Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Vitamin C: Difference between pages

{{Short description|Essential nutrient found in citrus fruits and other foods}}

{{Other uses}}

{{pp-move}}

{{Good article}}

{{Use mdy dates|date=January 2024}}

{{Use American English|date=February 2024}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 477315393

| drug_name = Ascorbic acid

| INN =

| type =

| image = L-Ascorbic_acid.svg

| alt = Natta projection of structural formula for L-ascorbic acid

| width =

| caption =

| image2 = Ascorbic-acid-from-xtal-1997-3D-balls.png

| alt2 = Ball-and-stick model of L-ascorbic acid

| width2 =

<!-- Clinical data -->

| pronounce = {{IPAc-en|ə|ˈ|s|k|ɔːr|b|ɪ|k}}, {{IPAc-en|ə|ˈ|s|k|ɔːr|b|eɪ|t|,_|-|b|ɪ|t}}

| tradename = Ascor, Cecon, Cevalin, others

| Drugs.com = {{drugs.com |monograph |ascorbic-acid}}

| MedlinePlus = a682583

| DailyMedID = Ascorbic acid

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]], [[Intramuscular injection|intramuscular]] (IM), [[Intravenous therapy|intravenous]] (IV), [[Subcutaneous injection|subcutaneous]]

| class =

| ATC_prefix = A11

| ATC_suffix = GA01

| ATC_supplemental = {{ATC|A11|GB01}} {{ATC|G01|AD03}} {{ATC|S01|XA15}}

<!-- Legal status -->

| legal_AU = Unscheduled

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment = /&nbsp;GSL<ref name="(emc)-2015">{{cite web |title=Ascorbic acid injection 500mg/5ml |website=(emc) |date=15 July 2015 |url=https://www.medicines.org.uk/emc/product/1520/smpc |access-date=October 12, 2020 |archive-date=14 October 2020 |archive-url=https://web.archive.org/web/20201014011840/https://www.medicines.org.uk/emc/product/1520/smpc |url-status=live }}</ref><ref name="(emc)-2018">{{cite web |title=Ascorbic acid 100mg tablets |website=(emc) |date=29 October 2018 |url=https://www.medicines.org.uk/emc/product/9615/smpc |access-date=October 12, 2020 |archive-date=September 21, 2020 |archive-url=https://web.archive.org/web/20200921155221/https://www.medicines.org.uk/emc/product/9615/smpc |url-status=dead }}</ref>

| legal_US = Rx-only

| legal_US_comment = /&nbsp;OTC/&nbsp;Dietary Supplement<ref name="DailyMed-2020">{{cite web |title=Ascor- ascorbic acid injection |website=DailyMed |date=October 2, 2020 |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=388aad52-fc01-4784-9791-1dbc80c69306 |access-date=October 12, 2020 |archive-date=29 October 2020 |archive-url=https://web.archive.org/web/20201029093116/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=388aad52-fc01-4784-9791-1dbc80c69306 |url-status=live }}</ref>

| legal_EU =

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status =

<!-- Pharmacokinetic data -->

| bioavailability = Rapid, diminishes as dose increases<ref name=NIH2021 />

| protein_bound = Negligible

| metabolism =

| metabolites =

| onset =

| elimination_half-life = Varies according to plasma concentration <!-- can be 30 min to weeks, depending on body stores -->

| duration_of_action =

| excretion = [[Kidney]]

<!-- Identifiers -->

| index2_label = as salt

| CAS_number_Ref = {{cascite |correct |??}}

| CAS_number = 50-81-7

| CAS_number2_Ref = {{cascite |correct |??}}

| CAS_number2 = 134-03-2

| CAS_supplemental =

| PubChem = 54670067

| PubChem2 = 23667548

| IUPHAR_ligand = 4781

| DrugBank_Ref = {{drugbankcite |correct |drugbank}}

| DrugBank = DB00126

| DrugBank2_Ref = {{drugbankcite |correct |drugbank}}

| DrugBank2 = DB14482

| ChemSpiderID_Ref = {{chemspidercite |correct |chemspider}}

| ChemSpiderID = 10189562

| ChemSpiderID2_Ref = {{chemspidercite |correct |chemspider}}

| ChemSpiderID2 = 16736174

| UNII_Ref = {{fdacite |correct |FDA}}

| UNII = PQ6CK8PD0R

| UNII2_Ref = {{fdacite |correct |FDA}}

| UNII2 = S033EH8359

| KEGG_Ref = {{keggcite |correct |kegg}}

| KEGG = D00018

| KEGG2_Ref = {{keggcite |correct |kegg}}

| KEGG2 = D05853

| ChEBI_Ref = {{ebicite |correct |EBI}}

| ChEBI = 29073

| ChEBI2_Ref = {{ebicite |correct |EBI}}

| ChEBI2 = 113451

| ChEMBL_Ref = {{ebicite |correct |EBI}}

| ChEMBL = 196

| ChEMBL2_Ref = {{ebicite |correct |EBI}}

| ChEMBL2 = 591665

| NIAID_ChemDB = 002072

| PDB_ligand = ASC

| synonyms = {{sm|l}}-ascorbic acid, ascorbic acid, ascorbate

<!-- Chemical and physical data -->

| IUPAC_name = {{sm|l}}-''threo''-Hex-2-enono-1,4-lactone<br />''or''<br />(''R'')-3,4-Dihydroxy-5-((''S'')- 1,2-dihydroxyethyl)furan-2(5''H'')-one

| C = 6 | H = 8 | O = 6

| SMILES = OC[C@H](O)[C@H]1OC(=O)C(O)=C1O

| StdInChI_Ref = {{stdinchicite |correct |chemspider}}

| StdInChI = 1S/C6H8O6/c7-1-2(8)5-3(9)4(10)6(11)12-5/h2,5,7-10H,1H2/t2-,5+/m0/s1

| StdInChI_comment =

| StdInChIKey_Ref = {{stdinchicite |correct |chemspider}}

| StdInChIKey = CIWBSHSKHKDKBQ-JLAZNSOCSA-N

| density = 1.694

| density_notes =

| melting_point = 190

| melting_high = 192

| melting_notes =

| boiling_point = 552.7

| boiling_notes = <ref name="Chem-Spider-2020-Vitamin-C">{{cite web |title=Vitamin C |url=http://www.chemspider.com/Chemical-Structure.10189562.html |access-date=July 25, 2020 |website=Chem Spider |publisher=Royal Society of Chemistry |archive-date=July 24, 2020 |archive-url=https://web.archive.org/web/20200724030511/http://www.chemspider.com/Chemical-Structure.10189562.html |url-status=live }}</ref>

| solubility =

| sol_units =

| specific_rotation =

'''Vitamin C''' (also known as [[Chemistry of ascorbic acid|ascorbic acid]] and '''ascorbate''') is a water-soluble [[vitamin]] found in [[citrus]] and other fruits, berries and vegetables. It is also a [[Generic drug|generic]] prescription medication and in some countries is sold as a non-prescription [[dietary supplement]]. As a therapy, it is used to prevent and treat [[scurvy]], a disease caused by [[vitamin C deficiency]].

Vitamin C is an [[Nutrient#Essential nutrients|essential nutrient]] involved in the repair of [[Tissue (biology)|tissue]], the formation of [[collagen]], and the [[Enzyme|enzymatic]] production of certain [[neurotransmitter]]s. It is required for the functioning of several enzymes and is important for [[immune system]] function.<ref name=lpi2018>{{cite web |title=Vitamin C |url=http://lpi.oregonstate.edu/mic/vitamins/vitamin-C |publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR |access-date=June 19, 2019 |date=July 1, 2018 |archive-date=July 12, 2019 |archive-url=https://web.archive.org/web/20190712000113/https://lpi.oregonstate.edu/mic/vitamins/vitamin-C |url-status=live }}</ref> It also functions as an [[antioxidant]]. Vitamin C may be taken by mouth or by intramuscular, subcutaneous or intravenous injection. Various [[health claim]]s exist on the basis that moderate vitamin C deficiency increases disease risk, such as for the [[common cold]], [[cancer]] or [[COVID-19]]. There are also claims of benefits from vitamin C supplementation in excess of the [[Dietary Reference Intake|recommended dietary intake]] for people who are not considered vitamin C deficient. Vitamin C is generally well-tolerated. Large doses may cause [[Gastrointestinal disease|gastrointestinal discomfort]], headache, trouble sleeping, and flushing of the skin. The United States [[National Academy of Medicine|Institute of Medicine]] recommends against consuming large amounts.<ref name=DRItext>{{cite book |chapter=Vitamin C |publisher=The National Academies Press |year=2000 |location=Washington, DC |pages=95–185 |doi=10.17226/9810 |pmid=25077263 |chapter-url=https://www.nap.edu/read/9810/chapter/7 |access-date=September 1, 2017 |isbn=978-0-309-06935-9 |url-status=live |archive-url=https://web.archive.org/web/20170902180153/https://www.nap.edu/read/9810/chapter/7 |archive-date=September 2, 2017 |author1=Institute of Medicine (US) Panel on Dietary Antioxidants Related Compounds |title=Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids }}</ref>{{rp|pages=155-165}}

Most animals are able to [[#Synthesis|synthesize their own vitamin C]]. However, [[ape]]s (including humans) and monkeys (but not all [[primates]]), most [[bat]]s, most fish, some rodents, and certain other animals must acquire it from dietary sources because a gene for a synthesis enzyme has mutations that render it dysfunctional.

Vitamin C was discovered in 1912, isolated in 1928, and in 1933, was the first vitamin to be [[Chemical synthesis|chemically produced]]. Partly for its discovery, [[Albert Szent-Györgyi]] was awarded the 1937 [[Nobel Prize in Physiology or Medicine]].

{{TOC limit}}

== Chemistry ==

{{Multiple image |direction=vertical |align=left |image1=Ascorbic acid structure.svg |image2=Dehydroascorbic acid 2.svg |width=150 |caption1=[[ascorbic acid]]<br />([[reducing agent|reduced form]]) |caption2=[[dehydroascorbic acid]]<br />([[oxidizing agent|oxidized form]])}}

{{anchor |Enantiomeric notation of vitamin C vitamers and their biological significance}}

{{Main|Chemistry of ascorbic acid}}

The name "vitamin C" always refers to the [[Enantiomer|{{sm|l}}-enantiomer]] of [[ascorbic acid]] and its [[Redox|oxidized]] form, dehydroascorbate (DHA). Therefore, unless written otherwise, "ascorbate" and "ascorbic acid" refer in the nutritional literature to {{sm|l}}-ascorbate and {{sm|l}}-ascorbic acid respectively. Ascorbic acid is a [[weak acid|weak]] [[sugar acid]] structurally related to [[glucose]]. In biological systems, ascorbic acid can be found only at low [[pH]], but in solutions above pH 5 is predominantly found in the [[ionized]] form, ascorbate.<ref name=PKIN2020VitC/>

Numerous analytical methods have been developed for ascorbic acid detection. For example, vitamin C content of a food sample such as fruit juice can be calculated by measuring the volume of the sample required to decolorize a solution of [[dichlorophenolindophenol]] (DCPIP) and then calibrating the results by comparison with a known concentration of vitamin C.<ref name="British Nutrition Foundation-2004">{{cite web |url=http://www.foodafactoflife.org.uk/attachments/ff2caf4a-75e5-4aa129132873.pdf |title=Testing foods for vitamin C (ascorbic acid) |publisher=British Nutrition Foundation |date=2004 |url-status=live |archive-url=https://web.archive.org/web/20151123101705/http://www.foodafactoflife.org.uk/attachments/ff2caf4a-75e5-4aa129132873.pdf |archive-date=November 23, 2015 }}</ref><ref name="Nuffield Foundation-2011">{{cite web |url=http://www.nuffieldfoundation.org/practical-biology/measuring-vitamin-c-content-foods-and-fruit-juices |title=Measuring the vitamin C content of foods and fruit juices |publisher=Nuffield Foundation |date=November 24, 2011 |url-status=live |archive-url=https://web.archive.org/web/20150721181046/http://www.nuffieldfoundation.org/practical-biology/measuring-vitamin-c-content-foods-and-fruit-juices |archive-date=July 21, 2015 }}</ref>

==Deficiency==

Plasma vitamin C is the most widely applied test for vitamin C status.<ref name=PKIN2020VitC>{{cite book |title = Present Knowledge in Nutrition, Eleventh Edition |chapter = Vitamin C | veditors = Marriott MP, Birt DF, Stallings VA, Yates AA |publisher = Academic Press (Elsevier) |year=2020 |location = London, United Kingdom |pages = 155–70 |isbn=978-0-323-66162-1}}</ref> Adequate levels are defined as near 50 μmol/L. [[Hypovitaminosis]] of vitamin C is defined as less than 23 μmol/L, and [[Vitamin deficiency|deficiency]] as less than 11.4 μmol/L.<ref name=Schleicher2009>{{cite journal |vauthors=Schleicher RL, Carroll MD, Ford ES, Lacher DA |title=Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES) |journal=The American Journal of Clinical Nutrition |volume=90 |issue=5 |pages=1252–63 |date=November 2009 |pmid=19675106 |doi=10.3945/ajcn.2008.27016 | doi-access = free | title-link = doi }}</ref> For people 20 years of age or above, data from the US 2017-18 [[National Health and Nutrition Examination Survey]] showed mean serum concentrations of 53.4 {{nbsp}}μmol/L. The percent of people reported as deficient was 5.9%.<ref name="Narayanan-2021">{{cite journal |vauthors=Narayanan S, Kumar SS, Manguvo A, Friedman E |title=Current estimates of serum vitamin C and vitamin C deficiency in the United States |journal=Curr Dev Nutr |volume=7 |issue=5 |pages=1067 |date=June 2021 |doi=10.1093/cdn/nzab053_060|pmc=8180804 }}</ref> Globally, vitamin C deficiency is common in low and middle-income countries, and not uncommon in high income countries. In the latter, prevalence is higher in males than in females.<ref name=Rowe2020>{{cite journal |vauthors=Rowe S, Carr AC |title=Global vitamin C status and prevalence of deficiency: A cause for concern? |journal=Nutrients |volume=12 |issue=7 |date=July 2020 |page=2008 |pmid=32640674 |pmc=7400810 |doi=10.3390/nu12072008 |doi-access=free |url=}}</ref>

Plasma levels are considered saturated at about 65 μmol/L, achieved by intakes of 100 to 200&nbsp;mg/day, which are well above the recommended intakes. Even higher oral intake does not further raise plasma nor tissue concentrations because absorption efficiency decreases and any excess that is absorbed is excreted in urine.<ref name=PKIN2020VitC/>

=== Diagnostic testing ===

Vitamin C content in plasma is used to determine vitamin status. For research purposes, concentrations can be assessed in [[leukocyte]]s and tissues, which are normally maintained at an order of magnitude higher than in plasma via an energy-dependent transport system, depleted slower than plasma concentrations during dietary deficiency and restored faster during dietary repletion,<ref name="DRItext" />{{rp|pages=103-109}} but these analysis are difficult to measure, and hence not part of standard diagnostic testing.<ref name=PKIN2020VitC/><ref name="pmid15820776">{{cite journal | vauthors = Emadi-Konjin P, Verjee Z, Levin AV, Adeli K | title = Measurement of intracellular vitamin C levels in human lymphocytes by reverse phase high performance liquid chromatography (HPLC) | journal = Clinical Biochemistry | volume = 38 | issue = 5 | pages = 450–6 | date = May 2005 | pmid = 15820776 | doi = 10.1016/j.clinbiochem.2005.01.018 }}</ref>

==Diet==

===Recommended consumption===

Recommendations for vitamin C intake by adults have been set by various national agencies:

* 40&nbsp;mg/day: India [[National Institute of Nutrition, Hyderabad]]<ref name="NIN">{{cite web |url=http://ninindia.org/DietaryGuidelinesforNINwebsite.pdf |title=Dietary guidelines for Indians |publisher=National Institute of Nutrition, India |date=2011 |page=90 |access-date=February 10, 2019 |archive-date=December 22, 2018 |archive-url=https://web.archive.org/web/20181222101538/http://www.ninindia.org/DietaryGuidelinesforNINwebsite.pdf |url-status=dead }}</ref>

* 45&nbsp;mg/day or 300&nbsp;mg/week: the [[World Health Organization]]<ref name="isbn92-4-154612-3">{{cite book | vauthors = ((World Health Organization)) | title = Vitamin and mineral requirements in human nutrition | edition = 2nd | publisher = World Health Organization | location = Geneva | year = 2005 | isbn = 978-92-4-154612-6 | chapter = Chapter 7: Vitamin C | hdl = 10665/42716 | author-link = World Health Organization}}</ref>

* 80&nbsp;mg/day: the [[European Commission]] Council on nutrition labeling<ref name="EU RDA">{{cite web |url=http://eur-lex.europa.eu/legal-content/en/TXT/?uri=CELEX%3A32008L0100 |title=Commission Directive 2008/100/EC of 28 October 2008 amending Council Directive 90/496/EEC on nutrition labeling for foodstuffs as regards recommended daily allowances, energy conversion factors and definitions |publisher=The Commission of the European Communities |url-status=live |archive-url=https://web.archive.org/web/20161002233059/http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32008L0100 |archive-date=October 2, 2016 |date=October 29, 2008 }}</ref>

* 90&nbsp;mg/day (males) and 75&nbsp;mg/day (females): [[Health Canada]] 2007<ref name="urlNatural Health Product Monograph - Vitamin C [Health Canada, 2007]">{{cite web |url=http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/monograph/mono_vitamin_c-eng.php |work=Natural Health Product Monograph |title=Vitamin C |publisher=Health Canada |url-status=dead |archive-url=https://web.archive.org/web/20130403150228/http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/monograph/mono_vitamin_c-eng.php |archive-date=April 3, 2013 }}</ref>

* 90&nbsp;mg/day (males) and 75&nbsp;mg/day (females): [[United States National Academy of Sciences]]<ref name="DRItext" />{{rp|pages=134-152}}

* 100&nbsp;mg/day: Japan National Institute of Health and Nutrition<ref name="JapanDRI2015">{{cite web |url=https://www.mhlw.go.jp/file/06-Seisakujouhou-10900000-Kenkoukyoku/Overview.pdf |title=Overview of dietary reference intakes for Japanese |website=Ministry of Health, Labor and Welfare (Japan) |date=2015 |page=29 |access-date=August 19, 2021 |archive-date=October 21, 2022 |archive-url=https://web.archive.org/web/20221021004240/https://www.mhlw.go.jp/file/06-Seisakujouhou-10900000-Kenkoukyoku/Overview.pdf |url-status=live }}</ref>

* 110&nbsp;mg/day (males) and 95&nbsp;mg/day (females): [[European Food Safety Authority]]<ref name=EFSA-Recommended>{{cite journal |title=Scientific Opinion on Dietary Reference Values for vitamin C |date=November 2013 |journal=EFSA Journal |volume=11 |issue=11 |doi=10.2903/j.efsa.2013.3418 |doi-access=free }}</ref>

{|class="wikitable" style="float:right;"

|-

! style="text-align:center;" colspan="2"|US vitamin C recommendations ([[milligram|mg]] per day)<ref name="DRItext" />{{rp|pages=134-152}}

|-

|RDA (children ages 1–3 years)

|15

|-

|RDA (children ages 4–8 years)

|25

|-

|RDA (children ages 9–13 years)

|45

|-

|RDA (girls ages 14–18 years)

|65

|-

|RDA (boys ages 14–18 years)

|75

|-

|RDA (adult female)

|75

|-

|RDA (adult male)

|90

|-

|RDA (pregnancy)

|85

|-

|RDA (lactation)

|120

|-

|UL (adult female)

|2,000

|-

|UL (adult male)

|2,000

|}

In 2000, the chapter on Vitamin C in the North American [[Dietary Reference Intake]] was updated to give the [[Recommended Dietary Allowance]] (RDA) as 90 milligrams per day for adult men, 75&nbsp;mg/day for adult women, and setting a [[Tolerable upper intake level]] (UL) for adults of 2,000&nbsp;mg/day.<ref name="DRItext" />{{rp|pages=134-152}} The table (right) shows RDAs for the United States and Canada for children, and for pregnant and lactating women,<ref name="DRItext" />{{rp|pages=134-152}} as well as the ULs for adults.

