Methylcobalamin is an essential nutrient and is needed to treat vitaminB12 deficiency in people with pernicious anemia, diabetes and other disorders but the ban imposed on methylcobalamin warrants scrutiny in the wake of dual standards followed by the regulatory authorities. FSSAI has been drawing flak from the industry because of the ban on methylcobalamin which has rather become a contentious issue today. There is also a nationwide ban on methylcobalamin by state drug regulators citing that FSSAI has imposed the ban based on ICMR recommendation.

On behalf of the nutraceutical industry, Dr. Sanjay Agrawal has repeatedly urged the country’s apex food regulator and other Government authorities with numerous correspondences to revoke the ban on Methylcobalamin but till date they haven’t received a favorable reply from the concerned authority.

The recommended dietary allowance value and upper tolerance limit of Methylcobalamin fixed by the autonomous body (FSSAI) under the Ministry of Health & Family Welfare is unclear too, leading to total confusion in the nutraceutical industry. Once methylcobalamin is notified, the approved recommended dietary allowance value can be defined in a scientific way, based on evidence.

The industry has argued for clarity on the technical aspect under which, methylcobalamin,on one hand is approved as a drug with recommended dietary allowance value of 2000 mcg,whereas for nutraceuticals,it has been permitted with recommended dietary allowance value of 1 mcg only.DCGI recommends 2000 mcg of methylcobalamin even in injectable form and brands are also available as patients take methylcobalamin based on their medical condition.

Also the issue on missing exact information on tolerable upper limit of vitamin B12 or methylcobalamin for neurological disorders and in boosting immunity has been festering in the public domain.

Gujarat state based many nutraceutical manufacturers have alleged that the dual standards of FSSAI is very much evident with the presence of FSSAI approved brands of methylcobalamin in the market with 1500 microgram (mcg) quantity/per serving. Some of the widely sold brands are Rejunex CD3,Locopen capsule, Neugaba M 75 capsule, Nervup 500 mcg injection, Nuroz Forte, Nurofine 2500 injection, Actavis 2500 injection, etc. There are more than half a dozen of other brands with the same formula.

On January 7, 2020, FSSAI had issued a notification regarding recommended dietary allowance value of vitamin B12 which is specified as 1 mcg without mentioning type of vitamin B12 like methylcobalamin, adenosylcobalamin, hydroxycobalamin and cyanocobalamin. But the Drugs Controller General of India has recommended 2000 mcg of methylcobalamin in injectable form and respective brands are available as physicians are prescribing it for patients.

Previously, in a draft guideline issued in 2017, which is also considered as extension of regulation 2016, the FSSAI added the word ‘derivatives of vitamins’ to the approved list. Manufacturers continued to manufacture methylcobalamin considering it as a derivative of methylcobalamin.

The Section 22 of FSS Act, 2006 mentions foods for special dietary uses or functional foods or nutraceuticals or health supplements shall contain minerals or vitamins or proteins or metals or their compounds or amino acids in amounts not exceeding the recommended dietary allowances for Indians. As the regulations are bound to follow provisions mentioned under Act, the same has been enshrined into the Food Safety and Standards (Health Supplements, Nutraceuticals, Food for Special Dietary Use, Food for Special Medical Purpose, Functional Foods and Novel Foods) Regulations 2016.

But, in a letter to the FSSAI, CDSCO brought to the notice that various brands of products containing methylcobalamin are manufactured and sold having therapeutic intervention under the FSSAI license.The CDSCO had then urged the FSSAI to take action against Gujarat-based manufacturers for manufacture and sale of methylcobalamin meant for therapeutic intervention in contravention of norms.

Recently Dr Sanjay Agrawal has raised alarm on the blatant violation of administrative protocols in the regulatory regime in India citing the FSSAI’s directive to all State Drug Controllers to take action against manufacturers for production and sale of methylcobalamin meant for therapy in cases of diabetes and neurological disorders, in contravention to norms.

According to him, it is evident that the issue about taking action on methylcobalamin manufacturers is totally uncalled for and it indicates lobbying and malafide intent to discourage the industry to satisfy vested interests.

Thus, in a recent representation made to Union Ministry of Chemicals and Fertilizers, Dr Agrawal has recommended the Drugs Controller General of India (DCGI) to be given the sole authority for implementation of nutraceutical policies and regulations citing both FSSAI and ICMR as toothless authorities, giving reference that ten years back the nutraceutical industry was under the DCGI only and was well regulated.

He further mentions in the letter, ‘it is pertinent to mention here that there are only two variants of vitamin B12 namely cyanocobalamin and hydroxycobalamin which are covered under Food Safety and Standards (Health Supplements, Nutraceuticals, Food for Special Dietary use, Food for Special Medical Purpose, Functional Food And Novel Food Regulation 2016) (FSSAI-2016) but does not cover methylcobalamin’.

Few months ago, Dr Agrawal had also urged the Union Minister of Chemicals and Fertilizers to urgently notify methylcobalamin for neurological disorders and informed that regulatory action cannot be taken against those who are manufacturing methylcobalamin-based formulations without scientifically defining the efficacious recommended dietary allowance value.

