JANA Vol 4 #2 - American Nutraceutical Association

The Journal of the American Nutraceutical Association 

Vol. 4, No. 2 Summer 2001 

IN THIS EDITION 

• The Role of Lutein in Human Health 

• Efficacy of Vinpocetine in the Management of Cognitive 

Impairment and Memory Loss 

• Pilot Study: Whole Food Nutritional Supplement Increases 

Antioxidant Levels in the Blood 

• The Synergistic Approach:The Future of Nutrition Therapy 

• ANA Commentary on the GAO Report on Health 

Products for Seniors 

AND MORE 

A Forum for Wellness and Optimal Health 

ISSN-1521-4524

Varro E. Tyler, PhD 

1926 - 2001 

Professor Tyler, or Tip as he was affectionately known to his friends and colleagues, was a true giant in the field 

of pharmacognosy and herbal medicine education in the U.S. and abroad. His many accomplishments, books, articles, 

and professional presentations are well known to all in the herbal field. 

Dr. Tyler had a distinguished career in academia. He served as Dean of the School of Pharmacy and 

Pharmaceutical Sciences at Purdue University for 20 years, and was Executive Vice-President for Academic Affairs 

and Provost at Purdue for five years before retiring. He held the Lilly Distinguished Chair in Pharmacognosy, and 

still remained active at Purdue as Dean and Distinguished Professor of Pharmacognosy Emeritus. 

After retirement his life became busier, with an almost peripatetic travel schedule to deliver speeches at professional 

conferences across the U.S. and internationally. As busy as he was, he always found time to help his friends, 

edit an article, and mentor someone on their book. He was always the consummate gentleman and diplomat, and his 

generosity of spirit was boundless. 

Despite experiencing several health challenges in the past decade, he was undaunted in pursuing his goal to establish 

rational herbalism as an appropriate healthcare modality in the U.S. 

Among his many roles, board positions, and consultancies, Professor Tyler was a Trustee of the American 

Botanical Council and served on the editorial advisory board of JANA. 

He will be missed by his many family, friends, and colleagues.

Journal of the 

American 

Nutraceutical 

Association 

EDITORIAL STAFF 

EDITOR-IN-CHIEF 

Mark Houston, MD 

EDITORS 

Medicine - Christopher M. Foley, MD 

Pharmacy - Allen M. Kratz, PharmD 

ASSOCIATE EDITORS 

Bernd Wollschlaeger, MD 

Lisa Colodny, PharmD 

TECHNICAL EDITOR 

Jane Lael 

ART DIRECTOR 

Gary Bostany 

EDITORIAL BOARD 

Russell Blaylock, MD 

Jerome B. Block, MD 

Lisa Colodny, PharmD, BCNSP 

Derrick DeSilva, MD 

Jeanette Dunn, EdD, RN, CNS 

Clare M. Hasler, PhD 

Mark C. Houston, MD, FACP 

Robert Krueger, PhD 

Alexander Mauskop, MD 

Mark J.S. Miller, PhD 

Anthony J. Silvagni, DO, PharmD, MSc 

C.Wayne Weart, PharmD, BCPS, FASHP 

Farred Wassef, RPh 


_____________________________ 

American Nutraceutical Association 

Executive Office 

5120 Selkirk Drive, Suite 100 

Birmingham,AL 35242 

Phone: (205) 980-5710 Fax: (205) 991-9302 

Website: www.Ana-Jana.org 

CEO & PUBLISHER 

Allen Montgomery, RPh 

ANA is an alliance of individuals with interest in 

nutraceutical science, technology, marketing and 

production. It was established to develop and provide 

educational materials and continuing education 

programs for health care professionals on nutraceutical 

technology and science. ANA publishes a quarterly 

newsletter, The Grapevine, and the Journal of the 

American Nutraceutical Association (JANA). 

_____________________________ 

The Journal of the American Nutraceutical Association 

(ISSN-1521-4524) is published four times annually, 

with frequent supplements, by the American 

Nutraceutical Association (ANA). Send all inquiries, 

letters, and submissions to the ANA Editorial 

Department at 5120 Selkirk Drive, Suite 100, 

Birmingham,AL 35242. Contents © 2001 ANA, all 

rights reserved. Printed in the United States of 

America. Reproduction in whole or part is not 

permitted without written permission. It is the 

responsibility of every practitioner to evaluate the 

appropriateness of a particular opinion in the context 

of actual clinical situations. Authors, editors, 

and the publisher cannot be held responsible for 

any typographical or other errors found in this 

journal. Neither the editors nor the publisher 

assume responsibility for the opinions expressed 

by the authors. 

Cover Photograph - Sierra Productions, Irvine, CA. 

Contents – Summer 2001, Vol. 4, No. 2 

C O M M E N T A R Y 

ANA Commentary on the September 10th, 2001 

GAO Report on Health Products for Seniors ........................................ 1 

Allen Montgomery, RPh - ANA CEO and Executive Director 

Barry Fox, PhD - Chair, ANA Consumer Advisory Council 

I N T E R V I E W 

Interview with Barry Fox, PhD 

Chair of the ANA Consumer Advisory Council ......................................3 

L E G I S L A T I V E U P D A T E 

Federal Legislative Update on Dietary Supplements ..........................5 

Kevin J. Kraushaar 

E D I T O R I A L 

Lutein - An Opportunity For Improved Eye Health .............................. 6 

Stuart Richer, OD, PhD, FAAO 

R E V I E W A R T I C L E 

The Role of Lutein in Human Health ...................................................... 8 

Andrew Shao, PhD 

Efficacy of Vinpocetine in the Management of 

Cognitive Impairment and Memory Loss ............................................ 25 


Dietary Supplementation with Chlorella pyrenoidosa 

Produces Positive Results in Patients with Cancer or 

Suffering From Certain Common Chronic Illnesses ............................31 

Randall E. Merchant, PhD, Cynthia A. Andre,Msc 

P E R S P E C T I V E 

The Synergistic Approach: The Future of Nutrition Therapy..............39 

Robert Crayhon, MS 

O R I G I N A L R E S E A R C H 

Pilot Study: Whole Food Nutritional Supplement 

Increases Antioxidant Levels in the Blood ..........................................44 

Rita R. Ellithorpe, MD 

To subscribe to JANA Phone 800-566-3622, 

outside USA 205-833-1750. 

_____________ 

To order reprints of articles, or additional copies of JANA, 

write to or call: 

Deana Hunter, Public Relations Director 

5120 Selkirk Drive, Suite 100, Birmingham,AL 35242 

Phone 205-980-5710 Fax 205-991-9302 

Website: www.Ana-Jana.org

C O M M E N T A R Y 

ANA Commentary on the September 10 th, 2001 

GAO Report on Health Products for Seniors 

Summer 2001 

Allen Montgomery, RPh – ANA CEO and Executive Director 

Barry Fox, PhD – Chair, ANA Consumer Advisory Council 

On September 10, 2001, the U.S. Government 

Accounting Office (GAO) published a report titled: “Health 

Products for Seniors: Anti-aging Products Pose Potential 

For Physical and Economic Harm.” A full copy of this 

report can be found on the Internet by going to 

www.gao.gov. then clicking on GAO Reports. On the next 

screen, click on Daily Reports, then September 10, 2001. 

The GAO Report highlights various topics of concern 

to both healthcare professionals and consumers. Below are 

several topics addressed in the report, with our overview 

and perspective. 

GAO Report: Dietary supplements marketed as antiaging 

therapies may pose a potential for physical harm to 

senior citizens. 

ANA Perspective: Not unlike drug-drug interactions 

and drug contraindications, a number of dietary supplements 

(nutraceuticals) may pose a potential harm for anyone, 

not just senior citizens. There are published reports of 

drug-nutrient and drug-nutraceutical interactions and depletions. 

Specific contraindications include: 

• Ginseng is not recommended for people with hypoglycemia. 

• Kava kava may worsen symptoms of Parkinson’s disease. 

• Saw palmetto is contraindicated for patients with breast 

cancer, while valerian should not be used by those with 

liver or kidney disease without first consulting a physician. 

• Certain supplements should be avoided prior to surgery, 

including Ginkgo biloba, ginseng, St. John’s wort, garlic, 

and valerian. 

• Potential supplement interactions with prescription medications 

should be pointed out to all patients by pharmacists, 

physicians and other healthcare professionals. 

For example: evening primrose oil, garlic, Ginkgo 

biloba, ginseng, and St. John’s wort magnify the effect of 

blood thinning drugs such as warfarin or coumadin, and 

some reports suggest that Ginkgo biloba may reduce the 

effects of seizure medications. These are just a few examples 

of the potential for supplement-drug interactions. 

While this problem is certainly not limited to “seniors,” it 

may be magnified among them as seniors consume more 

prescription drugs. More research and monitoring is needed 

to identify potential problems in this area 

It is the responsibility of healthcare professionals, especially 

pharmacists and physicians, to educate themselves, 

and to make it standard procedure to question their patients 

about the use of both nutraceuticals and pharmaceuticals. 

They must also acknowledge that their patients are consuming 

increasing amounts of nutraceutical products, according 

to this GAO report, spending as much as $5.8 billion dollars 

a year on supplements! Yet pharmacy schools and medical 

schools still do not require formal training in this area 

The ANA is taking steps to help remedy the situation 

by providing continuing education programs on nutraceuticals 

for healthcare professionals. At the ANA Conference 

on Nutraceuticals and Medicine, October 12-13, 2001, in 

Nashville, one presentation, “Drug-Herb-Nutrient 

Interactions: A Guide for the Healthcare Professional,” by 

Bernd Wollschlaeger, MD, Assistant Clinical Professor of 

Medicine, University of Miami School of Medicine, is 

approved for CME and CE for pharmacists and nurses. For 

healthcare professionals who cannot attend the conference, 

this presentation will be available from the ANA on audiotape 

and can be ordered by telephone at 800-566-3622, or 

from the ANA website (www.ana-jana.org). 

Beginning in November, the ANA website will contain 

a list of potential adverse effects, contraindications, and 

potential drug interactions for some of the more popular 

supplements mentioned in the GAO report. 

GAO Report: Unproven anti-aging and alternative 

medicine products pose a risk of economic harm to seniors. 

Vol. 4, No. 2 JANA 1

ANA Perspective: We agree. Before consumers purchase 

health-related products, they should ask for third party 

validation of manufacturers’ claims. For dietary supplements, 

consumers should ask for clinical studies that support any 

dramatic claim of curing diseases such as cancer or AIDS. 

When a company cannot provide data to back up a marketing 

claim, the ANA suggests that the consumer contemplate the 

saying, “if it sounds too good to be true, it probably is”! 

We encourage consumers to use common sense. When 

a product is said to cure cancer, or help you lose 30 pounds 

in one week, there would be more media exposure than a 

press release on the Internet, or an infomercial on television. 

There have been numerous lawsuits against major 

U.S. companies outside of the nutraceutical industry for 

misleading senior citizens with their ads. Deceptive advertising 

affects all industries. Therefore, we encourage senior 

citizens to be cautious when advertisers use dramatic language 

to make claims for their products. 

For consumer guidance, the law that applies to health 

claims that can be made by dietary supplement companies 

is the Dietary Supplement Health and Education Act 

(DSHEA). DSHEA does not allow a company to make a 

disease or health claim for any nutraceutical product. For 

example, if a company advertises that their product will 

cure cancer, treat diabetes, reverse AIDS, or even treat a 

common cold, the company is in violation of a federal law 

and an FDA regulation. Under DSHEA, companies may 

make a “structure/function claim.” For example, a company 

can advertise that its product i.e., echinacea, or beta glucan, 

supports the immune system. 

Responsible companies comply with DSHEA regulations. 

A list of companies found to be in violation of 

DSHEA regulations by the FDA will be posted on the ANA 

website beginning in December. 

On the point in the GAO report dealing with the harmful 

economic impact of supplements, one must put this in 

perspective. The GAO report admits that they could not find 

“any recent, reliable estimates of the economic harm to 

seniors from these products.” However, the report did state 

that 20 companies marketing products to seniors have been 

the subject of law enforcement activities. The report did 

not, however, differentiate between companies manufacturing 

supplements, and those manufacturing other alternative 

medicine devices. According to the GAO report, the average 

economic impact was about $1.8 million per company 

cited. According to the GAO report, “U.S. sales for the 

herbal and specialty supplement industry reached $5.8 billion 

in 2000.” This means that the companies found in violation 

by the FDA – who may not all have been nutraceutical 

manufacturers – represent the sale of about $36 million 

out of $5.8 billion. In our opinion, this does not demonstrate 

a crisis atmosphere that calls for more legislation and regulations 

for dietary supplements. We would, however, like to 

see that $36 million reduced to zero. 

2 JANA Vol. 4, No. 2 

GAO Report: The potential for harm to senior citizens 

from health products making questionable claims has been 

a concern for public health and law enforcement officials, 

and federal and state agencies have activities underway to 

protect consumers of these products. 

ANA Perspective: We applaud government agencies 

that work to stop fraud perpetrated on the American consumer, 

especially senior citizens. However, more needs to 

be done by the government agency that has already been 

granted authority by Congress to deal with these issues. 

It is often stated in the lay and medical press that 

dietary supplements are not regulated by the FDA. This is 

false. Quoting from the GAO Report, “FDA has taken 

enforcement actions against firms selling anti-aging products 

alleged to be dangerous or illegally marketed. It has 

taken actions to remove from the market anti-aging products 

that the agency found were actually unapproved new 

drugs, or medical devices, and actions against firms that 

promoted their dietary supplements for the treatment or 

cure of a disease.” 

If FDA is lacking in funds to expand these efforts, then 

the issue is to find such funds. Should Congress want to 

increase the surveillance of dietary supplement companies 

that make illegally marketed and inaccurate claims, it 

should provide financing to FDA for this service. 

GAO Report: A series of commercial laboratory 

analyses of herbal products showed that 22 percent of 

herbal supplements, and 19 percent of specialty supplements, 

contained substantially less active ingredient than 

that indicated on the label. 

ANA Perspective: We agree. As pointed out in a study 

published in the Journal of the American Nutraceutical 

Association, (Eddington et al. JANA. Spring 2000), a team 

from the University of Maryland School of Pharmacy 

showed that of the 32 products containing chondroitin sulfate 

analyzed, there was a range of 0 to 115% of the actual 

ingredients found in the products, pointing out the need for 

FDA to establish Good Manufacturing Procedures (GMPs) 

for this industry. Government-established GMPs would 

provide an enforceable framework for analysis and acceptable 

methods for evaluating dietary supplements. 

How can the consumer maneuver through this field of 

good and bad quality products? In addition to using common 

sense, consulting the historical record, and getting 

assistance from knowledgeable healthcare practitioners, we 

suggest that consumers find out whether or not a product 

category has been studied in a clinical trial. When it has, 

identify which brand or product performed best and use it. It 

is our suggestion to consumers that they seek out those companies 

and their products that are supported by strong science, 

not simply advertising hype. 

Need for GMPs: These problems highlight the need 

for good manufacturing practices (GMPs) for the dietary 

Summer 2001

supplement industry. While the FDA was granted the 

authority under DSHEA to establish GMPs for the industry 

in 1994, it has not done so. While many companies have 

generated their own high standards, there remain no governmentally-established 

standards with which to comply. 

The focus now should be on implementing existing laws 

and regulations established with the passage of DSHEA, not 

new calls for additional government regulations. 

There is shared responsibility here. Responsible companies 

and trade groups for the industry have called for the 

FDA to respond with the establishment of GMPs for dietary 

supplements. The burden is on the FDA to meet the challenge, 

and on Congress to provide needed funds to meet this 

need and establish GMPs. 

GAO Report: Reports on adverse events associated 

with the use of dietary supplements signal possible risks. 

ANA Perspective: As pointed out earlier, there is a need 

for both healthcare professionals and consumers to recognize 

that some dietary supplements, like pharmaceutical drugs, 

can be dangerous when used improperly, or when consumed 

with certain drugs. In 1993, FDA published a list of dietary 

I N T E R V I E W 

Summer 2001 

supplements for which evidence of harm existed. In 1998, 

the agency also published a guide to dietary supplements that 

included a list of those associated with illnesses and injuries. 

The FDA has also issued warnings and alerts for dietary supplements, 

and posted these to its website. 

This must be put into perspective. There is no paper 

trail of reported adverse events at the FDA to indicate that 

this is a new problem or a crisis. We do agree that the FDA’s 

Center for Food Safety and Applied Nutrition (CFSAN) 

should be adequately funded to upgrade and modernize the 

adverse event reporting system for dietary supplements. 

FDA has stated that it is designing an efficient, reliable system 

to file, categorize, and assist in the evaluation of 

adverse event reports related to the use of dietary supplements. 

The ANA applauds this effort and encourages 

Congress to provide the required funds, considering the 

dramatic growth of this market, and the increased consumption 

of dietary supplements by consumers. 

For more information on regulations and updates on 

dietary supplements, visit the FDA website at 

http://www.cfsan.fda.gov 

Interview with Barry Fox, PhD 

Chair of the ANA Consumer Advisory Council 

The ANA is pleased to announce that Barry Fox, PhD, 

has accepted an appointment as Chair of the ANA 

Consumer Advisory Council. Allen Montgomery, RPh, 

ANA CEO and Executive Director conducted the following 

interview with Dr. Fox. 

Montgomery: Dr. Fox, welcome to the ANA. You’re filling 

a much-needed and long overdue position as liaison 

between our association and the sometimes frustrated and 

confused consumers of nutraceuticals. 

Dr. Fox: Thanks very much. I’m honored to be a part of 

your terrific organization that is dedicated to providing validated 

scientific information on the proper use of nutraceu- 

Montgomery: You’ve made 

quite an interesting career talking 

to and for the consumer 

about health. Tell us a little 

about your background. 

Dr. Fox: I began by writing 

magazine articles on various 

aspects of health with a physician, 

back in the early 1980s. 

We did somewhere in the 

vicinity of 160 articles, covering 

the health spectrum from 

drugs to diet, positive thinking 

to surgery, exercise to endorphins. 

Later I began writing 

ticals to both healthcare professionals and consumers. Barry Fox, PhD 


ooks on health directed to the consumer, and in the past 15 

or so years I’ve written or coauthored over 20 books on topics 

such as the immune system, the prostate, chronic pain, 

death, foods, alternative health, positive thinking, supplements, 

and arthritis. 

Montgomery: Speaking of arthritis, you had a New York 

Times #1 bestseller a couple of years ago called The 

Arthritis Cure, didn’t you? 

Dr. Fox: Yes, that’s the book that introduced glucosamine 

and chondroitin sulfate to the public here in the United 

States as treatments for osteoarthritis. And today, those supplements 

are two of the biggest sellers on the market and 

have provided millions of people relief from pain. 

Montgomery: What made you decide to write about glucosamine 

and chondroitin? 

Dr. Fox: Well, I’d been taking both of them for some time for 

my own knee pain, and they worked. When the initial studies 

conducted in the United States by Nutramax Laboratories validated 

the efficacy of the product, a book communicating this 

information to the consumer made sense. 

Montgomery: And you’re continuing to help people find 

relief from pain with your new book on migraines, What 

Your Doctor May Not Tell You About Migraines. 

Dr. Fox: Yes. This book was the first major project the 

Consumer Advisory Board launched, with ANA member 

Dr. Alexander Mauskop, a leading neurologist who had a 

novel approach to treating migraines. 

Montgomery: And what was his approach? 

Dr. Fox: A combination of magnesium, riboflavin and the 

herb feverfew. Warner Books recently published the book. 

Dr. Mauskop and I are receiving very positive feedback 

from people who have read it. The book is now available in 

major bookstores, through Amazon.com, as well as from 

the ANA website (www.ana-jana.org). 

Montgomery: We also mention those three supplements in 

our first ANA book, Nutraceuticals: The Complete 

Encyclopedia of Supplements, Herbs, Vitamins and Healing 

Foods, published earlier this year by Penguin Putnam. But 

you and Dr. Mauskop really go into detail. So, now that the 

migraine book has been published, what’s next? 

Dr. Fox: After talking with numerous physicians and “regular 

folks” about their major concerns, I’ve decided to focus 

on fatigue and cardiovascular disease. I’m working with the 

chairperson of ANA’s Medical Advisory Council, Dr. Mark 

Houston, on a book about supplements that can help control 

hypertension. And I’m discussing a “new look” at dealing 

with fatigue with Dr. Steven Rosenblatt, MD, PhD, which 

we hope will become a book. Meanwhile, I’m looking forward 

to working with supplement companies, other health 

experts, and consumers on developing new projects that 

will be of assistance to consumers. 

Montgomery: What types of new projects do you anticipate? 

