usual doses of any of the drugs currently used to treat ADHD, including modafinil. I am not sure how to get Division of Drug Risk Evaluation (DDRE) reviews, so there are no numbers on these symptoms. Pages 12-14 of the FDA summary discuss juvenile reports in the first year of surveillance; the 4 relevant events were temporary increases in aggression, permanent worsening of ADHD & oppositional defiant behavior, suicidal thoughts in an obese depressed girl, and epilepsy with visual hallucinations. These presumably are what the DDRE reviews are talking about. If we make that assumption, and reason that any fast-acting schizophrenics would be caught in the adverse effects database, we could suggest that any schizophrenia risk increases would be in one per hundred-thousand patient-years order of magnitude. As schizophrenia has prevalence rates in the fraction of a percentage rate (Wikipedia suggests 0.3-0.7%), a doubling may not be as noticeable as it is for SJS with prevalence more like 0.0001%, but would still lead to unusual numbers of schizophrenics linked with modafinil use. ### Schizophrenics on modafinil Another approach would be to ask, does modafinil exacerbate schizophrenia symptoms or cause additional symptoms? Presumably if modafinil could cause schizophrenia, it could also worsen cases of full-fledged schizophrenia. This is not a perfect strategy as it is quite plausible that a drug might worsen symptoms of a disorder without causing it, but it may shed some light. Fortunately, sleepiness is a side-effect of many psychotropic drugs employed for schizophrenia, and modafinil’s general cognitive improvements have attracted attention, so we have a fair number of studies and case reports where modafinil was administered to schizophrenics which we can look at: 1. Scoriels et al 2013 is a systematic review of modafinil treatment of schizophrenics; as far as our concern goes (causing or worsening schizophrenia): …However, some studies have failed to find the expected cognitive enhancing properties in schizophrenia (Hunter et al., 2006; Pierre et al., 2007; Sevy et al., 2005; Spence et al., 2005), although no case of worsening of symptoms or cognitive functions have been observed in any of these studies. [from the systematic review] …Outcome measures included psychiatric symptoms, cognition, emotion, global functioning, motor functioning, fatigue, and drug effect. Side effects were also accounted for. Psychotic symptoms were assessed for overall symptoms, positive and negative symptoms and depression symptoms…Assessment of psychiatric symptoms was performed in chronic modafinil administration studies. The studies carried out by Pierre et al. (2007) and Arbabi et al. (2012) showed improvement in three clinical global impression symptoms scales. However, the remaining 12 measures on psychiatric symptoms did not show any difference with drug administration; neither did the three measures of global functioning, nor the five measures of fatigue. Farrow and colleagues showed that acute administration of modafinil enhanced unconstrained motor activity (Farrow et al., 2006). This has not been replicated in studies with acute or chronic dosage designs. However, these studies were based on questionnaires that reported subjective perception of motoric activity, unlike Farrow’s study that measured the effect of modafinil in actual motor activity in patients. 2. Kumar 2008 examined 4 randomized trials of <80 schizophrenics. Modafinil helped symptoms only a smidgen (such as working memory performance). 2 active schizophrenics, in their first week, developed psychosis and discontinued use, out of 62 subjects given modafinil. This is worrisome but I don’t know how statistically reliable this is or what the base rate is. 3. Turner et al 2004, Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia; mentions background: Stimulant treatment has been used previously in the treatment of schizophrenia, most commonly in an attempt to treat patients with prominent negative symptoms (Angrist et al, 1982). However, most of these studies have reported a re-emergence or worsening of positive symptoms as a result of the dopaminergic activity