According to nutraceutical industry experts, no adverse effect has been associated with excess methylcobalamin intake from food or supplements in healthy individuals. Methylcobalamin has a history of safe long term use as a therapeutic agent given in high dosage or via intramuscular injection for the treatment of disorders associated with impaired vitamin B12 absorption but industry is yet to see the much awaited notification on the same.

Dr Agrawal has been pursuing the issue of revoking the ban on methylcobalamin by FSSAI for more than a year but yet this issue has not come to a logical conclusion. On the contrary, FSSAI has allowed usage of cyanocobalamin- which has cyanide content within, but banned methylcobalamin- which is a superior form of vitamin B12.

Dr Agrawal has again sought clarity from FSSAI on Indian Council of Medical Research stipulated values of recommended dietary allowance value for methylcobalamin as prophylactic use in neurological disorders. Dr Agrawal’s recent correspondences to FSSAI in spite of being addressed in a holistic manner have turned into a blame game between FSSAI and ICMR.

According to sources, taking an entirely U-turn, the national food safety regulator has instead directed the industry to refer the issue to the ICMR in blatant denial of laid down protocols and ethics. This is leading to confusion and hence detrimental to the public interest.

Industry, after almost more than a year, is still perplexed with FSSAI clarification regarding recommended dietary allowance values on methylcobalamin (vitamin B12). Any food business operator who wants to manufacture, import, market or sell the afore mentioned products shall have to comply with the provisions of these regulations.

Dr Agrawal had received a letter in December 2019 from FSSAI about Methylcobalamin being soon to be approved and to be provided recommended dietary allowance value of it for neurological disorders, but industry is yet to see the much awaited notification on the same.

Even as the notification regarding approval of the right recommended dietary allowance value for methylcobalamin remains pending for almost more than a year despite FSSAI scientific panel’s nod of notifying it in last December, the drug and nutraceutical industry rues that the nationwide ban on methylcobalamin has proved to be an extortion bid by state drug controllers in the guise of regulations.

This is all the more contradictory considering that ICMR and National Institute of Nutrition have recently issued another report which have different stipulated recommended dietary allowance values of methylcobalamin and estimated average nutrient requirements for Indians. In the Norwegian Vitamin (NORVIT) intervention trial also, patients with acute myocardial infarction received 400 mcg of vitamin B12 daily for three years and reported no serious adverse events.

On behalf of the nutraceutical industry, Dr Agrawal is planning to again make a representation on this matter with the Union Ministry of Chemicals and Fertilizers since their previous correspondences (December 2019 and June 2020) and pleas to FSSAI have not been addressed with due diligence and rationality.

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Industry is at crossroads as the Union Health Ministry is being misguided with reference to putting in place the right regulatory regime to control nutraceuticals and drugs. A silent and yet intense anger is also raging in the industry in the absence of a clear regulatory regime today.  Industry insiders and experts have upped their ante against the intense lobbying related to delegating power to regulate nutraceuticals to a toothless body like Food Safety and Standards Authority of India (FSSAI).

Besides this, the Union Health Ministry is also being misguided to approve an irrational move to bring about certain amendments in the provisions of the Drugs and Cosmetics (D&C) Act towards regulating nutraceuticals on the premise of recommended dietary allowance (RDA) value without even informing and consulting industry. This probably according to industry insiders is happening as a part of lobbying at the Centre towards appeasing a section of people in the industry and Ministry.

This is also very much evident as the state licensing authorities (SLAs) are trying to enforce the ban invoked by the Centre in June 2019. Drugs and nutraceutical manufacturers have since then been defying the one-year old arbitrary and draconian ban on methylcobalamin due to dubious nature of Indian Council of Medical Research (ICMR) and FSSAI recommended dietary allowance (RDA) values and tolerable upper limit (TUL) even in major micronutrients like vitamin C.

The Central Drugs Standard Control Organisation (CDSCO) has also been following with FSSAI to take action against Gujarat based manufacturers for production and sale of methylcobalamin meant for therapeutic intervention in contravention to norms. In a recent representation made to Union Ministry of Chemicals And Fertilizers, industry has also once again recommended Drugs Controller General of India (DCGI) to be given the sole authority for implementation of nutraceutical policies and regulations, citing FSSAI and ICMR as toothless bodies, giving reference that ten years back nutraceuticals were under DCGI only and was properly regulated.

Gujarat based manufacturers have alleged that the dual standards of FSSAI is very much evident with the presence of already FSSAI approved brands available with 1500 microgram (mcg) quantity/per serving. Some of the widely sold brands are Locopen capsule, Neugaba M 75 capsule, Nervup 500 mcg injection, Nuroz Forte, Nurofine-2500 injection, Actavis 2500 injection, etc.

There are more than half a dozen other brands with the same formula. Rejunex CD3 of Intas is a FSSAI approved product containing 1500 mcg methylcobalamin. In a letter to the FSSAI, CDSCO had brought to the notice that various brands of products containing methylcobalamin are manufactured and sold having therapeutic intervention under the FSSAI license.

