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.

   Cre­a­tine mono­hy­drate (CM) is the most com­mon, but also used in a study is cre­a­tine ethyl ester (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.

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

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

Data

Results

Rae 2003

Rae et al 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 ($y=ax+b$). 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

Ling et al 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:

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