LINUS
PAULINGINSTITUTE
OREGON STATE UNIVERSITYRESEARCH NEWSLETTER
JUNE-AUGUST 2022

VITAMIN C AND COVID: AN UPDATE
In our previous issue of the LPI ResearchNewsletter, we began a series on dietaryfactors and COVID with a review of theliterature on vitamin D and zinc. Here,we continue by examining the scientific
literature surrounding vitamin C and
COVID.
Vitamin C has a place of prominence within
the Linus Pauling Institute. Dr. Linus Paulingand his close supporters established theInstitute to explore the roles of vitamin C
in health, with the foundation being Dr.
Pauling’s research on vitamin C and thecommon cold.
Although the COVID pandemic began morethan two years ago, only a limited numberof scientific studies on vitamin C and COVID
have been published. However, a great dealof misinformation has circulated on this
topic. This article aims to clarify the current
state of the research.

IN THIS ISSUE

Vitamin C and the
Immune System

Vitamin C and COVID:
An Update...............1

Vitamin C plays many roles in a healthy
immune system, including acting as
a vital antioxidant. Since free radicals
are generated by immune cells when
combating an infection, a poorly
controlled immune response can harm
the body’s own cells and tissues throughexcessive inflammation and oxidative
damage. Antioxidants like vitamin C help
to limit these harmful effects.

From the Director.....2

A large body of evidence supports the useof vitamin C supplements (at least 250
mg per day) in shortening the duration ofcommon cold symptoms in both children
and adults. Vitamin C supplementation
may also reduce common cold incidence
in individuals undergoing high levels ofphysical stress.
Continued on page 4

Accolades................2
In Memoriam: Dr.
Donald J. Reed .........3
Student Fellowships..3
Q&A on Dietary
Indoles.....................6
Beyond the Common
Cold: A Recap of theVitamin C Webinar....7

FROM THE DIRECTOR
Photo credit: Hannah O’LearyAt the Linus Pauling Institute, we arelooking forward to summer. Summers
in Oregon bring us the best weather ofthe year, and a quieter OSU campus
gives students, staff, and principal
investigators at the Institute an
opportunity to focus on research.
Summer is often our most productive
time of the year.

Emily Ho, PhD
Endowed Chair and Director,
Linus Pauling Institute

Dr. Traber’s webinar on
vitamin E can be viewed
at lpi.pub/Traber2022
Dr. Williams’ webinar
on dietary indoles canbe viewed at
lpi.pub/Williams2022

First, I wanted to mention the latest
webinars in our 2022 seminar series.
On June 23, we presented a webinar
featuring our own resident expert onvitamin E, Dr. Maret Traber. In All You
Wanted to Know About Vitamin E
But Were Afraid To Ask, Dr. Traberdiscussed what vitamin E is, what it
does, and why people aren’t getting
enough in the food that they eat.
Our webinar on dietary indoles is alsoavailable on the Linus Pauling InstituteYouTube channel. Dr. David Williams
answers some of your questions fromthat webinar on page 6 of this issue.
In late April, the Linus Pauling Institutetook part in Dam Proud Day. This
fundraising event at Oregon State
University was a complete success for
the Institute – we raised over $40,000
and placed in the top 15 fundraisingunits at OSU. Thank you for making
this possible!

A special thanks goes out to the
Director’s Circle members who provided
matching gifts (see back cover). And
thanks also to everyone who supported
us during this annual day of giving.
Sadly, it is also my duty to mention
the passing of Dr. Donald Reed (seepage 3). As the first interim director of
the Institute, Dr. Reed played a criticalrole in establishing LPI at Oregon
State University. He was not only abrilliant scientist but also a responsible
caretaker of the Pauling legacy.
In my time as director, I had the privilegeof conversing with Dr. Reed many times
over. He often wanted to know about thestudents his fellowship was supporting.
We will all miss Dr. Reed at theInstitute. In honor of his life andaccomplishments, the Linus Pauling
Institute will be co-sponsoring amemorial symposium in Corvallis on
September 9, 2022 at the Linus Pauling
Science Center. All are invited to attend.
I wish everyone a great summer. Our
next newsletter will be a special onlineonly edition, but if you would like aprint copy, let us know by the end of
September (write, call, or email).
Talk to you again in the fall,

Emily HoACCOLADESThe American Society for Nutrition (ASN) recently announced its Class of 2022
Fellows, which includes the Institute’s Principal Investigator Dr. Donald Jump.
To be inducted as a Fellow of the Society is “the highest honor ASN bestows,
recognizing individuals for significant discoveries and distinguished careers in thefield of nutrition.” Congratulations to Dr. Jump on achieving this honor!

