Modafinil

Effects, health concerns, suppliers, prices & rational ordering.
biology, psychology, nootropics, politics, statistics, predictions, law, Bayes
2009-02-202018-06-04 finished certainty: highly likely importance: 9


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.

is a wake­ful­ness stim­u­lant 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 , 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.

Modafinil costs about $25-12 a day6; non-pre­scrip­tion sources are too unpre­dictable to say.7

Usage

Modafinil can be reli­ably deter­mined in plasma and urine (Schw­ert­ner and Kong, 2005; Tseng et al, 2005), and is read­ily absorbed (40-65%, as mea­sured by uri­nary recov­ery) after sin­gle (Wong et al, 1999a) or mul­ti­ple oral doses (Wong et al, 1999b), reach­ing peak plasma con­cen­tra­tions 2-4 h after admin­is­tra­tion (Wong et al, 1999a). The pres­ence of food in the gas­troin­testi­nal tract can slow the rate but does not affect the total extent of absorp­tion. Steady-s­tate plasma con­cen­tra­tions are achieved between 2 and 4 days with repeated dos­ing. It is highly lipophilic, and approx­i­mately 60% bound to plasma pro­teins, pri­mar­ily albu­min. Major phar­ma­co­ki­netic para­me­ters are inde­pen­dent of doses in the range of 200-600 mg/day (Robert­son and Hell­riegel, 2003). The major cir­cu­lat­ing metabo­lites modafinil acid and modafinil sul­fone do not appear to exert any sig­nif­i­cant activ­ity in the brain or periph­ery (Robert­son and Hell­riegel, 2003). The elim­i­na­tion half-life is approx­i­mately 12-15 h (Wong et al, 1999a), and sin­gle daily dos­ing is ade­quate and com­mon in clin­i­cal prac­tice.8

Effects

Modafinil has a cou­ple dif­fer­ent but closely related ben­e­fits. You can sum them up as pretty much it cuts your sleep need by about 2⁄3s9:, or it allows you to go with­out sleep for a day with lit­tle men­tal penalty10 with increas­ing penal­ties there­after. (If you aren’t sleep­-de­prived, it seems to just increase your alert­ness and energy lev­els, with mixed effects on other things.) It is over­all a bet­ter stim­u­lant than caf­feine or the amphet­a­mines11, and tar­gets dif­fer­ent recep­tors than the amphet­a­mines.12 The pic­ture is good enough that some bioethi­cists are dar­ing enough to go off their usual script (“the long-term effects are unclear; there may be unex­pected side-­ef­fects or long-term con­se­quences13—more study is required”) and aban­don the and sug­gest that maybe healthy peo­ple using modafinil might be a good thing14.

Besides com­pen­sat­ing for sleep­-re­lated men­tal deficits in gen­eral15 espe­cially com­bined with short naps (Baté­jat & Lagarde 1999), it may make you smarter16—even if you’re healthy:

In addi­tion, modafinil (at well-­tol­er­ated dos­es) improves func­tion in sev­eral cog­ni­tive domains, includ­ing work­ing mem­ory and episodic mem­o­ry, and other processes depen­dent on and cog­ni­tive con­trol. These effects are observed in rodents, healthy adults, and across sev­eral psy­chi­atric dis­or­ders.17

And the grip­ping hand: the 100mg dose may be the prob­lem and be too high; the exact shape of the dose-re­sponse curve and between-­sub­ject vari­abil­ity remains unclear, with some anom­alies like “Modafinil affects mood, but not cog­ni­tive func­tion, in healthy young vol­un­teers” (Ran­dall et al 2003), noted no ben­e­fits on the test suite due to the lower dose tested hav­ing greater anx­io­genic effects:

