The Prevalence of Dietary Supplement Use for the Purpose of COVID-19 Prevention in Japan

COVID-19 is still the biggest issue worldwide. Many dietary supplements on the market claim to have anti-COVID-19 effects without scientific evidence. To elucidate the prevalence of dietary supplement usage for the prevention of COVID-19, we conducted an online cross-sectional questionnaire survey among Japanese adults in January 2022. The prevalence of dietary supplement use for the prevention of COVID-19 was 8.3%, and there was no gender difference. We also conducted additional research on these dietary supplement users (1000 males and 1000 females). The most popular ingredient used was vitamin C (61.0%), with vitamin D (34.9%) and probiotics (33.4%) following. Half of these participants reported using supplements for more than one year. The information sources that reportedly led them to start using dietary supplements for the prevention of COVID-19 were the Internet (44.0%), television and radio (29.9%), and family or friends (26.0%), and these information sources differed among generations. In conclusion, some of the population used vitamin/mineral supplements for the prevention of COVID-19 that might be beneficial for their health, but some used ingredients with no scientifically proven effects against the virus at this time. Therefore, information-based scientific evidence is important to prevent the inappropriate use of dietary supplements by consumers.


Introduction
The novel coronavirus disease COVID-19 still influences lives around the world. Although several anti-SARS-CoV-2 vaccines and medicines have been developed [1,2], the cumulative number of cases and deaths are still increasing [3]. Some countries have conducted lockdowns to prevent community-acquired infection at the local level and have limited immigration to prevent the transportation of new/mutated viruses at the national level. However, many countries have moved to the next step to sustain economic activity, with a new lifestyle of living with COVID-19 having been proposed. In this regard, it is important to prevent SARS-CoV-2 infection as much as possible. Most national governments have encouraged their people to avoid the three Cs (closed spaces, crowded places, and close-contact settings) from the beginning of the pandemic. On the contrary, a lot of research into the cause of SARS-CoV-2 infection and COVID-19 severity has been conducted, and it has been reported that malnutrition, especially vitamin A, vitamin D, zinc, and selenium deficiencies, is associated with SARS-CoV-2 infection and COVID-19 severity [4,5].
The World Health Organization Regional Office for the Eastern Mediterranean (WHO EMRO) released "Nutrition advice for adults during the COVID-19 outbreak." This advice includes the following recommendations: (1) Eat fresh and unprocessed foods every day, (2) drink enough water every day, (3) eat moderate amounts of fat and oil, (4) eat less salt and sugar, and (5) avoid eating out [6]. These recommendations are almost the same as the "Healthy Diet" recommendations published by the WHO before the pandemic [7]. This

Participants and Procedures
An online cross-sectional survey was conducted by Neo Marketing Inc. (Tokyo, Japan) from 19 to 24 January 2022. The 48,925 respondents, aged 20-79 years old, comprised 25,739 males and 23,186 females that were randomly chosen from the research company's monitors. This study was conducted with the approval of the Research Ethics Committee of the National Institutes of Biomedical Innovation, Health and Nutrition (No. 358, approved on 22 December 2021) and in accordance with the Declaration of Helsinki. Participants who had never been diagnosed COVID-19 and who were currently using dietary supplements for the prevention of COVID-19 were selected from the preliminary survey and were asked to answer a targeted survey questionnaire. In the targeted survey, questions were included about the dietary supplements that they used, their information sources, and whether they recognized the National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN) COVID-19-related website (https://hfnet.nibiohn.go.jp/notes/detail.php?no= 2142.html, Japanese only, accessed on 25 July 2022) (Supplementary File S1). Detailed procedures of the Internet survey are described in our previous report [18].

Statistical Analysis
Differences in the distribution among groups were compared using the chi-squared (χ 2 ) test. All statistical analyses were performed using IBM SPSS Statistics ver. 28.0.1.0 (IBM Corporation, Armonk, NY, USA), and a p-value of <0.05 was considered statistically significant. Dietary supplement usage is influenced by consumers' background (sex, age), and dietary supplement users tend to have a positive image about the prevention and treatment of diseases with dietary supplements [16]. In addition, a cumulative number of newly confirmed SARS-CoV-2 infection per 100,000 population in their resident prefecture [19] might have influenced to use dietary supplements. These factors were entered into bivariate logistic regression, and candidate variables were entered into the multivariable logistic regression model. To identify the factors of the prevalence of dietary supplement usage for the prevention of SARS-CoV-2 infection, binary logistic regression was done to assess. All variables having a p-value ≤ of 0.2 were considered as candidates for multivariable logistic regression and calculated odds ratio (OR) and 95% confidence interval (95% CI) using EZR ver. 4.0.3, which is a modified version of R commander designed to add statistical functions frequently used in biostatistics.

