Vitamin B2

Common Name: Vitamin B2

Clinical Name: Riboflavin

Summary

Vitamin B2

chemical name: Riboflavin

overview of interactions:
• nutrient affected by drug: Doxorubicin (Adriamycin®)

• nutrient affected by drug: Oral Contraceptives

• nutrient affected by drug: Tetracyclines

• nutrient affected by drug: Tricyclic Antidepressants

chemistry:
• Stable to heat, oxidation, and acid, riboflavin is somewhat soluble in water.
• Light and alkali destroy it.
• It should be noted that bottled milk (which has a relatively large amount of B2) loses a significant amount of B2 if it is left in the sunlight.

metabolism:
• Absorption occurs mainly in the upper GI tract. 60% of a 30mg dose is absorbed when taken with meals compared to 15% when taken separately.
• Synthetic thyroid medication decreases absorption, but thyroid in general increases the absorption.
• It should be noted that gastric acid is responsible for releasing B-2 from noncovalent bonding in foods so that it may be absorbed.
• Riboflavin is stored to some extent in the liver. However, when supplies are low the liver will only go down to 50% of its maximum storage.
• Riboflavin is also found in high amounts in the retina of the eye.

function:
• Riboflavin is involved with production of FMN and FAD, both of which are involved in redox reactions.
• Riboflavin causes the activation of vitamin B6.
• Riboflavin is involved in the conversion of tryptophan to niacin.
• Riboflavin is involved in the conversion of folate to its coenzymes.
• Riboflavin aids in Beta oxidation in fat metabolism.
• Riboflavin is involved as a coenzyme component of the dehydrogenases in the first step in glucose metabolism.
• Riboflavin is needed for the production of corticosteroids; erythropoiesis; gluconeogenesis; and thyroid enzyme regulation.

dietary sources: Milk, liver, meat, fish, eggs, cereal products, green leafy vegetables, whole grains, brewer's yeast, torula yeast, wheat germ, almonds, sunflower seeds.

deficiency:
• A deficiency of riboflavin usually occurs in concert with other B vitamin deficiencies. However, clinical signs are less dramatic than other deficiencies. Cheilosis and glossitis are classic deficiency symptoms. Dry and scaly skin (seborrheic dermatitis) along with itchy eyes and sensitivity to light are also common. In animals riboflavin deficiencies cause alopecia, anemia, neuropathy, corneal vascularization (precataracts) and congenital malformations.
(Sauberlich, et al. Am J Clin Nutr 1972;25:756.)
• Alcoholics are at increased risk for vitamin B2 deficiency.
• Research indicates that individuals with cataracts and sickle cell anemia are more likely to demonstrate a vitamin B2 deficiency pattern than others.

known or potential therapeutic uses: Acne rosacea, anemia (rare), athletic performance, cataracts, depression, migraine headaches.

maintenance dose: 30 mg per day.

therapeutic dose: 10-100 mg per day.

note: Vitamin B2 should be taken as part of a B-complex formula because it works in combination with vitamins B1, B3, and B6.

side effects: None known to date.

toxicity: No toxicities have been reported or suspected as being associated with vitamin B2 at typical dietary and supplemental levels. However, large doses may result in increased urinary excretion of other B vitamins, leading to imbalances

contraindications: None known to date.



Interactions

nutrient affected by drug: Doxorubicin (Adriamycin®)

• mechanism: Doxorubicin can interfere with the normal metabolism and function of vitamin B2 and increase it urinary excretion. Doxorubicin has been shown to form a 1:1 stoichiometric complex with riboflavin, as well as to compete for binding to tissue proteins.
(Pinto J, et al. Cancer 1986 Oct 15;58(8 Suppl):1911-1914.)

