Creatine Cognition Meta-analysis

Does creatine increase cognitive performance? Maybe for vegetarians but probably not.
psychology, meta-analysis, R, IQ, bibliography
2013-09-062019-01-29 finished certainty: unlikely importance: 5

I at­tempt to meta-an­a­lyze con­flict­ing stud­ies about the cog­ni­tive ben­e­fits of cre­a­tine sup­ple­men­ta­tion. The wide va­ri­ety of psy­cho­log­i­cal mea­sures by uni­formly small stud­ies ham­pers any ag­gre­ga­tion. 3 stud­ies mea­sured IQ and turn in a pos­i­tive re­sult, but sug­ges­tive of veg­e­tar­i­an­ism caus­ing half the ben­e­fit. Dis­cus­sions in­di­cate that pub­li­ca­tion bias is at work. Given the va­ri­ety of mea­sures, small sam­ple sizes, pub­li­ca­tion bi­as, pos­si­ble mod­er­a­tors, and smal­l­-s­tudy bi­as­es, any fu­ture cre­a­tine stud­ies should use the most stan­dard mea­sures of cog­ni­tive func­tion like RAPM in a rea­son­ably large pre-reg­is­tered ex­per­i­ment.

is a chem­i­cal found through­out the body in a num­ber of roles; it is most fa­mous for its pres­ence in mus­cles and en­abling greater ex­er­tion, but it also plays a role in the ner­vous sys­tem. Some small psy­chol­ogy ex­per­i­ments in healthy adults have found cog­ni­tive ben­e­fits to sup­ple­men­ta­tion but oth­ers dis­agree (, Ex­am­ine.­com), and these differ­ences may be due to co­vari­ates like be­ing veg­e­tar­ian & hence cre­atine-d­e­fi­cient.

When small stud­ies con­flict, one way to get an­swers is to try to meta-an­a­lyze them into a sin­gle more ro­bust sum­ma­ry. In par­tic­u­lar, I am in­ter­ested in whether cre­a­tine sup­ple­men­ta­tion in­creases IQ. One prob­lem here is that the stud­ies may not use enough of the same mea­sures to in­clude in the same meta-analy­sis; be­sides that, the stud­ies are likely se­verely un­der­pow­ered to de­tect plau­si­ble effects: IQ in­creases have been often claimed, but have rarely panned out (see, for ex­am­ple, ) and “ex­tra­or­di­nary claims re­quire ex­tra­or­di­nary proof”.


While cre­a­tine is fa­mous for its ath­letic uses1, there is also bi­o­log­i­cal ev­i­dence sug­gest­ing cre­a­tine is in­volved in men­tal per­for­mance, serv­ing as a fast source of en­er­gy, cre­atine-re­lated re­tar­da­tion & dis­abil­i­ty, cor­re­lates be­tween meat-eat­ing and per­for­mance etc. For one sur­vey, and a more de­tailed dis­cus­sion of the ra­tio­nale for ex­pect­ing cre­a­tine to help, see Lit­tle­ton 2013; for dis­cus­sion of the neu­ro­pro­tec­tive effects, see Cunha 2017. An in­ter­est­ing lon­gi­tu­di­nal cor­re­la­tion be­tween cre­a­tine lev­els and later in­creased salary is found in Böck­er­man et al 2014. And re­views some an­i­mal ex­per­i­ments sug­gest­ing po­ten­tial ben­e­fits in neu­rode­gen­er­a­tive dis­eases like ag­ing.

Ex­per­i­men­tal­ly, cre­a­tine turns out to boost men­tal per­for­mance in some cir­cum­stances (eg. Ling et al 2009 saw the cre­a­tine group post-s­core 4 points higher than con­trols, or Watan­abe 2002’s less oxy­gen use dur­ing men­tal arith­metic; Jonathan Toomim rec­om­mends it high­ly, claim­ing that “I’m more con­fi­dent that I’ve no­ticed effects [on men­tal per­for­mance] of cre­a­tine than of DnB.”)

These re­sults are a lit­tle mixed. There are stud­ies show­ing ben­e­fits in:

  1. Veg­e­tar­i­ans (Rae 2003)
  2. the sleep­-de­prived (Mc­Mor­ris 2006; Mc­Mor­ris 2007)
  3. the el­derly (Mc­Mor­ris et al 2007)

How­ev­er, Raw­son et al 2008 is a broad null re­sult for healthy om­ni­vores, who are prob­a­bly most of the read­ers of this FAQ. (Jonathan Toomim has crit­i­cized Raw­son et al 2008 as sta­tis­ti­cally weak and us­ing a pos­si­bly not sen­si­tive test of men­tal per­for­mance; oth­ers have pointed out Raw­son et al 2008 ad­min­is­tered a to­tal of cre­atine, which is less than half that of Rae 2003 and 16% less than Ling et al 2009.)