2

IN MEMORIAM:

Dr. Donald J. Reed (1930-2022)
In 1996, the Linus Pauling Institute
moved from Palo Alto, California to
Corvallis, Oregon. After that move,
Dr. Donald Reed led the Institute asits first interim director at Oregon
State University.
Dr. Reed’s pioneering researchon glutathione was a good fit within
the Institute. Glutathione is anantioxidant compound produced by
the body that is central to protection
against oxidative stress and toxins.
Dr. Reed’s work shaped how today’s
scientists view the intersection
between toxicity, antioxidants,
and stress response – with many
parallels to how Dr. Linus Paulingviewed vitamin C.
Dr. Donald Reed (pictured above)
was a prominent figure within
Oregon State University. When he
was named the first interim directorof the Institute, he was concurrently
serving as the director of theEnvironmental Health Sciences
Center at OSU – a position he heldfor 17 years.

STUDENTFELLOWSHIPS
Every year, the Institute awards
fellowships to outstanding graduate
students who are being mentored
by one of the Institute’s
investigators. The financial
support for these awards comesfrom endowed funds contributedby our generous donors. These
fellowships create a lasting impact
on student success and help shape
the next generation of nutrition
scientists.

Although Dr. Reed directed theLinus Pauling Institute for only ayear, he remained an importantpart of the Institute. Director
Balz Frei asked him to serve on
the Institute’s Scientific Advisory
Committee, a role he maintainedeven after his retirement from OSU.

Dr. Reed also established theCaron and Donald Reed Fellowship
Endowment Fund at the Linus
Pauling Institute. This fellowshipprovides critical support for
students in the early years of theirdoctoral training.
Dr. Reed passed away peacefullyon March 10, 2022 at the age of 91.
In honor of this great scientist,
the Linus Pauling Institute and thePacific Northwest Center forTranslational and Environmental
Health Research will hold a joint
symposium at the Linus Pauling
Science Center in Corvallis on
September 9. If you are interested
in attending, see lpi.pub/
ReedSymposium for more
information.
The family welcomes a donation
to the Caron and Donald Reed
Fellowship Endowment Fund insupport of graduate students at theInstitute. You may select their fundin the drop-down box atbit.ly/GiveToLPIThe awardees of the 2022 student fellowships are as follows:
Paige Jamieson (Stevens Laboratory)
The Marion T. Tsefalas Graduate Fellowship and the Caron and
Donald Reed Fellowship
Daniel Elson (Kolluri Laboratory)
The Mark Sponenburgh Graduate Fellowship
Yi Zhang (Kolluri Laboratory)
The Audrey & George Varseveld LPI Graduate FellowshipJohn “Yanni” Bouranis (Ho Laboratory)
The Harvey H. and Donna Morre Basic Cancer Research Fellowship
Lauren Chan (Haendel Laboratory)
The Simone & Balz Frei Graduate Fellowship and the George Bailey
Graduate Fellowship3

Continued from cover

Intravenous (IV) vitamin C is employedby clinicians in the treatment ofviral and bacterial infections, but its
efficacy is controversial. Since there
is some evidence that IV vitamin C
works differently than oral vitamin C,
it is prudent to discuss these routes ofadministration separately.
Trials conducted nearly
50 years ago suggestthat oral doses ofvitamin C of 2,000 mg
per day or more may
reduce the incidence ofthe common cold andpneumonia. However,these findings have notbeen substantiated bymodern clinical trials.

