Andrographolide Reduces Day-7 CRP and IL-6 in Mild COVID-19 but Fails to Beat Favipiravir by Day 14

In an 82-patient, multicenter randomized controlled trial (RCT) comparing andrographolide plus favipiravir against favipiravir monotherapy in mild COVID-19, the andrographolide arm showed serum C-reactive protein (CRP) of 5.8 mg/L versus 18.4 mg/L in controls at day 7 (p=0.019), and interleukin-6 (IL-6) of 2.0 versus 21.8 pg/mL (p=0.001). By day 14, those differences had vanished (Kanokkangsadal et al., 2023). A 2025 meta-analysis of six RCTs confirmed the pattern: at final follow-up, pooled estimates showed no significant difference in fever resolution (RR 1.12; 95% CI: 0.90–1.38), cough resolution (RR 0.98; 95% CI: 0.74–1.31), CRP (MD −0.04; 95% CI: −0.26 to 0.18), or IL-6 (MD −0.07; 95% CI: −0.17 to 0.03) between AP extract and antivirals (Prabhakornritta et al., 2025). The headline conclusion is inconclusive. The mechanistic detail is not.

The Molecular Target

Andrographolide, a labdane diterpenoid lactone (molecular formula C₂₀H₃₀O₅) from Andrographis paniculata (Burm.f.) Nees, inhibits nuclear factor κB (NF-κB) by covalently binding to the Cys-38 residue of the p50 subunit — blocking translocation of the p50–p65 heterodimer into the nucleus and thereby suppressing transcription of IL-1β, IL-6, TNF-α, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) (Xia et al., 2004). This is not competitive inhibition; it is a covalent interaction, which explains why the anti-inflammatory effect can persist beyond the compound's plasma half-life. Additionally, andrographolide has been shown to inhibit viral RNA-dependent RNA polymerase (RdRp) in silico and in vitro models of SARS-CoV-2, though no human pharmacokinetic data yet confirm that oral dosing achieves RdRp-inhibitory concentrations at the pulmonary mucosa (Enmozhi et al., 2021).

Andrographolide also suppresses the NLRP3 inflammasome, a cytoplasmic multiprotein complex responsible for the maturation and release of IL-1β — the cytokine most strongly associated with the hyperinflammatory phase of severe COVID-19 (Ahmed et al., 2021). Whether this inflammasome-suppressing effect operates within the therapeutic window achievable by oral 180 mg/day dosing remains unconfirmed in human tissue samples.

What the Clinical Evidence Shows

The strongest signal comes from early timepoints. In the Kanokkangsadal 2023 RCT (n=82; multicenter, open-label; 180 mg andrographolide/day for 5 days plus favipiravir vs. favipiravir alone), cough resolution was significantly greater at week 1 in the andrographolide arm; the inflammatory biomarker advantage was measurable but had equalized by day 14. Separately, Wanaratna et al. (2022) reported that by day 5, a significantly greater proportion of patients in the extract group achieved CRP ≤10 mg/L compared to supportive care.

The 2025 meta-analysis (Prabhakornritta et al., 2025) synthesized six RCTs from Thailand and China, covering oral AP extract (predominantly 180 mg andrographolide/day in divided doses) versus favipiravir or standard supportive care in mild-to-moderate COVID-19. Despite trends favouring AP on inflammation and symptom trajectories in individual early-measurement timepoints, pooled estimates at final follow-up were consistently non-significant across all four primary outcomes. The analysis carried a high risk of bias rating for fever resolution outcomes and noted substantial heterogeneity in study design and comparator regimens. Pneumonia prevention data from the Wanaratna preprint (0/29 vs 3/28; p=0.039) is suggestive but came from an underpowered study not yet through full peer review for that endpoint.

For uncomplicated upper respiratory tract infection (URTI) outside COVID-19, the evidence base is older but more consistent. A systematic review of four RCTs (n=433) found AP significantly superior to placebo in symptom severity with a mean difference of 10.85 points (95% CI: 10.36–11.34; p<0.0001) (Poolsup et al., 2004).

The Classical Record

In Ayurveda, A. paniculata is classified as Bhunimba (also Kalmegh, Mahatikta). Charaka Samhita, Chikitsa Sthana 3/198 and 7/69, lists Bhunimba among the bitter (tikta) group of drugs indicated in jvara chikitsa — fever management — particularly for fevers driven by Pitta and Kapha imbalance (Charaka, redacted Dridhabala, c. 2nd century CE; trans. Sharma PV, 1998). The classical indication of Bhunimba as Jvaraghna (fever-resolving), Krimighna (antimicrobial), and Yakrituttejaka (liver-stimulating) maps mechanistically to andrographolide's documented NF-κB and iNOS suppression — pathways that sit downstream of pyrogenic cytokines such as IL-1β. The classical toxicity warning around excessive bitter herbs in Pittaprakrti individuals also finds a correlate: andrographolide at doses above standard shows mild transaminase elevation (AST elevation confirmed at day 7 and day 14 in Kanokkangsadal et al., 2023), requiring hepatic monitoring in prolonged use.

Clinical Implications

The data do not yet support prescribing andrographolide as a replacement for antivirals in COVID-19. What they do support is a time-sensitive adjunctive role: the early CRP and IL-6 reduction signal at day 5–7 suggests that andrographolide may be most useful in the first inflammatory window, before the hyperinflammatory phase, rather than as a sustained antiviral. For uncomplicated URTI, symptom relief at 200 mg/day standardised extract (minimum 4–6% andrographolide) for 5 days has the most replicable evidence. Mild transaminase elevations (AST, ALT) were recorded in the andrographolide arm of the 2023 RCT — not clinically significant in the short term, but hepatic function monitoring is warranted if use extends beyond 5–7 days. Practitioners should not use commercial Kalmegh churna as a substitute for standardised extracts in clinical settings; the andrographolide content in unprepared plant powder is variable and typically sub-therapeutic.

What Remains Unanswered

No RCT has compared andrographolide to a placebo (rather than an active antiviral) across the full clinical course of COVID-19 while measuring pneumonia incidence as the primary endpoint — the Wanaratna data are preliminary and the sample size was inadequate for a definitive answer. The NLRP3 inflammasome suppression observed in mouse Parkinson models (Ahmed et al., 2021) has no direct human pharmacodynamic confirmation in respiratory infection. A dose-finding RCT establishing the andrographolide plasma concentration required for NF-κB p50 covalent inhibition in human bronchial tissue does not yet exist. Studies are also absent in immunocompromised populations, elderly patients above 70, and paediatric cohorts — the groups where early cytokine control would matter most.

References

1. Kanokkangsadal P, Sangkitporn S, Manosuthi W, Kiertiburanakul S, Prabhasawat P, Thammawijaya P, Poovorawan Y. (2023). Efficacy and safety of andrographolide and favipiravir versus favipiravir monotherapy in patients with mild COVID-19 infection: a multicenter randomized controlled trial. OBM Integrative Complement Med. 9(1):013.
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7. Charaka, Dridhabala. Charaka Samhita, Chikitsa Sthana 3/198 and 7/69. In: Sharma PV (Trans. & Ed.). (1998). Chaukhamba Orientalia, Varanasi. Vol. 2.