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 of drugs be­lieved to cause SJS. SJS is gen­er­ally rare (“about 300 new di­ag­noses per year” in the USA). It’s not clear how much modafinil in­creases SJS risk the FDA re­port spec­i­fies that there was only 1 ‘pos­si­ble’ syn­drome dur­ing the clin­i­cal tri­als of around 1,585 peo­ple (a child who had a fever & rash; Cephalon ar­gued stren­u­ously that it was not SJS). Pre­sum­ably if modafinil re­ally did cause SJS at a rate of 1 in 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 value of in­for­ma­tion (4 ex­am­ples).

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

But a wrin­kle comes to mind: $1000 is a lot of mon­ey. Quite a lot, re­al­ly. You could buy a lot of modafinil with $1000; even if we played it safe and bought from Nubrain, $1000 would get us , 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.

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  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.

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  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.

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  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.

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  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.

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  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.

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  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 ().

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  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.

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  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.

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  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.

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  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.

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  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; ).

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  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.

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  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!

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  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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