There was a sig­nif­i­cant post-treat­ment change in the fac­tor mea­sur­ing ‘somatic anx­i­ety’ and in indi­vid­ual rat­ings of ‘shak­ing’, ‘pal­pi­ta­tions’, ‘dizzi­ness’, ‘rest­less­ness’, ‘mus­cu­lar ten­sion’, ‘phys­i­cal tired­ness’ and ‘irri­tabil­ity’, which was mainly due to sig­nif­i­cantly higher rat­ings of somatic anx­i­ety in the 100 mg group com­pared with the other two groups [placebo & 200mg]. Fur­ther changes in mood were revealed after the stress of cog­ni­tive test­ing, with the 100 mg group show­ing greater increases in the ‘psy­cho­log­i­cal anx­i­ety’ and the ‘aggres­sive mood’ fac­tors.18

The effect of modafinil on mood is cloudy19 (part of the prob­lem being, I sus­pect, vary­ing doses and pop­u­la­tion­s); “A Ran­dom­ized, Dou­ble-Blind, Crossover Trial of Modafinil on Mood” (Taneja et al 2007) used doses of 400mg, find­ing:

Nor­mal healthy vol­un­teers (n = 12, 10 men and 2 wom­en; 30-44 years) under­went a 3-day, coun­ter­bal­anced, ran­dom­ized, crossover, inpa­tient trial of modafinil (400 mg dai­ly) ver­sus placebo with 4-day washout period between 2 treat­ments. Mood was assessed daily using both the Pos­i­tive and Neg­a­tive Affect Sched­ule and a gen­eral mood scale, which con­sisted of 10 bipo­lar adjec­tive rat­ings based on a sever­ity scale rang­ing from 1 to 10. Modafinil increased gen­eral mood and Neg­a­tive Affect scales rel­a­tive to placebo and had a sig­nif­i­cant effect on Pos­i­tive Affect scales. These results sug­gest that modafinil may have gen­eral mood-el­e­vat­ing effects accom­pa­nied by increased neg­a­tive affect (anx­i­ety). The find­ings may have impli­ca­tions for clin­i­cal prac­tice, in par­tic­u­lar for the adjunc­tive use of modafinil in treat­men­t-re­sis­tant depres­sion20.

Goss et al 2013, meta-­an­a­lyz­ing the depres­sion tri­als, finds

Data from 6 RCTs, with a total of 910 patients with MDD [ma­jor depres­sive dis­or­der] or bipo­lar depres­sion, con­sist­ing of 4 MDD RCTs (n = 568) and 2 bipo­lar depres­sion RCTs (n = 342) were ana­lyzed. The meta-­analy­sis revealed sig­nif­i­cant effects of modafinil on improve­ments in over­all depres­sion scores (point esti­mate = −0.35; 95% CI, −0.61 to −0.10) and remis­sion rates (odds ratio = 1.61; 95% CI, 1.04 to 2.49). The treat­ment effects were evi­dent in both MDD and bipo­lar depres­sion, with no dif­fer­ence between dis­or­ders. Modafinil showed a sig­nif­i­cant pos­i­tive effect on fatigue symp­toms (95% CI, −0.42 to −0.05). The adverse events were no dif­fer­ent from place­bo.

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 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 , which is one of the SNPs that ser­vices like 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 (repli­ca­tion being the ). 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.

Costs

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 22
  • 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 27. 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 (SJS). Modafinil, like aceta­minophen, is one of the unfor­tu­nate cat­e­gory . 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 1500, 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 (e.g., vom­it­ing, leukope­ni­a). The median time to rash that resulted in dis­con­tin­u­a­tion was 13 days. No such cases were observed among 380 pedi­atric patients who received place­bo. No seri­ous skin rashes have been reported in adult clin­i­cal tri­als (0 per 4,264) of modafinil. Rare cases of seri­ous or life-threat­en­ing rash, includ­ing SJS, Toxic Epi­der­mal Necrol­y­sis (TEN), and Drug Rash with Eosinophilia and Sys­temic Symp­toms (DRESS) have been reported in adults and chil­dren in world­wide post-­mar­ket­ing expe­ri­ence. The report­ing rate of TEN and SJS asso­ci­ated with modafinil use, which is gen­er­ally accepted to be an under­es­ti­mate due to under­re­port­ing, exceeds the back­ground inci­dence rate. Esti­mates of the back­ground inci­dence rate for these seri­ous skin reac­tions in the gen­eral pop­u­la­tion range between 1 to 2 cases per mil­lion-per­son years.

