The Riordan Intravenous Vitamin C (IVC) Protocol
THE RIORDAN INTRAVENOUS VITAMIN C (IVC) PROTOCOL FOR
ADJUNCTIVE CANCER CARE: IVC AS A CHEMOTHERAPEUTIC
AND BIOLOGICAL RESPONSE MODIFYING AGENT
by Hugh Riordan, MD, Neil Riordan, PhD, Joseph Casciari, PhD, James Jackson, PhD,
Ron Hunninghake, MD, Nina Mikirova, PhD, and Paul R. Taylor
Grateful appreciation is expressed to the
Riordan Clinic for permission to publish their
complete intravenous vitamin C protocol.
Vitamin C (ascorbate, ascorbic acid) is a major
water-soluble antioxidant that also increases extracellular collagen production and is important for
proper immune cell functioning (Hoffman, 1985;
Cameron, et al., 1979). It also plays key roles in Lcarnitine synthesis, cholesterol metabolism,
cytochrome P-450 activity, and neurotransmitter
synthesis (Geeraert, 2012). The Riordan intravenous vitamin C (IVC) protocol involves the slow
infusion of vitamin C at doses on the order of 0.1 to
1.0 grams (g) of ascorbate per kilogram (kg) body
mass (Riordan, et al., 2003). IVC use has increased
recently among integrative and orthomolecular
medicine practitioners: a survey of roughly 300
practitioners conducted between 2006 and 2008
indicated that roughly 10,000 patients received
IVC, at an average dose of 0.5 g/kg, without significant ill effects (Padayatty, et al., 2010). While IVC
may have a variety of possible applications, such
as combating infections (Padayatty, et al., 2010),
treating rheumatoid arthritis (Mikirova, et al.,
2012), it has generated the most interest for its
potential use in adjunctive cancer care.
Vitamin C was first suggested as a tool for cancer treatment in the 1950s: its role in collagen production and protection led scientists to hypothesize
that ascorbate replenishment would protect normal
tissue from tumor invasiveness and metastasis
(McCormick, 1959; Cameron, et al., 1979). Also,
since cancer patients are often depleted of vitamin C
(Hoffman, 1985; Riordan, et al., 2005), replenishment may improve immune system function and
enhance patient health and well-being (Henson, et
al., 1991). Cameron and Pauling observed fourfold
survival times in terminal cancer patients treated
with intravenous ascorbate infusions followed by
oral supplementation (Cameron & Pauling, 1976).
However, two randomized clinical trials with oral
ascorbate alone conducted by the Mayo Clinic
showed no benefit (Creagan, et al., 1979; Moertel, et
al., 1985). Most research from that point on focused
on intravenous ascorbate. The rationales for using
intravenous ascorbate infusions to treat cancer,
which are discussed in detail below, can be summarized as follows:
• Plasma ascorbate concentrations in the millimolar (mM) range can be safely achieved with IVC
• At mM concentrations, ascorbate is preferentially toxic to cancer cells in vitro and is able to
inhibit angiogenesis in vitro and in vivo.
• Vitamin C can accumulate in tumors with significant tumor growth inhibition seen (in guinea pigs)
at intra-tumor concentrations of 1 mM or higher.
• Published case studies report anticancer efficacy,
improved patient well-being, and decreases in
markers of inflammation and tumor growth.
• Phase I clinical studies indicate that IVC can be
administered safely with relatively few adverse
The Riordan Clinic has treated hundreds of
cancer patients (Figure 1) using the Riordan protocol. At the same time, Riordan Clinic Research
Institute (RCRI) has been researching the potential
of intravenous vitamin C therapy for over thirty
years. Our efforts have included in vitro studies,
animal studies, pharmacokinetic analyses, and
clinical trials. The Riordan IVC protocol, along
with the research results (by the RCRI and others)
that have motivated its use, is described below.
Vitamin C is water soluble, and is limited in how
well it can be absorbed when given orally. While
ascorbate tends to accumulate in adrenal glands,
the brain, and in some white blood cell types,
plasma levels stay relatively low (Keith & Pelletier,
1974; Hornig, 1975; Ginter, et al., 1979; Kuether, et
al., 1988). Data by Levine and coworkers indicate
that plasma levels in healthy adults stayed below
100 micrometer microns (µM), even if 2.5 grams
were taken when administered once daily by the
oral route. (Levine, et al., 1996.)
Cancer patients tend to be depleted of vitamin
C: fourteen out of twenty-two terminal cancer
patients in a phase I study we depleted of vitamin
C, with ten of those having zero detectable ascorbate in their plasma (Riordan, et al., 2005). This is
shown in Figure 2. In a study of cancer patients in
hospice care, Mayland and coworkers found that
thirty percent of the subjects were deficiency in
vitamin C (Mayland, et al., 2005). Deficiency
(below 10 µM) was correlated with elevated CRP
(C-reactive protein, an inflammation marker) levels and shorter survival times. Given the role of
vitamin C in collagen production, immune system
functioning, and antioxidant protection, it is not
surprising that subjects depleted of ascorbate
would fare poorly in mounting defenses against
cancer. This also suggests that supplementation to
replenish vitamin C stores might serve as adjunctive therapy for these patients.