Nutraceutical and drug industry have alleged that FSSAI and CDSCO have been turning a blind eye to the contentious issues raised with reference to RDA values of vitamin C and other micro-nutrients like methylcobalamin which are vital for boosting immunity, mental health and other co-morbid chronic ailments in the crucial juncture of COVID-19 pandemic. The central government has also recommended 1000 mcg of vitamin C as prophylactic use against COVID-19 whereas its RDA is 40 mcg due to poor regulatory and policy interventions from apex and responsible authorities like ICMR, FSSAI and DCGI.

Unmindful of the concerns regarding RDA for mental health conditions and neurological disorders, industry has dubbed FSSAI as white elephant and urged the centre that there is no need of FSSAI as the authority is not competent enough to talk on technical and scientific aspects and only relies on the dictates of ICMR. It is a sheer wastage of public money which has been pooled in to maintain an authority which is doing more harm than good.

Industry players have also voiced concern that methylcobalamin’s RDA value has been approved by CDSCO up till 2000 mcg but FSSAI is approving only 1 mcg which is of no use. DCGI has approved 2,000 mcg of methylcobalamin even in injectable form and brands are available as patients take methylcobalamin based on the medical condition. Until and unless, FSSAI does not inform the industry that methylcobalamin is approved, there is no value of prescribing RDA value for the same.

Surprisingly the mails which we have received from FSSAI on methylcobalamin and cyanocobalamin, both have the same RDA value for manufacturing. Please be advised we are talking about per serving usage value which the manufacturer can refer to and not the RDA value for a healthy person.

FSSAI and CDSCO have been drawing flak from the industry as there is no clarity on TUL and RDA values of many micronutrients including vitamin C and methylcobalamin. The issue has been festering due to missing exact information on TUL of vitamin B12 [methylcobalamin to be specific] from the public domain. No adverse effect has been associated with excess methylcobalamin intake from food or supplements in healthy individuals.

Methylcobalamin has a history of safe long term use as a therapeutic agent given in high dosage or via intramuscular injection for the treatment of disorders associated with impaired vitamin B12 absorption. Additionally, we had received a letter in December 2019 from FSSAI about methylcobalamin’s approved RDA value for neurological disorders by the technical committee but industry is yet to see the notification on the same.

Methylcobalamin is an essential nutrient and is required to treat vitamin B12 deficiency, in people with pernicious anaemia, diabetes and other conditions as well. It is important for the brain, nerves and for the production of red blood cells (RBCs). On January 7, 2020, FSSAI issued a notification regarding RDA of vitamin B12 which is specified as 1 mcg without mentioning type of vitamin B12 like methylcobalamin, adenosylcobalamin, hydroxycobalamin and cyanocobalamin.

Former CEO of FSSAI Pawan Agrawal had promised in December 2019 that methycobalamin has been approved by the scientific committee and will take due course of its time to be included in the gazette. Nevertheless, the industry has waited for almost 1 year without any progress for inclusion of methylcobalamin in the gazette.

Dr Sanjay Agrawal
Leading Pharmaceutical Consultant and Inventor
Editor-in Chief of IJM Today
6/146, Malviya Nagar ,
Jaipur, Rajasthan-302017
Phone : 0141 2550814

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Methylcobalamin has been in clinical use since the 1990s. Methylcobalamin is an essential nutrient and is required to treat vitamin B12 deficiency, in people with pernicious anaemia, diabetes and other conditions as well. It is important for the brain, nerves and for the production of red blood cells (RBCs).

Methylcobalamin as a supplement is very essential specifically for Indians where the majority of the population is vegetarian as naturally it is present in nonvegetarian products. When a supplement is taken for prophylactic cause it must at least be of the therapeutic dose. Methylcobalamin is approved by CDSCO till 2000 mcg but FSSAI is approving only 1 mcg which is of no use to manufacture.

In a recent representation made to union ministry of chemicals and fertilizers, industry has once again recommended Drugs Controller General of India (DCGI) to be given the sole authority for implementation of nutraceutical policies and regulations citing Food Safety and Standards Authority of India (FSSAI) as a toothless body. Ten years back nutraceutical was under DCGI only.

A therapeutic dose for conditions requiring methylcobalamin would be a minimum of 1500 µg and a maximum of 6000 µg per day. No significant therapeu­tic advantage appears to occur from dosages exceeding this maximum dose; however, it is likely that beneficial physiological effects occur at dosages as low as 100 µg per day, especially if this dose is given for long time.

Nutraceutical and drug industry have alleged that FSSAI has been turning a blind eye to the contentious issues raised with reference to RDA values of Vitamin C and other micro-nutrients like methylcobalamin which are vital for boosting immunity, mental health and other co-morbid chronic ailments in the crucial juncture of COVID-19 pandemic.