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, to Jan­u­ary 30, 2007, 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 1998-2007; 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 & Ault 2003) and 2003 sales $300 mil­lion (Vastag 2004). We could try to the over­all sales between 1999-2007 as ; Nor­mann & Berger 2008 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, 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? How many sales were there after 2007? 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 $1000 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 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 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 (>2.4g?); no deaths are known to be attrib­ut­able to modafinil (which curi­ously makes it safer, acute dose-­wise, than ). 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 .)

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 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 , 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:

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 ; 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 than the other addic­tive drugs.

Analysis

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

Benefits

As in my , we’ll assume the value of our time is mea­sured by the . 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 , or , 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 prob­a­bil­i­ty. Apply­ing the usual expected gain/loss for­mu­la, each day we incur an expected loss of , 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 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
  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.
  • 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:

  • of any rel­e­vant fac­tors

    • eg. regres­sion to the mean of the owner: what hap­pens when the pas­sion­ate founder sells or leaves?
  • charg­ing a inverse 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 2013-11-15; 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
189 200 540 570 0 Modalert Sun­Modalert.ru
155 200 270 348 0 Modalert Sun­Modalert.ru
152 200 180 237 0 Modalert Sun­Modalert.ru
144 200 90 125 0 Modalert Sun­Modalert.ru
126 200 60 95 0 Modalert Sun­Modalert.ru
85 100 180 213 0 Modalert Sun­Modalert.ru
105 200 30 57 0 Modalert Sun­Modalert.ru
83 100 270 325 0 Modalert Sun­Modalert.ru
75 100 90 120 0 Modalert Sun­Modalert.ru
66 100 60 91 0 Modalert Sun­Modalert.ru
62 200 10 32 0 Modalert Sun­Modalert.ru
57 100 30 53 0 Modalert Sun­Modalert.ru
32 100 10 31 0 Modalert Sun­Modalert.ru
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 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 2013-11-14.)

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)

  5. the Chi­nese sup­plier Top ChemTek is still offer­ing modafinil (re­port­edly $918/kg).

  6. the Cana­dian sup­plier reChem Labs offers to Cana­dian cus­tomers only, for research pur­poses of course, 1g of armodafinil for $20, 3g for $45, 5g for $60, and 10g for $100. reChem labs “strictly for­bids con­sump­tion of any of the prod­ucts.”

  7. the major Chi­nese mar­ket­place offers a con­stantly chang­ing selec­tion of whole­salers who claim to sell modafinil; unfor­tu­nately it (the import-­ex­port sec­tion in par­tic­u­lar) is a lais­sez-­faire mar­ket where caveat emp­tor!, with many sto­ries of burned buy­ers. One importer says

    …I have worked with a lot of dif­fer­ent Chi­nese sup­pli­ers; not this one specif­i­cal­ly, though. Alibaba gold rat­ing means absolutely noth­ing, and Alibaba will not be help­ful in a dis­pute. I have been scammed by mul­ti­ple 5 year gold sup­pli­ers on there. Even when I showed Alibaba 3rd party test­ing prov­ing they sold me bak­ing soda as pitolisant or EDTA as colu­rac­etam, I was SOL. I was out the mon­ey, and Alibaba did noth­ing to demote the sup­plier rat­ing. So as far as any­one should be con­cerned, that rat­ing is use­less…We were also scammed by a sup­plier on Look Chem. Same sto­ry. We showed them proof it was fake, but they did noth­ing about it. The sup­plier is still listed as a ver­i­fied sup­pli­er. So I con­sider the whole “ver­i­fied” thing on all the sites to be BS. We have a few trusted sup­pli­ers that we stick to now. The oth­ers are just a gam­ble.

    It seems unsafe to con­sume any modafinil or armodafinil bought over Aliba­ba.­com with­out third-­party test­ing one arranges one­self (and def­i­nitely not through or pro­vided by the Aliba­ba.­com sell­er). For the dif­fi­cul­ties of test­ing modafinil, see the later sec­tion.