Dr. Fox: Well, I’d love to do something about how to analyze 

medical studies so that consumers know which are 

worthwhile and which aren’t. And perhaps an article with 

helpful hints for consumers about talking with their doctor 

about the use of dietary supplements, which can be a bit 

tricky when your physician isn’t like-minded. I’d also like to 

develop easy ways for people to select the best brands of 

supplements for themselves. Many people have told me they 

become absolutely bewildered when they stand in front of 

rows and rows of supplements in the stores. They just don’t 

know which ones to buy. And I’m open to other ideas. 

Montgomery: Those all sound like really helpful consumer 

projects. Once again, we’re glad to have you aboard. We 

look forward to a productive relationship – and to helping 

lots of people. 

Dr. Fox can be contacted by email at 

TayFox@aol.com, or by telephone at 818-594-0379. 

For Consumer 

Information on 

Nutraceuticals 

visit the ANA 

website: 

www.ana-jana.org 

4 JANA Vol. 4, No. 2 Summer 2001

L E G I S L A T I V E U P D A T E 

* Correspondence: 

Kevin J. Kraushaar 

CHPA 

1150 Conneticut Avenue, NW 

Washington, DC 20036 

Phone: 202-429-9260 Fax: 202-223-6835 

Summer 2001 

Federal Legislative Update 

on Dietary Supplements 

Kevin J. Kraushaar* 

Vice President and Director of Government Relations 

Consumer Healthcare Products Association–Washington, DC 

FEDERAL FUNDING FOR DIETARY 

SUPPLEMENTS 

One of the many legislative challenges for the dietary 

supplement industry on Capitol Hill has been to seek 

Congressional funding for the dietary supplement regulatory 

system at FDA. As FDA moves toward full implementation 

of the Dietary Supplement Health and Education Act 

(DSHEA), the Agency must be given the necessary 

resources to comply with their regulatory obligations. Up 

until this year, Congress has been reluctant to appropriate 

federal funds so that the Agency can implement the law. 

In its annual request to Congress for next year’s budget, 

FDA’s Center for Food Safety and Applied Nutrition 

(CFSAN) requested $1 million to upgrade and modernize 

the adverse event reporting (AER) system for dietary supplements. 

In making the request, CFSAN stated that consumption 

of dietary supplements has grown dramatically 

over the last decade. The Agency stated that it was designing 

an efficient, reliable system to file, categorize, and assist 

in the evaluation of adverse event reports related to the use 

of dietary supplements. 

Most of the dietary supplement industry has strongly 

supported a modernization of the adverse event reporting 

system for several years. Therefore, industry officials 

immediately began lobbying members of the Congressional 

appropriations committees in support of the request. 

The U.S. House of Representatives has approved an 

appropriations bill for FDA for the next fiscal year. The 

House report that accompanied the bill stated that the 

Appropriations Committee was concerned that FDA has not 

taken proper steps to address problems with AERs for dietary 

supplements. Therefore, the Committee directed FDA to follow 

recommendations made by the General Accounting 

Office and the Department of Health and Human Services 

(HHS) Office of Inspector General as part of the Agency’s 

overall plan to consolidate and improve the AER system. 

The Senate Appropriations Committee has approved a 

similar FDA appropriations request and sent the bill to the 

Senate floor. However, the Senate bill has designated an 

additional $2 million over the $1 million requested to 

improve and upgrade the AER system. 

Once the Senate approves its version of the FDA 

Appropriations Bill, a House-Senate conference committee 

will meet to iron out the differences between the two bills. 

Dietary supplement industry advocates will be urging 

members of the House of Representatives to agree to the 

Senate version on this issue. 

Assuming that FDA will be able to promulgate rules 

for good manufacturing practices (GMPs) for dietary supplements 

in the near future, an additional lobbying effort 

next year will be necessary to ensure that Congress appropriates 

money for FDA to implement GMPs and provide 

enforcement. While FDA has been slow to seek appropriate 

funding to implement and enforce DSHEA since it 

passed the Congress in 1994, current leadership at CFSAN 

has developed a comprehensive strategic plan for dietary 

supplements. For its part, Congress is beginning to find the 

money to implement that plan. 

SENATORS HARKIN AND HATCH ASK HHS FOR 

GMPS 

U.S. Senators Tom Harkin (D-IA) and Orrin Hatch (R- 

UT) again united to urge the Department of Health and 

Human Services (HHS) to move forward on FDA’s proposed 

good manufacturing practice (GMP) regulations for 

dietary supplements. In a July 17 joint letter to HHS 

Secretary Tommy Thompson, the Senators expressed their 

disappointment that, seven years after the enactment of the 

Dietary Supplement Health and Education Act (DSHEA), 

GMP standards have not yet been adopted. They strongly 

recommended that HHS “end the long delay and move 

quickly to finalize these important consumer protection 

standards” and asked that Thompson inform them as to 

when he expects the regulation will be finalized. 


E D I T O R I A L 


Lutein – An Opportunity For 

Improved Eye Health 

Stuart Richer, OD, PhD, FAAO* 

Chief, Optometry- Eye Clinic/Operative and Invasive Procedures – DVA Medical Center, and 

Clinical Associate Professor, Family Medicine, FUHS/Chicago Medical School, 

North Chicago, Illinois 

Dr. Andrew Shao is among few scientists, and even 

fewer clinicians, who appreciate the weight of evidence and 

emerging potential for improved eye health and vision in 

the aging industrialized population centers of the world. In 

his article: The Role of Lutein in Human Health, Dr. Shao 

devotes his review to a neglected dihydroxy carotenoid that 

plays both preventative and therapeutic roles in optimizing 

eye health. Lutein as well, shows early promise in cardiovascular 

health and myriad cancers. 

I have devoted a good part of my career to the study of 

Age Related Macular Degeneration (ARMD). It remains 

the leading cause of untreated vision loss in aging western 

Caucasian societies, accounting for 45 % of all visual disability 

in the US. 1,2 ARMD is three times more common 

than glaucoma. Unlike glaucoma, however, there is no medical 

treatment for the most common dry atrophic form of the 

disease, which affects 90% of all visually disabled people. 

ARMD is a bilateral disease, gradually robbing a person of 

critical central visual function – the vision each of us 

requires to read or drive a car. Increasing age is associated 

with increasing prevalence of ARMD in all studies, 1-4 with 

approximately 60 % of 90- year-olds and above effected. 5 

ARMD has increased in Britain in the last 60 years, ruling 

out genetic predisposition as the primary etiologic factor.4 

It has begun to emerge in Japan as the Japanese shift to a 


Stuart Richer, OD, PhD, FAAO 

Chief, Optometry- Eye Clinic/Operative and 

Invasive Procedures 

DVA Medical Center, North Chicago, IL 60064 

Phone: (847) 688-1900 ext. 85406 

Fax: (847) 578-6924 

E-mail: Stuart.Richer@Med.VA.Gov 

more westernized diet. 3 Dark green leafy vegetables, a 

major food source of lutein and other important nutrients, 

are consumed on a limited basis in the western diet. While 

reduced consumption of lutein is specifically associated 

epidemiologically with both cataract and ARMD, for perspective, 

there are more than a dozen nutrients associated 

with ocular health. 7 

ARMD is a complex disorder involving genetic, cardiovascular 

and environmental components. From a genetic 

standpoint, the disease is of multifactorial etiology with 

multiple genes modifying susceptibility to exogenous 

interrelated factors. 8 In 1993, we hypothesized that ARMD 

might, in part, be a nutrition responsive disorder. 9 In 1996 

we demonstrated in a Department of Veterans Affairs double-blind, 

randomized, multicenter prospective clinical 

trial, that atrophic ARMD could be stabilized with nutritional 

intervention in the form of broad-spectrum antioxidants 

(sans lutein). 10,11 Although vision stabilized, no 

study patients actually improved. The situation changed 

dramatically in early 1999 when we published preliminary 

pilot data demonstrating improvement in visual function in 

the majority of ARMD patients placed on either increased 

dark green leafy vegetables (lutein-rich spinach), or lutein 

supplements.12 Our unpublished case reports since 1999 

have been equally striking. With a proper evaluation system, 

based upon both retinal physiology/pathophysiology 

and physiological optics, 13 it now appears feasible to 

reverse or regenerate visual function in atrophic ARMD 

patients. Results of a 90-patient prospective, randomized, 

double-masked, placebo controlled lutein/lutein-antioxidant–ARMD 

study awaits peer review. 14 

It has been said that the eyes mirror health. In his 

excellent review, Dr. Shao raises the exciting prospect that 

macular pigment density may serve as an in vivo surrogate 

Summer 2001

marker of systemic carotenoid status and ocular health. Of 

course, establishing a nutrient to be essential (i.e. a vitamin) 

requires proving causality in depletion/repletion experiments. 

Although, the Malinow et al. depletion studies were 

unable to assess visual acuity, the retinal appearance of 

monkeys deprived of lutein is identical in appearance to that 

of humans with atrophic ARMD, the most common ARMD 

subtype we see in the clinic. 15 Add to this the epidemiological, 

biologic structure/function, and emerging prospective 

clinical repletion data, and it all suggests that lutein is positioned 

to have an important, if not essential role, in 21 st century 

eye care. 

REFERENCES 

1. Klein R, Klein B. Prevalence of age-related maculopathy: The 

Beaver Dam Eye Study. Ophthalmology. 1992;99:933-943. 

2. Klein R, Klein B, Jensen S. The five-year incidence and progression 

of age-related maculopathy: The Beaver Dam Eye 

Study. Ophthalmology. 1997;104:7-21. 

3. Maruo T, Ikebukuro N, Kawanabe K, Kubota N. Changes in 

causes of visual handicaps in Tokyo. Jpn J Ophthalmol. 

1991;35:268-272. 

4. Evans J, Wormald R. Is the incidence of registrable age-related 

macular degeneration increasing? Br J Ophthalmol. 

1996;80:9-14. 

5. VanNewkirk M, Nanjan M, Wang J, Mitchell P, Taylor H, 

McCarty C. The prevalence of age-related maculopathy: The 

visual impairment project. Ophthalmology. 2000;107:1593-1600. 

6. Yuzawa M, Hagita K, Egawa I, Minato H, Matsui M. Macular 

lesions predisposing to senile disciform macular degeneration. 

Jpn J Ophthalmol. 1991;35:268-272. 

7. Richer S. Antioxidants and the Eye. In: Friedlaender MH, ed. 

International Ophthalmology Clinics. Philadelphia: Lippincott 

Williams & Wilkins; 2000:1-16. 

8. Ryan S. Retina. Chapters 67 & 68. St. Louis,MO: CV Mosby; 1994. 

9. Richer SP. Is there a prevention and treatment strategy for macular 

degeneration? J Am Optom Assoc. 1993;64:1-13. 

10. Richer S. ARMD Study Group -VA/PUCO Multicenter ophthalmic/nutritional 

ARMD Study - Part 1: Design, subjects & 

procedures. J Am Optom Assoc. 1996;67:12-29. 

11. Richer S. ARMD Study Group: Multicenter ophthalmic and 

nutritional age-related macular degeneration study-Part 2: 

antioxidant intervention and conclusions. J Am Optom Assoc. 

1996;67:30-49. 

12. Richer S. Part II: ARMD Pilot (case series) environmental 

intervention data. J Am Optom Assoc. 1999;70:24-36. 

13. Richer S. Part I: A protocol for the evaluation and treatment of 

atrophic age-related macular degeneration. J Am Optom 

Assoc. 1999;70:13-23. 

14. Levy S. Researchers suggest new way to treat macular degeneration. 

Drug Topics. 1999:56. 

15. Malinow M, Feeney-Burns L, Peterson L, Klein M, Neuringer 

M. Diet related macular anomalies in monkeys. Invest 

Ophthalmol Vis Sci. 1980;19:857-863. 

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Summer 2001 Vol. 4, No. 2 JANA 7



The Role of Lutein in Human Health 



Kemin Foods, LC 

600 East Court Avenue, Suite A 

Des Moines, IA 50309 

Phone: 515-248-4000 Fax: 515-248-4051 

Email: ashao@keminfoods.com 


Technical Services Manager – Vitamins and Dietary Supplements 

Kemin Foods, L.C., Des Moines, Iowa 

ABSTRACT 

Lutein is a unique dihydroxy-carotenoid (or xanthophyll) 

present in many plants consumed in the human diet. 

In humans, as in plants, lutein is believed to function in two 

ways: first as a filter of high energy blue light, and second 

as an antioxidant that quenches photo-induced free radicals 

and reactive oxygen species (ROS). Epidemiologic evidence 

suggests that lutein consumption is inversely related 

to eye diseases such as age-related macular degeneration 

(AMD) and cataracts. This is supported by the finding that 

lutein (and a related compound, zeaxanthin) are specifically 

and selectively deposited in the macula lutea, an area of 

the retina responsible for central and high acuity vision. 

Macular pigment, a yellow color in the center of the macula, 

functions as a filter of the high energy blue light that 

protects the sensitive rods and cones, and is comprised solely 

of lutein and zeaxanthin. Human intervention studies 

show that lutein supplementation results in increased macular 

pigment. This suggests that lutein supplementation 

may protect against AMD. There is also evidence suggesting 

that lutein may have a protective effect against other 

chronic diseases, such as certain cancers and cardiovascular 

disease. However, further research is needed to determine 

optimal lutein doses. The following paper represents a 

comprehensive review of the available evidence supporting 

a beneficial role for lutein in human health. 

INTRODUCTION 

Carotenoids are a class of compounds responsible for 

the yellow and red pigments present in many commonlyconsumed 

fruits and vegetables with large amounts found 

in green leafy vegetables such as spinach. 1,2 Hundreds of 

these compounds exist in nature, yet only a handful have 

been detected in human serum (Table 1) and tissues. 3,4 

These select few may have some biologic function in 

humans. Consequently, their consumption may play a role in 

maintaining human health. (5,6) Many observational epidemiologic 

studies have shown an inverse relationship between 

carotenoid intake and serum levels, and risk for diseases such 

as cancer and cardiovascular diseases. 5 While these studies 

suggest that carotenoids may protect against chronic disease, 

they have not firmly established a basis for the biologic plausibility 

that they are involved in human health. For the majority 

of the carotenoids present in the human body, little investigation 

has been done on specific function or tissue deposition. 

In addition, intervention studies have primarily focused 

Table 1. Distribution of the major carotenoids in human serum 

Carotenoid % Distribution in Serum 

Lutein 20 

Lycopene 20 

α-carotene 10 

ζ-carotene 10 

Phytofluene 8 

β-cryptoxanthin 8 

β-carotene 6 

α-cryptoxanthin 4 

Phytoene 4 

Anhydrolutein 3 

Zeaxanthin 3 

γ-carotene 2 

Neurosporene 2 

Summer 2001

on the use of β-carotene and its effect on various forms of cancer, 

and have been met with equivocal results. 7-9 

Lutein is a well-known carotenoid found readily in the 

human diet, serum, and tissues (Table 1). 10 Similar to other 

carotenoids, epidemiologic data supports the hypothesis that 

lutein intake is inversely associated with chronic diseases, 

such as cancer of the breast11-13 and colon, 14-16 and ocular diseases 

such as cataracts17-20 and AMD. 21-22 Lutein has also 

been shown to be selectively and specifically deposited in 

ocular tissues such as the macula, supporting the biologic 

plausibility of lutein as a bioactive carotenoid. 23 Furthermore, 

macular pigment optical density (MPOD), which consists 

entirely of the carotenoids lutein and zeaxanthin, may be a 

potential biologic marker of both lutein status and macular 

health. 24 These findings and others have helped to establish 

lutein as a unique carotenoid, and are reviewed extensively in 

this article. 

Lutein in nature 

Carotenoids were originally thought to serve solely as 

vitamin A precursors in the human body, but this has since 

been shown to be limited primarily to the hydrocarbon 

carotenoid, β-carotene (Figure 1). 25 Research over several 

decades has revealed that carotenoids are capable of far 

more than provitamin A activity. They are known to act naturally 

in plants in two important ways: first in a photoprotective 

manner by absorbing damaging blue light from sunlight; 

second as a quencher of photo-induced free radicals 

and reactive oxygen species (ROS). 26,27 

Figure 1. Cleavage of β-carotene to form retinal and 

retinol (vitamin A).Note that certain xanthophylls such as 

lutein do not possess provitamin A activity. 

Lutein, and a related compound zeaxanthin, are classified 

together in nature as dihydroxy xanthophylls, possessing 

two hydroxyl groups. In contrast, hydrocarbon 

carotenoids such as β-carotene and lycopene possess no 

oxygen atoms (Figure 2). 28,29 The hydroxyl groups render 

lutein and zeaxanthin more polar than the hydrocarbon 

carotenoids, and may contribute to their unique role in ocular 

tissues. Lutein is found extensively in the human diet, 

primarily in dark, leafy green vegetables such as spinach 

and kale. 30 Although purified and crystallized lutein displays 

a distinct orange-yellow color (Figure 3), its color is 

not evident in green leafy vegetables due to a masking 

effect by chlorophyll. Lutein intake appears to be declining 

in the US to between 1.5 and 2 mg/day, likely due to a 

decrease in the consumption of dark greens. 31 

II. LUTEIN AND EYE HEALTH 

Age-related macular degeneration 

AMD, a degradation of the central portion of the retina 

(the macula lutea), is the principal cause of blindness 

among people age 65 and older. 32 The macula is located in 

the posterior portion of the retina and possesses the highest 

concentration of photoreceptors responsible for central 

vision and high resolution visual acuity. 33 It is a circular 

area 5-6 mm in diameter with the fovea located at its center 

(Figure 4). Age-related macular degeneration can be 

classified into two categories: (1) early (or dry AMD) characterized 

by accumulation of soft drusen (oxidatively damaged 

cells and their components), and depigmentation of 

Figure 2. Hydrocarbon carotenoids and xanthophylls. 

Shown top to bottom are lycopene, β-carotene, zeaxanthin, 

and lutein. 


the retinal epithelium, and (2) late (or wet AMD) is characterized 

by neovascularization of the macula and retina, and 

accumulation of scar tissue. 34 Advanced AMD often leads 

to irreversible blindness, and there is currently no effective 

treatment. 35 Many factors contribute to an increased risk for 

AMD, including age, cigarette smoking, female sex, light 

iris color, family history, sunlight exposure, and poor nutritional 

status (Table 2). 36,37 

Epidemiological evidence supporting a protective effect 

of lutein against AMD 

In 1988 Goldberg et al. analyzed a cross-sectional sample 

from the National Health and Nutritional Examination 

Survey (NHANES), which used questionnaires to assess 

nutrient intake in AMD cases and controls with healthy maculae. 

It was found that diets high in fruits and vegetables 

were inversely associated with AMD risk. 38 Such diets are 

also high in many carotenoids, including lutein. 30 In 1992 

the Eye Disease Case-Control Study Group obtained personal, 

medical, physiological, biochemical, and ocular data 

on 421 AMD patients and 615 controls. 

Serum carotenoids (lutein, zeaxanthin, β-carotene, acarotene, 

cryptoxanthin, and lycopene) were found to be 

inversely related with AMD risk. 21 Further analysis showed 

that prevalence of AMD among those in this sample with 

total serum carotenoid concentrations ≥ 2.39 µmol/L was 

66% lower than the prevalence among those with levels 

≤1.02 µmol/L. 21 Although these studies provided a basis 

for the hypothesis that dietary carotenoids in general may 

Figure 3. Purified crystalline lutein. Purified lutein crystals 

isolated from marigold flower extract. Photo courtesy of 

Kemin Foods. 


have a protective effect against AMD, lutein and zeaxanthin 

(and their metabolites) are the only carotenoids found in the 

macula, and constitute the entire macular pigment. 33 This 

suggests that the observed protective effects of high fruit 

and vegetable intake and high carotenoid consumption may 

be due solely to lutein and zeaxanthin intake. 

Figure 4. The human eye. Shown is the macula lutea, 

located in the mid portion of the retina. 

