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_21ya), it is not statistically-significant either but does lower the estimate further (given that Rae 2003_21ya 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

Rae2003

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_32ya).

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 eg. for improving memory, retentivity, long-term memory and for preventing mental fatigue condition, comprising eg. Ginkgo biloba, ginseng and niacin” (English translation, original): German patent filed in June 2007_17ya 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 eg. 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.

§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_524ya mg maltodextrin)

2. creatine monohydrate (1500_524ya mg)

3. Ginkgo biloba leaves dry extract (120 mg)

4. creatine monohydrate (1500_524ya 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_69ya) 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_36ya) 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_22ya), 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_17ya turns out to refer to McMorris et al 2007_17ya.) 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_22ya.

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.

Ling2009

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 (eg. Raven et al 1998_26ya) presented on a PC using Macromedia Flash Player [https://iqtest.dk/main.swf]. 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

Hammett2010

“Dietary supplementation of creatine monohydrate reduces the human fMRI BOLD signal”, Hammett et al 2010_14ya; 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-statistically-significantly by 9.6% following Cr (t = 1.882, df = 10, p = 0.0745) and reduced non-statistically-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_11yaA

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_11yaa: combined the placebo & placebo+strength-training groups, and the creatine & creatine+strength-training groups