For the European Union, the EFSA set higher recommendations for adults, and also for children: 20&nbsp;mg/day for ages 1–3, 30&nbsp;mg/day for ages 4–6, 45&nbsp;mg/day for ages 7–10, 70&nbsp;mg/day for ages 11–14, 100&nbsp;mg/day for males ages 15–17, 90&nbsp;mg/day for females ages 15–17. For pregnancy 100&nbsp;mg/day; for lactation 155&nbsp;mg/day.<ref name=EFSA-Recommended />

Cigarette smokers and people exposed to secondhand smoke have lower serum vitamin C levels than nonsmokers.<ref name=Schleicher2009/> The thinking is that inhalation of smoke causes oxidative damage, depleting this antioxidant vitamin.<ref name="DRItext" />{{rp|pages=152-153}} The US Institute of Medicine estimated that smokers need 35&nbsp;mg more vitamin C per day than nonsmokers, but did not formally establish a higher RDA for smokers.<ref name="DRItext" />{{rp|pages=152-153}}

The US National Center for Health Statistics conducts biannual National Health and Nutrition Examination Survey (NHANES) to assess the health and nutritional status of adults and children in the United States. Some results are reported as What We Eat In America. The 2013–2014 survey reported that for adults ages 20 years and older, men consumed on average 83.3&nbsp;mg/d and women 75.1&nbsp;mg/d. This means that half the women and more than half the men are not consuming the RDA for vitamin C.<ref name="National Health and Nutrition Examination Survey: What We Eat in America, DHHS-USDA Dietary Survey Integration-2">{{cite web | url = https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1314/Table_1_NIN_GEN_13.pdf | title = TABLE 1: Nutrient intakes from food and beverages | work = National Health and Nutrition Examination Survey: What We Eat in America, DHHS-USDA Dietary Survey Integration | publisher = Centers for Disease Control and Prevention, U.S. Department of Health & Human Services| archive-url = https://web.archive.org/web/20170224042515/https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1314/Table_1_NIN_GEN_13.pdf | archive-date=February 24, 2017 }}</ref> The same survey stated that about 30% of adults reported they consumed a vitamin C dietary supplement or a multi-vitamin/mineral supplement that included vitamin C, and that for these people total consumption was between 300 and 400&nbsp;mg/d.<ref name="National Health and Nutrition Examination Survey: What We Eat in America, DHHS-USDA Dietary Survey Integration">{{cite web | url = https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1314/Table_37_SUP_GEN_13.pdf | title = TABLE 37: Nutrient intakes from dietary supplements | work = National Health and Nutrition Examination Survey: What We Eat in America, DHHS-USDA Dietary Survey Integration | publisher = Centers for Disease Control and Prevention, U.S. Department of Health & Human Services | archive-url = https://web.archive.org/web/20171006162231/https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1314/Table_37_SUP_GEN_13.pdf | archive-date=October 6, 2017 }}</ref>

====Tolerable upper intake level====

In 2000, the Institute of Medicine of the US National Academy of Sciences set a [[Tolerable upper intake level]] (UL) for adults of 2,000&nbsp;mg/day. The amount was chosen because human trials had reported diarrhea and other gastrointestinal disturbances at intakes of greater than 3,000&nbsp;mg/day. This was the Lowest-Observed-Adverse-Effect Level (LOAEL), meaning that other adverse effects were observed at even higher intakes. ULs are progressively lower for younger and younger children.<ref name="DRItext" />{{rp|pages=155-165}} In 2006, the [[European Food Safety Authority]] (EFSA) also pointed out the disturbances at that dose level, but reached the conclusion that there was not sufficient evidence to set a UL for vitamin C,<ref name="European Food Safety Authority-2006">{{cite web|year=2006|title=Tolerable upper intake levels for vitamins and minerals|url=http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf|url-status=live|archive-url=https://web.archive.org/web/20160316225123/http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf|archive-date=March 16, 2016|publisher=European Food Safety Authority}}</ref> as did the Japan National Institute of Health and Nutrition in 2010.<ref name="JapanDRI2015" />

===Food labeling===

For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin C labeling purposes, 100% of the Daily Value was 60&nbsp;mg, but as of May 27, 2016, it was revised to 90&nbsp;mg to bring it into agreement with the RDA.<ref name="FedReg">{{cite web |url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |title=Federal Register May 27, 2016 food labeling: Revision of the nutrition and supplement facts labels. FR page 33982. |url-status=live |archive-url=https://web.archive.org/web/20160808164651/https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |archive-date=August 8, 2016 }}</ref><ref name="Dietary Supplement Label Database (DSLD)-2020">{{cite web | title=Daily Value Reference of the Dietary Supplement Label Database (DSLD) | website=Dietary Supplement Label Database (DSLD) | url=https://www.dsld.nlm.nih.gov/dsld/dailyvalue.jsp | access-date=May 16, 2020 | archive-date=April 7, 2020 | archive-url=https://web.archive.org/web/20200407073956/https://dsld.nlm.nih.gov/dsld/dailyvalue.jsp | url-status=dead }}</ref> A table of the old and new adult daily values is provided at [[Reference Daily Intake]].

European Union regulations require that labels declare energy, protein, fat, saturated fat, carbohydrates, sugars, and salt. Voluntary nutrients may be shown if present in significant amounts. Instead of Daily Values, amounts are shown as percent of Reference Intakes (RIs). For vitamin C, 100% RI was set at 80&nbsp;mg in 2011.<ref name="REGULATION-EU-2009">[http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2011:304:0018:0063:EN:PDF REGULATION (EU) No 1169/2011 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL] {{Webarchive|url=https://web.archive.org/web/20170726215901/http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ%3AL%3A2011%3A304%3A0018%3A0063%3AEN%3APDF |date=July 26, 2017 }} Official Journal of the European Union. page 304/61. (2009).</ref>

==Sources==

Although also present in other plant-derived foods, the richest natural sources of vitamin C are fruits and vegetables.<ref name=NIH2021/><ref name=lpi2018 /> Vitamin C is the most widely taken [[dietary supplement]].<ref name=lpi2018 />

===Plant sources===

{{For|vitamin C content in ten common staple foods such as corn, rice, and wheat|Staple food#Nutrition}}

The following table is approximate and shows the relative abundance in different raw plant sources.<ref name=NIH2021/><ref name=lpi2018/><ref name="USDA Nutrient Data Laboratory, the Food and Nutrition Information Center and Information Systems Division of the National Agricultural Library.">{{cite web |url=https://fdc.nal.usda.gov/ |title=NDL/FNIC food composition database home page |access-date=30 November 2014 |publisher=USDA Nutrient Data Laboratory, the Food and Nutrition Information Center and Information Systems Division of the National Agricultural Library. |archive-date=January 15, 2023 |archive-url=https://web.archive.org/web/20230115162310/http://fdc.nal.usda.gov/ |url-status=live }}</ref> The amount is given in milligrams per 100&nbsp;grams of the edible portion of the fruit or vegetable:

<div style="float:left; padding: 1em;">

{|class="wikitable"

|-

!Raw plant source<ref name=USDA-NDL>{{cite web |url=https://www.nal.usda.gov/sites/www.nal.usda.gov/files/vitamin_c.pdf |title=USDA national nutrient database for standard reference legacy: vitamin C |date=2018 |website=U.S. Department of Agriculture, Agricultural Research Service |access-date=September 27, 2020 |archive-date=November 18, 2021 |archive-url=https://web.archive.org/web/20211118013136/https://www.nal.usda.gov/sites/www.nal.usda.gov/files/vitamin_c.pdf |url-status=live }}</ref>

!Amount<br /> (mg / 100g)

|-

|[[Terminalia ferdinandiana|Kakadu plum]] || 1000–5300<ref name="Brand-1987">{{cite journal |title=The nutritional composition of Australian aboriginal bushfoods. I |year=1987 |vauthors=Brand JC, Rae C, McDonnell J, Lee A, Cherikoff V, Truswell AS |journal=Food Technology in Australia |volume=35 |issue=6 |pages=293–6 }}</ref>

|-

|[[Camu camu]] || 2800<ref name="pmid11464674">{{cite journal | vauthors = Justi KC, Visentainer JV, Evelázio de Souza N, Matsushita M | title = Nutritional composition and vitamin C stability in stored camu-camu (''Myrciaria dubia'') pulp | journal = Archivos Latinoamericanos de Nutricion | volume = 50 | issue = 4 | pages = 405–8 | date = December 2000 | pmid = 11464674 }}</ref>

|-

|[[Acerola]] || 1677<ref name="Vendramini-2000">{{cite journal |title=Chemical composition of acerola fruit (Malpighia punicifolia L.) at three stages of maturity |vauthors=Vendramini AL, Trugo LC |journal=Food Chemistry |volume=71 |issue=2 |year=2000 |pages=195–8 |doi=10.1016/S0308-8146(00)00152-7 }}</ref>

|-

|[[Indian gooseberry]] || 445<ref name="Begum-2008">{{cite book | vauthors = Begum RM |title=A textbook of foods, nutrition & dietetics |date=2008 |publisher=Sterling Publishers Pvt. Ltd |isbn=978-81-207-3714-3 |page=72 |url=https://books.google.com/books?id=tMNnaw3lN7oC&pg=PP82}}</ref><ref name="Sinha-2012">{{cite book | vauthors = Sinha N, Sidhu J, Barta J, Wu J, Cano MP |title=Handbook of fruits and fruit processing |date=2012 |publisher=John Wiley & Sons |isbn=978-1-118-35263-2 |url=https://books.google.com/books?id=1qwuBXeczzgC&pg=PT1734}}</ref>

|-

|[[Rose hip]] || 426

|-

|[[Common sea-buckthorn]] || 400<ref name="pmid19021790">{{cite journal|vauthors=Gutzeit D, Baleanu G, Winterhalter P, Jerz G|date=2008|title=Vitamin C content in sea buckthorn berries (Hippophaë rhamnoides L. ssp . rhamnoides) and related products: A kinetic study on storage stability and the determination of processing effects|journal=J Food Sci|volume=73|issue=9|pages=C615–C20|doi=10.1111/j.1750-3841.2008.00957.x|pmid=19021790}}</ref>

|-

|[[Guava]] || 228

|-

|[[Blackcurrant]] || 200

|-

|Yellow [[Bell pepper|bell pepper/capsicum]] || 183

|-

|Red [[Bell pepper|bell pepper/capsicum]] || 128

|-

|[[Kale]] || 120

|-

|[[Broccoli]] || 90

|-

|[[Kiwifruit]] || 90

|}

</div>

<div style="float:left; padding: 1em;">

{|class="wikitable"

|-

!Raw plant source<ref name=USDA-NDL />

!Amount<br /> (mg / 100g)

|-

|Green [[Bell pepper|bell pepper/capsicum]] ||80

|-

|[[Brussels sprout]]s || 80

|-

|[[Loganberry]], [[redcurrant]] ||80

|-

|[[Cloudberry]], [[elderberry]] || 60

|-

|[[Strawberry]] || 60

|-

|[[Papaya]] || 60

|-

|[[Orange (fruit)|Orange]], [[lemon]] || 53

|-

|[[Cauliflower]] || 48

|-

|[[Pineapple]] || 48

|-

|[[Cantaloupe]] || 40

|-

|[[Passion fruit]], [[raspberry]] || 30

|-

|[[Grapefruit]], [[Lime (fruit)|lime]] || 30

|-

|[[Cabbage]], [[spinach]] || 30

|}

</div>

<div style="float:left; padding: 1em;">

{|class="wikitable"

|-

!Raw plant source<ref name=USDA-NDL />

!Amount<br /> (mg / 100g)

|-

|[[Mango]] || 28

|-

|[[Blackberry]], [[cassava]] || 21

|-

|[[Potato]] || 20

|-

|[[Honeydew melon]] || 20

|-

|[[Tomato]] || 14

|-

|[[Cranberry]] || 13

|-

|[[Blueberry]], [[grape]] || 10

|-

|[[Apricot]], [[plum]], [[watermelon]] || 10

|-

|[[Avocado]] || 8.8

|-

|[[Onion]] || 7.4

|-

|[[Cherry]], [[peach]] || 7

|-

|[[Apple]] || 6

|-

|[[Carrot]], [[asparagus]] || 6

|}

</div>{{Clear}}

===Animal sources===

Compared to plant sources, animal-sourced foods do not provide so great an amount of vitamin C, and what there is is largely destroyed by the heat used when it is cooked. For example, raw chicken liver contains 17.9&nbsp;mg/100&nbsp;g, but fried, the content is reduced to 2.7&nbsp;mg/100&nbsp;g. Vitamin C is present in [[Breastfeeding#Benefits|human breast milk]] at 5.0&nbsp;mg/100&nbsp;g. Cow's milk contains 1.0&nbsp;mg/100&nbsp;g, but the heat of pasteurization destroys it.<ref name="Clark-2007">{{cite web |url=http://www.saanendoah.com/compare.html |title= Comparing milk: human, cow, goat & commercial infant formula |access-date=February 28, 2007 |date=8 January 2007 | vauthors = Clark S |publisher=[[Washington State University]] |archive-url=https://web.archive.org/web/20070129024619/http://www.saanendoah.com/compare.html |archive-date=January 29, 2007}}</ref>

===Food preparation===

Vitamin C [[chemical decomposition|chemically decomposes]] under certain conditions, many of which may occur during the cooking of food. Vitamin C concentrations in various food substances decrease with time in proportion to the temperature at which they are stored.<ref name="pmid7621082">{{cite journal | vauthors = Roig MG, Rivera ZS, Kennedy JF | title = A model study on rate of degradation of L-ascorbic acid during processing using home-produced juice concentrates | journal = International Journal of Food Sciences and Nutrition | volume = 46 | issue = 2 | pages = 107–15 | date = May 1995 | pmid = 7621082 | doi = 10.3109/09637489509012538 }}</ref> Cooking can reduce the vitamin C content of vegetables by around 60%, possibly due to increased enzymatic destruction.<ref name="pmid14801407">{{cite journal | vauthors = Allen MA, Burgess SG | title = The losses of ascorbic acid during the large-scale cooking of green vegetables by different methods | journal = The British Journal of Nutrition | volume = 4 | issue = 2–3 | pages = 95–100 | year = 1950 | pmid = 14801407 | doi = 10.1079/BJN19500024 | doi-access = free | title-link = doi }}</ref> Longer cooking times may add to this effect.<ref name="Oxford">{{cite web |url=http://physchem.ox.ac.uk/MSDS/AS/ascorbic_acid.html |title=Safety (MSDS) data for ascorbic acid |access-date=February 21, 2007 |date=October 9, 2005 |publisher=[[Oxford University]] |url-status=live |archive-url=https://archive.today/20070209221915/http://physchem.ox.ac.uk/MSDS/AS/ascorbic_acid.html |archive-date=February 9, 2007 }}</ref> Another cause of vitamin{{nbsp}}C loss from food is [[Leaching (chemistry)|leaching]], which transfers vitamin{{nbsp}}C to the cooking water, which is decanted and not consumed.<ref name=VitCFort1997/>

===Supplements===

Vitamin C dietary supplements are available as tablets, capsules, drink mix packets, in multi-vitamin/mineral formulations, in antioxidant formulations, and as crystalline powder.<ref name=AHFS2016>{{cite web |title=Ascorbic acid (Monograph) |url=https://www.drugs.com/monograph/ascorbic-acid.html |publisher=The American Society of Health-System Pharmacists |access-date=December 8, 2016 |url-status=live |archive-url=https://web.archive.org/web/20161230161611/https://www.drugs.com/monograph/ascorbic-acid.html |archive-date=December 30, 2016 }}</ref> Vitamin C is also added to some fruit juices and juice drinks. Tablet and capsule content ranges from 25&nbsp;mg to 1500&nbsp;mg per serving. The most commonly used supplement compounds are ascorbic acid, sodium ascorbate and calcium ascorbate.<ref name=AHFS2016 /> Vitamin C molecules can also be bound to the fatty acid palmitate, creating [[ascorbyl palmitate]], or else incorporated into liposomes.<ref name="pmid27375360">{{cite journal | vauthors = Davis JL, Paris HL, Beals JW, Binns SE, Giordano GR, Scalzo RL, Schweder MM, Blair E, Bell C | title = Liposomal-encapsulated ascorbic acid: influence on vitamin C bioavailability and capacity to protect against ischemia-reperfusion injury | journal = Nutrition and Metabolic Insights | volume = 9 | pages = 25–30 | year = 2016 | pmid = 27375360 | pmc = 4915787 | doi = 10.4137/NMI.S39764 }}</ref>

===Food fortification===

Countries fortify foods with nutrients to address known deficiencies.<ref name=WhyFortify>{{cite web |url=https://www.ffinetwork.org/savelives |title=Why fortify? |website=Food Fortification Initiative |date=December 2023 |access-date=January 3, 2024 |archive-date=March 8, 2023 |archive-url=https://web.archive.org/web/20230308151817/https://www.ffinetwork.org/savelives |url-status=live }}</ref> While many countries mandate or have voluntary programs to fortify wheat flour, maize (corn) flour or rice with vitamins,<ref name=Map>{{cite web|url=https://fortificationdata.org/map-number-of-nutrients/|title=Map: Count of nutrients in fortification standards|website=Global Fortification Data Exchange|access-date=January 3, 2024|archive-date=April 11, 2019|archive-url=https://web.archive.org/web/20190411123853/https://fortificationdata.org/map-number-of-nutrients/|url-status=live}}</ref> none include vitamin C in those programs.<ref name=Map/> As described in ''Vitamin C Fortification of Food Aid Commodities'' (1997), the United States provides rations to international food relief programs, later under the asupices of the [[Food for Peace|Food for Peace Act]] and the Bureau for Humanitarian Assistance.<ref name="USAID-2023">{{cite web|title=USAID's Bureau for Humanitarian Assistance website|date=November 21, 2023 |url=https://www.usaid.gov/who-we-are/organization/bureaus/bureau-humanitarian-assistance}}</ref> Vitamin C is added to corn-soy blend and wheat-soy blend products at 40&nbsp;mg/100 grams. (along with minerals and other vitamins). Supplemental rations of these highly fortified, blended foods are provided to refugees and displaced persons in camps and to beneficiaries of development feeding programs that are targeted largely toward mothers and children.<ref name=VitCFort1997>{{cite book |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK230149/ |title=Vitamin C fortification of food aid commodities: final report |chapter=Introduction |date=1997 |publisher=National Academies Press (US) |access-date=January 3, 2024 |archive-date=January 21, 2024 |archive-url=https://web.archive.org/web/20240121044202/https://www.ncbi.nlm.nih.gov/books/NBK230149/ |url-status=live }}</ref> The report adds: "The stability of vitamin C (L-ascorbic acid) is of concern because this is one of the most labile vitamins in foods. Its main loss during processing and storage is from oxidation, which is accelerated by light, oxygen, heat, increased pH, high moisture content (water activity), and the presence of copper or ferrous salts. To reduce oxidation, the vitamin C used in commodity fortification is coated with ethyl cellulose (2.5 percent). Oxidative losses also occur during food processing and preparation, and additional vitamin C may be lost if it dissolves into cooking liquid and is then discarded."<ref name=VitCFort1997/>