Table 2. Risk factors for AMD 

Parameter Hypothesis 

Age Accumulation of 

photo-oxidative damage 

Smoking Increase in amount of free 

radicals; depletes body of antioxidants 

Body fat Increased storage, 

less utilization of xanthophylls 

Female sex Increased storage, less 

utilization of xanthophylls 

due to body fat 

Light iris color Decreased capacity to filter 

damaging blue light 

Family history Genetic component to susceptibility 

Sunlight exposure Increased amount of 

damaging blue light 

Poor nutritional status Insufficient antioxidant supply 

Fat intake Increased source of PUFAs 

promoting lipid peroxidation 

Caucasians Lower melanin content, 

less protection against blue light 

Summer 2001

The true ground-breaking epidemiological study showing 

a direct relationship between lutein intake and AMD 

risk was reported by Seddon et al. in 1994. Among the specific 

carotenoids, lutein and zeaxanthin were most strongly 

associated with decreased AMD risk (57% lower risk for 

highest quintile of lutein intake, 6mg/day, relative to the 

lowest quintile, 0.5 mg/day). 22 Consistent with this finding 

was the inverse association between intake of spinach and 

collard greens, two foods richest in lutein and zeaxanthin, 

and AMD risk. This suggests that individuals deficient in 

lutein intake are at higher risk for AMD. Subsequent epidemiological 

studies have not reported such striking relationships, 

with an inverse association between lutein intake 

and serum levels and AMD risk being marginal at best. 39,40 

However, it should be acknowledged that many of these 

study outcomes may be affected by unaccounted for physiologic 

and nonphysiologic confounders. For example, 

Mares-Perlman et al. reported finding no relationship 

between lutein intake and AMD risk, but a weak association 

between serum levels and AMD risk in a group of 

NHANES III subjects. 40 This inconsistency may be due to 

effects of bioavailability, unreported carotenoid supplementation 

by subjects, and even inaccuracies in the nutrient 

content of reported foods, all of which would contribute to 

diluting relationships by increasing variability. Thus, while 

future epidemiological studies (ideally prospective in 

nature) should take these confounders into account, the 

available evidence supports the hypothesis that lutein plays 

a protective role against AMD. 

Biologic plausibility and mechanism of action 

Light-induced retinal damage depends largely on 

wavelength, exposure time, and power level, with blue light 

(440 nm) requiring 100 times less energy to cause damage 

than orange light (590 nm). 41 Because of its molecular 

structure, lutein does not absorb UV light (maximum 

absorption at 446 nm, at the blue range of the electromagnetic 

spectrum). 

Rather, all UV light entering the eye is absorbed by the 

lens. Elevation of blood oxygen levels in monkeys exposed 

to blue light is associated with increased macular damage, 

suggesting that the basic mechanism of photo-induced damage 

involves free radicals produced by light and reactive 

oxygen species. 42 Characteristics of the macular pigment 

make it well suited to serve as a filter of incoming blue light, 

such as its orientation (back of the retina), and its absorption 

spectrum (420-460 nm). It is well accepted that the macular 

pigment’s primary purpose is to function in a photoprotective 

manner by filtering out damaging blue light. 24 Indeed, 

Hammond et al. revealed that, in older subjects, the 

strongest positive association between MPOD and visual 

sensitivity was observed at 440 nm (vs. 550 nm) light. 43 In 

a recent report by Beatty et al., macular pigment was shown 

to be significantly inversely related to age and predisposition 

to AMD in a group of 46 subjects. 44 These findings from 

human studies suggest that the macular pigment serves to 

protect the ocular cells of the macula, and that age-related 

decreases in MPOD may increase susceptibility to macular 

degeneration. 

Perhaps the most compelling piece of evidence supporting 

a protective role for lutein in AMD is its selective 

and specific deposition in the macula. Of all the carotenoids 

found in human serum, only lutein and zeaxanthin (and their 

metabolites) are located in the macula, with their concentration 

being greatest at the center of the fovea, diminishing 

with increasing eccentricity (Figure 4). 45 A number of studies 

have reported that lutein and zeaxanthin are solely 

responsible for macular pigment. 23,46,47 Not surprisingly, 

these two xanthophylls absorb light of the characteristic 

blue wavelength. 48 Researchers have discovered what is 

believed to be an intermediate metabolite in the conversion 

of lutein to zeaxanthin, meso-zeaxanthin, in the macula. 49 

This suggests that in addition to having its own biologic 

activity, lutein may act as a precursor of zeaxanthin. 

As a highly vascularized tissue possessing a high concentration 

of polyunsaturated fatty acids (PUFAs), the macula 

is particularly susceptible to free radical oxidative damage. 

33 The presence of oxidative metabolites in the macula50 

suggests that lutein may also offer protection to the 

cells of the macula by acting as an antioxidant. Several 

investigators have published reviews proposing that antioxidants, 

including lutein and zeaxanthin, help to inhibit 

drusen formation and preserve macular health by acting as 

free radical quenchers (Figure 5). 28,34 Use of retinal pigment 

epithelium (RPE) cells in culture as an in vitro model 

has shown that treatment with antioxidants, including zeaxanthin, 

dramatically decreased oxidative stress-induced 

lipid peroxidation and apoptosis (cell death). 51 Thus, the 

available evidence supports the notion that lutein and zeaxanthin 

comprise the macular pigment, and provide photochemical 

protection to the macula. 

While it is clear that lutein and zeaxanthin comprise 

the macular pigment, which in turn is proposed to protect 

the cells of the macula from photo oxidative damage, little 

has been done to investigate whether or not the concentrations 

of lutein and zeaxanthin in the macula, per se, are 

associated specifically with AMD risk in humans. A group 

that includes two of the world’s leaders in ophthalmology 

research, Dr. Richard Bone and Dr. John Landrum, 

addressed this issue in a recent publication. Investigators 

obtained donor eyes from AMD patients and control subjects, 

and measured the concentrations of lutein and zeaxanthin 

in the central regions of the retina (area including 

and surrounding the macula). Within the inner region (area 

most closely surrounding the macula), those subjects possessing 

the highest quartile of concentration were 99.9% 

less likely to have AMD relative to those with the lowest 

quartile (Figure 6). 52 This study was the first to specifical- 


Figure 5. Proposed model for AMD protection by antioxidants. (From Winkler 1999.) 

Oxidation 

Photoxidation 

ly examine the relationship between lutein and zeaxanthin 

concentration in the macular region and AMD risk in 

humans. Such a relationship has not been reported for any 

other carotenoid. 

Although research at the cellular level directed at defining 

lutein’s mechanism of action in the macula is in its 

infancy, initial studies offer encouraging insights. The 

group headed by Dr. Paul Bernstein from the University of 

Utah addressed this issue by isolating and purifying a puta- 


Dark Sunglasses 

Macular pigment 

(Lutein/zeaxanthin) 

Oxidants 

Free Radicals 

Reactive Oxygen 

Species 

Figure 6. Odds ratio (risk) for AMD as a function of lutein 

concentration quartile in the inner region of the fovea in 

AMD cases vs. controls. Retinas were collected from donor 

eyes (AMD patient cases, n = 56; and controls, n = 56) and 

analyzed for lutein and zeaxanthin concentration by HPLC. 

The above figure is representative of data collected from 

concentrations in the inner part of the fovea, where the relationship 

was strongest. *95% CI; p = 0.0005 for trend. 

From Bone et al. 2001. 

Antioxidants/Enzymes 

Carotenoids 

Lutein 

Glutathione 

Vitamins C & E 

Lipid Peroxides 

Oxidized Proteins 

DNA Breaks 

ARMORY OF PROTECTANTS 

Repair/Replace 

Disease 

Figure 7. Binding of various carotenoids to XBP. Indicated 

carotenoids were added at 4 µM concentrations to xanthophyll-binding 

protein (XBP) preparations from human 

peripheral retina. Shown is the mean ±SEM for the peak 

A 260/A 280 ratio (measurement of binding) determined by 

gel filtration chromatography; n = 3 – 5. From Yemelyanov 

et al. 2001. 

tive xanthophyll-binding protein (XBP) from human retina 

tissue. Using a combination of ion-exchange and gel-filtration 

chromatography, this group isolated two putative xanthophyll-binding 

proteins from human macular tissue of 25 

and 55 kDa, respectively, with the former likely being a 

truncated form of the latter. 53 The XBP was shown to bind 

selectively and specifically to the xanthophylls (lutein, 

zeaxanthin, β-cryptoxanthin) with the highest affinity being 

for lutein (Figure 7). In contrast, other plasma-binding pro- 

Summer 2001

teins, such as albumin and low-density lipoprotein had little 

or no affinity for any of the carotenoids. These data are the 

first to demonstrate the presence of a specific lutein-binding 

protein in ocular tissues. It is the first insight into establishing 

a potential transport pathway for lutein from the 

serum and/or retina to the macula. 

Nutritional importance of lutein in AMD 

Although epidemiological studies offer strong support 

for the notion that lutein consumption may be inversely 

related to AMD risk, they are associative, and do not test 

causality. Controlled intervention studies are needed to 

determine whether lutein consumption per se results in a 

direct health benefit. Due to the lengthy nature of AMD 

development, it is very costly to test this using the disease 

as the endpoint. Thus, for nutritional intervention studies, 

scientists have turned to using macular pigment as a surrogate 

“biomarker” for lutein action. As previously discussed, 

MPOD, readily measured in animals and humans, is 

well accepted as a marker of macular health. 24 One of the 

first lutein nutritional intervention studies was performed 

on rhesus monkeys, a well-known human model, by 

Malinow et al. in 1980. 54 Monkeys maintained on a standard 

laboratory diet containing lutein possessed normal 

MPOD levels, and drusen was nearly undetectable. 

However, monkeys maintained on a xanthophyll-free diet 

possessed no macular pigment, a high level of drusen in the 

pigment epithelium, and serum xanthophylls were undetectable. 

This study has been followed by a recent report by 

Neuringer et al. showing once again that maintaining rhesus 

monkeys on a xanthophyll-free diet results in zero macular 

pigment. They also showed that repleting the monkeys 

with a diet supplemented with 6 mg/kg/day lutein and 2.2 

mg/kg/day zeaxanthin, restored MPOD to near normal levels 

in 6 to 12 months. 55 These studies provide evidence 

from a well-utilized human model that lutein and zeaxanthin 

are required for macular pigment, and that they must be 

obtained from the diet. 

Controlled intervention studies in humans have now 

begun to appear in the literature (summarized in Table 3). 

Collectively, these studies have shown that providing lutein 

to humans from foods, 56,57 marigold flower extract (lutein 

esters), 58,59 or purified/crystalline lutein from marigold 

flowers, 60 results in significant increases in serum lutein 

and MPOD in normal subjects. While serum lutein levels 

typically increase within hours of ingestion, several or 

more weeks are required before increases in MPOD are 

detected. However, as shown by Johnson et al. (Figure 8) 

the MPOD density and serum lutein do follow the same 

pattern, suggesting that the increase in MPOD is supplied 

by serum lutein obtained from supplementation. 57 In contrast 

to lutein serum levels, the MPOD remains elevated for 

at least two months after supplementation. Doses as low as 

2.4 mg lutein/day (purified form of lutein supplement) for 

six months increased MPOD by 10% (Figure 9). 60 As 

expected, the bioavailability of lutein from vegetables, such 

as spinach is lower than purified lutein (Johnson et al. 2000 

vs. Landrum et al. 1997), but greater than lutein esters. The 

largest response per mg in both serum lutein and MPOD 

was observed with purified crystalline lutein (Table 3). 

Human intervention studies examining visual function 

as an endpoint to dietary supplementation are ongoing. The 

largest of these prospective, randomized, placebo-controlled 

studies, the Age-Related Eye Disease Study 

Table 3. Summary of human intervention studies investigating the effect of lutein on serum and MPOD responses. 

Study n Supplement Dose Product/Form Supplementation Peak Response 

(mg/day) Period (weeks) (% increase/mg lutein or lutein esters) 

Serum Time to Peak MPOD Time to Peak 

(weeks) (weeks) 

Johnson 

et al. 2000 7 10.2 Spinach/corn (lutein) 15 ↑9.3% 4 ↑2.6% 4 

Landrum 

et al. 1997 2 60* Lutein esters 20 ↑8.0% 17 ↑0.4% 25 

Berendschot 

et al. 2000 8 20* Lutein esters 12 ↑20.0% 4 ↑0.8% 16 

Landrum 

et al. 2000 24 2.4 Purified lutein 24 ↑43.3% 24 + ↑4.1% 24 + 

*Based on 2:1 lutein ester to lutein equivalency ratio. Peak response refers to the highest levels attained in the study. 

+Peak response not assessed; increases based on pre- and post-supplementation values only. 


Figure 8. Effect of 10 mg lutein/day (from spinach and corn consumption) 

on serum lutein and MPOD. Normal subjects ingested 

a diet supplemented with spinach (60g/day) and corn (150 g/day), 

equivalent to about 10 mg/day lutein, for 15 weeks. Serum lutein 

and MPOD were measured periodically. Shown is mean ±SEM 

for n = 7 subjects; *p < 0.05 vs. wk 0 for serum; † p < 0.05 vs. wk 

0 for MPOD. From Johnson et al. 2000. 

† 

* 

* 

† 

* 

† 

* † 

(AREDS), was initiated prior to lutein’s emerging role, and 

thus does not contain lutein or zeaxanthin supplements. 

Smaller trials, including case-studies that incorporated lutein 

as a supplement are nearing completion, and some have been 

published already. In 1999, Dr. Stuart Richer reported 

improvements of up to 92% in 14 AMD patients assessed by 

various visual acuity tests following diets containing five 

ounces of spinach (equivalent to approximately 14 mg lutein) 

and supplemented with purified lutein 4-7 times/week for up 

to a year. 61 However, this study was not placebo-controlled 

and did not address changes in macular pathology. A recent 

study from a group in Milan, Italy, showed that supplementation 

of AMD patients with a daily vitamin/antioxidant 

cocktail that included 15 mg of lutein for eighteen months 

resulted in a 2-fold higher improvement in visual acuity relative 

to the placebo group. 62 No changes were observed in 

the number and size of drusen from either group. 

Further human intervention studies are needed to better 

define the protective effects of lutein supplementation on 

AMD and visual acuity. Two expert researchers, Dr. Stuart 

Richer and Dr. Max Snodderly, have ongoing double-blind, 

placebo-controlled human intervention studies. Their 

results will help determine the safety and efficacy of lutein 

supplementation on visual acuity in patients with AMD. 

Lutein and other eye diseases: cataracts and retinitis pigmentosa 

Cataracts are prevalent in 40% of US adults over age 

75. 63 and their extraction is one of the most frequent and 

costly surgeries performed on the elderly. 64 Cataracts are 

characterized by the presence of an ocular opacity, partial or 

complete in one or both eyes, on or in the lens or capsule, 

often impairing vision or causing blindness. The cause is 

Figure 9. Effect of 2.4 mg/day supplemental lutein on serum levels 

and MPOD. Normal subjects were supplemented with 2.4 mg 

purified lutein/day for six months. Serum lutein and MPOD were 

measured pre- and post-supplementation. Shown is mean ±SEM 

for n = 24 subjects; *† p < 0.05. From Landrum et al. 2000. 

likely due to the oxidation of proteins, and subsequent precipitation 

of these damaged proteins in the lens of the eye. 65 

As is the case with AMD, a number of epidemiological 

studies have reported that lutein intake and/or serum levels 

are inversely associated with cataract risk. 66,67 In 1992, 

Hankinson et al. used a prospective cohort to show that 

specifically spinach consumption (high in lutein), as 

opposed to carrots (high in β-carotene) was inversely related 

to cataract extraction. 17 Three recent prospective studies 

all showed that of the carotenoids analyzed, only the intake 

of lutein and zeaxanthin were inversely associated with 

cataract extraction (20-50% risk reduction). 18,20 In addition, 

while total serum carotenoids were not related to 

nuclear cataract, there was at least a marginal inverse association 

with serum lutein reported by Lyle et al. 68 Results 

of these studies are summarized in Table 4. 

With respect to biologic plausibility, if lutein does confer 

a protective effect against cataracts, one would expect it 

deposited in the lens of the eye. In a manner parallel to that 

with AMD, research has shown that of the handful of 

carotenoids found in serum, once again it is the xanthophylls 

that are selectively deposited in the lens. A group 

from the USDA Human Nutrition Research Center on 

Aging at Tufts University reported that lutein and zeaxanthin 

were the only carotenoids detected in the lens of the 

human eye. 69 A group at the University of Utah headed by 

Dr. Paul Bernstein showed recently that lutein is present in 

other ocular tissues as well, including the retinal pigment 

epithelium and ciliary body. 70 While other carotenoids that 

occur readily in the serum were detected, lutein was present 

anywhere from 2- to 7-fold higher than β-carotene or 

lycopene. 70 This once again reinforces the importance of 

lutein relative to other carotenoids in eye health. Though a 

strong case can be made for a protective effect of lutein 

14 JANA Vol. 4, No. 2 Summer 2001 

* 

†

Table 4. Summary of epidemiological studies investigating lutein and cataract risk 

Study Parameter Assessed Endpoint Assessed Comparison Outcome 

Hankinson Spinach intake Incidence of Consumption ≥ 5 

et al. 1992 cataract extraction times/week ↓ risk 39% 

vs. ≤ 1 time/month 

Chasan-Tabar Carotenoid intake Incidence of cataract 13.7 vs. 1.1 mg/day lutein ↓ risk 22% 

et al. 1999 extraction 

Brown Carotenoid intake Incidence of cataract 7.0 vs. 1.3 mg/day lutein ↓ risk 19% 

et al. 1999 extraction 

Lyle Antioxidant intake Incidence of nuclear 1.3 vs. 0.3 mg/day lutein ↓ risk 50% 

et al. 1999 cataract 

Lyle Serum carotenoids Incidence of nuclear 0.4 vs. 0.18 µmol/L lutein ↓ risk 30%* 

et al. 1999 cataract 

*not statistically significant 

against cataracts, whether lutein supplementation has a direct 

effect on this disease remains to be established. More data 

are required from prospective epidemiological studies and 

from double-blind, placebo-controlled intervention studies 

especially, to better define the role of lutein in cataracts. 

Retinitis pigmentosa (RP), is a degenerative disease 

characterized by atrophy of the retinal pigment, that leads to 

damage of the photoreceptors and eventually blindness. 71 

There are few, if any, treatments available, although supplementation 

with high doses of vitamin A has been shown 

to slow the degenerative process. 72 One internet study suggests 

that lutein supplementation improves visual acuity in 

RP patients. Sixteen RP patients recruited and maintained 

in the study via the internet were supplemented with 40 mg 

lutein/day for 9 weeks. Using computer-simulation, patient 

self-tested visual acuity improved significantly. 73 While 

these data are subjective, they suggest that lutein may have 

a protective effect against RP. Double-blind, placebo-controlled 

intervention studies are forthcoming. 

Collectively, these data suggest that lutein may not 

only be protective against AMD, but may play an important 

role in eye health in general. This is particularly apparent 

in light of the findings reported by Bernstein et al. showing 

how lutein levels outnumber other well-known carotenoids 

in several ocular tissues. 70 

III. LUTEIN AND CHRONIC DISEASE: CANCER, 

HEART DISEASE, AND IMMUNE FUNCTION 

In addition to their potential role against eye disease, 

carotenoids have been hypothesized to have a role in the 

prevention of cancer. 5 At the cellular level, environmental 

and metabolically-derived free radicals and reactive oxygen 

species are believed to cause oxidative damage to DNA, 

inducing mutations in key genes that control cell growth 

(see Figure 5). 74,75 As photoprotectors, carotenoids act as 

absorbers of blue light and as barriers to photo-induced free 

radical production. 76 As antioxidants, they are believed to 

protect cellular DNA by quenching free radicals and reactive 

oxygen species, and by replenishing other antioxidants. 

74,77 Finally, evidence suggests carotenoids exert 

antiproliferative and differentiating effects that may prevent 

transformed cells from becoming cancerous. 78-80 

As a relatively new member of the carotenoid family, 

the protective role of lutein against cancer has not been fully 

established. Fruit and vegetable intake has been the focus of 

most research testing this hypothesis, with β-carotene being 

the main carotenoid of interest. However, a growing body 

of evidence suggests that lutein may have protective effects 

against cancers of the breast, colon, lung, skin, cervix, and 

ovaries. 5 Table 5 summarizes the available evidence supporting 

a protective role of lutein in various cancers. 

Breast cancer 

Breast cancer is the most common form of cancer in 

women of developed countries, afflicting one in eight US 

women. 81 The largest body of evidence linking lutein intake 

and decreased cancer risk comes from studies on breast cancer. 