• research: Research with rats has demonstrated riboflavin deficiency due to doxorubicin, even when dietary sources of riboflavin have been sufficient. Studies by Pinto et al has demonstrated that the increased levels in aldosterone associated with doxorubicin are the result of the drug's inhibition of flavin coenzyme biosynthesis. They concluded that their findings with rat studies suggest that flavins play a decisive role in regulating the levels of aldosterone and raise the possibility that the doxorubicin-induced increase in serum aldosterone may be part of the pathogenetic mechanisms of cardiovascular toxicity and overall muscular weakness. Research looking at adverse effects, especially doxorubicin-induced mortality, has indicated that supplementation with riboflavin may reduce adverse side effects and enhance survival rates.
(Ogura R, et al. J Nutr Sci Vitaminol (Tokyo). 1991 Oct;37(5):473-477; Raiczyk GB, et al. Proc Soc Exp Biol Med 1988 Sep;188(4):495-499; Pinto JT, et al. Endocrinology 1990 Sep;127(3):1495-1501.)

• nutritional support: Individuals taking doxorubicin may benefit from supplementation with vitamin B2. A daily dosage of 20-25 mg of vitamin B2, the amounts found in many multi-vitamin supplements, is most likely sufficient to compensate for doxorubicin-induced deficiency. Riboflavin is non-toxic, even in high amount. Even so, individuals taking doxorubicin should consult their prescribing physician and/or a nutritionally trained healthcare professional about nutritional deficiencies related to the drug and dietary or supplemental means of protecting against adverse effects.

nutrient affected by drug: Oral Contraceptives

• research: The use of oral contraceptives can be associated with decreased levels of Vitamin B2. The clinical implications of this potential interaction are uncertain at this time. However, insufficient intake of riboflavin is associated with an increased risk of cervical dysplasia.
(Wynn V. Lancet 1975 Mar 8;1(7906):561-564.)

• nutritional support: The supplemental levels of riboflavin, 20-25 mg, found in most multivitamins are probably adequate to compensate for any potential deficiency due to the use of oral contraceptives.

nutrient affected by drug: Tetracyclines

• mechanism: Research indicates that tetracycline can interfere with the activity of vitamin B2.
(Holt GA. 1998, 258.)

• nutritional support: While depletion of riboflavin may not have clinical significance with short-term use of tetracycline, individuals using the drug for periods longer than two weeks may benefit from supplementation with riboflavin. Although vitamin B2 is essentially non-toxic, anyone using tetracycline for an extended period should consult with their prescribing physician and/or a nutritionally trained healthcare professional before starting riboflavin supplementation. A moderate supplemental dose of riboflavin is usually in the range of 20-25 mg per day, easily obtained through most multivitamin formulas. These levels can also be obtained through a diet rich in leafy green vegetables and whole grains.

nutrient affected by drug: Tricyclic Antidepressants

• mechanism: Tricyclic antidepressants decrease riboflavin absorption.
(Goodman and Gilman A, eds. 1980: 1331-1346, 1551-1601; Pinto J, et al. J Clin Invest. 1981 May;67(5):1500-1506.)

• nutritional support: Individuals undergoing therapy with tricyclic antidepressants should consult their prescribing physician and/or a nutritionally trained healthcare professional concerning potential benefits from supplementing with riboflavin. Riboflavin can be found in significant amounts in eggs, milk products, and meat, and in moderate amounts in leafy green vegetables and whole grains. Supplements providing daily dosages of 20-25 mg of riboflavin can offset depletion due to the use of tricyclic antidepressants.

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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

Ahmed F, Bamji MS. Vitamin supplements to women using oral contraceptives (studies of vitamins B1, B2, B6 and A). Contraception 1976 Sep;14(3):309-318.

Bamji MS, Safaya S, Prema K. Low dose injectable contraceptive norethisterone enanthate 20mg monthly - II. Metabolic side effects. Contraception 1981 Jan;23(1):23-36.
Abstract: Metabolic effects of a long-acting low dose injectable contraceptive, norethisterone enanthate 20-mg, monthly injections (Neten-20), was tested in 13 women belonging to the low income groups over a period of 1 year. No change was observed in hemoglobin, hematocrit, glucose tolerance, plasma lipids, iron, calcium, or serum glutamate-oxaloacetate transaminase after treatment. Marginal rise in albumin and fall in some globulin fractions was observed. The slight fall seen in serum alkaline phosphatase could be attributed to a change in lactation status. Vitamin A, pyridoxine and riboflavin status were not altered. A peculiar aberration in the tryptophan-niacin pathway as indicated by rise in kynurenic acid excretion after tryptophan load was observed. This could be corrected by multivitamin therapy. These data suggest that the use of Neten-20 for one year does not lead to adverse metabolic effects analogous to those seen with combination type oral contraceptives.