==Food preservation additive==

Ascorbic acid and some of its [[salt (chemistry)|salts]] and [[ester]]s are common [[food additive|additives]] added to various foods, such as [[canning|canned]] fruits, mostly to slow [[redox|oxidation]] and [[Food browning|enzymatic browning]].<ref name="Washburn-2017">{{cite web|url=https://digitalcommons.usu.edu/cgi/viewcontent.cgi?article=2781&context=extension_curall|title=Pretreatments to prevent darkening of fruits prior to canning or dehydrating|vauthors=Washburn C, Jensen C|date=2017|publisher=Utah State University|access-date=January 26, 2020|archive-date=December 15, 2020|archive-url=https://web.archive.org/web/20201215135857/https://digitalcommons.usu.edu/cgi/viewcontent.cgi?article=2781&context=extension_curall|url-status=live}}</ref> It may be used as a [[flour treatment agent]] used in [[breadmaking]].<ref name="fobvc">{{cite news |title=Ingredients |url=https://www.fob.uk.com/about-the-bread-industry/how-bread-is-made/ingredients/ |access-date=April 3, 2021 |publisher=The Federation of Bakers |archive-date=February 26, 2021 |archive-url=https://web.archive.org/web/20210226064815/https://www.fob.uk.com/about-the-bread-industry/how-bread-is-made/ingredients/ |url-status=live }}</ref> As food additives, they are assigned [[E number]]s, with safety assessment and approval the responsibility of the [[European Food Safety Authority]].<ref name="Food Additives and Ingredients Association UK & Ireland- Making life taste better">{{cite web|url=http://www.faia.org.uk/faq2_4.php|title=Frequently asked questions {{!}} why food additives|website=Food Additives and Ingredients Association UK & Ireland- Making life taste better|access-date=October 27, 2010|url-status=live |archive-url=https://web.archive.org/web/20190601015633/https://www.faia.org.uk/faqs/|archive-date=June 1, 2019}}</ref> The relevant E numbers are:

# E300 ascorbic acid (approved for use as a food additive in the UK,<ref name="food.gov.uk">UK Food Standards Agency: {{cite web |url=http://www.food.gov.uk/safereating/chemsafe/additivesbranch/enumberlist |title=Approved additives and their E numbers |access-date=October 27, 2011 |archive-date=October 7, 2010 |archive-url=https://web.archive.org/web/20101007124435/http://www.food.gov.uk/safereating/chemsafe/additivesbranch/enumberlist |url-status=live }}</ref> US<ref name="fda.gov">US Food and Drug Administration:{{cite web|url=https://www.fda.gov/Food/FoodIngredientsPackaging/FoodAdditives/FoodAdditiveListings/ucm091048.htm |title=Listing of food additives status part I |website=Food and Drug Administration |access-date=October 27, 2011 |url-status=dead |archive-url=https://web.archive.org/web/20120117060614/https://www.fda.gov/Food/FoodIngredientsPackaging/FoodAdditives/FoodAdditiveListings/ucm091048.htm |archive-date=January 17, 2012 }}</ref> Canada,<ref name="health.canada.ca">Health Canada {{cite web |title=List of permitted preservatives (lists of permitted food additives) - Government of Canada |url=https://www.canada.ca/en/health-canada/services/food-nutrition/food-safety/food-additives/lists-permitted/11-preservatives.html |website=Government of Canada |date=November 27, 2006 |access-date=October 27, 2022 |archive-date=October 27, 2022 |archive-url=https://web.archive.org/web/20221027020735/https://www.canada.ca/en/health-canada/services/food-nutrition/food-safety/food-additives/lists-permitted/11-preservatives.html |url-status=live }}</ref> Australia and New Zealand<ref name="comlaw.gov.au">Australia New Zealand Food Standards Code{{cite web |url=http://www.comlaw.gov.au/Details/F2011C00827 |title=Standard 1.2.4 – labeling of ingredients |date=September 8, 2011 |access-date=October 27, 2011 |archive-date=September 2, 2013 |archive-url=https://web.archive.org/web/20130902084805/http://www.comlaw.gov.au/Details/F2011C00827 |url-status=live }}</ref>)

# E301 [[sodium ascorbate]] (approved for use as a food additive in the UK,<ref name="food.gov.uk"/> US,<ref name="US Food and Drug Administration">{{cite web |url=https://www.fda.gov/Food/FoodIngredientsPackaging/FoodAdditives/ucm191033.htm#ftnT |title=Listing of food additives status part II |website=US Food and Drug Administration |access-date=October 27, 2011 |archive-date=November 8, 2011 |archive-url=https://web.archive.org/web/20111108002304/https://www.fda.gov/Food/FoodIngredientsPackaging/FoodAdditives/ucm191033.htm#ftnT |url-status=live }}</ref> Canada,<ref name="health.canada.ca"/> Australia and New Zealand<ref name="comlaw.gov.au"/>)

# E302 [[calcium ascorbate]] (approved for use as a food additive in the UK,<ref name="food.gov.uk"/> US<ref name="fda.gov"/> Canada,<ref name="health.canada.ca"/> Australia and New Zealand<ref name="comlaw.gov.au"/>)

# E303 [[potassium ascorbate]] (approved in Australia and New Zealand,<ref name="comlaw.gov.au"/> but not in the UK, US or Canada)

# E304 fatty acid esters of ascorbic acid such as [[ascorbyl palmitate]] (approved for use as a food additive in the UK,<ref name="food.gov.uk"/> US,<ref name="fda.gov"/> Canada,<ref name="health.canada.ca"/> Australia and New Zealand<ref name="comlaw.gov.au"/>)

The stereoisomers of Vitamin C have a similar effect in food despite their lack of efficacy in humans. They include [[erythorbic acid]] and its sodium salt (E315, E316).<ref name="food.gov.uk"/>

==Pharmacology==

{{See also|Chemistry of ascorbic acid}}

[[Pharmacodynamics]] is the study of how the drug – in this instance vitamin C – affects the organism, whereas [[pharmacokinetics]] is the study of how an organism affects the drug.

===Pharmacodynamics===

Pharmacodynamics includes enzymes for which vitamin C is a cofactor, with function potentially compromised in a deficiency state, and any enzyme cofactor or other physiological function affected by administration of vitamin C, orally or injected, in excess of normal requirements. At normal physiological concentrations, vitamin C serves as an [[enzyme]] [[substrate (biochemistry)|substrate]] or [[cofactor (biochemistry)|cofactor]] and an [[electron donor]] antioxidant. The enzymatic functions include the synthesis of [[collagen]], [[carnitine]], and [[neurotransmitter]]s; the synthesis and [[catabolism]] of [[tyrosine]]; and the metabolism of [[microsome]]s. In nonenzymatic functions it acts as a reducing agent, donating electrons to oxidized molecules and preventing oxidation in order to keep iron and copper atoms in their reduced states.<ref name=PKIN2020VitC/> At non-physiological concentrations achieved by intravenous dosing, vitamin C may function as a [[pro-oxidant]], with therapeutic toxicity against cancer cells.<ref name="Bottger2021">{{cite journal |vauthors=Böttger F, Vallés-Martí A, Cahn L, Jimenez CR |title=High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer |journal=J Exp Clin Cancer Res |volume=40 |issue=1 |pages=343 |date=October 2021 |pmid=34717701 |pmc=8557029 |doi=10.1186/s13046-021-02134-y |doi-access=free |url=}}</ref><ref name="Park2018">{{cite journal |vauthors=Park S, Ahn S, Shin Y, Yang Y, Yeom CH |title=Vitamin C in cancer: a metabolomics perspective |journal=Front Physiol |volume=9 |issue= |pages=762 |date=2018 |pmid=29971019 |pmc=6018397 |doi=10.3389/fphys.2018.00762 |doi-access=free |url=}}</ref>

Vitamin C functions as a cofactor for the following [[enzyme]]s:<ref name=PKIN2020VitC/>

* Three groups of enzymes ([[prolyl-3-hydroxylase]]s, [[P4HA1|prolyl-4-hydroxylase]]s, and [[lysyl hydroxylase]]s) that are required for the [[hydroxylation]] of [[proline]] and [[lysine]] in the synthesis of [[collagen]]. These reactions add [[hydroxide|hydroxyl groups]] to the amino acids [[proline]] or [[lysine]] in the collagen molecule via [[prolyl hydroxylase]] and [[lysyl hydroxylase]], both requiring vitamin C as a [[cofactor (biochemistry)|cofactor]]. The role of vitamin C as a cofactor is to oxidize prolyl hydroxylase and lysyl hydroxylase from Fe{{sup|2+}} to Fe{{sup|3+}} and to reduce it from Fe{{sup|3+}} to Fe{{sup|2+}}. Hydroxylation allows the collagen molecule to assume its triple [[helix]] structure, and thus vitamin C is essential to the development and maintenance of [[granulation tissue|scar tissue]], [[blood vessel]]s, and [[cartilage]].

* Two enzymes ([[trimethyllysine dioxygenase|ε-N-trimethyl-L-lysine hydroxylase]] and [[gamma-butyrobetaine dioxygenase|γ-butyrobetaine hydroxylase]]) are necessary for synthesis of [[carnitine]]. Carnitine is essential for the transport of [[fatty acid]]s into [[mitochondria]] for [[Adenosine triphosphate|ATP]] generation.

* [[Hypoxia-inducible factor-proline dioxygenase]] enzymes (isoforms: [[EGLN1]], [[EGLN2]], and [[EGLN3]]) allows cells to respond physiologically to low concentrations of oxygen.

* [[Dopamine beta-hydroxylase]] participates in the biosynthesis of [[norepinephrine]] from [[dopamine]].

* [[Peptidylglycine alpha-amidating monooxygenase]] amidates [[peptide hormone]]s by removing the glyoxylate residue from their c-terminal glycine residues. This increases peptide hormone stability and activity.

As an antioxidant, ascorbate scavenges reactive oxygen and nitrogen compounds, thus neutralizing the potential tissue damage of these [[free radical]] compounds. Dehydroascorbate, the oxidized form, is then recycled back to ascorbate by endogenous antioxidants such as [[glutathione]].<ref name=DRItext />{{rp|pages=98-99}} In the eye, ascorbate is thought to protect against photolytically generated free-radical damage; higher plasma ascorbate is associated with lower risk of cateracts.<ref name="pmid30878580"/> Ascorbate may also provide antioxidant protection indirectly by regenerating other biological antioxidants such as [[α-tocopherol]] back to an active state.<ref name=DRItext />{{rp|pages=98-99}} In addition, ascorbate also functions as a non-enzymatic reducing agent for mixed-function oxidases in the microsomal drug-metabolizing system that inactivates a wide variety of substrates such as drugs and environmental carcinogens.<ref name=DRItext />{{rp|pages=98-99}}

===Pharmacokinetics===

Ascorbic acid is absorbed in the body by both active transport and passive diffusion.<ref>{{cite journal |vauthors=Lykkesfeldt J, Tveden-Nyborg P |title=The pharmacokinetics of vitamin C |journal=Nutrients |volume=11 |issue=10 |date=October 2019 |page=2412 |pmid=31601028 |pmc=6835439 |doi=10.3390/nu11102412 |doi-access=free |url=}}</ref> Approximately 70%–90% of vitamin C is active-transport absorbed when intakes of 30–180&nbsp;mg/day from a combination of food sources and moderate-dose dietary supplements such as a multi-vitamin/mineral product are consumed. However, when large amounts are consumed, such as a vitamin C dietary supplement, the active transport system becomes saturated, and while the total amount being absorbed continues to increase with dose, absorption efficiency falls to less than 50%.<ref name=NIH2021 /> Active transport is managed by Sodium-Ascorbate Co-Transporter proteins (SVCTs) and Hexose Transporter proteins (GLUTs). [[SLC23A1|SVCT1]] and [[SLC23A2|SVCT2]] import ascorbate across plasma membranes.<ref name="Savini_2008">{{cite journal | vauthors = Savini I, Rossi A, Pierro C, Avigliano L, Catani MV | title = SVCT1 and SVCT2: key proteins for vitamin C uptake | journal = Amino Acids | volume = 34 | issue = 3 | pages = 347–55 | date = April 2008 | pmid = 17541511 | doi = 10.1007/s00726-007-0555-7 | s2cid = 312905 }}</ref> The Hexose Transporter proteins [[GLUT1]], [[GLUT3]] and [[GLUT4]] transfer only the oxydized dehydroascorbic acid (DHA) form of vitamin C.<ref name="pmid9228080">{{cite journal | vauthors = Rumsey SC, Kwon O, Xu GW, Burant CF, Simpson I, Levine M | title = Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid | journal = The Journal of Biological Chemistry | volume = 272 | issue = 30 | pages = 18982–9 | date = July 1997 | pmid = 9228080 | doi = 10.1074/jbc.272.30.18982 | doi-access = free | title-link = doi }}</ref><ref name=Linster2007 /> The amount of DHA found in plasma and tissues under normal conditions is low, as cells rapidly reduce DHA to ascorbate.<ref name="pmid12729925">{{cite journal | vauthors = May JM, Qu ZC, Neel DR, Li X | title = Recycling of vitamin C from its oxidized forms by human endothelial cells | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1640 | issue = 2–3 | pages = 153–61 | date = May 2003 | pmid = 12729925 | doi = 10.1016/S0167-4889(03)00043-0 | doi-access = | title-link = doi }}</ref>

SVCTs are the predominant system for vitamin C transport within the body.<ref name="Savini_2008" /> In both vitamin C synthesizers (example: rat) and non-synthesizers (example: human) cells maintain ascorbic acid concentrations much higher than the approximately 50 micromoles/liter (µmol/L) found in plasma. For example, the ascorbic acid content of pituitary and adrenal glands can exceed 2,000&nbsp;µmol/L, and muscle is at 200–300&nbsp;µmol/L.<ref name=Padayatty2016>{{cite journal | vauthors = Padayatty SJ, Levine M | title = Vitamin C: the known and the unknown and Goldilocks | journal = Oral Diseases | volume = 22 | issue = 6 | pages = 463–93 | date = September 2016 | pmid = 26808119 | pmc = 4959991 | doi = 10.1111/odi.12446 }}</ref> The known coenzymatic functions of ascorbic acid do not require such high concentrations, so there may be other, as yet unknown functions. A consequence of all this high concentration organ content is that plasma vitamin C is not a good indicator of whole-body status, and people may vary in the amount of time needed to show symptoms of deficiency when consuming a diet very low in vitamin C.<ref name=Padayatty2016 />

Excretion (via urine) is as ascorbic acid and metabolites. The fraction that is excreted as unmetabolized ascorbic acid increases as intake increases. In addition, ascorbic acid converts (reversibly) to DHA and from that compound non-reversibly to 2,3-diketogulonate and then oxalate. These three metabolites are also excreted via urine. During times of low dietary intake, vitamin C is reabsorbed by the kidneys rather than excreted. This salvage process delays onset of deficiency. Humans are better than guinea pigs at converting DHA back to ascorbate, and thus take much longer to become vitamin C deficient.<ref name=PKIN2020VitC/><ref name=Linster2007 />

==Synthesis==

Most animals and plants are able to synthesize vitamin C through a sequence of [[enzyme]]-driven steps, which convert [[monosaccharides]] to vitamin C. Yeasts do not make {{sm|l}}-ascorbic acid but rather its [[stereoisomer]], [[erythorbic acid]].<ref name="pmid17971855">{{cite journal | vauthors = Branduardi P, Fossati T, Sauer M, Pagani R, Mattanovich D, Porro D | title = Biosynthesis of vitamin C by yeast leads to increased stress resistance | journal = PLOS ONE | volume = 2 | issue = 10 | pages = e1092 | date = October 2007 | pmid = 17971855 | pmc = 2034532 | doi = 10.1371/journal.pone.0001092 | bibcode = 2007PLoSO...2.1092B | doi-access = free | title-link = doi }}</ref> In plants, synthesis is accomplished through the conversion of [[mannose]] or [[galactose]] to ascorbic acid.<ref name="pmid9620799">{{cite journal | vauthors = Wheeler GL, Jones MA, Smirnoff N | title = The biosynthetic pathway of vitamin C in higher plants | journal = Nature | volume = 393 | issue = 6683 | pages = 365–9 | date = May 1998 | pmid = 9620799 | doi = 10.1038/30728 | bibcode = 1998Natur.393..365W | s2cid = 4421568 }}</ref><ref name="Stone">{{cite journal | url = http://orthomolecular.org/library/jom/1972/pdf/1972-v01n02%2603-p082.pdf | title = The natural history of ascorbic acid in the evolution of the mammals and primates and is significance for present-day man evolution of mammals and primates | vauthors = Stone I | year = 1972 | journal = Journal of Orthomolecular Psychiatry | volume = 1 | issue = 2 | pages = 82–9 | access-date = December 31, 2023 | archive-date = October 2, 2023 | archive-url = https://web.archive.org/web/20231002185424/http://orthomolecular.org/library/jom/1972/pdf/1972-v01n02%2603-p082.pdf | url-status = live }}</ref> In animals, the starting material is [[glucose]]. In some species that synthesize ascorbate in the liver (including [[mammal]]s and [[Passerine|perching bird]]s), the glucose is extracted from [[glycogen]]; ascorbate synthesis is a glycogenolysis-dependent process.<ref name="pmid11458272">{{cite journal | vauthors = Bánhegyi G, Mándl J | title = The hepatic glycogenoreticular system | journal = Pathology & Oncology Research | volume = 7 | issue = 2 | pages = 107–10 | year = 2001 | pmid = 11458272 | doi = 10.1007/BF03032575 | citeseerx = 10.1.1.602.5659 | s2cid = 20139913 }}</ref> In humans and in animals that cannot synthesize vitamin C, the enzyme [[gulonolactone oxidase|{{sm|l}}-gulonolactone oxidase]] (GULO), which catalyzes the last step in the biosynthesis, is highly mutated and non-functional.<ref name="valpuesta">{{cite journal | title = Biosynthesis of L-ascorbic acid in plants: new pathways for an old antioxidant | vauthors = Valpuesta V, Botella MA | journal = Trends in Plant Science | year = 2004 | volume = 9 | issue = 12 | pages = 573–7 | pmid = 15564123 | doi = 10.1016/j.tplants.2004.10.002 | url = http://www.bmbq.uma.es/lbbv/index_archivos/pdf/Valpuesta%202004.pdf | access-date = October 8, 2018 | archive-date = December 25, 2020 | archive-url = https://web.archive.org/web/20201225062850/http://www.bmbq.uma.es/lbbv/index_archivos/pdf/Valpuesta%202004.pdf | url-status = live }}</ref><ref name="pmid1962571">{{cite journal | vauthors = Nishikimi M, Yagi K | title = Molecular basis for the deficiency in humans of gulonolactone oxidase, a key enzyme for ascorbic acid biosynthesis | journal = The Amer J Clin Nutr | volume = 54 | issue = 6 Suppl | pages = 1203S–8S | date = December 1991 | pmid = 1962571 | doi = 10.1093/ajcn/54.6.1203s| doi-access = free | title-link = doi }}</ref><ref name="pmid1400507">{{cite journal | vauthors = Nishikimi M, Kawai T, Yagi K | title = Guinea pigs possess a highly mutated gene for L-gulono-gamma-lactone oxidase, the key enzyme for L-ascorbic acid biosynthesis missing in this species | journal = The Journal of Biological Chemistry | volume = 267 | issue = 30 | pages = 21967–72 | date = October 1992 | doi = 10.1016/S0021-9258(19)36707-9 | pmid = 1400507 | doi-access = free | title-link = doi }}</ref><ref name="pmid10572964">{{cite journal | vauthors = Ohta Y, Nishikimi M | title = Random nucleotide substitutions in primate nonfunctional gene for L-gulono-gamma-lactone oxidase, the missing enzyme in L-ascorbic acid biosynthesis | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1472 | issue = 1–2 | pages = 408–11 | date = October 1999 | pmid = 10572964 | doi = 10.1016/S0304-4165(99)00123-3 }}</ref>