In 1996 Freudenheim et al. conducted the first casecontrol 

study showing a 53% decreased risk for breast cancer 

for lutein and zeaxanthin intakes in the highest quartile 

(≥ 7.2 mg/day) vs. the lowest (≤ 3.6 mg/day). 11 Consistent 

with these results is another case-control study by 

Longnecker et al. showing that consumption of spinach or 

carrots more than twice weekly was associated with half the 


Table 5. Summary of lutein effects on cancer 

Cancer Tissue Deposition Epidemiology Intervention Studies 

Showing Inverse association 

Breast Yes Intake & serum Inhibition of mammary 

tumor development* 

Colon Yes Intake Inhibition of colon 

carcinoma propagation* 

Lung Yes Intake & serum NA 

Skin Yes NA Inhibition of UV-induced 

erythema and dermatitis 

Cervix Yes Intake & serum NA 

Ovarian Yes Intake NA 

NA = research not available; *based on animal and/or cell culture studies 

risk of developing breast cancer relative to those who did not 

consume these vegetables. 82 This is consistent with a subsequent 

prospective study by Zhang et al. showing that women 

with intakes of lutein and zeaxanthin in the highest quintile 

(9 mg/day) had a significant 21% decrease in breast cancer 

risk relative to those in the lowest quintile (2mg/day). 13 Two 

studies have also reported an inverse association between 

serum lutein and breast cancer risk. 12,83 

As is the case with other carotenoids, deposition of 

lutein in tissues of interest helps to substantiate a hypothesis 

of bioactivity. Lutein is readily present in both breast 

tissue and breast milk. 84,85 While intervention studies examining 

the effect of lutein supplementation on breast cancer 

are absent, studies have shown that increasing carotenoid 

intake increases serum lutein levels, 86,87 which correlate 

well with breast tissue levels. 88 This suggests that increasing 

lutein intake from foods or supplements increases the 

amount deposited in breast tissue. Currently no human 

intervention studies have examined the effect of lutein supplementation 

on breast cancer incidence or progression. 

However, a recent study by Brown et al. reported at the 

Association for Research in Vision and Ophthalmology 

2001 Annual Meeting showed that the inhibition of mammary 

tumor development in mice on a high-lutein diet was 

due to a decrease in tumor angiogenic (blood vessel growth) 

activity. 89 Reducing the blood supply to tumors is known to 

effectively shrink their size. These data from mice indicate 

that not only may lutein exert anticancer effects, but does so 

when consumed in the diet. 

Colon cancer 

While it has decreased slightly in recent years, colon 

cancer is a leading cause of death in the US. 90 As with 

breast cancer, a number of epidemiological studies have 

revealed an inverse relationship between lutein intake and 


colon cancer. 16,91,92 In the most recent US-based study 

(Slattery et al. in 2000), of all carotenoids analyzed, lutein 

intake had the strongest inverse relationship with colon 

cancer risk. 16 Subjects consuming the highest quintile of 

lutein (3 mg/day) had a 35% decreased risk for colon cancer 

relative to those in the lowest quintile (0.3 mg/day). 

Lutein also accumulates in colonic epithelial cells in subjects 

consuming a diet rich in vegetables. 93 This helps to 

establish a basis for the biologic plausibility for lutein and 

colon cancer prevention or protection. 

Lung cancer 

More Americans die from lung cancer than any other 

cancer. 94 Data from epidemiologic studies support a protective 

effect of fruit and vegetable consumption on lung cancer 

risk. 95 However, researchers have proceeded cautiously 

when examining whether or not lutein has a beneficial 

effect on lung cancer in light of intervention studies that 

showed that β-carotene supplementation increased cancer 

incidence in smokers. 8,96 Inverse associations have been 

reported between lutein intake and serum levels and lung 

cancer risk in both retrospective case-control studies and 

prospective cohorts. 97-102 The strongest association for 

lutein was reported by De Stefani et al. who showed that 

subjects consuming lutein in the highest quartile (≥ 3.2 mg 

lutein/day) had nearly half the risk of lung cancer relative 

to those in the lowest quartile (< 1 mg/day). 100 

Oxidative stress from smoke may play an important 

role in lung carcinogenesis. 103-105 The protective effect of 

carotenoids and other antioxidants may be related to their 

ability to scavenge free radicals contained in smoke. 106 

Concurrently, smoking depletes the body of these important 

antioxidants107 as smokers tend to have lower plasma levels 

of antioxidants relative to nonsmokers. 108 Even exposure 

to passive smoke is associated with lower serum carotenoid 

Summer 2001

Figure 10. Effect of carotenoid supplementation on UV-induced 

skin redness (erythema). Subjects were given a carotenoid supplement 

that included 0.12 mg lutein daily for 12 weeks. Dorsal 

skin was then exposed to UV light, and erythema was measured 

24-hours later. Each subject served as their own control. Shown 

is the mean ±SD for n = 20 subjects; *p < 0.05 vs. control. From 

Stahl et al. 2000. 

Control Carotenoid 

Supplement 

levels. 109 This effect not only predisposes smokers to lung 

cancer, but decreases macular pigment 110 and increases the 

risk for AMD. 111 Increasing intake of green leafy vegetables 

can increase serum lutein in smokers to levels comparable 

to those in nonsmokers. 112 Thus, smokers especially 

may require supplementation of their diet with antioxidants 

to offset the depleting effects of smoking. 

Skin cancer 

Skin cancer is a growing concern in the US. With one 

million cases diagnosed each year, skin cancer is contributing 

more and more to overall mortality. 113 Increased sun 

exposure (UV light) is thought to be largely responsible. Of 

all the organ systems in which lutein may have a protective 

role, none may be more relevant than skin. Carotenoids 

function in plants as blue light filters and free-radical-scavenging 

compounds. 26 In skin, lutein and other carotenoids 

may function in a similar manner, either by topical application114 

or by ingestion. 115 Despite this apparently obvious 

relationship, very little data are available in the literature. 

Epidemiologic studies examining relationships between 

lutein intake or serum levels, sun exposure, and skin cancer 

risk are unavailable. However, there is some evidence 

showing that lutein along with other carotenoids may have 

a protective effect. The presence of lutein in the skin suggests 

that it may have a biologic function there. 116 In a 

recent study by Stahl et al., subjects who ingested a 

carotenoid supplement daily for 12 weeks that included 0.12 

mg lutein developed significantly less erythema (skin redness) 

in response to UV irradiation at week 12 relative to 

week 0 (Figure 10). 117 This study does not establish a direct 

* 

Figure 11. Effect of lutein supplementation on UV-induced 

inflammation in mice. Mice were fed a standard laboratory diet 

containing no lutein, 0.04% lutein, or 0.4% lutein, respectively. 

24 hours after exposure to UVB irradiation (ears), ear swelling 

was assessed. Shown is the mean ± SEM from n = 10 mice per 

group; *p = 0.025 vs. control diet. From Faulhaber et al. 2001. 

link between lutein supplementation and protection of the 

skin, but it does suggest that lutein may be involved. Higher 

levels of lutein are present in skin amyloid from subjects 

suffering from systemic amyloidosis (deposition of glycoproteins 

in various tissues and organs), relative to normal 

skin. 118 Given that accumulation of these glycoproteins can 

lead to oxidative damage, accumulation of lutein suggests 

the presence of a natural defense mechanism that relies on 

the free-radical-scavenging ability of lutein. 

The remainder of the evidence comes from cell culture 

and animal models. Taylor et al. showed that addition of 5 

mg lutein to the skin of mice inhibited ultraviolet B radiation 

(UVB)-induced epidermal cell proliferation and erythema by 

50%. 119 This is direct evidence that topically-applied lutein 

exerts photoprotective effects. The recent observation that 

mice fed a diet supplemented with purified lutein (0.04 or 

0.4%, respectively) had significantly decreased UVB 

induced skin inflammation (Figure 11) is the first of its kind 

to demonstrate the direct effect of dietary lutein on UVB 

induced skin damage. 120 These findings suggest that specifically 

dietary sources of lutein may offer a protective effect 

against oxidative damage induced by UVB light. 

Furthermore, in a different study the same researchers also 

showed a decreased UVB induced immunosuppressive 

response in mice fed purified lutein, suggesting again a protective 

role of lutein against UVB damage. 

These findings support the hypothesis that either topical 

application or ingestion of lutein protects the skin from 

UVB-induced damage. This in turn suggests that lutein may 

play a protective role against skin cancer, primarily as a filter 

of blue light, but also as a free-radical scavenger. Further 


intervention studies are required to confirm these effects in 

humans, and determine safe and efficacious doses. 

Cervical and ovarian cancers 

In addition to the more common cancers, it appears that 

lutein intake may be inversely associated with risk of cervical 

and ovarian cancers. While the research is much less 

extensive relative to other carotenoids, there are sufficient 

data to support a role for lutein. Lutein is readily found in 

both cervical and ovarian tissues, 121 and the serum level of 

lutein from patients with cancerous or precancerous cervical 

tissue was shown to be lower than that of noncancer 

subjects. 122 This suggests lutein may play a protective role 

against cervical cancer. However, the majority of the available 

epidemiologic data do not show such a relationship 

with cervical cancer as the endpoint. It is possible that 

lutein may exert its effects earlier in the process of cervical 

cancer development. Infection by the human papilloma 

virus (HPV) is believed to be a significant contributor to 

cervical carcinogenesis. 123 In 1997 Giuliano et al. reported 

that women who screened negative for HPV had, on average, 

nearly a 30% higher serum level of lutein than those 

who had screened positive. 124 A similar relationship was 

found for other carotenoids as well. These data suggest that 

women with a lower intake of some carotenoids, including 

lutein, may be more susceptible to HPV infection and subsequent 

development of cervical cancer. It has been proposed 

that this effect may be related to the ability of potent 

antioxidants, such as carotenoids and tocopherols, to maintain 

a normal immune response, which in turn helps to 

negate viral infection. 124 

While studies investigating effects of lutein on ovarian 

cancer are scarce, there is enough evidence to suggest that it 

may be protective. In addition to the presence of lutein in 

ovarian tissue, 121 the results from a case-control study 

released earlier this year by Berton et al. indicate that lutein 

intake may be inversely associated with ovarian cancer 

risk. 125 Investigators found that lutein consumption of 24 

mg/week was associated with a 40% decreased risk for ovarian 

cancer relative to an intake of less than 4 mg/week. No 

associations were observed for α- and β-carotene. When 

analyzed by food, the data showed a similar relationship 

between spinach (high in lutein) intake and decreased risk. 125 

In summary, lutein appears to exert effects at all three 

stages of cancer progression: acting as a filter of blue light, as 

a free-radical scavenger to inhibit initiation of DNA damage 

and subsequent transformation of cells, and as an antiproliferative 

agent, inhibiting the propagation of cancer cells. 

However, limitations inherent in epidemiologic studies (i.e., 

lack of proper controls, recall bias, confounding effects of 

other nutrients) prevent us from drawing clear conclusions 

from them regarding independent effects of lutein. The 

effects observed in these studies are likely due to the combined 

influence of many carotenoids and other antioxidants. 


In contrast to AMD, a specific role for lutein in cancer 

has not been as well defined, and human intervention studies 

are unavailable. However, currently available evidence 

in the literature suggests that a diet low in lutein may be 

associated with an increased risk for certain cancers. The 

notion that lutein may play a protective role against the 

development of various forms of cancer enforces the need 

for its increased consumption in the form of foods and/or 

supplements. Further research is needed to better define this 

effect of lutein, and better establish safe and effective doses. 

Heart disease 

Cardiovascular disease is the leading cause of death in 

the US: more people die from this disease than from any other 

single cause. 126 A plethora of epidemiologic studies and 

research reviews have tested and implicated the intake of 

antioxidants, such as carotenoids and vitamins C and E, as 

having an inverse association with and protective effect 

against heart disease. 5,6.127-129 As is the case with cancer, the 

majority of studies have focused on β-carotene, with clinical 

intervention studies displaying equivocal results. 127 Emerging 

evidence suggests that intake of the hydroxycarotenoids (xanthophylls: 

lutein, zeaxanthin, and β-cryptoxanthin) may be 

associated with a decreased risk for cardiovascular disease 

and events associated with it, such as stroke. 

The two prospective epidemiologic studies examining 

stroke incidence that have specifically included lutein in the 

analysis (Hirvonen et al. and Ascherio et al.) reported that 

lutein intake is inversely related to stroke risk. 130-131 Of all 

the carotenoids analyzed by Ascherio et al., only lutein 

intake was shown to be even marginally inversely related to 

ischemic stroke risk (37% decreased risk for highest quintile, 

6.8 mg/day vs. lowest quintile, 1.3 mg/day; p = 0.1 for 

trend). 130 Hirvonen et al. reported that lutein intake was 

inversely associated (less than half the risk) with hemorrhagic 

stroke. 131 Until recently, epidemiologic data showing 

a relationship between serum lutein levels and heart 

disease were not available. Dwyer et al. reported this year 

that serum lutein levels were inversely related to arterial 

wall thickness in a group of subjects from the Los Angeles 

area over an 18-month follow up period. 132 This is consistent 

with results reported in the same paper indicating that 

mice supplemented with lutein had significantly less atherosclerotic 

lesions than control mice. 132 

One model to explain heart disease maintains that free 

radicals and ROS oxidize low density lipoproteins (LDL), 

which damages the endothelial cells lining the arterial 

walls. Studies have shown that carotenoids, and specifically 

lutein, inhibit LDL oxidation in vitro. 133,134 There are 

other studies that show marginal effects ex vivo (i.e., supplementation 

with carotenoids, and analysis of serum samples 

for LDL oxidation). 135,136 Some research also suggests 

that carotenoids exert their antiatherogenic effect by 

Summer 2001

inhibiting the signaling from damaged endothelial cells that 

attracts monocytes. Once damaged, the endothelial cells 

express “adhesion” molecules on their cell surface that are 

recognized by monocytes, which engulf the damaged cells 

in an attempt to destroy them. This step initiates the atherogenic 

pathway, and development of cardiovascular disease. 

137,138 Indeed, it has been shown that lutein, β-carotene, 

and lycopene all decrease the expression of adhesion molecules 

on the surface of interleukin-stimulated human aortic 

endothelial cells in culture. This results in a decrease in 

adhesion to subsequently added monocytes. 132,139 

Immune function 

Evidence has existed for more than 10 years showing 

that supplementation with carotenoids, such as β-carotene 

may boost immune function in humans. 140,141 While this is 

a relatively new area of research with respect to lutein, there 

are compelling data from recent dog and cat model studies. 

Kim et al. reported that lutein provided in the diet of cats 

and dogs increased the humoral immunity of both 

species142,143 In both studies, investigators observed that 

lutein-supplemented animals significantly increased lymphocyte 

and antibody production in response to a vaccination 

relative to animals on a control diet. 142,143 This suggests 

that lutein boosted the immune function of these animals. 

More studies are needed to determine if the same 

effects can be elicited in humans. 

IV. SUPPLEMENTS AS A SOURCE OF LUTEIN 

Safety and bioavailability 

To validate epidemiologic studies linking lutein intake 

to human health, researchers have begun to perform controlled 

supplementation studies focusing on bioavailability, 

tissue deposition, and biomarkers of disease outcome or 

disease itself. Questions have subsequently arisen concerning 

the bioavailability of lutein from foods and supplements 

alike. How bioavailable is lutein from supplements? What 

factor(s) influence this? Can supplemental lutein affect the 

bioavailability of other carotenoids? 

Bioavailability is defined as both the intestinal absorption 

and usage of a given nutrient by the body. 25 Studies have 

shown that lutein from supplements appears readily in the 

plasma (absorption), is deposited in tissues such as the eye, 

and even results in positive effects on potential disease biomarkers 

i.e., macular pigment, skin erythema (utilization). 

Doses as low as 2.4 mg/day have been shown to increase 

serum lutein levels and increase macular pigment. 60 Doses 

up to 40 mg/day have been shown to improve visual acuity 

in patients suffering from certain ocular diseases62,73 with no 

negative side effects or toxic effects reported. Furthermore, 

a purified lutein product extracted from marigold flowers 

(Kemin Foods, L.C., Des Moines, IA) has just been deter- 

mined GRAS (generally recognized as safe for use in certain 

foods and beverages) by a panel of experts. Thus, it is clear 

that supplements are a readily bioavailable and safe source 

of lutein that can be used to increase dietary intake of this 

nutrient. This is especially important in light of the findings 

that consumption of lutein from green leafy vegetables has 

declined in the US31 and that smokers and patients suffering 

from chronic diseases often present with low serum antioxidant 

levels. 83,108,144 

Several factors can affect carotenoid bioavailability, 

the majority of which appear to influence carotenoids from 

foods. 145-147 In contrast to foods, the absorption of supplemental 

forms of carotenoids are not influenced by food 

matrices, cooking, etc. 148 However, two important factors 

affect absorption of supplemental carotenoids, such as 

lutein. (1) Because lutein is a fat-soluble compound, 

absorption across the brush-border membrane is dependent 

on the presence of a small amount of fat (approximately 

5g/meal). 147 Fat triggers the release of bile acids from the 

gall bladder which help to disperse the fat (and fat-soluble 

nutrients and vitamins) into small droplets (micelles) which 

are readily absorbed by the intestinal cells. Without this 

small amount of fat (for example, if a carotenoid supplement 

were taken alone, on an empty stomach), fat-soluble 

compounds will pass through the gastrointestinal tract 

unabsorbed. 147 (2) As is the case with similarly charged 

minerals, carotenoids with similar structure can compete 

for absorption. 146,147 This issue has specific relevance to 

supplements. Often supplemental forms of nutrients are 

ingested in doses more concentrated than those found in 

foods, and which are free from the constraining matrix of 

food (i.e.,water, fiber,). It has been proposed that supplement 

use of carotenoids could disrupt the balance of 

absorption resulting in decreased bioavailability of certain 

nutrients, 29 as has been shown to occur between lutein and 

β-carotene. However, the effects observed have been 

inconsistent, with lutein shown to inhibit β-carotene 

absorption and vice-versa. 149,150 Moreover, this interaction 

is so inconsistent to the extent that it varies markedly from 

individual to individual. 151 Hence, inter-carotenoid interactions 

that exist in the gut may be more pronounced with 

supplementation. What effect these interactions have on the 

body’s nutrient status or susceptibility to disease is 

unknown and warrants further research. 

Thus, the available evidence supports a clear role for 

sources of lutein in human health. The studies cited in 

this review suggest that consumption of lutein from foods 

or from dietary supplements will result in a health benefit 

to the public. 

V. FOCUS FOR FUTURE RESEARCH 

Establishing lutein as a vitamin 

By definition, a vitamin is an essential nutrient 


equired by the body that must be obtained from the diet. 152 

Research supporting a protective role for lutein in human 

health has increased dramatically in the last six years in epidemiologic 

studies, animal and human intervention trials, 

and in in vitro cell culture studies. However, as a variety of 

phytonutrients contained in fruits and vegetables, including 

carotenoids, and others yet to be identified, are all needed 

for optimal health and protection from chronic disease, specific 

carotenoids have not been identified as required and 

essential nutrients. With the exception of lutein and AMD, 

there is no disease state that can be linked specifically to a 

deficiency in any one carotenoid. With the exception of 

MPOD, there are no accepted methods for carotenoid status 

assessment to even begin to determine what a “deficiency” 

is. No epidemiologic or intervention study shows a consistent 

inverse relationship with one particular carotenoid and 

any chronic disease risk or outcome. However, the argument 

can be made that lutein may be required in the diet to 

protect from macular degeneration. Humans cannot synthesize 

lutein, therefore it must be obtained in the diet. 26 

The fact that lutein and zeaxanthin are the only carotenoids 

found in the macula suggests that these compounds have a 

specific function in this tissue. 45 The macular pigment is 

known to be a vital protector of the cells and tissue of the 

macula from blue light. 24 Lutein and zeaxanthin are known 

to comprise the macular pigment, 47 and research showing 

that lutein is converted to zeaxanthin in the macula suggests 

that lutein is the required starting material. 49 Providing 

lutein in the diet (either as foods or supplements) increases 

macular pigment (Table 3), and may increase visual acuity 

in patients with AMD. 61,62 These findings also suggest that 

MPOD can not only be used as a biomarker of macular 

health, but may also be a marker of lutein status. For many 

nutrients, serum levels are not an accurate reflection of 

nutritional status. Tissue levels verify absorption and are a 

far better reflection of the body’s overall status. However, 

measurement of tissue levels can be an invasive and 

impractical method of assessment. MPOD accurately 

reflects the amount of lutein in the macula, and its measurement 

involves a noninvasive procedure. 

The gold standard for vitamin classification is the depletion-repletion 

study. 153 Such studies have been performed 

with lutein using the rhesus monkey model. Feeding monkeys 

a lutein-free diet (depletion), causes eventual loss of all 

macular pigment. 54,55 Repleting monkeys with lutein and 

zeaxanthin results in restoration of macular pigment. 55 These 

studies were unable to assess visual acuity nor examine ocular 

pathology. However, they indicate that lutein is required 

in the diet for macular pigment, and that a diet low in lutein 

can result in deficiency (as assessed by macular pigment). 

Because macular pigment is known to be a marker for macular 

health, this suggests lutein is required in the diet for 

macular health. No evidence exists to support any such 

claim for other carotenoids. 153 


Despite the strides made in lutein research, further studies 

are still needed in several areas. First, using the rhesus 

monkey model it may be possible to determine if lutein 

depletion results in AMD and if the macular pathology can 

be reversed with lutein repletion. Second, epidemiologic and 

intervention studies have cited a wide range of lutein doses, 

with no one amount or range clearly defined. Using MPOD 

as a lutein status assessment tool, we must better define daily 

doses of lutein that can be recommended in the human diet. 

