Since the start of the COVID-19 pandemic, symptoms such as pneumonia, clotting complications, acute respiratory distress syndrome, septic shock are reported in many cases of the infection. While these symptoms may arise in severe cases (~19% of the total cases), symptoms like fever, headache, cough, malaise, muscle pain, sore throat, nasal congestion, etc. can occur in mild-to-moderate cases (Wu, Z. et al. 2020). However, some patients experience no symptoms of the infection and are referred to as ‘asymptomatic’.

On October 6, 2020, Union Health Minister Harsh Vardhan released an “AYUSH standard treatment protocol” for the clinical management of COVID-19, that lists dietary measures, yoga, and Ayurvedic herbs with formulations. A long list of specific Ayurvedic recommendations for COVID-19 prevention and treatment were announced. This included the herb Ashwagandha (Withania somnifera) for:

1. For prevention of COVID-19 in a high-risk population such as healthcare workers, those living in COVID-19 hotspots, primary contacts of COVID-19 patients, etc.
2. For prevention of COVID-19 complications in infected patients like fatigue, lung fibrosis (scarring of lung tissue) and for the changes in the mental well-being associated with the COVID-19 infection.

Claims:
1. According to Dr. Harsh Vardhan, the COVID-19 treatment protocol is based on research studies conducted by AYUSH.
2. In healthy people, Ashwagandha can prevent COVID-19 infection.
3. In COVID-19 patients, Ashwagandha can prevent disease complications like fatigue, lung scarring and the impact of COVID-19 infection on mental health.

1. Clinical studies for Ashwagandha against COVID-19

A total of nine studies were registered with their respective ethics protocols on the CTRI. As per the timeline of these studies on CTRI: one out of the nine has been completed (but unpublished), three are are ‘open to recruitment’ for participants, and the remaining five have not even started. Thus, close to 50% of the studies have not started recruiting any patients for the study at the time when the AYUSH protocol was released (6th October 2020). Also, two-thirds of the studies will be conducted only in healthy people who do not have the infection. The remaining three are labelled as clinical trials in COVID-19 patients. Only one of the total three clinical trials registered is labelled as completed, the other two trials are either in the recruitment phase or have not started the study.
Table 1: Summary of the registered clinical trials on Ashwagandha against COVID-19
Status Healthy volunteers COVID-19 positive patients Total no. of studies
Not yet recruited 3 1 4
Recruiting 3 1 4
Completed 0 1 1
Total no. of studies 6 3 9

Thus, the AYUSH treatment protocol is not based on any published evidence for Ashwagandha.

2. Ashwagandha as a preventative drug in uninfected people
While there are no published clinical trials showing any efficacy of Ashwagandha in preventing COVID-19 infection, we found six protocols included in the ethics application on the CTRI website. These studies were either ongoing, or in the process of starting, but not completed. Further, the experimental methods or protocols in these six studies listed some unethical and unscientific design flaws as described in table 2 below:
Table 2: The status of six unpublished, ongoing studies on Ashwagandha in healthy people to prevent COVID-19. The table also lists their sub-standard methodology that may incorporate research bias in the final data (Data from CTRI, India as of 6th October 2020).
Study Researcher Group Status Methodology from the ethics application
1 Saketh Ram High-risk, healthy Recruiting • Not randomised
• Unclear exclusion sample

2 Muralikrishna Healthy Recruiting • Used as an immune-booster but excludes those with lowered immunity

3 Jayanthi High-risk,
Healthy Not started • A concoction of Ashwagandha with 10 other herbs as an immune booster
• No information for safety against drug interactions or adverse effects before the study

4 Chopra High-risk,
Healthy Not started • Comparison with hydroxychloroquine (HCQ) which has little evidence against COVID-19
• No other control group to compare with Ashwagandha– if both groups have the same effect

5 Singhal High-risk,
Healthy Recruiting • No control group
• Protocol vague between healthy and asymptomatic cases, unclear which will be included
• Enlists vague and generalised outcomes like ‘communicable diseases’
• Outcomes with which mental well-being will be quantified are undefined

6 Chopra Healthy Not started • To compare Ashwagandha with HCQ
• No mention of healthy participants in the inclusion

3. Ashwagandha as a treatment measure in COVID-19 patients
Unlike section 2 of testing Ashwagandha in healthy people, three studies were registered as trials for COVID-19 patients. Out of which one was found to be completed, which was the only completed study featuring Ashwagandha against COVID-19. The second study was in the recruitment phase and the third had not yet started. However, the completed study has not been published or peer-reviewed and its data is not available in the public domain. Additionally, many severe methodological flaws were found in these three studies such that even if they are completed with positive outcomes related to COVID-19, their data cannot be trusted as it will include unprecedented bias (see table 3) as compared to most clinical trials conducted in COVID-19 patients.
Table 3: The status of three unpublished, ongoing studies on Ashwagandha’s effect in COVID-19 patients. The table also lists their sub-standard methodology that may incorporate research bias in the final data. The study labelled ‘*’ suggests that it has completed data collection (Table 3, study 1). However, study 1 has not been reported as published or peer-reviewed. Data from CTRI, India as of 6th October 2020.
Study Researcher Group Status Methodology from the ethics application