=== Animal synthesis ===

There is some information on serum vitamin C concentrations maintained in animal species that are able to synthesize vitamin C. One study of several breeds of dogs reported an average of 35.9&nbsp;μmol/L.<ref name="pmid11666145">{{cite journal |vauthors=Wang S, Berge GE, Sund RB |title=Plasma ascorbic acid concentrations in healthy dogs |journal=Res. Vet. Sci. |volume=71 |issue=1 |pages=33–5 |date=August 2001 |pmid=11666145 |doi=10.1053/rvsc.2001.0481 }}</ref> A report on goats, sheep and cattle reported ranges of 100–110, 265–270 and 160–350&nbsp;μmol/L, respectively.<ref name=Ranjan2012>{{cite journal |vauthors=Ranjan R, Ranjan A, Dhaliwal GS, Patra RC |s2cid=1674389 |title=l-Ascorbic acid (vitamin C) supplementation to optimize health and reproduction in cattle |journal=Vet Q |volume=32 |issue=3–4 |pages=145–50 |date=2012 |pmid=23078207 |doi=10.1080/01652176.2012.734640 }}</ref>

The biosynthesis of ascorbic acid in [[vertebrates]] starts with the formation of UDP-glucuronic acid. UDP-glucuronic acid is formed when UDP-glucose undergoes two oxidations catalyzed by the enzyme UDP-glucose 6-dehydrogenase. UDP-glucose 6-dehydrogenase uses the co-factor NAD⁺ as the electron acceptor. The transferase UDP-glucuronate pyrophosphorylase removes a [[Uridine monophosphate|UMP]] and [[glucuronokinase]], with the cofactor ADP, removes the final phosphate leading to [[glucuronic acid|{{sm|d}}-glucuronic acid]]. The aldehyde group of this compound is reduced to a primary alcohol using the enzyme [[glucuronate reductase]] and the cofactor NADPH, yielding {{sm|l}}-gulonic acid. This is followed by lactone formation{{Em dash}}utilizing the hydrolase [[gluconolactonase]]{{Em dash}}between the carbonyl on C1 and hydroxyl group on C4. {{sm|l}}-Gulonolactone then reacts with oxygen, catalyzed by the enzyme [[L-gulonolactone oxidase]] (which is nonfunctional in humans and other [[Haplorrhini]] primates; see [[Pseudogene#Unitary pseudogenes|Unitary pseudogenes]]) and the cofactor FAD+. This reaction produces 2-oxogulonolactone (2-keto-gulonolactone), which spontaneously undergoes [[enolization]] to form ascorbic acid.<ref name="Stone" /><ref name="West Sussex 2009">{{cite book | vauthors = Dewick PM | title = Medicinal natural products: a biosynthetic approach | edition = 3rd | year = 2009 | isbn = 978-0-470-74167-2 | publisher = John Wiley and Sons | page = 493}}</ref><ref name=Linster2007>{{cite journal | vauthors = Linster CL, Van Schaftingen E | title = Vitamin C. Biosynthesis, recycling and degradation in mammals | journal = The FEBS Journal | volume = 274 | issue = 1 | pages = 1–22 | date = January 2007 | pmid = 17222174 | doi = 10.1111/j.1742-4658.2006.05607.x | s2cid = 21345196 | doi-access = free | title-link = doi }}</ref> Reptiles and older orders of birds make ascorbic acid in their kidneys. Recent orders of birds and most mammals make ascorbic acid in their liver.<ref name="Stone" />

====Non-synthesizers====

Some mammals have lost the ability to synthesize vitamin C, including [[simian]]s and [[tarsier]]s, which together make up one of two major [[primate]] suborders, [[Haplorhini]]. This group includes humans. The other more primitive primates ([[Strepsirrhini]]) have the ability to make vitamin C. Synthesis does not occur in some species in the rodent family [[Caviidae]], which includes [[guinea pig]]s and [[capybara]]s, but does occur in other rodents, including [[rat]]s and [[mouse|mice]].<ref name="Miller-2014">{{cite book | vauthors = Miller RE, Fowler ME | title = Fowler's zoo and wild animal medicine, volume 8 | page = 389 | url = https://books.google.com/books?id=llBcBAAAQBAJ&q=Caviidae+%22vitamin+C%22&pg=PA389 |access-date=2 June 2016 |url-status=live |archive-url=https://web.archive.org/web/20161207032904/https://books.google.com/books?id=llBcBAAAQBAJ&pg=PA389&lpg=PA389&dq=Caviidae+%22vitamin+C%22&source=bl&ots=ofF-Bu-mx-&sig=nPEZZ68O7v26lmGS9eAGfmaUZ1o&hl=en&sa=X&ved=0ahUKEwiIk471gInNAhUT0WMKHWlpAqAQ6AEISDAH#v=onepage&q=Caviidae%20%22vitamin%20C%22&f=false |archive-date=December 7, 2016 | isbn = 978-1-4557-7399-2 |date=2014 | publisher = Elsevier Health Sciences }}</ref>

Synthesis does not occur in most bat species,<ref name="Jenness-1980">{{cite journal |doi=10.1016/0305-0491(80)90131-5 |title=Variation of l-gulonolactone oxidase activity in placental mammals |year=1980 |vauthors=Jenness R, Birney E, Ayaz K |journal=Comparative Biochemistry and Physiology B |volume=67 |issue=2 |pages=195–204 }}</ref> but there are at least two species, frugivorous bat ''[[Rousettus leschenaultii]]'' and insectivorous bat ''[[Hipposideros armiger]]'', that retain (or regained) their ability of vitamin C production.<ref name="pmid21037206">{{cite journal | vauthors = Cui J, Pan YH, Zhang Y, Jones G, Zhang S | title = Progressive pseudogenization: vitamin C synthesis and its loss in bats | journal = Molecular Biology and Evolution | volume = 28 | issue = 2 | pages = 1025–31 | date = February 2011 | pmid = 21037206 | doi = 10.1093/molbev/msq286 | doi-access = free | title-link = doi }}</ref><ref name="pmid22069493">{{cite journal | vauthors = Cui J, Yuan X, Wang L, Jones G, Zhang S | title = Recent loss of vitamin C biosynthesis ability in bats | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e27114 | date = Nov 2011 | pmid = 22069493 | pmc = 3206078 | doi = 10.1371/journal.pone.0027114 | doi-access = free | title-link = doi | bibcode = 2011PLoSO...627114C }}</ref> A number of species of passerine birds also do not synthesize, but not all of them, and those that do not are not clearly related; it has been proposed that the ability was lost separately a number of times in birds.<ref name="Martinez del Rio_1997">{{cite journal |title=Can passerines synthesize vitamin C? | vauthors = Martinez del Rio C |journal= The Auk |date=July 1997 |volume=114 |issue=3 |pages=513–6 |jstor=4089257 |doi=10.2307/4089257 | doi-access = free | title-link = doi }}</ref> In particular, the ability to synthesize vitamin C is presumed to have been lost and then later re-acquired in at least two cases.<ref name="pmid22294879">{{cite journal | vauthors = Drouin G, Godin JR, Pagé B | title = The genetics of vitamin C loss in vertebrates | journal = Current Genomics | volume = 12 | issue = 5 | pages = 371–8 | date = August 2011 | pmid = 22294879 | pmc = 3145266 | doi = 10.2174/138920211796429736 }}</ref> The ability to synthesize vitamin{{nbsp}}C has also been lost in about 96% of [[Extant taxon|extant]] fish<ref name=Berra>{{cite book | vauthors = Berra TM |title=Freshwater fish distribution |url=https://books.google.com/books?id=K-1Ygw6XwFQC&pg=PA55 |year=2008 |publisher=[[University of Chicago Press]] |isbn=978-0-226-04443-9|page=55}}</ref> (the [[teleosts]]).<ref name="pmid22294879" />

On a milligram consumed per kilogram of body weight basis, simian non-synthesizer species consume the vitamin in amounts 10 to 20 times higher than what is recommended by governments for humans.<ref name="pmid10378206">{{cite journal | vauthors = Milton K | title = Nutritional characteristics of wild primate foods: do the diets of our closest living relatives have lessons for us? | journal = Nutrition | volume = 15 | issue = 6 | pages = 488–98 | date = June 1999 | pmid = 10378206 | doi = 10.1016/S0899-9007(99)00078-7 | url = http://www.direct-ms.org/pdf/EvolutionPaleolithic/primaten.pdf | archive-url = https://web.archive.org/web/20170810090049/http://www.direct-ms.org/pdf/EvolutionPaleolithic/primaten.pdf | df = mdy-all | url-status = live | archive-date = 10 August 2017 | citeseerx = 10.1.1.564.1533}}</ref> This discrepancy constituted some of the basis of the controversy on human recommended dietary allowances being set too low.<ref name=pmid5275366 /> However, simian consumption does not indicate simian requirements. Merck's veterinary manual states that daily intake of vitamin C at 3–6&nbsp;mg/kg prevents scurvy in non-human primates.<ref name="Parrott-2022">{{cite web |url=https://www.msdvetmanual.com/exotic-and-laboratory-animals/nonhuman-primates/nutritional-diseases-of-nonhuman-primates |title=Nutritional diseases of nonhuman primates | vauthors = Parrott T |date=October 2022 |website=Merck Veterinary Manual |access-date=24 December 2023 |archive-date=December 24, 2023 |archive-url=https://web.archive.org/web/20231224173242/https://www.msdvetmanual.com/exotic-and-laboratory-animals/nonhuman-primates/nutritional-diseases-of-nonhuman-primates |url-status=live }}</ref> By way of comparison, across several countries, the recommended dietary intake for adult humans is in the range of 1–2&nbsp;mg/kg.

====Evolution of animal synthesis====

Ascorbic acid is a common enzymatic [[cofactor (biochemistry)|cofactor]] in mammals used in the synthesis of [[collagen]], as well as a powerful [[reducing agent]] capable of rapidly scavenging a number of [[reactive oxygen species]] (ROS). Given that ascorbate has these important functions, it is surprising that the ability to synthesize this molecule has not always been conserved. In fact, anthropoid primates, ''[[Guinea pig|Cavia porcellus]]'' (guinea pigs), [[teleost]] fishes, most bats, and some [[passerine]] birds have all independently lost the ability to internally synthesize vitamin C in either the kidney or the liver.<ref name="pmid21140195">{{cite journal | vauthors = Lachapelle MY, Drouin G | title = Inactivation dates of the human and guinea pig vitamin C genes | journal = Genetica | volume = 139 | issue = 2 | pages = 199–207 | date = February 2011 | pmid = 21140195 | doi = 10.1007/s10709-010-9537-x | s2cid = 7747147 }}</ref><ref name="pmid22294879"/> In all of the cases where genomic analysis was done on an ascorbic acid [[Auxotrophy|auxotroph]], the origin of the change was found to be a result of loss-of-function mutations in the gene that encodes <small>L</small>-gulono-γ-lactone oxidase, the enzyme that catalyzes the last step of the ascorbic acid pathway outlined above.<ref name="pmid23404229">{{cite journal | vauthors = Yang H | s2cid = 14393449 | title = Conserved or lost: molecular evolution of the key gene GULO in vertebrate vitamin C biosynthesis | journal = Biochemical Genetics | volume = 51 | issue = 5–6 | pages = 413–25 | date = June 2013 | pmid = 23404229 | doi = 10.1007/s10528-013-9574-0 }}</ref> One explanation for the repeated loss of the ability to synthesize vitamin C is that it was the result of [[genetic drift]]; assuming that the diet was rich in vitamin{{nbsp}}C, natural selection would not act to preserve it.<ref name="pmid20210993">{{cite journal | vauthors = Zhang ZD, Frankish A, Hunt T, Harrow J, Gerstein M | title = Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates | journal = Genome Biology | volume = 11 | issue = 3 | pages = R26 | date = 2010 | pmid = 20210993 | pmc = 2864566 | doi = 10.1186/gb-2010-11-3-r26 | doi-access = free | title-link = doi }}</ref><ref name="pmid3338984">{{cite journal | vauthors = Koshizaka T, Nishikimi M, Ozawa T, Yagi K | title = Isolation and sequence analysis of a complementary DNA encoding rat liver L-gulono-gamma-lactone oxidase, a key enzyme for L-ascorbic acid biosynthesis | journal = The Journal of Biological Chemistry | volume = 263 | issue = 4 | pages = 1619–21 | date = February 1988 | doi = 10.1016/S0021-9258(19)77923-X | pmid = 3338984 | doi-access = free | title-link = doi }}</ref>

In the case of the simians, it is thought that the loss of the ability to make vitamin C may have occurred much farther back in evolutionary history than the emergence of humans or even apes, since it evidently occurred soon after the appearance of the first primates, yet sometime after the split of early primates into the two major suborders [[Haplorrhini]] (which cannot make vitamin C) and its sister suborder of non-tarsier prosimians, the [[Strepsirrhini]] ("wet-nosed" primates), which retained the ability to make vitamin C.<ref name="pmid3113259">{{cite journal | vauthors = Pollock JI, Mullin RJ | title = Vitamin C biosynthesis in prosimians: evidence for the anthropoid affinity of Tarsius | journal = American Journal of Physical Anthropology | volume = 73 | issue = 1 | pages = 65–70 | date=1987 | pmid = 3113259 | doi = 10.1002/ajpa.1330730106 }}</ref> According to molecular clock dating, these two suborder primate branches parted ways about 63 to 60 million years ago.<ref name="pmid15085543">{{cite journal | vauthors = Poux C, Douzery EJ | title = Primate phylogeny, evolutionary rate variations, and divergence times: a contribution from the nuclear gene IRBP | journal = American Journal of Physical Anthropology | volume = 124 | issue = 1 | pages = 01–16 | date=2004 | pmid = 15085543 | doi = 10.1002/ajpa.10322 }}</ref> Approximately three to five million years later (58 million years ago), only a short time afterward from an evolutionary perspective, the infraorder [[Tarsiiformes]], whose only remaining family is that of the tarsier ([[Tarsiidae]]), branched off from the other haplorrhines.<ref name="pmid9668008">{{cite journal | vauthors = Goodman M, Porter CA, Czelusniak J, Page SL, Schneider H, Shoshani J, Gunnell G, Groves CP | title = Toward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence | journal = Molecular Phylogenetics and Evolution | volume = 9 | issue = 3 | pages = 585–98 | date=June 1998 | pmid = 9668008 | doi = 10.1006/mpev.1998.0495 | s2cid = 23525774 }}</ref><ref name="Porter_1997">{{cite journal |vauthors=Porter CA, Page SL, Czelusniak J, Schneider H, Schneider MP, Sampaio I, Goodman M |s2cid=1851788 |title=Phylogeny and evolution of selected primates as determined by sequences of the ε-globin locus and 5′ flanking regions |journal=Int J Primatology |date= April 1997 |volume=18 |issue=2 |pages=261–95 |doi=10.1023/A:1026328804319 |hdl=2027.42/44561 |hdl-access=free }}</ref> Since tarsiers also cannot make vitamin C, this implies the mutation had already occurred, and thus must have occurred between these two marker points (63 to 58 million years ago).<ref name="pmid3113259" />

It has also been noted that the loss of the ability to synthesize ascorbate strikingly parallels the inability to break down [[uric acid]], also a characteristic of primates. Uric acid and ascorbate are both strong [[reducing agent]]s. This has led to the suggestion that, in higher primates, uric acid has taken over some of the functions of ascorbate.<ref name="pmid5477017">{{cite journal | vauthors = Proctor P | s2cid = 4146946 | title = Similar functions of uric acid and ascorbate in man? | journal = Nature | volume = 228 | issue = 5274 | pages = 868 | date = 1970 | pmid = 5477017 | doi = 10.1038/228868a0 | bibcode = 1970Natur.228..868P | doi-access = free | title-link = doi }}</ref>

=== Plant synthesis ===

[[File:Vitamin C Biosynthesis in Plants.svg|thumb|upright=1.75|Vitamin C biosynthesis in plants]]

