Analysis of in vitro serotonergic activity of black cohosh (Cimicifuga racemosa) and identification of a potential active constituent, N-methylserotonin

Cimicifuga racemosa (L.) Nutt. (black cohosh), a well known medicinal plant, is used to provide relief of menopausal hot flashes, although various clinical trials have provided conflicting efficacy data. Although black cohosh is a common component of several dietary supplements, the active constituents remain unknown. Previously we reported that a 75% ethanol extract had serotonergic activity [1] and could have a similar mechanism of action as some anti-depressants known to relieve hot flashes. The serotonergic system, particularly the 5-HT₇ receptor and the serotonin transporter, are intimately involved with temperature and mood regulation. All extracts and compounds were evaluated for serotonergic activity using competitive ligand binding assays for the 5-HT₇ receptor, cAMP induction, and a selective serotonin reuptake inhibition (SSRI) assay. Studies found the crude extracts displaced the specific binding of [³H] lysergic acid diethylamide (LSD) to the 5-HT₇ receptor and caused modest cAMP production. Bioassay guided fractionation of the MeOH extract led to isolation of the pure compounds, cimicifugic acids A, B, E, F, fukinolic acid, and N-methylserotonin. The triterpenes and phenolic acids weakly bound to the 5-HT₇ receptor, yet failed to induce cAMP production, or have SSRI activity. In contrast, N-methylserotonin showed potent 5-HT₇ receptor binding (IC₅₀=21 nM), induced cAMP production (EC₅₀=21.8 nM), and was able to block the serotonin transporter activity (IC₅₀=493 nM). To our knowledge, this is the first report of N-methylserotonin in black cohosh which may account for the serotonergic activity.

Acknowledgements: Office of Dietary Supplements, National Institute for General Medical Sciences, Office for Research on Women's Health, National Center for Complementary and Alternative Medicine for jointly funding NIH Grant P50AT00155 provided to the UIC/NIH Center for Botanical Dietary Supplements Research and NCCAM for funding NIH/NRSA F31AT003995.

References: 1. Burdette, J.B., et al. (2003)J. Agric. Food Chem. 51:5661–5670