When vitamin C is given by intravenous infusion, peak concentrations over 10 mM can be
attained (Casciari, et al., 2001; Padayatty, et al.,
2004) without significant adverse effects to the
recipient. Figure 3 (page 000) shows plasma ascorbate concentrations attained via IVC infusion at
the Riordan Clinic, while Figure 4 shows pharmacokinetic data for two subjects given eighty-minute
IVC infusions. These peak plasma concentrations
are two orders of magnitude above what is
observed with oral supplementation. This suggests
that IVC may be more effective than oral supplementation in restoring depleted ascorbate stores in
cancer patients. Physicians at the Riordan Clinic
have observed that (a) peak plasma concentrations
THE RIORDAN CLINIC INTRAVENOUS VITAMIN C PROTOCOL
AND BACKGROUND RESEARCH
The Riordan Clinic, which focuses on nutritional
medicine, was founded in 1975 as the Center for the
Improvement of Human Functioning under the
leadership of Dr. Hugh Riordan, a medical doctor who
Dr. Riordan originally focused on treating mentally
ill patients through nutritional medicine. The value of
vitamin C as a potential cancer treatment first came
into light after an article published in 1976 by Ewan
Cameron and Linus Pauling, in which the authors
suggested an increased survival in cancer patients
receiving intravenous (IV) ascorbate treatments.
Dr. Riordan first became aware of this therapy in
the early 1980s, when a 70-year-old patient suffering
from metastatic renal cell carcinoma that had spread
to his liver and lungs came to the clinic requesting IV
ascorbate infusions. The patient had read Pauling’s
research, and Dr. Riordan was the only doctor in
Wichita using IV vitamin C. Upon his request, he began
IV vitamin C treatment, starting at 30 grams twice per
week. Fifteen months after initial therapy, the
patient’s oncologist reported that the patient had no
signs of progressive cancer. The patient remained
cancer-free for 14 years.
Based on his experience, Dr. Riordan set a goal for
a cancer research project. In 1989 Dr. Riordan
announced the 11-year RECNAC (cancer spelled
backward), a project devoted to finding of the nontoxic cancer treatment. The project manager of the
research was Dr. Neil Riordan and the research group
included many devoted scientists such as Dr. J.
Casciari, Dr. J. Jackson, Dr. X. Meng, Dr. J. Zhong, P.
Taylor, BS, Dr. N. Mikirova, and others.
The group validated the use of the IV vitamin C for
cancer therapy. Using in vitro studies, more than 60
cell lines were tested for the toxicity to high dosages
of ascorbate. It was demonstrated that at a high
enough dose ascorbate can kill cancer cells while not
affecting normal cells. The Riordan Clinic researchers
were the first to demonstrate that selectively toxic
plasma levels of ascorbate could be achieved in
cancer patients (Med Hypothesis, 1995).
In 1997 the IVC treatment was patented by Drs.
Neil Riordan and Hugh Riordan; the title of the patent
is “Intravenous ascorbate as tumor cytotoxic
chemotherapeutic agent.” Other important results
included: synergism between vitamin C and alphalipoic acid (Br J Cancer, 2001), protocol for reaching
tumor cytotoxic blood levels of ascorbate in plasma
(P R Health Sci J, 2003), inhibition of the angiogenesis
by vitamin C (J Transl Med, 2008), effect of ascorbate
on immune function and Phase I trial of the safety of
the proposed treatment.
In addition, it was found that IVC treatment
improves the quality of life of advanced cancer
patients, corrects deficiencies of vitamin C that often
occur in cancer patients and optimizes white blood
cell concentrations of vitamin C. Analysis of the
markers of inflammation in cancer patients showed
that high dose intravenous ascorbic acid treatment
reduces inflammation in cancer patients. Treatment
by IVC can improve response to radiation treatment
and reduce the side effects of chemotherapy. In
addition, the therapeutic effect of ascorbic acid can be
enhanced by vitamin K3 and alpha-lipoic acid. Very
important clinical trials inspired by the success of IVC
at the Riordan Clinic were conducted at Thomas
Jefferson University in Philadelphia.
