Black Cohosh

證據等級: L5

預測適應症: 10 個

BLACK COHOSH: From Menopausal Symptom Relief to Heart Disease

One-Sentence Summary

Black Cohosh (Cimicifuga racemosa) is a herbal supplement widely used as an alternative to hormone replacement therapy for relieving menopausal symptoms, particularly hot flashes and vasomotor complaints. The TxGNN model predicts it may have potential in Heart Disease, supported by 1 relevant Phase 3 clinical trial (terminated early) and 10 publications including 1 RCT and multiple observational and mechanistic studies examining cardiovascular endpoints. A critical safety signal — a case report of reversible complete heart block — combined with the absence of any US market authorization means the risk-benefit profile must be clarified before this direction can be pursued.

Quick Overview

Item	Content
Original Indication	Not officially approved; used as herbal supplement for menopausal symptoms (hot flashes, vasomotor symptoms)
Predicted New Indication	Heart Disease
TxGNN Prediction Score	99.19%
Evidence Level	L3
US Market Status	✗ Not marketed
Number of NDAs	0
Recommended Decision	Hold

Why Is This Prediction Reasonable?

Currently, detailed mechanism of action data from DrugBank is not available. Based on published research, Black Cohosh (Actaea racemosa / Cimicifuga racemosa) is a North American medicinal plant whose rhizome contains triterpene glycosides (actein, 23-epi-26-deoxyactein), phenolic acids (ferulic acid, isoferulic acid), and alkaloids (cimicifugamide). It has been widely used as a plant-based alternative to hormone replacement therapy in postmenopausal women, and several Asian Cimicifuga species are approved in China for cardiovascular and cerebrovascular indications.

The mechanistic connection to heart disease emerges from at least two distinct pathways. First, PMID 28347916 identified cimicifugamide as a non-selective β-adrenergic receptor (β-AR) agonist, demonstrating direct cardiac effects — increased heart rate and myocardial contractility — in preclinical models. Second, PMID 17430734 showed that an Actaea racemosa-containing supplement significantly reduced asymmetric dimethylarginine (ADMA), a validated biomarker of endothelial dysfunction and cardiovascular risk, in an RCT of menopausal women. PMID 30176632 further observed improved hemodynamic parameters in perimenopausal women with arterial hypertension. PMID 40382826 adds an anti-inflammatory mechanism: C. racemosa extract Ze 450 reprograms macrophage immunometabolism and suppresses pro-inflammatory signaling, relevant because chronic “inflammaging” after estrogen loss is increasingly recognized as a cardiovascular disease driver.

However, the same β-AR agonist activity that could be cardioprotective in some contexts carries direct safety risk in others. PMID 20955128 documents a case of reversible complete heart block in a patient taking Black Cohosh, and PMID 16007232 notes that sodium ferulate — a phenolic compound found in Cimicifuga heracleifolia — has antithrombotic and platelet aggregation inhibitory activity (approved in China for cardiovascular disease), suggesting the plant’s cardiovascular bioactivity is real but complex. The net clinical effect in patients with established heart disease remains undefined.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00663104	Phase 3	Terminated	126	Exercise ± Cimicifuga racemosa BNO 1055 vs. wellness control in early postmenopausal women over 12 months. The TRACE study (PMID 20220537) reported that exercise + CR significantly reduced 10-year CHD risk (Framingham score) vs. wellness control. Primary endpoint was bone mineral density; cardiovascular risk was a secondary endpoint. Trial terminated early; findings are exploratory.