A 2018 meta-analysis/systematic re­view, Avgeri­nos et al 2018, “Effects of cre­a­tine sup­ple­men­ta­tion on cog­ni­tive func­tion of healthy in­di­vid­u­als: A sys­tem­atic re­view of ran­dom­ized con­trolled tri­als”, reached sim­i­lar con­clu­sions as I did in 2013: some ev­i­dence of het­ero­ge­neous ben­e­fits in a lit­er­a­ture which uses too many differ­ent mea­sures.


The searches & alerts yielded the fol­low­ing po­ten­tially use­ful stud­ies:

We are look­ing for stud­ies of the effects of cre­a­tine on cog­ni­tive per­for­mance in nor­mal healthy pop­u­la­tions un­der nor­mal con­di­tions (ie no dis­eases, no ge­netic dis­or­ders, no ex­otic con­di­tions like hy­pox­i­a).

Us­able stud­ies turn out to em­ploy a wide va­ri­ety of psy­cho­log­i­cal mea­sures:

Study Test
Watan­abe 2002 Uchi­da-Krae­pelin se­r­ial cal­cu­la­tion test
Rae 2003 Raven’s Ad­vanced Pro­gres­sive Ma­tri­ces; Back­ward Digit Span
Mc­Mor­ris 2006 Ran­dom move­ment gen­er­a­tion test; for­ward ver­bal re­call; back­wards ver­bal re­call; 4-choice vi­sual re­ac­tion time test; Hem­mings mood state in­ven­tory
Mc­Mor­ris 2007 Ran­dom num­ber gen­er­a­tion task; num­ber re­call test; four-choice vi­sual re­ac­tion time test; Hem­mings mood state in­ven­to­ry; NASA-TLX effort sub­-s­cale
Mc­Mor­ris et al 2007 Ran­dom num­ber gen­er­a­tion task; for­ward ver­bal re­call; back­wards ver­bal re­call; for­ward Corsi Block Tap­ping test; back­ward Corsi Block Tap­ping test; long-term mem­ory test
Gast­ner et al 2007 Raven’s Ad­vanced Pro­gres­sive Ma­tri­ces; Uchi­da-Krae­pelin se­r­ial cal­cu­la­tion test; Back­ward Digit Span
Raw­son et al 2008 Sim­ple re­ac­tion time; code sub­sti­tu­tion; code sub­sti­tu­tion de­layed; log­i­cal rea­son­ing sym­bol­ic; math­e­mat­i­cal pro­cess­ing; run­ning mem­o­ry; Stern­berg mem­ory re­call
Ling et al 2009 Raven’s Ad­vanced Pro­gres­sive Ma­tri­ces; Mem­ory Scan­ning task; Num­ber-Pair Match­ing task; Sus­tained At­ten­tion task; Ar­row Flanker task
Ham­mett et al 2010 Raven’s Ad­vanced Pro­gres­sive Ma­tri­ces; Back­ward Digit Span
Ben­ton & Dono­hoe 2011 Word re­call; re­ac­tion-time; vig­i­lance rapid in­for­ma­tion pro­cess­ing task; Con­trolled Oral Word As­so­ci­a­tion Test
Alves et al 2013 For­ward Digit Span; Back­ward Digit Span; Mini-Men­tal State Ex­am­i­na­tion; Stroop Test; Trail Mak­ing Test; De­lay Re­call Test
Merege-Filho et al 2016 Stroop Test; Rey Au­di­tory Ver­bal Learn­ing Test; Raven Pro­gres­sive Ma­tri­ces; Trail Mak­ing Test
Cook et al 2011 Rugby ball pass­ing

In to­tal, these stud­ies use ~33 dis­tinct mea­sures of cog­ni­tive func­tion­ing; this het­ero­gene­ity ren­ders any sum­mary diffi­cult as most mea­sures were used in only one ex­per­i­ment, and en­cour­ages se­lec­tive re­port­ing. The Hem­mings mood state in­ven­to­ry, ran­dom num­ber gen­er­a­tion task, for­ward ver­bal re­call, & Uchi­da-Krae­pelin se­r­ial cal­cu­la­tion test are used in 2 ex­per­i­ments each, but the back­ward digit span is used in 4 ex­per­i­ments, and the RAPM is used in 4 ex­per­i­ments - so it would be best to an­a­lyze those two.