Oral Vitamin C Supplements
Observational studies have found that
hospitalized COVID patients tend to have
low blood vitamin C levels. While thesedata focus on those with severe COVID
symptoms, they support a relationshipbetween the immune response and blood
vitamin C levels.
Do vitamin C supplements prevent
COVID? No scientific evidence supports
this hypothesis. Observational studies
show that people who take vitamin C are
equally at risk of contracting COVID as
non-supplement users.
Can vitamin C help in the treatmentof COVID? Unfortunately, the data areunclear. Four studies have examined theuse of vitamin C supplements in COVID
patients, but the results were inconsistent.

Only two of the studies reported a benefitof vitamin C supplementation. One
randomized controlled trial showed thatadministering vitamin C supplements(500 mg per day for 14 days) to critically
ill COVID patients improved their odds
of survival versus a control group. An
observational study associated vitamin C
supplement use (1,000 mg per day for
7-18 days) with decreased incidence ofthrombosis (blood clots blocking bloodvessels).
Two other randomized controlled trials
did not report any benefits of taking
vitamin C supplements when compared tocontrol groups. However, the conclusionsof one of these trials were controversial(see highlight below).
Current study data are inconclusive inregard to the use of vitamin C supplementsin the treatment of COVID. Morerandomized controlled trials are needed.
However, it is worth noting that vitamin C
supplement use is widespread in COVID
trials, and vitamin C supplements areoccasionally given to “placebo” controls in
randomized controlled trials for drugs or
dietary supplements.

The Cleveland Clinic trial examined the utility of vitamin C andzinc supplements in reducing COVID symptoms. For 10 days, one
group of COVID patients took 8 g per day of vitamin C, anothergroup took 50 mg per day of zinc gluconate, and the third group
took a combination of zinc and vitamin C. A fourth “usual care”
group served as the control.
This trial was terminated “for futility” with less than half of its goal
number of participants. Terminating a trial for futility means that an
independent review committee elected to stop the trial early since
the likelihood of finding a treatment effect is low. After statisticalanalysis, the authors concluded that zinc and vitamin C were
ineffective treatments for COVID.
However, a reanalysis of the Cleveland Clinic data by Dr. Harri
Hemilä, Dr. Elizabeth Chalker, and Dr. Anitra Carr suggested that
this conclusion was premature. These investigators found thatpatients taking vitamin C supplements recovered from COVID
about 18% faster, on average, than those who did not receive
vitamin C, suggesting that vitamin C supplements may offer somebenefit (see figure on right, adapted from the supplemental data
provided with this reanalysis).

4

References
Hemilä et al. Front. Immunol. May 10 (2021)
doi: 10.3389/fimmu.2021.674681
Tomas et al. JAMA Netw. Open. 4 (2021) doi:
10.1001/jamanetworkopen.2021.0369

Intravenous Vitamin C

Bottom LineTaking vitamin C orally may have limited
effectiveness in severe COVID because
blood vitamin C concentrations candecline rapidly, and vitamin C transport
proteins in the gut slow the absorption ofvitamin C. IV vitamin C has been proposed
as a strategy to quickly restore blood
vitamin C levels in COVID patients.

While it is clear that vitamin C isneeded in COVID patients, there iscurrently no evidence that taking
vitamin C supplements will prevent a
COVID infection. There is also limited
evidence that vitamin C supplements
can effectively treat COVID symptoms.

In addition, when provided at high doses(25 grams or more), IV vitamin C has bothantioxidant and pro-oxidant properties. It
is thought that IV vitamin C may produce
free radicals that damage pathogens andmay help the body fight off infections.
Eight observational studies and six
randomized controlled trials haveexamined the use of IV vitamin C in thetreatment of COVID. Although the datafrom observational studies are mixed,
the randomized trials consistently
demonstrate benefits to COVID patients
who receive IV vitamin C. Depending on
the trial, patients receiving this treatment
showed improved oxygenation parameters,
reduced inflammatory markers, faster
resolution of COVID symptoms, ordecreased risk of poor outcomes, such as
cardiac arrest or death.
Although these results are encouraging,
the available trials are small and theresults are not always consistent across allstudies. For instance, a faster resolutionof symptoms or improvements inoxygenation parameters were seen in only
some of the trials. Ongoing randomized
controlled trials will hopefully provide
more clarity on the effects of IV vitamin C
in COVID patients.

