History of the regulation of dietary supplements (US Food Regulation series: Part 3)

In the previous post entitled “US Food Law and Regulation Series: Part 1”, we focused our discussion on the different regulatory body FDA, USDA, CDC, NMFS, EPA, DHS etc and their interaction in the food safety regulation. In the second part of the series entitled “US Food Law and Regulation Series: Part 2”, we tried to discuss the issues in the definition of food, dietary supplements and drug. We also discussed the concept of “intended use” and how it can have impact on the definition.

This is the third part of the series. In this post, we will shortly discuss the EU and Japanese system of regulation of dietary supplement. However, our main focus will be the regulatory mechanism of dietary supplement in USA. The history of FDA with dietary supplement is the learning for the entire world. The issues and challenges faced by FDA, court decisions, background and the driving force for the development of a separate dietary supplement regulation will be discussed chronologically.

Let’s start with EU and Japanese system.

European Food Safety Authority uses a term food supplements. European Union (EU) has analogous regulatory system compared to US. The main dietary regulation is found in 2002 EU directive, Directive 2002/46/EC. It has a list of permitted vitamin and mineral components for specific intended uses. The regulation 1924/2006 related to nutrition and health claims was adopted in 2006 and it demands the verification for substantiation and approval for the claims.

In Japan, all the supplements are treated as food. Yet it offers the most restrictive regulation of dietary supplements. Supplements are categorized into 4 categories: Food for special dietary uses; Food for specified health uses; Health foods; and Health foods with nutrient function claims. The structure/function claims are not allowed and only the few health claims are allowed in certain supplements.

The details of the discussion on EU and Japanese regulatory systems have been skipped for the moment to focus our discussion on history of regulation of dietary supplement in USA.

Regulation of dietary supplement by US FDA
Let's start our discussion chronologically starting form the beginning of 19th century.

In the past, only a small number of ingredients (usually common food constituents) were used as supplement. Cod liver oil having vitamins A and D is probably the first dietary supplement in USA. The 1906 Act provided the first distinction between food and drug, however the regulation of both products were identical. The classification was mainly based on active molecules and the packaging claim.

With increasing public interest in vitamin supplements, FDA started working in the vitamin claims and established a Vitamin Division in 1935. It also started working on new ingredients/ compounds with claimed health benefits. FDA filed a criminal case against a vitamin product containing milk, sugar, wheat starch and vitamins with health claims of curing high blood pressure, low blood pressure, dropsy, toxic goiter, and heart disease. It was probably the first attempt to take legal action against the vitamin product with disease claims in USA. The FDA experience with such case did influence and shape the upcoming regulation in the field of dietary supplement. The 1938 act provided authority to FDA for the regulation of supplement type products having labeling of “food for special dietary uses” under the misbranding provisions. Three groups of foods were initially focused in the regulation under the 1938 act: (1) “staple foods fortified with vitamins and minerals” were regulated with standards of identities, limits on the amount of nutritional ingredients and barring any health claims; (2) “foods for special dietary uses” (e.g. infant foods and foods for diabetics ); (3) dietary supplements were regulated either as conventional food or food for special dietary purposes. In the early days, parenteral supplements, despite not having labeling of disease claims, were exclusively regulated as drugs. Nevertheless, the products with an intended use to supplement the daily diet were regulated as foods.

This approach didn’t work well to regulate claims on vitamins, minerals and dietary supplements, as regulations for special dietary food was not designed in that way. In a series of court case between FDA and different manufacturers (such as Nutrilite, Abbott, Dextra, Vitasafe, Nutrilab) the concept and classification of dietary supplement emerged. Among them the most significant case was the one that of Nutrilab. The court decided that “intended use” could be the greatest tool to classify supplements. FDA was allowed to classify the product with alleged disease claims or medicinal use as drugs, and should pass through premarket clearance. On the other hand, FDA should regulate the dietary supplements without claims or with nutritional claims as food.