Dr. Hugh Riordan’s vision of treating and
preventing ailments with a non-toxic nutritional
approach led him to become one of the first doctors
to use IV vitamin C as a treatment protocol in patients
with terminal cancers. This vision led to original
research at the clinic, as well as numerous articles,
patents, a series of IVC symposiums, and health
attained after IVC infusions tend to be lower in
cancer patients than in healthy volunteers, suggesting their depleted tissues act as a “sink” for the
vitamin; and (b) in cancer patients given multiple
IVC treatments, baseline plasma ascorbate concentrations tend to increase to normal levels slowly
over time as reserves are restored with adequate
In addition to providing ascorbate replenishment, IVC may allow oncologists to exploit some
interesting anticancer properties, including high
dose IVC’s ability to induce tumor cell apoptosis,
inhibit angiogenesis, and reduce inflammation. In
vitro and in vivo data supporting these potential
mechanisms of action, discussed below, suggest that
they may be relevant at ascorbate concentrations on
the order of 2 mM. As shown in Figures 3 and 4
(above), these concentrations are attainable in
plasma using progressive dosing of IVC. A 2-compartment model can be used to predict peak and
“average” (over 24 hours) plasma ascorbate concentrations for an average-sized adult at a given IVC
dose as shown in Figure 5 (page 000). This calculation suggests that a 50 gram, 1 hr. infusion would
yield a peak plasma concentration of roughly 18
mM and an integral average of roughly 2.6 mM, a
reasonable target for producing anticancer effects.
Vitamin C, at normal physiological concentrations
(0.1 mM), is a major water-soluble antioxidant
(Geeraert, 2012). At concentrations on the order of
1 mM, however, continuous perfusion of ascorbate
at doses that trigger “redox cycling” can cause a
build-up of hydrogen peroxide, which is preferentially toxic toward tumor cells (Benade, et al., 1969; Riordan, et al., 1995; Casciari, et al.,
2001; Chen, et al., 2005; Frei & Lawson,
2008), often leading to autophagy or apoptosis. To examine this cytotoxic effect in a
three-dimensional model, the RCRI
employed hollow-fiber in vitro solid
Figure 6 (right) shows a
histological section of colon cancer cells
growing in this configuration. Dual staining annexin V and propidium iodide flow
cytometry showed as significant increase
in apoptosis, along with decreased surviving fractions, at ascorbate concentrations in
the 1 mM to 10 mM range. Ascorbate concentrations required for toxicity in the
HFST model (LC50 = 20 mM), with only
two days incubation, were much higher
than those typically observed in cell monolayers. The cytotoxic threshold could be
reduced significantly (LC50 = 4 mM) by
using ascorbate in combination with alphalipoic acid. Other reports suggest that
ascorbate cytotoxicity against cancer cells
can be increased by using it in combination with
menadione (Verrax, et al., 2004) or copper containing compounds (Gonzalez, et al., 2002).
Studies from many laboratories in a variety
animal models, using hepatoma, pancreatic cancer,
colon cancer, sarcoma, leukemia, prostate cancer,
and mesothelioma confirm that ascorbate concentrations sufficient for its cytotoxicity can be
attained in vivo, and that treatments can reduce
tumor growth (Chen, et al., 2008; Verrax &
Calderon, 2009; Belin, et al., 2009; Yeom, et al.,
2009; Du, et al., 2010; Pollard, et al., 2010). Figure 7
(right) shows data using the L-10 model in guinea
pigs. L-10 tumor cells implanted subcutaneously
metastasize to the lymph nodes. The overall tumor
burden (primary plus metastases) was then determined after 30 days of tumor growth and 18 days
of ascorbate therapy. Note that here the actual
intra-tumor ascorbate concentrations were measured, and the correlation between tumor mass and
tumor ascorbate concentration is strong regardless
of the mode of ascorbate administration. The precentage of tumor growth inhibition, relative to controls, was roughly 50% at intra-tumor ascorbate
concentrations of 1 mM tumor and roughly 65%
once the intra-tumor ascorbate level went above 2
mM. The ascorbate dosage used in this study was
500 mg/kg/day. Our scientists also looked at survival times of BALP/C mice with S180 sarcomas.
The results are shown in Figure 8 (right). The
median survival time for the untreated mice was
35.7 days post implantation, while that for ascorbate treated mice (700 mg/kg/day) was 50.7 days.
Of course, the efficacy observed in these animal
studies may be due to some combination of direct
cytotoxicity and other factors, such as angiogenesis
inhibition (Yeom, et al., 2009) or other biological
response modifications (Cameron, et al., 1979).
Tumor angiogenesis is the process of new blood
vessel growth toward and into a tumor. It is considered to be critical in tumor growth and metastasis. Reports in the literature suggest that
ascorbate’s effect on collagen synthesis can act to
inhibit formation of new vascular tubules (Ashino,
et al., 2003), that ascorbate can inhibit genes
necessary for angiogenesis (Berlin, et al., 2009), and that
it might influence angiogenesis through its effect
on hypoxia inducable factor (Page, et al., 2007).
