Ascorbic Acid: The Natural Source and Science Behind Klenner’s Work

Everything Frederick Klenner did in his Reidsville practice rested on one small molecule: ascorbic acid, the substance most people know as vitamin C. It is a plant product before it is a medicine. It sits in lemons, peppers, guavas and green leaves; sailors carried it in citrus juice centuries before anyone could name it; and almost every animal on earth makes its own supply in its liver or kidneys. Humans are among the few that cannot. Klenner thought that fact, and the chemistry of the molecule itself, explained why the amounts he injected could do things that ordinary dietary amounts never did.

This page follows the science behind his work: how the lemon-juice remedy became a named chemical, which foods carry it, the lost enzyme that makes humans depend on their diet, the “hypoascorbemia” idea of Irwin Stone and Linus Pauling’s 1970 evolutionary argument, Klenner’s own explanation of how the vitamin worked, the sodium salt he injected, and what laboratory and pharmacokinetic research later showed about mouth versus vein. Later reported hazards are set out as findings beside his own view. His virus-disease reports themselves are told on the companion page, Vitamin C and the Virus Diseases.

Table of Contents

  1. “Bring Juice of Lemons”: From Winslow to Szent-Györgyi
  2. Where Vitamin C Comes From in Food
  3. The Missing Enzyme: Why Humans Need Dietary Vitamin C
  4. Stone’s Hypoascorbemia and Pauling’s 1970 Argument
  5. Reducing Agent and “Flash Oxidizer”: Klenner’s Explanation
  6. Sodium Ascorbate and the Injected Route
  7. Mouth Versus Vein: What Pharmacokinetics Later Showed
  8. Hydrogen Peroxide at High Concentrations
  9. Oxalate, Kidneys and G6PD Deficiency: Reported Hazards
  10. Key Research Papers
  11. Connections

1. “Bring Juice of Lemons”: From Winslow to Szent-Györgyi

Klenner liked to begin with history. His 1953 paper “The Use of Vitamin C as an Antibiotic,” published in the Journal of Applied Nutrition, opens not with a laboratory but with a letter. On 11 December 1621, he wrote, Edward Winslow, one of the Pilgrim settlers of Plymouth, advised a friend in England who was preparing to cross the Atlantic: “Bring juice of lemons; and take it fasting. It is of good use.” Klenner then jumped forward “three hundred and eleven years” to December 1932, when, in his telling, the American chemists W. A. Waugh and Charles Glen King found that this “important” lemon juice contained “a six carbon chain acid which is now known as vitamin C.”

Between those two dates lies the long story of scurvy, told on the site’s Vitamin C History page.

Hexuronic acid, 1928

The chemical side began in 1928, when the Hungarian biochemist Albert Szent-Györgyi, then working in the Biochemical Laboratory at Cambridge, published a long paper in the Biochemical Journal on peroxidase systems and the chemistry of the adrenal cortex. Its subtitle announced “a new carbohydrate derivative” — a strongly reducing six-carbon compound from the adrenal glands, cabbage and oranges, which he named hexuronic acid. Four years later, in 1932, King and Waugh in Pittsburgh, and Szent-Györgyi with his colleague Joseph Svirbely in Szeged, reported that this compound was the long-sought antiscorbutic factor. It was renamed ascorbic acid — literally “the anti-scurvy acid” — and Szent-Györgyi received the 1937 Nobel Prize in Physiology or Medicine, partly for this work. His life is told on the site’s Albert Szent-Györgyi page.

Klenner held on to the older name. In his 1949 polio paper in Southern Medicine and Surgery he wrote of “massive frequent doses of hexuronic acid (vitamin C)” and of “the detoxication effected by hexuronic acid.” In 1953 he added that the hexuronic acids are “derivatives of the simple sugars” — vitamin C is a chemical cousin of glucose, from which animals that make it build it.

