SNPs

Interestingly, there seem to be some groups for which modafinil does little, and this ineffectiveness may not be due to counterfeit product or poor self-monitoring, but genetics (Bodenmann et al 2009, see also Bodenmann & Landolt2010 on the same subjects):

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

The genotype variation specifically refers to the Rs4680 SNP, which is one of the SNPs that services like 23andMe test for. So someone could sign up for 23andMe testing and only start buying modafinil if the results are favorable; considering that 23andMe sometimes holds sales at $100 or $200 and that one could easily spend this much on a single order of modafinil, testing first may not be a bad idea. But on the other hand: anecdotes are hard to come by of people who have used modafinil, been genotyped, and checked that SNP, yet I have been told by 2 Val/Val users that sublingual Modalert/Waklert did nothing for them (personal communication; 2) and by 4 Met/Met users that modafinil worked for them and there are 2 further anecdotes on Hacker News & Reddit (1, 2, multiple). Besides the dubiousness of such a large effect size from a single SNP, candidate-gene results frequently disappear (Ioannidis et al 2011), like what happened when 12 highly cited IQ-related SNPs failed to replicate in a well-powered 2011_15ya GWAS and subsequent GWASes (replication being the coin of science). As of 2013-05-23, there do not seem to have been any followup citing studies of this SNP association. Given the weakness of the evidence, one would probably have to be on the razor’s edge of deciding to try or not try modafinil before your result would make the difference.

Side Effects

Modafinil has a few side-effects. (I omit adrafinil’s possible liver damage since it doesn’t apply to modafinil.) The FDA in general seems to take a pretty optimistic view about any side-effects or long-term issues²¹. The known issues generally are:

• Hormonal birth control may be less effective, as well as methadone²²

• General symptoms of over-stimulation: confusion, nervousness, tremors, irritability, etc.²³

• Weight loss²⁴

• Bad-smelling urine is very commonly reported²⁵. Apparently is related to sulfur breakdown products²⁶.

From the abstract of a journal review of modafinil (“Modafinil: A Review of Neurochemical Actions and Effects on Cognition”, Minzenberg et al 2008):

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

But a low rate of adverse events is still a rate. (And—this is a truism that applies to every single drug or substance which I should not have to point out—everyone is unique in that some substance will be horrible for them while great for others and vice versa; this is as true for modafinil—eg. one person I know experienced ‘serious muscle pain’ which he described as proportional to the dose—as it is for much more dangerous drugs like aspirin²⁷. Lists of side-effects are available in the FDA prescribing info (linked below) and online, but are unhelpfully generic; to take the first half of the list of regular side-effects: “headache” (obvious for any stimulant), “dizziness” (generic), “difficulty falling asleep or staying asleep” (of course!), “drowsiness” (maybe you’re using modafinil too much?), “nausea” (does anything not cause nausea?), “diarrhea”, “constipation”, “gas”, “heartburn”, “loss of appetite” (some people want that), and “unusual tastes” (is that really a bad thing?). The “serious” side-effects are more interesting; again taking the first half: “rash”, “blisters”, “peeling skin”, “mouth sores”, “hives”, “itching”, “hoarseness”, and “difficulty breathing or swallowing”—these all sound like they may be related to the histamine effects of modafinil. But overall, I am left unimpressed by them: if you develop a rash, stop taking modafinil! If you have peeling skin, stop taking modafinil! If you’re taking it for its utility, you can stop at any time—the side-effects you are most worried about are the ones which may develop into a real danger or which are permanent. So let’s move on to a closer look at the more serious risks.

Interested readers can compare the FDA adverse events reports for modafinil/armodafinil and for aspirin, but should remember these are raw reports, unscaled by number of prescriptions, and adverse event reports are probably less likely to be reported by illicit users.) What are those adverse events?

The most serious reported side-effect I know of is Stevens-Johnson syndrome (SJS). Modafinil, like acetaminophen, is one of the unfortunate category of drugs believed to cause SJS. SJS is generally rare (“about 300 new diagnoses per year” in the USA). It’s not clear how much modafinil increases SJS risk the FDA report specifies that there was only 1 ‘possible’ syndrome during the clinical trials of around 1,585 people (a child who had a fever & rash; Cephalon argued strenuously that it was not SJS). Presumably if modafinil really did cause SJS at a rate of 1 in 1,500, then the millions of users since would have caused >667 cases of SJS. Page 2 of Cephalon’s physician guide goes into all the details:

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

The specific increased incidence rate in another FDA publication is specified to be 5.7 per 1 million patients as compared to the background rate of 1-2 per million patients.