The Riordan Clinic researchers evaluated angiogenesis inhibition using four different experimental
models. In all cases, there is an inhibitory effect on
angiogenesis at ascorbate concentrations of 1 to 10
mM (Mikirova, et al., 2008; Mikirova, et al, 2012; see
Figures 9A and 9B right).
• The growth of new micro-vessels from aortic
rings ex vivo is inhibited by ascorbate at concentrations of 5 mM of more.
• Ascorbate inhibits endothelial cell tubule formation in Matrigel in vitro in a concentration-dependent fashion. Number of intact tubule loops was
decreased by half at concentrations of 11 mM for
endothelial progenitor cells and 17 mM for
• The rate at which endothelial cells can migrate
on a petri dish to fill a gap between them was
reduced when 5.7 mM ascorbate was added after
the gap was created. The ascorbate also reduced
ATP production in these endothelial cells by
twenty percent, but did not affect cell viability.
• For Matrigel plugs implanted subcutaneously in
mice, the micro-vessel density we significantly
lower in mice treated with 430 mg/kg every other
day for two weeks.
In animal experiments and clinical case studies
where high ascorbate doses show efficacy against
tumors, this benefit may represent therapeutic synergism due to both angiogenesis inhibition as well
as to direct cytotoxicity or other causes.
Analysis of clinical data from the Riordan Clinic
suggests that inflammation is an issue for cancer
patients, and that it can be lessened during IVC
therapy (Mikirova, et al., 2012). C-reactive protein
was used as a marker of inflammation, as reports in
the literature indicate that elevated CRP is correlated with poor patient prognosis (St. Sauver, et al.,
2009). Over sixty percent of analyzed Riordan Clinic
cancer patients had CRP levels above 10 mg/L prior
to IVC therapy. In 76 ± 13% of these subjects, IVC
reduced CRP levels. This improvement was more
prevalent, 86 ± 13%, in subjects with elevated (above 10
mg/L) CRP. Comparisons of individual values before
and after treatments are shown in Figure 10A (right).
Since many of the subjects in this database were
prostate cancer patients, we examined prostate specific
antigen (PSA) levels before and after therapy. This is
shown in Figure 10B (right). Most of the prostate cancer
patients showed reductions in PSA levels during the
course of their IVC therapy. This was not true with other
markers, as shown in Figure 10C (right). In some subjects, both tumor marker and CRP data were available
both before and after IVC therapy. In those cases, there
was a strong correlation (r2 = 0.62) between the change
in tumor marker and the change in CRP during IVC
therapy. This is consistent with observations from the literature showing a correlation between CRP levels and
PSA levels in prostate cancer patients (Lin, et al., 2010).
The potential effect of IVC in reducing inflammation is also supported by cytokine data: serum concentrations of the pro-inflammatory cytokines IL-1α,
IFN-γ, IL-8, IL-2, TNF-α and eotaxin were acutely
reduced after a 50-gram ascorbate infusion, and in the
case of the last three cytokines listed, reductions were
maintained throughout the course of IVC therapy
(Mikirova, et al., 2012).
The observations that ascorbate is an antioxidant and
that it preferentially accumulates in tumors (Agus, et
al., 1999) have raised fears that ascorbate supplementation would compromise the efficacy of chemotherapy (Raloff, 2000). In support of this, Heaney and
coworkers found that tumor cells in vitro and
xenografts in mice were more resistant to a variety of
anticancer agents when the tumor cells were pretreated with dehydroascorbic acid (Heaney, et al.,
2008). Questions have been raised, however, whether
the experimental conditions used in the Heaney study
are clinically or biochemically relevant, considering,
among other issues, that dehydroascorbic acid rather
than ascorbic acid was used (Espey, et al., 2009). It
should also be noted that the goal of IVC is to attain
mM intra-tumor concentrations (for the reasons
described above) and thus the accumulation of ascorbate in tumors is considered an advantage.
A variety of laboratory studies suggest that, at
high concentrations, ascorbate does not interfere
with chemotherapy or irradiation and may
enhance efficacy in some situations (Fujita, et al.,
1982; Okunieff & Suit, 1987; Kurbacher, et al., 1996;
Taper, et al., 1996; Fromberg, et al., 2011; Shinozaki,
et al., 2011; Espey, et al., 2011). This is supported by
meta-analyses of clinical studies involving cancer
and vitamins; these studies conclude that antioxidant supplementation does not interfere with the
toxicity of chemotherapeutic regimens (Simone, et
al., 2007; Block, et al., 2008).
The situation with intravenous ascorbate therapy is
different from that with new chemotherapeutic
agents in that Food and Drug Administration (FDA)
approval was not strictly required in order for
physicians to administer IVC. As a result, clinical
investigations tended to run concurrently with laboratory research. Two early studies indicated that
intravenous ascorbate therapy could increase survival times beyond expectations in cancer patients
(Cameron & Pauling, 1976; Murata, et al., 1982).