Jungeblut’s test tubes

Once pure crystalline vitamin C existed, researchers could test it against microbes. The experiment Klenner cited most often came from Claus W. Jungeblut at Columbia University. In 1935 Jungeblut reported in the Journal of Experimental Medicine that multiple paralytic doses of poliomyelitis virus, “when mixed with very small amounts of crystalline vitamin C,” were rendered non-infectious when the mixtures were injected into the brains of rhesus monkeys. That was a test-tube (in vitro) inactivation, not a treatment; what followed in living animals, and how Klenner read it, is told on the virus diseases page.

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2. Where Vitamin C Comes From in Food

Vitamin C is overwhelmingly a plant nutrient. Peppers, citrus, berries, kiwifruit, tropical fruits and the cabbage family dominate every food table, while meat, fish, eggs and dairy carry little. On the figures the site uses on its Vitamin C Sources page (from the USDA FoodData Central database), a cup of guava holds about 228 mg, a medium raw red bell pepper about 128 mg, a cup of kiwifruit about 93 mg, a cup of strawberries about 59 mg and a medium orange about 45 mg. For comparison, the US recommended dietary allowance set by the Institute of Medicine is 90 mg a day for men and 75 mg for women.

The acerola cherry and the “health tree”

Klenner’s long 1971 paper in the Journal of Applied Nutrition opens with folk remedies. “In Puerto Rico,” he wrote, “the story has long been told ‘that to have the health tree Acerola in one’s back yard would keep colds out of the front door.’” He added that the ascorbic acid content of this cherry-like fruit was “thirty times that found in oranges.” Acerola (Malpighia emarginata, the Barbados or West Indian cherry) is indeed among the richest known whole-food sources, alongside the Indian gooseberry described on the site’s Amla page.

The same paper turns to his own Pennsylvania childhood, when the family drank bitter boneset tea for colds and fevers; he wrote that he later assayed the plant and believed it held large amounts of “natural vitamin C.” Boneset is not otherwise recognised as a vitamin C source, and that claim is reported here only as his own. The plant itself has a page at Boneset.

Klenner’s food list, 1953

For all his interest in injections, Klenner’s 1953 paper includes a section headed “Dietary Considerations With Vitamin C.” “Fortunately,” he wrote, “vitamin C is a vitamin supplied by Nature in a variety of foods,” and he listed citrus fruits, tomatoes, berries and a long run of green vegetables from broccoli and kale to parsley and peppers. He also described how bruising, crushing and long storage release plant enzymes (oxidases) which, “in the presence of air,” destroy the vitamin.

Food amounts and Klenner’s amounts belonged to different worlds: a day of vitamin-C-rich eating supplies a few hundred milligrams, while his 1948 injections were 1,000 mg each and his 1971 doses ran to tens of grams — ascorbic acid, in his phrase, “employed beyond the range of a vitamin.”

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3. The Missing Enzyme: Why Humans Need Dietary Vitamin C

Most mammals do not need vitamin C in their food at all. A rat, a dog, a cow or a goat converts glucose into ascorbic acid through a short chain of enzyme steps. The last step is carried out by an enzyme called L-gulonolactone oxidase (often abbreviated GULO). Humans and the other apes and monkeys of the haplorhine primate line, guinea pigs, many bats and some birds have lost a working version of that enzyme. In humans the gene is still present in the genome, but as a broken “pseudogene” riddled with mutations, so the chain stops one step short and the body has to take the finished vitamin from food.

Klenner set out this idea in his own 1971 paper under the heading “Ascorbic acid not synthesized by man.” “It has been proposed,” he wrote, “that the biochemical lesion which produces the human need for exogenous sources of ascorbic acid, is the absence of the active enzyme, l-gulonolactone oxidase from the human liver.” A defect or loss of the gene, he continued, “blocks the final phase in the series for converting glucose to ascorbic acid.” He placed the condition alongside other inherited enzyme defects such as phenylketonuria and galactosemia.