Finally, we must continue to execute human intervention 

studies to better define efficacy of lutein supplements. 

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Summer 2001


Summer 2001 

Efficacy of Vinpocetine in the Management 

of Cognitive Impairment and Memory Loss 

* Correspondence 


16899 NE 15 th Avenue, 

North Miami Beach, FL 33162 

Phone: 305-940-8717 Fax: 305-940-8871 

Email: info@miamihealth.com 


Clinical Assistant Professor of Medicine and Family Medicine, 

University of Miami School of Medicine 

ABSTRACT 

Objective: To determine the effect of Vinpocetine on 

objective measures of cognitive function and memory 

based on a critical review of the current literature. 

Methods: An attempt was made to identify all English 

and non-English-language articles in which Vinpocetine 

was used for the treatment of dementia, memory deficits, or 

cognitive impairment. The methodological quality of clinical 

trials utilizing Vinpocetine for the purpose of cognition 

and memory enhancement was assessed. Trial outcomes 

were interpreted in relation to their quality and predefined 

criteria of good study methodology was used. 

Results: Of 39 articles reviewed only three met all 

inclusion criteria. In total 327 patients in the Vinpocetine or 

placebo group participated in the selected clinical trials. 

Overall there was a statistically significant improvement in 

the Clinical Global Impression (CGI) scale, Sandoz Clinical 

Assessment Geriatric (SCAG) scale, and Mini Mental 

Status Questionnaire (MMSQ) in the Vinpocetine treatment 

arm. No adverse events were reported and side effects were 

mostly related to gastrointestinal discomfort. 

Conclusions: Based on the selected clinical trials 

there is a significant effect of Vinpocetine in the management 

of cognitive impairment and memory loss in patients 

with early dementia or other related symptoms of cere- 

brovascular diseases. Vinpocetine is not indicated in the 

treatment of Alzheimer disease due to limited and inconsistent 

data. Additional research is needed to define the 

clinical application of Vinpocetine in the management of 

cognitive impairment. 

INTRODUCTION 

Vinpocetine, a vincamine derivative, is a synthetic 

ethyl ester of apovincamine (3,16-eburnamenine-14-carboxylic 

acid ethyl ester). Vincamine is an extract of the 

periwinkle plant (Vinca Minor) and chemically is an indole 

alkaloid (eburnamine-type, 25-65%). Other alkaloids 

include vincin, apovincamine and vincadifformin. The 

plant is indigineous to northern Spain, and grows throughout 

western France, eastwards via central and southern 

Europe as far as the Caucasus. The dried leaves, the fresh 

aerial parts of the flowering plant, and the whole fresh flowering 

plant are used for medicinal purposes. Vinpocetine 

has been widely used and studied in Europe for over 25 

years, but is not well known in the United States and has 

only recently been introduced in the United States for use 

as a nutraceutical supplement. 

The therapeutic utilization of Vinpocetine is based on 

pharmacological research of cognitive deficits caused by 

hypoxia and ischemia as well as in the cellular and biochemical 

investigations related to cyclic nucleotides. 

In animal experiments Vinpocetine and its derivatives 

have been shown to increase cerebral blood flow, 1,2,3 

increase blood flow in the vertebral and coronary arteries of 

dogs, 4-9 and increase brain glucose uptake in mice. 10 The 

reduction in cerebral vascular resistance is due to an 

increase in the cGMP content in smooth vasculature by 

selective inhibition of Ca 2+/Calmodulin-dependent 

cGMP-phosphodiesterase. 11-15 


Phosphodiesterase inhibitors (PDEIs) suppress the production 

of tumor necrosis factor (TNF-alpha) in various 

cells and are also reported to reduce experimental demyelination 

of brain cells. 16 Vinpocetine is a PDE-1 selective 

inhibitor and is a potentially useful anti-inflammatory agent 

via down-regulating inflammatory cytokines and up-regulating 

inhibitory cytokines in the central nervous system 

(CNS). 17-18 One study cites prevention of contrast medium 

induced renal vasospasm. 19 Vinpocetine was also reported 

to protect against excitotoxic cell death in cell cultures of rat 

cerebral cortex 20 and in striatal slices of rat brain. 21 In vitro 

models of cerebral ischemia indicated calcium antagonist 

activity22 and neuroprotective and anticonvulsant effects by 

blocking voltage-gated NA-channels in cortical neurons of 

rats23 and gerbils. 24 Vinpocetine prevented postischemic 

increase in glucose utilization and decrease in local blood 

flow in the hippocampus of rats, 25 decreased neuronal cell 

loss in a rat model of forebrain ischemia, 26 and increased the 

neuroprotective effect of adenosine in hypoxemic cultures. 27 

Vinpocentine’s indirect adenosine-like activity 28,29 might 

explain the protective cerebral action. 

Furthermore Vinpocetine was reported to decrease the 

size of cerebral infarction after middle cerebral artery 

occlusion in both rats 30 and mice. 31 In human studies, vinpocetine 

was reported to increase cerebral blood flow in 

previously ischemic cerebral regions, 32 had a viscosity-lowering 

effect on blood and plasma, 33 decreased platelet and 

red cell aggregation, 34,35 and increased erythrocyte 

deformability in patients after ischemic stroke. 36 Based on 

the findings of animal experiments and the result of pharmacological 

studies, 37 Vinpocetine was recommended as a 

treatment modality for patients with stroke in several 

European countries (Hungary, Poland, Germany, Russia) 

and Japan. A recently published meta-analysis38 does not 

support the assumption that the use of Vinpocetine can 

decrease the morbidity and mortality in acute stroke. 

It was also reported that Vinpocetine enhances the 

intracerebral metabolism of biogenic monoamins, including 

serotonin, dopamine, and norepinephrine, 39,40 the intracerebral 

concentration of ATP, 41 and facilitates neurotransmitter 

turnover particularly 5-HIAA and serotonin. 1 

The above pharmacological and biochemical actions 

can be summarized in five groups: 

• Enhancement of brain circulation and oxygen utilization; 

• Increased brain tolerance of hypoxia and ischemia; 

• Anticonvulsant activity; 

• Inhibitory effect on phosphodiesterase enzyme; 

• Improvement of the rheological properties of the blood 

and inhibition of platelet aggregation. 

These effects combined might synergistically contribute 

to the significant neuroprotective action of 

Vinpocetine demonstrated in both in vitro and in vivo exper- 


iments. To help to define the efficacy of Vinpocetine in the 

clinical management of cognitive impairment and memory 

disorders, a review of the current literature was performed 

and studies identified that met minimally acceptable scientific 

standards. 

METHODS 

The search for potentially relevant studies was performed 

through MEDLINE and EMBASE using the keywords 

“vinpocetine,” “apovincamine”, “Vincamine” and 

”Periwinkle.” Additional search words included manufacturer 

brand , code and trade names for Vinpocetine ( e.g., 

Cavinton, Kavinton). Furthermore the manufacturers of 

Vinpocetine products were contacted to provide information 

of all known randomized controlled trials. All scientific 

studies including animal experiments, in-vitro trials, and 

clinical studies were evaluated (both English and non- 

English language) to identify randomized placebo-controlled 

clinical trials in which Vinpocetine was administered 

to patients with and without cognitive impairment. Trials 

referenced by articles that were found were also screened. 

The goal was to identify and evaluate only those studies 

that met minimally acceptable scientific standards 

applying the following inclusion criteria: 

1. Patients or test subjects needed to be sufficiently characterized 

by stated diagnosis of cognitive impairment, 

cerebrovascular disease, stroke, Alzheimer disease or 

dementia either by the Diagnostic And Statistical 

Manual of Mental Disorder or International 

Classification of Diseases 10th Revision, or there was 

enough clinical description to determine the clinical 

diagnosis by the review. 

2. The use of a standardized Vinpocetine extract in any stated 

dose was required. 

3. The clinical studies needed to be randomized, placebocontrolled 

and double-blind. Details of the randomization 

procedure were not required. 

4. To assess cognitive function, at least one outcome measure 

needed to be clearly stated. 

5. Listing of descriptive statistics used to assess clinical 

effects and outcome was required. 

All studies that met those inclusion criteria are listed in 

Table 1. 

A meta-analysis of the available studies could not be 

performed due to variation in methodology used in the 

studies. Studies often did not state exclusion criteria for 

dementia or other neurological diseases causing cognitive 

impairment, did not use standardized Vinpocetine formulas, 

or omitted a clear definition of outcome criteria. 

Summer 2001

Table 1. Studies Satisfying Inclusion Criteria 

Source Diagnosis Subjects Age Duration Dosage Outcome 

Mean wk mg Measures 

Balestreri 

1987 (43) 

CVD 84 78.3 12 30,15 CGI, 

SCAG,MMSQ 

Manconi 

1986 (44) 

Dementia 40 68.3 8.5 30,15 CGI,SCAG,MMSQ 

Hindmarch 

et al 1991 (45) 

Dementia 

OBS 203 73.7 16 30, 60 CGI,SKT 

CVD = Cerebrovascular Disease, CGI = Clinical Global Impression Scale, MMSQ = Mini-Mental Status Questionnaire, SCAG = Sandoz 

Clinical Assessment Geriatric Scale, SKT = Cognitive Performance 

RESULTS 

Description of reviewed studies 

Thirty-nine articles regarding the clinical application of 

Vinpocetine and its derivatives were identified and 

reviewed. 42-80 The clinical studies involved 1,912 subjects 

aged 8 to 93. Multiple articles were published in German, 

Hungarian, Italian, Japanese, and Russian literature, requiring 

the assistance of interpreters to evaluate the scientific 

value of their content. The majority of the articles reported 

positive effects of Vinpocetine administration (oral, intravenous) 

in the treatment of cerebral insufficiency and cerebrovascular 

disease. Other applications include the use of 

Vinpocetine and its derivatives in the treatment of ischemic 

stroke, 58-60 Alzheimer disease, 65 convulsive disorders as the 

result of birth injuries, 66 treatment of sensorineural hearing 

impairment, 67 and acoustic trauma. 68 Articles using diagnostic 

descriptions not listed in the Diagnostic and Statistical 

Manual of Mental Disorders, and those using terms such as 

dizziness, fatigue, and tinnitus to describe symptoms of 

cerebral insufficiency were excluded from the analysis. 

Methodological analysis and qualities of selected studies 

The three randomized, placebo-controlled and doubleblind 

studies selected43,44,45 reported analyzable data for 

174 patients treated with a standardized Vinpocetine extract 

and 114 with placebo. A total of 327 patients participated in 

the clinical trials; 35 were excluded due to lack of compliance, 

or from deviating from the protocol. Four patients 

dropped out due to side effects including anxiety, vertigo, 

gastric discomfort, and unrelated problems such as glaucoma 

and biliary colic with previous history of gallbladder 

stones. No death occurred during the study periods and no 

data of fatalities were reported after conclusion of the clinical 

trials. Individual group sample size ranged from 18 to 

56 and the mean age from 68.3 to 78.3. Outcome measures 

were clearly defined, documented, and utilized in the statistical 

analysis. Neurophysiological outcome measures, 

including electroencephalographic data analysis, from 

small animal62 and human studies, 63 were utilized. 

Balestreri, Fontana, and Astengo43 reported a consistently 

significant improvement in all evaluations of treatment 

including measurements of the CGI scale (44%), 

SCAG scale (26%), and the MMSQ. Applying a similar 

methodology Manconi, Binaghi and Pitzus44 demonstrated 

statistically significant improvements in the SCAG and 

MMSQ scale with impressive improvement of the CGI 

assessment in the Vinpocetine group, ranging from 73% (30 

days) to 87% (90 days). Hindmarch, Fuchs, and Erzigkeit45 documented a significant change of the CGI–Global 

improvement rating in the vinpocetine group of more than 

21%, and on the SKT, a short cognitive performance test 

for the assessment of memory and attention, an improvement 

by as much as 87%. 

Adverse Effects 

In all reviewed studies listed, and those included in our 

analysis, no significant adverse effects were reported. The 

three studies selected provide documentation of twenty-five 

side effects including seven in the placebo group. 

Gastrointestinal discomfort was the most common reported 

side effect, affecting sixteen patients in the Vinpocetine 

group. 45 Two patients complained about vertigo compared 

to one in the placebo group. 45 Vinpocetine treatment was 

stopped after six days in one patient who experienced an 

episode of biliary colic, 43 and was suspended for ten days in 

a second patient due to dyspepsia after 20 days of treatment. 

Discussion 

The treatment of cognitive impairment and memory 

loss associated with senile dementia and Alzheimer disease 

often addresses the symptoms of the disease rather than the 

causative factors involved. Pharmacological interventions 

intended to improve the quality of life and to slow progress 


of the disease can demonstrate well-documented efficacy 

but not effectiveness. Nootropic agents including vitamin 

E, 81 folic acid, 82 and Ginkgo biloba83 have been studied and 

have demonstrated some clinical benefits in the treatment of 

Alzheimer’s disease and senile dementia. 

Unfortunately, most treatment approaches are initiated 

during the clinical phase of the disease manifestation. It has 

been documented84 that the diagnosis of Alzheimer’s disease 

is preceded by a long preclinical phase in which cognitive 

impairment and deficits in memory performance are 

common. These symptoms, classified as mild cognitive 

impairment, remain often unrecognized85 and stable until 

the time that a dementia or Alzheimer’s disease diagnosis 

can be rendered. The early diagnosis of mild cognitive 

impairment can identify individuals with an increasing risk 

of developing Alzheimer’s disease at the rate of 10%-12% 

per year. 86 Those patients have significant memory impairment, 

while other cognitive functions and activities of daily 

living are only slightly abnormal. 

In this “window of opportunity” between mild cognitive 

impairment and the development of senile dementia or 

Alzheimer’s disease, the utilization of nootropic agents 

such as Vinpocetine might slow the disease process and 

decrease its incidence. 

All three studies suggest a significant improvement 

during the treatment with Vinpocetine in the cognitive function 

of patients suffering from dementia or other symptoms 

of cerebrovascular diseases. The demonstrated safety, 

absence of serious adverse effects, and the significant 

improvement of cognitive function even in healthy individuals87 

suggest a clinical application of Vinpocetine in the 

early phases of mild cognitive impairment. 

However, it should be noted that other than the studies 

by Baliestreri et al., Manconi et al., and Hindmarch et al., 

most of the published studies that were reviewed had no 

functional, behavioral, or global outcome measures. The 

sample size and duration of the clinical studies is at this 

point insufficient to develop clinical treatment guidelines. 

Further large-scale clinical trials should be performed 

with long-term follow-up ( >2 years) to determine the longterm 

neuroprotective effect of Vinpocetine and to ascertain 

its beneficial effect for cognitive function and memory. 

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Summer 2001


Dietary Supplementation with Chlorella 

pyrenoidosa Produces Positive Results in 

Patients with Cancer or Suffering From 

Certain Common Chronic Illnesses 

Randall E. Merchant, PhD* 1, Cynthia A. Andre, Msc 2 

1.Professor of Anatomy and Neurosurgery, Virginia Commonwealth University, Medical College of Virginia 

2. Clinical Research Coordinator and Social Worker, Virginia Commonwealth University, 

Medical College of Virginia. 

INTRODUCTION 

Laboratory and clinical studies from Japan have reported 

that broken cell wall preparations and extracts of 

Chlorella pyrenoidosa, a unicellular green alga, as well as 

other Chlorella species when either given orally or injected, 

promote growth and healing. Furthermore, these preparations 

stimulate the immune system in such a way that the host is 

protected from infection and cancer. Chlorella pyrenoidosa 

grows naturally in fresh water and has the highest content of 

chlorophyll (28.9 g/kg) of any known plant on earth. This 

species’ proteins contain all the amino acids known to be 

essential for the nutrition of animals and human beings. 

There are also vitamins found in Chlorella pyrenoidosa 

including: vitamin C, provitamin A (B-carotene), thiamine 


Randall E. Merchant, PhD 

Virginia Commonwealth University, 

Medical College of Virginia, 

Richmond, Virginia 23298-0709 

E-mail: rmerchan@hsc.vcu.edu 

(BI), riboflavin (B2), pyridoxine (B6), niacin, pantothenic 

acid, folic acid, vitamin B12, biotin, choline, vitamin K, 

lipoic acid, and inositol. Minerals in Chlorella pyrenoidosa 

include: phosphorus, calcium, zinc, iodine, magnesium, iron, 

and copper. Chlorella has a strong cell wall that prevents its 

native form from being adequately broken down and 

absorbed by the human digestive system and so special processing 

is required to break its cell wall. 1 In addition to 

amino acids, peptides, proteins, vitamins, sugars and nucleic 

acids, Chlorella pyrenoidosa contains a water-soluble substance 

known as Chlorella Growth Factor (CGF). 2 

Approximately 5% of raw Chlorella pyrenoidosa is CGF; 

composed primarily of amino acids, proteins, and nucleic 

acids believed to be derived from the nuclei of the algae. 

WHAT CHLORELLA IS AND HOW CHLORELLA 

PRODUCTS ARE GROWN 

Chlorella pyrenoidosa is a species of green algae that 

grows in fresh water. This life form emerged over 2.5 billion 

years ago, and was the first form of plant with a 

well-defined nucleus. There are fossils from the 

pre-Cambrian period that clearly indicate the presence of 

Chlorella. Because Chlorella is a microscopic organism, it 

was not discovered until the late 19th century, deriving its 


name from the Greek, “chloros” meaning green and “ella” 

meaning small. 

Each Chlorella pyrenoidosa microorganism is composed 

of a nucleus, starch grains, chloroplasts and 

mitochrondria surrounded by a cell wall composed mainly 

of cellulose. Under normal conditions, Chlorella divides 

into four daughter cells in less than 24 hours. The length of 

Chlorella’s life cycle depends on the strength of the sunlight, 

temperature and availability of nutrients. 

Although the algae grow naturally in fresh water, 

Chlorella pyrenoidosa destined for human consumption is 

generally cultivated in large, fresh mineral water pools 

under direct sunlight. The growing process must be carefully 

inspected and sanitary conditions are meticulously maintained 

to ensure there is no contamination of the Chlorella 

with other microorganisms. Once the fresh-water pools 

have enough Chlorella cells in them, the algae are harvested 

and the tough cell walls of the Chlorella must then be 

broken down to increase the algae’s digestibility. This can 

only be accomplished with the patented process utilizing 

the DYNO-Mill, a unique method developed under the 

guidance of Mr. Hideo Nakayama of the Sun Chlorella 

Corporation. All of the other methods, which include heating 

or treatment with enzymes, compromise Chlorella’s 

digestibility, therefore eliminating full health benefits of 

Chlorella. The DYNO-Mill physically disintegrates the 

cell wall by using only natural, mechanical means and 

therefore there is no need for chemicals, enzymes or heating 

that can compromise its nutritional value, while assuring 

optimum assimilation and digestion. 1 With the 

DYNO-Mill technique, Chlorella is more than 85% 

digestible. Once the cell wall has been broken, Chlorella is 

spray-dried producing powder and molded into tablets 

using a direct press machine. The final results are solid 

tablets of pure Chlorella pyrenoidosa. 

The recommendations as to the number of Chlorella 

tablets and Chlorella liquid extract which should be consumed 

daily may vary. For example, the maintenance 

dosage of Chlorella tablets and Chlorella liquid extract for 

those in good health is 15 tablets (3g) and 30 ml. Those with 

severe medical conditions may increase the daily dosage as 

much as three times, depending on their specific needs. 

PROMOTION OF HEALTH AND HEALING BY 

CHLORELLA 

We know that neither disintegrated cell-wall preparations 

of Chlorella pyrenoidosa nor CGF has any direct action 

against cancer cells or infective agents, and so the exact 

mechanism by which Chlorella enhances immunoreactivity 

remains unclear. Animal studies have demonstrated that 

Chlorella pyrenoidosa affects the immune system by stimulating 

an increase in number and activities of macrophages 

and polymorphonuclear leukocytes. 3-7 An acidic polysac- 


charide prepared from Chlorella cell wall has also been 

shown to induce the production of interferon in vitro and in 

mice8 and therefore, part of Chlorella pyrenoidosa’s anticancer 

effect in part may be mediated through the actions of 

this cytokine. 

Miyazawa et al. 4 examined the effects of Chlorella 

pyrenoidosa on anti-tumor activities of C3H/He mice. 

They reported that mice acquired anti-tumor immunity by 

inoculation with some derivatives from Chlorella. 

Autoclaved and heat-extracts of Chlorella enhanced 

macrophage activity and cytotoxic activity of lymphocytes. 