FDA attempted to issue a separate regulation for dietary supplements in 1962 with a set dosage levels of supplements. FDA proposed to permit a single nutrient dietary supplement with levels close to US Recommended Daily Allowance (RDA), while limiting the number of multivitamin and mineral products. The proposed regulation was to classify the “high potency” dietary supplements as drug, which created a series of spark and outcry. FDA eventually needed to drop its proposal. Afterwards, Congress attempted to regulate vitamins and minerals with therapeutic claims using “Vitamin and Mineral Amendment of 1976”. This was the first specific attempt to address dietary supplements by stopping the FDA to regulate threshold based “high potency” dietary supplement as drug. However, the scope of the legislation was narrow for regulating different dietary supplement products. FDA continued its attempt to regulate number of supplements using drug regulations.

In 1990, nutrient content and other claims for food were established in Nutritional Labeling and Education Act (NELA). It established the concept of nutritional labeling. NELA made it mandatory to declare any vitamin and mineral supplementation in the label. It also opened the door for health claims for dietary supplements to make certain claims about the benefits of nutrients it contained. It allowed the established claims related to the reduced risk of disease or health conditions. However, a general dietary guidance (such as fruits and vegetables as part of healthy diet) is not considered a health claim. FDA was authorized to review and approve the health claims using the criteria set by NLEA. FDA needed to conduct an exhaustive review of scientific literatures to obtain “significant scientific agreement” on the health claims. Only the FDA approved health claims were allowed.

The history of L-tryptophan regulation by FDA should be remembered here. FDA was concerned with an supplement ingredient L-tryptophan (an amino acid) over the adverse health effect of eosinophilla myalgia syndrome. FDA issued a consumer advisory warning to the public about that supplement and established a task force to examine. That task force recommended the FDA to regulate that supplement as drug, without considering the possibility of health claims under NELA. It was ultimately considered an aggressive enforcement approach of FDA by different experts and law makers.

The era of confusion on the regulation of dietary supplements ranged from 1906 till 1994. A rapidly growing market with unscrupulous claims of dietary supplements was an increasing challenge for FDA. Even judiciary struggled to develop consistent interpretation of the act in the field of dietary supplements. It ultimately demanded for the Dietary Supplement Health and Education Act (DSHEA) of 1994. Congress passed DSHEA to restrict FDA ability to impose unnecessary control on dietary supplements, because of unrealistic and aggressive enforcement of FDA in the case of L-tryptophan case. Enactment of DSHEA was a ground breaking step in the regulation of dietary supplement. It established a framework for new Good Manufacturing Practices (GMPs) for the dietary supplement industries.

Vitamin and mineral requirements in human nutrition

PDF Document: "WHO (2004): Vitamin and mineral requirements in human nutrition"

 

 

Compilation of nutrition and health claims evaluated by EFSA

The following is a list of nutrition and health claims evaluated by European Food Safety Authority (EFSA). The authorized claims are shown with green text and the rejected claims are shown in red text.

Fish Oil Supplement

Fish oil is generally obtained from mackerel, herring, tuna, salmon, cod liver, whale blubber, and seal blubber. It is rich in omega-3 fatty acids mainly Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA). Let's read the details about fish oil below: 

EFSA evaluation of health claims related to COPPER

The following is a list of claims related to the copper. The claim explaining “ copper contributes to the cholesterol and glucose” was not authorized by European Food Safety Authority (EFSA).

Claims	EFSA opinion reference	Status
Copper contributes to maintenance of normal connective tissues	2009;7(9):1211	Authorised
Copper contributes to normal energy-yielding metabolism	2009;7(9):1211 2011;9(4):2079	Authorised
Copper contributes to normal functioning of the nervous system	2009;7(9):1211 2011;9(4):2079	Authorised
Copper contributes to normal hair pigmentation	2009;7(9):1211	Authorised
Copper contributes to normal iron transport in the body	2009;7(9):1211	Authorised
Copper contributes to normal skin pigmentation	2009;7(9):1211	Authorised
Copper contributes to the normal function of the immune system	2009;7(9):1211 2011;9(4):2079	Authorised
Copper contributes to the protection of cells from oxidative stress	2009;7(9):1211	Authorised
Copper contributes to the cholesterol and glucose	2009;7(9):1211	Non-authorised

Non-Authorized (Rejected) Health Claims related to Calcium

The following claims were rejected by the EFSA (European Food Safety Authority).