How much do other animals make?

From the missing enzyme Klenner drew his main conclusion about dose. Based on what he called “scant data on mammalian synthesis, available for the rat,” he calculated that a 70-kilogram animal making its own vitamin C “would produce 1.8 grams to 4.0 grams of ascorbic acid per day in the unstressed condition. Under stress, up to 15.2 grams.” He set those figures against the 70 mg then recommended for daily needs and wrote that “the physiological requirements in man are no different from other mammals capable of carrying out this synthesis.” “Let us start thinking in terms of maximum requirements,” he wrote.

These are Klenner’s extrapolations from animal figures, as he stated them; the main Vitamin C page covers today’s official intakes.

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4. Stone’s Hypoascorbemia and Pauling’s 1970 Argument

Klenner was not alone in this reasoning. The biochemist Irwin Stone had argued through the 1960s that humanity’s lost enzyme was best understood not as a dietary curiosity but as an inherited disease, which he called “hypoascorbemia” — a low level of ascorbate in the blood caused by a genetic fault, to be corrected by much larger intakes than the scurvy-preventing minimum. Klenner adopted the word. In his 1971 paper, under the heading “Biochemist Irwin Stone’s concept has practical value,” he wrote: “The inability of man to manufacture his own ascorbic acid, due to genetic fault, has been called ‘hypoascorbemia’ by Irwin Stone. This is another reason for abolishing the present concept of daily minimal requirements.” Stone gathered his case in his 1972 book The Healing Factor.

Pauling in the Proceedings, 1970

The argument reached its widest audience through Linus Pauling, the two-time Nobel laureate whose orthomolecular ideas are covered on the site’s Linus Pauling page. In December 1970 Pauling published “Evolution and the need for ascorbic acid” in the Proceedings of the National Academy of Sciences. His abstract states the reasoning compactly: ascorbic acid “differs from other vitamins in that an exogenous source is required by only a few animal species,” and this fact “indicates that the amount contained in a diet of raw natural plant food is less than the optimum intake, corresponding to the best health.” The argument, he wrote, “leads to the conclusion that the optimum daily intake is about 2.3 g or more, for an adult with energy requirement 2500 kcal” a day.

Put simply, Pauling argued from evolution: our ancestors lost the enzyme while living on raw plant foods that supplied grams of vitamin C a day, so the loss did them no harm; modern diets supply far less. Pauling later wrote the foreword to Lendon Smith’s 1988 collection of Klenner’s papers. The Canadian psychiatrist Abram Hoffer, co-founder of orthomolecular psychiatry, is quoted on Klenner’s doses in the 2005 Orthomolecular Medicine Hall of Fame citation.

These were arguments from evolution and from comparison with other animals, as their authors presented them. How the body actually handles gram doses was measured much later, as described in section 7.

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5. Reducing Agent and “Flash Oxidizer”: Klenner’s Explanation

Chemically, ascorbic acid is a reducing agent: it gives up electrons easily, turning reversibly into dehydroascorbic acid. Klenner called it in 1949 “an integral part of the oxidation-reduction system of the body,” and built his explanation on this chemistry in three overlapping ways.

Binding and destroying toxins and viruses (1949)

In his 1949 polio paper he drew on earlier laboratory writers. “This dual action of vitamin C against certain toxins and the virus organism,” he wrote, “becomes more intelligible with the work of Kligler, Warburg and others who believed that the detoxication effected by hexuronic acid is brought about by a direct combination of the vitamin with the toxin or virus, this followed by oxidation of the new compound which destroys both the virus or toxin and the vitamin.” He added that “Borsook et al. decided that the main chemical action of ascorbic acid is as a powerful reducing agent, and the virus causing poliomyelitis is known to be susceptible to the oxidizing action of various agents.”