Prime Minister Narendra Modi has also recommended 1000 mcg of Vitamin C as prophylactic use against COVID-19 whereas its RDA is 40 mcg due to poor interventions from apex and responsible authorities like ICMR, FSSAI and DCGI. Manufacturers of methylcobalamin have also been defying the arbitrary and draconian ban on methylcobalamin in Gujarat due to dubious nature of Indian Council of Medical Research and FSSAI recommended RDA value and upper tolerance limits in major micronutrients.

Unmindful of the concerns regarding RDA for mental health conditions and neurological disorders, industry has dubbed FSSAI as white elephant and urged the Centre that there is no need of FSSAI as the authority is not competent enough to talk on technical and scientific aspects and rely on the dictates of Indian Council of Medical Research (ICMR). It is a sheer wastage of public money which have been pooled in to maintain an authority which is doing more harm than good.

FSSAI has been drawing flak from the industry as there is no clarity on tolerable upper limit (TUL) and RDA value. There is a nationwide ban on the methylcobalamin with state drug regulators citing that FSSAI has imposed the ban based on ICMR recommendation.

This is all the more contradictory considering that ICMR and National Institute of Nutrition (NIN) has recently issued another report which have different stipulated RDA values of methylcobalamin and estimated average nutrient requirements for Indians.

According to an industry expert, “The dual standards of FSSAI can also be seen by the presence of already FSSAI approved brands available with 1500 mcg qty/per serving. Rejunex CD3 of Intas is a FSSAI approved product containing 1500 mcg methylcobalamin. Some of the widely sold brands are Locopen capsule, Neugaba M 75 capsule, Nervup 500 mcg injection, Nuroz Forte, Nurofine-2500 injection, Actavis 2500 injection, etc. There are more than half a dozen other brands with the same formula.”

According to Gujarat FDCA Commissioner Dr H G Koshia, “There is a ban on methylcobalamin pan-India and the states need to follow it as per FSSAI directive.” The Central Drugs Standard Control Organisation (CDSCO) had earlier urged the FSSAI to take action against Gujarat-based manufacturers for manufacture and sale of methylcobalamin meant for therapeutic intervention in contravention of norms.

Industry can’t comprehend that under which policies CDSCO and FSSAI are directing each other. Both are two autonomous regulatory body with their independent domain expertise. Specifically a letter was addressed to Dr H. G Koshia by Deputy Director RCD Shri Sanjeev Kumar to investigate the issue having higher Methylcocbalamin concentration without intimating FSSAI Delhi office and the Ministry of Chemical and Fertilizer. In another letter Gujarat FDA office has informed FSSAI regarding manufacturing of methylcobalamin in Gujarat.

In a letter to the FSSAI, CDSCO has brought to the notice that various brands of product containing methylcobalamin are manufactured and sold having therapeutic intervention under the FSSAI license.

In view of the same, it has been recommended on priority basis to instruct drug inspectors and food safety officers to launch surveillance drives against various brands of products containing methylcobalamin being manufactured and sold under FSSAI license, the letter further stated.

Industry players have also voiced concern that methylcobalamin RDA value has been approved by Central Drugs Standard Control Organisation (CDSCO) uptill 2000 mcg but FSSAI is approving only 1 mcg which is of no use. Drugs Controller General of India (DCGI) recommended 2,000 mcg of methylcobalamin even in injectable form and brands are available as patients take methylcobalamin based on the medical condition.

“Until and unless, FSSAI does not inform the industry that methylcobalamin is approved, there is no value of prescribing RDA value for the same. Surprisingly the mails which we have received from FSSAI on methylcobalamin and cyanocobalamin, both have the same RDA value for manufacturing. Please be advised we are talking about per serving usage value which the manufacturer can refer to and not the RDA value for a healthy person,” Ahmedabad based pharma consultant Dr Sanjay Agrawal argued.

On January 7, 2020, FSSAI issued a notification regarding RDA of vitamin B12 which is specified as 1 mcg without mentioning type of vitamin B12 like methylcobalamin, adenosylcobalamin, hydroxocobalamin and cyanocobalamin.

Former CEO of FSSAI Pawan Agrawal had promised in December 2019 that methylcobalamin has been approved by the scientific committee and will take due course of its time to be included in the gazette. Nevertheless, the industry has waited for almost 10 months without any progress for inclusion of the methylcobalamin in the gazette, an industry expert remarked.

RDA for methylcobalamin in the US is 2.4 mcg where most of the population is vegetarian whereas India with a vegetarian population mcg is set as 1mcg. I would like to apprise you that Vitamin B12 is present in non vegetarian sources only. Also other countries have kept RDA and per serving usage value as a separate entity that is being goofed up by FSSAI in India.

There is an urgent need for inclusion of methylcobalamin in the gazette and reviewing the RDA for nutraceutical manufacturers by not forgetting that products are already available at higher concentrations, informed pharma expert Anshu Yadav adding that until and unless FSSAI does not inform the industry that methylcobalamin is approved, there is no value of prescribing RDA value for the same. Surprisingly the mails which we have received from FSSAI regarding methylcobalamin and cyanocobalamin both have the same RDA value to manufacture. We are talking about per serving usage value which the manufacturer can refer to and not the RDA value for a healthy person.

