Dear Editor
The CONSORT (2025) statement [1] writes about blinding as follows:
“Unblinded outcome assessors may differentially assess subjective outcomes, and unblinded data analysts may introduce bias through the choice of analytical strategies, such as the selection of favourable time points or outcomes and by decisions to remove patients from the analyses. These biases have been well documented,” p.27 in [1].
One of the references to this statement, ref. no. 328, is to the trial by Karlowski, Chalmers et al. (1975) [2]. In the randomized, double-blind, placebo-controlled trial, Thomas Karlowski, Thomas Chalmers et al. observed that 6 g/day vitamin C significantly shortened the duration of colds, yet they concluded “that the effects demonstrated might be explained equally well by a break in the double blind.”
The Karlowski (1975) trial has been widely used as evidence for the existence of the placebo effect, and also as evidence that the observed effects of vitamin C on the common cold are explained by the placebo effect [3]. However, it was shown already in 1996 that the placebo-effect interpretation of Karlowski, Chalmers, et al. was not valid [4-6]. Key issues include:
First, in their subgroup analysis by guessing, Karlowski gives the impression that all the participants were divided into two complementary groups. However, 42% (105/249) of the recorded common cold episodes were missing from the subgroup analysis. Paradoxically, vitamin C showed even greater benefit in the excluded group—yet this was ignored by Karlowski.
Second, Karlowski et al. ignored the fact that there were two kinds of capsules: regular and therapeutic. In their subgroup analysis (those who guessed correctly and those who did not), they did not describe which of the two capsules were guessed correctly or not. There was no evidence that participants correctly guessed the contents of the therapeutic capsules, which were more effective, whereas there was evidence that participants correctly guessed the regular capsules, which were much less effective. Such a finding is inconsistent with the placebo argument.
Third, in vitamin C trials, the placebo for ascorbic acid has usually been citric acid. Ascorbic acid and citric acid cannot be distinguished by taste. However, in the Karlowski trial, the placebo used was lactose, which is sweet. Thus, in the Karlowski trial, a participant administered vitamin C would have had difficulty distinguishing whether their capsule contained ascorbic acid or citric acid, but a participant might infer they were taking the placebo because of the sweet taste of lactose. Surprisingly, more vitamin C (ascorbic acid) participants guessed correctly than placebo participants. This is also inconsistent with the placebo effect speculation.
Fourth, Karlowski did not properly consider other explanations for the ability of participants to correctly guess the contents of their capsules. The ability to guess correctly might reflect real symptom improvement, not a broken blind. Subgroup analyses based on post-randomization factors like guesses are inherently biased.
A re-analysis exposed these issues [4], and Thomas Chalmers’ only rebuttal was that the re-analysis incorrectly referred to “tablets” instead of “capsules” [5,6]. Because of these methodological flaws, the Karlowski trial should not be used as evidence of the placebo effect [3-6].
References:
[1] Hopewell S, et al. CONSORT 2025 explanation and elaboration: updated guideline for reporting randomised trials. BMJ. 2025;389:e081124.
https://pubmed.ncbi.nlm.nih.gov/40228832
[2] Karlowski TR, Chalmers TC, Frenkel LD, Kapikian AZ, Lewis TL, Lynch JM. Ascorbic acid for the common cold. A prophylactic and therapeutic trial. JAMA. 1975;231(10):1038-42.
https://pubmed.ncbi.nlm.nih.gov/163386
[3] Hemilä H, Chalker E. Bias against vitamin C in mainstream medicine: examples from trials of vitamin C for infections. Life (Basel). 2022;12(1):62.
https://pubmed.ncbi.nlm.nih.gov/35054455
[4] Hemilä H. Vitamin C, the placebo effect, and the common cold: a case study of how preconceptions influence the analysis of results. J Clin Epidemiol. 1996;49(10):1079-84; discussion 1085, 1087.
https://pubmed.ncbi.nlm.nih.gov/8826986
https://doi.org/10.1016/0895-4356(96)00189-8
[5] Chalmers TC. To the preceding article by H. Hemilä. J Clin Epidemiol. 1996;49(10):1085.
https://doi.org/10.1016/0895-4356(96)00190-4
[6] Hemilä H. To the dissent by Thomas Chalmers. J Clin Epidemiol. 1996;49(10):1087.
https://doi.org/10.1016/0895-4356(96)00191-6