For more about theapplications of IV
vitamin C, see our article
on page 7

However, IV vitamin C may be a helpful
adjuvant to conventional COVID
therapies and should not be dismissed.
Because there are special precautions
for its use, IV vitamin C should only
be administered in a medical setting.
You cannot achieve the same bloodconcentrations of vitamin C with any
type of oral supplement (including
liposomal forms of vitamin C), so there
is no way to reproduce the effects of IV
vitamin C on your own.
Without additional data, a doserecommendation for vitamin C
supplements for the treatment of
COVID is premature. At a minimum,
the Linus Pauling Institute recommends
all adults get 400 mg of vitamin C
every day from food and supplements
combined.
If you choose to take additional
vitamin C supplements during theongoing pandemic, keep in mind that
this could cause an upset stomach,gas, or diarrhea. Smaller doses taken
throughout the day may mitigate someof these effects. The National Academyof Medicine set the tolerable upper
intake level for vitamin C at 2,000 mg
per day for adults due to the risk ofthese gastrointestinal side effects.

Vitamin C and theCommon Cold
For more about vitamin C(and zinc) in the common
cold, see the Micronutrient
Information Center at
lpi.pub/CommonCold

The citations for all of the scientific publications reviewed here areavailable on our website at lpi.pub/COVIDrefs
In addition, Dr. Anitra Carr from the University of Otago, Christchurch
is maintaining an up-to-date repository of published research on
vitamin C and COVID. Study summaries and other details can befound on her webpage at lpi.pub/VitCandCOVID

5

Q&A ON DIETARY INDOLESIn April, Dr. David Williams presented a webinar about the anticancer properties of Brussels sprouts, arecording of which is available on the Linus Pauling Institute YouTube channel (for link, see page 2).
Dr. Williams focused his presentation on indole-3-carbinol (I3C), a compound formed from glucobrassicinfound in cruciferous vegetables, and a beneficial compound called 3,3'-diindolylmethane (DIM), which is
produced from I3C in the stomach after consumption or taken directly as a supplement.
This popular webinar inspired many questions from the audience, some of which we have included herewith Dr. Williams’ answers.
In your trial, Brussels sprouts were steamed. Does
this mean that cooking has little effect on the active
phytochemicals in these and in broccoli?

How much DIM or Brussels sprouts would be needed
to treat cancer?

Prolonged cooking can degrade beneficial
phytochemicals and the enzymes necessary to activate
some of them. However, other active enzymes present in
raw vegetables can also degrade phytochemicals.

This is an important question, but one that is hardto answer. Many cancers take 20 years or more toprogress from initiation (DNA mutations) to malignant
tumors, making it difficult to know when to employ anintervention with DIM.

The trick is to find a balance. Light steaming has beensuggested as a middle ground between the two, butthere may also be benefits to eating them both cooked
and raw.

Although there is some evidence that DIM acts throughmechanisms that would lend itself to therapeuticinterventions, we need to wait for additional trials incancer patients to know for sure.
Is there a suggested dose of DIM to take?

How do other cruciferous vegetables compare in I3C
content?

The Linus Pauling Institute has not evaluated the safety of
DIM supplements. However, no adverse effects have been
observed in people taking 150-200 mg per day.

Brussels sprouts have the highest glucobrassicin content
of all cruciferous vegetables and thus can produce
the most I3C and DIM. At most, broccoli, cauliflower,
kale, and cabbage only have 30% of the glucobrassicin
content of Brussels sprouts.

Larger doses increase the risk of side effects, such as
headache, nausea, vomiting, gas, and diarrhea. If you
choose to take DIM supplements, follow the dosing
instructions suggested by the manufacturer. It is also
important to speak to your primary care provider about
possible drug interactions.

Can fermenting cruciferous vegetables preserve
these benefits?

During fermentation, I3C is liberated from theglucobrassicin molecule. However, some studies haveshown that I3C levels in sauerkraut decline with storage
time. This makes it difficult to estimate how much I3C willremain by the time you eat it.
Does the timing make a difference in the protective
effect of DIM?