Reports of West­ern­ers suc­cess­fully tak­ing this route are rare (the only claims of suc­cess I have seem are in the Longecity thread linked pre­vi­ous­ly). Addi­tional infor­ma­tion is wel­comed.

Darknet Markets

There are other sources; the DNM & its suc­ces­sors usu­ally have generic modafinil & armodafinil52, at rea­son­able prices; but given the anonymiz­ing mea­sures, use of rather than dol­lars, and the inher­ent flux of an online mar­ket­place, I can­not pos­si­bly incor­po­rate it into the chart. How­ev­er, I am inter­ested in modafinil price trends over time and have been monthly com­pil­ing prod­uct pages from SR/BMR/Atlantis/Sheep/SR2 for future analy­sis:

  1. 2013-05-28
  2. 2013-07-03
  3. 2013-08-03
  4. 2013-09-04
  5. 2013-09-20 (a pre­ma­ture col­lec­tion trig­gered by the Atlantis shut­down)
  6. 2013-10-01
  7. 2013-11-03
  8. 2013-11-12 (check­ing in on the new SR2; turned out, no modafinil list­ings were up yet)
  9. 2013-11-28 (over con­cerns about Sheep; SR2 now has modafinil list­ings)
  10. 2014-01-01 (SR2, Blue Sky Mar­ket­place)
  11. 2014-04-04 (SR2, Ago­ra, Blue Sky Mar­ket­place, evo­lu­tion, Cloud-Nine)
  12. 2014-05-21 (Ago­ra, Androm­e­da, Black Bank, Blue Sky, Cloud-Nine, Evo­lu­tion, SR2)
  13. 2014-06-03 (Ago­ra, Alpaca, Androm­e­da, Black Bank, Blue Sky, Cloud-Nine, Evo­lu­tion, SR2—en­tries from 8 June, when their search engine worked again)
  14. 2014-07-05 (Ago­ra, Alpaca, Androm­e­da, Black Bank, Blue Sky, Cloud-Nine, Evo­lu­tion, Pan­do­ra, SR2 entries from 6 July)
  15. 2014-08-05 (Ago­ra, Cloud-Nine, Hydra, Evo­lu­tion, SR2)
  16. 2014-09-28 (Ago­ra, Androm­e­da, Black Bank, Blue Sky, Cloud-Nine, Evo­lu­tion, Hydra, Pan­do­ra, SR2)
  17. 2014-10-02 (Ago­ra, Androm­e­da, Cloud-Nine, Evo­lu­tion, Hydra, Pan­do­ra, SR2)
  18. Novem­ber 2014: can­celed due to Oper­a­tion Ony­mous
  19. 2014-12-05 (Ago­ra, Evo­lu­tion, Dia­bo­lus, Nucle­us, TOM)
  20. 2015-01-02 (Ago­ra, Black Bank, Dia­bo­lus, Evo­lu­tion, Mid­dle Earth, Nucle­us)
  21. 2015-02-05 (Black Bank, Dia­bo­lus, Dream, Evo­lu­tion, Nucle­us; Agora the next day)
  22. 2015-03-03 (Ago­ra, Black Bank, Dia­bo­lus, Dream, Evo­lu­tion, Nucle­us)
  23. 2015-04-03 (Abrax­as, Ago­ra, AlphaBay, Crypto Mar­ket Nucle­us, Mid­dle Earth)
  24. 2015-05-03 (Abrax­as, Ago­ra, AlphaBay, Black Bank, Crypto Mar­ket, Dia­bo­lus, Mid­dle Earth, Nucle­us, Out­law)
  25. 2015-06-04 (Abrax­as, Ago­ra, Alphabay, Cryp­to, Dream, East India Com­pa­ny, Haven, Mid­dle Earth, Nucle­us, Out­law)
  26. 2015-07-03 (Abrax­as, Ago­ra, Alphabay, Crypto/Diabolus, Dream, East India Com­pa­ny, Mid­dle Earth, Nucle­us, Out­law, Oxy­gen)

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.

