As of May 25th, 2023, 766 million COVID-19 cases and over 6.9 million deaths worldwide had been reported to the World Health Organization.[1] In the pursuit of combating this global crisis, innovative approaches like reverse vaccinology offer a ray of hope for developing effective vaccines against COVID-19.[2] [3] These advancements not only address the urgent demands of the pandemic but also pave the way for proactive and resilient responses to future infection threats. Whilst current COVID-19 treatment primarily relies on supportive care, monoclonal antibodies or non-specific medications, the persistently high mortality rate among vulnerable populations underscores the critical need for therapeutic alternatives.[4] [5] By embracing the principles of integrative medicine, including homeopathy, continued research and exploration of novel therapeutic strategies are vital in our collective battle against COVID-19 and the prevention of future epidemics.[6] [7]

In addition to its recognized use in treating chronic diseases, individualized homeopathy may also be effective in resolving or managing acute cases, including epidemic diseases.[8] [9] However, it is important to emphasize that the use of customized homeopathy requires precise diagnosis and treatment to ensure its efficacy and safety. In epidemic diseases, which often present similar symptomatology in affected individuals, the individualized homeopathic medicine should be selected based on the signs and symptoms that the patient presents at different stages or phases of the outbreak. According to Samuel Hahnemann's principles, these remedies should be administered individually, sequentially or alternatingly, but never as a homeopathic complex (mixtures of homeopathic medicines) or disregarding previous pathogenetic experiments and individualization according to the symptomatic totality characteristic of each stage of the contemporary epidemic.[10]

In the past, homeopathic treatment has been used with varying degrees of success in managing cholera, Spanish flu, dengue, chikungunya, and acute encephalitis syndrome (ACS).[11] Notably, there is compelling anecdotal evidence associating homeopathy to the 1918 Spanish flu outbreak, highlighting lower mortality rates among patients treated with Gelsemium.[12] [13] Clinical studies have demonstrated positive outcomes, such as thrombocytopenia improvement in dengue hemorrhagic fever[14] and reduced mortality in ACS.[15] However, it is crucial to conduct structured and internationally recognized clinical research to evaluate the efficacy and safety of customized homeopathic medications in treating and preventing the COVID-19 epidemic. By upholding rigorous research protocols, we can generate robust evidence that contributes to evidence-based practices in homeopathy, fostering the advancement of patient care and well-being.[16]

Despite the lack of this methodological standard during the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, several scientific communities involved in homeopathic therapy have made efforts. The Ministry of AYUSH, Government of India, has recommended various homeopathic medicines for both preventive and symptomatic management of COVID-19. Several medicinal plants, including Arsenicum album 30C (ʻimmunomodulatorʼ with prophylactic application), Bryonia alba (for lung inflammation), Rhus toxicodendron (for viral infections), Atropa belladonna (for asthma and chronic lung disease), Bignonia sempervirens (for asthma) and Eupatorium perfoliatum (for respiratory symptoms), are described as possible homeopathic therapeutic approaches for COVID-19 symptomatic treatment.[17]

These findings have prompted researchers to search for homeopathic therapies that could potentially reduce the risk of SARS-CoV-2 infection or alleviate COVID-19 symptoms.[18] Pathogenesis information in homeopathic materia medica books shows that Cinchona (China) officinalis 6C has a wide range of effects on most of the symptoms of this pandemic, especially at the recommended dose of six drops per day for up to 6 months.[18]

Several acute homeopathic medicines are also recommended for each stage or phase of disease manifestation, based on circumstantial evidence. According to Gosik et al, Ferrum phosphoricum 6C, Gelsemium 6C, Justicia adhatoda 6C, Carbo vegetabilis 6C and Polygala senega 6C, with six drops three times a day, are recommended for acute symptoms in the first (pulmonary) stage.[18] However, blinded, randomized controlled clinical trials (RCTs) are necessary to confirm these results. For oral hygiene and disinfection, use 10 drops of Calendula officinalis 2DH in a half-glass of warm water to gargle three times a day.[19] In addition, the extract from the flower of Calendula officinalis showed a faster resolution of the inflammatory phase with increased production of granulation tissue in acute wound healing.[20]