Dr. Sanjay Agrawal
Leading Pharmaceutical Consultant
Editor- in Chief of IJMToday
Email: drsanjay@drsanjayagrawal.com
Mob: 98253 81729

The post FSSAI red faced as Industry lambasts authority for denigrating science by subscribing to ICMR arbitrary RDA values appeared first on Health Vision.

Methylcobalamin plays very important role in maintaining good health system. It is a cofactor for the cytosolic methionine synthase. It is needed for conversion of homocysteine to methionine. Methylcobalamin is the only form of vitamin B12 that can cross the blood brain barrier without biotransformation. Its methyl group stimulates serotonin secretion, a neurotransmitter which is responsible for mood enhancement and protects the brain from damage against excitatory neurotransmitters.

Several pharmaceutical experts and consultants have opposed Food Safety and Standards Authority of India’s blanket ban on methylcobalamin in Gujarat State. FSSAI notification on the ban was issued on June 11, 2019 and FSSAI also issued a list of 73 approved formulations which included methylcobalamin. The FSSAI regulation has listed two forms of vitamin B12 namely methylcobalamin and cyanocobalamin which are widely available in the market across the country.

Cyanocobalamin, a form of vitamin B12 is cheap, synthetic, mild toxic and an inactive form of B12 not absorbed well orally and is converted to methylcobalamin after 48 hours of entering into the human body system where only a small amount is converted. Methylcobalamin is a naturally found ingredient in food sources. It bypasses several phases of absorption cycle and helps reverse symptoms.

The FSSAI has been established under the Food Safety and Standards Act, 2006 which is a consolidating statute related to food safety and regulation in India. The FSSAI is headed by a non-executive chairperson, appointed by the Central government, either holding or has held the position of not below the rank of secretary to the Government of India and it is an autonomous body but Gujarat commissioner of Food and Drug Control Administration is reporting to both Drug authority and Food Authority.

So in such case there is conflict of interest as the commissioner, FDCA Gujarat can approve the product methylcobalamin under drug regulation while ban it under food regulation. Methylcobalamin is included in the approved list of Drugs Controller General of India and it is continuously manufacturing under drug regulation whereas FSSAI has put a ban on it. The Gujarat FDA office had received a letter from deputy director RCD FSSAI Delhi which is copied only to DCGI.

 Two authorities i.e CDSCO and FSSAI- too complications:

This has raised a very serious concern that whether it is needed two authorities in India i.e CDSCO and FSSAI, and why a product is approved by one authority and banned by other authority. These concerns are raised by many pharmaceutical experts and consultants, but not getting response from the authorities concerned. It is contradictory that methylcobalamin is in the approved list by DCGI and it has been manufactured under drug regulation whereas FSSAI has put a blanket ban on methylcobalamin in Gujarat state only, experts conclude.

Recently many industry experts have raised concern over the blanket ban on methylcobalamin in Gujarat state. In other states of the country, there is no ban on methylcobalamin, which is a significant pharmacopoeial ingredient employed in drugs and other food supplements. Experts have pinpointed that ban on methylcobalamin warrants scrutiny in the wake of dual standards followed in such case by the regulatory authorities.

Methylcobalamin is approved across the globe:

Methylcobalamin is also approved across the globe for use in nutraceutical and food supplements. Methylcobalamin is the only form of vitamin B12 that can cross the blood brain barrier without biotransformation. Its methyl group stimulates serotonin secretion, a neuro-transmitter, which is responsible for mood enhancement and protects the brain from damage against excitatory neurotransmitters.

FSSAI in its Food Safety and Standards (Health Supplements, Nutraceuticals, Food for special Dietary use, Food for special medical purpose, Functional food and novel food regulation 2016) has approved only cynocobalamin and hydroxycobalamin. The cynocobalamin, which when enters into the human body system leaves the cynide group and take methyl group from the human body to form methylcobalamin as methylcobalamin is the active form of vitamin B12 in the human body. On the other hand Methylcobalamin is approved across the globe in nutraceutical and food use. In a draft guideline issued in 2017 which is also considered as extension of regulation 2016, FSSAI added the word derivatives of vitamins to the approved list.

Methylcobalamin was introduced to the medical profession by the pharmaceutical market as it is the active metabolite of cyanocobalamin and is also an active form of vitamin cyanocobalamin. It plays very important role in to maintain good health system. Dietary cobalamin deficiency causes very serious health issues. Recent many research reports shown that methylcobalamin significantly improves visual accommodation, while cyanocobalamin appears to be ineffective.

Cyanocobalamin takes a lot of effort to reduce it to the active form; hence cyanocobalamin absorption varies greatly between individuals. Methylcobalamin is better utilized and is direct active form and it is a cofactor for the cytosolic methionine synthase. It is needed for the function of the folate-dependent enzyme and methionine synthase. This enzyme is required for the synthesis of methionine from homocysteine. Methionine in turn is needed for the synthesis of S-adenosylmethionine, a methyl group donor employed in several biological methylation reactions, including the methylation of a number of sites within DNA, RNA, and proteins.