of these drugs (Sharma et al, 1991; Szeszko et al, 1999). Nevertheless, circumstantial evidence has accumulated to suggest that stimulant treatment might be of benefit to cognitive and negative symptoms in patients with schizophrenia (Davidson and Keefe, 1995). Chiarello and Cole (1987) reported some improvement in approximately half of patients with schizophrenia who received psychostimulants, while Goldberg et al (1991) showed that amphetamine yielded a significant improvement in performance on the WCST in a group of patients sustained on haloperidol. Following methylphenidate, Carpenter et al (1992) showed possible improvements in self-reported symptoms and ward staff opinion in three out of eight patients with schizophrenia and a childhood history of hyperactivity (although no changes were noted using various other rating scales). However, in two other studies, methylphenidate significantly increased thought disorder in patients with schizophrenia (Levy et al, 1993) and increased redundant responding on an oral word production test (Szeszko et al, 1999)….Two case studies examining the use of modafinil in schizophrenia showed improvement in the negative symptoms of both patients and a decrease the sedating side effects of their antipsychotic medications(Yu et al, 2002). One patient showed an increase in activity and a reversal of weight gain with modafinil. Modafinil has also been shown to improve antipsychotic-associated sedation in three patients with schizophrenia (Makela et al, 2003). As modafinil has possible or weak effects on the dopaminergic system, it may help but may also hurt schizophrenia symptoms. 4. Sevy et al 2005, Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic medications 5. Spence et al 2005, Modafinil modulates anterior cingulate function in chronic schizophrenia 6. Pierre et al 2007, A randomized double-blind, placebo-controlled trial of modafinil for negative symptoms in schizophrenia 7. Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial, Freudenreich et al 2008, treated 35 schizophrenics; no additional psychosis. 8. Rosenthal & Bryant 2004’s non-blinded 11 patients included 2 with additional hallucinations. 9. Kane et al 2009 had a placebo patient drop out for psychosis. 10. Peloian & Pierre 2008 Modafinil: A Candidate for Pharmacotherapy of Negative Symptoms in Schizophrenia had 1 active psychosis but 2 placebo; they remark: Anecdotal case reports that emerged prior to and after the start of our trial have raised the potential for modafinil to cause psychotic exacerbation (Mariani & Hart, 2005; Narendran et al., 2002) or manic induction (Wolf et al., 2006; Ranjan & Chandra, 2005; Vorspan et al., 2005). On the other hand, no liability has emerged from larger samples or controlled studies (Frye et al., 2007; Nasr et al., 2006; Fava et al., 2005; Rosenthal & Bryant, 2004; Turner et al., 2004). Nevertheless, in order to minimize risk, we chose to limit the maximum dose of modafinil to 200 mg/day, since manic or psychotic worsening has typically been reported at doses greater than 300 mg/day. 11. A Review of the Effects of Modafinil on Cognition in Schizophrenia (Morein-Zamir et al 2007) is bullish on the potential benefits of treatment: Recent research has focused on enhancing cognition in patients with schizophrenia because of the association between cognitive performance and functional outcome. Initial findings indicate that modafinil may lead to better executive functioning and attentional performance in patients with schizophrenia. The results further suggest that patient characteristics such as overall current cognitive functioning levels, genetic polymorphisms, and medication status may be important mediators for the effectiveness of modafinil, allowing for future treatment to be targeted to those most likely to benefit…Numerous studies have reported that modafinil was well tolerated in their samples of patients with schizophrenia.93,94,99 Often only mild side effects are reported including headaches, insomnia and dry mouth.98 Nevertheless, while most patients appear to tolerate the drug well, several cases have been reported where patients who received modafinil suffered