I de­cided to code mul­ti­ple rel­e­vant vari­ables:

  1. di­et: if no diet was spec­i­fied, as­sume om­niv­o­rous­ness since as lit­tle as 5% of West­ern pop­u­la­tion are veg­e­tar­i­ans

    • 0: om­ni­vore
    • 1: ve­gan or veg­e­tar­ian
  2. sleep:

    • 0: no men­tion is made of sleep de­pri­va­tion
    • 1: if sleep de­pri­va­tion in the ex­per­i­men­tal as op­posed to con­trol group
  3. IQ:

    • 0: RAPM
  4. dose: to­tal amount of cre­a­tine ad­min­is­tered, in grams; av­er­age is to­tal amount of cre­a­tine di­vided by num­ber of days on which cre­a­tine is taken by a sub­ject

  5. age: av­er­age mean of all sub­jects’ age; me­di­ans were treated as means if that was pro­vided in­stead, and means given of range end­points if only that was pro­vided

  6. type: cre­a­tine can be con­sumed in mul­ti­ple forms.

    (CM) is the most com­mon, but also used in a study is (CEE). While CEE was de­vel­oped to al­low smaller doses than CM, Kat­seres et al 2009 sug­gests it breaks down far too fast to be effec­tive and so CEE doses may not be 1:1 equiv­a­lent with CM.

year study n.e mean.e sd.e n.c mean.c sd.c type dose to­tal dose av­er­age age diet sleep
2003 Rae 25 13.7 4.1 25 9.7 3.8 mono­hy­drate 210 5 25.59 1 0
2009 Ling 17 120.3 5.945 17 116.1 9.086 ethyl es­ter 75 5 21 0 0
2010 Ham­mett 11 13.45 2.25 11 11.45 3.8 mono­hy­drate 110 15.7 27.59 0 0
2016 Merege-Filho 35 30.4 4.6 32 31.8 3.8 mono­hy­drate 13.74 1.96 11.5 0 0


The 4 stud­ies do not turn in a sta­tis­ti­cal­ly-sig­nifi­cant pos­i­tive re­sult in the ran­dom-effects meta-analy­sis:

Random-Effects Model (k = 4; tau^2 estimator: REML)

tau^2 (estimated amount of total heterogeneity): 0.2731 (SE = 0.3128)
tau (square root of estimated tau^2 value):      0.5226
I^2 (total heterogeneity / total variability):   72.62%
H^2 (total variability / sampling variability):  3.65

Test for Heterogeneity:
Q(df = 3) = 12.8147, p-val = 0.0051

Model Results:

estimate       se     zval     pval    ci.ub
  0.4259   0.3095   1.3761   0.1688  -0.1807   1.0325
A for­est plot of the 4 stud­ies

When veg­e­tar­i­an­ism is used as a co­vari­ate (this ap­plies only to Rae 2003), it is not sta­tis­ti­cal­ly-sig­nifi­cant ei­ther but does lower the es­ti­mate fur­ther (given that Rae 2003 was also the largest effec­t):

Mixed-Effects Model (k = 4; tau^2 estimator: REML)

tau^2 (estimated amount of residual heterogeneity):     0.2034 (SE = 0.3213)
tau (square root of estimated tau^2 value):             0.4510
I^2 (residual heterogeneity / unaccounted variability): 64.29%
H^2 (unaccounted variability / sampling variability):   2.80
R^2 (amount of heterogeneity accounted for):            25.52%

Test for Residual Heterogeneity:
QE(df = 2) = 5.9274, p-val = 0.0516

Test of Moderators (coefficient(s) 2):
QM(df = 1) = 1.5477, p-val = 0.2135

Model Results:

         estimate      se    zval    pval   ci.ub
intrcpt    0.2095  0.3261  0.6423  0.5207  -0.4297  0.8487
diet       0.7865  0.6322  1.2441  0.2135  -0.4526  2.0257

Un­for­tu­nate­ly, with so few stud­ies I can’t in­ves­ti­gate dose mean­ing­fully

Publication bias

The com­mon pub­li­ca­tion bias checks like the fun­nel plot are use­less with 3 stud­ies. As it hap­pens, there is no need to do any hy­poth­e­sis-test­ing here: Ling (per­sonal com­mu­ni­ca­tion 2013) men­tions that 2 stu­dent the­ses were done in­volv­ing cre­a­tine sup­ple­men­ta­tion & cog­ni­tion with ap­par­ently un­in­ter­est­ing re­sults, but did not have any copies and the uni­ver­sity li­brary had not re­tained any; this is prima fa­cie pub­li­ca­tion bias. Hence, we know that the meta-an­a­lytic re­sults are bi­ased up­wards by pub­li­ca­tion bias.

