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”.

Background

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. 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 ()
  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.

Overview

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.

RAPM

Data

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

Results

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.lb    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.lb   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

Data

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

Results

Source

set.seed(7777) # for reproducible numbers
# TODO: factor out common parts of `png` (& make less square), and `rma` calls
library(XML)
creatine <- readHTMLTable(colClasses = c("integer", "factor", rep("numeric", 6), "factor", rep("numeric", 5)),
                          "https://www.gwern.net/Creatine")[[2]]
# install.packages("metafor") # if not installed
library(metafor)

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 = ", "))
invisible(dev.off())

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 iqtest.dk 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; http://www.cnpprofessional.co.uk).

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
1,120
1,118
1,126
1,121
1,119
1,118
1,125
1,117
1,133
1,116
1,124
1,114
1,110
1,130
1,123
1,116
1,115
2,110
2,112
2,105
2,106
2,115
2,105
2,112
2,124
2,119
2,133
2,116
2,123
2,122
2,110
2,125
2,105
2,131
summary(ling)
#     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

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.↩︎