In Vitro Serotonergic Activity of Black Cohosh and Identification of N_ω-Methylserotonin as a Potential Active Constituent

Abstract

Cimicifuga racemosa(L.) Nutt. (syn. Actaea racemosa L., black cohosh) is used to relieve menopausal hot flashes, although clinical studies have provided conflicting data, and the active constituent(s) and mechanism(s) of action remain unknown. Since serotonergic receptors and transporters are involved with thermoregulation, black cohosh and its phytoconstituents were evaluated for serotonergic activity using 5-HT7 receptor binding, cAMP induction, and serotonin selective reuptake inhibitor (SSRI) assays. Crude extracts displayed 5-HT7 receptor binding activity and induced cAMP production. Fractionation of the methanol extract lead to isolation of phenolic acids and identification of Nω-methylserotonin by LC/MS-MS. Cimicifuga triterpenoids and phenolic acids bound weakly to the 5-HT7 receptor with no cAMP or SSRI activity. In contrast, Nω-methylserotonin showed 5-HT7 receptor binding (IC50 23 pM), induced cAMP (EC50 22 nM), and blocked serotonin reuptake (IC50 490 nM). These data suggest Nω-methylserotonin may be responsible for the serotonergic activity of black cohosh.

Black Cohosh and Breast Cancer

“…14 With respect to serotonin, black cohosh has shown 5-HT7 receptor binding and activation in vitro. 57,58 The recently identified black cohosh compound, N-ω-methylserotonin, has been shown to bind the 5-HT7 receptor with strong affinity, induce cAMP as a second messenger, and block serotonin reuptake, suggesting serotonergic activity for black cohosh. 58 Burdette et al 50 found that black cohosh bound strongly to 3 receptor subtypes (5-HT 1A, 1D, and 7), thereby acting as a partial agonist.…”

“…57,58 The recently identified black cohosh compound, N-ω-methylserotonin, has been shown to bind the 5-HT7 receptor with strong affinity, induce cAMP as a second messenger, and block serotonin reuptake, suggesting serotonergic activity for black cohosh. 58 Burdette et al 50 found that black cohosh bound strongly to 3 receptor subtypes (5-HT 1A, 1D, and 7), thereby acting as a partial agonist. Since the 5-HT 1A and 7 receptor subtypes are present in the hypothalamus, it has been proposed that serotonergic activity in the hypothalamic thermoregulatory centers may be responsible for the reduction in hot flashes.…”

Efficacy of Cimicifuga Racemosa on Menopausal Symptoms in Women with Breast Cancer

“…Recently, it has been demonstrated the presence of N-methylserotonin (a derivative of serotonin) and triterpenes (with GABA-ergic action) in various extracts of CR [23]: their synergistic action seems to improve the climacteric symptoms.…”

Efficient, Season-Independent Seed Germination in Black Cohosh (<i>Actaea racemosa</i> L.)

“…The recognition of black cohosh, which apparently lacks estrogenic activity, as a natural alternative to Hormone Replacement Therapy led to a significant increase in its demand and, since 2008 it has been one of the top-ten selling herbal dietary supplement in the United States with total sales of more than $8 million [3]. Although a large number of secondary metabolites have been identified from roots and rhizomes, a mechanism for black cohosh containing extracts is unknown, and even controversial [1,4,5], with recent evidence suggesting a serotonergic mechanism of action [6].…”