Is the Famous TCM Formula Angong Niuhuang Wan Effective or Ineffective?

 Tiejun Tang   

Recently, I came across a video on YouTube by a highly popular online commentator, Mr. Wang, who claimed that the traditional Chinese patent medicine Angong Niuhuang Wan has no therapeutic benefit in treating acute stroke and performs no better than a placebo. Based on this, he concluded that this long-celebrated and expensive remedy is completely ineffective. Could it really be true that a classic formula used by traditional Chinese medicine (TCM) practitioners for hundreds of years is useless? This article aims to analyze and discuss this issue in detail.

 Source of the Controversy

 Mr. Wang’s argument was based on a recently published study in the Chinese Medical Journal (English edition) ^[1]. The study included 117 patients from 17 hospitals across China — 57 in the Angong Niuhuang Wan treatment group and 60 in the placebo group. The conclusion stated that there was no significant difference in efficacy between the two groups. The research was conducted by the Peking Union Medical College Hospital, one of the most prestigious Western medical institutions in China, and published in a top-tier Chinese medical journal. Unsurprisingly, the findings quickly drew attention and spread widely across both mainstream and social media.

 Angong Niuhuang Wan was formulated by Wu Jutong (1758-1836), a renowned physician of the Qing dynasty and an expert in the study of febrile diseases. The formula has the functions of clearing heat, resolving phlegm, detoxifying, and opening the orifices. It has been used for over 200 years to treat high fever with coma, stroke-induced unconsciousness, and convulsions in children. It is known as one of the “Three Cooling and Orifice-Opening Treasures” for treating stroke of the Close Symdrome in TCM. So, why did a formula with long-standing clinical efficacy fail to show benefit in a randomized, double-blind clinical trial?

 Clinical Research Evidence

 A research team from the China Academy of Chinese Medical Sciences published a meta-analysis with a much larger sample size, reporting different conclusions ^[2]. The study included 28 randomized controlled trials (RCTs) with a total of 2,745 acute stroke patients (1,375 in the experimental group and 1,370 in the control group). The results showed that Angong Niuhuang Wan  significantly improved the overall effective rate, Glasgow Coma Scale (GCS) score, Mini-Mental State Examination (MMSE) score, Activities of Daily Living (ADL) score, and Barthel Index score. It also reduced the National Institutes of Health Stroke Scale (NIHSS) score and serum brain natriuretic peptide (BNP) levels. No serious adverse events were reported, indicating good safety.

 Experimental Research Evidence

Experimental studies have also provided insights into the mechanisms of Angong Niuhuang Wan.

 One study established a cerebral ischemia–reperfusion injury (CIRI) model via middle cerebral artery occlusion and used acetylomics and proteomics to explore the neuroprotective effects of  Angong Niuhuang Pill (ANP). The results showed that ANP pretreatment significantly reduced neurological deficit scores and infarct volume, increased regional cerebral blood flow (rCBF), and decreased neuronal apoptosis. Further analysis revealed that ANP regulates autophagy at the transcriptional level via H4K16ac modification, promotes sirtuin 1 (SIRT1) accumulation, and modulates the SIRT1–H4K16ac axis to inhibit excessive autophagy, thereby exerting neuroprotective effects^[3].

 Another study used network pharmacology to identify key active compounds in ANP and predict its potential pathways. Five bioactive equivalent combinatorial components (BECCs) were identified, which demonstrated comparable effects to ANP in improving motor recovery in zebrafish and reducing neurological deficits and infarct volume in MCAO mice, mainly through the PI3K/AKT signaling pathway^[4].

More recently, researchers applied ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Exactive-Orbitrap-MS) to identify chemical constituents in ANP and its serum-absorbed components. Using network pharmacology and transcriptomic analysis, they found that 169 compounds were identified in total, 13 of which were detected in serum and interacted with 91 key targets. ANP significantly reduced serum TNF-α and IL-6 levels, as well as hypothalamic COX-2 and PGE2 levels. It upregulated NRF2 and KEAP1 expression while downregulating TLR4, IL-17A, p-P65/P65, TNF-α, and NLRP3. In LPS-induced RAW264.7 cells, ANP inhibited excessive secretion of inflammatory mediators (NO, IL-6, TNF-α), suppressed iNOS and CD86 expression, and enhanced NRF2 expression, thereby demonstrating strong anti-inflammatory and antioxidant effects^[5].

Discussion

Experimental studies have clearly demonstrated the multi-target mechanisms and material basis underlying the efficacy of Angong Niuhuang Wan. Why, then, do some clinical trials report conflicting results? What causes these discrepancies? And ultimately — is the medicine effective or not?

In my view, the key to evaluating the efficacy of a Chinese medicine lies in syndrome differentiation. No matter how famous or expensive a medicine is, if it is not prescribed according to the correct diagnosis (zheng), it will not be effective — and vice versa.

In TCM, stroke patients with impaired consciousness are classified under the category of Close Syndrome (闭证), which can be further divided into Heat Close syndrome  and Cold Close syndrome. For heat close syndrome, depending on whether heat or phlegm predominates, and whether convulsions are present, practitioners select different formulas. The “Three Cooling and Orifice-Opening Treasures” — Angong Niuhuang Wan, Zhibao Dan, and Zixue Dan— are used for heat closed syndrome, whereas Suhexiang Wan is used for cold close syndrome.

Western medicine researchers often administer Angong Niuhuang Wan to all stroke patients with coma, without distinguishing between heat and cold syndromes — which contradicts TCM principles. Wu Jutong would never have used a randomized double-blind method to treat patients; instead, he and generations of TCM practitioners after him applied individualized treatments according to syndrome differentiation, saving countless lives in the process. The enduring use of this formula for over 200 years is itself strong evidence of its clinical value.

Therefore, evaluating Chinese medicine efficacy using Western evidence-based criteria alone is inappropriate and misleading. TCM requires its own evaluation system — one that respects syndrome differentiation and the holistic principles of Chinese medicine. Only through research designed on these foundations can we truly assess the therapeutic effects of formulas like Angong Niuhuang Wan.

 References

1. Li S. Safety and efficacy of Angong Niuhuang Pills in patients with moderate-to-severe acute ischemic stroke (ANGONG TRIAL): A randomized double-blind placebo-controlled pilot clinical trial. Chin Med J (Engl). 2025 Mar 5;138(5):579–588.
2. Meng X. Effectiveness and safety of Angong Niuhuang Pill in treatment of acute stroke: A systematic review and meta-analysis.  J Tradit Chin Med. 2023 Aug;43(4):650–660.
3. Wang L.  Angong Niuhuang Pill pretreatment alleviates cerebral ischemia-reperfusion injury by inhibiting excessive autophagy through the SIRT1-H4K16ac axis.  J Ethnopharmacol. 2025 Jan 31;340:119214.
4. Zhang X. A newly discovered bioactive equivalence of combinatorial components of Angong Niuhuang Pill improves ischemic stroke via the PI3K/AKT axis.  J Ethnopharmacol. 2025 Mar 13;343:119453.
5. Gao F.  Explore the chemical components of Angong Niuhuang Pill and its potential mechanisms for fever treatment based on UHPLC-Q-Exactive Orbitrap HRMS, transcriptomics, and experiment verification.  J Ethnopharmacol. 2025 Sep 5;354:120542.