There have been several case studies published by
the Riordan Clinic team (Jackson, et al., 1995; Riordan, et al., 1996; Riordan, et al., 1998) and collaborators (Drisko, et al., 2003; Padayatti, et al., 2006).
While these case studies do not represent conclusive
evidence in the same way that a well-designed
Phase III study would, they are nonetheless of interest for comparing methodologies and motivating
future research, in addition to being of monumental
importance to the individuals who were their subjects. Some key case studies are summarized here:
A.A 51-year-old female with renal cell carcinoma
(nuclear grade III/IV) and lung metastasis declined
chemotherapy and instead chose to intravenous
ascorbate at an initial dose of 15 grams. Her dose
was increased to 65 grams after two weeks. She continued at this dose for ten months. Patient received
no radiation or chemotherapy. The patient supplemented with thymus protein extract, N-acetylcysteine, niacinamide, beta-glucan, and thyroid extract.
Seven of eight lung masses resolved. Patient went
four years without evidence of regression. Four
years later, patient showed a new mass (consistent
with small-cell lung cancer, not with recurrent renal
carcinoma metastasis) and died shortly afterward
(Padayatti, et al., 2006).
B. A 49-year-old male with a bladder tumor (invasive grade 3/3 papillary transitional cell carcinoma) and multiple satellite tumors declined
chemotherapy and instead chose to receive intravenous ascorbate. He received 30 grams twice
weekly for three months, followed by 30 grams
monthly for four years. Patient supplementation
included botanical extract, chondroitin sulfate,
chromium picolinate, flax oil, glucosamine sulfate,
alpha-lipoic acid, lactobacillus acidophilus, L. rhamnosus, and selenium. Nine years after the onset of
therapy, patient is in good health with no signs of
recurrence or metastasis (Padayatti, et al., 2006).
C.A 66-year-old woman with diffuse Stage III
large B-cell lymphoma with a brisk mitotic rate
and large left paraspinal mass (3.5–7 cm transverse
and 11 cm craniocaudal) showing evidence of bone
invasion agreed to a five-week course of radiation
therapy, but refused chemotherapy and instead
chose to receive intravenous ascorbate concurrent
with radiation. She received 15 grams twice
weekly for two months, once per week for seven
months, and then once every two-three months for
one year. Patient supplementation included coenzyme Q10, magnesium, beta-carotene, parasidal,
vitamin B and C supplements, Parex, and Nacetylcysteine. The original mass remained palpable after radiation therapy and a new mass
appeared. Vitamin C therapy continued. Six weeks
later, masses were not palpable. A new lymph
mass was detected after four months, but the
patient showed no clinical signs of lymphoma after
one year. Ten years diagnosis, the patient remained
in normal health (Padayatti, et al., 2006).
D. A 55-year-old woman with stage IIIC papillary
adenocarcinoma of the ovary and an initial CA-125
of 999 underwent surgery followed by six cycles of
chemotherapy (Paclitaxel, Paraplatin) combined
with oral and parenteral ascorbate. Ascorbate infusion began at 15 grams twice weekly and increased to 60 grams twice weekly. Plasma ascorbate levels
above 200 mg/dL were achieved during infusion.
After six weeks, ascorbate treatment continued for
one year, after which patient reduced infusions to
once every two weeks. The patient also supplemented with vitamin E, coenzyme Q10, vitamin C,
beta-carotene, and vitamin A. At the time of publication, she was over 40 months from initial diagnosis
and remained on ascorbate infusions. All computed
tomography (CT) and positron emission tomography (PET) scans were negative for disease, and her
CA-125 levels remained normal (Drisko, et al., 2003).
E. A 60-year-old woman with stage IIIC adenocarcinoma of the ovary and an initial CA-125 of 81
underwent surgery followed by six cycles of
chemotherapy (paclitaxel, carboplatin) with oral
antioxidants. After six cycles of chemotherapy,
patient began parenteral ascorbate infusions.
Ascorbate infusion began at 15 grams once weekly
and increased to 60 grams twice weekly. Plasma
ascorbate levels above 200 mg/dL were achieved
during infusion. Treatment continued to date of
publication. The patient supplemented with vitamin E, coenzyme Q10, vitamin C, beta-carotene,
and vitamin A. Her CA-125 levels normalized after
one course of chemotherapy. After the first cycle of
chemotherapy, the patient was noted to have residual disease in the pelvis. At this point, she opted
for intravenous ascorbate. Thirty months later,
patient showed no evidence of recurrent disease
and her CA-125 levels remained normal.
Note that these case studies involve a variety
of cancer types, sometimes involve the use of IVC
in conjunction with chemotherapy or irradiation,
and usually involve the use of other nutritional
supplements by the subject.