Inadequate function of methionine synthase can lead to an accumulation of homocysteine, which has been associated with increased risk of cardiovascular and neuropsychiatric disorders. Methylcobalamin due to its high plasma protein binding capacity is accumulated and retained in the body much better than cyanocobalamin therefore the retention time is more. In any form, methylcobalamin has higher bioavailability than cyanocobalamin. It is so efficient that even orally it was found effective in pernicious anemia – a disease with deficiency of red blood cells.

Methylcobalamin  a natural form of vitamin B12:

Methylcobalamin is a naturally occurring form of vitamin B12 which can be obtained through supplements, as well as food sources and it is the most important vitamin in the group and one of the two active and natural forms of B12. It helps in reducing homocysteine concentrations and generates S-adenosyl methionine, which is the most significant methyl donor in human body, and supplying methyl groups for critical chemical reactions to help maintain health system. Methylcobalamin shows its greatest utility with people suffering from acute or chronic degenerative neurological symptoms, here it is considered as the only promising treatment available. It bypasses several potential issues in the absorption cycle and helps relieve or completely reverse symptoms.

Nutritional inadequacies, enzyme defects, and pathological changes to tissues can all contribute to a reduced ability of the body to accomplish the synthesis of the active forms of vitamin B12 from cyanocobalamin. Commercial cyanocobalamin exists because after creating hydroxocobalamin (from bacteria), some cobalamins bind to cyanide during the charcoal filtration process. That is what they use to make the cyanocobalamin. Cyanocobalamin is a form of vitamin B12 and is considered to be a cheap, synthetic, mild toxic and an inactive form of B12. It consists of a cyanide donor in its chemical structure and is the most commonly used commercial preparation of vitamin B12 used.

It is considered as the most stable form, because of the cyanide molecule present in the structure has the great attraction to the cobalamin and protects it from extreme conditions like high temperatures. It is not absorbed well orally and requires methyl groups to detoxify it. The molecule that is attached to the cobalamin is known as a donor. The two most common donors in the available supplements are cyanide (making cyanocobalamin B12, or cyano B12), and methyl (making methylcobalamin B12, or methyl B12). When cyanocobalamin enters in to human body, it is converted to either methylcobalamin or adenosylcobalamin, these are the two active forms of vitamin B12 in mankind.

When cyanocobalamin is absorbed, it converts to hydroxocobalamin (which means discarding of the cyanide in the process) and then to methylcobalamin and adenosylcobalamin. When taken through oral route, absorption of this form is enormously reduced in case of any gastric acid problems. Besides, cyanocobalmin takes more than 48 hours to eventually convert to usable and active component methylcobalamin, and even then also only a small amount is converted. During this conversion it requires the interaction of possibly depletion of glutathione and other agents.

Manufacturing companies of methylcobalamin continue their production by considering it as a derivative of Methylcobalamin. In June 2019, the manufacturers of Gujarat are at stake when a letter was issued by FDA commissioner, Gujarat stating ban on Methylcobalamin. Such action has not yet initiated in other states therefore the products are continued to manufacture.

Beneficial actions

The recent many laboratory and clinical studies have shown that methylcobalamin has following beneficial actions: Nerve protection through healthy myelin synthesis; Promotes  regeneration of injured nerves; Analgesic action: Relieves nerve pain associated with nerve degeneration, nerve compression, nerve inflammation; and Anti-oxidant action. Methylcobalamin has excellent tolerability, whether given orally or parenterally and many laboratory, research and clinical studies using doses as high as 25-50 mg, given twice weekly, have shown that Methylcobalamin therapy is free from any serious side effects.

Methylcobalamin therapy

Methylcobalamin therapy has been found very useful in prevention as well as treatment of vitamin B12 deficiency. Recent many laboratory and clinical studies have demonstrated efficacy of methylcobalamin in the treatment of following disorders: Diabetic peripheral neuropathy; Chronic low back pain; Radicular pain like sciatica; Carpal tunnel syndrome; Post-herpetic neuralgia; Trigeminal neuralgia; Bell’s palsy and Amyotrophic lateral sclerosis.

Dr Sanjay Agrawal
Leading Pharmaceutical Consultant
Editor-in Chief of IJMToday

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Methylcobalamin is an activated form of vitamin B12 and it has been used to treat nutritional diseases and also some other diseases such as Alzheimer’s disease and rheumatoid arthritis. As an auxiliary agent, it exerts neuronal protection by promoting regeneration of injured nerves and antagonizing glutamate-induced neurotoxicity. Recently several lines of evidence shows that methylcobalamin may have potential analgesic effects in experimental and clinical studies.

A deficiency in vitamin B12 can cause serious symptoms

Vitamin B12 deficiency is observed more in elderly and pregnant women. Methylcobalamin (commonly known as mecobalamin or methyl B12) is an analog of vitamin B12 which treats or prevents the pathology arising from the deficiency of vitamin B12. It contains methyl alkyl bonds and is different from cyanocobalamin because it contains cynide. A deficiency in vitamin B12 can cause serious symptoms, including fatigue, nerve damage, digestive issues, and neurological disorders such as depression and memory loss.