In a retrospective cohort study of 178 COVID-19 patients with mild symptoms, 138 homeopathic medicines were prescribed, with Bryonia alba being the most frequently indicated (46/138 = 33.3%), followed by Arsenicum album (25/138 = 18.1%), Pulsatilla nigricans (19/138 = 13.8%), Nux vomica (11/138 = 8.0%), Rhus toxicodendron (10/138 = 7.2%) and Gelsemium sempervirens (8/138 = 5.8%), all in potency 30C (80%).[21] Similarly, a placebo-controlled RCT of the addition of homeopathy to standard treatment of COVID-19, conducted on 300 patients, showed that Arsenicum album, Bryonia alba and Phosphorus were the most frequently prescribed medicines, selected based on the totality of symptoms.[11]

Savera et al[22] and Manchanda et al[23] analyzed the homeopathic treatment of 177 and 211 infected patients respectively, and found that the most commonly used remedies were Bryonia alba, Phosphorus, Arsenicum album, Gelsemium sempervirens, and either Carboneum oxygenisatum or Pulsatilla nigricans.

In Spain, Clapers et al[24] performed a prospective case series study of 103 patients with mild or moderate COVID-19, 11 of whom had concomitant chronic lung disease, eight had obesity and three had cardiovascular disease. Based on the analysis conducted, Bry, Ars, Phos and Gels emerged as the most commonly prescribed drugs. Meanwhile, Sulphur (6/6 = 100%), Pulsatilla (4/5 = 80%) and Bryonia alba (21/29 = 72%) had the highest rates of ʻgood responseʼ. Depending on the remedy used, the period for full healing after homeopathic treatment ranged from 3.5 to 14.4 days. The 200C dose resulted in the quickest rates of full recovery and required the least amount of treatment modification. However, a poor response rate of 20% and 0% was observed with the use of Gelsemium and China officinalis respectively, despite the broad recommendation emphasized in several studies.[18] [22] [25] [26]

Another RCT[27] studied the effectiveness of five different homeopathic medicines in preventing COVID-19 in a quarantined population of 2,233 individuals that had been exposed to at least one case of COVID-19 in their building, community or workplace. Those randomized to receive either Bryonia alba or coronavirus nosode CVN01 had a lower incidence of laboratory-confirmed COVID-19 (4/310 and 5/312 respectively) and shorter duration of illness (median of 7.5 and 5 days respectively), with fewer hospitalizations, compared with those taking placebo (13/330; 12 days). However, there was no statistical difference from placebo in subjects receiving Arsenicum album 30C (7/311; 10 days), Camphora 1M (12/315; 13 days), or a combination of Arsenicum album 30C, Influenzinum 30C and Gelsemium sempervirens 30C (18/655; 9.5 days). The symptom complex of Camphora does not fit well with the acute infection symptoms of the disease, which may explain its poor results compared with the placebo group. Treatment consisted of the administration of six tablets twice daily for 3 days.

These positive results cannot be solely attributed to homeopathic medicines since some patients also received conventional medicines. Moreover, COVID-19 has a self-limiting course of 5 to 14 days in mild cases, and since there was no control arm, it was not possible to evaluate efficacy. Therefore, double-blinded RCTs with placebo control are necessary, particularly to investigate the role of homeopathy in severe cases and critical stages where inflammation and hypercoagulability drive the organism to multiorgan failure.

To address these methodological issues, Mukherjee et al[28] designed a four-arm RCT with a sample size of 20,000 participants. The study population was randomly assigned to receive one of three different homeopathic medications (Bryonia alba 30C, Gelsemium sempervirens 30C, Phosphorus 30C) or an indistinguishable placebo for a period of three days for children or six days for adults. All participants between 5 and 75 years of age received 500 mg of ascorbic acid (vitamin C) in tablet form once daily for 6 days. Whilst the incidence of unconfirmed COVID-19 cases was significantly lower in the Phosphorus group (weeks 1–4) compared with the placebo, no significant difference was observed in the Bryonia or Gelsemium groups. Overall, the study was inconclusive, and further investigation is needed to determine the potential effect of Phosphorus.

Asymptomatic COVID-19 individuals can transmit the disease for up to 14 days and have been major contributors to the rapid spread of the COVID-19 pandemic. In an open-label, placebo-controlled exploratory RCT, 200 COVID-19 patients receiving standard care were given homeopathic medicines, including Bryonia alba 30C (Bry). By day 15, 98% of individuals who received Bry became RT-PCR negative for SARS-Cov-2, compared with 88%, 80% and 88% from the Arsenicum album 30C, Camphora 1M and placebo groups respectively.[29] However, additional studies are required to examine the potential implications.