Several other clinical studies looked into the
effect of vitamin C on quality of life in cancer
patients. In a Korean study, IVC therapy significantly improved global quality of life scores, with
benefits including less fatigue, reduction in nausea
and vomiting, and improved appetite (Yeom, et al.,
2007). In a recent German study, breast cancer
patients receiving IVC along with standard therapy were compared to subjects receiving standard
therapy alone (Vollbracht, et al., 2011). Patients
given IVC benefited from less fatigue, reduction in
nausea, improved appetite, reductions in depression and fewer sleep disorders. Overall intensity
scores of symptoms during therapy and aftercare
were twice as high in the control group as the IVC
group. No side effects due to ascorbate were
observed, nor were changes in tumor status compared to controls reported.
Phase I Clinical Trials
The safety of intravenous ascorbate has been
addressed in recently published Phase I clinical
studies (Riordan, et al., 2005; Hoffer, et al., 2008;
Monti, et al., 2012). The first Phase I study was conducted with twenty-four terminal cancer patients
(mostly liver and colorectal cancers) (Riordan, et al.,
2005). The study used doses up to 710 mg/kg/day.
Figure 11 (page 000) shows how parameters associated with renal function changed during the course
of treatment. These indicators remained steady or
decreased over time; this is significant since they
would be expected to rise during treatment if ascorbate was having an acute detrimental effect on renal
function. Blood chemistries suggested no compromise in renal function, and one patient showed stable disease, continuing treatment for an additional
48 weeks. Adverse effects reported were mostly
minor (nausea, edema, dry mouth or skin). Two
grade three adverse events “possibly related” to the
agent were reported: a kidney stone in a patient
with a history of renal calculus and a patient who
experienced hypokalemia. These patients were generally vitamin C deficient at the start of treatment,
and plasma ascorbate concentrations did not exceed
In the study by Hoffer and coworkers (Hoffer,
et al., 2008), twenty-four subjects with advanced
cancer or hematologic malignancy not amenable to
standard therapy were given IVC at doses of 0.4
g/kg to 1.5 g/kg (equivalent to a range of 28 to 125
grams in a 70 kg adult) three times weekly. In this
study, peak plasma concentrations in excess of 10
mM were obtained, and no serious side effects
were reported. Subjects at higher doses maintained
physical quality of life, but no objective anticancer
response was reported. The study by Monti and
coworkers (Monti, et al., 2012), fourteen patients
received IVC in addition to nucleoside analogue
gemcitabine and the tyrosine-kinase inhibitor
erlotinib. Observed adverse events were attributable to the chemotherapeutic agents, but not to the
ascorbate, but no added efficacy due to the ascorbate was observed.
Thus far, Phase I studies indicate that IVC can
be safely administered to terminal cancer patients
at high doses (10 to 100 grams or more), but anticancer efficacy of the sort reported in case studies
has not yet been observed. Of course, the terminal
subjects used in Phase I studies would be expected
to be the most difficult to treat. Phase II studies,
with longer durations, are needed at this point.
Safety Issues Reported In Literature
Evidence indicates that patients who show no
prior signs or history of renal malfunction are
unlikely to suffer ill effects to their renal systems as
a result of intravenous ascorbate (Riordan, et al.,
2005). In cases where there are preexisting renal
problems, however, caution is advised. In addition
a kidney stone forming in one patient with a history of stone formation (Riordan, et al., 2005), a
patient with bilateral urethral obstruction and
renal insufficiency suffered acute oxalate neuropathy (Wong, et al., 1994). A full blood chemistry and
urinalysis work-up is thus recommended prior to
the onset of intravenous ascorbate therapy.
Campbell and Jack (Campbell & Jack, 1979)
reported that one patient died due to massive
tumor necrosis and hemorrhaging following an
initial dose of intravenous ascorbate. It is thus recommended that treatment start at a low dose and
be carried out using slow “drip” infusion. Fatal
hemolysis can occur if a patient has glucose-6-
phosphate dehydrogenase deficiency (G6PD). It is thus recommended that G6PD levels be assessed
prior to the onset of therapy. The treatment is contraindicated in situations where increased fluids,
sodium, or chelating may cause serious problems.
These situations include congestive heart failure,
edema, ascites, chronic hemodialysis, unusual iron
overload, and inadequate hydration, or urine void
volume (Rivers, 1987).
The Riordan IVC Protocol
Inclusion Criteria and Candidates
1. Candidates include those who have failed standard treatment regimens; those seeking to improve
the effectiveness of their standard cancer therapy;
those seeking to decrease the severity and carcinogenicity of side effects from standard cancer therapy; those attempting to prolong their remission
with health-enhancing strategies; those declining
standard treatment, yet wishing to pursue primary,
2. Patient (guardian or legally recognized caregiver) must sign a consent-to-treat or release form
for the IVC treatment. Patient should have no significant psychiatric disorder, end-stage congestive
heart failure (CHF), or other uncontrolled comorbid conditions.