There are many different biosynthesis pathways to ascorbic acid in plants. Most proceed through products of [[glycolysis]] and other [[metabolic pathway]]s. For example, one pathway utilizes plant [[cell wall]] polymers.<ref name="valpuesta"/> The principal plant ascorbic acid biosynthesis pathway seems to be via {{sm|l}}-galactose. The enzyme [[L-galactose 1-dehydrogenase|{{sm|l}}-galactose dehydrogenase]] catalyzes the overall [[Organic redox reaction|oxidation]] to the [[lactone]] and isomerization of the lactone to the C4-hydroxyl group, resulting in {{sm|l}}-galactono-1,4-lactone.<ref name="West Sussex 2009"/> {{sm|l}}-Galactono-1,4-lactone then reacts with the mitochondrial flavoenzyme [[Galactonolactone dehydrogenase|{{sm|l}}-galactonolactone dehydrogenase]]<ref name="pmid18190525">{{cite journal | vauthors = Leferink NG, van den Berg WA, van Berkel WJ | title = l-Galactono-gamma-lactone dehydrogenase from Arabidopsis thaliana, a flavoprotein involved in vitamin C biosynthesis | journal = The FEBS Journal | volume = 275 | issue = 4 | pages = 713–26 | date = February 2008 | pmid = 18190525 | doi = 10.1111/j.1742-4658.2007.06233.x | s2cid = 25096297 | doi-access = free | title-link = doi }}</ref> to produce ascorbic acid.<ref name="West Sussex 2009"/> {{sm|l}}-Ascorbic acid has a negative feedback on {{sm|l}}-galactose dehydrogenase in spinach.<ref name="pmid15509850">{{cite journal | vauthors = Mieda T, Yabuta Y, Rapolu M, Motoki T, Takeda T, Yoshimura K, Ishikawa T, Shigeoka S | title = Feedback inhibition of spinach L-galactose dehydrogenase by L-ascorbate | journal = Plant & Cell Physiology | volume = 45 | issue = 9 | pages = 1271–9 | date = September 2004 | pmid = 15509850 | doi = 10.1093/pcp/pch152 | doi-access = free | title-link = doi }}</ref> Ascorbic acid efflux by embryos of dicot plants is a well-established mechanism of iron reduction and a step obligatory for iron uptake.{{efn| Dicot plants transport only [[ferrous iron]] (Fe²⁺), but if the iron circulates as [[ferric]] complexes (Fe³⁺), it has to undergo a reduction before it can be actively transported. Plant embryos efflux high amounts of ascorbate that chemically reduce iron(III) from ferric complexes.<ref name="pmid24347170">{{cite journal | vauthors = Grillet L, Ouerdane L, Flis P, Hoang MT, Isaure MP, Lobinski R, Curie C, Mari S | title = Ascorbate efflux as a new strategy for iron reduction and transport in plants | journal = The Journal of Biological Chemistry | volume = 289 | issue = 5 | pages = 2515–25 | date = January 2014 | pmid = 24347170 | pmc = 3908387 | doi = 10.1074/jbc.M113.514828 | doi-access = free | title-link = doi }}</ref>}}

All plants synthesize ascorbic acid. Ascorbic acid functions as a cofactor for enzymes involved in photosynthesis, synthesis of plant hormones, as an antioxidant and regenerator of other antioxidants.<ref name=Gallie2013>{{cite journal | vauthors = Gallie DR | title = L-ascorbic acid: a multifunctional molecule supporting plant growth and development | journal = Scientifica | volume = 2013 | pages = 1–24 | year = 2013 | pmid = 24278786 | pmc = 3820358 | doi = 10.1155/2013/795964 | doi-access = free | title-link = doi }}</ref> Plants use multiple pathways to synthesize vitamin C. The major pathway starts with glucose, [[fructose]] or [[mannose]] (all simple sugars) and proceeds to {{sm|l}}-[[galactose]], {{sm|l}}-galactonolactone and ascorbic acid.<ref name=Gallie2013 /><ref name=Mellidou2017 /> This biosynthesis is regulated following a [[diurnal rhythm]].<ref name="Mellidou2017" /> Enzyme expression peaks in the morning to supporting biosynthesis for when mid-day sunlight intensity demands high ascorbic acid concentrations.<ref name=Mellidou2017>{{cite journal | vauthors = Mellidou I, Kanellis AK | title = Genetic control of ascorbic acid biosynthesis and recycling in horticultural crops | journal = Frontiers in Chemistry | volume = 5 | pages = 50 | year = 2017 | pmid = 28744455 | pmc = 5504230 | doi = 10.3389/fchem.2017.00050 | bibcode = 2017FrCh....5...50M | doi-access = free | title-link = doi }}</ref><ref name="pmid27179323">{{cite journal | vauthors = Bulley S, Laing W | title = The regulation of ascorbate biosynthesis | journal = Current Opinion in Plant Biology | volume = 33 | pages = 15–22 | date = October 2016 | pmid = 27179323 | doi = 10.1016/j.pbi.2016.04.010 | series = SI: 33: Cell signalling and gene regulation 2016 | bibcode = 2016COPB...33...15B }}</ref> Minor pathways may be specific to certain parts of plants; these can be either identical to the vertebrate pathway (including the GLO enzyme), or start with inositol and get to ascorbic acid via {{sm|l}}-galactonic acid to {{sm|l}}-galactonolactone.<ref name=Gallie2013 />

===Industrial synthesis===

{{Main|Chemistry of ascorbic acid}}

Vitamin C can be produced from [[glucose]] by two main routes. The no longer utilized [[Reichstein process]], developed in the 1930s, used a single fermentation followed by a purely chemical route. The modern two-step [[fermentation (biochemistry)|fermentation]] process, originally developed in [[China]] in the 1960s, uses additional fermentation to replace part of the later chemical stages. The Reichstein process and the modern two-step fermentation processes both use [[glucose]] as the starting material, convert that to [[sorbitol]], and then to [[sorbose]] using fermentation.<ref name="pmid23208776">{{cite journal | vauthors = Eggersdorfer M, Laudert D, Létinois U, McClymont T, Medlock J, Netscher T, Bonrath W | title = One hundred years of vitamins-a success story of the natural sciences | journal = Angewandte Chemie | volume = 51 | issue = 52 | pages = 12960–12990 | date = December 2012 | pmid = 23208776 | doi = 10.1002/anie.201205886 }}</ref> The two-step fermentation process then converts sorbose to 2-keto-l-gulonic acid (KGA) through another fermentation step, avoiding an extra intermediate. Both processes yield approximately 60% vitamin C from the glucose starting point.<ref name="Competition Commission-2001">{{cite web |url=http://www.competition-commission.org.uk/rep_pub/reports/2001/fulltext/456a4.2.pdf |archive-url=http://webarchive.nationalarchives.gov.uk/20120119194657/http://www.competition-commission.org.uk/rep_pub/reports/2001/fulltext/456a4.2.pdf |url-status=dead |archive-date=January 19, 2012 |title=The production of vitamin C |access-date=February 20, 2007 |year=2001 |publisher=Competition Commission }}</ref> Researchers are exploring means for one-step fermentation.<ref name="pmid33717042">{{cite journal |vauthors=Zhou M, Bi Y, Ding M, Yuan Y |title=One-step biosynthesis of vitamin C in Saccharomyces cerevisiae |journal=Front Microbiol |volume=12 |issue= |pages=643472 |date=2021 |pmid=33717042 |pmc=7947327 |doi=10.3389/fmicb.2021.643472 |url= | doi-access = free | title-link = doi }}</ref><ref name="pmid35996146">{{cite journal |vauthors=Tian YS, Deng YD, Zhang WH, Yu-Wang, Xu J, Gao JJ, Bo-Wang, Fu XY, Han HJ, Li ZJ, Wang LJ, Peng RH, Yao QH |title=Metabolic engineering of Escherichia coli for direct production of vitamin C from D-glucose |journal=Biotechnol Biofuels Bioprod |volume=15 |issue=1 |pages=86 |date=August 2022 |pmid=35996146 |pmc=9396866 |doi=10.1186/s13068-022-02184-0 |url= | doi-access = free | title-link = doi }}</ref>

China produces about 70% of the global vitamin C market. The rest is split among European Union, India and North America. The global market is expected to exceed 141 thousand metric tons in 2024.<ref name="Vantage market research-2022">{{cite press release |url=https://www.globenewswire.com/en/news-release/2022/11/08/2550571/0/en/Global-Vitamin-C-Market-Size-Share-to-Surpass-1-8-Bn-by-2028-China-Produces-80-of-Commercial-Vitamin-C-Vantage-Market-Research.html |title=Vantage market research: global vitamin C market size & share to surpass $1.8 Bn by 2028 |date=November 8, 2022 |website=Globe Newswire |access-date=December 21, 2023 |archive-date=December 21, 2023 |archive-url=https://web.archive.org/web/20231221215223/https://www.globenewswire.com/en/news-release/2022/11/08/2550571/0/en/Global-Vitamin-C-Market-Size-Share-to-Surpass-1-8-Bn-by-2028-China-Produces-80-of-Commercial-Vitamin-C-Vantage-Market-Research.html |url-status=live }}</ref> Cost per metric ton (1000&nbsp;kg) in US dollars was $2,220 in Shanghai, $2,850 in Hamburg and $3,490 in the US.<ref name="ChemAnalyst-2023">{{cite web |url=https://www.chemanalyst.com/Pricing-data/vitamin-c-1258 |title=Vitamin C price trend and forecast |date=September 2023 |website=ChemAnalyst |access-date=December 21, 2023 |archive-date=December 21, 2023 |archive-url=https://web.archive.org/web/20231221215224/https://www.chemanalyst.com/Pricing-data/vitamin-c-1258 |url-status=live }}</ref>

==Medical uses==

[[File:VitaminSupplementPills2.jpg|thumb|alt=Rows and rows of dietary supplement bottles on shelves |Vitamin C supplements among other dietary supplements at a US drug store]]

Vitamin C has a definitive role in treating scurvy, which is a disease caused by vitamin{{nbsp}}C deficiency. Beyond that, a role for vitamin{{nbsp}}C as prevention or treatment for various diseases is disputed, with reviews often reporting conflicting results. No effect of vitamin{{nbsp}}C supplementation reported for overall mortality.<ref name="pmid22419320">{{cite journal | vauthors = Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C | title = Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 3 | pages = CD007176 | date = March 2012 | pmid = 22419320 | doi = 10.1002/14651858.CD007176.pub2 | pmc = 8407395 | hdl = 10138/136201 | hdl-access = free }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]] and on the World Health Organization's Model Forumulary.<ref name = "WHO Formulary 2008">{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 978-92-4-154765-9 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free }}</ref> In 2021, it was the 255th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref name="ClinCalc-2024">{{cite web | title = Ascorbic acid - drug usage statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/AscorbicAcid | access-date = January 14, 2024 | archive-date = January 18, 2024 | archive-url = https://web.archive.org/web/20240118044033/https://clincalc.com/DrugStats/Drugs/AscorbicAcid | url-status = live }}</ref>

===Scurvy===

{{Main|Scurvy}}

[[Scurvy]] is a disease resulting from a deficiency of vitamin C. Without this vitamin, [[collagen]] made by the body is too unstable to perform its function and several other [[enzyme]]s in the body do not operate correctly. Early symptoms are malaise and lethargy, progressing to shortness of breath, bone pain and susceptibility to bruising. As the disease progressed, it is characterized by [[Hyperkeratosis|spots]] on and [[Ecchymosis|bleeding]] under the skin and bleeding gums. The skin lesions are most abundant on the thighs and legs. A person with the ailment looks pale, feels depressed, and is partially immobilized. In advanced scurvy there is fever, old wounds may become open and [[suppuration|suppurating]], loss of [[Tooth|teeth]], convulsions and, eventually, death. Until quite late in the disease the damage is reversible, as healthy collagen replaces the defective collagen with vitamin{{nbsp}}C repletion.<ref name=lpi2018 /><ref name=AHFS2016 /><ref name="pmid21402244">{{cite journal | vauthors = Magiorkinis E, Beloukas A, Diamantis A | title = Scurvy: past, present and future. | journal = The European Journal of Internal Medicine | volume = 22 | issue = 2 | pages = 147–52 | date = April 2011 | pmid = 21402244 | doi = 10.1016/j.ejim.2010.10.006}}</ref>

Notable human dietary studies of experimentally induced scurvy were conducted on [[conscientious objector]]s during World War II in Britain and on Iowa state prisoners in the late 1960s to the 1980s. Men in the prison study developed the first signs of scurvy about four weeks after starting the vitamin C-free diet, whereas in the earlier British study, six to eight months were required, possibly due to the pre-loading of this group with a 70&nbsp;mg/day supplement for six weeks before the scorbutic diet was fed. Men in both studies had blood levels of ascorbic acid too low to be accurately measured by the time they developed signs of scurvy. These studies both reported that all obvious symptoms of scurvy could be completely reversed by supplementation of only 10&nbsp;mg a day.<ref name="pmid4977512">{{cite journal | vauthors = Hodges RE, Baker EM, Hood J, Sauberlich HE, March SC | title = Experimental scurvy in man | journal = The American Journal of Clinical Nutrition | volume = 22 | issue = 5 | pages = 535–48 | date = May 1969 | pmid = 4977512 | doi = 10.1093/ajcn/22.5.535}}</ref><ref name="pmid16510534">{{cite journal | vauthors = Pemberton J | title = Medical experiments carried out in Sheffield on conscientious objectors to military service during the 1939-45 war | journal = International Journal of Epidemiology | volume = 35 | issue = 3 | pages = 556–8 | date = June 2006 | pmid = 16510534 | doi = 10.1093/ije/dyl020 | doi-access = free | title-link = doi }}</ref> Treatment of scurvy can be with vitamin{{nbsp}}C-containing foods or dietary supplements or injection.<ref name=AHFS2016/><ref name="DRItext" />{{rp|page=101}}

===Sepsis===

People in [[sepsis]] may have micronutrient deficiencies, including low levels of vitamin C.<ref name="pmid29984680">{{cite journal | vauthors = Belsky JB, Wira CR, Jacob V, Sather JE, Lee PJ | title = A review of micronutrients in sepsis: the role of thiamine, L-carnitine, vitamin C, selenium and vitamin D | journal = Nutrition Research Reviews | volume = 31 | issue = 2 | pages = 281–90 | date = December 2018 | pmid = 29984680 | doi = 10.1017/S0954422418000124 | s2cid = 51599526 }}</ref> An intake of 3.0 g/day, which requires intravenous administration, appears to be needed to maintain normal plasma concentrations in people with sepsis or severe burn injury.<ref name=Liang2023/><ref name="pmid25635594">{{cite journal |vauthors=Berger MM, Oudemans-van Straaten HM |title=Vitamin C supplementation in the critically ill patient |journal=Curr Opin Clin Nutr Metab Care |volume=18 |issue=2 |pages=193–201 |date=March 2015 |pmid=25635594 |doi=10.1097/MCO.0000000000000148 |s2cid=37895257 |url=}}</ref> Sepsis mortality is reduced with administration of intravenous vitamin C.<ref name="pmid37111066">{{cite journal |vauthors=Xu C, Yi T, Tan S, Xu H, Hu Y, Ma J, Xu J |title=Association of oral or intravenous vitamin C supplementation with mortality: A systematic review and meta-analysis |journal=Nutrients |volume=15 |issue=8 |date=April 2023 |page=1848 |pmid=37111066 |pmc=10146309 |doi=10.3390/nu15081848 |doi-access=free |url=}}</ref><ref name="pmid37599680">{{cite journal |vauthors=Liang H, Mu Q, Sun W, Liu L, Qiu S, Xu Z, Cui Y, Yan Y, Sun T |title=Effect of intravenous vitamin C on adult septic patients: a systematic review and meta-analysis |journal=Front Nutr |volume=10 |issue= |pages=1211194 |date=2023 |pmid=37599680 |pmc=10437115 |doi=10.3389/fnut.2023.1211194 |doi-access=free |url=}}</ref>

===Common cold===

[[File:Linus Pauling.jpg|alt=1955 black-and-white photo of Nobel Prize winner, Linus Pauling.|thumb|upright|The Nobel Prize winner [[Linus Pauling]] advocated taking vitamin C for the [[common cold]] in [[Vitamin C and the Common Cold (book)|a 1970 book]].]]

Research on vitamin{{nbsp}}C in the common cold has been divided into effects on prevention, duration, and severity. Oral intakes of more than 200&nbsp;mg/day taken on a regular basis was not effective in prevention of the common cold. Restricting analysis to trials that used at least 1000&nbsp;mg/day also saw no prevention benefit. However, taking a vitamin{{nbsp}}C supplement on a regular basis did reduce the average duration of the illness by 8% in adults and 14% in children, and also reduced the severity of colds.<ref name=Hem2013>{{cite journal |vauthors = Hemilä H, Chalker E |title = Vitamin C for preventing and treating the common cold |journal = The Cochrane Database of Systematic Reviews |issue = 1 |pages = CD000980 |date = January 2013 |volume = 2013 |pmid = 23440782 |doi = 10.1002/14651858.CD000980.pub4 |pmc = 1160577}}</ref> Vitamin C taken on a regular basis reduced the duration of severe symptoms but had no effect on the duration of mild symptoms.<ref name=Hem2023>{{cite journal |vauthors=Hemilä H, Chalker E |title=Vitamin C reduces the severity of common colds: a meta-analysis |journal=BMC Public Health |volume=23 |issue=1 |pages=2468 |date=December 2023 |pmid=38082300 |pmc=10712193 |doi=10.1186/s12889-023-17229-8 |url= | doi-access = free | title-link = doi }}</ref> Therapeutic use, meaning that the vitamin was not started unless people started to feel the beginnings of a cold, had no effect on the duration or severity of the illness.<ref name="Hem2013" />

Vitamin C distributes readily in high concentrations into [[immune system|immune cells]], promotes [[natural killer cell]] activities, promotes [[lymphocyte]] proliferation, and is depleted quickly during infections, effects suggesting a prominent role in immune system function.<ref name="Wintergerst-2006">{{cite journal | vauthors = Wintergerst ES, Maggini S, Hornig DH | s2cid = 21756498 | title = Immune-enhancing role of vitamin C and zinc and effect on clinical conditions | journal = Annals of Nutrition & Metabolism | volume = 50 | issue = 2 | pages = 85–94 | year = 2006 | pmid = 16373990 | doi = 10.1159/000090495 | url = http://doc.rero.ch/record/303675/files/S0029665108006927.pdf | access-date = August 25, 2019 | archive-date = July 22, 2018 | archive-url = https://web.archive.org/web/20180722160530/http://doc.rero.ch/record/303675/files/S0029665108006927.pdf | url-status = live }}</ref> The [[European Food Safety Authority]] concluded there is a [[causality|cause and effect relationship]] between the dietary intake of vitamin C and functioning of a normal immune system in adults and in children under three years of age.<ref name="efsa09">{{cite journal |author=EFSA Panel on Dietetic Products, Nutrition and Allergies |title=Scientific Opinion on the substantiation of health claims related to vitamin C and protection of DNA, proteins and lipids from oxidative damage (ID 129, 138, 143, 148), antioxidant function of lutein (ID 146), maintenance of vision (ID 141, 142), collagen formation (ID 130, 131, 136, 137, 149), function of the nervous system (ID 133), function of the immune system (ID 134), function of the immune system during and after extreme physical exercise (ID 144), non-haem iron absorption (ID 132, 147), energy-yielding metabolism (ID 135), and relief in case of irritation in the upper respiratory tract (ID 1714, 1715) pursuant to Article 13(1) of Regulation (EC) No 1924/2006 |journal=EFSA Journal |volume=7 |issue=9 |year=2009 |page=1226 |doi=10.2903/j.efsa.2009.1226| doi-access = free | title-link = doi }}</ref><ref name="efsa15">{{cite journal |author=EFSA Panel on Dietetic Products, Nutrition and Allergies |title=Vitamin C and contribution to the normal function of the immune system: evaluation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006 |journal=EFSA Journal |year=2015 |volume=13 |issue=11 |page=4298 |doi=10.2903/j.efsa.2015.4298| doi-access = free | title-link = doi |hdl=11380/1296052 |hdl-access=free }}</ref>

===COVID-19===

{{see also|COVID-19 drug repurposing research#Vitamin C|COVID-19 misinformation#Vitamin C}}

During March through July 2020, vitamin C was the subject of more US FDA warning letters than any other ingredient for claims for prevention and/or treatment of COVID-19.<ref name="pmid33001378">{{cite journal |vauthors=Bramstedt KA |title=Unicorn poo and blessed waters: COVID-19 quackery and FDA Warning Letters |journal=Ther Innov Regul Sci |date=October 2020 |volume=55 |issue=1 |pages=239–44 |pmid=33001378 |pmc=7528445 |doi=10.1007/s43441-020-00224-1 }}</ref> In April 2021, the US [[National Institutes of Health]] (NIH) COVID-19 Treatment Guidelines stated that "there are insufficient data to recommend either for or against the use of vitamin{{nbsp}}C for the prevention or treatment of COVID-19."<ref name="COVID-19 Treatment Guidelines-2021">{{cite web |title=Vitamin C |url=https://www.covid19treatmentguidelines.nih.gov/therapies/supplements/vitamin-c/ |website=COVID-19 Treatment Guidelines |date=April 21, 2021 |access-date=January 2, 2022 |archive-date=November 20, 2021 |archive-url=https://web.archive.org/web/20211120131306/https://www.covid19treatmentguidelines.nih.gov/therapies/supplements/vitamin-c/ |url-status=live }}</ref> In an update posted December 2022, the NIH position was unchanged:

* There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of vitamin C for the treatment of COVID-19 in nonhospitalized patients.