Bhat KS. Nutritional status of thiamine, riboflavin and pyridoxine in cataract patients. Nutr Rep Internat 1987;36:685-692.

Carney MW, Ravindran A, Rinsler MG, Williams DG. Thiamine, riboflavin and pyridoxine deficiency in psychiatric in-patients. Br J Psychiatry. 1982 Sep;141:271-272.
Abstract: One hundred and seventy-two successive admissions to a district general hospital psychiatric unit were examined. Routine psychiatric, drug and dietary histories were taken and signs of avitaminosis B specifically noted. Red cell transketolase (for thiamine deficiency), glutathione reductase (for riboflavin deficiency) and aspartate transaminase (for pyridoxine deficiency) were measured. Of the patients, 53 per cent were deficient in at least one vitamin, 12 per cent in more than one (30 per cent in thiamine, 27 per cent in riboflavin and 9 per cent in pyridoxine). Schizophrenics and alcoholics were significantly over-represent in those patients low in thiamine and in more than one vitamin. Patients with an affective disorder had low riboflavin and low pyridoxine. It is suggested that affective changes are characteristic of riboflavin and pyridoxine deficiency.

Goodman and Gilman A, eds. The Pharmacological Basis of Therapeutics. 6th Edition. New York: MacMillan Co., 1980: 1331-1346, 1551-1601.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998, 82-83.

Johnson, Eckardt. Rosacea keratitis and conditions with vascularization of the cornea treated with B2. Arch Ophthamol. 1940;23:899.
Abstract: 32 of 36 patients with rosacea keratitis had prompt healing following small doses: 1-4.5 mg/day orally or by injection of B2. 9 of these patients also had cutaneous rosacea and 5 of them improved. All of these patients had inadequate dietary B2 or were hypochlorhydric.

Lewis CM, King JC. Effect of oral contraceptives agents on thiamin, riboflavin, and pantothenic acid status in young women. Am J Clin Nutr 1980 Apr;33(4):832-838.

Liu T, Soong SJ, Wilson NP, Craig CB, Cole P, Macaluso M, Butterworth CE Jr. A case control study of nutritional factors and cervical dysplasia. Cancer Epidemiol Biomarkers Prev 1993 Nov-Dec;2(6):525-30.
Abstract: The association of nutritional factors with cervical dysplasia was examined through a case-control study. Analysis was conducted in 257 cases and 133 controls confirmed both by cytological examination and colposcopic findings. A 24-h dietary recall questionnaire was used to assess nutritional intake. Various risk factors (including age at first intercourse, number of sexual partners, parity, cigarette smoking, oral contraceptive use, human papillomavirus type 16 infection, and age and race) were adjusted for their potential confounding effects. While analyses were also performed to adjust for total calories, results were not changed significantly. Among the nutrients examined, vitamin A intake showed a significantly increased risk at the lowest quartile compared to the highest quartile, with an odds ratio of 2.2 (95% confidence interval, 1.2-4.2). A significant trend of increasing risk was also observed with lower intake of vitamin A (P = 0.05). Riboflavin showed increased risk at the two lower quartiles of intake with a trend test P value of 0.04. Increased risk was also found for lower intakes of vitamin C compared to the highest intake level. For folate, increased risk was found in the second highest quartile compared with the highest quartile with an odds ratio of 2.0 (95% confidence interval, 1.0-3.8). The calcium:phosphorus ratio showed an increased risk at the lowest level (odds ratio, 2.0; 95% confidence interval, 1.0-4.3). Insufficient intake of vitamin A, riboflavin, ascorbate, and folate is associated with an increased risk of cervical dysplasia.

Marz R. Medical Nutrition From Marz. Second Edition. Portland, OR. 1997.