Mice were given subcutaneous transplants of MM-2 

tumor cells and then divided into 4 treatment groups. At 

designated times when tumors reached a certain size or 

prior to tumor inoculation, mice received multiple injections 

of 1 X 107. Chlorella pyrenoidosa cells or 3 mg of its 

extract by 6 intraperitoneal injections made every other 

day. Groups receiving autoclaved cells or protein-containing 

Chlorella extracts showed an anti-tumor effect. 

Administration only following tumor inoculation had no 

significant impact on survival. 

Komiyama et al. 7 reported that an acidic polysaccharide 

purified from the hot water extract of Chlorella 

pyrenoidosa possessed anti-tumor activity against five 

transplantable murine tumors in vivo. The extract showed 

remarkable life prolongation effects in mice bearing sarcoma 

180, and was also active against Lewis lung carcinoma, 

Meth-A fibrosarcoma, IMC carcinoma, and B16 melanoma 

growing in the peritoneal cavity. Meth-A cells admixed 

with the extract and then subcutaneously inoculated, 

showed remarkable inhibition of tumor growth. The extract 

enhanced cytotoxicity of murine macrophages for EL-4 

tumor cells in vitro, lymphoproliferative effects in vitro, 

and carbon clearance in vivo. 

Treatment of cancer and chronic diseases with drugs 

may relieve symptoms and slow progression or as in the 

case of hypertension, reduce the risk of cardiovascular disease. 

Drug treatment may also, unfortunately, require the 

life-long use of an agent that may have adverse side effects. 

For this reason, there is a great deal of interest in non-pharmacological 

interventions which can reduce or eliminate the 

need for drugs for various illnesses. Based on the research 

from Japan, we have hypothesized that adding Chlorella to 

the diet could be one such non-pharmacological approach. 

The principal focus of the research reviewed here, therefore, 

was to provide solid evidence from small clinical trials that 

dietary supplementation with two products derived from 

Chlorella pyrenoidosa tablets and Chlorella liquid extract, 

could relieve symptoms and improve quality of life in people 

suffering from a primary brain tumor, fibromyalgia syndrome, 

hypertension, or ulcerative colitis. 

Summer 2001

MALIGNANT BRAIN TUMOR 

The prognosis for patients with the type of brain tumor 

known as a malignant glioma is extremely poor with 

expected survival in the range of one to two years. 

Standard treatment for these tumors usually consists of surgical 

debulking followed by radiotherapy and/or 

chemotherapy. It is also known that patients harboring a 

malignant glioma have a marked, generalized depression 

of immune competence affecting both cellular and humoral 

immune mechanisms. 9,10 These immune deficiencies are 

present in the preoperative period, prior to radiotherapy, 

chemotherapy or steroid administration. 

Our clinical study in patients with a history of glioma 

was designed to test whether dietary supplements derived 

from Chlorella pyrenoidosa would help them maintain their 

health and resistance to infection, as well as restore their 

immune functions. 11 A total of 21 patients participated in 

the study; 15 had a glioblastoma multiforme (GBM), four 

with low-grade astrocytoma, one had an anaplastic astrocytoma 

(AA), and one with a high-grade oligodendroglioma. 

They supplemented their daily diet with 20 g Chlorella 

tablets and 150 ml of Chlorella liquid extract for up to two 

years. During this time, each patient’s general health was 

monitored by monthly physical and neurological examinations, 

as long as they survived or for the two years they participated. 

Complete blood counts, differentials, cytometric 

determinations of natural killer (NK) cells and T cell subsets, 

and in vitro lymphocyte activation assays to assess 

level of immunosuppression, were performed on the blood 

samples. Imaging studies of the brain and blood tests were 

performed at 3-4 months intervals. Time to tumor recurrence 

(TTR) was defined as the number of months between 

the start of Chlorella supplementation and the MRI/CT scan 

that indicated the area of the glioma had increased. Survival 

was defined as the number of months that the patient 

remained alive after joining the study, irrespective of 

whether there had been any evidence of tumor growth. 

Over the course of the investigation, we noted that our 

patients as a whole, experienced fewer than expected respiratory 

infections and influenza-like illnesses. From a purely 

subjective standpoint, most patients also commented that 

they felt that the Chlorella supplement had helped them 

maintain their strength and decreased their usual number of 

colds and other common illnesses. These findings appear to 

support the theory of Tanaka et al. 5 that some Chlorella 

species protect a host from causative agents of opportunistic 

infections in immunocompromised states related to malignancy, 

chronic disease, and organ transplantation. We also 

found it a positive factor for the patient that the nutritional 

supplementation with Chlorella allowed them to participate 

more actively in their own treatment and care. The discipline 

and positive attitude of our patients along with their strong 

will to survive their tumor certainly contributed to the maintenance 

of their better than expected clinical status. 

Summer 2001 

Blood tests provided more objective data on the status 

of each patient’s hematologic and immune functions. 

Quantitative analyses of erythrocyte components indicated 

that 90% of our patients’ values remained within normal 

limits (WNL) of variation or returned to the normal range 

within four months of adding Chlorella to the diet. Baseline 

total leukocyte counts and differentials were within the normal 

range for 60% of the patients, but by eight months in 

the study, all but one of the patients’ counts were within the 

normal range. The maintenance of standard peripheral 

blood cell values or their return to normal limits indicated 

that circulating leukocytes and myeloid progenitors in 

patients consuming Chlorella were less affected by tumor, 

chemotherapeutic drugs, and/or the immunosuppressive 

medication, dexamethasone. 

We also examined the relative proportions of lymphocytes 

bearing specific T cell and NK markers in blood samples. 

Baseline concentrations of CD3+ T cells were abnormally 

low in eleven patients, but these values returned to 

normal percentages in six. The proportion of CD3+ lymphocytes 

in three patients with normal baselines, however, 

moved below the normal range. The percentage of CD4+ 

helper T cells in eleven patients was in the normal range at 

baseline, while seven were below and two above. Both of 

the high and three of the low eventually had normal percentages 

of cells expressing the CD4+ phenotype. The proportion 

of CD4+ eventually fell in only three patients 

whose baseline proportion of CD4+ cells was normal. 

Baseline percentages of lymphocytes expressing the suppressor/cytotoxic 

T cell phenotype (CD8+) were normal in 

twelve patients and low in five and high in three. All three 

of the high and two of the low had their proportion of CD8+ 

cells become normal after joining the study. These results 

suggested that dietary Chlorella supplementation helped 

glioma patients maintain normal quantities and proportions 

of peripheral blood T lymphocytes. When cell numbers 

which were normal fell below the normal range, this generally 

correlated with tumor recurrence. 

Although, the number of peripheral blood NK cells do 

not appear to be affected in patients harboring a glioma, 10 

we determined the percentages of CD56 + NK cells in the 

blood of most of our patients. Nine of the sixteen patients 

tested had normal numbers of CD56 + lymphocytes and in 

the others, the values were below the normal range. For 

most of our patients, the percentages of NK cells, however, 

proved to be quite variable, moving between normal and 

low over the time they were supplementing their diets with 

Chlorella. From our results, we could not determine whether 

Chlorella had any modulatory or protective effect on the 

number and functions of circulating NK cells in our patients. 

The response of peripheral blood lymphocytes to mitogens 

is suppressed in malnourished cancer patients as well 

as those with a glioma. 10 In our study, in vitro mitogenic 

assays using phytohemagglutinin, indicated that most (13 


out of 19) patients’ baseline samples showed a normal lymphocytic 

response, while in the other patients this reaction 

was suppressed. Within two months of adding Chlorella 

pyrenoidosa to their diet, however, lymphocytes from four 

of the latter group showed normal mitogenic reactivity. 

Only one patient whose baseline lymphocyte mitogenic 

response was WNL was suppressed later. Collectively, 

these results suggested that the nutritional benefits of 

dietary Chlorella may have helped our patients’ lymphocytes 

maintain a normal reactivity to pathogens, and thus 

contributed to the decreased incidence of infections that 

was observed in our pool. 

While patients were in our study, we monitored their 

functional condition by monthly interviews and physical 

examinations. We also observed the status of their glioma 

by MRI/CT scan. These latter studies revealed a tumor 

recurrence or death (without evidence of tumor progression) 

in nine of the evaluable patients during the first year 

of the study. Three of the eleven patients who completed 

one year of the study without evidence of tumor recurrence, 

had renewed growth of their tumor in the second year. At 

the end of two years, nine patients, six with GBM and all 

three with low-grade astrocytoma, were alive and of these, 

only two of the GBM patients had shown MRI/CT evidence 

of tumor recurrence. 

Collectively, these results suggest that dietary supplementation 

with Chlorella pyrenoidosa alone or in combination 

with surgery, radiation and/or chemotherapy did not 

alter the prognostic parameters significantly for survival in 

patients with high-grade gliomas. Older patients and those 

with massive tumors, still survived fewer months in a predictable 

fashion. However, we believe that survival and 

TTR in younger patients and/or with smaller burdens on 

MRI/CT scan were better than expected. The median total 

survival for the eleven patients who died over the course of 

the trial was 17 months; 17 months for the five who had a 

large tumor when they began the study and 19 months for 

those with a lower baseline tumor burden. 

The results of our small clinical trial suggested that 

adding Chlorella pyrenoidosa to the diets of brain tumor 

patients may offer some protection from the deleterious 

effects of tumor, chemotherapy, and radiation. In our patients, 

immune responses and leukocyte counts remained in the normal 

range or improved regardless of tumor burden and other 

types of treatment they received. The supplement, however, 

appeared to have little influence on the natural progression of 

disease in patients who were very ill or incapacitated from 

their disease when they began taking Chlorella pyrenoidosa. 

Most of the patients who had a low tumor burden and were 

in good physical condition when they began the study clearly 

had longer than expected TTRs and survival. Overall, they 

also remained relatively free of unrelated maladies and 

opportunistic infections, which commonly afflict those on 

myelosuppressive therapies and/or corticosteroids. 

FIBROMYALGIA SYNDROME 

It has been estimated that 2-4% of the American population 

suffers from fibromyalgia syndrome (FMS); a condition 

where the major complaint is a generalized achiness 

accompanied by fatigue, sleep problems, morning stiffness, 

and/or headaches. The definitive diagnosis of FMS is based 

on standards established by The American College of 

Rheumatology (ACR); these criteria relate to the severity of 

a patient’s tenderness at a minimum of 11 tender points in 

18 characteristic locations measured by palpation. 12,13 

From this, a tender point index (TPI) is then calculated by 

taking into account the level of pain a patient demonstrates 

at each site. 

Some patients with FMS can get relief of their symptoms 

with non-pharmacologic methods such as gentle aerobic 

exercise or by increasing the amount of sleep while at 

the same time maintaining a regular sleep schedule. 

Tricyclic anti-depressants are also commonly used in the 

treatment of FMS and randomized, controlled trials of these 

anti-depressants have shown them to improve sleep and 

provide modest relief of stiffness and tenderness. 12 Up to 

the present, however, no food, dietary supplement, or 

herbal preparation has been proven effective for FMS in 

controlled studies. 

Over the past four years, we conducted two consecutive 

clinical trials of Chlorella in subjects with FMS. The 

first investigation was an open-label pilot study which 

involved 18 highly symptomatic people who had 2+ palpable 

tenderness at 11 or more of the 18 ACR-defined tender 

points, and a TPI of at least 22. 14 Each day for two months, 

they added to their diets 10 g of Chlorella tablets and 100 

ml of Chlorella liquid extract. Amelioration of FMS symptoms 

was validated and quantified using semi-objective and 

subjective outcome measures administered at the two 

monthly clinic visits. 

We found that the addition of the two Chlorella products 

to the diet led to a mean net decrease of two tender 

points; from 17 at baseline to 15 by the end of the study. 

Moreover, the average TPI which was 32 at baseline fell to 

25. This 22% decrease in the intensity of pain was statistically 

significant (p=0.01). Compilations of the results from 

patient interviews, self-assessment questionnaires, and 

visual analog scales also revealed improvements in pain (by 

21%), sleep (by 8%) and anxiety (by 15%). 

Although the results of our first, pilot study suggested 

that adding Chlorella to the diet improved symptoms of 

FMS, we recognized that some of these data were based on 

subjective responses given by our participants who knew 

they were consuming Chlorella. Therefore, there was a 

chance that these results could be biased and the patients 

could have experienced some placebo-effect. Nevertheless, 

the possibility that subjects with FMS could have their level 

of pain (as measured by the TPI) significantly decreased by 


simply adding the two Chlorella supplements to the diet 

suggested that a placebo-controlled and blinded clinical 

trial was warranted. Therefore, a larger, more comprehensive 

clinical trial in subjects with FMS was next undertaken 

to expand on these results, and determine if similar findings 

would occur following a double-blinded, placebo-controlled 

crossover design. 15 

For this second trial, a total of 43 people were enrolled 

and randomized such that approximately half consumed 50 

tablets (10 g) of Chlorella and 100 ml of Chlorella liquid 

extract each day for three months, and the other half consumed 

50 placebo tablets (10 g) and 100 ml of placebo liquid 

extract each day for a comparable period. Neither the 

patients nor the physician conducting the assessments knew 

which of the dietary supplements the subjects were consuming 

at any given time. Following a one month washout 

period, subjects crossed-over from Chlorella to placebo or 

visa versa. Thirty-four subjects completed the entire trial. 

Like the first clinical trial, the overall objective of the 

second study was to determine if adding Chlorella to the 

diet of the FMS patients produced improvements in their 

clinical and functional status. A baseline examination preceded 

each patient’s commencing the diet and each subject 

was reexamined monthly during the seven-month period of 

the study. Physician assessments included a physical exam 

with blood studies, articular examination, and determination 

of the number of tender points and TPI were done at the 

beginning and end of each arm of the crossover. Patientrated 

outcome measures included the Fibromyalgia Impact 

Questionnaire (FIQ), 16 a patient questionnaire, and the 

Hassles Scale. 

The tender point exams showed that after three months 

of dietary supplementation with the two Chlorella products, 

there was a statistically significant (p=0.009) decrease of 

1.1 tender points on average and a statistically significant 

(p=0.024) difference in the number of tender points 

between the two diet supplements. The average TPI after 

three months on the Chlorella supplements fell by 1.8 

points (7.6%) which approached statistical significance 

(p=0.068). After three months on the placebo, the average 

TPI decreased by only 0.5 points. While the differences in 

the average percentage improvement in TPI after three 

months on either of the two groups of dietary supplements 

was not significant, it was noted that 62% of the subjects 

showed a better TPI (i.e. less pain) after consuming 

Chlorella compared to that after they took the placebo. 

Assessment of functional abilities or limitations by the 

FIQ showed that when they were consuming Chlorella, 

there was a steady, statistically significant, improvement. 

When they were taking placebo, levels of improvement varied 

and were not statistically significant. When the subjects 

were consuming Chlorella, there was a steady decrease in 

the FIQ score, from an average of 58.4 at baseline to 47.0 at 

the end of the three-month supplement period. This mean 

drop of 11.4 (19.5%) in the score indicated the improvement 

in function was highly statistically significant (p

e effective in lowering blood pressure and have been 

emphasized increasingly as useful ways for both prevention 

and treatment of hypertension. The four principal non-pharmacological 

methods for lowering blood pressure are 

weight control (or loss), diet modification, exercise, and 

reduced alcohol consumption. Dietary modifications are 

designed to reduce the intake of sodium and dietary fat 

while at the same time increasing the consumption of calcium, 

magnesium, potassium, and dietary fiber. Diet studies 

have led to the hypothesis that cations and fiber which occur 

together in such “whole foods” as fruits, nuts, vegetables, 

and cereals, act in synergy to produce a hypotensive effect. 

More clinical trials of specific foods, food groups and 

dietary patterns, however, are clearly warranted. Therefore, 

the objective of our clinical trial was to determine if daily 

dietary supplementation with Chlorella lowered the blood 

pressure of individuals with a history of mild to moderate 

hypertension and who otherwise ingested a normal, nonvegetarian 

diet. 15 

Our study was open to people of either sex, 21 years of 

age or older with mild (mean SiDBP 90-104 mm Hg) to 

moderate (mean SiDBP 105-115 mm Hg) hypertension and 

who were willing to discontinue all medication given 

specifically for their hypertension. A total of 33 subjects 

were enrolled and they ranged in age from 22 to 73 years 

(mean of 50). Subjects had been diagnosed with hypertension 

for 11 years on average (range 0-47 years), and all but 

six were taking a drug daily for their hypertension. The 

mean heart rate of the group was 73.7 ± 10.2, and their 

SiSBP was 136.8 ± 11.5 and mean SiDBP was 90.8 ± 6.2. 

Following a one-month washout of drug and the daily 

consumption of placebo, 24 subjects remained in the trial. 

Seven were dropped because they no longer met eligibility 

criteria for mild to moderate hypertension, and two withdrew 

because of side effects of having stopped taking their 

anti-hypertensive drug treatment. After a month off their 

hypertension medicine and dietary supplementation with 

placebo, their mean heart rate rose slightly to 76.5 ± 9.9 and 

their SiSBP rose to an average of 141.6 ± 14.4, and mean 

SiDBP rose by 4.3 mm Hg to 96.5 ± 6.6. While the increase 

in mean SiSBP was not statistically significant, the rise in 

mean SiDBP was (p=0.004). 

Using these levels, blood pressure changes in the subjects 

were assessed. After one or two months of dietary 

Chlorella supplementation with 10 g of Chlorella tablets 

and 100 ml of Chlorella liquid extract, their heart rates, 

SiSBP, and SiDBP changed only slightly from the end of 

the placebo/washout period. Coming off the anti-hypertensive 

medications for a month, alone may have been responsible 

for the increase in SiDBP and during dietary Chlorella 

supplementation there was essentially no increase (i.e. 

worsening) on average of the SiDBP. 

Since only working with “average” changes in SiDBP 

might mask individual responses (i.e. decreases in SiDBP) 


among the subjects, each subject’s response was also characterized 

by three different criteria. Using criteria of the 

pharmaceutical industry, six of the subjects enrolled had an 

excellent response to the dietary supplement; that is that 

after two months of taking Chlorella, their SiDBP was 

below 90 mm Hg. Furthermore, another three subjects 

although having a SiDBP above 90 mm Hg, still showed 

between a 4 and 9 mm Hg drop in their SiDBP. The remaining 

15 subjects, however, were considered inadequately 

treated by stopping their anti-hypertensive medication and 

adding Chlorella to their diet; i.e. SiDBP either rose during 

this period or fell by less than 4 mm Hg. Thus, following 

the conventional pharmacological criteria for assessing 

response, it can be stated that 38% of our subjects showed 

some improvement in their hypertension by adding 

Chlorella to their diet. 

This improvement with Chlorella supplementation, 

however was amplified when only a 4 mm Hg change in 

SiDBP was used to evaluate the response. When the first 

SiDBP of subjects (when most were taking an anti-hypertensive 

medication) was compared to their last visit (after 

three months off medication and two months of taking 

Chlorella), five subjects showed improvement, six had an 

essentially unchanged SiDBP, and 13 had a worsening of 

their hypertension. Therefore, according to these criteria, 

the SiDBP of eleven subjects had as good or better control 

of their blood pressure with the dietary supplement as they 

had by taking an anti-hypertensive drug. This effect was 

even more dramatic when these same criteria were applied 

to compare the SiDBP after one month off medication and 

placebo and after two months of dietary Chlorella. Here 

nine subjects showed improved SiDBP, seven were stable, 

and one-third showed a worsening of their hypertension. 

This finding that two-thirds of the subjects’ SiDBP either 

improved or was stable without their anti-hypertensive 

medications suggested that for these subjects dietary supplementation 

with Chlorella either improved or kept their 

hypertension under control. 

Physical exams and electrocardiograms did not change 

between the beginning and end of the study period. Blood 

cell counts, routine serum chemistries and urinalysis of the 

study population were within normal limits and no single 

variable significantly changed over the three-month course 

of the investigation. However, when serum total cholesterol, 

high- and low-density cholesterol were measured, the 

averages and standard deviations were WNL, but there 

were numerous statistically significant changes over the 

course of the investigation. First, there was a significant 

drop in serum cholesterol from the beginning until the end 

of the study; p=0.003. High-density cholesterol dropped 

after two months of dietary Chlorella (p=0.03) as did lowdensity 

cholesterol (p=0.003). 