In the previous adult trial, with ~3x as many patients, no rashes were reported and no SJS. With a background incidence rate of 1 to 2 cases per million-person-years, to be distinguishable, the rate would only have to rise a little. I’d especially want to know whether those ‘adults and children’ is really just ‘children’. As it stands, it looks like the problem is primarily in juveniles, and they are not the ones considering whether to experiment with modafinil. For adults, adverse side-effects are generally in the 0-4% range of the population (see table 3, page 4 of the guide). Another FDA page gives us details:

From the date of initial marketing, December 1998_28ya, to January 30, 2007_19ya, FDA received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) involving adult and pediatric patients. The 6 cases from the United States occurred in four females and two males aged 49, 42, 27, 17, 15, and 7 years old, respectively. The median time-to-onset of adverse dermatologic effects following initiation of modafinil therapy was 17.5 days, ranging from 5 days to 5 weeks…There were no deaths. 5 of 6 patients required hospital admission for management, including one patient with TEN who was admitted to the surgical burn unit 20 days after starting modafinil at recommended doses to treat a sleep disorder.

Consistent with the listed onset and claims that females have increased risk, the one report of modafinil-induced SJS on Reddit was a female who developed it after 10 days. 3 pediatrics seems like a substantial fraction of the cases; calculating what rate in millions these 6 cases represent is harder. I haven’t yet found direct estimates of how many people took modafinil 1998^–₉2007_19ya; an article on Cephalon’s anti-competitive practices says “United States sales of Provigil increased from $25 million in 1999 to $475 million in 2005 to $800 million in 2007.” 2002 sales were $196.3 million (Pollack & Ault2003) and 2003 sales $300 million (Vastag2004). We could try to guesstimate the overall sales between 1999^–₈2007_19ya as $\frac{25+475+800}{3}\cdot (2007-1999)=\$3,466.7\text{m}$; Normann & Berger2008 put 2007 global sales at >$700m. The FDA cases are for the USA only as far as I know, so we want only US consumption (although helping external validity, ~90% of prescriptions are for off-label use according to Cephalon in 2004). If each US pill is $10 in sales (probably low), then 346.67m pills were sold; if each person uses one pill a day for 2 years on average, then we divide the pill count by 2 years of days, $\frac{346,670,000}{2\cdot 365.25}=\frac{346670000}{730.5}=474,565$ people. Half a million is in roughly the right range, which is fine for a guesstimate—we could easily double our result or more by changing some of our assumptions (how many people used modafinil before 1999_27ya? How many sales were there after 2007_19ya? Does the average person prescribed it really use it for as much as 2 years, or do people tend to switch or get better much faster than that? etc.). A better estimate can be extracted from the MIDAS database of drug sales which tells us that Provigil sold from Q1 2011-Q1 2012 $1,411,547,000 in 2,376,000 “units”; I believe units are monthly prescriptions of 30 pills, since that gives me a per-pill estimate of $19.8/pill which is consistent with people’s reports of monthly prescriptions costs (eg. $440 for 30 is $15 a pill, or $1,000 for 30 is $33 a pill, which bracket that average). So that implies 71,280,000 pills sold (which at a daily dose affects 195,154 man-years); there were 6 cases previously which we estimated at 346.67m pills but from $10 a pill which we now know to be too low by half, so we cut the 346 to 173, and 6 cases per 173m implies 1 case per 29m, and if 2011-early-2012 were sold 71.28m pills, we’d expect 2.5 new cases in that period. (This ~2 annual rate seems reasonably consistent with the rarity of online anecdotes of actual SJS, as opposed to people being worried that their common—~1%—side-effects of rashes etc. may progress to SJS.) For armodafinil, the first reported case-study of SJS came in 2018, with Holfinger et al 2018 reporting a 21yo female who developed symptoms 12 days after starting (fortunately, she apparently made a full recovery and “only subtle skin discolorations over previously blistered skin areas remained”).

Few long-term studies have been done of modafinil’s safety outside of the drug approval trials. The LD50 is so high that it is currently not known for humans²⁸; one troubled woman attempted suicide with an overdose of 4.5 grams of modafinil but failed²⁹, and another man apparently tried & failed with a blister pack (>2.4g?); no deaths are known to be attributable to modafinil (which curiously makes it safer, acute dose-wise, than caffeine). Of course, one cannot rule out that there might be drastic consequences which manifest only decades later, but given that modafinil could be called a pseudo-life-extension drug due to its famous wakefulness effects, there’re arguments that modafinil is a net gain even with any (a priori unlikely) long-term backfiring.

So overall, assuming one does not use modafinil too frequently, or to skip more than 1 night at a time³⁰, and remembers to remain hydrated & eat extra food to compensate for the additional activity & appetite suppression, modafinil does not seem to have any major risks for healthy users as far as I can tell, and certainly no such scaremongering like the following quote is justified:

“You’re taking a high risk”, Baroness Susan Greenfield, neuroscientist and Director of the Royal Institution of Great Britain, told me. “Our brains are who we are. They are hugely delicate. You’re risking your whole life.”