Matsui MS, Rozovski SJ. Drug-nutrient interaction. Clin Ther 1982;4(6):423-440. (Review)
Abstract: The effect of certain drugs on nutrient metabolism is discussed. Antituberculotic drugs such as INH and cycloserine interfere with vitamin B6 metabolism and may produce a secondary niacin deficiency. Oral contraceptives interfere with the metabolism of folic acid and ascorbic acid, and in cases of deficient nutrition, they also seem to interfere with riboflavin. Anticonvulsants can act as folate antagonists and precipitate folic acid deficiency. Therefore, in some cases, supplementation with folate has been recommended simultaneously with anticonvulsant therapy. Cholestyramine therapy has been associated with malabsorption of vitamins; several reports suggest that cholestyramine affects absorption of the fat-soluble vitamins K and D and, in addition, may alter water-soluble vitamins, including folic acid. The study of the interaction of drugs and nutrients is an area that deserves a greater attention in the future, especially in groups where nutrient deficiencies may be prevalent.

Ogura R, Ueta H, Hino Y, Hidaka T, Sugiyama M. Riboflavin deficiency caused by treatment with adriamycin. J Nutr Sci Vitaminol (Tokyo). 1991 Oct;37(5):473-477.
Abstract: The present study was undertaken to determine whether administration of adriamycin causes the depletion of riboflavin content. Rats received intraperitoneal injections of adriamycin (4 mg per kg body weight) for 6 consecutive days. Urinary riboflavin excretion began to increase after 2 days of treatment with adriamycin. Erythrocyte FAD levels decreased gradually and plasma lipid peroxide contents increased markedly at the 6th day. The activity coefficient of erythrocyte glutathione reductase showed a significant increase before the decrease of flavin content and the elevation of lipid peroxide level. Therefore, the value of this coefficient obtained from erythrocyte appears to be a reliable index of riboflavin deficiency, particularly during the early stage.

Ogura R, Toyama H, Shimada T, Murakami M. The role of ubiquinone (Coenzyme Q10) in preventing Adriamycin-induced mitochondrial disorders in rat heart. J Appl Biochem 1979,1:325.
Abstract: The combined use of CoQ10 with adriamycin has been recommended for reduction of the cardiotoxicity that occurs during cancer chemotherapy. Vitamin B2-butyrate was also investigated in order to determine anti-oxidative effects on adriamycin cardiotoxicity. This vitamin analysis prevented enhanced lipid peroxidation and rectified the respiratory disorders of heart mitochondria induced by adriamycin, however, the deficiency of the CoQ10-pool was not rectified. The combined approach of using CoQ10 for rectifying the deficiency of this component and of using B2-butyrate for reducing lipid peroxidation was indicated for adriamycin cancer chemotherapy.

Okamoto K, Ogura R. Effects of vitamins on lipid peroxidation and suppression of DNA synthesis induced by adriamycin in Ehrlich cells. J Nutr Sci Vitaminol (Tokyo) 1985 Apr;31(2):129-137.
Abstract: The effects of various vitamins on lipid peroxidation and the suppression of DNA synthesis induced by adriamycin (ADR) in vitro using Ehrlich ascites carcinoma (EAC) cells were studied. ADR produced a concentration-dependent stimulation of lipid peroxidation in EAC cells. alpha-Tocopherol and coenzyme Q10 inhibited ADR-induced lipid peroxidation to about the same extent and these effects were the greatest for all antioxidants added. The inhibitory effect of riboflavin 2',3',4',5'-tetrabutyrate was greater than that of riboflavin 5'-phosphate. On measuring incorporation of [3H]thymidine into EAC cells, these vitamins did not alter appreciably the magnitude of the ADR-induced suppression of DNA synthesis in EAC cells.