Experience of SARS-CoV-2 Infection
Data on participants' experiences of SARS-CoV-2 infection are shown in Table 2. Only 1.9% of the participants had been diagnosed with COVID-19. However, 2.0% of the participants had experienced symptoms but had not visited a clinic. In the case of the people around them, 24.9% of them answered that some people around them had experienced SARS-CoV-2 infection, such as school friends or workplace colleagues (11.5%), acquaintances (8.9%), and family members (5.1%).

The Prevalence of Dietary Supplement Usage for the Prevention of SARS-CoV-2 Infection
The prevalence of dietary supplement usage for the prevention of SARS-CoV-2 infection is shown in Table 3. Most participants (91.7%) reported not currently using dietary supplement for the prevention of SARS-CoV-2 infection, but 8.3% reported that they did. There was no gender difference. The most common reason given for not using dietary supplements was "I don't think that they can be prevented with dietary supplements" (57.6%), followed by "I think we have sufficient infection control measures (wearing masks, hand washing, gargling, avoiding 3C's)" (40.9%) and "I can't afford to buy them" (19.0%). Only 1.3% and 2.9% of the participants had seen the "Information for Consumers Related to COVID-19" published by the Consumer Affairs Agency and NIBIOHN. In addition, we analyzed the prevalence of dietary supplement usage for the prevention of SARS-CoV-2 infection according to experiences of SARS-CoV-2 infection (Table 4). It was highest for those participants who had been diagnosed with COVID-19 (37.9%). The next highest prevalence was for those participants whose family members (live-in) had been diagnosed with COVID-19 (29.3%), followed by those participants who had had symptoms (21.0%). For residence area, the prevalence was the highest for Kanto, which includes Tokyo (9.1%), and the lowest was for Tohoku (6.9%).  The prevalence of dietary supplement usage other than for the prevention of SARS-CoV-2 infection is shown in Table 5. The prevalence of this was higher than that for the prevention of SARS-CoV-2 infection. A total of 37.4% of participants answered "I currently use dietary supplements other than for the prevention of SARS-CoV-2 infection", with females (40.1%) reporting a significantly higher prevalence than males (35.0%). The difference among groups was examined using the chi-square (χ 2 ) test.
The results of the logistic regression analysis for the identification of factors influencing the dietary supplement usage for the prevention of SARS-CoV-2 infection are shown in Table 6. No multicollinearity was suggested by the correlation analysis among the independent variables. In this survey, sex, age, cumulative number of newly confirmed SARS-CoV-2 infection per 100,000 population of their residential prefecture, and the prevalence of dietary supplement usage other than for the prevention of SARS-CoV-2 infection were identified as significant factors.

Duration of Dietary Supplement Use for the Prevention of SARS-CoV-2 Infection
Data on the duration of dietary supplement use for the prevention of SARS-CoV-2 infection are shown in Table 8. If participants used more than one dietary supplement, they answered the duration of longest one. In total, almost half of the participants reported using dietary supplements for more than one year (53.1%), with 12.8% reporting using them for four to six months, and 12.6% for two to three months (12.6%). Some participants had only started them one week prior (5.4%), because we conducted the survey at a point when the number of SARS-CoV-2 PCR-positive patients was increasing in Japan.

Information Source That Prompted Participants to Use Dietary Supplements for the Prevention of SARS-CoV-2 Infection
Data on the information source that prompted the participants to use dietary supplements for the prevention of SARS-CoV-2 infection are shown in Table 9. Among all participants, the Internet was the highest reported source (44.0%), followed by television or radio (29.9%), family or friends (26.0%), and SNS including LINE, Facebook, Twitter, Instagram (21.7%). It is well known that the information sources used differ among generations, so we analyzed these data according to generation. The Internet was the highest reported source for all generations except for participants in their twenties. For these, SNS was the highest (35.3%), which was the lowest for those in their seventies. Surprisingly, specialists were a higher reported source for young generations than for old generations.

The Perception and Usefulness of "Information for Consumers Related to COVID-19" Published by the NIBIOHN
Data on the perception and usefulness of "Information for Consumers Related to COVID-19" published by the NIBIOHN are shown in Table 10. For those participants who reported using dietary supplements for the prevention of SARS-CoV-2 infection, 15.3% of them knew and 17.6% had seen this site. Among them (657 participants), half of them answered that "This site is useful to some extent" (51.1%), with 28.9% answering that "This site is very useful" (Table 11). On the contrary, 67.2% of them answered that "I have never seen this site" (Table 10). However, most of them answered that "This site seems useful to some extent" (60.5%) and "This site seems very useful" (15.7%) ( Table 12).   23 3.5 I know this site, but I have not seen the information on it 5 0.8 n = 657 who answered "I know this site" and "I have seen this site" in Table 10. n = 1343 who answered "I have never seen this site" in Table 10.
Finally, we asked participants whether they would stop using the dietary supplements that they used for the prevention of SARS-CoV-2 infection or not; only 3.3% of them answered "I would stop it immediately." and 18.2% of them answered "I would stop it after it run out."