After documenting 143 individualized symptoms in 104 patients who were treated with homeopathy, Vaishampayan et al[30] converted these symptoms into rubrics and created a repertorization table. They found that the medication Mercurius solubilis was the top-ranking remedy on the combined repertorization table (fourth or fifth on all individual repertorization charts). The researchers identified 13 common symptoms of Merc Sol (highlighting tongue, salivation, perspiration, nocturnal aggravation) that occurred in varying degrees of intensity in the 104 patients and created a 13-item questionnaire. In a pilot study (not yet published), they observed a reduction in hospital stay of 5 to 7 days in all 68 hospitalized patients who had at least eight confirmed symptoms from the questionnaire and were treated with Merc Sol 200C three times daily for 1 week. The researchers then created a mathematical model and a digital clinical trial with 800 virtual patients that confirmed their findings.[31] Now the worldwide homeopathy community must validate the use of Mercurius solubilis as a genus epidemicus in the COVID-19 pandemic.

One of the most robust research protocols was developed by Adler et al.[32] They examined the efficacy and safety of the homeopathic remedy Natrum muriaticum LM2 in mild cases of COVID-19 in a placebo-controlled and double-blinded RCT. In this ʻCOVID-Simileʼ study, there was no evidence for efficacy of Natrum muriaticum LM2, and time to recovery (the primary endpoint) did not differ between the groups. However, secondary results suggested that in the homeopathy group, participants with a baseline symptom level of ≥5 obtained a 50% reduction in symptom score substantially earlier. In addition, the restricted mean survival scores showed that patients receiving homeopathy experienced a 0.9-day faster improvement during the first 5 days of follow-up (p = 0.022). Despite the pooling that took place in this study, further studies on the efficacy of homeopathic Natrum muriaticum LM2 require a larger sample size.

Through a retrospective report of a real-world experience, Daruiche et al[33] recently provided good support for the use of Arsenicum album 30cH as a genus epidemicus medicine that could aid in the prevention and treatment of COVID-19. Despite some methodological limitations, the results are remarkable: only 0.7% of employees taking the drug showed symptoms of COVID-19, compared with 67.8% of workers at other premises and 13.3% of teleworkers who did not receive the intervention. Furthermore, a cohort study[34] as well as a prospective, multicenter, community-based, open-label study of 32,186 people in seven Indian cities,[35] showed that Arsenicum album 30C had some protective effects against COVID-19 compared with no treatment.

The scientific information presented here illustrates the most recent findings about the use of homeopathic therapies ([Table 1]). As shown, many of the cited papers have performed retrospective data analysis on population cohorts, which have some limitations. One potential drawback is recall bias among participants during telephone or face-to-face follow-up. However, such data collection is more likely to result in under-reporting than over-reporting of events and therefore does not over-estimate the results of the study. A causal relationship between medication uses and protection against COVID-19 cannot be established in the absence of a control group. Nevertheless, observational studies are recommended to estimate the protective effect of an intervention.[36]

Although double-blinded and placebo-controlled RCTs are recommended to validate the research findings presented in this letter, we wish to emphasize the advantages of observational studies focusing on retrospective analysis of mass-level data, as proposed by previous research.[37] Such studies provide valuable insights into real-world effectiveness and outcomes. In contrast, RCTs can be limited by sampling bias, where the analyzed sample or randomized groups may not accurately represent the primary population from which they were obtained. Additionally, RCTs are often expensive to conduct, resulting in a limited sample size for analysis and relatively short follow-up times. As a result, randomization may not be sufficient to eliminate significant differences between the two groups in terms of both visible and non-visible confounding factors (even if these variations are attributable to random chance). Furthermore, randomizing an intervention within an RCT setting is not always possible due to ethical standards, or a treatment's positive effects on health may be so significant that observational studies on their own might be sufficient to prove its effectiveness.[38] [39] [40]

Finally, we stress that though most of the listed medicines have been identified solely from observational studies, they cannot be ignored because their prescription in most studies respects the repertorization techniques used in homeopathy.