Backward Digit Span


year study n.e mean.e sd.e n.c mean.c sd.c type dose to­tal dose av­er­age age diet
2010 Ham­mett 11 11 Mono­hy­drate 110 15.7 27.59 0
2003 Rae 25 8.5 1.76 25 7.05 1.19 Mono­hy­drate 210 5 25.59 1
2013 Alves 25 3.75 1.0 22 3.25 0.76 Mono­hy­drate 25 4.17 66.8 0



set.seed(7777) # for reproducible numbers
# TODO: factor out common parts of `png` (& make less square), and `rma` calls
creatine <- readHTMLTable(colClasses = c("integer", "factor", rep("numeric", 6), "factor", rep("numeric", 5)),
# install.packages("metafor") # if not installed

cat("Basic random-effects meta-analysis of all studies:\n")
res1 <- rma(measure="SMD", m1i = mean.e, m2i = mean.c, sd1i = sd.e, sd2i = sd.c, n1i = n.e, n2i = n.c,
            data = creatine); res1

png(file="~/wiki/images/creatine/forest.png", width = 580, height = 580)
forest(res1, slab = paste(creatine$study, creatine$year, sep = ", "))

cat("Random-effects with vegetarian covariate:\n")
rma(measure="SMD", m1i = mean.e, m2i = mean.c, sd1i = sd.e, sd2i = sd.c, n1i = n.e, n2i = n.c,
    data=creatine, mods = ~ diet)

system(paste('cd ~/wiki/images/creatine/ &&',
             'for f in *.png; do convert "$f" -crop',
             '`nice convert "$f" -virtual-pixel edge -blur 0x5 -fuzz 10% -trim -format',
             '\'%wx%h%O\' info:` +repage "$f"; done'))
system("optipng -o9 -fix ~/wiki/images/creatine/*.png", ignore.stdout = TRUE)

Study details

  • Watan­abe 2002, Mc­Mor­ris 2006, Mc­Mor­ris et al 2007, Mc­Mor­ris 2007, Raw­son et al 2008, Ben­ton & Dono­hoe 2011: ex­cluded for not us­ing a mea­sure of in­tel­li­gence.
  • Gast­ner et al 2007: ex­cluded for lack of nec­es­sary de­tails.

Rae 2003

In this work, we tested the hy­poth­e­sis that oral cre­a­tine sup­ple­men­ta­tion (5g daily for six weeks) would en­hance in­tel­li­gence test scores and work­ing mem­ory per­for­mance in 45 young adult, veg­e­tar­ian sub­jects in a dou­ble-blind, place­bo-con­trolled, cross-over de­sign. Cre­a­tine sup­ple­men­ta­tion had a sig­nifi­cant pos­i­tive effect (p = 0.0001) on both work­ing mem­ory (back­ward digit span) and in­tel­li­gence (Raven’s Ad­vanced Pro­gres­sive Ma­tri­ces), both tasks that re­quire speed of pro­cess­ing.

Forty-five ve­gan or veg­e­tar­ian sub­jects (12 males (me­dian age of 27.5, range of 19-37 years), 33 fe­males (me­dian age of 24.9, range of 18-40 years); 18 ve­gan (me­dian du­ra­tion of 4.6 years, range of 0.7-17 years) and 27 veg­e­tar­ian (me­dian du­ra­tion of 14.3, range of 1-23 years)) were re­cruited with in­formed con­sent from among the stu­dent pop­u­la­tion of The Uni­ver­sity of Syd­ney

The study fol­lowed a dou­ble-blind, place­bo-con­trolled, cross-over de­sign. Sub­jects were seen on four sep­a­rate oc­ca­sions, at six-week in­ter­vals, fol­low­ing an overnight fast to min­i­mize any fluc­tu­a­tions in blood glu­cose.

A cog­ni­tive test bat­tery was also ad­min­is­tered. At the end of the first and third test ses­sions, sub­jects were given an en­ve­lope marked with their study num­ber and con­tain­ing 5 g doses of sup­ple­ment (cre­a­tine mono­hy­drate ((2-methyl­guanido)acetic acid); Pan Phar­ma­ceu­ti­cals, Aus­tralia) or placebo (mal­todex­trin; Manil­dra Starch­es, Aus­tralia) in plas­tic vials. Sub­jects were asked to con­sume this sup­ple­ment at the same time each day for the next six weeks and re­ceived ad­vice on how best to take this sup­ple­ment to en­sure max­i­mum sol­u­bil­ity and ab­sorp­tion. Sub­jects re­turned the en­ve­lope with un­used vials at the end of each six-week pe­riod and the num­ber of vials re­main­ing was used to as­sess com­pli­ance, val­i­dated against in­creases in red cell (tis­sue) cre­a­tine. Be­tween vis­its 2 and 3, the sub­jects con­sumed no sup­ple­ment. Note: six weeks has been shown to be an ad­e­quate ‘wash-out’ pe­riod (Har­ris et al. 1992).