Discussion
Due to the COVID-19 pandemic, some people have been using dietary supplements for the prevention of SARS-CoV-2 infection. In the present study, it was found that the prevalence of dietary supplement use was higher for those participants who had experienced SARS-CoV-2 infection than for others. Multivariable regression analysis showed that sex, age, cumulative number of newly confirmed SARS-CoV-2 infection per 100,000 population of their residential area, and other dietary supplement usage, were identified as significant factors of dietary supplement usage for the prevention of SARS-CoV-2 infection. Among these factors, other dietary supplement usage was the strongest factor to use dietary supplement for the prevention of SARS-CoV-2 infection. Most participants reported obtaining information about COVID-19 from the Internet. The NIBIOHN provides evidence levels of dietary supplement ingredients for upper respiratory infections, including COVID-19, via their Internet website, but almost 70% of the participants reported not knowing about this site.
Two years have passed since COVID-19 was declared a pandemic by the WHO on 11 March 2020. Currently, vaccination is being carried out continuously, and therapeutic drugs have been put into practical use, but the momentum of infection has not yet subsided, and the number of infected people is increasing repeatedly [3]. Therefore, the prevention of SARS-CoV-2 infection is of the utmost importance. In these circumstances, since information on dietary supplements and ingredients that claim to be good for preventing new coronavirus infections, but which lack scientific evidence, is available on the Internet [21,22], the NIBIOHN have launched a new coronavirus information site to provide consumers with scientific evidence-based information (Japanese only). This site has been introduced several times in the media, and it is also displayed as the top-ranking result when the keywords "corona virus" and "health food" are searched for on Google Japan. Therefore, in this study, we investigated the awareness of this site among Japanese people, and found that 33% of those participants who were dietary supplement users for the purpose of preventing SARS-CoV-2 infection were aware of the site, and most of them were satisfied with it. This result indicates that this website might be helpful for consumers when choosing dietary supplements.
In this survey, there were generational differences in information sources that prompted the participants to use dietary supplements for the prevention of SARS-CoV-2 infection. SNS was more popular in younger generations. It might be the cause of the higher prevalence of dietary supplement use for the prevention SARS-CoV-2 infection in younger generations, because SNS can be a platform for fake news [23]. On the other hand, specialists were also a higher reported source for younger generations than for older generations.
There are some speculations about this situation. First, health literacy might be higher in younger generations than in older generations [24,25]. We also reported that awareness of health support pharmacies was higher in younger generations than in older generations [26]. Health support pharmacies is a new category of pharmacies in Japan, and not only patients but also community residents can consult with professionals about any aspect, including dietary supplement usage. Second, old age is one of the risk factors for severity and mortality of COVID-19 [27]. So, the older generations might avoid going out and contacting other people. However, most of them take medications and should consult with health care professionals about dietary supplement use.
To prevent COVID-19, a well-balanced diet is encouraged [6,28]. However, our previous study indicated that only one-third of Japanese people consumed a well-balanced diet almost every day during the COVID-19 pandemic [18]. In this regard, some Japanese people might have some nutrient deficiencies. Deficiencies/insufficiencies in vitamin D [29][30][31], vitamin C [32], zinc [29], magnesium [29,33], and selenium [34] have been associated with COVID-19 infection and severity. In addition, supplementing COVID-19 patients' vitamin D intake has been found to decrease ICU admission rates [35]. On the contrary, vitamin C [36] and zinc [37] supplementation for COVID-19 patients has failed to show any observable benefits. At this time, there is no evidence that dietary supplements that contain these nutrients can prevent SARS-CoV-2 infection, but insufficiencies/deficiencies in these nutrients are associated with risk of SARS-CoV-2 infection, severity, and mortality [12]. In addition, a well-balanced diet is also associated with a lower risk of mortality [38][39][40][41]. In this survey, we did not ask the participants about their dietary habits, so we did not define the association between dietary habits and COVID-19 diagnosis. However, we recommend a well-balanced diet or the appropriate use of vitamin/mineral supplements to maintain one's nutritional condition and reminded consumers not to overdose. Excess intake of each vitamin/mineral is also associated with adverse effects, so dietary reference intakes for Japanese people sets a tolerable upper intake level (UL) of each vitamin/mineral [42], as well as other authorities [43,44].