Our study also sought to determine if dietary supplementation 

with Chlorella improved the quality of life of 

Summer 2001

these hypertensive subjects. The Psychological General 

Well-Being Index was used for this assessment 17 with 

responses summed to create six subscales which measured 

anxiety, depressed mood, positive well-being, self-control, 

general health, and vitality. The subjects’ perceived level of 

anxiety was significantly decreased (p=0.02) while 

depressed mood was significantly improved (p=0.02) over 

the course of the study. The subjects’ sense of well-being 

was significantly better (p=0.007) and there was a trend for 

improvement of the subjects’ perceived changes in self-control, 

general health and vitality by the end of the study. The 

sum of the scores for the General Well-Being Index showed 

statistically significant (p=0.01) improvements. These 

results indicated that subjects were feeling better overall 

and particularly their anxiety and depression improved significantly, 

because of the combined effects of no longer 

having to take their regimen of anti-hypertensive drug(s) 

and supplementing their diets with Chlorella. 

ULCERATIVE COLITIS 

Ulcerative colitis is a common, chronic form of inflammatory 

bowel disease that is characterized histologically as 

inflammation involving the mucosa and submucosa of the 

rectum and colon. Its most common symptoms are abdominal 

pain and bloody diarrhea although those afflicted may 

also suffer from anemia, fatigue, weight loss, rectal bleeding, 

dehydration and malnutrition. The cause of ulcerative 

colitis is unknown and there is currently no cure. While 

available drug therapy for ulcerative colitis is often disappointing, 

most patients get some relief with a combination 

of sulfasalazine and corticosteroids. Up to now, no special 

diet or dietary supplement has been proven effective in the 

treatment of ulcerative colitis and, therefore, the purpose of 

our study was to determine if patients strongly symptomatic 

for ulcerative colitis would benefit from the inclusion of 

Chlorella in their diet. 15 

Ulcerative colitis is defined as having documented 

symptoms of hematochezia and diarrhea, negative stool cultures, 

and typical sigmoidoscopic findings such as superficial 

ulcerations, distorted mucosal vascular patterns, granularity, 

and exudate. From these data, a Disease Activity 

Index (DAI) can be computed from four subscales, consisting 

of: stool frequency, rectal bleeding, mucosal appearance, 

and physician’s overall assessment. 18 To be eligible 

for our study, subjects had to have suffered from mild to 

moderate disease for at least year and have a total DAI 

between 4 and 10, inclusive. The nine subjects enrolled 

ranged in age from 25 to 56 years and had at baseline, an 

average DAI of 7.2 ± 2.4. They supplemented their diets 

with 10 g of Chlorella tablets and 100 ml of Chlorella liquid 

extract daily for the two months of the study. Each participant 

returned to clinic every four weeks when blood 

samples were taken in order to assess any alterations in 

serum chemistries, cell counts, and sedimentation rate. A 

Summer 2001 

flexible sigmoidoscopic examination was conducted at the 

end of two months. 

Eight subjects completed the entire two-month study 

and changes in each subclass of their DAI improved such 

that the total DAI declined from an average 7.2 ± 2.4 to 2.8 

± 2.5 (i.e., symptoms improved). The mean decrease in 

DAI from the beginning to end of study was 61% and was 

highly statistically significant (P=0.008). The decrease in 

stool frequency was statistically significant (p=0.016). The 

physician’s sigmoidoscopic examination of rectal mucosa 

showed significantly less inflammation (p=0.02) and his 

overall assessment was that the patients’ ulcerative colitis 

was significantly better (p=0.008). While the occasions of 

rectal bleeding were less for most subjects, the change was 

not significant (p=0.18). All blood analyses indicated these 

values remained within the normal limits of variation. 

The effects of dietary Chlorella supplementation on 

their quality of life were quantified with the Inflammatory 

Bowel Disease Questionnaire19 which contained 32 questions 

which examined four aspects of the patients’ lives: 1) 

symptoms related to the primary bowel disturbance, 2) systemic 

symptoms, 3) emotional, and 4) social functions. Their 

responses on this questionnaire indicated statistically significant 

and strong trends for improvements in all four categories. 

Furthermore, they indicated that they believed the 

severity of their ulcerative colitis had decreased soon after 

the addition of Chlorella to their diet, and continued to lessen 

or remain stable over the study’s course. Taken together, the 

DAI results which indicated that every participant’s objective 

symptoms of ulcerative colitis improved, combined with 

the positive assessment each patient gave in their questionnaires, 

strongly suggested that all the subjects benefited from 

supplementing their diet with Chlorella. 

CONCLUSION 

It has been suggested that consumption of natural 

“whole foods” rich in macronutrients have many healthful 

benefits in individuals who otherwise ingest a normal, nonvegetarian 

diet. Our research has focused on the testing of 

dietary supplements derived from Chlorella pyrenoidosa, 

in clinical trials. To date, we have conducted trials in subjects 

suffering from either brain cancer, fibromyalgia, 

hypertension, or ulcerative colitis. They consumed 10-20 g 

of Chlorella tablets and 100-150 ml of Chlorella liquid 

extract each day for two or three months. For validity, these 

studies were designed and carried out according to current 

conventional methodologies used in the pharmaceutical 

industry for drug development and testing. The results of 

these clinical trials suggested that daily dietary supplementation 

with Chlorella may reduce high blood pressure, 

lower serum cholesterol, accelerate wound healing, and 

enhance immune functions. Its potential to relieve symptoms, 

improve quality of life, and normalize body functions 


in patients suffering from the illnesses studied here suggest 

that larger, more comprehensive clinical trials of Chlorella 

are warranted for these, as well as other chronic illnesses. 

ACKNOWLEDGEMENTS 

The authors wish to express their gratitude to Mister 

Tetsuaki Nakayama and the Sun Chlorella Corporation of 

Kyoto, Japan for their support of our clinical research projects. 

The authors wish to thank Harold F. Young, MD, 

Christopher M. Wise, MD, Domenic A. Sica, MD, Cynthia 

B. Bettinger, MD, and Donald F. Kirby, M.D. for their collaboration 

on these clinical trials. 

Reprinted with permission 

Townsend Letter for Doctors & Patients, 

911 Tyler Street, Pt. Townsend WA 98368; 

360-385-6021; www.tldp.com 

REFERENCES 

1. Mitsuda H, et al. Effect of the breaking of Chlorella cells on 

the digestibility of Chlorella protein. J Jpn Soc Food Nutr. 

1977;30:93-98. 

2. Steenblock D. Chlorella, Natural Medicinal Algae. Aging 

Research Institute, El Toro, CA, 1987. 

3. Kojima M, et al. A new Chlorella polysaccharide and its accelerating 

effect on the phagocytic activity of the reticuloendothelial 

system. Recent Adv. RES Res. 1973;13:11. 

4. Miyazawa Y, et al. Immunomodulation by unicellular green 

algae (Chlorella pyrenoidosa) in tumor-bearing mice. J 

Ethnopharmacol. 1988;24:135-146. 

5. Tanaka K, et al. Augmentation of host defense by a unicellular 

alga, Chlorella vulgaris, to Escherichia coli infection. Infect 

Immun. 1986;53:267-271. 

6. Konishi F, et al. Anti-tumor effect induced by a hot water 

extract of Chlorella vulgaris (CE): resistance to Meth-A tumor 

growth mediated by CE-induced polymorphonuclear leucocytes. 

Cancer Immunol Immunother. 1985;19:73-78. 

7. Komiyama K, et al. An acidic polysaccharide chlon A, from 

Chlorella pyrenoidosa. 2. Anti-tumor activity and immunological 

response. Chemotherapy 1986;34:302-307. 

8. Umezawa I, et al. An acidic polysaccharide. chlon A, from 

Chlorella pyrenoidosa. Chemotherapy. 1982;30:1041-1045. 

9. Young HF, and Merchant RE. Brain tumors. Curr. Opinion 

Neurol. Neurosurg. 1990;3:22-27. 

10. Young HF, et al. Immunocompetence of patients with malignant 

glioma. In: Neurobiology of Brain Tumors, M. Salcman (ed.), 

Williams and Wilkins, Baltimore, MD, pp. 211-227, 1991. 

11. Merchant RE, et al. Dietary Chlorella pyrenoidosa for 

patients with malignant brain tumor: Effects on immunocompetence, 

quality of life, and survival. Phytotherapy Res. 

1990;4:220-231. 


12. Russell IJ, et al. Is there a metabolic basis for the fibrositis 

syndrome? Am J Med. 1986;81:50-56. 

13. Wolfe F, et al. The American College of Rheumatology 1990 

Criteria for the Classification of Fibromyalgia. Report of the 

multi-center criteria committee. Arthritis Rheum. 

1990;33:160-172. 

14. Merchant RE, et al. Nutritional supplementation with 

Chlorella pyrenoidosa for patients with fibromyalgia syndrome: 

A pilot study. Phytotherapy Res. 2000;14:167-173. 

15. Merchant RE and Andre CA. A review of recent clinical trails 

of the nutritional supplement, Chlorella pyrenoidosa, for 

fibromyalgia, hypertension, and ulcerative colitis. J 

Alternative Therapies Health Medicine. 2001; In Press. 

16. Burckhardt CS, et al. The fibromyalgia impact questionnaire: 

development and validation. J Rheumatol. 1991;18:728-733. 

17. Dupuy HJ. The psychological general well-being (PGWE) 

index. In: Assessment of Quality of Life in Clinical Trials of 

Cardiovascular Therapies. NK Wenger, et al. (eds.), LeJacq 

Publ, New York, NY, pp. 170-183, 1984. 

18. Kam L, et al. A comparison of mesalamine suspension enema 

and oral sulfasalazine for treatment for treatment of active 

distal ulcerative colitis in adults. Am J Gastroenterol. 

1996;91:1338-1342. 

19. Guyatt G, et al. A new measure of health status for clinical trials 

in inflammatory bowel disease. Gastroenterology. 

1989;96:804-810. 

Summer 2001

P E R S P E C T I V E 

The Synergistic Approach: 

The Future of Nutrition Therapy 

INTRODUCTION 

No cell in the body requires only one nutrient, yet single 

nutrient therapy has comprised the bulk of all nutrient 

intervention studies. This is understandable, because the 

goal of research is to isolate the activity of nutrients so their 

individual roles in the prevention of deficiency and the 

treatment and prevention of disease can be discovered. 

Clinically, however, single nutrient therapy is not as 

effective as multiple nutrient intervention. Single nutrient 

deprivation and intervention studies are useful for research 

purposes, but as the research cited below will show, whenever 

synergistic nutrient combinations are compared to single 

nutrient interventions, the combined nutrient approach 

is both more safe and more effective. Perhaps this is 

because multiple nutrient intervention better approximates 

the nutrient distribution found in food. 

No cell in the body uses only one nutrient. No nutrient 

in the body acts alone. Therefore, it should come as no surprise 

that we need all nutrients to promote optimal cellular, 

organ, and overall health. Because nutrients have powerful 

interactions with other nutrients, the success of a nutrient 

therapy may depend more on the synergistic interaction 

with a particular nutrient than merely the dose given. This 

argues for both individualized therapies as well as synergistic 

ones. For example, the first National Health and 

Nutrition Examination Survey (NHANES I) data shows 

that the Na:K ratio was more strongly related to blood pressure 

than either nutrient alone. 1 


Robert Crayhon, MS 

Designs for Health Institute, Inc. 

5345 Arapahoe Ave. #3 

Boulder CO 80303 

Phone: 303-415-0229 Fax: 303-415-9154 

Robert@dfhi.com 

Robert Crayhon, MS* 

Designs for Health Institute, Inc., Boulder, Colorado 

One reason nutritional therapy should be done in synergy 

is that deficiencies occur in synergy. 2 It is difficult to 

study riboflavin deficiency in humans, for example, 

because it is so often accompanied by deficiencies of other 

nutrients. Therefore, repleting all nutrients is often beneficial 

in cases of a single nutrient deficiency. 

SYNERGISTIC INTERVENTIONS ARE SAFER 

The most important reason to use nutrients in combination 

is not efficacy, but safety. The ingestion of single, 

isolated nutrients by the human genus is but 70 years old. 

This is at odds with the 2.6 million years of only ingesting 

nutrients in synergistic combinations found in foods of 

plant and animal origin. Throughout our genetics’ long history, 

there is not a single instance where a food consumed 

supplied one, or even a small handful of nutrients. This is 

mirrored in our metabolism: all cellular functions, including 

glycolysis, the Krebs cycle, the energy transfer cycle, 

cellular housekeeping, eicosanoid metabolism, neurotransmitter 

metabolism, antioxidant defense, immune strength, 

and detoxification all depend on an optimal supply of virtually 

all nutrients. 

The homocysteine-raising effects of niacin have been 

noted in human studies. In a multicenter randomized, 

placebo-controlled trial, the effects of niacin compared 

with placebo on homocysteine levels in a subset of 52 participants 

with peripheral arterial disease were examined. 

During the screening phase, titration of niacin dose from 

100 mg to 1000 mg daily resulted in a 17% increase in 

mean plasma homocysteine levels from 13.1 to 15.3 micromol/L. 

At 18 weeks after randomization, there was an 

absolute 55% increase from baseline in mean plasma 

homocysteine levels in the niacin group and a 7% decrease 

in the placebo group. 3 Animal studies have shown that taking 

pyridoxine with niacin eliminates its homocysteineraising 

effects. Human trials using niacin along with all of 


the homocysteine-lowering nutrients—folate, cobalamin, 

and pyridoxine—are warranted. 4 

Beta carotene is another nutrient that does not offer 

complete safety when taken alone. By itself, beta carotene 

does lead to regression of oral leukoplakia, a precancerous 

lesion. 5 However, beta carotene supplements appear to 

increase the incidence of lung cancer in smokers. 6 This 

may be due, however, to the fact that taking beta carotene 

alone does not supply the other nutrients—vitamin E and 

vitamin C—that are needed to help prevent beta carotene 

from oxidizing and itself becoming a cell-damaging free 

radical. The Linxian study showed that vitamin E, selenium, 

and beta carotene supplementation led to lower cancer 

rates, 7 showing that a synergistic combination can lead to 

positive results. However, not all synergistic research in 

cancer prevention has yielded positive results. Beta 

carotene and vitamin E taken together did not lead to protection 

against pancreatic cancer8 or colorectal adenomas9 in the ATBC (alpha tocopherol beta carotene) trial. 

Beta carotene in its unoxidized form appears to be an 

anticarcinogen, but its oxidized products appear to facilitate 

carcinogenesis. The carcinogenic response in lung tissue to 

high-dose beta carotene supplementation reported in the 

human intervention trials may be caused by instability of 

beta carotene molecules in the free-radical-rich environment 

in the lungs, particularly in cigarette smokers. 10 This 

is especially possible because smoke decreases tissue levels 

of other antioxidants, such as ascorbate and alpha-tocopherol, 

which normally have a stabilizing effect on the 

unoxidized form of beta carotene. Nutritional intervention 

using a combination of antioxidants such as beta carotene, 

alpha-tocopherol, lycopene, and ascorbate as anticarcinogenic 

agents would be a more appropriate way to reduce 

cancer incidence in smokers. Were this intervention done, 

we could perhaps duplicate with supplementation the epidemiological 

results suggesting that a high beta carotene 

intake through diet is chemoprotective against lung cancer. 

Foods rich in beta carotene such as green leafy vegetables, 

yams, and carrots are rich in other antioxidants, including 

ascorbate, polyphenols, and other carotenoid and xanthophyll 

antioxidants. 11 

Iodine and selenium are two nutrients essential to thyroid 

function. Yet supplementing with iodine in the absence 

of selenium can do more harm than good. High iodine 

intake during selenium deficiency can permit thyroid tissue 

damage as a result of low thyroidal GSH-Px activity during 

thyroid stimulation. 12 

THE SYNERGISTIC EFFECT BENEFITS 

NUTRIENT ABSORPTION 

Vitamin C and other antioxidants are known to enhance iron 

absorption. 13 Zinc can be thought of as synergistic with 

almost every other nutrient, for a lack of adequate zinc can 


lead to a lack of absorption of other nutrients, particularly 

fat-soluble vitamins such as A and E. 14 Essential fatty acids 

have now been shown to increase calcium absorption from 

the gut, in part by enhancing the effects of vitamin D, to 

reduce urinary excretion of calcium, to increase calcium 

deposition in bone and improve bone strength, and to 

enhance the synthesis of bone collagen. 15 This is particularly 

true for calcium absorption and calcium balance. 

Supplementing with both eicosapentaenoic acid (EPA) and 

gamma linoleic acid (GLA) for three years led to increased 

bone density and decreased calcium turnover in women 

with an average age of 79.5. After three years on supplemental 

EPA and GLA, lumbar spine density increased 3.1% 

and femoral bone mineral density (BMD) increased 4.7%. 16 

Glutamine, short chain fatty acids (SCFAs), and 

nucleotides affect normal and pathologic intestinal mucosal 

development, function, adaptation, and repair, and when 

optimally supplied to the gut mucosa help promote optimal 

nutrient absorption. 17 

SYNERGISTIC ANTIOXIDANT STUDIES IN CANCER 

PREVENTION: SUCCESSES AND FAILURES 

Antioxidants are a great example of how nutrients 

work together, particularly for inhibition of cancer cell 

growth. The effect of the carotenoid lycopene alone or in 

association with other antioxidants was studied on the 

growth of two different human prostate carcinoma cell lines 

(PC-3 and the androgen-insensitive DU-145). Lycopene 

alone was not a potent inhibitor of prostate carcinoma cell 

proliferation. However, lycopene together with alpha-tocopherol, 

at physiological concentrations less than 1 microM 

and 50 microM, respectively, resulted in a strong inhibitory 

effect of prostate carcinoma cell proliferation, which 

reached values close to 90%. 18 Perhaps this synergistic 

effect of nutrients on cancer prevention in human epidemiological 

studies explains why fruits and vegetables19 appear 

to have more protective ability than interventions with single 

nutrients such as beta carotene. 20 

NIACIN AND CHROMIUM 

In order to reduce cholesterol, normally high doses of 

niacin are required. However, in two published case studies, 

when chromium and niacin were combined, it was 

found that a much lower dose of niacin was required to 

achieve a reduction in cholesterol. 21 

Two subjects given niacin and chromium experienced 

significant blood lipid lowering effects. The first subject 

had a cholesterol level of 10.33 mmol/L (399 mg/dL). 

Daily supplementation for four weeks with 100 mg of nicotinic 

acid (niacin) and 200 micrograms of chromium chloride 

led to a decrease in serum cholesterol to 8.86 mmol/L 

(342 mg/dL). Further supplementation for four months led 

to a further decrease in serum cholesterol to 7.25 mmol/L 

Summer 2001

(280 mg/dL). The second subject had a cholesterol level of 

8.73 mmol/L (337 mg/dL). Four weeks of supplementation 

lowered the level to 6.73 mmol/L (260 mg/dL). When supplementation 

was discontinued, the cholesterol level rose 

slightly. When supplementation was reinstituted, the cholesterol 

level decreased to 6.68 mmol/L (258 mg/dL). 21 

While the data from these two case studies requires confirmation 

in a larger trial, they demonstrate that the cholesterol 

lowering effects are typically achieved with large 

doses of niacin can be obtained with smaller doses of niacin 

taken with chromium. 

Chromium does not work effectively in the absence of 

niacin, according to animal research. This could explain why 

humans do not uniformly achieve lipid and/or blood sugar 

lowering effects on chromium supplementation. Sixteen 

healthy elderly volunteers were divided into three groups 

and given either 200 micrograms Cr, 100 mg nicotinic acid, 

or 200 micrograms Cr + 100 mg nicotinic acid daily for 28 

days and evaluated on days 0 and 28. Fasting glucose and 

glucose tolerance were unaffected by either chromium or 

nicotinic acid alone. In contrast, the combined chromiumnicotinic 

acid supplement caused a 15% decrease in a glucose 

area integrated total (p

should be employed. 53 

• HIV patients demonstrate deficiencies in zinc, selenium, and 

glutathione. There is a progressive decrease in carotenoids, 

zinc, selenium, and vitamin E with the severity of disease. 

Few serious and large trials of antioxidants have been conducted 

in HIV-infected patients. The more promising candidates 

for presenting synergistic effects seem to be Nacetyl 

cysteine, beta carotene, selenium, and zinc. 54 

Only through well-designed clinical trials will 

researchers be able to validate the potential synergistic 

actions and clinical benefits of these nutrients. 

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1. Gruchow HW, Sobocinski KA, Barboriak JJ. Calcium intake 

and the relationship of dietary sodium and potassium to blood 

pressure. Am J Clin Nutr. 1988;48:1463-1470. 

2. Munoz EC, Rosado JL, Lopez P, Furr HC, Allen LH. Iron and 

zinc supplementation improves indicators of vitamin A status 

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3. Garg R, Malinow M, Pettinger M, Upson B, Hunninghake D. 

