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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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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