In cancer chemoprevention studies in animals, I3C andDIM work best when given prior to or simultaneouslywith a carcinogen. Unfortunately, this has not beentested in humans.
DIM has a half-life in human blood of about 4 hours.
So, if a carcinogen exposure is 12 hours after DIM
dosing, there would only be one-eighth of the original
DIM dose left in the blood. It’s possible that this is too
low to have a beneficial effect.

6

BEYOND THE COMMON COLD:
A Recap of the Vitamin C Webinar

To celebrate Linus Pauling Day on February 28, 2022, the Institute hosted its
annual webinar on vitamin C and health in honor of Dr. Pauling. This year, we werejoined by Dr. Jeanne Drisko and Dr. Qi Chen from the University of Kansas Medical
Center. They both have been investigating the health applications of intravenous(IV) vitamin C, particularly in the treatment of cancer.
Below is a synopsis of the presentations, including some of the information fromthe Q&A session that followed. You can watch the video recording of the event on
The Linus Pauling Institute YouTube Channel at lpi.pub/VitaminC2022

Dr. Jeanne Drisko spoke about the distinct effects of oral versus IV vitamin C and
how few people appreciate these differences. Most importantly, IV vitamin C behaves
like a drug providing anticancer, antiviral, and antibacterial properties that cannot be
achieved with oral supplements, no matter what type of formulation or dose is used.
Although still in its early stages, there is increasing evidence to support the useof vitamin C for the treatment of various diseases. Randomized controlled trials,
including recent studies conducted during the COVID pandemic (see cover article),
provide some of the best evidence in support of this therapy. However, it will be achallenge to convince conventional medical practitioners that this is a worthwhile
option.
In the Q&A session, Dr. Drisko spoke about the preparation and administration oflarge doses of vitamin C (25-100 grams at a time). She also commented that doses
below 10 grams might not achieve therapeutic benefits, which could be why clinical
trials utilizing these lower doses often show no effect of IV vitamin C. She reiterated
that IV vitamin C should only be administered by healthcare professionals who haveknowledge and experience with this therapy, as serious complications are possible
in some individuals.

Dr. Qi Chen spoke about her early work with Dr. Mark Levine at the National
Institutes of Health, which explored the properties of IV vitamin C in humanvolunteers. This work led to studies demonstrating that doses of at least 25 gramsof vitamin C are likely to generate hydrogen peroxide, which could explain many of
its anticancer, antiviral, and antibacterial properties.
Studies in animal models have clearly shown that IV vitamin C is beneficial in cancer
treatment. In humans, the evidence is generally positive, but larger trials are stillneeded on specific types of cancer. Clinical studies suggest that IV vitamin C
reduces tumor growth in some cancer patients. Additional studies have shownthat when combined with chemotherapy, IV vitamin C may reduce the associatedside effects.
In the Q&A session, Dr. Chen emphasized that the goal of IV vitamin C therapies
for cancer is to achieve plasma concentrations of 20 millimolar or higher, roughly
100-500 times higher than those seen after oral supplementation. It is also
important that these high blood concentrations remain elevated for hours toachieve the desired effects. This sharply contrasts with oral vitamin C whereintestinal absorption is low and peak blood concentrations are not sustained.
This is the primary reason why vitamin C supplements are unable to reproduce
the anticancer effects of IV vitamin C.

7

LINUS PAULING INSTITUTERESEARCH NEWSLETTER
Alexander Michels, Newsletter Editor
Victoria J. Drake, Associate Editor
Sandra Uesugi, Assistant Editor
Oregon State University
307 Linus Pauling Science Center
2900 SW Campus Way
Corvallis, Oregon 97331
phone: 541-737-5075
fax: 541-737-5077
email: lpi@oregonstate.edu
website: lpi.oregonstate.edu

INSIDE: VITAMIN C FOR COVID-19 – THE SCIENTIFIC EVIDENCE
On Dam Proud Day, we raised over
$40,000 in support of the Simone& Balz Frei Fellowship and theMicronutrient Information Center!
Our gratitude and appreciation go
out to all of our Director’s Circle
members who provided matching
gifts on this day of giving:Dr. Emily HoDr. Balz and Simone Frei
Dr. Maret and Biff TraberDr. Mary McCarthy

THANK YOU FOR SUPPORTING OUR WORK!