Abstract: Medical Hypotheses 149 (2021) 110539
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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy
Correspondence
Folic acid as placebo in controlled clinical trials of hydroxychloroquine prophylaxis in COVID-19:
Is it scientifically justifiable?
A R T I C L E I N F O
A B S T R A C T
Keywords
Hydroxychloroquine
Folic acid
COVID-19
Using folic acid (FA) as placebo complicates the interpretation of the findings of few RCTs evaluating safety and
efficacy of hydroxychloroquine prophylaxis in COVID-19. FA is found to bind to furin-protease and spike: ACE2
interface of SARS-CoV-2. In clinical studies, FA level was lowest among severe patients compared to mild and
moderate disease. A single controlled study reported the benefit of combination of folic acid with Pyridoxine &
cyanocobalamin in terms of clinical and laboratory cure parameters. One hypothesis associates the differences in
geographical variation of disease severity with prevalence of methyl tertahydrofolic acid reductase (MTHFR)
C677T polymorphism. Other possible domains, where FA is hypothesized to be beneficial are COVID-19 asso
ciated pulmonary hypertension and hyper-homocystinemia. So, scientific justification of using folic acid as
placebo in COVID-19 trials seems scientifically not credible and this may be one of the major factors for failure of
many agents. We need to be more careful in choosing our placebo especially when conducting a placebo
controlled trial.
Folic acid is being used as placebo in few RTCs of evaluating safety
and efficacy of hydroxychloroquine prophylaxis in COVID-19 [1].
However, one issue complicates the interpretation of the findings of
these trials. Folic acid is gradually coming up an anti-COVID-19 agent. in
a multimodal network-biology based study on SARS-CoV-2 human
interactome, folic acid was predicted as a top candidate for drug
repurposition (16th rank) [2] as agent for re-purposing against COVID19. In in-silico studies, folic acid is found to bind to NSP-13 [3], furin
[4], spike:ACE2 interface [5,6], PLPro [5], MPro [5] and NSP15 [5] of
SARS-CoV-2, which are important targets from drug design perspective.
5,10 methyltetrahydrofolate is converted to 5-methyl-tetrahydrofo
late by the enzyme methyl tertahydrofolic acid reductase (MTHFR)
and thus helps in providing methyl groups for recycling of homocysteine
to methionine. A single study hypothesized that the differences in
geographical variation of COVID-19 disease severity may be related to
the prevalence of (MTHFR) C677T popymorphism [7]. High dose folic
acid is again hypothesized as a potential treatment of pulmonary hy
pertension (even when associated with COVID-19) and folic acid may
help in the same by reversing uncoupling of eNOS and restoring NO
production [8].
NSP14 of SARS-CoV is a guanine N7-methyl-transferase and is
crucial for viral transmission and replication of SARS-CoV-2 and thus
SARS-CoV-2 may use host S-adenosyl methionine (SAM) for viral RNA
capping [9], utilization of which results in production of homocysteine,
which enhance ACE-2 activation [10] and SARS-CoV-2 may take help of
this enhanced activated ACE2 system to get entry to host cell [9]. High
homocysteine is reported in the context of severe COVID-19 also or
patients with progression of disease [11]. In clinical studies, folic acid is
known to lower the level of homocysteine. In COVID-19 also, in a single
controlled study, patients treated with Angiovit..
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