from psychotic relapse or worsening of already existing psychotic symptoms.87,98 These reports have primarily included patients receiving chronic administration although there is 1 report of a single patient undergoing psychotic relapse 4 days after a single dose.91 The concern for safety may also limit the use of effective dosage levels (eg, 100-vs 200 mg). More definitive evidence regarding the safety and tolerability of modafinil will eventually be provided by the use of meta-analysis as well as by large-scale studies, such as the ongoing NIMH sponsored clinical trials. Spence et al 2005 contains possibly the first suggestion of modafinil + schizophrenia = psychosis; smaller case reports I have found include: • Is Psychosis Exacerbated by Modafinil?, Narendran et al 2002, a case report of one subject • Makela 2003, Three case reports of modafinil use in treating sedation induced by antipsychotic medications, which reported no side effects in 3 schizophrenia (and other disorders) patients • Aggarwal et al 2009 Psychotic Relapse in a Patient with Schizophrenia Associated with Modafinil Therapy reported an instance (mentioning the patient had unspecified reduction in sleep after a week of use). • Ozer S. Demir B. Hypomania in a Schizophrenic Patient Treated with Modafinil for Clozapine-Induced Sedation. Archives of Neuropsychiatry 2010;47(2):171-3 (Turkish). • Fountoulakis KN, Siamouli M, Panagiotidis P, Magiria S, Kantartzis S, Iacovides A, et al. Ultra short manic-like episodes after antidepressant augmentation with modafinil. Pro- g Neuropsychopharmacol Biol Psychiatry 2008;32(3):891-2. • Wolf J, Fiedler U, Anghelescu I, Schwertfeger N. Manic switch in a patient with treatment resistant bipolar depression treated with modafinil. J Clin Psychiatry 2006;67(11):1817. • Ginsberg DL. Modafinil Associated Mania. Primary Psychiatry 2007;14(1):23-5. • Modafinil in the treatment of excessive daytime sleepiness in children, Ivanenko et al 2003 was a chart review of 13 children (none diagnosed with schizophrenia); 2 possible examples: One child with a preexisting seizure disorder had seizure relapse that temporally coincided with initiation of modafinil administration. When sodium valproate was added, seizures resolved despite ongoing modafinil therapy. Another child with a history of visual and auditory hallucinations exhibited significant worsening in her psychotic symptoms with the initiation of modafinil administration, requiring temporary discontinuation of the drug, adjustment of psychotropic medications, and reinstatement of modafinil therapy without any recurrence of psychotic manifestations. A few case studies concern patients without prior psychiatric problems: • Wu P, Jones S, Ryan CJ, Michail D, Robinson TD. Modafinil induced psychosis. Intern Med J 2008;38(8):677-8. • Vorspan F, Warot D, Consoli A, Cohen D, Mazet P. Mania in a Boy Treated With Modafinil for Narcolepsy. Am J Psychiatry 2005;162(4):813-4 • Mariani J, Hart C. Psychosis associated with modafinil and shift work. Am J Psychiatry 2005;162(10):1983. • Late Onset Mania Possibly Related to Modafinil Use: A Case Report, Kanal et al 2012 The review Saavedra-Velez 2009 Modafinil as an adjunctive treatment of sedation, negative symptoms, and cognition in schizophrenia: a critical review found, surveying the above studies among others: The main adverse effect was found to be a small risk of psychosis exacerbation, which was seen in 5 of 83 patients (6.0%) in the active treatment groups as compared to 2 of 70 patients (2.9%) in the placebo groups. Given the previous studies, this seems to me to indicate a real risk in schizophrenic patients. But then again, schizophrenics are by definition abnormal brains, so we cannot say this overturns the previous section based on more general populations. One possible confound is the existing drugs used in patients (Deutch & Bubser 2007): The data with modafinil are impressive in that reported side effects have been quite benign. However, adverse effects are associated with all therapeutic drugs, and because modafinil is used as an adjunct to treatment with APDs, the risk for emergence of adverse interactions is