The “flash oxidizer” (1971)

By 1971 his description had become more striking. “Ascorbic acid has many important functions,” he wrote. “It is a powerful oxidizer and when given in massive amounts; that is, 50 grams to 150 grams, intravenously, for certain pathological conditions, and ‘run in’ as fast as 20 Gauge needle will allow, it acts as a ‘Flash Oxidizer,’ often correcting the pathology within minutes. Ascorbic acid is also a powerful reducing agent. Its neutralizing action on certain toxins, exotoxins, virus infections, endotoxins and histamine is in direct proportion to the amount of the lethal factor involved and the amount of ascorbic acid given.”

He applied the same idea to carbon monoxide poisoning, writing that “clinical experience suggests that if sufficient ascorbic acid is suddenly placed into the blood stream — 12 grams to 50 grams — that through ‘Flash Oxidation’ a concentration of oxygen is made high enough to pull carbon monoxide from hemoglobin to form carbon dioxide.” These quantities are reported here as historical record of what Klenner wrote, not as a description of any current practice.

An antibiotic “by needle” (1953)

In 1953 he described vitamin C as “the foundation of the oxidation redux system” which “now through greater dosage reveals its outstanding qualities as a non-toxic antibiotic.” He argued that physicians would not give it “in massive doses administered like other antibiotics — around the clock.”

The idea that a compound famous as an antioxidant could also act as an oxidiser sounded contradictory to many readers. Section 8 describes how later laboratory work found a related — though different — pro-oxidant action at the very high concentrations only injection can reach.

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6. Sodium Ascorbate and the Injected Route

Pure ascorbic acid is, as its name says, an acid. Its sodium salt, sodium ascorbate, carries the same vitamin activity but is close to neutral, which is why it is the usual form in injectable solutions.

Klenner’s papers almost always say “ascorbic acid.” But the physician Robert F. Cathcart, who corresponded with Klenner and with his wife Annie, added a note to the online transcription of the 1971 paper: “This paper repeatedly refers to intravenous ascorbic acid. My personal experience, my talking with Klenner, and with his wife, Annie Klenner, who served as his nurse, would indicate that he means sodium ascorbate.”

His own intake and the sodium question

The sodium in such large amounts drew official attention. In a reply printed with the 1971 paper, Klenner wrote that the Food and Drug Administration had published a warning “that too much soda-ascorbate might be harmful, referring to the sodium ion.” His answer was personal: “for many years I have taken 10 to 20 grams of sodium ascorbate by mouth daily, and my blood sodium remains normal.”

Calcium and the breakdown of the vitamin

Klenner wrote that he gave calcium gluconate alongside very large intravenous doses, because in his view they pulled free calcium ions from the blood as the vitamin broke down. He traced the breakdown path in the body: ascorbic acid “goes to dehydroascorbic acid, then to ketogulonic acid and later to oxalic acid as the calcium salt.” That last step — the conversion of part of the vitamin to oxalate — is the same chemistry behind the kidney findings described in section 9.

Why the needle?

Klenner insisted that the route mattered. In 1949 he wrote of diphtheria that “to the synthetic drug, by mouth, there is little response, even when 1000 to 2000 mg. is used every two hours,” whereas by injection he reported cures. He had no means of measuring why the two routes behaved so differently; that explanation came half a century later.

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7. Mouth Versus Vein: What Pharmacokinetics Later Showed

Pharmacokinetics is the study of how much of a substance reaches the blood and how quickly it leaves. For vitamin C, the decisive measurements came from Mark Levine’s group at the US National Institutes of Health.

Levine, 1996: the gut and kidneys keep blood levels tight

In a study published in the Proceedings of the National Academy of Sciences in 1996, seven healthy volunteers lived in hospital for four to six months on a diet with less than 5 mg of vitamin C a day, then received seven daily doses in turn, from 30 mg up to 2,500 mg. The researchers found that blood levels rose steeply between 30 and 100 mg a day and reached complete plasma saturation at 1,000 mg a day. A single 200 mg dose was completely absorbed, but at single doses of 500 mg and higher “bioavailability declined and the absorbed amount was excreted.” In other words, past a certain point the gut absorbs a shrinking fraction of each oral dose and the kidneys clear the excess.

