Nutraceuticals and dietary supplements should not be used to treat COVID-19 as pharmaceuticals

Abstract

A very recent preprint by Lordan and Rando reviewed the use of dietary supplements and nutraceuticals in COVID-19. Despite the bulk of evidence supporting a role for natural compounds in COVID-19, the authors reported paucity in the clinical evidence of tested compounds such as probiotics, vitamins, poly-unsaturated fatty acids (PUFAs) and zinc in treating COVID-19, assessing that if an improvement is observed, this is only due to the individual's optimal nutritional status, which is able to prime his own immune system and boosting a rapid clearance response against the virus [1]. Despite some evidence showing the beneficial action of ω-3 PUFAs in preventing COVID-19 has been yet reported [2], the use of nutraceuticals to treat mild or severe forms of COVID-19, raises several controversial issues. Actually, a very recent survey on 372,720 UK participants, of whom 175,652 nutritional supplement users and 197,068 not, reported that a very modest association might exist between lower risk in being SARS.CoV2 positive and diets enriched with probiotics, multivitamin, vitamin D and ω3 fatty acids, despite the study resulted positive only for female subjects [2]. Anyway, clinical trials are crucial to assess any purported effect. Phytochemicals sold as dietary supplements should be used only to potentiate and improve the nutritional status of a subject, particularly upon micronutrients deficiency, usually in order to prevent further damage due to the onset of an inflammation or an exacerbated immune and stress response. Interestingly, Lordan and Rando's contribution did not address polyphenolic compounds from plants, despite their widespread use as nutraceuticals [1]. A huge amount of reports, about 250 articles in “flavonoids AND COVID-19” on Pubmed/Medline, deals with the use of natural phytochemicals in addressing the COVID-19 pandemic, most of which are purported to possess specific ability in targeting virus entry, budding, replication and life cycle of SARS-CoV2, with high specificity [3]. This would erroneously suggest the naïve thesis that nature-derived phytochemicals may act in a pharmacological way. For example, the flavanone glycoside hesperidin, usually found in citrus fruit, has been considered as a possible compound to treat COVID-19 in some clinical trials (Clinical Trial NCT04452799, Tanta University; Egypt; Clinical Trial NCT04715932, Montreal Heart Institute, Canada), yet the only 35 papers retrieved on the Pubmed(Medline MESH term “hesperidin AND COVID”, did not contain any experimental study on humans or animal models, except from in silico, docking and computational methods on SARS-CoV2 targeting. The content of hesperetin, the aglycone flavanone of hesperidin, i.e. the 4’-methoxy derivative of eriodyctiol, ranges from 2.20 mg to 36.14 mg for 100 ml of orange juice, a mean of 12.80 mg/100 ml [4], whereas other studies reported an average amount of 23.70 mg/100 ml [5], an evidence suggesting that 4 glasses of orange juice might contain the level of hesperidin usually available in the market as a diet supplement. While it may appear quite foolish thinking that orange juice can remove COVID-19 early symptoms, thus rescuing the previous health status, research is going ahead in promoting hesperidin as a possible pharmaceutical compound against COVID-19 [6]. Yet, there are a lot of reasons to expand even a gentle criticism about this perspective. First, it is widely known that the actual bioavailability of any polyphenolic compound from either raw food or nutritional supplements, is hard to be assessed, as flavonoid pharmacokinetics is greatly affected by the gut microbiome composition, therefore is quite impossible establishing a reliable dosage and a reliable dose-effect on the patient. Second, the panoply of actions towards the oxidative stress signaling is highly complex and depending on a great number of factors related with the disease progress and the host's response. Third, the activity of a polyphenolic compound, such as a flavonoid, may be completely reversed or attenuated by other phytochemicals coming from diet, usually in a way very hard to be fully elucidated. The equivocal belief that flavonoids in nutritional supplementation may act in a pharmacological way, is related to the numerous in vitro reports showing the ability of aglycone flavonoids to suppress, enhance and modulate many cell molecular pathways, usually targeting defined signaling systems or receptors or other macromolecular complexes in a fashion very close to pharmaceuticals. Despite this perspective may appear convincing, actually flavonoids are highly pleiotropic and their activity can be perfectly restricted to the simple survival system of the oxidative stress response. Fundamentally, any phytochemical from plants is a toxic compound, which, in a narrow range of dosage, can trigger an oxidative stress response able to activate cell survival, via the production of reactive oxygen species (ROS) as signaling molecules. The correct dose to elicit a benefit is usually established by a certain empiricism, as flavonoids pharmacokinetic is very complex, and this may put the patient towards adverse effects due to the compound sub-clinical toxicity. In this context, clinical trials are crucial but the introduction of a nutraceutic form of a flavonoid can be affected by the unaware introduction of the same flavonoid (or other antagonists) from food. What the researcher probably observes is a beneficial action of the flavonoid on the nutritional status of the patient and the subsequent effect on the investigated clinical parameters. Nutraceutic supplementation should be avoided to treat severe sickness such as COVID-19 and patients should be correctly informed about the proper nutritional status to address the pathogenetic course of SARS-CoV2 infection, particularly during early symptoms. To date, no sound association between COVID-19 prevalence and flavonoid-rich food intake has been reported. Furthermore, while literature is endowed with a very large number of papers dealing with flavonoids beneficial effects (e.g. hesperidin), studies on toxicity are usually restricted to one or very few reports [7]. The paroxysmal attitude to rapidly plan a highly successful therapy against COVID-19, is crowding the scientific community of proposals from natural and complementary medicine, sometimes with even potential competing interests. Any proposal is settled to enhance the weapons against pandemic but the misleading consideration that a food-derived phytochemical may be considered a pharmaceutical, raises controversial issues and may hamper the ethical movement to correctly address COVID-19. CrediT author statement Conceptualization: Salvatore Chirumbolo Data curation: Salvatore Chirumbolo Formal analysis. Salvatore Chirumbolo Funding acquisition: NA Investigation: Salvatore Chirumbolo Methodology: Salvatore Chirumbolo Project administration: NA Resources: Salvatore Chirumbolo Software: Salvatore Chirumbolo Supervision: Salvatore Chirumbolo Validation: Salvatore Chirumbolo Visualization: Salvatore Chirumbolo Roles/Writing - original draft: Salvatore Chirumbolo Writing - review & editing: Salvatore Chirumbolo Authorship statements: the paper was completely conceived and written by Salvatore Chirumbolo Declaration of Competing Interest The author states he has no conflict of interest References [1] Lordan R, Rando HM; COVID-19 Review Consortium, Greene CS. Dietary Supplements and Nutraceuticals Under Investigation for COVID-19 Prevention and Treatment. Preprint. ArXiv. 2021;arXiv:2102.02250v1. Published 2021 Feb 3. 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