Therefore, it is necessary to turn to vitamin B12 supplements to help, meet the needs and to prevent a deficiency. Methylcobalamin has been used as a supplement in patients with vitamin B12 deficiency and in those with diabetes and other neuropathies. It has been used in clinical studies to reduce serum homocysteine levels, and it is an essential nutrient and is required to treat vitamin B12 deficiency in people with pernicious anaemia, diabetes and other conditions as well. For example, methylcobalamin alleviates pain behaviours in diabetic neuropathy, low back pain and neuralgia, and it improves nerve conduction, promotes the regeneration of injured nerves, and inhibited ectopic spontaneous discharges of injured primary sensory neurons.

It is important for the brain, nerves and for the production of red blood cells and it is the only form of vitamin B12 that can cross the blood brain barrier without bio-transformation. Methylcobalamin is the methyl form of cobalamin obtained from hydroxycobalamin, either by chemical manipulation in the lab or in the body as a natural process. Cyano- and hydroxocobalamin are considered the transport forms of cobalamin, while methylcobalamin and deoxyadenosylcobalamin are the active forms involved in enzymatic reactions. Information suggests methylcobalamin may play a role in immune modulation and in cancer.

Methylcobalamin  used in clinical studies

Methylcobalamin has been used in clinical studies to reduce serum homocysteine levels. Methylcobalamin is the most abundant form in human plasma, whereas in most human tissues, deoxyadenosyl cobalamin is the most abundant, with aquacobalamin coming second. Methylcobalamin plays a key role in maintaining good health. It is needed for integrity of myelin, neuronal function, proper red blood cell formation and DNA synthesis. It is a beneficial drug to most of the common disorders such as cardiovascular disorders, diabetes, anemia, hyperhomocysteinemia and degenerative disorders, diabetic neuropathy, degenerative disorders and in the preliminary treatment of amyotropic lateral sclerosis.

It has been used to treat some nutrition based disease such as dementia and exerts neuronal protection by promoting regeneration to injured nerves. It antagonizes the glutamate induced neurotoxicity and also manifests analgesic effects. It alleviates pain behavior in diabetic neuropathy, low back pain, neuralgia and promotes nerve conduction. It helps the body to use fats and carbohydrates for energy.

Methylcobalamin’s oral administration of 500 mcg three times daily for four weeks results in improvement of peripheral neuropathy and it produces very significant effect after 12 weeks of treatment. An improvement in vibration sense, lower motor neuron weakness and sensitivity to pain is also observed in various studies.

For stress relief, methylcobalamin can be taken in the dose of 500 mcg per day. In the acute cases of neuropathy, dose of 1500 mcg per day can be taken. Dose of 1 mg per day is required to be taken for age related brain decay. Methylcobalamin can be combined with similar dose of folic acid and pyridoxine. Deficiency of vitamin B12 is strictly seen in pure vegetarian, dose of 100 mg day can rebalance its requirement in the intestine. All human being need at least 3 mg per day of this drug for the basic nerve support.

Safe use even at high dosages:

Vitamin B12 has a long history of safe use even at high dosages. At usual dosages, the cobalt and cyanide content are not considered to be toxicologically relevant. Vitamin B12 is obtained from animal products (eg, meat, fish, shellfish, poultry, eggs, milk, and milk products). Tempeh, made from fermented soybeans, contains the beneficial bacteria responsible for producing vitamin B12.

Commercial forms of methylcobalamin are produced in the lab through the conversion of cyanocobalamin. Cyanocobalamin is a synthetic form of vitamin B12 that is not naturally available. It is used more frequently in supplements, as it is considered more stable and cost-effective than other forms of vitamin B12. When cyanocobalamin enters human body, it is converted into either methylcobalamin or adenosylcobalamin, which are the two active forms of vitamin B12 in human body. Vitamin B12 deficiency can be solved with the administration of cobalamin. Usually either cyano- or hydroxo-cobalamin is used to restore normal levels. However, there is no reason to suggest lack of efficacy; and reports exist of therapeutic efficacy of methylcobalamin.

A systematic review shows evidence supporting vitamin B12 supplementation to reduce the risk of diabetes or cardiovascular disease. A 2013 meta-analysis that included 15 studies and 1,106 diabetic patients found combination therapy for 2 to 4 weeks with intravenous alpha lipoic acid 300 to 600 mg/day plus intravenous methylcobalamin 500 to 1,000 mg/day to be superior to methylcobalamin  monotherapy for improving nerve conduction. Similarly, combination therapy with prostaglandin (10 or 20 mcg intravenous), methylcobalamin (500 to 1,500 mcg intravenous/intramuscularly plus lipoic acid (300 or 600 mg/day intravenous) significantly improves nerve conduction velocity compared with combination therapy without the lipoic acid in a 2015 meta-analysis of 18 randomized clinical trials involving patients with diabetic peripheral neuropathy.