Rejected Claims	EFSA opinion Reference
Calcium contributes to normal functioning of cells.	2010;8(10):1725
Calcium helps manage your weight	2010;8(10):1725
Calcium contributes to weight control. Calcium modulates energy metabolism
Calcium helps to keep a healthy blood pressure.	2009;7(9):1210
Calcium naturally present in dairy products is important for weight management	2010;8(10):1725
Dairy calcium has been shown to stimulate lipolysis.
Consumption of dairy calcium aids weight loss.
Dairy calcium modulates fat metabolism.
Dairy calcium helps promote fat loss.
Calcium promotes a healthy heart. Calcium maintains a healthy heart. Calcium helps build a healthy heart. Calcium helps promote a healthy heart	2009;7(9):1210
Oyster shells are rich source of calcium that contributes to healthy blood cholesterol level/ Oyster shells are a rich source of calcium that helps to maintain normal cholesterol level/Oyster shells are a rich source of calcium that decreases LDL cholesterol and increase HDL cholesterol.	2010;8(10):1725
Diet which includes several daily servings of low-fat milk products (about 1200 mg of calcium/day) helps to control blood pressure.	2009;7(9):1210
Supplementation with B-vitamins, iron, magnesium as well as vitamin C can reduce fatigue and tiredness in situations of inadequate micro-nutrient status.	2010;8(10):1725
Water-soluble vitamins, calcium, magnesium and zinc are essential for mental function and performance	2010;8(10):1725
In situations of inadequate micronutrient status, supplementation with water-soluble vitamins, minerals and zinc can sustain mental performance (e.g. concentration, learning, memory, reasoning).
Calcium supports the regulation of the acid base balance	2011;9(6):2201
Calcium strengthens the nails.	2010;8(10):1725
Calcium phosphoryl oligosaccharide  restores tooth enamel after meals, increases tooth surface hardness, helps strengthen teeth.	2011;9(6):2267
Calcium-containing fruit juices:  Reduced risk for dental erosion	Q-2009-00501

List of EFSA approved Health Claims for Calcium

The following claims were rejected by the EFSA (European Food Safety Authority).

Approved Claims	EFSA opinion Reference
Calcium contributes to normal blood clotting	2009;7(9):1210
Calcium contributes to normal energy-yielding metabolism	2009;7(9):1210
Calcium contributes to normal muscle function	2009;7(9):1210
Calcium contributes to normal neurotransmission	2009;7(9):1210
Calcium contributes to the normal function of digestive enzymes	2009;7(9):1210
Calcium has a role in the process of cell division and specialisation	2010;8(10):1725
Calcium is needed for the maintenance of normal bones	2009;7(9):1210 2009;7(9):1272 2010;8(10):1725 2011;9(6):2203
Calcium is needed for the maintenance of normal teeth	2009;7(9):1210 2010;8(10):1725 2011;9(6):2203

Conditions of use of the claim: The claim may be used only for food which is at least a source of calcium as referred to in the claim SOURCE OF [NAME OF VITAMIN/S] AND/OR [NAME OF MINERAL/S] as listed in the Annex to Regulation (EC) No 1924/2006.

Nepalese National Formulary 2018 (3rd edition)

PDF Document: "Nepalese National Formulary 2018 (3rd Edition)"

Synthesis and spectroscopic analysis of potent radical scavenger: Canolol

Please find the information about the canolol from the previous post.

All the information below is a part of my article in Journal of Agricultural and Food Chemistry (J. Agric. Food Chem. 2012, 60, 30, 7506–7512). For details, please read the original article

In this post, we will focus our discussion on the chemistry of canolol. First, we will discuss the chemical synthesis in the laboratory. Afterwards, we will discuss NMR (Nuclear Magnetic Resonance) spectroscopy and mass spectrometric methods to confirm the structure of the synthesized compounds.