Sub­jects com­pleted timed (10 min) par­al­lel ver­sions of Raven’s Ad­vanced Pro­gres­sive Ma­tri­ces (RAPMs) con­structed to have equal lev­els of diffi­culty based on the pub­lished nor­ma­tive per­for­mance data and ver­i­fied by us on an in­de­pen­dent sam­ple of 20 sub­jects.

Sup­ple­men­ta­tion with oral cre­a­tine mono­hy­drate sig­nifi­cantly in­creased in­tel­li­gence (as mea­sured by RAPMs done un­der time pres­sure, fig­ure 1a) com­pared with placebo (F3 ,33 = 32.3, p , 0.0001; re­peat­ed-mea­sures ANOVA). There was no sig­nifi­cant effect of treat­ment or­der (F1 ,33 = 1.62, p = 0.21), al­though there was a sig­nifi­cant in­ter­ac­tion with treat­ment or­der (F3 ,99 = 6.7, p = 0.0004). The mean RAPMs raw score un­der placebo was 9.7 (s.d. = 3.8) items cor­rect in 10 min ver­sus 13.7 (s.d. = 4.1) items cor­rect un­der the ex­per­i­men­tal treat­ment. Sup­ple­men­ta­tion with oral cre­a­tine mono­hy­drate (fig­ure 1b) sig­nifi­cantly affected per­for­mance on BDS (F3 ,34 = 29.0, p , 0.0001), with no effect of or­der (F3 ,10 2 = 0.98, p = 0.40). Mean BDS un­der the placebo was 7.05 items (s.d. = 1.19), com­pared with a mean of 8.5 items un­der cre­a­tine treat­ment (s.d. = 1.76).

Gastner et al 2007

“Use of cre­a­tine con­tain­ing prepa­ra­tion e.g. for im­prov­ing mem­o­ry, re­ten­tiv­i­ty, long-term mem­ory and for pre­vent­ing men­tal fa­tigue con­di­tion, com­pris­ing e.g. Ginkgo biloba, gin­seng and niacin” (Eng­lish trans­la­tion, orig­i­nal): Ger­man patent filed in June 2007 by Dr. Thomas Gast­ner, Frauke Selz­er, Dr. Han­s-Peter, Dr. Bendikt Ham­mer, for Alzchem Trost­berg Gmbh:

Use of a cre­a­tine con­tain­ing prepa­ra­tion for im­prov­ing mem­o­ry, re­ten­tiv­i­ty, long-term mem­ory and for pre­vent­ing men­tal fa­tigue con­di­tions, com­pris­ing e.g. at least a fur­ther phys­i­o­log­i­cally effec­tive com­po­nent of the se­ries Ginkgo biloba, gin­seng, taiga root, yam root, lecithin, choline, phos­phatidylser­ine, di­methy­lamino ethanol, acetyl choline, acetyl-L-car­nitine, glu­tathione, glu­t­a­mine, cys­teine, vi­t­a­min A, E, B1, B2, B6, B12, folic acid, pan­tothenic acid and/or zinc, is claimed. Use of a cre­atine-com­po­nent con­tain­ing prepa­ra­tion for im­prov­ing mem­o­ry, re­ten­tiv­i­ty, long-term mem­ory and for pre­vent­ing men­tal fa­tigue con­di­tions, com­pris­ing at least a fur­ther phys­i­o­log­i­cally effec­tive com­po­nent of the se­ries Ginkgo biloba, gin­seng, taiga root, yam root, lecithin, choline, phos­phatidylser­ine, di­methy­lamino ethanol, acetyl choline, acetyl-L-car­nitine, glu­tathione, glu­t­a­mine, cys­teine, vi­t­a­min A, E, B1, B2, B6, B12, E, niac­in, bi­ot­in, folic acid, pan­tothenic acid, zinc, man­gane­se, se­le­ni­um, mag­ne­sium, coen­zyme Q10, glu­cose, colostrum, synephrine, oc­topamine, caffeine, theo­phylline, al­pha -li­nolenic acid, eicos­apen­taenoic acid, omega-3-fatty acid, pirac­etam, anirac­etam, me­man­ti­ne, pyriti­nol, galan­t­a­mine, vin­pocetin, pangamic acid and/or op­tion­ally or­ganic or in­or­ganic salts and/or op­tion­ally es­ters, is claimed.