Padayatty, 2004: the injected route bypasses those controls

In 2004 the same group, writing in the Annals of Internal Medicine, compared oral and intravenous doses directly in 17 healthy hospitalised volunteers. Peak blood levels were higher after injection at every dose, and the gap grew as the dose rose. A 1.25-gram dose by mouth produced a mean peak plasma concentration of about 135 micromoles per litre; the same dose by vein produced about 885. Using pharmacokinetic modelling, the authors predicted that the largest tolerated oral dosing (3 grams every four hours) would peak at about 220 micromoles per litre, while a 50-gram intravenous dose would peak at about 13,400 — roughly sixty times higher — and urine levels 140-fold higher. “Oral vitamin C produces plasma concentrations that are tightly controlled,” they concluded. “Only intravenous administration of vitamin C produces high plasma and urine concentrations.”

These two studies supplied, decades after his papers, a physical explanation for the difference Klenner described between his oral and injected results: by vein, blood levels reach a range that mouth dosing cannot approach. Padayatty and colleagues noted that trials using only oral dosing cannot judge intravenous use (see the Pauling wing’s Cancer and the Cameron Collaboration). Present-day intravenous research is covered on the site’s High-Dose IV Vitamin C and Cancer page.

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8. Hydrogen Peroxide at High Concentrations

If injected vitamin C reaches concentrations no food or tablet can, what does it do at those levels? In 2005 Qi Chen, Mark Levine and colleagues reported a laboratory answer in the Proceedings of the National Academy of Sciences. They exposed 10 types of cancer cells and 4 types of normal cells to ascorbate for one hour. Normal cells were unaffected by 20 millimolar ascorbate, while five of the cancer lines died at concentrations below 4 millimolar — “a concentration easily achievable i.v.”

The mechanism surprised the researchers. Cell death depended entirely on the formation of hydrogen peroxide: in the fluid around cells, at these concentrations, ascorbate generated hydrogen peroxide, and that peroxide did the killing. In blood itself, by contrast, ascorbate generated no detectable hydrogen peroxide. The authors concluded that ascorbate “at concentrations achieved only by i.v. administration may be a pro-drug for formation of H2O2, and that blood can be a delivery system of the pro-drug to tissues.” They added that the findings had “unexpected implications for treatment of infections where H2O2 may be beneficial.”

An echo of the “flash oxidizer”

This is the pro-oxidant face of a molecule usually described as an antioxidant. Klenner’s 1971 “Flash Oxidizer” was his own clinical description, written without these measurements and resting on a different proposed chemistry (oxygen release and toxin binding). The 2005 study is a cell-culture experiment, not a clinical trial, and did not test any of Klenner’s conditions; it shows that vitamin C behaves oxidatively in the concentration range only the injected route reaches.

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9. Oxalate, Kidneys and G6PD Deficiency: Reported Hazards

Klenner maintained that vitamin C was without toxic effect in his hands. Later case reports and studies described specific hazards of high doses, set out below as reported.

Klenner’s view of oxalate and kidney stones (1971)

Part of any vitamin C dose is broken down to oxalate, the substance that forms the most common type of kidney stone. Klenner addressed this directly in 1971, calling the oxalate concern one of the “scare” weapons used by critics. He argued that stone formation depends chiefly on urinary stasis and concentrated urine; that oxalic acid forms from ascorbic acid only when its ring opens above pH 5; that urine on 10 grams of vitamin C a day was usually around pH 6, whereas oxalic acid precipitates only from neutral or alkaline urine; and that large doses acted as a diuretic, leaving “no urinary stasis; no urine concentration.” He cited a study by Lamden and colleagues in which volunteers taking 9 grams a day had oxalate outputs close to those of controls. “The ascorbic acid kidney stone story,” he concluded, “is a myth.”