Niacin treatment increases plasma homocyst(e)ine levels. Am 

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6. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen 

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7. Blot WJ, Li JY, Taylor PR, Guo W, Dawsey SM, Li B. The 

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8. Rautalahti MT, Virtamo JR, Taylor PR, Heinonen OP, Albanes 

D, Haukka JK, Edwards BK, Karkkainen PA, Stolzenberg- 

Solomon RZ, Huttunen J. The effects of supplementation with 

alpha-tocopherol and beta-carotene on the incidence and mortality 

of carcinoma of the pancreas in a randomized, controlled 

trial. Cancer. 1999;86:37-42. 

9. Malila N, Virtamo J, Virtanen M, Albanes D, Tangrea JA, 

Huttunen JK. The effect of alpha-tocopherol and betacarotene 

supplementation on colorectal adenomas in middleaged 

male smokers. Cancer Epidemiol Biomarkers Prev. 

1999;8:489-493. 

10. Wang XD, Russell RM. Procarcinogenic and anticarcinogenic 

effects of beta-carotene. Nutr Rev. 1999;57:263-272. 

11. Khachik F, Bernstein PS, Garland DL. Identification of lutein 


and zeaxanthin oxidation products in human and monkey retinas. 


12. Hotz CS, Fitzpatrick DW, Trick KD, L’Abbe MR. Dietary 

iodine and selenium interact to affect thyroid hormone metabolism 

of rats. J Nutr. 1997;127:1214-1218. 

13. Yang M, Collis CS, Kelly M, Diplock AT, Rice-Evans C. Do 

iron and vitamin C co-supplementation influence platelet 

function or LDL oxidizability in healthy volunteers? Eur J 

Clin Nutr. 1999;53:367-374. 

14. Kim ES, Noh SK, Koo SI. Marginal zinc deficiency lowers 

the lymphatic absorption of alpha-tocopherol in rats. J Nutr. 

1998;128:265-270. 

15. Vannucchi H, Kutnink MD, Sauberlich M, Howerde E. 

Interaction among niacin, vitamin B6 and zinc in rats receiving 

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16. Kruger MC, Coetzer H, de Winter R, Gericke G, van 

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17. LeLeiko NS, Walsh MJ. The role of glutamine, short-chain 

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18. Pastori M, Pfander H, Boscoboinik D, Azzi A. Lycopene in 

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27. Hounsom L, Horrobin DF, Tritschler H, Corder R, Tomlinson 

DR. A lipoic acid-gamma linolenic acid conjugate is effective 

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Summer 2001

28. Peth JA, Kinnick TR, Youngblood EB, Tritschler HJ, 

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29. Leffler CT, Philippi AF, Leffler SG, Mosure JC, Kim PD. 

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30. Ito T, Kawahara K, Das A, Strudwick W. The effects of 

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32. Levine J. Controlled trials of inositol in psychiatry. Eur 

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33. Benton D, Cook R. The impact of selenium supplementation 

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36. Edwards R, Peet M, Shay J, Horrobin D. Omega-3 polyunsaturated 

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37. Brooks JO III, Yesavage JA, Carta A, Bravi D. Acetyl L-carnitine 

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38. Little A, Levy R, Chuaqui-Kidd P, Hand D. A double-blind, 

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39. Lombardi GF. [Pharmacological treatment with phosphatidyl 

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of dementia patients in comparison with tacrine. 

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42. Grundman M. Vitamin E and Alzheimer disease: the basis for 

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43. Penland JG, Johnson PE. Dietary calcium and manganese 

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44. Bates CJ, Walmsley CM, Prentice A, Finch S. Does vitamin C 

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47. Ahsan SK. Magnesium in health and disease. J Pak Med 

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54. Favier A, Sappey C, Leclerc P, Faure P, Micoud M. 

Antioxidant status and lipid peroxidation in patients infected 

with HIV. Chem Biol Interact. 1994;91:165-180. 


O R I G I N A L R E S E A R C H 

Pilot Study: Whole Food 

Nutritional Supplement 

Increases Antioxidant Levels in the Blood 


Staff Physician, Great Smokies Medical Clinic, Asheville, North Carolina 

ABSTRACT 

The purpose of this pilot study is to compare the 

antioxidant protection provided by whole food supplementation 

when added to a random sampling of commercially 

available, tailored nutrients and antioxidant supplements. 

Thirteen patients with degenerative diseases were evaluated 

for antioxidant status via blood sample testing using 

the FIA Antioxidant Profile 4000 from Spectracell 

Laboratories, Inc., Houston, Texas. The profile is composed 

of three test components: glutathione, cysteine and the 

FIA Total Antioxidant Function Test (Spectrox) assay. 

Patients’ baseline levels were measured while using their 

self-chosen ongoing regimes of various nutrients and 

antioxidant supplements representing some 85 commercially 

available products. Once their study-outset baselines 

were documented, patients were given a whole food supplement 

(Juice Plus+ ®) that contains phytonutrients from 

17 fruits, vegetables and grains. Repeat blood samples were 

performed over time and compared for antioxidant levels. 

These were summarized and expressed as percentages with 

0% representing the lowest possible antioxidant protection 

and 100% the highest. 



Great Smokies Medical Center, PA 

Park Terrace Center 

1312 Patton Avenue 

Asheville, NC 28806 

Phone: 828-252-9833 Fax: 828-255-8118 

email: jmelliz2@gateway.net 

All patients except one showed improved antioxidant 

protection after adding the whole food supplement. The 

overall antioxidant average before whole food supplementation 

was 33.05%, and 79.13% after. Average improvement 

was 239.7% (p

preparations do not match nature’s recipe. Because current 

concepts focusing on oxidative stress and free radical damage 

to cell physiology are powerful constructs regarding the 

pathogenesis of degenerative diseases, 2,3 most vitamin preparations 

include numerous antioxidants. The most familiar are 

vitamins C, E, A, beta-carotene, and selenium. As additional 

antioxidants with potential preventive roles in degenerative 

diseases are identified, they are added to commercial 

preparations and marketed as new and improved versions. 

Three examples of such popular new antioxidants are: 

(1) dietary carotenoids, especially lutein, that have been 

included in vision-enhancing supplements to help protect 

against the development of macular degeneration, 4 (2) 

lycopene, which may be added to supplements marketed to 

men as part of a formulation for the prevention of prostate 

cancer, 5 and (3) tocotrienols, which are included in supplements 

marketed as enhancements for circulation. 6,7 

The implication for the consumer is that such antioxidant 

supplementation will protect them from oxidative 

damage and reduce their risk for degenerative diseases. 

Americans have been conditioned to the pharmaceutical-like 

treatment concept of “one drug, one disease,” 

which may be carrying over to nutritional supplementation: 

if penicillin prevents post-streptococcal rheumatic heart 

disease, then lycopene may prevent prostate cancer, 10 and 

carotenes may prevent digestive cancers. 11,12 

An example is the Linxian, China study11 where isolated 

nutrient supplements were given to approximately 

29,000 people. The objective was to reduce one of the 

world’s highest rates of digestive tract cancers through 

nutritional intervention. It was also one of the world’s 

largest cancer verses diet deficiency studies ever undertaken. 

At the outset, subjects were found to have low levels of 

at least vitamins A,C,E, carotenes, and riboflavin. The population 

was divided into four study groups. Each were provided 

one of the following nutrient combinations: vitamin 

C, molybdenum; retinol, zinc; riboflavin, niacin; or vitamin 

E, beta-carotene and selenium. No group was provided 

nutrient dense-whole food. Only one group showed 

decreased cancer rates – that of the vitamin E, beta-carotene 

and selenium group. 

Colorectal cancer risks appear to be reduced when the 

carotenoid lycopene is consumed. 13 Tomatoes are a rich 

source of lycopene, yet when rats were grouped into those 

supplemented with either tomato juice or pure lycopene and 

exposed to the carcinogen n-methylnitrosourea, the tomato 

juice group showed significant protection from development 

of digestive tract cancer. 14 This suggests that for lycopene to 

be effectual, it may encompass an interdependent relationship 

with other phytonutrients present in the whole juice 

product. The dose of lycopene may have been supraphysiologic 

when given in an isolated fashion, disrupting some as 

yet unknown, undiscovered, phytonutrient balance. 

Summer 2001 

This interdependence could explain why research on 

isolated antioxidants has yielded some disappointments in 

the role in cancer prevention. For example, the Harvard 

Physician Study of 22,000 physicians showed that 50 mg of 

the antioxidant beta carotene every other day was of no 

benefit. 15 The Ten Year Finnish Smokers Study of 29,000 

smokers was prematurely interrupted at eight years because 

lung cancer deaths in those supplementing with beta 

carotene exceeded the control group. 16 The Beta-Carotene 

and Retinol Efficacy Trial15 involved smokers and asbestos 

workers at high risk for lung cancer. Again, this study was 

terminated prematurely when the beta-carotene/vitamin A 

treatment group had higher death rates than the non-supplemented 

control group. 

Some researchers17 and clinicians believe that antioxidants 

and other yet undiscovered phytonutrients work synergistically 

within cell antioxidant systems when in appropriate 

concentrations. It is known, for example, that humans 

cannot produce vitamins C or E. Consuming vitamins C 

and E in supplement form or through whole foods is known 

to help regenerate naturally-produced antioxidants such as 

glutathione and lipoic acid from the oxidized to the reduced 

form, 17 thus helping to maintain antioxidant protection. 

Practitioners are increasingly aware that all beneficial 

nutrients have yet to be identified and placed into supplements. 

Some also suspect that the molecular relationships 

between known and unknown antioxidants and phytonutrients, 

not just the quantity present, is crucial. This has 

been verified by studies that show that the protective 

effects of known antioxidants have not always yielded the 

expected results. 

Although the recommendations are to have seven to 

nine servings of fresh fruit, vegetables and grains daily to 

significantly reduce several health risks, less than 10% of 

adults in the U.S. consume at least five servings of fruits and 

vegetables per day. 8 More disturbing is the fact that this 

dietary pattern has been a model for children. Studies indicate 

that 99% of children do not get the USDA recommended 

number of servings of the five food groups per day. 9 

Medical practices are beginning to emphasize the preventive 

role of good nutrition and lifestyle, with a patient 

base typically presenting with preexisting large and varied 

nutritional supplement programs. Patients generally seek 

guidance from their physician on supplements and lifestyle 

programs, which in part led to this study. 

SUBJECTS AND METHODS 

Subjects: Subjects in this pilot study were thirteen 

patients in the author’s medical practice who qualified initially 

by their motivation to participate in and complete the 

study, including a willingness to pay for the antioxidant 

assays and the requisite whole food nutritional supplement. 


These qualifications were established to enhance patient 

compliance and reduce attrition. The study group included 

6 females and 7 males, with a range in age of 35 to 84, an 

average of 64. 

The degenerative diseases represented as the patient’s 

chief complaint, and their frequency (in parentheses as 

number of patients) were as follows: osteoarthritis (5), noninsulin 

dependent diabetes mellitus (1), insulin dependent 

diabetes mellitus (1), post cerebrovascular accident (1), atherosclerotic 

heart disease (1), fatigue (8), menopausal 

symptoms (1), hyperlipidema (2), hypertension (3), depression 

(4), insomnia (1), anxiety (1), and memory loss (1). 

The nutritional and antioxidant regimens of the patients 

in this study were diverse, with individual contents and frequency 

(in parentheses as number of patients) as follows: 

combined total number of supplements of all patients, 85; 

average total number of supplements per patient, 6.5, range 

1 to 16; multivitamin/mineral (10); vitamin C (9), range 

500-5,000 mg/d; vitamin E (8), range 400-2,000 IU/day; 

selenium (4), range 200-225 mcg/d; CoQ10 (6), range 100- 

600 mg/d; essential fatty acids, primarily omega-3 (7), 

range 120-3,000 mg/d. 

Other supplements included barley and other greens, 

probiotics, magnesium-potassium, Ginkgo biloba, B-complex, 

calcium, glucosamine sulfate, amino acids, vitamins A, 

B-12, and D, beta carotene, folic acid, zinc, boron, trace minerals, 

echinacea, green tea, flavonoid preparations, alpha 

lipoic acid, saw palmetto, garlic, digestive aids, and bilberry. 

Study Design: This study provided for only one alteration 

to the patient’s current nutritional supplement program: 

addition of a whole-food nutritional supplement 

derived from 17 raw fruits, vegetables, and grains. The 

patients were informed of this author’s belief that whole 

food nutrition may enhance antioxidant protection by providing 

phytonutrients that have not yet been discovered, 

and therefore are possibly lacking in their current regimens. 

Regarding diet, all patients were instructed to avoid 

refined carbohydrates, which some patients had already 

done. Each patient was educated about the glycemic index 

of foods and provided reference materials to assist them to 

avoid high-glycemic-index foods. 

No pill count was conducted, as this study relied on 

patient compliance strengthened through spending their 

own money on the whole food supplement and the cost of 

the antioxidant assays. 

Before the follow-up assay was performed, patient 

compliance was reviewed to confirm consistent daily use of 

the whole food supplement for a minimum of 28 days prior 

to repeating the assays. 

MATERIALS AND METHODS 

Whole Food Supplement: The phytonutrient supple- 


ment used in this pilot study was a commercially available 

whole food nutrient product, Juice Plus +® [National Safety 

Association, Memphis, TN], that contains phytonutrients 

from 17 different raw fruits, vegetables, and grains in capsule 

form. The recommended standard daily serving for this 

phytonutrient product is two fruit capsules in the morning 

and two vegetable capsules in the evening. 

Antioxidant Assay: The antioxidant assay used to 

evaluate each patient’s level of antioxidant status was the 

FIA (Functional Intracellular Analysis) Antioxidant 

Profile 1400, commercially available from SpectraCell 

Laboratories Inc. [Houston, TX]. The profile is comprised 

of three test components; glutathione, cysteine, and the 

FIA Total Antioxidant Function test (Spectrox) assay. 

This antioxidant profile assay was chosen because this 

author believes that SpectraCell Laboratories’ use of isolated 

lymphocytes to assess antioxidant capacity provides 

more specific data on antioxidant activity, in contrast to 

most other analyses, which utilize chemical assays of oxidation 

end-products or measurement of enzyme activities 

involved in antioxidant pathways. 

The Spectrox assay evaluates total antioxidant function 

by exposing the patient’s cultured lymphocytes to a 

free-radical-generating compound, cumene hydroperoxide. 

The test indicates that the greater the inhibition of lymphocyte 

growth, the less the patient’s cells are capable of generating 

antioxidant activity. 

Analysis of Antioxidant Assays: The analysis provided 

by SpectraCell Laboratories compares the results of the 

Spectrox assay with each of the GSH and cysteine tests. 

As an example of the analysis, a low Spectrox reading 

and a significantly higher GSH reading suggest that the 

patient’s total antioxidant function is low but GSH function 

is not. As a result, nutritional intervention with a GSH precursor 

such as n-acetyl cysteine may not be the optimal 

approach to raise overall antioxidant capacity. 

RESULTS 

The results of the antioxidant assays for the 13 patients 

are listed in Table 1 and presented graphically in Figure 1. All 

patients except one showed improved antioxidant protection 

after adding the whole food supplement. The results of the 

antioxidant assays below are expressed as percentages, with 

0% representing the lowest possible antioxidant protection 

identified by this assay, and 100% representing the highest. 

In all but one case, the assays demonstrated a significant 

improvement in antioxidant protection, summarized 

as follows and in Figure 2: 

1. Overall assay average before whole food supplementation 

was 33.0% (range 13.1 to 64.4). 

2. Overall assay average after was 79.1% (range 37.5 to 

96.3). 

Summer 2001

3. Average improvement between before and after assays 

was 239.7% [single-tailed t test, t(1,26) = 0.72, p 75; their average 

before was 33.7% (range 13.1 to 64.4) and average after 

was 88.5% (range 75.6 to 96.3), yielding an average 

improvement of 262.6%. 

5. Four patients (31%) had final assays > 95; their average 

before was 37.7% (range 21.3 to 55.6) and average after 

was 95.3% (range 95.0 to 96.3), yielding an average 

improvement of 173.2%. 

6. One patient (C) showed a 27.7% decrease in antioxidant 

protection by a drop of 14.4% (from 51.9 to 37.5). 

Table 1. Antioxidant Assay Results (in percentage points of 

antioxidant protection) 

Patient Before Whole After Whole 

Food Supplement Food Supplement 

DISCUSSION 

A clear trend toward improved antioxidant protection 

was noted early in this study. This suggests that the growth 

inhibition of leukocytes in the antioxidant assay had been 

overcome by factors supplied by the whole food nutritional 

supplement in 12 of the 13 patients. 

This clinical study manipulated one variable, the 

addition of a whole food nutritional supplement to the 

patients’ pre-existing supplement programs. Initial observations 

in tracking these patients are obviously on the 

scale of a pilot study. However, such early, dramatic 

improvements in oxidative protection or reserve evidenced 

in these live-cell functional assays should help 

encourage research directed at the improved diets sug- 

Summer 2001 

A 33.8 73.1 

B 55.6 95.0 

C 51.9 37.5 

D 64.4 75.6 

E 25.0 83.1 

F 19.4 66.3 

G 44.4 96.3 

H 21.3 95.0 

I 25.0 85.0 

J 13.1 85.6 

K 29.4 95.0 

L 21.3 55.6 

M 25.0 85.6 

As shown in Table 1, antioxidant assays were taken 

before and after adding the whole food supplement to the 

patients’ current regimens. The interval between initial and 

follow-up antioxidant assays ranged from 2.5 months to 8.2 

months, with an average of 4.3 months. 

Figure 1. 

% % Antioxidant Protection 

120 

100 

80 

60 

40 

20 

0 

Figure 2. 

Antioxidant Protection Levels: Before & After Whole 

Food Nutritional Supplementation 

Percent of 

Antioxidant 

Activity 

Measured 

by the 

Spectrox TM 

Assay 

A B C D E F G H I J K L M 

Patients 

Average Percent Changes in 

Antioxidant Blood Levels 

Before Whole 

Food Supplement 

1st Draw 

After Whole Food 

Supplement 

2nd Draw 

gested by such organizations as the American Cancer 

Society and the American Heart Association. 

It should be noted that in this pilot study, only 

patients with degenerative diseases were evaluated for 

their antioxidation status. Future studies should also evaluate 

the impact of whole food nutritional supplementation 

in normal healthy individuals. 

The fact that the only intervention in this study was the 

addition of a concentration of fruits and vegetables points 

to the powerful impact that the poor quality of the 

American diet has on health. This study identifies the 

potential for whole food nutrition to be provided in convenient 

capsule form. Conversely, attempts to create commercial 

vitamins with only known, isolated, antioxidant 

components may be missing the mark. 

The one patient whose antioxidant protection dropped 

27.7% stands out as an indication of the complexity of the 

innumerable factors involved in antioxidant research. One 

possible explanation is that the patient’s results correlated 

to his most significant complaint, lack of memory. 

This study suggests that consumers attempting to derive 

antioxidant protection with pharmaceutical-like preparations 


of isolated or combinational antioxidants appear to be failing, 

as measured by the assays of these subjects. Prevention in a 

convenient capsular form is their goal, but as cited earlier, 

some other antioxidant trials using that approach have failed 

to reduce the occurrence of cancer and heart disease significantly. 

The results of this study suggest the existence of an 

intricate antioxidant phytonutrient network found in whole 

foods, and that the antioxidants found in supplement preparations 

are but a subset of that larger network. 

CONCLUSION 

This author hypothesized that increasing patients’ 

intake of fruits and vegetables through whole food nutritional 

supplementation would increase antioxidant levels in 

the blood. Antioxidant assays on 12 of 13 subjects substantiated 

this hypothesis and detailed a substantial increase 

in antioxidant levels. Although the study wasn’t designed to 

control many variables affecting antioxidant protection, the 

author maintains that the observed overall increases were 

clinically significant, and justify larger, well-designed clinical 

trials to confirm the findings in this initial study. Also, 

a broader range of degenerative diseases needs to be included 

in future studies. 

Whole food nutritional preparations in capsular form 

appear to be the most reasonable method of supplementation 

to approximate the dietary recommendations known to positively 

impact risk for cancer and heart disease. As stated 

previously, this method may offset the typical American 

diet, one woefully lacking in size and number of servings 

rich with fruits, grains, and vegetables. This study provides 

encouragement and hope that the future will provide some 

remedies, and some insurance, for lifestyles falling short in 

the area of balanced and protective diets. Whole food nutritional 

supplements may be a great stopgap measure. 

ACKNOWLEDGEMENTS 

No external funding was provided for this pilot study. 

Each patient paid for their whole food supplement used in 

the study, as well as the antioxidation assay tests provided 

by Spectracell Laboratories, Inc. The principal investigator 

for the study recommends and uses the study product with 

her patients. 

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JANA Vol 4 #2 - American Nutraceutical Association

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