Sec­tion 2, “Effec­tive­ness”:

Sub­jects were di­vided ran­domly into four groups of 25 peo­ple each. The age of the sub­jects var­ied be­tween 18 and 64 years. The four groups (a-d) were given twice per day for six weeks fol­low­ing each test sub­stances in soft­gel cap­sules:

  1. placebo (1500 mg mal­todex­trin)
  2. cre­a­tine mono­hy­drate (1500 mg)
  3. Ginkgo biloba leaves dry ex­tract (120 mg)
  4. cre­a­tine mono­hy­drate (1500 mg) and Ginkgo biloba leaves dry ex­tract (120 mg)

It mea­sured:

  1. Back­ward Digit Span

    The num­ber of cor­rectly re­peated num­bers be­fore sup­ple­men­ta­tion and the num­ber of cor­rectly re­peated num­bers after six weeks of sup­ple­men­ta­tion are shown in the table. To bet­ter com­pare the re­sults, the differ­ence be­tween the nu­mer­i­cal val­ues is fur­ther il­lus­trat­ed.

    0 weeks 6 weeks Differ­ence
    Placebo (mal­todex­trin) 6.4 6.8 0.4
    Cre­a­tine mono­hy­drate 6.2 7.9 1.7
    Ginkgo biloba 6.7 7.5 0.8
    Cre­a­tine mono­hy­drate + Ginkgo biloba 6.5 9.2 2.7

    Test Method: Wech­sler, D .: Adult In­tel­li­gence Scale man­ual. (1955) New York: Psy­cho­log­i­cal Cor­po­ra­tion.

  2. Raven’s Ad­vanced Pro­gres­sive Ma­tri­ces

    0 weeks 6 weeks Differ­ence
    Placebo (mal­todex­trin) 8.7 10.2 1.5
    Cre­a­tine mono­hy­drate 8.1 12.7 4.6
    Ginkgo biloba 9.8 12.9 3.1
    Cre­a­tine mono­hy­drate + Ginkgo biloba 9.3 17.2 7.9

    Test Method: Rauen, JC et al .: Man­ual for Raven’s pro­gres­sive ma­tri­ces and vo­cab­u­lary scales. (1988) Lon­don: HK Lewis.

  3. Uchi­da-Krae­pelin test

    The test sub­jects a com­pu­ta­tional test was per­formed, which mea­sures the men­tal fa­tigue. They were given sim­ple com­put­ing tasks with an in­ter­val of 5 min­utes twice 15 min­utes. In the sec­ond 15 min­utes, the num­ber of solved prob­lems per minute were de­ter­mined. The test was per­formed be­fore tak­ing sup­ple­men­ta­tion and after 6 weeks. By lin­ear re­gres­sion analy­sis can be in­ferred from the mea­sured data on men­tal fa­tigue. In Ta­ble 3, the re­gres­sion co­effi­cient a is given (). An en­large­ment of the re­gres­sion co­effi­cient is a di­rect mea­sure of a re­duced men­tal fa­tigue.

    0 weeks 6 weeks Differ­ence
    Placebo (mal­todex­trin) -0.0076 -0.0089 -0.0013
    Cre­a­tine mono­hy­drate -0.0088 -0.0046 0.0042
    Ginkgo biloba -0.0105 -0.0081 0.0024
    Cre­a­tine mono­hy­drate + Ginkgo biloba -0.0097 -0.0021 0.0075

    Test Method: Watan­abe, A. et al .: Neu­ro­science Re­search (Ox­ford, United King­dom) (2002), 42 (4), 279-285

But Gast­ner et al re­ported only pre and post-test scores, and not stan­dard de­vi­a­tions; nor was any kind of sta­tis­ti­cal test re­port­ed, mak­ing it diffi­cult to in­fer any­thing about the re­sults.

It is un­clear where this ex­per­i­ment was done, by whom, or whether it was ever pub­lished. (The “in press” ci­ta­tion to Miel­carz et al 2007 turns out to re­fer to Mc­Mor­ris et al 2007.) Noth­ing in the Eng­lish trans­la­tion in­di­cates that it was pub­lished any­where else; searches failed to find any­thing re­lated to this but the patent it­self; the Uchi­da-Krae­pelin test is un­usual and I tried search­ing for any­thing re­lat­ing to it and cre­a­tine in Google/Google-Scholar in Eng­lish & Ger­man but turned up noth­ing be­sides dis­cus­sions of Watan­abe 2002.

