Safe prolonged prophylactic use and tolerability of Ashwagandha following COVISHIELD™ vaccination over 24 weeks: a multicentre randomized double-blind placebo-controlled trial

Introduction Ashwagandha ( Withania somnifera Dunal) is an Ayurveda medicine that was widely used during the COVID-19 pandemic. In the context of widespread use of herbal formulations alongside COVID-19 vaccination, this study evaluated the safety, tolerability, and exploratory immunological outcomes of Ashwagandha administered following COVISHIELD™ vaccination. Methods 1,200 consenting apparently healthy participants (age 18–70 years) with a negative SARS-CoV-2 RNA assay (RT-PCR using oral and nasal swab) were randomized within 7 days of vaccine administration (primary or booster) to receive oral standardized Ashwagandha (500 mg aqueous root extract) or a matching placebo daily. Participants were monitored every 4 weeks till weeks 28 (study completion) which included comprehensive clinical and laboratory assessment, specific viral RNA and IgG antibody assays (including Wuhan and Delta strain neutralization). Statistical analyses were performed using standard methods, with a two-sided p -value of < 0.05 considered statistically significant. Results Of the 1,200 randomized participants, 122 (10.2%) were assigned to the SDG (Single Dose Group), 503 (41.9%) to the DDG (Double Dose Group), and 575 (47.9%) to the BDG (Booster Dose Group); overall, 1,032 participants (86%) completed the trial. The safety and tolerability profile of Ashwagandha was comparable to placebo. Adverse events were predominantly gut related and mild, and none caused withdrawal. Following first Covishield™ injection, a persistently higher IgG antibody assay was observed in the Ashwagandha arm (not statistically significant). The cumulative incidence rate of breakthrough infections was 3.9% (95% confidence interval 3.0–5.2%) and did not differ by study intervention. The immunogenic effect of Ashwagandha could not be demonstrated, likely due to a persistently high post-vaccination immune response. In addition, approximately 70% of participants were seropositive for nucleocapsid antibodies at baseline, indicating prior SARS-CoV-2 infection. Conclusion Prolonged use and tolerability of Ashwagandha in post-vaccinated healthy participants was shown safe but adjunct immunogenicity could not be discerned. Further research is required. Clinical Trial Registration http://www.clinicaltrials.gov/ , identifier CTRI/2021/06/034496.