A Cochrane systematic review and meta-analysis of antioxidants for male sub fertility identified one double-blind, randomized, parallel study that administered vitamin B12; however, the lack of useable data prevented its inclusion in the meta-analysis. Japanese men with abnormal sperm count or motility received mecobalamin at a dose of either 1,500 or 6,000 mcg/day for 12 weeks. No statistically significant difference was observed in sperm parameters compared to placebo.

Folate and vitamin B12 are essential nutrients which are not synthesized in humans and whose deficiency is considered as heath problem globally such as anemia and neuronal dysfunction. Methylcobalamin (5 mg, 60 mg vegetarian lozenges) is active in the central nervous system outside the mitochondrion and is essential for cell growth and replication. Sometimes the liver cannot convert cyanocobalamin into adequate amount of methylcobalamin needed for proper neuronal functioning. Through enhanced methylation, it exerts its nerve cell protective effect and accelerates its growth. Methylcobalamin is the only form of vitamin B12 that can cross the blood brain barrier without biotransformation, and it converts homocysteine to methionine and reduces the potential to damage. It also forms adenosylcobalamine, the other form of vitamin B12 for mitochondrial energy production.

Working or acting mechanism of methylcobalamin

Methylcobalamin works by functioning in the production of a compound called myelin, which covers and protects nerve fibers, rejuvenates the damaged neuron. Without enough methylcobalamin, myelin sheath does not form properly due to which nerve fibers suffers and people experience irreversible nerve damage. An intrinsic factor made in the stomach, must be present in the intestinal tract to allow its proper absorption. People lacking this factor show vitamin B12 deficiencies such as pernicious anemia (a slow and insidious process that can end in death. Pernicious anemia in fact means ‘leading to death’). Methylcobalamin is used as a cofactor in methionine transferase enzyme, an enzyme which converts amino acid homocysteine to methionine through folate cycle.

Vitamin B12, also known as cobalamin, is an important water-soluble vitamin involved in red blood cell production, brain health, and DNA synthesis. Vitamin B12 has a long history of safe use even at high dosages. Vitamin B12 is obtained from animal products (eg, meat, fish, shellfish, poultry, eggs, milk and milk products). Tempeh, made from fermented soybeans, contains the beneficial bacteria responsible for producing vitamin B12. Methylcobalamin and cyanocobalamin can be converted to other forms of vitamin B12. Both methylcobalamin and cyanocobalamin are reduced to a cobalamin molecule that is converted to the active forms of this vitamin within the cells of the body.

Some researchers recommend treating vitamin B12 deficiency with either cyanocobalamin or a combination of methylcobalamin and adenosylcobalamin due to distinct properties of these latter two forms. Although distinct differences exist between methylcobalamin and cyanocobalamin, both have beneficial effects on health and can prevent vitamin B12 deficiency. Studies find that treating seven vitamin B12-deficient People with oral methylcobalamin normalized vitamin B12 levels in their blood within just 2 months.

Similarly, another study shows that taking cyanocobalamin capsules for 3 months also increased vitamin B12 levels in 10 people with pernicious anemia, a condition caused by impaired B12 absorption. Other some studies show that both methylcobalamin and a B-complex containing cyanocobalamin were effective in reducing symptoms of diabetic neuropathy, a complication of diabetes that leads to nerve damage. Additionally, many animal studies have found that each form could have neuroprotective effects and may be beneficial in treating conditions that affect your nervous system.

Conclusion

The blanket ban on methylcobalamin would soon to be revoked as it has been approved by FSSAI scientific panel as a nutraceutical ingredient. It is an essential nutrient and is required to treat vitamin B12 deficiency in people with pernicious anemia, diabetes and other disorders. Methylcobalamin aids in growth of healthy blood cells, nerve cells in the body. It is a best treatment as well as dietary supplement for the people who cannot absorb vitamin B12 and/or suffers from its deficiencies. Monotherapy of methylcobalamin improves plasma/serum homocysteine level and improve the neuropathic symptoms also. Combination therapy with other vitamin B complexes seems to be more effective. Hence, methylcobalamin may be considered as one of the promising dietary supplement and medicine having a number of potential benefits.

Methylcobalamin is widely marketed in the country as a drug for neurological disorders with a recommended dietary allowance of 2000 mcg intramuscular but according to FSSAI it is detrimental for patients when it used above 1 mcg for prevention and disease management. Industry experts pinpoint that a ban imposed on methylcobalamin warrants scrutiny in the wake of dual standards by the regulatory authorities of CDSCO and FSSAI.

Nutraceutical experts have contested that when gazette notification is talking about vitamin B12, it refers to which type of vitamin B12 as all four vitamin B12 such as methylcobalamin, cyanocobalamin, hydroxycobalamin and adenocylcobalamin are different and have different level of absorption in the human body, and therefore recommended dietary allowance and upper limit for each type of vitamin B12 must be different.

Dr Sanjay Agrawal
Leading Pharmaceutical Consultant
Editor-in Chief of IJMToday

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