On 2013-09-23, I at­tempted to reach Gast­ner via the Alzchem con­tact form. (Gast­ner knows Eng­lish, as demon­strated by co-au­thor­ing “Cre­a­tine - its chem­i­cal syn­the­sis, chem­istry, and le­gal sta­tus” in Cre­a­tine and Cre­a­tine Ki­nase in Health and Dis­ease.) 3 months later on 2013-12-14, I mailed a phys­i­cal let­ter to the Trost­berg, Ger­many ad­dress listed in Cre­a­tine and Cre­a­tine Ki­nase (“De­gussa AG, Dr. Al­bert-Frank-S­traße 32, D-83308 Trost­berg, Ger­many”). As of 2015-01-08, I have re­ceived no re­sponses to any of my at­tempts.

Ling 2009

saw the cre­a­tine group post-s­core 4 points higher than con­trols

There were 34 par­tic­i­pants (in­clud­ing 12 fe­males) who com­pleted the study, with a mean age of 21 years (SD: 1.38; range: 18-24). Par­tic­i­pants were ex­clud­ed, if they pre­sented with a med­ical his­tory of drug and/or al­co­hol abuse, di­ag­nosed psy­chi­atric dis­or­ders, di­a­betes, re­nal in­suffi­ciency (kid­ney dys­func­tion) or had re­cently or were cur­rently sup­ple­ment­ing with a cre­atine-based sub­stance. None of the par­tic­i­pants was veg­e­tar­i­an.

The fi­nal task par­tic­i­pants un­der­took was a mod­i­fied ver­sion of Raven’s Ad­vanced Pro­gres­sive Ma­tri­ces (e.g. Raven et al., 1998) pre­sented on a PC us­ing Macro­me­dia Flash Player. The diffi­culty of the 39 ques­tions grad­u­ally in­creased and was con­strained by a 40-min time lim­it.

The cited on­line IQ test con­tains only one set of ques­tions and does not ran­dom­ize or vary the se­lec­tion, im­ply­ing that sub­jects an­swered the same ques­tions twice, which is not good (usu­ally IQ tests will come split in equiv­a­lent halves, so one can do pre-tests with the A ques­tions and post-tests with new B ques­tion­s). This may in­val­i­date the ap­par­ent im­prove­ment.

At the end of the first test­ing phase, par­tic­i­pants were given a large en­ve­lope that con­tained 15 plas­tic vials of ei­ther 5 g doses of CEE (ob­tained through the on­line store Dis­count Sup­ple­ments) or a place­bo, mal­todex­trin (ob­tained from the man­u­fac­turer Chem­i­cal Nu­tri­tion;

There was a sig­nifi­cant effect of test phase on per­for­mance in the IQ test [F(1,32) = 88.98, P < 0.01] with par­tic­i­pants scor­ing a mean of 112 (SD: 9.44) at base­line, and 118 (7.89) at the end of the study. There was no sig­nifi­cant main effect of sup­ple­ment con­di­tion [F(1,32) = 0.56, NS]. How­ev­er, the in­ter­ac­tion was sig­nifi­cant [F(1,32) = 81.18, P < 0.01]. Pair­wise com­par­isons in­di­cated that par­tic­i­pants in the cre­a­tine con­di­tion per­formed worse than the placebo group in the first phase of test­ing, with base­line means for cre­a­tine group of 108 (SD: 7.42) and for place­bo, 116 (SD: 9.60) (Tukey HSD, P < 0.01). Per­for­mance of the cre­a­tine group also im­proved sig­nifi­cantly over the sup­ple­men­ta­tion pe­ri­od, with the mean of 108 at base­line in­creas­ing to 120 (SD: 5.95) at the end of study (Tukey HSD, P < 0.01). Fur­ther pair­wise com­par­isons in­di­cated that there was no sig­nifi­cant im­prove­ment in the per­for­mance of the placebo group over the sup­ple­men­ta­tion pe­riod (P > 0.05).