Two additional records retrieved by the database search (NCT05304416, NCT04496986) addressed post-cardiac surgery dysphagia and have no relevance to Black Cohosh’s cardiovascular effects. They are excluded.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
17430734	2007	RCT	Fertility and Sterility	Isoflavones + Actaea racemosa supplement significantly reduced ADMA (endothelial dysfunction marker) in menopausal women; lipids and CRP were not significantly changed
20220537	2010	Phase 3 RCT secondary analysis	Menopause	TRACE study: exercise + CR BNO 1055 vs. exercise alone reduced 10-year CHD risk (Framingham) in early postmenopausal women; effect on CHD risk was driven primarily by the exercise component
30176632	2018	Clinical observational	Wiadomości Lekarskie	Cimicifuga racemosa improved hemodynamic parameters and quality of life in perimenopausal women with arterial hypertension
28347916	2017	Mechanistic (in vitro + in vivo)	Biomedicine & Pharmacotherapy	Cimicifugamide from Cimicifuga rhizomes identified as non-selective β-AR agonist; cardiac, antipyretic, and sudorific effects confirmed in toad heart failure model and mouse models
20955128	2010	Case Report	Medical Journal of Australia	Safety signal: Reversible complete heart block (bradycardia) in a woman taking Black Cohosh; resolved upon discontinuation; consistent with β-AR agonist mechanism
16007232	2005	Review	Cardiovascular Drug Reviews	Sodium ferulate from Cimicifuga heracleifolia has antithrombotic, platelet aggregation inhibitory, and antioxidant activities; approved in China for cardiovascular/cerebrovascular disease treatment
39829189	2024	Systematic Review	Journal of Menopausal Medicine	HRT for hot flashes associated with increased coronary heart disease risk — provides context for why plant-based alternatives (including Black Cohosh) are sought in this population
16181020	2005	Review	Journal of Women’s Health	Comprehensive review of botanical supplements for menopausal symptoms including Black Cohosh; notes limited cardiovascular-specific evidence despite widespread use
15813159	2005	Review	Southern Medical Journal	Overview of integrative therapies for menopause; documents shift away from HRT after Women’s Health Initiative cardiovascular findings
16115005	2005	Survey/Observational	Journal of Women’s Health	Real-world prescribing patterns after WHI: documents widespread uptake of Black Cohosh as HRT alternative in a cardiovascular risk-aware population

US Market Information

Black Cohosh holds no US NDA, ANDA, or BLA approvals. It is commercially available in the United States as a dietary supplement (herbal product) under DSHEA regulation and does not have FDA-approved indications. No formal prescribing information or FDA-reviewed safety label exists.

Safety Considerations

Formal package insert data is unavailable given the supplement status. The following signals are drawn from published literature:

Cardiac arrhythmia risk: PMID 20955128 documents reversible complete heart block (complete AV nodal block) in a patient taking Black Cohosh. This is mechanistically consistent with cimicifugamide’s non-selective β-AR agonist activity (PMID 28347916). In patients with existing conduction abnormalities or heart disease, this represents a potentially serious risk.
Hepatotoxicity: Multiple publications document idiosyncratic hepatotoxicity associated with Black Cohosh use (PMID 24657312, PMID 19339903). Cases range from asymptomatic enzyme elevation to acute hepatitis confirmed by liver biopsy. The mechanism appears to involve quinoid metabolites formed during biotransformation (PMID 12870886). Causality has been confirmed in several cases via structured causality assessment (CIOMS/RUCAM scale).
Hematologic effects: NTP subchronic toxicology study in mice (PMID 36373576) revealed hematologic alterations with Black Cohosh extract; human clinical relevance requires further characterization.
Phytoestrogenic and serotonergic activity: Black Cohosh may exert weak estrogenic or serotonergic receptor effects; use in patients with hormone-sensitive conditions, or those on serotonergic drugs, warrants additional evaluation.

Conclusion and Next Steps

Decision: Hold

Rationale: Mechanistically plausible signals exist — cimicifugamide’s β-AR agonist activity, ADMA reduction in a small RCT, and hemodynamic improvements in observational data — but the evidence base is indirect (L3), no completed cardiovascular outcome trial exists, and the very mechanism underlying predicted benefit (β-AR agonism) has produced a documented case of complete heart block. Advancing this candidate into a cardiac patient population without first resolving this safety paradox would be premature.

To proceed, the following is needed:

Safety-first characterization: Clarify whether cimicifugamide’s non-selective β-AR agonist activity is net beneficial or harmful in patients with pre-existing cardiac disease; pharmacological profiling across β1/β2/β3 receptor subtypes is essential
Hepatotoxicity risk quantification: Establish background rate and risk factors for Black Cohosh–associated hepatotoxicity before any sponsored trial enrollment
Target disease refinement: Narrow “heart disease” to a mechanistically anchored subtype — e.g., postmenopausal cardiovascular risk reduction, endothelial dysfunction, or hypertension in perimenopausal women — rather than pursuing a broad indication
Active component identification: Determine which specific phytochemical(s) drive the cardiovascular signal and at what doses; standardized extract composition must be established for any clinical trial
Dedicated cardiovascular trial design: A properly powered trial with primary cardiovascular endpoints (not menopausal symptoms with cardiovascular risk as secondary) is needed to generate L2-level evidence
Regulatory pathway clarification: Determine whether a drug-level NDA pathway or an authorized health claim pathway is appropriate given the supplement regulatory history
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.