The full content of Annals is available to subscribers

Subscribe/Learn More  >
Original Research |

Long-Term Multivitamin Supplementation and Cognitive Function in Men: A Randomized Trial

Francine Grodstein, ScD*; Jacqueline O’Brien, ScD*; Jae Hee Kang, ScD; Rimma Dushkes, PhD; Nancy R. Cook, ScD; Olivia Okereke, MD; JoAnn E. Manson, MD, DrPH; Robert J. Glynn, PhD; Julie E. Buring, ScD; J. Michael Gaziano, MD, MPH; and Howard D. Sesso, ScD, MPH
[+] Article, Author, and Disclosure Information

* Drs. Grodstein and O’Brien contributed equally to this work.

From Brigham and Women's Hospital, Harvard Medical School, Harvard School of Public Health, and Veterans Affairs Boston Healthcare System, Boston, Massachusetts.

Acknowledgment: The authors thank the 14 641 physician participants for their long-standing dedication and conscientious collaboration; the long-term contributions of Charles Hennekens, MD, DrPH, Florida Atlantic University, to the Physicians’ Health Study; and the exemplary contributions of the staff of the Physicians’ Health Study at Brigham and Women's Hospital.

Grant Support: By grants CA 097193, CA 34944, CA 40360, HL 26490, HL 34595, AG 15933, and T32-AG000158 from the National Institutes of Health, and an investigator-initiated grant from BASF. Study agents and packaging were provided by BASF and Pfizer, and study packaging was provided by DSM Nutritional Products.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1340.

Reproducible Research Statement: Study protocol: Available from Drs. Sesso (hsesso@partners.org) and Gaziano (jmgaziano@partners.org). Statistical code: Not available. Data set: Not available.

Requests for Single Reprints: Francine Grodstein, ScD, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115; e-mail, phfrg@channing.harvard.edu.

Current Author Addresses: Drs. Grodstein, O’Brien, Kang, Dushkes, Cook, Orereke, Manson, Glynn, Buring, Gaziano, and Sesso: Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115.

Author Contributions: Conception and design: F. Grodstein, J.E. Manson, R.J. Glynn, J.E. Buring, J.M. Gaziano.

Analysis and interpretation of the data: F. Grodstein, J. O’Brien, J.H. Kang, R. Dushkes, N.R. Cook, O. Okereke, J.E. Manson, R.J. Glynn, J.M. Gaziano, H.D. Sesso.

Drafting of the article: J. O’Brien, J.E. Buring.

Critical revision of the article for important intellectual content: F. Grodstein, J. O’Brien, J.H. Kang, R. Dushkes, N.R. Cook, O. Okereke, J.E. Manson, R.J. Glynn, J.E. Buring, J.M. Gaziano, H.D. Sesso.

Final approval of the article: F. Grodstein, J. O’Brien, J.H. Kang, R. Dushkes, N.R. Cook, O. Okereke, J.E. Manson, R.J. Glynn, J.E. Buring, J.M. Gaziano, H.D. Sesso.

Provision of study materials or patients: J.M. Gaziano, H.D. Sesso.

Statistical expertise: F. Grodstein, J.H. Kang, N.R. Cook, R.J. Glynn.

Obtaining of funding: F. Grodstein, J.M. Gaziano, H.D. Sesso.

Administrative, technical, or logistic support: F. Grodstein, J.M. Gaziano, H.D. Sesso.

Collection and assembly of data: F. Grodstein, J.E. Buring, J.M. Gaziano.

Ann Intern Med. 2013;159(12):806-814. doi:10.7326/0003-4819-159-12-201312170-00006
Text Size: A A A

Background: Despite widespread use of multivitamin supplements, their effect on cognitive health—a critical issue with aging—remains inconclusive. To date, no long-term clinical trials have studied multivitamin use and cognitive decline in older persons.

Objective: To evaluate whether long-term multivitamin supplementation affects cognitive health in later life.

Design: Randomized, double-blind, placebo-controlled trial of a multivitamin from 1997 to 1 June 2011. The cognitive function substudy began in 1998. Up to 4 repeated cognitive assessments by telephone interview were completed over 12 years. (ClinicalTrials.gov: NCT00270647)

Setting: The Physicians’ Health Study II.

Patients: 5947 male physicians aged 65 years or older.

Intervention: Daily multivitamin or placebo.

Measurements: A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary end point was a verbal memory score combining 4 tests of verbal memory, which is a strong predictor of Alzheimer disease.

Results: No difference was found in mean cognitive change over time between the multivitamin and placebo groups or in the mean level of cognition at any of the 4 assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was −0.01 SU (95% CI, −0.04 to 0.02 SU) when treatment was compared with placebo. Similarly, cognitive performance did not differ between the multivitamin and placebo groups on the secondary outcome, verbal memory (mean difference in cognitive change over follow-up, −0.005 SU [CI, −0.04 to 0.03 SU]).

Limitation: Doses of vitamins may be too low or the population may be too well-nourished to benefit from a multivitamin.

Conclusion: In male physicians aged 65 years or older, long-term use of a daily multivitamin did not provide cognitive benefits.

Primary Funding Source: National Institutes of Health, BASF, Pfizer, and DSM Nutritional Products.


Grahic Jump Location

Study flow diagram.

PHS = Physicians’ Health Study.

Grahic Jump Location




Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).


Submit a Comment/Letter
Effects of contamination & adherence rates
Posted on December 18, 2013
David L. Keller, MD
Conflict of Interest: None Declared
The authors report that the overall adherence rate was about 2/3 (66%) over the entire study, and that 83.5% of the subjects randomized to multivitamins reporting that they took at least 2/3 of the pills provided. No figures were given for contamination in the placebo group, through the off-protocol self-administration of vitamins either in pill form or in the form of highly fortified foods such as Total cereal (which provides 100% of the RDA for multiple vitamins). Intention-to-treat analysis provides statistically meaningful results but small benefits may wash out due to contamination of the placebo group or non-adherence in the active intervention arm. I suggest that the data be re-analyzed, eliminating all placebo subjects who admitted to taking multivitamins on their own, and all intervention subjects who took less than 90% of the active vitamins they were supplied. While the results would not be statistically pure, they might generate some useful hypotheses about benefits that were missed in this trial due to the rigorous intention-to-treat analysis which was applied.
Submit a Comment/Letter

Summary for Patients

Does Long-Term Multivitamin Supplementation Help Cognitive Function in Men?

The full report is titled “Long-Term Multivitamin Supplementation and Cognitive Function in Men. A Randomized Trial.” It is in the 17 December 2013 issue of Annals of Internal Medicine (volume 159, pages 806-814). The authors are F. Grodstein, J. O’Brien, J.H. Kang, R. Dushkes, N.R. Cook, O. Okereke, J.E. Manson, R.J. Glynn, J.E. Buring, J.M. Gaziano, and H.D. Sesso.


Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.


Buy Now for $32.00

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Related Articles
Journal Club
Topic Collections
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.