Per­for­mance of the cre­a­tine group also im­proved sig­nifi­cantly over the sup­ple­men­ta­tion pe­ri­od, with the mean of 108 at base­line in­creas­ing to 120 (SD: 5.95) at the end of study

Us­ing the spread­sheet of data Ling pro­vided me:

# ling <- read.csv(stdin(),header=TRUE)
#     Creatine         IQ
#  Min.   :1.0   Min.   :105
#  1st Qu.:1.0   1st Qu.:112
#  Median :1.5   Median :118
#  Mean   :1.5   Mean   :118
#  3rd Qu.:2.0   3rd Qu.:124
#  Max.   :2.0   Max.   :133
i <- ling[ling$Creatine==1,]$IQ; mean(i); sd(i)
# [1] 120.3
# [1] 5.945
i <- ling[ling$Creatine==2,]$IQ; mean(i); sd(i)
# [1] 116.1
# [1] 9.086
# we use a _t_-test rather than a Wilcoxon to replicate Ling's probable analysis
t.test(IQ ~ Creatine, data=ling)
#     Welch Two Sample t-test
# data:  IQ by Creatine
# t = 1.608, df = 27.58, p-value = 0.1192
# alternative hypothesis: true difference in means is not equal to 0
# 95% confidence interval:
#  -1.163  9.634
# sample estimates:
# mean in group 1 mean in group 2
#           120.3           116.1

Hammett 2010

“Di­etary sup­ple­men­ta­tion of cre­a­tine mono­hy­drate re­duces the hu­man fMRI BOLD sig­nal”, Ham­mett et al 2010; quotes rel­e­vant for cal­cu­lat­ing the vari­ables:

To es­tab­lish whether the mag­ni­tude of the BOLD re­sponse is in­flu­enced by Cr lev­els, we have mea­sured re­sponses to vi­sual stim­uli in the pri­mary vi­sual cor­tex (V1) of 22 healthy hu­man vol­un­teers us­ing fMRI, be­fore and after oral ad­min­is­tra­tion of Cr or a placebo (11 in the Cr group and 11 in the placebo group).

The mean and me­dian age of the Cr group was 30.18 and 27 years (SD = 8.37) re­spec­tively and the mean and me­dian age of the placebo group was 25 years (SD = 4.82).

Cre­a­tine sup­ple­men­ta­tion (S­ci-Mx: Glouces­ter­shire, UK) was pro­vided at a dose of 20 g/day for five days, fol­lowed by two ad­di­tional days at a dose of 5 g/day.

In or­der to ver­ify pre­vi­ous re­ports of cog­ni­tive en­hance­ment fol­low­ing Cr sup­ple­men­ta­tion we also mea­sured per­for­mance on the Back­wards Digit Span (BDS) [28] and Raven’s Ad­vanced Pro­gres­sive Ma­tri­ces (RAPM) [24] prior to each scan. The BDS com­prises a set of num­ber se­quences of in­creas­ing length with two differ­ent se­quences of each length. Sub­jects were re­quired to re­peat each se­quence back­wards. The test was ter­mi­nated when the sub­ject failed to re­peat two se­quences of the same length. Differ­ent num­ber se­quences were used for the two test­ing ses­sions. Sub­jects were re­quired to com­plete as many items of the RAPM as pos­si­ble in 5 min. Since the RAPM tests are or­dered in terms of diffi­cul­ty, odd­-num­bered and even-num­bered tests were ad­min­is­tered on weeks 1 and 2 re­spec­tive­ly.

Per­for­mance on the RAPM in­creased non-sig­nifi­cantly by 9.6% fol­low­ing Cr (t = 1.882, df = 10, p = 0.0745) and re­duced non-sig­nifi­cantly by 4.5% (t = 0.7733, df = 10, p = 0.4572) fol­low­ing place­bo. A Group × Week ANOVA re­vealed a main effect of week (F(1, 20) = 5.75, p = 0.026, two-tailed) and a sig­nifi­cant in­ter­ac­tion be­tween week and com­pound (F(1, 20) = 8.58, p = 0.008, two-tailed) for BDS per­for­mance. No sig­nifi­cant effects were found for RAPM per­for­mance.

What’s the stan­dard de­vi­a­tion which pro­duces a p-value of 0.0745 on an in­crease of 9.6% & a sam­ple size of 11 in each group? Hard to tell, but Ham­mett pro­vided me the pre/post scores:

pre post
cre­a­tine mean 12.27 13.45
SD 3.31 2.25
placebo mean 12 11.45
SD 3.52 3.8

Alves et al 2013

Alves data ta­ble

The CR and CR+ST groups re­ceived 20 g of cre­a­tine mono­hy­drate (4 × 5 g/d) for five days fol­lowed by 5 g/d as a sin­gle dose through­out the tri­al.

Alves et al 2013: com­bined the placebo & place­bo+strength­-train­ing groups, and the cre­a­tine & cre­atine+strength­-train­ing groups

  1. The au­thor agrees with cre­atine’s util­ity for ath­let­ics, hav­ing used it for that pur­pose him­self.↩︎