significant while benefit remains unclear (see Glick et al81). The use of modafinil in normal control subjects is consistent with a significant increase in attention and other cognitive functions, but these effects are not dose dependent. While animal data strongly suggest that the orexin cells, histamine neurons, and 2 key afferent structures are strongly activated at low doses, higher doses cause widespread activation, and it is reasonable to assume that the risk of side effects increases in parallel. Interestingly, however, Rasmussen et al in this issue note that orexin antagonists block catalepsy, an animal model of extrapyramidal side effects. An additional confound is that the modafinil itself may not be causing these events, but the behavior allowed by modafinil. One letter to an editor suggested that instances of mania or other events could be due to patients omitting sleep (echoed in Harvey 2009, Pharmacological Cognitive Enhancement in Schizophrenia), and possibly observed in non-schizophrenia, with bipolar (Colombo C, Benedetti F, Barbini B, Campori E, Smeraldi E. Rate of switch from depression into mania after therapeutic sleep deprivation in bipolar depression. Psychiatry Res 1999;30(3):267-70). This makes sense given that sleep deprivation is already known to cause hallucinations and euphoria among other things, and is ironically borne out by the one mental event mentioned in the FDA prescribing information, based on the premarketing trials: There have been reports of psychotic episodes associated with PROVIGIL use. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of PROVIGIL and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation. Caution should be exercised when PROVIGIL is given to patients with a history of psychosis. (1.2g+ of modafinil daily can cause sleep deprivation and other bad things? That’s good to know…) There is a published Cochrane protocol towards a full review, Modafinil for schizophrenia, Scoriels et al 2010, which will examine the efficacy of modafinil treatment and of course the side effects; the meta-analysis has not yet been finished. I emailed the lead author. She wrote, to summarize, that the 4 clinical symptoms studies showed 1 improvement and 3 nulls; 7 studies focused on cognition, with 3 improvements and 1 no results with worsening on an attention task (the only negative effect in the 7 studies). All avoided doses >400mg. She also mentioned a study she had conducted, Scoriels et al 2011, which found cognitive benefits, and 3 mild adverse events (itchiness, and 2 one-night insomnias). The final published 2013 review Modafinil effects on cognition and emotion in schizophrenia and its neurochemical modulation in the brain does not seem to meaningfully differ. So, we are left with minimal observed consequences from modafinil use in a general population, and a potential small risk of psychosis in diagnosed schizophrenic populations (with at least 2 confounds which either do not apply to general populations or only matter when one engages in really irresponsible use of modafinil). 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. There’s some question whether the dismissal of adrafinil may be overblown. In his 2014 SSC nootropics survey, Scott Alexander comments: There is some theoretical concern about liver-related side effects from adrafinil, but some pharmacologists say these are overblown and that its liver profile is similar to Tylenol - ie don’t take a massive overdose on it or use it every day for years and you’ll be fine. None of my respondents reported ever having any liver problems with adrafinil - not even asymptomatic elevation of liver enzymes - but n = only 17 so the results don’t rule out even moderately common adverse reactions. 4. 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. 5. One American prescription user said ~2011 that his prescription was for 200mg pills; each box cost around$50 copay for 30 pills, or about $1.70 (120 mg/USD). He took one a day. In 2013, another American gave the same price, but a third listed a$5 copay; a person claiming to work in a pharmacy said the wholesale price for modafinil 200mg is 15 bucks per pill.