Tolerance

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

Anecdotally, the real troll under the bridge for modafinil seems to be that one can develop tolerance, where it no longer has the stimulant or anti-sleep effects that made it so awesome (it has been speculated to be related to liver metabolism). For example, poker player Paul Phillips took 2–300mg daily for a long period and said the effects “have attenuated over time. The body is an amazing adjusting machine, and there’s no upside that I’ve been able to see to just taking more.” (Such comments are common online among those who have used modafinil heavily, to the point where I have successfully predicted tolerance for such users, and I carefully avoid using modafinil more than weekly, if that.) The lack of academic support for these observations of tolerance is a little strange—users hardly have any incentive to make up downsides about their favorite drug.

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

But what does the research literature say? It seems to report no euphoria³¹, tolerance, withdrawal, or dependency:

• Biederman et al 2005; cited in FDA prescribing information on non-withdrawal.

• Some claims of no observed tolerance in patients: “Modafinil, used for at least 3 years in some patients, produces, in most cases, no peripheric sides effects, does not disturb night sleep and is never responsible of tolerance of drug dependence.” Bastuji & Jouvet1988, “Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil”; “Modafinil: the unique properties of a new stimulant”, Lyons & French1991; Nasr et al 2006; Teitelman2006, Rammohan et al 2001

• “Off-label uses of modafinil”, Teitelman E. Am J Psychiatry 2001_25ya.

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

• “Efficacy and safety profiles of Provigil (modafinil) maintained during long term (40 and 88 weeks) treatment of excessive daytime sleepiness associated with narcolepsy”, Emsellem HA. Neurology 2000_26ya, 54 (Suppl 3): A29

• “Modafinil is well tolerated, with no evidence of tolerance developing during 40 weeks of treatment.” from “Long-term efficacy and safety of modafinil (PROVIGIL®) for the treatment of excessive daytime sleepiness associated with narcolepsy”, Mitler2000.

• Deroche-Gamonet et al 2002 experimented on rats with modafinil and cocaine: “Modafinil did not produce reinforcing or rewarding effects and did not modify the effects of cocaine…However, as shown previously in nonhuman primates and in humans, modafinil could possibly have reinforcing effects in cocaine-experienced individuals.” Shuman et al 2012 found modafinil-caused sensitization in cocaine-using mice, but only at high doses (75 mg⧸kg in their mice vs <5 mg⧸kg in normal humans). A later mouse study found no sensitization to amphetamines or that modafinil increased preferences for modafinil-associated locations, and a later rat study found no reinforcement in modafinil use. One such study, using rhesus monkeys, was “Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil” where: “The reinforcing and discriminative stimulus effects of modafinil-required very high doses: modafinil was over 200 times less potent than d-amphetamine and was also less potent than l-ephedrine.” Mereu et al 2020 found modafinil did not cause modafinil self-administration in rats, only cocaine, and ultimately concluded that the reinforcing didn’t involve dopamine at all (contra Volkow et al 2009), and Haney et al 2021 find modafinil reduces human cocaine self-administration.

• Jasinski2000 ³²

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

• The abstract to the Danish “Modafinil in the treatment of depression—a systematic review” mentions that “discontinuation of the drug should be tried after a couple of months, as one study suggests that the effect wears off.”

• only a few case-studies of addiction have been reported, but despite often hair-raising doses, the effects appear mild: eg. Kate et al 2012, Mete et al 2015, Krishnan & Chary2015, Alacam et al 2018.

There has been speculation³³ and reports of subjects acting as if there were tolerance³⁴. One tiny (n = 10) study, that garnered inordinate amounts of media attention, was “Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications” (Volkow et al 2009) which, somewhat against earlier non-human research³⁵, found some dopamine upregulation; while a feature commonly found in addictive drugs, that’s a long way from actual addiction, especially given the real-world data on the lack of addiction (“…no published case reports of addiction”, Shuman et al 2012) and modafinil binding differently than the other addictive drugs.

Legal Risk

Benefits

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

So, our very first calculation goes $\text{minimum wage}\cdot \text{hours saved}$, or $6.55\cdot 4$, 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 $\frac{1}{50\cdot 365.25}$ probability. Applying the usual expected gain/loss formula, each day we incur an expected loss of $10,000,000\cdot \frac{1}{50\cdot 365.25}$, 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 1⁄21 chance of killing you, it could be worth while. Do you think modafinil has a less than 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.)

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

2. Modalert

3. Alertec

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.

