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Black cohosh has central opioid activity in postmenopausal women: evidence from naloxone blockade and positron emission tomography neuroimaging

Reame, Nancy E. MSN, PhD1; Lukacs, Jane L. MSN, PhD2; Padmanabhan, Vasantha PhD3,4; Eyvazzadeh, Aimee D. MD3; Smith, Yolanda R. MD, MS3; Zubieta, Jon-Kar MD, PhD5,6,7

doi: 10.1097/gme.0b013e318169332a

Objective: To test whether black cohosh (BC) exhibits an action on the central endogenous opioid system in postmenopausal women.

Design: This was a mechanistic study conducted in the same individuals of luteinizing hormone pulsatility with a saline/naloxone challenge (n = 6) and positron emission tomography with [11C]carfentanil, a selective μ-opioid receptor radioligand (n = 5), before and after 12 weeks of unblinded treatment with a popular BC daily supplement.

Results: BC treatment for 12 weeks at a standard dose (Remifemin, 40 mg/day) had no effect on spontaneous luteinizing hormone pulsatility or estrogen concentrations. With naloxone blockade, there was an unexpected suppression of mean luteinizing hormone pulse frequency (saline vs naloxone = 9.0 ± 0.6 vs 6.0 ± 0.7 pulses/16 h; P = 0.056), especially during sleep when the mean interpulse interval was prolonged by approximately 90 minutes (saline night interpulse interval = 103 ± 9 min vs naloxone night interpulse interval = 191 ± 31 min, P = 0.03). There were significant increases in μ-opioid receptor binding potential in the posterior and subgenual cingulate, temporal and orbitofrontal cortex, thalamus, and nucleus accumbens ranging from 10% to 61% across brain regions involved in emotional and cognitive function. In contrast, binding potential reductions of lesser magnitude were observed in regions known to be involved in the placebo response (anterior cingulate and anterior insular cortex).

Conclusions: Using two different challenge paradigms for the examination of central opioid function, a neuropharmacologic action of BC treatment was demonstrated in postmenopausal women.

Using two different challenge paradigms for the examination of central opioid function, a neuropharmacologic action of black cohosh treatment was demonstrated in postmenopausal women.

From the 1School of Nursing, Columbia University, New York, NY; 2School of Nursing, Departments of 3Obstetrics and Gynecology, 4Pediatrics, 5Psychiatry, and 6Radiology, School of Medicine, and the 7Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI.

Received December 7, 2007; revised and accepted January 16, 2008.

Funding/support: Supported in part by the University of Michigan General Clinical Research Center (National Institutes of Health [NIH] M01-RR00042), the University of Michigan Office of the Vice President for Research Faculty Grants and Awards Program, and NIH grants AG15083 (to N.K.R.), NCRR K23RR017043 (to Y.S.), and AT 001415 (to J.-K.Z.).

Financial disclosure: None reported.

Presented in part as a late-breaking paper at the 17th Annual Meeting of The North American Menopause Society, Nashville, TN, October 6, 2006.

Address correspondence to: Nancy King Reame, MSN, PhD, Columbia University, 630 West 168th Street, Suite 246, New York, NY 10032. E-mail:

©2008The North American Menopause Society