* There is insufficient evidence for the Panel to recommend either for or against the use of vitamin C for the treatment of COVID-19 in hospitalized patients.<ref name="U.S. National Institutes of Health-2022">{{cite web |url=https://www.covid19treatmentguidelines.nih.gov/therapies/supplements/vitamin-c/ |title=COVID-19 treatment guidelines |date=December 26, 2022 |website=U.S. National Institutes of Health |access-date=December 18, 2023 |archive-date=November 20, 2021 |archive-url=https://web.archive.org/web/20211120131306/https://www.covid19treatmentguidelines.nih.gov/therapies/supplements/vitamin-c/ |url-status=live }}</ref>

For people hospitalized with severe COVID-19 there are reports of a significant reduction in the risk of all-cause, in-hospital mortality with the administration of vitamin C relative to no vitamin C. There were no significant differences in ventilation incidence, hospitalization duration or length of intensive care unit stay between the two groups. The majority of the trials incorporated into these meta-analyses used intravenous administration of the vitamin.<ref name=Kow2023>{{cite journal |vauthors=Kow CS, Hasan SS, Ramachandram DS |title=The effect of vitamin C on the risk of mortality in patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials | journal=Inflammopharmacology |volume=31 |issue=6 |pages=3357–62 |date=December 2023 |pmid= 37071316|pmc=10111321 |doi=10.1007/s10787-023-01200-5 |url=}}</ref><ref name=Huang2022>{{cite journal |vauthors=Huang WY, Hong J, Ahn SI, Han BK, Kim YJ |title=Association of vitamin C treatment with clinical outcomes for COVID-19 patients: A systematic review and meta-analysis |journal=Healthcare |volume=10 |issue=12 |date=December 2022 |page=2456 |pmid=36553979 |pmc=9777834 |doi=10.3390/healthcare10122456 |url= | doi-access = free | title-link = doi }}</ref><ref name=Olczak2022>{{cite journal |vauthors=Olczak-Pruc M, Swieczkowski D, Ladny JR, Pruc M, Juarez-Vela R, Rafique Z, Peacock FW, Szarpak L |title=Vitamin C supplementation for the treatment of COVID-19: A systematic review and meta-analysis |journal=Nutrients |volume=14 |issue=19 |date=October 2022 |page=4217 |pmid=36235869 |pmc=9570769 |doi=10.3390/nu14194217 |url= | doi-access = free | title-link = doi }}</ref> Acute kidney injury was lower in people treated with vitamin C treatment. There were no differences in the frequency of other adverse events due to the vitamin.<ref name=Olczak2022 /> The conclusion was that further large-scale studies are needed to affirm its mortality benefits before issuing updated guidelines and recommendations.<ref name=Kow2023 /><ref name=Huang2022 /><ref name=Olczak2022 />

===Cancer===

There is no evidence that vitamin C supplementation reduces the risk of lung cancer in healthy people or those at high risk due to smoking or asbestos exposure.<ref name="pmid32130738">{{cite journal | vauthors = Cortés-Jofré M, Rueda JR, Asenjo-Lobos C, Madrid E, Bonfill Cosp X | title = Drugs for preventing lung cancer in healthy people | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | pages = CD002141 | date = March 2020 | issue = 3 | pmid = 32130738 | pmc = 7059884 | doi = 10.1002/14651858.CD002141.pub3 }}</ref> It has no effect on the risk of prostate cancer,<ref name="Stratton J, Godwin M 243–52">{{cite journal | vauthors = Stratton J, Godwin M | title = The effect of supplemental vitamins and minerals on the development of prostate cancer: a systematic review and meta-analysis | journal = Family Practice | volume = 28 | issue = 3 | pages = 243–52 | date = June 2011 | pmid = 21273283 | doi = 10.1093/fampra/cmq115 | doi-access = free | title-link = doi }}</ref> and there is no good evidence vitamic C supplementation affects the risk of [[colorectal cancer]]<ref name="pmid25335850">{{cite journal |vauthors=Heine-Bröring RC, Winkels RM, Renkema JM, Kragt L, van Orten-Luiten AC, Tigchelaar EF, Chan DS, Norat T, Kampman E |title=Dietary supplement use and colorectal cancer risk: a systematic review and meta-analyses of prospective cohort studies |journal=Int J Cancer |volume=136 |issue=10 |pages=2388–401 |date=May 2015 |pmid=25335850 |doi=10.1002/ijc.29277 |s2cid=44706004 |url=}}</ref> or breast cancer.<ref name="pmid21761132">{{cite journal | vauthors = Fulan H, Changxing J, Baina WY, Wencui Z, Chunqing L, Fan W, Dandan L, Dianjun S, Tong W, Da P, Yashuang Z | title = Retinol, vitamins A, C, and E and breast cancer risk: a meta-analysis and meta-regression | journal = Cancer Causes & Control | volume = 22 | issue = 10 | pages = 1383–96 | date = October 2011 | pmid = 21761132 | doi = 10.1007/s10552-011-9811-y | s2cid = 24867472 }}</ref>

===Cardiovascular disease===

There is no evidence that vitamin C supplementation decreases the risk cardiovascular disease,<ref name="pmid28301692">{{cite journal | vauthors = Al-Khudairy L, Flowers N, Wheelhouse R, Ghannam O, Hartley L, Stranges S, Eres K | title = Vitamin C supplementation for the primary prevention of cardiovascular disease | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD011114 | date = March 2017 | issue = 3 | pmid = 28301692 | doi = 10.1002/14651858.CD011114.pub2 | pmc = 6464316 }}</ref> although there may be an association between higher circulating vitamin C levels or dietary vitamin C and a lower risk of stroke.<ref name="pmid24284213">{{cite journal | vauthors = Chen GC, Lu DB, Pang Z, Liu QF | title = Vitamin C intake, circulating vitamin C and risk of stroke: a meta-analysis of prospective studies | journal = J Amer Heart Assoc | volume = 2 | issue = 6 | pages = e000329 | date = November 2013 | pmid = 24284213 | pmc = 3886767 | doi = 10.1161/JAHA.113.000329 }}</ref> There is a positive effect of vitamin C on [[endothelial dysfunction]] when taken at doses greater than 500&nbsp;mg per day. (The endothelium is a layer of cells that line the interior surface of blood vessels.)<ref name="pmid24792921">{{cite journal | vauthors = Ashor AW, Lara J, Mathers JC, Siervo M | title = Effect of vitamin C on endothelial function in health and disease: a systematic review and meta-analysis of randomized controlled trials | journal = Atherosclerosis | volume = 235 | issue = 1 | pages = 9–20 | date = July 2014 | pmid = 24792921 | doi = 10.1016/j.atherosclerosis.2014.04.004 }}</ref>

===Blood pressure===

Serum vitamin C was reported to be 15.13 μmol/L lower in people with [[hypertension]] compared to normotensives. The vitamin was inversely associated with both [[systolic blood pressure]] (SBP) and [[diastolic blood pressure]] (DBP).<ref name="pmid32426036">{{cite journal |vauthors=Ran L, Zhao W, Tan X, Wang H, Mizuno K, Takagi K, Zhao Y, Bu H |title=Association between serum vitamin C and the blood pressure: A systematic review and meta-analysis of observational studies |journal=Cardiovasc Ther |volume=2020 |issue= |pages=4940673 |date=April 2020 |pmid=32426036 |pmc=7211237 |doi=10.1155/2020/4940673 |url= | doi-access = free | title-link = doi }}</ref> Oral supplementation of the vitamin resulted in a very modest but statistically significant decrease in SBP in people with hypertension.<ref name=Guan2020>{{cite journal |vauthors=Guan Y, Dai P, Wang H |title=Effects of vitamin C supplementation on essential hypertension: A systematic review and meta-analysis |journal=Medicine (Baltimore) |volume=99 |issue=8 |pages=e19274 |date=February 2020 |pmid=32080138 |pmc=7034722 |doi=10.1097/MD.0000000000019274 |url=}}</ref><ref name=Llban2023>{{cite journal |vauthors=Lbban E, Kwon K, Ashor A, Stephan B, Idris I, Tsintzas K, Siervo M |title=Vitamin C supplementation showed greater effects on systolic blood pressure in hypertensive and diabetic patients: an updated systematic review and meta-analysis of randomized clinical trials |journal=Int J Food Sci Nutr |volume=74 |issue=8 |pages=814–25 |date=December 2023 |pmid=37791386 |doi=10.1080/09637486.2023.2264549 |s2cid=263621742 |url=https://figshare.com/articles/journal_contribution/24241426 |access-date=December 23, 2023 |archive-date=January 21, 2024 |archive-url=https://web.archive.org/web/20240121044305/https://figshare.com/articles/journal_contribution/Vitamin_C_supplementation_showed_greater_effects_on_systolic_blood_pressure_in_hypertensive_and_diabetic_patients_an_updated_systematic_review_and_meta-analysis_of_randomised_clinical_trials/24241426 |url-status=live }}</ref> The proposed explanation is that vitamin C increases intracellular concentrations of [[tetrahydrobiopterin]], an endothelial [[nitric oxide synthase]] cofactor that promotes the production of [[nitric oxide]], which is a potent vasodilator. Vitamin C supplementation might also reverse the nitric oxide synthase inhibitor [[NG-monomethyl-L-arginine|NG-monomethyl-L-arginine 1]], and there is also evidence cited that vitamin C directly enhances the biological activity of nitric oxide, a vasodilator.<ref name=Guan2020 />

===Type 2 diabetes===

There are contradictory reviews. From one, vitamin C supplementation cannot be recommended for management of [[type 2 diabetes]].<ref name="mason">{{cite journal |vauthors=Mason SA, Keske MA, Wadley GD |title=Effects of vitamin C supplementation on glycemic control and cardiovascular risk factors in people With type 2 diabetes: A GRADE-assessed systematic review and meta-analysis of randomized controlled trials |journal=Diabetes Care |volume=44 |issue=2 |pages=618–30 |date=February 2021 |pmid=33472962 |doi=10.2337/dc20-1893 |url=https://diabetesjournals.org/care/article/44/2/618/35482/Effects-of-Vitamin-C-Supplementation-on-Glycemic |doi-access=free |title-link=doi |hdl=10536/DRO/DU:30147432 |hdl-access=free |access-date=December 21, 2023 |archive-date=January 21, 2024 |archive-url=https://web.archive.org/web/20240121044253/https://diabetesjournals.org/care/article/44/2/618/35482/Effects-of-Vitamin-C-Supplementation-on-Glycemic |url-status=live }}</ref> However, another reported that supplementation with high doses of vitamin C can decrease [[Glucose test|blood glucose]], [[insulin]] and [[Glycated hemoglobin|hemoglobin A1c]].<ref name="nos">{{cite journal |vauthors=Nosratabadi S, Ashtary-Larky D, Hosseini F, Namkhah Z, Mohammadi S, Salamat S, Nadery M, Yarmand S, Zamani M, Wong A, Asbaghi O |title=The effects of vitamin C supplementation on glycemic control in patients with type 2 diabetes: A systematic review and meta-analysis |journal=Diabetes and Metabolic Syndrome |volume=17 |issue=8 |pages=102824 |date=August 2023 |pmid=37523928 |doi=10.1016/j.dsx.2023.102824 |s2cid=259581695 }}</ref>

=== Iron deficiency ===

One of the causes of [[iron-deficiency anemia]] is reduced absorption of iron. Iron absorption can be enhanced through ingestion of vitamin C alongside iron-containing food or supplements. Vitamin C helps to keep iron in the reduced ferrous state, which is more soluble and more easily absorbed.<ref name="pmid28189173">{{cite journal |vauthors=DeLoughery TG |title=Iron deficiency anemia |journal=Med Clin North Am |volume=101 |issue=2 |pages=319–32 |date=March 2017 |pmid=28189173 |doi=10.1016/j.mcna.2016.09.004 |type=Review}}</ref>

===Cognitive impairment and Alzheimer's disease===

Lower plasma vitamin C concentrations were reported in people with cognitive impairment and [[Alzheimer's disease]] compared to people with normal cognition.<ref name="pmid24144963">{{cite journal |vauthors=Lopes da Silva S, Vellas B, Elemans S, Luchsinger J, Kamphuis P, Yaffe K, Sijben J, Groenendijk M, Stijnen T |title=Plasma nutrient status of patients with Alzheimer's disease: Systematic review and meta-analysis |journal=Alzheimer's & Dementia |volume=10 |issue=4 |pages=485–502 |date=2014 |pmid=24144963 |doi=10.1016/j.jalz.2013.05.1771 | doi-access = free | title-link = doi }}</ref><ref name="pmid22543848">{{cite journal | vauthors = Li FJ, Shen L, Ji HF | title = Dietary intakes of vitamin E, vitamin C, and β-carotene and risk of Alzheimer's disease: a meta-analysis | journal = Journal of Alzheimer's Disease | volume = 31 | issue = 2 | pages = 253–8 | year = 2012 | pmid = 22543848 | doi = 10.3233/JAD-2012-120349 }}</ref><ref name="pmid22366772">{{cite journal | vauthors = Harrison FE | title = A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease | journal = Journal of Alzheimer's Disease | volume = 29 | issue = 4 | pages = 711–26 | year = 2012 | pmid = 22366772 | pmc = 3727637 | doi = 10.3233/JAD-2012-111853 }}</ref>

===Eye health===

Higher dietary intake of vitamin C was associated with lower risk of age-related cataracts.<ref name="pmid30878580">{{cite journal |vauthors=Sideri O, Tsaousis KT, Li HJ, Viskadouraki M, Tsinopoulos IT |title=The potential role of nutrition on lens pathology: a systematic review and meta-analysis |journal=Surv Ophthalmol |volume=64 |issue=5 |pages=668–78 |date=2019 |pmid=30878580 |doi=10.1016/j.survophthal.2019.03.003 |s2cid=81981938 |url=}}</ref><ref>{{cite journal |vauthors=Jiang H, Yin Y, Wu CR, Liu Y, Guo F, Li M, Ma L |title=Dietary vitamin and carotenoid intake and risk of age-related cataract |journal=Am J Clin Nutr |volume=109 |issue=1 |pages=43–54 |date=January 2019 |pmid=30624584 |doi=10.1093/ajcn/nqy270 |url=|doi-access=free }}</ref> Vitamin C supplementation did not prevent age-related macular degeneration.<ref>{{cite journal |vauthors=Evans JR, Lawrenson JG |title=Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration |journal=Cochrane Database Syst Rev |volume=2017 |issue=7 |pages=CD000253 |date=July 2017 |pmid=28756617 |pmc=6483250 |doi=10.1002/14651858.CD000253.pub4 |url=}}</ref>

===Periodontal disease===

Low intake and low serum concentration were associated with greater progression of [[periodontal disease]].<ref name="pmid38245765">{{cite journal |vauthors=Mi N, Zhang M, Ying Z, Lin X, Jin Y |title=Vitamin intake and periodontal disease: a meta-analysis of observational studies |journal=BMC Oral Health |volume=24 |issue=1 |pages=117 |date=January 2024 |pmid=38245765 |pmc=10799494 |doi=10.1186/s12903-024-03850-5 |doi-access=free |url=}}</ref><ref name="pmid31336735">{{cite journal |vauthors=Tada A, Miura H |title=The relationship between vitamin C and periodontal diseases: A systematic review |journal=Int J Environ Res Public Health |volume=16 |issue=14 |date=July 2019 |page=2472 |pmid=31336735 |pmc=6678404 |doi=10.3390/ijerph16142472 |doi-access=free |url=}}</ref>

==Adverse effects==

Oral intake as dietary supplements in excess of requirements are poorly absorbed,<ref name="NIH2021">{{cite web |title=Vitamin C: Fact sheet for health professionals |url=https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/ |publisher=Office of Dietary Supplements, US National Institutes of Health |date=March 26, 2021 |accessdate=25 February 2024 |archive-date=July 30, 2017 |archive-url=https://web.archive.org/web/20170730052126/https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/ |url-status=live }}</ref> and excesses in the blood rapidly excreted in the urine, so it exhibits low acute toxicity.<ref name=lpi2018 /> More than two to three grams, consumed orally, may cause nausea, abdominal cramps and diarrhea. These effects are attributed to the osmotic effect of unabsorbed vitamin C passing through the intestine.<ref name="DRItext" />{{rp|page=156}} In theory, high vitamin C intake may cause excessive absorption of iron. A summary of reviews of supplementation in healthy subjects did not report this problem, but left as untested the possibility that individuals with hereditary [[hemochromatosis]] might be adversely affected.<ref name="DRItext" />{{rp|page=158}}

There is a longstanding belief among the mainstream medical community that vitamin C increases risk of [[kidney stone]]s.<ref name=BattlingQuackery>{{cite journal | vauthors = Goodwin JS, Tangum MR | title = Battling quackery: attitudes about micronutrient supplements in American academic medicine | journal = Archives of Internal Medicine | volume = 158 | issue = 20 | pages = 2187–91 | date = November 1998 | pmid = 9818798 | doi = 10.1001/archinte.158.20.2187 }}</ref> "Reports of kidney stone formation associated with excess ascorbic acid intake are limited to individuals with renal disease".<ref name="DRItext" />{{rp|pages=156-157}} A review states that "data from epidemiological studies do not support an association between excess ascorbic acid intake and kidney stone formation in apparently healthy individuals",<ref name=VCreview2003>{{cite journal | vauthors = Naidu KA | title = Vitamin C in human health and disease is still a mystery? An overview | journal = Nutrition Journal | volume = 2 | issue = 7 | pages = 7 | date = August 2003 | pmid = 14498993 | pmc = 201008 | doi = 10.1186/1475-2891-2-7 | url = http://www.nutritionj.com/content/pdf/1475-2891-2-7.pdf | archive-url = https://web.archive.org/web/20120918153239/http://www.nutritionj.com/content/pdf/1475-2891-2-7.pdf | df = mdy-all | url-status = live | archive-date = September 18, 2012 | doi-access = free | title-link = doi }}</ref> although one large, multi-year trial did report a nearly two-fold increase in kidney stones in men who regularly consumed a vitamin C supplement.<ref name="pmid23381591">{{cite journal | vauthors = Thomas LD, Elinder CG, Tiselius HG, Wolk A, Akesson A | title = Ascorbic acid supplements and kidney stone incidence among men: a prospective study | journal = JAMA Internal Medicine | volume = 173 | issue = 5 | pages = 386–8 | date = March 2013 | pmid = 23381591 | doi = 10.1001/jamainternmed.2013.2296 | doi-access = free | title-link = doi }}</ref>