1 Jayanthi* Patients Completed,
unpublished • Included low-risk patients with mild symptoms or no symptoms.
• Included patients that received ongoing modern medical care.
• Lack of control group for comparison.
• Low sample size of 50 patients.
• Concoction drug of Ashwagandha– unclear which active ingredient will have efficacy in the patients.
• Drug tested as an immunity enhancer in a low-risk group but excluded patients with low immunity.

2 Singhal Patients Recruiting • Testing many interventions with Ashwagandha at the same time like Kwath, Yoga, diet plan, etc.
• Includes patients that are asymptomatic or with mild symptoms.
• Both patients and researchers are aware of the treatments administered, e.g. lack of blinding.
• Includes a low-risk age of less than 60 years of age, with no comorbidities. The majority of complications and deaths are related to older patients with comorbidities.
• Enlists an unclear primary outcome, e.g. reduced mortality or reduced severity of disease.
• Unethical exclusion criteria of removing any patient from the study if their disease severity increases or develops side effects.

3 Singh Patients Not started • Includes only mild-moderate cases.
• Excludes co-morbidities, low immunity patients, cases with respiratory complication and those require ventilators.
• Excludes any other condition in patients that jeopardises the outcome of the study. That is, only positive outcomes will be reported and the negative outcomes like mortality, progression of disease severity will be excluded.
• While the average duration of COVID-19 illness is 24.7 days (Verity R et al. 2020), patients will be only tested on day 7 & 15. This can lead to incomplete follow-up of the study and underreporting of the complications.
• The primary outcome: Clinical cure rate defined as time to negative conversion of the virus (clearance from the body). However, clinical features of COVID-19 can be independent of the presence of the infection.
The AYUSH researchers have designed studies in healthy people using conveniently small numbers of participants with no control groups, and excluded patients with low immunity, older people, and people with other comorbidities – who are at a higher risk for severe COVID-19 symptoms. They also evaluated the herb as an immunity booster, while keeping the study outcomes ambiguous so that they can account for natural improvement of mild cases, and unchanged asymptomatic cases as proof of efficacy of the herb.
Not only the reduction in the increased severity of patients but also reduction in mortality in patients should be an important primary outcome of any treatment tested against COVID-19. None of the 3 listed clinical trials on COVID-19 positive patients have set out to measure the important outcome of reduced death due to Ashwagandha treatment, even though some patients without the usual risk factors may die due to COVID-19. None of the studies of Ashwagandha measure the severity of the disease progression, in a controlled manner while being on the drug. Only 2/9 studies measure hospitalisation as one of the secondary outcomes. The one study listed as completed has not published any data, even as a preprint, to suggest any proof of efficacy that Dr Harsh Vardhan claimed as a basis of the AYUSH treatment protocol.
Additionally, the protocol of these trials are based on several inclusion and exclusion criteria in such a way, that the research is only conducted in cases with low-moderate symptoms which have a good chance of recovering by itself. These trials conveniently exclude those patients that require hospitalisation after recruitment or mechanical ventilation. Thus, without including those who progressed to a severe version of the disease, it is unclear how the research will conclude the efficacy of Ashwagandha. It is without a doubt a sham way to conduct research that will always give results in the favour of the hypothesis regardless of any drug.
Conclusion:
To evaluate the efficacy of Ashwagandha, we reviewed the protocol applications on CTRI that are required to be approved by a panel from the ethical perspective of medical research. We found a total of 9 studies that were registered on Ashwagandha’s effect against COVID-19.
Upon close analysis, only one study was completed on Ashwagandha, and the remaining 8 studies were either in the phase of recruitment of study participants or had not been started on the day the AYUSH protocol was released by Dr Harsh Vardhan. Without completion or published with peer review or analysing the quality of the evidence of multiple studies, the usage of herbal treatments in clinical patients is not only unethical, but also dangerous in a condition that has a high patient suffering leading to mortality.
While the AYUSH ministry has been promoting alternative medicines to prevent COVID-19 since January 2020 without evidence, this promotion has taken a turn for the worse when the Minister of Health and Family Welfare (and not the AYUSH minister who had contracted COVID-19) launches alternative medicine protocols with no publically available evidence.
It is essential to continue testing herbs for COVID-19 and other illnesses, but it is also imperative that they go through the same rigorous standards of scientifically designed clinical trials and peer review as any other modern medicine drug.