Modafinil

Modalert

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

Strips:

  • Weight: 4.62 +/- 0.05g
  • Size: 4.8x12.0cm
  • Tex­ture: Dim­pled, with dim­ples approx 0.5mm apart
  • Mate­ri­al: Two lay­ers of alu­minum, with two thin lay­ers of glue in between them (one on each side of the pouch). The glue is a clear, thin, stretchy plas­tic; it is not sticky unless heat­ed.
  • Tex­ture: Solid sil­ver, dim­pled except in the round­ed-rec­tan­gle pouches that con­tain the pills. The dim­ples are approx­i­mately 0.5mm apart. The spac­ing between the pil­l-pouches is 6-7 dim­ples in size
  • The front has pur­ple printed text and a red stripe down the left. The red stripe is 2 dim­ples wide.
2 strips, front & back
The front of 1 10x100mg strip, and rotated
The back of said strip, also with rotated view

Pills:

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

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

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

In Feb­ru­ary 2012, myModafinil.net sent me a free sam­pler of 200mg Modalert; one pack­age:

10x200 Modalert, sent from myModafinil.net

Modapro

Paul New­comb:

10x200 Modapro, ordered from Nubrain

Modvigil

Pho­tos of an order of Mod­vigil ordered from Modup.net were posted on Red­dit June 2013: front, back.

Orifarm/Mylan

Swedish pre­scrip­tion, 100mg Mylan:

Blis­ter­pack back of 100mg Mylan modafinil (2016)
Front pack­ag­ing of 100mg Mylan modafinil (2016)

Armodafinil

Waklert

I’ve bought 150mg Wak­lert (generic armodafinil man­u­fac­tured by Sun Phar­ma) twice on Silk Road 1; the first ship­ment:

4 of the pills are left after I tested the first one overnight.

Sec­ond:

a ship­ment of 80 Wak­lert (8 pack­ages of 10)
close up of the front and back of one pack­age

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.

Affiliates

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

For phar­ma­ceu­ti­cal affil­i­ate mar­ket­ing pro­grams, par­tic­u­larly the Russian/East-European part­nerka ecosys­tem like GlavMed which dom­i­nated modafinil sales until the early 2010s, com­mis­sions his­tor­i­cally were around 30-50%. I signed up for 3 affil­i­ate pro­grams between April 2011 and Jan­u­ary 201254; in order, by price per mg as given in the above chart (cheap­est first):

  1. EDAndMore: 20%55
  2. TheP­har­ma­cy­Ex­press: 15%
  3. Good Health Phar­ma­cy: 15%
  4. OneMed­Store: 30%

Inter­est­ing­ly, there is only a weak pat­tern of com­mis­sions shrink­ing with prices, which sug­gests we may be see­ing at work56; if EDAndMore can offer both the cheap­est prices and higher com­mis­sions, that sug­gests there is con­sid­er­able mar­gin to cut. Fur­ther, EDAndMore offers ship­ping ‘for free’, but of course, there is no such thing as a free lunch so what that actu­ally means is that the ship­ping is built into the price. If we assume that ship­ping costs them $10 a pack­age of 200x200 and exclude it from their modafinil cost, and we cut 20% for com­mis­sion, that sug­gests a price of , or ~300 mg/$—substantially higher than the 222 mg/$ avail­able to the con­sumer.

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 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 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 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 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 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 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 (). And then I might decide United Phar­ma­cies smells a bit bet­ter and give them a 70% chance, for a total of 145.6 (); and per­haps Airsealed gets a whop­ping 95% trust from me, for a total of 71.25 (). 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 . (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”.)

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):

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: means ‘how likely is foo now that I have observed bar’ (you could men­tally rewrite it to some­thing like ). 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. 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. 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. 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. 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. = prob­a­bil­ity of being a good sup­plier = 90% = 0.90
  4. = prob­a­bil­ity of being a bad sup­plier = 10% = 0.10
  5. = prob­a­bil­ity a good sup­plier will send fakes = 5% = 0.05
  6. = prob­a­bil­ity a bad sup­plier will send fakes = 95% = 0.95

We sub­sti­tute in to the orig­i­nal equa­tion:

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 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 , 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 , which says the odds of a fake in the next order, given s fail­ures and n total orders, is —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 . (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 .)