Chemical synthesis

Canolol was synthesized from Syringaldehyde by reacting with Malonic acid in the presence of Acetic acid and Piperidine under microwave condition. The chemistry of the reaction is shown in the Figure. The reaction involves series of condensation, dehydration and decarboxylation steps. Microwave supports the formation of polar intermediates during the reaction. The synthesized canolol was purified using a silica gel column chromatography. Crystallization was applied as an additional step to increase the purity. A saturated solution of the synthesized compound in hexane was prepared at ambient temperature, and crystallization was induced by storing it inside the freezer (−28 °C). Crystals (white) were separated from the mother liquor and dried under nitrogen. The structure of the purified compound was confirmed by NMR and mass spectrometry.

Figure: chemical synthesis of canolol from syringaldehyde

NMR Spectroscopy:

NMR Chemical Shifts of the compound is shown below. The position of the proton responsible for different NMR spectra has been indicated in the table. The NMR spectroscopy confirms the structure of the purified compound as canolol.

Liquid Chromatography−Time of Flight Mass Spectrometry (LC−TOF MS) :

The LC-MS spectra indicated different fragments of the compound having m/z values of 203.06, 181.08, 166.06, 149.06, 121.06 and 103.05. The ms fragmentation pattern of the compound has been shown in the figure below.

Both the NMR and LC-TOF MS confirmed the structure of the synthesized compound. Canolol can be used in functional foods, Nutraceutical products, pharmaceutical products, chemicals industries etc. The compound is known to be formed during roasting of mustard and rapeseed. The roasted mustard and rapeseed oil is a good source of canonol. Roasted oil is an integral part of the Newari cuisines. Researchers from Canada and Germany have already started developing a commercial technology for the manufacturing of this compound.

Canolol as a potent antioxidant

Canolol is a potent antioxidant. The antioxidant property of the canolol is due to its’ radical scavenging activity. Canolol can easily donate a proton to the free radical to form a stable resonance structures. The mechanism of radical scavenging activity of this compound is shown in the figure below.

For those interested in the methodology:

NMR Spectroscopy:

The purified compound was dissolved in deuterated chloroform. The proton (1H) and carbon (13C) NMR spectra were taken using a Jeol EX300 Eclipse NMR (300 MHz) spectrophotometer (Japan).

Liquid Chromatography−Time of Flight Mass Spectrometry (LC−TOF MS) Spectroscopy :

The LC−MS analysis of the purified compound was carried out using UltiMate 3000 ultrahigh-pressure liquid chromatography (UHPLC, Dionex) equipped with a degasser, four solvent delivery modules, an autosampler, a column oven, and an UV detector coupled with a MicroTOF MS instrument (Bruker). The purified compound was dissolved in an isopropanol/water/acetic acid (90:10:0.1, v/v/v) mixture (10 μg/mL) and then injected on a C8 Zorbax 300 SB column (Agilent, Santa Clara, CA). Mobile phase A was a water/acetonitrile/acetic acid mixture (90:10:0.1, v/v/v), and mobile phase B was an acetonitrile/ water/acetic acid mixture (90:10:0.1, v/v/v). The method was run with 10% mobile phase B for 1 min, then a gradient was applied to reach 100% of mobile phase B in 11 min, which was held for 5 min. Afterward, the initial conditions were reached in 0.5 min, and the column was allowed to equilibrate for 4.5 min before a subsequent analytical run. The solvent flow rate was 0.2 mL/min. Electrospray ionization (ESI) in positive-ion mode was used, and m/z values were scanned from 50 to 1000. The capillary voltage was set at 4500 V, and the end plate offset was at −500 V. The nebulizer pressure was 0.5 bar and was heated to 190 °C with dry nitrogen at a flow rate of 4 mL/ min.

All the information above is a part of my article in Journal of Agricultural and Food Chemistry (J. Agric. Food Chem. 2012, 60, 30, 7506–7512). For details, please read the original article. Contact me if you have trouble accessing it.