3. Obtain baseline and screening laboratory:
a. Serum chemistry profile with electrolytes
b. Complete blood count (CBC) with differential
c. Red blood cell G6PD (must be normal)
d. Complete urinalysis
4. In order to properly assess the patient’s response
to IVC therapy, obtain complete patient record
information prior to beginning IVC therapy:
a. Tumor type and staging, including operative
reports, pathology reports, special procedure
reports, and other staging information. (Re-staging
may be necessary if relapse and symptom progression has occurred since diagnosis.)
b. Appropriate tumor markers, CT, MRI, PET
scans, bone scans, and x-ray imaging.
c. Prior cancer treatments, the patient’s response
to each treatment type, including side effects.
d. The patient’s functional status with an Eastern Cooperative Oncology Group (ECOG) Performance Score.
e. Patient weight.
Precautions and Side Effects
In the Riordan Clinic’s experience giving over
40,000 onsite IVC treatments, the side effects of
high-dose IVC are rare. However, there are precautions and potential side effects to consider.
1. The danger of diabetics on insulin incorrectly
interpreting their glucometer finger stick has been
found. It is important to notice to health care workers using this protocol for the treatment of cancer
in patients who are also diabetic: high-dose intravenous vitamin C (IVC) at levels 15 grams and
higher will cause a false positive on finger-stick
blood glucose strips (electrochemical method) read
on various glucometers (Jackson & Hunninghake,
2006). Depending on the dose, the false-positive
glucose and occasionally “positive ketone” readings may last for eight hours after the infusion.
Blood taken from a vein and run in a laboratory
using the hexokinase serum glucose method is not
affected! The electrochemical strip cannot distinguish between ascorbic acid and glucose at high
levels. Oral vitamin C does not have this effect.
Please alert any diabetic patients of this potential
complication! Diabetics wishing to know their
blood sugar must have blood drawn from a vein
and run in the laboratory using the hexokinase
glucose determination method.
2. Tumor necrosis or tumor lysis syndrome has
been reported in one patient after high-dose IVC
(Campbell & Jack, 1979). For this reason, the protocol always begins with a small 15 gram dose.
3. Acute oxalate nephropathy (kidney stones) was
reported in one patient with renal insufficiency
who received a 60 gram IVC. Adequate renal function, hydration, and urine voiding capacity must
be documented prior to starting high-dose IVC
therapy. In our experience, however, the incidence
of calcium oxalate stones during or following IVC
is negligible (Riordan, et al., 2005).
4. Hemolysis has been reported in patients with
G6PD deficiency when given high-dose IVC (Campbell, et al., 1975). The G6PD level should be
assessed before beginning IVC. (At the Riordan
Clinic, G6PD readings have yielded five cases of
abnormally low levels. Subsequent IVC at 25 grams
or less showed no hemolysis or adverse effects.)
5. IV-site irritation may occur at the infusion site
when given in a vein and not a port. This can be
caused by an infusion rate exceeding 1.0
gram/minute. The protocol suggests adding magnesium to reduce the incidence of vein irritation
6. Due to the chelating effect of IVC, some patients
may complain of shakiness due to low calcium or
magnesium. An additional 1.0 mL of MgCl added
to the IVC solution will usually resolve this. If
severe, it can be treated with an IV push of 10 mLs
of calcium gluconate, 1.0 mL per minute.
7. Eating before the IVC infusion is recommended
to help reduce blood sugar fluctuations.
8. Given the amount of fluid used as a vehicle for
the IVC, any condition that could be adversely
affected by fluid or sodium overload (the IV ascorbate is buffered with sodium hydroxide and bicarbonate) is a relative contraindication (i.e.
congestive heart failure, ascites, edema, etc).
9. There have been some reports of iron overload
with vitamin C therapy. We have treated one
patient with hemochromatosis with high-dose IVC
with no adverse effects or significant changes in
the iron status.
10. As with any IV infusion, infiltration at the site
is possible. This is usually not a problem with
ports. Our nursing staff has found that using #23
butterfly needles with a shallow insertion is very
reliable with rare infiltrations (depending upon the
status of the patient’s veins!).
11. IVC should only be given by slow intravenous drip at a rate of 0.5 grams per minute.
(Rates up to 1.0 gram/minute are generally tolerable, but close observation is warranted. Patients
can develop nausea, shakes, and chills.)