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

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

7. 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.

8. Minzenberg again.

9. 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 sleep rebound/recovery sleep’. (If a drug lets you skip a night of sleep and then you sleep 16 hours the next day, would it be honest or dishonest to claim it cuts your sleep need by 100%?) How much of a penalty is unclear. From Bonnet et al 2005:

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.

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

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

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

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

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

10. 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.

Similar results were reached by the review Bagot & Kaminer 2013. Gill et al 2006:

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

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

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

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

12. 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.

13. The Ethical Consequences of Modafinil Use (Cahill 2005) summarizes the general vein of thinking:

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

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

14. 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.

15. 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

16. Some relevant citations (omitting a mouse 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 (Mueller et al) tested healthy non-sleep-deprived volunteers on 200mg doses:

Two computerized working memory tasks were administered, a numeric manipulation task that requires short-term maintenance of digit-sequences and different degrees of manipulation as well as delayed matching task that assesses maintenance of visuo-spatial information over varying delay lengths. The battery was supplemented by standardized paper pencil tasks of attentional functions….Modafinil significantly reduced error rates in the long delay condition of the visuo-spatial task and in the manipulation conditions, but not in the maintenance condition of the numeric task. Analyses of reaction times showed no speed-accuracy trade-off. Attentional control tasks (letter cancellation, trail-making, catch trials) were not affected by modafinil.

• Effects of modafinil on cognitive performance and alertness during sleep deprivation (Wesensten 2006) 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.

• Acute Effects of Modafinil on Brain Resting State Networks in Young Healthy Subjects, Esposito et al 2013
• Some unfortunate results for the bright young nerds interested in modafinil:

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

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

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

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

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

(One odd result is Killgore et al 2006, The Effects of Caffeine, Dextroamphetamine, and Modafinil on Humor Appreciation During Sleep Deprivation: Humor appreciation for cartoon stimuli was enhanced by modafinil relative to both placebo and caffeine, but there was no effect of any stimulant medication on the appreciation of verbal humor during sleep loss.)
• Mueller et al 2012

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

• 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 [cf. healthy controls in Schmaal et al 2013) 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). Mueller et al. (2004) found that the positive effects of modafinil (200 mg) in students (IQ not specified) were limited to two relatively difficult and monotonous computerised working memory tests. Improved performance in the RVIP test of sustained attention had been previously found by Randall et al. (2005) 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)

The 2012 meta-analysis Cognition Enhancement by Modafinil: A Meta-Analysis wound up drawing on only 3 studies, and is not very informative. The 2015 review, Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: a systematic review, likewise found only a few studies.

17. See Repantis et al 2010.

18. 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.

19. 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 non-significant improvements in the NA and depression subscales and concluded that there were no adverse effects of modafinil on mood.4 However, another study using the Profile of Mood States in patients with myotonic dystrophy concluded that modafinil significantly increased the tension-anxiety factor while improving other aspects of mood.3 Clouding the picture further, Randall et al 2003 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.

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

21. Advisory Panel Endorses More Uses for Stimulant, by Andrew Pollack with Alicia Ault, New York Times 2003:

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

22. Erowid covers both in its interaction page:

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

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

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

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. 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.

26. 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.

27. 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.

28. Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil, Bastuji & Jouvet 1988.

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

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.)

Mueller et al 2012 tested healthy naive adults:

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

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

31. 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.

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

32. 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.

33. 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.

34. 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 (De Séréville et al., 1994), alter the electrophysiology of dopaminergic (nigrostriatal) or noradrenergic (locus coeruleus) neurons; and is not anxiogenic (Simon et al., 1994). Dopamine antagonists attenuate only the wakefulness and hyperlocomotion promoted by amphetamine, not modafinil (Duteil et al., 1990; Lin et al., 1992).

35. Sniffing out the internet drug barons, Guardian:

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

36. 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.

37. 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.

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

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

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

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

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

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

44. The owner announced 10 November 2013 that he was temporarily backlogged and took down price information.

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

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

47. Not accepting new orders as of 15 November 2013.

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

49. 10x10 at £3.59

50. 4NRX may no longer be offering Waklert. Calculated at 10x10 with free S&H.

51. I once ordered armodafinil off Silk Road.

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

53. I dropped them when I checked into my accounts and discovered I had been credited with $0 after that time-span. Why bother? 54. 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
55. For example, if multiple sites/businesses were set up, each with different prices, then the true owners may be able to engage in price discrimination and capture more of the consumer surplus. It’s impossible to know for sure how many online pharmacies are just independent-looking fronts for one real business; it has been asserted that this is the case, eg. dontj:

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

56. 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)

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

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

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

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

60. Miyamoto Musashi, Book of Water, _Book of Five Rings

61. John Dryden, Act IV of Aureng-zebe (1675)

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

65. Commenter Spike questions the terminology here:

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

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

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