• Nubrain^{37 38} 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 an 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_17ya; last updated 2013-11-15; previous versions: October 2010, March 2011, December 2011, May 2012, March 2013):

Examples

Counterfeits seem to be responsible for many negative experiences with modafinil; in the absence of effective assaying or contacting the manufacturer⁵³, this section is an experiment with providing data on what believed genuine product looks like, inasmuch as the counterfeits sometimes not do a good job of replicating the packaging & appearance of genuine products.

Margin Estimation

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

One-Shot Ordering

For an 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 ($222\cdot 0.6$). And then I might decide United Pharmacies smells a bit better and give them a 70% chance, for a total of 145.6 ($208\cdot 0.7$); and perhaps Airsealed gets a whopping 95% trust from me, for a total of 71.25 ($75\cdot 0.95$). 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”.)

$$P\left(a|b\right)=\frac{P\left(b|a\right)\cdot P\left(a\right)}{P\left(b\right)}$$

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):

$$P\left(a|b\right)=\frac{P\left(b|a\right)\cdot P\left(a\right)}{\left(P\right(b|a)\cdot P(a\left)\right)+\left(P\right(b|\neg a)\cdot P(\neg a\left)\right)}$$

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: $P\left(foo|bar\right)$ means ‘how likely is foo now that I have observed bar’ (you could mentally rewrite it to something like $P(bar\to foo)$). 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. $P\left(a\right)$

   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. $P\left(\neg a\right)$

   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. $P\left(b|a\right)$

   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. $P\left(b|\neg a\right)$

   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. $P\left(a\right)$ = probability of being a good supplier = 90% = 0.90

4. $P\left(\neg a\right)$ = probability of being a bad supplier = 10% = 0.10

5. $P\left(b|a\right)$ = probability a good supplier will send fakes = 5% = 0.05

6. $P\left(b|\neg a\right)$ = probability a bad supplier will send fakes = 95% = 0.95

We substitute in to the original equation:

$$P\left(a|b\right)=\frac{P\left(b|a\right)\cdot P\left(a\right)}{\left(P\right(b|a)\cdot P(a\left)\right)+\left(P\right(b|\neg a)\cdot P(\neg a\left)\right)}=\frac{0.05\cdot 0.9}{\left(\right(0.05\cdot 0.9)+(0.95\cdot 0.1\left)\right)}=\frac{0.045}{\left(\right(0.05\cdot 0.9)+(0.95\cdot 0.1\left)\right)}=\frac{0.045}{(0.045+(0.95\cdot 0.1\left)\right)}=\frac{0.045}{(0.045+0.095)}=\frac{0.045}{0.14}=0.32$$

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 an 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 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 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 $1,000 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: $1,000 is a lot of money. Quite a lot, really. You could buy a lot of modafinil with $1,000; even if we played it safe and bought from Nubrain, $1,000 would get us $62\cdot 1000$, 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 $1,000 just to be sure? Even if we plan to buy for years, decades, or the rest of our life, that $1,000 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 $1,000 right now? If we’re saying $1,000 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:

$$\text{NPV}=\frac{\text{annualPayoff}}{\ln (\text{discountRate}+1)}=\frac{20}{\ln (1+0.07)}=\frac{20}{\ln \left(1.07\right)}=\frac{20}{0.06765}=295.6$$

But it would cost us $1,000 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, $1,000 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.

Discount Rate Applications: Swapping Time for Time

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

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

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

$$\text{presentValue}=\frac{\text{futureValue}}{(1+\text{discountRate}{)}^{\text{years}}}$$

We say a year right now is worth 100% and we are asking what fraction of a present year a far distant year would be worth; while real people have discount rates much higher⁶³, we will generously assume the improbably low discount rate of 2%⁶⁴; and then ask how much a year is worth 50 years from now:

$$\text{presentValue}=\frac{100}{(1+0.02{)}^{5}0}=\frac{100}{2.692}=37\%$$

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

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

Coordination Problems: Assaying

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

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

Now, it’s easy to avoid this problem and create a reliable rating system for modafinil sellers. All one has to do is order every few months, and send the product to a lab for assays. (This would be the Consumer Reports model for drugs.) But this requires a spare couple thousand dollars, and is a public good susceptible to the free rider problem. I certainly don’t have $2,000 to buy $100 of product (plus S&H) from 10 retailers and then pay for 10 lab assays. So really, the best I can do is catalogue what they advertise.

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

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

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

Unsurprisingly, there are only a few examples of modafinil testing:

• EcstasyData tested a Modvigil tablet and found no issues

• ModUP tested Modvigil at an unknown lab and found no issues

• Rechem.ca’s modafinil tested at a Dutch lab with apparent issues; a test of Sun modafinil at the same lab yielded similar results (but the interpretation is not 100% clear, given the lab’s focus on safety-testing, and may simply be detecting leftover traces of intermediate steps in the modafinil synthesis or something like that)

Schizophrenia