12. It should never be given as an IV push, as the
osmolality at high doses may cause sclerosing of
peripheral veins, nor should it be given intramuscularly or subcutaneously. Table 1 lists the calculated osmolality of various amounts of fluid volume. Our experience has found that an osmolality
of less than 1,200 milliosmole (mOsm)/kg H2O is
tolerated by most patients. A low infusion rate (0.5
grams IVC per minute) also reduces the tonicity,
although up to 1.0 grams per minute can be used
in order to achieve higher post-IVC saturation levels. (Pre- and post-serum osmolality measurements are advisable at this dose.)
13. We presently use a sodium ascorbate solution,
MEGA-C-PLUS®, 500 mg/mL, pH range 5.5–7.0
from Merit Pharmaceuticals, Los Angeles, CA, 90065.
Administration of IVC
Having taken all precautions listed above and having obtained informed consent from the patient,
the administering physician begins with a series of
three consecutive IVC infusions at the 15, 25, and
50 gram dosages followed by post-IVC plasma
vitamin C levels in order to determine the oxidative burden for that patient so that subsequent
IVCs can be optimally dosed.
The initial three infusions are monitored with
post-IVC infusion plasma vitamin C levels. As
noted in Table 2 (below), research and experience
has shown that a therapeutic goal of reaching a
peak-plasma concentration of ~20 mM (350–400
mg/dL) is most efficacious. (No increased toxicity
for post-IVC plasma vitamin C levels up to 780
mg/dL has been observed.) The first post-IVC
plasma level following the 15-gram IVC has been
shown to be clinically instructive: levels below 100
mg/dL correlate with higher levels of existent
oxidative stress, presumably from higher tumor burden, chemo/radiation damage, hidden infection, or other oxidative insult, such as smoking.
Following the first three IVCs, the patient can be
scheduled to continue either a 25- or 50-gram IVC
dose (doctor’s discretion) twice a week until the postIVC plasma level results are available from the lab. If
the initial 50-gram post-IVC level did not reach the
therapeutic range of 350–400 mg/dL, another postIVC vitamin C level should be obtained after the next
scheduled 50 gram IVC. If the therapeutic range is
achieved, the patient is continued on a 50 gram twice
a week IVC schedule with monthly post-IVC determinations to assure continued efficacy. If the therapeutic range is still not achieved, the IVC dosage is
increased to 75 grams of vitamin C per infusion for
four infusions, at which time a subsequent post-IVC
plasma level is obtained. If the patient remains in a
sub-therapeutic range, the IVC dosage is increased to
the 100 gram level.
If after four infusions the post-IVC dosage
remains sub-therapeutic, the patient may have an
occult infection, may be secretly smoking, or may
have tumor progression. While these possibilities
are being addressed, the clinician can elect to
increase the 100-gram IVC frequency to three times
per week. Higher infusion doses beyond 100
grams are not recommended without serum osmolality testing before and after infusions in order to
properly adjust the infusion rate to maintain a near
physiologic osmolality range.
If higher dosages are not tolerated, or there is
tumor progression in spite of achieving the therapeutic range, lower dosages can still augment the
biological benefits of IVC, including enhanced
immune response, reduction in pain, increased
appetite, and a greater sense of well-being.
Very small patients, such as children, and very
large obese patients need special dosing. Small
patients [less than] 110 lbs. with small tumor burdens and without infection may only require
25-gram vitamin C infusions 2x/week to maintain
therapeutic range. Large patients > 220 lbs. or
patients with large tumor burdens or infection are
more likely to require 100-grams IVC infusions
3x/week. Post-IVC plasma levels serve as an excellent clinical guide to this special dosing.
In our experience, the majority of cancer patients
require 50-gram IVC infusions 2–3x/week to maintain therapeutic IVC plasma levels. All patients
reaching therapeutic range should still be monitored
monthly with post-IVC plasma levels to ensure that
these levels are maintained long term. We advise
patients to orally supplement with at least 4 grams
of vitamin C daily, especially on the days when no
infusions are given, to help prevent a possible vitamin C “rebound effect.” Oral alpha lipoic acid is also
recommended on a case by case basis.
Vitamin C can be safely administered by intravenous infusion at maximum doses of 100 grams
or less, provided the precautions outlined in this
report are taken. At these doses, peak plasma
ascorbate concentrations can exceed 20 mM.
There are several potential benefits to giving
IVC to cancer patients that make it an ideal adjunctive care choice:
• Cancer patients are often depleted of vitamin C,
and IVC provides an efficient means of restoring
• IVC has been shown to improve quality of life in
cancer patients by a variety of metrics.
• IVC reduces inflammation (as measured by Creactive protein levels) and reduces the production
of pro-inflammatory cytokines.
• At high concentrations, ascorbate is preferentially toxic to tumor cells and is an angiogenesis
The next key step in researching the use of IVC
for cancer would be Phase II studies, some of
which are currently underway. IVC may also have
a variety of other applications, such as combating
infections, treating rheumatoid arthritis, and treating ADHD and other mental illnesses where
inflammation may play a role.
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