Oxalate rise at 1 gram a day (Levine, 1996)

In the NIH depletion-repletion study described in section 7, Levine and colleagues reported that “oxalate and urate excretion were elevated at 1000 mg of vitamin C daily compared to lower doses.”

Acute oxalate nephropathy after 45 grams IV (Lawton, 1985)

In 1985 Lawton and colleagues described, in the Archives of Internal Medicine, a patient with primary amyloidosis and the nephrotic syndrome — that is, already-damaged kidneys — who received a single 45-gram intravenous dose of ascorbic acid as adjuvant therapy. Acute oliguric kidney failure followed. At autopsy the kidney tubules were filled with crystalline material confirmed as calcium oxalate, and plasma oxalate and ascorbic acid levels were raised. The authors concluded that high-dose ascorbic acid “is a potential cause of oxalate nephropathy.” Later case reports of oxalate kidney injury after high-dose vitamin C are gathered on the site’s Vitamin C and Kidney Stones page.

Haemolysis in G6PD deficiency (Rees, 1993)

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited condition in which red blood cells are unusually vulnerable to oxidative stress. In 1993 Rees and colleagues at University College Hospital, London, published a case report in the BMJ titled “Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency.” Haemolysis is the bursting of red blood cells; in G6PD deficiency it is set off by oxidative stress, the same broad pro-oxidant chemistry described in section 8. The condition is described on the site’s G6PD Deficiency page; the research raises a particular concern about high doses for people with this enzyme deficiency.

Reading the record side by side

Klenner’s argument concerned stones in the urine of people with healthy kidneys; Lawton’s case was crystal injury in already-diseased kidneys after one very large injection; the Rees report concerned an inherited blood-cell defect he did not discuss. The broader safety record of vitamin C, including the upper intake level of 2,000 mg a day set by the US Institute of Medicine for oral intake by adults, is on the site’s Vitamin C Toxicity page.

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Key Research Papers

  1. Szent-Györgyi A. Observations on the function of peroxidase systems and the chemistry of the adrenal cortex: Description of a new carbohydrate derivative. Biochem J. 1928;22(6):1387-409. PubMed PMID: 16744155
  2. Jungeblut CW. Inactivation of poliomyelitis virus in vitro by crystalline vitamin C (ascorbic acid). J Exp Med. 1935;62(4):517-21. PubMed PMID: 19870431
  3. Klenner FR. Virus pneumonia and its treatment with vitamin C. South Med Surg. 1948;110(2):36-8. PubMed PMID: 18900646
  4. Klenner FR. The treatment of poliomyelitis and other virus diseases with vitamin C. South Med Surg. 1949;111(7):209-14. PubMed PMID: 18147027
  5. Pauling L. Evolution and the need for ascorbic acid. Proc Natl Acad Sci U S A. 1970;67(4):1643-8. PubMed PMID: 5275366
  6. Lawton JM, Conway LT, Crosson JT, Smith CL, Abraham PA. Acute oxalate nephropathy after massive ascorbic acid administration. Arch Intern Med. 1985;145(5):950-1. PubMed PMID: 3994472
  7. Rees DC, Kelsey H, Richards JD. Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. BMJ. 1993;306(6881):841-2. PubMed PMID: 8490379
  8. Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A. 1996;93(8):3704-9. PubMed PMID: 8623000
  9. Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140(7):533-7. PubMed PMID: 15068981
  10. Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A. 2005;102(38):13604-9. PubMed PMID: 16157892

PubMed Topic Searches

  1. Klenner FR — papers indexed in PubMed
  2. Intravenous ascorbic acid pharmacokinetics
  3. L-gulonolactone oxidase and ascorbic acid synthesis
  4. Ascorbic acid and oxalate nephropathy
  5. Ascorbic acid, haemolysis and G6PD deficiency

Further Reading

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Connections