Pinto JT, Delman BN, Dutta P, Nisselbaum J. Adriamycin-induced increase in serum aldosterone levels: effects in riboflavin-sufficient and riboflavin-deficient rats. Endocrinology 1990 Sep;127(3):1495-1501.
Abstract: Previous studies in rats have demonstrated that 1) aldosterone enhances biosynthesis of renal flavin coenzymes; 2) riboflavin analogs inhibit the synthesis of aldosterone; and 3) adriamycin inhibits flavin coenzyme biosynthesis. In their entirety, these findings suggest that both diminished flavin coenzyme biosynthesis induced by adriamycin and a dietary riboflavin deficiency would result in decreased formation of aldosterone. The present study examined the effects of adriamycin treatment on serum aldosterone in rats consuming either a diet adequate in riboflavin or a riboflavin-deficient diet. Groups of rats fed specially prepared diets were injected for 3 days with adriamycin (cumulative dose range, 6-24 mg/kg BW). Pair-fed controls were given saline. After death, adrenal glands were excised, and blood samples were analyzed for aldosterone levels. No changes in adrenal weights or protein and potassium concentrations were observed after adriamycin treatment. In contrast to initial predictions, in riboflavin-sufficient rats, serum aldosterone levels were markedly enhanced by adriamycin in a dose-related manner. Riboflavin-deficient animals had lower basal aldosterone levels and markedly attenuated responses to adriamycin than did riboflavin-sufficient rats. In separate groups of adriamycin-treated rats fed a normal chow diet, serum aldosterone levels increased, and serum corticosterone levels showed a small but significant decline. In addition, adriamycin treatment caused an increase in urinary potassium excretion and a decrease in sodium excretion. These results suggest that flavins play a decisive role in regulating the levels of aldosterone and raise the possibility that the adriamycin-induced increase in serum aldosterone may be part of the pathogenetic mechanisms of cardiovascular toxicity and overall muscular weakness.

Pinto J, Huang YP, Pelliccione N, Rivlin RS. Cardiac sensitivity to the inhibitory effects of chlorpromazine, imipramine and amitriptyline upon formation of flavins. Biochem Pharmacol 1982 Nov 1;31(21):3495-3499.
Abstract: Chlorpromazine, imipramine and amitriptyline, drugs structurally related to riboflavin, each inhibited the formation in vivo of flavin adenine dinucleotide (FAD) from riboflavin in rat heart at 2-5 mg/kg body weight, doses comparable on a weight basis to those used clinically. All three drugs inhibited FAD formation in heart within 5 hr after a single dose of 25 mg/kg. Chlorpromazine under these conditions also inhibited FAD formation in liver, cerebrum and cerebellum. A series of psychoactive agents structurally unrelated to riboflavin did not inhibit flavin formation in the organs tested. These findings indicate that the inhibitory effects of the drugs studied have organ specificity with respect to FAD formation.

Pinto J, Huang YP, Rivlin RS. Inhibition of riboflavin metabolism in rat tissues by chlorpromazine, imipramine, and amitriptyline. J Clin Invest. 1981 May;67(5):1500-1506.

Pinto J, Raiczyk GB, Huang YP, Rivlin RS. New approaches to the possible prevention of side effects of chemotherapy by nutrition. Cancer 1986 Oct 15;58(8 Suppl):1911-1914.
Abstract: In an effort to develop new methods for preventing side effects of chemotherapy, the authors initiated studies to determine whether Adriamycin (doxorubicin) inhibits the metabolism of riboflavin (vitamin B2). Adriamycin has been shown to form a 1:1 stoichiometric complex with riboflavin, as well as to compete for binding to tissue proteins. Adult rats treated with Adriamycin in clinically relevant doses were compared to control animals in ability to convert riboflavin into flavin adenine dinucleotide (FAD), the active flavin coenzyme derivative, in heart, skeletal muscle, liver, and kidney. Rats treated with Adriamycin exhibited diminished formation of carbon 14 (14C)FAD in skeletal muscle to nearly 50% that of controls, and in heart to about 70% to 80% of controls. Under these conditions, (14C)FAD formation in liver and kidney was largely unaffected by Adriamycin. In preliminary studies, riboflavin-deficient animals treated with Adriamycin had accelerated mortality rates compared to those of food restricted controls treated with similar doses of Adriamycin. The data as a whole suggest a potential mechanism for Adriamycin-induced cardiac and skeletal myopathy, i.e., inhibition of synthesis of FAD, a flavin coenzyme which is involved in electron transport, lipid metabolism, and energy generation. These findings in an animal model raise the possibility that defects of riboflavin nutriture, either dietary or drug-induced, may be a determinant of Adriamycin toxicity. Further studies are required to explore the potential for preventing side effects due to Adriamycin by administration of this vitamin.

Prchal JT, Conrad ME, Skalka HW. Association of presenile cataracts with heterozygosity for galactosaemic states and with riboflavin deficiency. Lancet 1978;12-13.