There is extensive research on the purported benefits of intravenous vitamin C for treatment of sepsis,<ref name=Liang2023>{{cite journal |vauthors=Liang B, Su J, Shao H, Chen H, Xie B |title=The outcome of IV vitamin C therapy in patients with sepsis or septic shock: a meta-analysis of randomized controlled trials |journal=Crit Care |volume=27 |issue=1 |pages=109 |date=March 2023 |pmid=36915173 |pmc=10012592 |doi=10.1186/s13054-023-04392-y |url= | doi-access = free | title-link = doi }}</ref> severe COVID-19<ref name=Kow2023 /><ref name=Huang2022 /> and cancer.<ref name="Jacobs2015">{{cite journal |vauthors=Jacobs C, Hutton B, Ng T, Shorr R, Clemons M |date=February 2015 |title=Is there a role for oral or intravenous ascorbate (vitamin C) in treating patients with cancer? A systematic review |journal=The Oncologist |volume=20 |issue=2 |pages=210–23 |doi=10.1634/theoncologist.2014-0381 |pmc=4319640 |pmid=25601965}}</ref> Reviews list trials with doses as high as 24 grams per day.<ref name=Kow2023 /> Concerns about possible adverse effects are that intravenous high-dose vitamin C leads to a supraphysiological level of vitamin C followed by oxidative degradation to dehydroascorbic acid and hence to oxalate, increasing the risk of oxalate kidney stones and oxalate nephropathy. The risk may be higher in people with [[renal impairment]], as kidneys efficiently excrete excess vitamin C. Second, treatment with high dose vitamin C should be avoided in patients with [[glucose-6-phosphate dehydrogenase deficiency]] as it can lead to acute [[hemolysis]]. Third, treatment might interfere with the accuracy of glucometer measurement of blood glucose levels, as both vitamin C and [[glucose]] have similar molecular structure, which could lead to false high blood glucose readings. Despite all these concerns, meta-analyses of patients in intensive care for sepsis, septic shock, COVID-19 and other acute conditions reported no increase in new-onset kidney stones, acute kidney injury or requirement for renal replacement therapy for patients receiving short-term, high-dose, intravenous vitamin C treatment. This suggests that intravenous vitamin C is safe under these short-term applications.<ref name="pmid34684565">{{cite journal |vauthors=Shrestha DB, Budhathoki P, Sedhai YR, Mandal SK, Shikhrakar S, Karki S, Baniya RK, Kashiouris MG, Qiao X, Fowler AA |title=Vitamin C in critically ill patients: An updated systematic review and meta-analysis |journal=Nutrients |volume=13 |issue=10 |date=October 2021 |page=3564 |pmid=34684565 |pmc=8539952 |doi=10.3390/nu13103564 | doi-access = free | title-link = doi |url=}}</ref><ref name="pmid34833042">{{cite journal |vauthors=Holford P, Carr AC, Zawari M, Vizcaychipi MP |title=Vitamin C intervention for critical COVID-19: A pragmatic review of the current level of evidence |journal=Life |volume=11 |issue=11 |date=November 2021 |page=1166 |pmid=34833042 |pmc=8624950 |doi=10.3390/life11111166 | doi-access = free | title-link = doi |bibcode=2021Life...11.1166H |url=}}</ref><ref name=Abobaker2020>{{cite journal |vauthors=Abobaker A, Alzwi A, Alraied AH |title=Overview of the possible role of vitamin C in management of COVID-19 |journal=Pharmacol Rep |volume=72 |issue=6 |pages=1517–28 |date=December 2020 |pmid=33113146 |pmc=7592143 |doi=10.1007/s43440-020-00176-1 |url=}}</ref>

== History ==

Scurvy was known to [[Hippocrates]], described in book two of his ''Prorrheticorum'' and in his ''Liber de internis affectionibus'', and cited by James Lind.<ref name="Lind-1772">{{cite book | vauthors = Lind J | title = A Treatise on the Scurvy | location = London, England | publisher = G. Pearch and W. Woodfall | date= 1772 | edition = 3rd | url = https://archive.org/details/treatiseonscurvy1772lind/page/285 | page = 285 | archive-url=https://web.archive.org/web/20160101135046/https://books.google.com/books?id=T1OT3tYmh5wC&pg=PA285&lpg=PA285 | archive-date=January 1, 2016 }}</ref> Symptoms of scurvy were also described by [[Pliny the Elder]]: (i) {{cite book | vauthors = Pliny | title = Naturalis historiae | volume = 3 | chapter = 49 }}; and (ii) Strabo, in ''Geographicorum'', book 16, cited in the 1881 International Encyclopedia of Surgery.<ref name="William Wood and Co.-1881">{{cite encyclopedia | veditors = Ashhurst J | title = The International Encyclopedia of Surgery | volume = 1 | location = New York, New York | publisher = William Wood and Co. | date = 1881 | url = https://books.google.com/books?id=mDV11NpZyNgC&pg=PA278 | page = 278 | archive-url = https://web.archive.org/web/20160505051643/https://books.google.com/books?id=mDV11NpZyNgC&pg=PA278&lpg=PA278 | archive-date=May 5, 2016}}</ref>

===Scurvy at sea===

[[File:Wiki Loves Cocktails at WikiCon 2016, 2017 (1Y7A1464).jpg|thumb|left|alt=Limes, lemons and oranges identified as preventing scurvy|Limes, lemons and oranges were among foods identified early as preventing or treating scurvy on long sailing voyages.]]

In the 1497 expedition of [[Vasco da Gama]], the curative effects of citrus fruit were known.<ref name="pmid11581484">{{cite journal | vauthors = Rajakumar K | title = Infantile scurvy: a historical perspective | journal = Pediatrics | volume = 108 | issue = 4 | pages = E76 | date = October 2001 | pmid = 11581484 | doi = 10.1542/peds.108.4.e76 | url = http://pediatrics.aappublications.org/content/108/4/e76.full | archive-url = https://web.archive.org/web/20150904021206/http://pediatrics.aappublications.org/content/108/4/e76.full | archive-date=September 4, 2015 | quote = As they sailed farther up the east coast of Africa, they met local traders, who traded them fresh oranges. Within six days of eating the oranges, da Gama's crew recovered fully | citeseerx = 10.1.1.566.5857 }}</ref> In the 1500s, Portuguese sailors put in to the island of [[Saint Helena]] to avail themselves of planted vegetable gardens and wild-growing fruit trees.<ref name="Livermore-2004">{{cite journal | vauthors = Livermore H | title = Santa Helena, a forgotten Portuguese discovery | journal = Estudos Em Homenagem a Luis Antonio de Oliveira Ramos | trans-journal = Studies in Homage to Luis Antonio de Oliveira Ramos. | date = 2004 | pages = 623–631 | url = http://ler.letras.up.pt/uploads/ficheiros/4999.pdf | archive-url= https://web.archive.org/web/20110529065201/http://ler.letras.up.pt/uploads/ficheiros/4999.pdf | archive-date = May 29, 2011 | quote = On returning, Lopes' ship had left him on St Helena, where with admirable sagacity and industry he planted vegetables and nurseries with which passing ships were marvelously sustained. [...] There were 'wild groves' of oranges, lemons and other fruits that ripened all the year round, large pomegranates and figs. }}</ref> Authorities occasionally recommended plant food to prevent scurvy during long sea voyages. [[John Woodall]], the first surgeon to the British [[East India Company]], recommended the preventive and curative use of [[lemon]] juice in his 1617 book, ''The Surgeon's Mate''.<ref name="Woodall-1617">{{cite book | vauthors = Woodall J | title = The Surgion's Mate | location = London, England | publisher = Edward Griffin | date = 1617 | page = 89 | url = https://archive.org/stream/surgionsmateortr00wood#page/89/mode/1up | archive-url = https://web.archive.org/web/20160411083503/https://archive.org/stream/surgionsmateortr00wood | archive-date=April 11, 2016 | quote = Succus Limonum, or juice of Lemons ... [is] the most precious help that ever was discovered against the Scurvy[;] to be drunk at all times; ... }}</ref> In 1734, the [[Netherlands|Dutch]] writer [[Johann Bachstrom]] gave the firm opinion, "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens."<ref name="Armstrong-1858">{{cite journal | vauthors = Armstrong A |journal=British and Foreign Medico-chirurgical Review: Or, Quarterly Journal of Practical Medicine and Surgery |title=Observation on naval hygiene and scurvy, more particularly as the later appeared during the Polar voyage |volume=22 |pages=295–305 |year=1858 |url =https://books.google.com/books?id=7VJYAAAAMAAJ&pg=PA295 }}</ref><!--https://books.google.com/books?id=azXx4cbrMZMC&pg=PA74 would also work out--><ref name="Bachstrom-1734">{{cite book | vauthors = Bachstrom JF | title = Observationes circa scorbutum | trans-title = Observations on scurvy | language = Latin | location = Leiden (Lugdunum Batavorum), Netherlands | publisher = Conrad Wishof | date = 1734 | page = 16 | url = https://books.google.com/books?id=bj8_AAAAcAAJ&pg=PA16 | archive-url = https://web.archive.org/web/20160101135046/https://books.google.com/books?id=bj8_AAAAcAAJ&pg=PA16 | archive-date = January 1, 2016 | quote = ... sed ex nostra causa optime explicatur, que est absentia, carentia & abstinentia a vegetabilibus recentibus, ... ( ... but [this misfortune] is explained very well by our [supposed] cause, which is the absence of, lack of, and abstinence from fresh vegetables, ... }}</ref> Scurvy had long been a principal killer of sailors during the long sea voyages.<ref name="url_BBC_Captain_Cook_Scurvy">{{cite web |url=https://www.bbc.co.uk/history/british/empire_seapower/captaincook_scurvy_01.shtml |title=Captain Cook and the scourge of scurvy |publisher=BBC |work=British History in depth | vauthors = Lamb J |date=February 17, 2011 |url-status=live |archive-url=https://web.archive.org/web/20110221073823/http://www.bbc.co.uk/history/british/empire_seapower/captaincook_scurvy_01.shtml |archive-date=February 21, 2011 }}</ref> According to Jonathan Lamb, "In 1499, Vasco da Gama lost 116 of his crew of 170; In 1520, Magellan lost 208 out of 230;&nbsp;... all mainly to scurvy."<ref name="Lamb-2001">{{cite book | vauthors = Lamb J |title=Preserving the self in the south seas, 1680–1840 |publisher=University of Chicago Press |year=2001 |page=117 |isbn=978-0-226-46849-5 |url=https://books.google.com/books?id=hSoj1DR4ZSMC |url-status=live |archive-url=https://web.archive.org/web/20160430065803/https://books.google.com/books?id=hSoj1DR4ZSMC&pg=&dq |archive-date=April 30, 2016 }}</ref>

[[File:James Lind by Chalmers.jpg|thumb|upright|[[James Lind]], a British Royal Navy surgeon who, in 1747, identified that a quality in fruit prevented scurvy in one of the first recorded [[Scientific control#Controlled experiments|controlled experiments]]<ref name="Baron2009">{{cite journal | vauthors = Baron JH | title = Sailors' scurvy before and after James Lind--a reassessment | journal = Nutrition Reviews | volume = 67 | issue = 6 | pages = 315–32 | date = June 2009 | pmid = 19519673 | doi = 10.1111/j.1753-4887.2009.00205.x | s2cid = 20435128 }}</ref>]]

The first attempt to give scientific basis for the cause of this disease was by a ship's surgeon in the [[Royal Navy]], [[James Lind]]. While at sea in May 1747, Lind provided some crew members with two oranges and one lemon per day, in addition to normal rations, while others continued on [[cider]], [[vinegar]], [[sulfuric acid]] or [[seawater]], along with their normal rations, in one of the world's first controlled experiments.<ref name="Baron2009" /> The results showed that citrus fruits prevented the disease. Lind published his work in 1753 in his ''Treatise on the Scurvy''.<ref name="lind_james">{{cite book | vauthors = Lind J |title=A treatise of the scurvy |publisher=A. Millar |location=London |year=1753 }} In the 1757 edition of his work, Lind discusses his experiment starting on {{cite web |title=A treatise of the scurvy | url = https://archive.org/stream/treatiseonscurvy00lind#page/149/mode/1up | page = 149 | archive-url = https://web.archive.org/web/20160320155753/https://archive.org/stream/treatiseonscurvy00lind | archive-date=March 20, 2016 }}</ref>

Fresh fruit was expensive to keep on board, whereas boiling it down to juice allowed easy storage, but destroyed the vitamin (especially if it was boiled in copper kettles).<ref name="Oxford" /> It was 1796 before the British navy adopted [[lemon]] juice as standard issue at sea. In 1845, ships in the West Indies were provided with [[Lime (fruit)|lime]] juice instead, and in 1860 lime juice was used throughout the Royal Navy, giving rise to the American use of the nickname [[Glossary of names for the British|"limey"]] for the British.<ref name="Baron2009" /> [[James Cook|Captain James Cook]] had previously demonstrated the advantages of carrying [[Sauerkraut|"Sour krout"]] on board by taking his crew on a 1772-75 Pacific Ocean voyage without losing any of his men to scurvy.<ref name="isbn0-14-043647-2">{{cite book |vauthors=Beaglehole JH, Cook JD, Edwards PR |title=The journals of Captain Cook |publisher=Penguin |location=Harmondsworth [Eng.] |year=1999 |isbn=978-0-14-043647-1 |url=https://archive.org/details/journalsofcaptai00jame }}</ref> For his report on his methods the British Royal Society awarded him the Copley Medal in 1776.<ref name="The Royal Society-2015">{{cite web |url=https://royalsociety.org/grants-schemes-awards/awards/copley-medal/ |title=Copley Medal, past winners |date= |website=The Royal Society |access-date=January 1, 2024 |archive-date=September 6, 2015 |archive-url=https://web.archive.org/web/20150906190948/https://royalsociety.org/grants-schemes-awards/awards/copley-medal/ |url-status=live }}</ref>

The name ''antiscorbutic'' was used in the eighteenth and nineteenth centuries for foods known to prevent scurvy. These foods included lemons, limes, oranges, sauerkraut, cabbage, [[malt]], and [[portable soup]].<ref name="isbn1-74114-200-8">{{cite book |vauthors=Reeve J, Stevens DA |title=Navy and the nation: the influence of the navy on modern Australia |publisher=Allen & Unwin Academic |year=2006 |page=74 |isbn=978-1-74114-200-6 |chapter-url=https://books.google.com/books?id=BGs6__kbqKIC&pg=PA74 |chapter=Cook's Voyages 1768–1780 }}</ref> In 1928, the Canadian Arctic anthropologist [[Vilhjalmur Stefansson]] showed that the [[Inuit]] avoided scurvy on a diet largely of raw meat. Later studies on traditional food diets of the [[Yukon]] [[First Nations in Canada|First Nations]], [[Dene]], [[Inuit]], and [[Métis#Métis people in Canada|Métis]] of Northern Canada showed that their daily intake of vitamin C averaged between 52 and 62&nbsp;mg/day.<ref name="pmid15173410">{{cite journal | vauthors = Kuhnlein HV, Receveur O, Soueida R, Egeland GM | title = Arctic indigenous peoples experience the nutrition transition with changing dietary patterns and obesity | journal = The Journal of Nutrition | volume = 134 | issue = 6 | pages = 1447–53 | date = June 2004 | pmid = 15173410 | doi = 10.1093/jn/134.6.1447| df = mdy-all | doi-access = free | title-link = doi }}</ref>

=== Discovery ===

{{Further|Vitamin#History}}

Vitamin C was discovered in 1912, isolated in 1928 and synthesized in 1933, making it the first vitamin to be synthesized.<ref name=Squires>{{cite book |vauthors=Squires VR |title=The role of food, agriculture, forestry and fisheries in human nutrition - Volume IV |date=2011 |publisher=EOLSS Publications |isbn=978-1-84826-195-2 |page=121 |url=https://books.google.com/books?id=VJWoCwAAQBAJ&pg=PA121 |access-date=September 17, 2017 |archive-date=January 11, 2023 |archive-url=https://web.archive.org/web/20230111085247/https://books.google.com/books?id=VJWoCwAAQBAJ&pg=PA121 |url-status=live }}</ref> Shortly thereafter [[Tadeus Reichstein]] succeeded in synthesizing the vitamin in bulk by what is now called the [[Reichstein process]].<ref name="pmid356548">{{cite book | vauthors = Stacey M, Manners DJ | title = Advances in carbohydrate chemistry and biochemistry | chapter = Edmund Langley Hirst | volume = 35 | pages = 1–29 | year = 1978 | pmid = 356548 | doi = 10.1016/S0065-2318(08)60217-6 | isbn = 978-0-12-007235-4 }}</ref> This made possible the inexpensive mass-production of vitamin C. In 1934, [[Hoffmann–La Roche]] bought the Reichstein process patent, trademarked synthetic vitamin C under the brand name [[Redoxon]], and began to market it as a dietary supplement.<ref name=Roche1934>{{cite web|url=http://www.trademarkia.com/redoxon-71350953.html|title=Redoxon trademark information by Hoffman-la Roche, Inc. (1934)|access-date=December 25, 2017|archive-date=November 16, 2018|archive-url=https://web.archive.org/web/20181116044212/https://www.trademarkia.com/redoxon-71350953.html|url-status=live}}</ref><ref name="Wang-2016">{{cite book | chapter-url = https://books.google.com/books?id=WgamCgAAQBAJ&pg=PA161 | chapter = Industrial fermentation of Vitamin C | vauthors = Wang W, Xu H | year = 2016 | page = 161 | title = Industrial biotechnology of vitamins, biopigments, and antioxidants | veditors = Vandamme EJ, Revuelta JI | publisher = Wiley-VCH Verlag GmbH & Co. KGaA. | isbn = 978-3-527-33734-7 }}</ref>

In 1907, a laboratory animal model which would help to identify the antiscorbutic factor was discovered by the Norwegian physicians [[Axel Holst]] and [[Theodor Frølich]], who when studying shipboard [[beriberi]], fed [[guinea pig]]s their test diet of grains and flour and were surprised when scurvy resulted instead of beriberi. Unknown at that time, this species did not make its own vitamin C (being a [[caviomorph]]), whereas mice and rats do.<ref name="pmid12555613">{{cite journal | vauthors = Norum KR, Grav HJ | title = [Axel Holst and Theodor Frolich--pioneers in the combat of scurvy] | language = no | journal = Tidsskrift for den Norske Laegeforening | volume = 122 | issue = 17 | pages = 1686–7 | date = June 2002 | pmid = 12555613 }}</ref> In 1912, the [[Poland|Polish]] biochemist [[Casimir Funk]] developed the concept of [[vitamin]]s. One of these was thought to be the anti-scorbutic factor. In 1928, this was referred to as "water-soluble C", although its chemical structure had not been determined.<ref name="pmid9105273">{{cite journal | vauthors = Rosenfeld L | title = Vitamine--vitamin. The early years of discovery | journal = Clinical Chemistry | volume = 43 | issue = 4 | pages = 680–5 | date = April 1997 | doi = 10.1093/clinchem/43.4.680 | pmid = 9105273 | doi-access = free | title-link = doi }}</ref>