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 by the rule of three or .

And the real rates? One sup­plier told me of 20-30 ship­ments with­out seizure, which would be or , 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 (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 , 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 ‘’ of that pay­off stream is larger than our present poten­tial invest­ment.

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

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:

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 dol­lars with UP.­co.uk and 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%:

We turn a profit of around $210. This lit­tle model isn’t cor­rect since it covertly implies one of the two sup­pli­ers is send­ing fakes, yet back in expected value we gave 90% for both sup­pli­ers send­ing gen­uine prod­uct­s—a con­tra­dic­tion.

We can try again with some­thing fair­er. Imag­ine you have the sam­ples from both sup­pli­ers sit­ting at hand wait­ing to be test­ed. What do you expect to find? Well, if there’s a 90% chance that each of them is ship­ping gen­uine prod­ucts, then there’s a 10% for each ship­ping coun­ter­feits, which is pretty small and so the odds are good that our test will sim­ply tell us that both sup­pli­ers are hon­est. Let’s look at all 4 pos­si­ble out­comes:

  1. What are the odds that both are hon­est sup­pli­ers? (H H)

    Well, 90% times 90% is 81%.

  2. And that both are dis­hon­est? (D D)

    10% times 10% is just 1%.

  3. That the first one is dis­hon­est and the sec­ond is hon­est? (D H)

    90% times 10% is 9%.

  4. And vice ver­sa? (H D)

    Well, same thing, 9%. (So the prob­a­bil­ity of either is 9% + 9% or 18%.)

If both sup­pli­ers are hon­est, one gained noth­ing from the test, so we start with an 81% chance of not ben­e­fit­ing. Then, if the sec­ond one (the one you aren’t order­ing from) is dis­hon­est and the first one is hon­est, you still gain noth­ing (you picked cor­rect­ly, huz­za­h!) so that’s 81% and 9%. If the first one (the one you are order­ing from) is dis­hon­est and the sec­ond one is hon­est, then you gain (9%), and the final 1% is also use­ful (you can scrap them both and look at sup­pli­ers fur­ther down the list). So all in all, there’s only a 10% chance of gain­ing from the assay!

So here’s another oppor­tu­nity to apply expected val­ue: the value of our assay times that 10% chance it’ll actu­ally lead to a finan­cial gain:

Oh well!

A final thought about modafinil:

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

Discount rate applications: swapping time for time

When I con­sider Life, ’tis all a cheat,
Yet, fool’d with hope, men favour the deceit;
Trust on, and think to mor­row will repay:
To mor­row’s falser than the for­mer day;
Lies worse; and while it says, We shall be blest
With some new joys, cuts off what we pos­s­est.
Strange coz­enage! none would live past years again,
Yet all hope plea­sure in what yet remain;
And, from the dregs of Life, think to receive,
What the first sprightly run­ning could not give.62

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 is a much-de­bated prob­lem. But whether you like it or not, you 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 capac­i­ties63.

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:

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 higher64, we will gen­er­ously assume the improb­a­bly low dis­count rate of 2%65; and then ask how much a year is worth 50 years from now:

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 that one cig­a­rette costs 11 min­utes). So the reader could ask them­selves: with every­thing they know and have heard about modafinil (and have ), how likely is it that modafinil is even worse than smok­ing?

Coordination problems: assaying

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

Stew­art Brand to Steve Woz­niak (1984; first )

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

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

/r/Nootropics

In 2013, the /r/Nootropics sub­red­dit mod­er­a­tors began a series of inde­pen­dent tests. (I am one of the mod­er­a­tors but have not par­tic­i­pated in the pro­ject, being skep­ti­cal of the con­flicts of inter­est involved.) How did they fund it? Not via an assur­ance con­tract. What actu­ally hap­pened was that they solicited dona­tions of funds from vendors/websites/businesses listed in the sub­red­dit FAQ as places to buy nootrop­ics from; some ven­dors responded with funds, the mod­er­a­tors bought the nec­es­sary sam­ples, and sent them off to the labs with the results posted pub­licly. This sys­tem works as long as the mod­er­a­tors are will­ing to vol­un­teer their time and remain incor­rupt­ible; but it could eas­ily col­lapse if, for exam­ple, a bogus ven­dor pays a mod­er­a­tor & sends a non-rep­re­sen­ta­tive sam­ple—the mod­er­a­tor has no direct inter­est in get­ting the truth­ful results except per­haps if they wanted to buy that exact prod­uct from that exact ven­dor. It’s true that it’s harder for a ven­dor to cor­rupt a third-­par­ty’s COAs than their own COAs, but it’s still doable. So we’ll see how well the sys­tem works out.