Pronsky Z. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991.

Raiczyk GB, Rivlin RS, Pinto J. Enhancement of adriamycin-induced mortality during riboflavin administration and riboflavin deficiency in rats. Proc Soc Exp Biol Med 1988 Sep;188(4):495-499.
Abstract: Adriamycin-treated rats were monitored for survivorship while consuming a normal diet adequate in riboflavin, a normal diet and receiving daily high-dose injections of riboflavin-5'-phosphate (flavin mononucleotide, FMN), or a riboflavin-deficient diet. Each animal was compared to a corresponding pair-fed, saline-treated control. In Adriamycin-treated rats fed the normal chow diet alone, survivorship declined within 7 days and remained constant after 12 days to about 50%. Adriamycin-treated rats consuming the normal diet and injected with FMN initially showed similar survivorship; however, after 20 days survival fell to 14%. Adriamycin-treated, riboflavin-deficient rats showed within 5 days a precipitous decline in survivorship which leveled to 5%. These results suggest that during Adriamycin treatment, proper riboflavin nutriture may be a crucial determinant of survival.

Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: MacMillan, 1984.

Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989.

Roe DA. Drug-induced Nutritional Deficiencies. 2nd ed. Westport, CT: Avi Publishing, 1985.

Roe DA. Risk factors in drug-induced nutritional deficiencies. In: Roe DA, Campbell T, eds. Drugs and Nutrients: The Interactive Effects. New York: Marcel Decker, 1984: 505-523.

Sauberlich HE, Judd JH Jr, Nichoalds GE, Broquist HP, Darby WJ. Application of the erythrocyte glutathione reductase assay in evaluating riboflavin nutritional status in a high school student population. Am J Clin Nutr. 1972 Aug;25(8):756-762.
Abstract: 431 high school students showed 16% of the girls and 6% of the boys had glutathione reductase activity coefficients indicative of inadequate riboflavin intakes. This evidence of deficiency was eliminated by B2 supplementation at 0.5mg/day for one week.

Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology 1998 Feb;50(2):466-470.
Abstract: A deficit of mitochondrial energy metabolism may play a role in migraine pathogenesis. We found in a previous open study that high-dose riboflavin was effective in migraine prophylaxis. We now compared riboflavin (400 mg) and placebo in 55 patients with migraine in a randomized trial of 3 months duration. Using an intention-to-treat analysis, riboflavin was superior to placebo in reducing attack frequency (p = 0.005) and headache days (p = 0.012). Regarding the latter, the proportion of patients who improved by at least 50%, i.e. "responders," was 15% for placebo and 59% for riboflavin (p = 0.002) and the number-needed-to-treat for effectiveness was 2.3. Three minor adverse events occurred, two in the riboflavin group (diarrhea and polyuria) and one in the placebo group (abdominal cramps). None was serious. Because of its high efficacy, excellent tolerability, and low cost, riboflavin is an interesting option for migraine prophylaxis and a candidate for a comparative trial with an established prophylactic drug.

Trovato A, Nuhlicek DN, Midtling JE. Drug-nutrient interactions. Am Fam Physician 1991 Nov;44(5):1651-1658.(Review)

Varma RN, Mankad VN, Phelps DD, et al. Depressed erythrocyte glutathione reductase activity in sickle cell disease. Am J Clin Nutr 1983;38:884-887.

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997. (Review).

Wynn V. Vitamins and oral contraceptive use. Lancet 1975 Mar 8;1(7906):561-564.
Abstract: Reports concerning the interaction between steroidal contraceptives (the combined pill) and vitamins indicate that in users the mean serum-vitamin-A level is raised and the mean serum-vitamin-B2 (riboflavine), vitamin-B6 (pyridoxine), vitamine-C, folic-acid, and vitamin-B12 levels are reduced. Other vitamins have been insufficiently studied for comment. Biochemical evidence of co-enzyme deficiency has been reported for vitamin B2, vitamin B6, and folic acid. Clinical effects due to vitamin deficiency have been described for vitamin B6--namely, depression and impaired glucose tolerance. Folic-acid deficiency with megaloblastic anaemia has been reported in only 21 cases.