It is reported that a lot of people used dietary supplements and over-the counter drugs as self-medication for the prevention and treatment of COVID-19, and a systematic review was conducted [45]. This systematic review included 14 studies from 14 countries (Japan was not included), and the prevalence of self-medication for the prevention of COVID-19 was 44.9% (from 3.9% to 96.2% among studies). In this report, the prevalence of vitamins (vitamin B, C, D, E, folic acid, and multivitamins) was 64%, herbal and natural products (ginger, honey, propolis, garlic, ginkgo biloba, omega-3 fatty acids) was 50%, minerals (zinc, calcium, iron, magnesium) was 43%, and most ingredients corresponded with our results. In addition, it is reported that some herbal supplement sales increased in the USA during COVID-19 pandemic [46]. Sales of elderberry, ashwagandha, apple cider vinegar, ginger, and echinacea were increased, but some of them were not reported in our survey. This might be due to the different regulations concerning herbal products between Japan and USA. On the other hand, CBD sales decreased in the USA during the COVID-19 pandemic [46].
In this study, 2.0% of those participants who reported using dietary supplements for the prevention of SARS-CoV-2 infection reported using CBD. CBD has become popular recently not only in Japan, but across the world. CBD is one of the cannabinoids derived from hemp (Cannabis sativa). Different from delta-9-tetrahydrocannabinol (THC), CBD is known as a non-psychoactive cannabinoid and seems safe under appropriate usage. CBD shows anti-inflammatory properties [47] and inhibitory effects on SARS-CoV-2 infection [48] and replication [49]. However, only two reports have been conducted on humans. One of the studies reported that CBD administration in COVID-19 patients failed to prevent the deterioration of the clinical status of COVID-19 symptoms [50], whereas the other study reported that CBD administration in healthcare workers during the COVID-19 pandemic could reduce the symptoms of burnout and emotional exhaustion [51]. This means that there is no evidence that CBD can prevent or reduce SARS-CoV-2 infection or severity in human studies, but it might be effective for reducing pandemic-related stress. However, it has been reported that excess CBD intake can cause adverse effects, such as hepatitis [52], respiratory depression [53], and diarrhea [54]. In addition, interactions with drugs have also been reported [55,56], so patients who take medication should not use CBD based on their own judgment.
This study was conducted through an online survey, which is both a strength and a limitation. Due to the pandemic, face-to-face and mail surveys are difficult to carry out. However, an online survey offers easy and contact-free participation. In addition, many people receive information about health, dietary supplements, drugs, and diseases via the Internet [57]. This means that the registrants of online survey companies might correspond to the target population of dietary supplement users. However, many consumers also receive information from mass media other than the Internet, which means that our study could not gather data on people who do not use the Internet and belong especially to older generations. In addition, this survey was conducted in January 2022, but anxiety among consumers might have been highest during the stay-at-home request in Japan (March-April to May 2020), and this might be associated with starting dietary supplement use for COVID-19 prevention. In addition, we found a higher prevalence of dietary supplement usage in participants who had experienced SARS-CoV-2 infection. However, we did not ask whether they had begun using supplements before or after they were diagnosed, and whether they had taken adequate infection control measures. In today's circumstances, it is not clear whether dietary supplements are helpful for COVID-19 prevention, although vitamin/mineral supplements might help maintain people's nutritional condition. In this study, some participants reported using dietary supplements that have no scientifically proven effects against COVID-19, such as catechins, echinacea, and CBD. To avoid the inappropriate use of dietary supplements, consumers should be provided with relevant information.

Conclusions
In this study, 8.3% of the participants reported using dietary supplements for the prevention of SARS-CoV-2 infection, and they mainly used nutrients, such as vitamin C, vitamin D, and zinc. These nutrients might be beneficial for their health by helping to avoid excess nutritional intake, even though there is no scientific evidence that they can help prevent SARS-CoV-2 infection. However, some participants reported using non-nutrient ingredients, such as probiotics, catechin, and CBD. CBD is generally recognized as safe, but there is no evidence that CBD is effective for the prevention of SARS-CoV-2 infection, and adverse events have also been reported. Therefore, the inappropriate use of these dietary supplements should be avoided. In addition, dietary supplement usage other than for the prevention of SARS-CoV-2 infection was a strong factor of dietary supplement usage for the prevention of SARS-CoV-2 infection. It is important to provide consumers, especially current supplement users, with information for proper use. Informed Consent Statement: Informed consent was obtained from all participants involved in the study. The page of informed consent was presented so that only those who agreed could proceed to the questionnaire.

Data Availability Statement:
The data presented in this study are available upon request from the corresponding author.