[[File:GyorgyiNIH.jpg|thumb|right|upright|[[Albert Szent-Györgyi]], pictured here in 1948, was awarded the 1937 [[Nobel Prize in Physiology or Medicine|Nobel Prize in Medicine]] "for his discoveries in connection with the biological combustion processes, with special reference to vitamin{{nbsp}}C and the catalysis of fumaric acid".<ref name="pmid19239412"/>|alt=Albert Szent-Györgyi was awarded the Nobel Prize in Medicine in part for his research on vitamin C]]

From 1928 to 1932, [[Albert Szent-Györgyi]] and Joseph L. Svirbely's Hungarian team, and [[Charles Glen King]]'s American team, identified the anti-scorbutic factor. Szent-Györgyi isolated hexuronic acid from animal adrenal glands, and suspected it to be the antiscorbutic factor.<ref name="pmid16744896">{{cite journal | vauthors = Svirbely JL, Szent-Györgyi A | title = The chemical nature of vitamin C | journal = The Biochemical Journal | volume = 26 | issue = 3 | pages = 865–70 | year = 1932 | pmid = 16744896 | pmc = 1260981 | doi = 10.1126/science.75.1944.357-a | bibcode = 1932Sci....75..357K }}</ref> In late 1931, Szent-Györgyi gave Svirbely the last of his adrenal-derived hexuronic acid with the suggestion that it might be the anti-scorbutic factor. By the spring of 1932, King's laboratory had proven this, but published the result without giving Szent-Györgyi credit for it. This led to a bitter dispute over priority.<ref name="pmid16744896" /> In 1933, [[Walter Norman Haworth]] chemically identified the vitamin as {{sm|l}}-hexuronic acid, proving this by synthesis in 1933.<ref name="pmid11963399">{{cite journal | vauthors = Juhász-Nagy S | title = [Albert Szent-Györgyi--biography of a free genius] | language = hu | journal = Orvosi Hetilap | volume = 143 | issue = 12 | pages = 611–4 | date = March 2002 | pmid = 11963399 }}</ref><ref name="pmid4589872">{{cite journal | vauthors = Kenéz J | title = [Eventful life of a scientist. 80th birthday of Nobel prize winner Albert Szent-Györgyi] | language = de | journal = Munchener Medizinische Wochenschrift | volume = 115 | issue = 51 | pages = 2324–6 | date = December 1973 | pmid = 4589872 }}</ref><ref name="pmid4612454">{{cite journal | vauthors = Szállási A | title = [2 interesting early articles by Albert Szent-Györgyi] | language = hu | journal = Orvosi Hetilap | volume = 115 | issue = 52 | pages = 3118–9 | date = December 1974 | pmid = 4612454 }}</ref><ref name="url_NLM_Profiles_Szent-Gyorgyi">{{cite web |url=http://profiles.nlm.nih.gov/WG/Views/Exhibit/narrative/szeged.html |title=The Albert Szent-Gyorgyi Papers: Szeged, 1931-1947: Vitamin C, Muscles, and WWII |work=Profiles in Science |publisher=United States National Library of Medicine |url-status=live |archive-url=https://web.archive.org/web/20090505232208/http://profiles.nlm.nih.gov/WG/Views/Exhibit/narrative/szeged.html |archive-date=May 5, 2009 }}</ref> Haworth and Szent-Györgyi proposed that L-hexuronic acid be named a-scorbic acid, and chemically {{sm|l}}-ascorbic acid, in honor of its activity against scurvy.<ref name="url_NLM_Profiles_Szent-Gyorgyi"/><ref name=Squires /> The term's etymology is from Latin, "a-" meaning away, or off from, while -scorbic is from Medieval Latin ''scorbuticus'' (pertaining to scurvy), cognate with Old Norse ''skyrbjugr'', French ''scorbut'', Dutch ''scheurbuik'' and Low German ''scharbock''.<ref name="Online Entymology Dictionary-2015">{{cite web |url=https://www.etymonline.com/word/scurvy |title=Scurvy |publisher=Online Entymology Dictionary |access-date=November 19, 2017 |archive-date=December 15, 2020 |archive-url=https://web.archive.org/web/20201215135611/https://www.etymonline.com/word/scurvy |url-status=live }}</ref> Partly for this discovery, Szent-Györgyi was awarded the 1937 [[Nobel Prize in Physiology or Medicine|Nobel Prize in Medicine]],<ref name="pmid19239412">{{cite journal | vauthors = Zetterström R | title = Nobel Prize 1937 to Albert von Szent-Györgyi: identification of vitamin C as the anti-scorbutic factor | journal = Acta Paediatrica | volume = 98 | issue = 5 | pages = 915–19 | date = May 2009 | pmid = 19239412 | doi = 10.1111/j.1651-2227.2009.01239.x | s2cid = 11077461 }}</ref> and Haworth shared that year's [[Nobel Prize in Chemistry]].<ref name="pmid15416703">{{cite journal |vauthors=Hirst EL |title=Sir Norman Haworth |journal=Nature |volume=165 |issue=4198 |pages=587 |date=April 1950 |pmid=15416703 |doi=10.1038/165587a0 |bibcode=1950Natur.165..587H |url=}}</ref>

In 1957, J. J. Burns showed that some mammals are susceptible to scurvy as their [[liver]] does not produce the [[enzyme]] [[L-gulonolactone oxidase|{{sm|l}}-gulonolactone oxidase]], the last of the chain of four enzymes that synthesize vitamin C.<ref name="pmid13385237">{{cite journal | vauthors = Burns JJ, Evans C | title = The synthesis of L-ascorbic acid in the rat from D-glucuronolactone and L-gulonolactone | journal = The Journal of Biological Chemistry | volume = 223 | issue = 2 | pages = 897–905 | date = December 1956 | doi = 10.1016/S0021-9258(18)65088-4 | pmid = 13385237 | url = https://www.jbc.org/article/S0021-9258(18)65088-4/pdf | doi-access = free | title-link = doi | format = PDF | access-date = December 3, 2022 | archive-date = December 3, 2022 | archive-url = https://web.archive.org/web/20221203231846/https://www.jbc.org/article/S0021-9258(18)65088-4/pdf | url-status = live }}</ref><ref name="pmid13380431">{{cite journal | vauthors = Burns JJ, Moltz A, Peyser P | title = Missing step in guinea pigs required for the biosynthesis of L-ascorbic acid | journal = Science | volume = 124 | issue = 3232 | pages = 1148–9 | date = December 1956 | pmid = 13380431 | doi = 10.1126/science.124.3232.1148-a | bibcode = 1956Sci...124.1148B }}</ref> American biochemist [[Irwin Stone]] was the first to exploit vitamin C for its food preservative properties. He later developed the idea that humans possess a mutated form of the {{sm|l}}-gulonolactone oxidase coding gene.<ref name="pmid1672383">{{cite journal | vauthors = Henson DE, Block G, Levine M | title = Ascorbic acid: biologic functions and relation to cancer | journal = Journal of the National Cancer Institute | volume = 83 | issue = 8 | pages = 547–50 | date = April 1991 | pmid = 1672383 | doi = 10.1093/jnci/83.8.547 | url = https://zenodo.org/record/1234351 | access-date = March 18, 2020 | archive-date = December 25, 2020 | archive-url = https://web.archive.org/web/20201225062602/https://zenodo.org/record/1234351 | url-status = live | doi-access = free | title-link = doi }}</ref>

Stone introduced Linus Pauling to the theory that humans needed to consume vitamin C in quantities far higher than what was considered a recommended daily intake in order to optimize health.<ref name=IrwinStone>{{cite web |url=http://www.orthomolecular.org/history/index.shtml |title=Orthomolecular Medicine Hall of fame - Irwin Stone, Ph.D. | vauthors = Saul A |date= |website=Orthomolecular Organization |access-date=December 25, 2023 |archive-date=August 9, 2011 |archive-url=https://web.archive.org/web/20110809145751/http://www.orthomolecular.org/history/index.shtml |url-status=live }}</ref>

In 2008, researchers discovered that in humans and other primates the [[red blood cell]]s have evolved a mechanism to more efficiently utilize the vitamin C present in the body by recycling oxidized {{sm|l}}-dehydroascorbic acid (DHA) back into ascorbic acid for reuse by the body. The mechanism was not found to be present in mammals that synthesize their own vitamin C.<ref name="pmid18358815">{{cite journal | vauthors = Montel-Hagen A, Kinet S, Manel N, Mongellaz C, Prohaska R, Battini JL, Delaunay J, Sitbon M, Taylor N |s2cid = 18128118 |title = Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C |journal = Cell |volume = 132 |issue = 6 |pages = 1039–48 |date = March 2008 |pmid = 18358815 |doi = 10.1016/j.cell.2008.01.042| doi-access = free | title-link = doi }}</ref>

===History of large dose therapies===

{{Further|Vitamin C megadosage|Intravenous ascorbic acid}}

Vitamin C megadosage is a term describing the consumption or injection of vitamin C in doses comparable to or higher than the amounts produced by the livers of mammals which are able to synthesize vitamin C. An argument for this, although not the actual term, was described in 1970 in an article by [[Linus Pauling]]. Briefly, his position was that for optimal health, humans should be consuming at least 2,300&nbsp;mg/day to compensate for the inability to synthesize vitamin C. The recommendation also fell into the consumption range for gorillas&nbsp;— a non-synthesizing near-relative to humans.<ref name=pmid5275366>{{cite journal | vauthors = Pauling L | title = Evolution and the need for ascorbic acid | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 67 | issue = 4 | pages = 1643–8 | date = December 1970 | pmid = 5275366 | pmc = 283405 | doi = 10.1073/pnas.67.4.1643 | bibcode = 1970PNAS...67.1643P | doi-access = free | title-link = doi }}</ref> A second argument for high intake is that serum ascorbic acid concentrations increase as intake increases until it plateaus at about 190 to 200 micromoles per liter (µmol/L) once consumption exceeds 1,250 milligrams.<ref name=Mandl2009>{{cite journal | vauthors = Mandl J, Szarka A, Bánhegyi G | title = Vitamin C: update on physiology and pharmacology | journal = British Journal of Pharmacology | volume = 157 | issue = 7 | pages = 1097–110 | date = August 2009 | pmid = 19508394 | pmc = 2743829 | doi = 10.1111/j.1476-5381.2009.00282.x }}</ref> As noted, government recommendations are a range of 40 to 110&nbsp;mg/day and normal plasma is approximately 50&nbsp;µmol/L, so "normal" is about 25% of what can be achieved when oral consumption is in the proposed megadose range.

Pauling popularized the concept of high dose vitamin C as prevention and treatment of the common cold in 1970. A few years later he proposed that vitamin C would prevent cardiovascular disease, and that 10 grams/day, initially administered intravenously and thereafter orally, would cure late-stage cancer.<ref name="pmid1068480">{{cite journal | vauthors = Cameron E, Pauling L | title = Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 73 | issue = 10 | pages = 3685–9 | date = October 1976 | pmid = 1068480 | pmc = 431183 | doi = 10.1073/pnas.73.10.3685| bibcode = 1976PNAS...73.3685C | doi-access = free | title-link = doi }}</ref> Mega-dosing with ascorbic acid has other champions, among them chemist [[Irwin Stone]]<ref name=IrwinStone/> and the controversial [[Matthias Rath]] and [[Patrick Holford]], who both have been accused of making unsubstantiated treatment claims for treating cancer and [[HIV]] infection.<ref name="Boseley-2008">{{cite web |url= https://www.theguardian.com/world/2008/sep/12/matthiasrath.aids2 |title=Fall of the vitamin doctor: Matthias Rath drops libel action | vauthors = Boseley S |date=September 12, 2008 |website=The Guardian |access-date=January 5, 2024 |archive-date=December 1, 2016 |archive-url=https://web.archive.org/web/20161201225117/https://www.theguardian.com/world/2008/sep/12/matthiasrath.aids2 |url-status=live }}</ref><ref name="Colquhoun-2007">{{cite news |url=https://www.theguardian.com/science/2007/aug/15/endarkenment |title=The age of endarkenment &#124; Science &#124; guardian.co.uk |newspaper=Guardian |date=August 15, 2007 |access-date=January 5, 2024 | vauthors = Colquhoun D |archive-date=March 6, 2023 |archive-url=https://web.archive.org/web/20230306023533/https://www.theguardian.com/science/2007/aug/15/endarkenment |url-status=live }}</ref> The idea that large amounts of intravenous ascorbic acid can be used to treat late-stage cancer or ameliorate the toxicity of chemotherapy is&nbsp;— some forty years after Pauling's seminal paper&nbsp;— still considered unproven and still in need of high quality research.<ref name="Barret-2014">{{cite web|url=https://www.quackwatch.org/01QuackeryRelatedTopics/pauling.html |title=The dark side of Linus Pauling's legacy| vauthors = Barret S |date=September 14, 2014|website=www.quackwatch.org|archive-url= https://web.archive.org/web/20180904155649/https://www.quackwatch.org/01QuackeryRelatedTopics/pauling.html |archive-date=September 4, 2018|access-date=December 18, 2018}}{{Unreliable source?|date=April 2024}}</ref><ref name=Wil2014>{{cite journal | vauthors = Wilson MK, Baguley BC, Wall C, Jameson MB, Findlay MP | title = Review of high-dose intravenous vitamin C as an anticancer agent | journal = Asia-Pacific Journal of Clinical Oncology | volume = 10 | issue = 1 | pages = 22–37 | date = March 2014 | pmid = 24571058 | doi = 10.1111/ajco.12173 | s2cid = 206983069 | doi-access = free | title-link = doi }}</ref><ref name=Jacobs2015 />

==Research directions==

=== Cancer ===

There is research investigating whether high dose intravenous vitamin C administration as a co-treatment will suppress [[cancer stem cell]]s, which are responsible for tumor recurrence, metastasis and chemoresistance.<ref name="pmid38067361">{{cite journal |vauthors=Lee Y |title=Role of vitamin C in targeting cancer stem cells and cellular plasticity |journal=Cancers (Basel) |volume=15 |issue=23 |date=November 2023 |page=5657 |pmid=38067361 |pmc=10705783 |doi=10.3390/cancers15235657 |doi-access=free |url=}}</ref><ref name="pmid31947879">{{cite journal |vauthors=Satheesh NJ, Samuel SM, Büsselberg D |title=Combination therapy with vitamin C could eradicate cancer stem cells |journal=Biomolecules |volume=10 |issue=1 |date=January 2020 |page=79 |pmid=31947879 |pmc=7022456 |doi=10.3390/biom10010079 |doi-access=free}}</ref> Preliminary research suggest that there may be an inverse relationship between vitamin C intake and [[lung cancer]].<ref name="pmid25145261">{{cite journal | vauthors = Luo J, Shen L, Zheng D | title = Association between vitamin C intake and lung cancer: a dose-response meta-analysis | journal = Scientific Reports | volume = 4 | pages = 6161 | date = 2014 | pmid = 25145261 | pmc = 5381428 | doi = 10.1038/srep06161 | bibcode = 2014NatSR...4E6161L }}</ref>

=== Skin aging ===

There is also ongoing research on topical application of vitamin C to prevent signs of skin aging. Human skin physiologically contains small amounts of vitamin C, which support collagen synthesis, decreases collagen degradation, and assists in antioxidant protection against UV-induced photo-aging, including [[photocarcinogenesis]]. This knowledge is often used as a rationale for the marketing of vitamin C as a topical "serum" ingredient to prevent or treat facial skin aging, [[melasma]] (dark pigmented spots) and wrinkles, however, these claims are unsubstantiated and are not supported by research conducted so far; the supposed efficacy of topical treatment as opposed to oral intake is poorly understood.<ref name="Pullar2017">{{cite journal |vauthors=Pullar JM, Carr AC, Vissers MC |title=The roles of vitamin C in skin health |journal=Nutrients |volume=9 |issue=8 |date=August 2017 |page=866 |pmid=28805671 |pmc=5579659 |doi=10.3390/nu9080866 |url= | doi-access = free | title-link = doi }}</ref><ref name="Niaimi2017">{{cite journal |vauthors=Al-Niaimi F, Chiang NY |title=Topical vitamin C and the skin: Mechanisms of action and clinical applications |journal=J Clin Aesthet Dermatol |volume=10 |issue=7 |pages=14–17 |date=July 2017 |pmid=29104718 |pmc=5605218 |doi= |url=}}</ref> The purported mechanism on supposed benefit of topical vitamin C application to slow skin aging is that vitamin C functions as an antioxidant, neutralizing [[Free-radical theory of aging|free radicals]] from sunlight exposure, air pollutants or normal metabolic processes.<ref name="Harvard2021">{{cite web |url=https://www.health.harvard.edu/blog/why-is-topical-vitamin-c-important-for-skin-health-202111102635 |title=Why is topical vitamin C important for skin health? |vauthors=Nathan N, Patel P |date=10 November 2021 |website=Harvard Health Publishing, Harvard Medical School |access-date=October 14, 2022 |archive-date=October 14, 2022 |archive-url=https://web.archive.org/web/20221014100454/https://www.health.harvard.edu/blog/why-is-topical-vitamin-c-important-for-skin-health-202111102635 |url-status=live }}</ref> The clinical trial literature is characterized as insufficient to support health claims; one reason being put forward was that "All the studies used vitamin C in combination with other ingredients or therapeutic mechanisms, thereby complicating any specific conclusions regarding the efficacy of vitamin C."<ref name="Sanabria2023">{{cite journal |vauthors=Sanabria B, Berger LE, Mohd H, Benoit L, Truong TM, Michniak-Kohn BB, Rao BK |title=Clinical efficacy of topical vitamin C on the appearance of wrinkles: A systematic literature review |journal=Journal of Drugs in Dermatology |volume=22 |issue=9 |pages=898–904 |date=September 2023 |pmid=37683066 |doi=10.36849/JDD.7332 |doi-broken-date=March 5, 2024 |doi-access=free |url=https://jddonline.com/articles/clinical-efficacy-of-topical-vitamin-c-on-the-appearance-of-wrinkles-a-systematic-literature-review-S1545961623P0898X/ |access-date=February 25, 2024 |archive-date=February 25, 2024 |archive-url=https://web.archive.org/web/20240225202726/https://jddonline.com/articles/clinical-efficacy-of-topical-vitamin-c-on-the-appearance-of-wrinkles-a-systematic-literature-review-S1545961623P0898X/ |url-status=live }}</ref><ref name="Correia2023">{{cite journal |vauthors=Correia G, Magina S |title=Efficacy of topical vitamin C in melasma and photoaging: A systematic review |journal=J Cosmet Dermatol |volume=22 |issue=7 |pages=1938–45 |date=July 2023 |pmid=37128827 |doi=10.1111/jocd.15748 |s2cid=258439047 |url=| doi-access = free | title-link = doi }}</ref>

==Notes==

{{Notelist}}

==References==

{{Reflist}}

== External links ==

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{{Commons category|Ascorbic acid}}

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