Please find the information about the canolol from the previous post.

Read the original article below:

Dietary Supplement Regulation around the world: Part 2

This is a continuation of the previous post on DietarySupplement Regulation around the world-part1.  

If you have not read that part, please have a look at that first, before reading this second part. I have only tried to add some conceptual clarification in this second post.

Let’s start with different regulatory approach applied for food supplement by different countries.

1. Registration Vs Notification vs Pre-market approval approach

For the most countries worldwide, Nutraceuticals, Dietary supplement, Food supplements are regulated as a category of food. In some regions or countries, there are a specific set of regulations governing supplements (e.g. EU, US, ASEAN, India) under the food-based regulatory paradigm. Most of these countries have some form of a notification or registration based system, which is required to be fulfilled to bring a new product in the market. This is in contrast to the premarket approval approach required for drugs. This is due to the fact that food supplements appropriately fits in the food category and they pose very low safety risks compared to drugs.

Dietary Supplement Regulation around the world : Part 1

For most countries worldwide, Conventional Foods, Functional Foods, Dietary Supplements, Nutraceuticals are regulated as a category of Food. Some form of registration or notification approach has been established in different countries.

Regulators mainly rely on established formal “positive” and/or “negative” ingredient lists during evaluation. 

A Novel Nutraceutical molecule : Canolol

Canolol is a novel Nutraceutical molecule isolated from roasted Rapeseed oil. It was isolated from roasted Mustard seed oil by Kshitij Shrestha. 

(Link to publication). You can Download original article.
It is also known as:
4-vinyl-2,6-dimethoxyphenol
4-vinylsyringol
2,6-dimethoxy-4-vinylphenol
CAS Number 28343-22-8

For general information, Link to wikipedia, Link to chemspider, Link to Pubchem

Some important Nutraceutical properties are:

COVID-19 infection: the perspectives on immune responses

Yufang Shi, Ying Wang, Changshun Shao, Jianan Huang, Jianhe Gan, Xiaoping Huang, Enrico Bucci, Mauro Piacentini, Giuseppe Ippolito & Gerry Melino
Abstract

Clinically, the immune responses induced by SARS-CoV-2 infection are two phased. During the incubation and non-severe stages, a specific adaptive immune response is required to eliminate the virus and to preclude disease progression to severe stages. Therefore, strategies to boost immune responses (anti-sera or pegylated IFNα) at this stage are certainly important. For the development of an endogenous protective immune response at the incubation and non-severe stages, the host should be in good general health and an appropriate genetic background (e.g. HLA) that elicits specific antiviral immunity.

Lung damage is a major hurdle to recovery in severe patients. Through producing various growth factors, MSCs may help repair of the damaged lung tissue. It is important to mention that various studies have shown that in animal models with bleomycin-induced lung injury, vitamin B3 (niacin or nicotinamide) is highly effective in preventing lung tissue damage. It might be a wise approach to supply this food supplement to the COVID-19 patients.

Doctors should try to boost immune responses during the first, while suppressing it in the second phase. Since Vitamin B3 is highly lung protective, it should be used as soon as coughing begins. When breathing difficulty becomes apparent, hyaluronidase can be used intratracheally and at the same time 4-MU can be given to inhibit HAS2. Of course, HLA typing will provide susceptibility information for strategizing prevention, treatment, vaccination, and clinical approaches. We hope that some of the above ideas can be employed to help combat this deadly contagious disease of increasing incidence around the world. 

Cell Death & Differentiation volume 27, pages1451–1454(2020), Download PDF

COVID-19: is there a role for immunonutrition, particularly in the over 65s?