The attempts to test did yield another ben­e­fit: infor­ma­tion about how one would go about lab-test­ing modafinil. Not eas­i­ly, it turns out, since it requires DEA approval on some lev­el:

Colin spoke to Sigma Aldrich, and said that the modafinil test­ing has to go through Sig­ma’s DEA approval. So he has declined to get involved in that test­ing. Even with a pre­scrip­tion, the test­ing has to have dif­fer­ent approvals appar­ent­ly. So if we want to test it, we will have to find another lab will­ing to get the approval

This is the first I’ve heard about DEA approval nec­es­sary for test­ing. Is this Sigma only or is this some­thing that’ll be a prob­lem for any­one doing Amer­i­can lab test­ing?

Colin said that it was a Sigma Aldrich thing. They won’t sell the ref­er­ence sam­ple unless the lab pur­chas­ing it goes through their DEA approval. I won­der what would hap­pen if I called up Sigma with a pre­scrip­tion…I just did. They said that it’s actu­ally not them, but the DEA rules them­selves. The lab has to be DEA autho­rized to test any sched­uled sub­stances. They told me that even with a pre­scrip­tion, they are not allowed to sell it to me, since they are not a licensed phar­ma­cy. They are a sup­pli­er, and the rules are totally dif­fer­ent. So it looks like we need to find a lab that already has DEA autho­riza­tion to test sched­uled sub­stances. It’s always got to be dif­fi­cult!…It’s news to me too, but kind of makes sense when you think about all the reg­u­la­tions there are.

The price quote is “$2,000 per test”.

Assaying

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

Professional
  1. 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 pos­si­ble to extract purer modafinil by crush­ing & dis­solv­ing pills in water.

Tra­jork writes:

Modafinil is a sulfa drug, con­tain­ing a cer­tain chem­i­cal group called a 66. 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 . I then mixed it up and heated it over an alco­hol burn­er. This should pro­duce , 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 —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 . 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 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 neg­a­tives67, 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.

Those with access to , , or may find help­ful. Another pos­si­bil­ity is to attempt to rule out pos­si­ble sub­sti­tutes like amphet­a­mines using a stan­dard reagent test like the or tests; this has been tried before, appar­ently suc­cess­fully.

Appendix

Schizophrenia

Epidemiology

Gen­eral obser­va­tions: modafinil does not seem to be sus­pected as a cause of 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-butt 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. from ’s “The 10Q Detec­tive: Los­ing Sleep Over Cephalon”, 2009:

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

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

    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.

    Estrada et al 2012:

    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 , 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:

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  11. Caf­feine is pretty inef­fec­tive because tol­er­ance devel­ops. One amus­ing com­par­i­son of modafinil ver­sus caf­feine, , 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”.

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  14. “The Ethics of Designer Brains”, , 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.

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  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

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  16. Some rel­e­vant cita­tions (omit­ting a ):

    • (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.