Emma Derbyshire and Joanne Delange

Abstract

In late December 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged in Wuhan, Hubei, China, resulting in the potentially fatal COVID-19. It went on to be officially recognised as a pandemic by the World Health Organisation on 11 March 2020. While many public health strategies have evolved, there has been little mention of the immune system and how this could be strengthened to help protect against viral infections such as SARS-CoV-2. The present paper evaluates the current evidence base relating to immunonutrition, with a particular focus on respiratory viruses. Within the nutrition sector a promising body of evidence studying inter-relationships between certain nutrients and immune competence already exists. This could potentially be an important player in helping the body to deal with the coronavirus, especially among elders. Evidence for vitamins C, D and zinc and their roles in preventing pneumonia and respiratory infections (vitamins C and D) and reinforcing immunity (zinc) appears to look particularly promising. Ongoing research within this important field is urgently needed. 

http://dx.doi.org/10.1136/bmjnph-2020-000071

Enhancing immunity in viral infections, with special emphasis on COVID-19: A review

Ranil Jayawardena Piumika Sooriyaarachchi Michail Chourdakis Chandima Jeewandara Priyanga Ranasinghe

Abstract

Balanced nutrition which can help in maintaining immunity is essential for prevention and management of viral infections. While data regarding nutrition in coronavirus infection (COVID-19) are not available, in this review, we aimed to evaluate evidence from previous clinical trials that studied nutrition-based interventions for viral diseases (with special emphasis on respiratory infections), and summarise our observations. A systematic search strategy was employed using keywords to search the literature in 3 key medical databases: PubMed®, Web of Science® and SciVerse Scopus®. Studies were considered eligible if they were controlled trials in humans, measuring immunological parameters, on viral and respiratory infections. Clinical trials on vitamins, minerals, nutraceuticals and probiotics were included. A total of 640 records were identified initially and 22 studies were included from other sources. After excluding duplicates and articles that did not meet the inclusion criteria, 43 studies were obtained (vitamins: 13; minerals: 8; nutraceuticals: 18 and probiotics: 4). Among vitamins, A and D showed a potential benefit, especially in deficient populations. Among trace elements, selenium and zinc have also shown favourable immune-modulatory effects in viral respiratory infections. Several nutraceuticals and probiotics may also have some role in enhancing immune functions. Micronutrients may be beneficial in nutritionally depleted elderly population.  https://doi.org/10.1016/j.dsx.2020.04.015

Early Supplementation in COVID-19

Early nutritional supplementation in non-critically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): Rationale and feasibility of a shared pragmatic protocol

Riccardo Caccialanza M.D. Alessandro Laviano M.D. Federica Lobascio M.D. Elisabetta Montagna R,D Raffaele Bruno M.D. Serena Ludovisi M.D. Angelo Guido Corsico M.D., Ph.D. Antonio Di Sabatino M.D. Mirko Belliato M.D. Monica Calvi Pharm .D. IsabellaIacona Pharm .D. Giuseppina Grugnetti R.N. Elisa Bonadeo M.D. Alba Muzzi M.D. Emanuele Cereda M.D. Ph.D.

Abstract

Beginning in December 2019, the 2019 novel coronavirus disease (COVID-19) has caused a pneumonia epidemic that began in Wuhan, China, and is rapidly spreading throughout the whole world. Italy is the hardest hit country after China. Oral supplementation of whey proteins as well as intravenous infusion of multivitamin, multimineral trace elements solutions are implemented at admission. In the presence of 25-hydroxyvitamin D deficit, cholecalciferol is promptly supplied. If nutritional risk is detected, two to three bottles of protein-calorie oral nutritional supplements (ONS) are provided. If <2 bottles/d of ONS are consumed for 2 consecutive days and/or respiratory conditions are worsening, supplemental/total parenteral nutrition is prescribed. 

https://doi.org/10.1016/j.nut.2020.110835

Vitamin D & COVID-19

Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths

William B. Grant ^1,*,Henry Lahore ²,Sharon L. McDonnell ³,Carole A. Baggerly ³,Christine B. French ³,Jennifer L. Aliano ³ andHarjit P. Bhattoa ⁴

Abstract

The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D₃ for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/mL (100–150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D₃ doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations. 
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Nutrients 2020, 12(4), 988; https://doi.org/10.3390/nu12040988