    • , 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. “A ran­dom­ized trial on the effi­cacy of methylphenidate and modafinil for improv­ing cog­ni­tive func­tion­ing and symp­toms in patients with a pri­mary brain tumor”, Gehring et al 2011:

        …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. , 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. The 2019 meta-­analy­sis , Kred­low et al 2019, man­ages to pull together 19 usable stud­ies on cog­ni­tion in healthy non-sleep­-de­prived sub­jects, and finds a small over­all aver­age effect of g = 0.10, much like the meta-­analy­sis.↩︎

  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 with the 100mg dose.↩︎

  19. Taneja et al 2007, describ­ing pre­vi­ous research:

    Becker and col­leagues used the 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 []. 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 () looks like it’s “sta­tis­ti­cally sig­nif­i­cant” but the 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 , 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:

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

    Exam­ple feed­back, from Makris 2004:

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

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

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

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

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

    ↩︎
  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. “Urine smells of sul­fur”↩︎

  27. , 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 . 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 , 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) ( in the rest of the world). Johnson&Johnson/MacNeil are appar­ently get­ting tired of pay­ing for liver trans­plants and pay­ing out judg­ments for peo­ple who die of liver fail­ure because this hepa­to­toxic drug has spread into almost every prod­uct on the mar­ket for pain or dis­com­fort, rang­ing from nos­trums for men­strual cramps to sleep aids. APAP tox­i­c­ity is the most com­mon cause of hepatic fail­ure requir­ing liver trans­plan­ta­tion in Great Britain. In the United States, APAP tox­i­c­ity has replaced viral hepati­tis as the most com­mon cause of acute liver fail­ure, and it is the sec­ond most com­mon cause of liver fail­ure requir­ing trans­plan­ta­tion in the US.The per­cent­age of cases of acute liver fail­ure caused by an over­dose of aceta­minophen increased con­sid­er­ably from 1998 to 2003, with unin­ten­tional over­dose account­ing for at least half of these case. Aceta­minophen (APAP) is now the drug of choice for sui­cide in the US & UK and the num­ber of deaths and hos­pi­tal­iza­tions from APAP has risen steadily since its wide­spread intro­duc­tion in the 1960s (it was ini­tially intro­duced in the 1950s). I can’t find the num­bers for the US, but in Eng­land and Whales there are ~700 suc­cess­ful suicides/yr using APAP. The drug inter­acts unpre­dictably with alco­hol in many indi­vid­u­als to cause seri­ous liver tox­i­c­ity and the eco­nomic costs of APAP tox­i­c­ity are esti­mated to be in the hun­dred of mil­lions of dollars/yr. I note that few,if any other PRESCRIPTION, let alone OTC drug, with a decades long his­tory of steadily esca­lat­ing injury and death to the pop­u­la­tion. By con­trast, Vioxx was a dream drug! So it is the hypocrisy and unfair­ness of the treat­ment of Vioxx that I find objec­tion­able.

    ↩︎
  28. , cit­ing no sources unfor­tu­nate­ly, reports that:

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

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

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

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

    ↩︎
  31. 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.

    ↩︎
  32. From a Cephalon-­funded study, , 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 . 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”.↩︎

  33. 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.↩︎

  34. 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.↩︎

  35. 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; ).

    ↩︎
  36. “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.

    ↩︎
  37. 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.↩︎

  38. 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.↩︎

  39. Prices in pounds are con­verted to dol­lars. Mil­ligrams per dol­lar is cal­cu­lat­ed: ↩︎

  40. 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.↩︎

  41. 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.↩︎

  42. 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. ↩︎

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

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

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

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

  47. Prices in pounds are con­verted to dol­lars. Mil­ligrams per dol­lar is cal­cu­lat­ed: ↩︎

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

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

  50. 10x10 at £3.59↩︎

  51. 4NRX may no longer be offer­ing Wak­lert. Cal­cu­lated at 10x10 with free S&H.↩︎

  52. I once ordered armodafinil off Silk Road.↩︎

  53. 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.↩︎

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

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

    1. 200x200 sells for $197.95, com­mis­sion of $39.59
    2. 100x200 sells for $131.95, com­mis­sion of $26.39
    ↩︎
  56. For exam­ple, if mul­ti­ple sites/‘busi­nesses’ were set up, each with dif­fer­ent prices, then the true own­ers may be able to engage in and cap­ture more of the . 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!

    ↩︎
  57. 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)↩︎

  58. 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.↩︎

  59. 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).

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

  61. , “Book of Water”, _↩︎

  62. , Act IV of (1675)↩︎

  63. When announced he had devel­oped 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.

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

  65. 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.↩︎

  66. 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.

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  67. 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 , 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.

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