More on negative black cohosh results

As we discussed briefly on Tuesday, trial results published in the Annals of Internal Medicine revealed that alternative botanical supplements containing black cohosh were without benefit relative to placebo in treating the vasomotor symptoms (e.g., hot flashes, night sweats) of peri- and postmenopausal women.

The Cheerful Oncologist followed up with a post entitled, "Oh M'Gosh! Black Cohosh Squashed and That's No Bosh!, where Doc Hildreth cited another 2006 study from Mayo Clinic investigators demonstrating lack of efficacy of black cohosh extracts against hot flashes. (He noted later that The NY Post would not be outdone with the wordplay in titling their story, Flash: Put Kibosh on 'Cohosh').

I'll go ahead and add my two cents in the form of an even older (2001) negative outcome trial for black cohosh (run jointly at Columbia and Cornell's Weill Medical College), also in the Journal of Clinical Oncology, citing lack of efficacy in women with breast cancer suffering hot flashes induced pharmacologically as a result of tamoxifen treatment.

With ongoing concerns about estrogen-based hormone replacement therapy (HRT), there has been legitimate interest in therapies that relieve hot flashes without the side effects of estrogen/progestin HRT. Let's not forget, however, that another reason to take HRT is to prevent severe osteoporosis, a claim that has never been made for black cohosh.

Black cohosh is known as Cimicifuga racemosa, although a change in nomenclature over the last few years puts it in the Actaea genus. A European formulation of an isopropanol extract of black cohosh, Remifemin, gained some notoriety (and legitimacy, presumably) in the US because it was briefly distributed by the consumer products division of the multinational pharmaceutical company, GlaxoSmithKline. Perhaps the drug company considered carefully its association with an herbal remedy for which negative clinical trials have accumulated - sometime in the last two years, GSK disappeared from the Remifemin box and it is now sold by Enzymatic Therapy using a classic approach of anecdotal testimonials and association with television programs (see Airborne discussion).

The Actaea/Cimicifuga extracts used in the current Annals of Internal Medicine report came instead from PureWorld Botanicals, a New Jersey-based botanical wholesaler with an excellent reputation for high-quality chemical analyses of their products. (Note: PureWorld has been acquired recently by the French firm, Naturex - yes, mergers and acquisitions in the botanical industry are as frequent as in any other).

The Appendix of the paper describes in some detail the composition of the single agent black cohosh preparation (160 mg daily of a product containing triterpine glycosides; 2.5% labeled, 3.125% detected). However, no specific triterpine glycosides were explicitly named and confusion remains in the field as to which compounds might have the potential to relieve hot flashes. A recent report suggests that a novel cyclic guanidine alkaloid in the plant may have serotonergic activity, but the authors of the current report did not quantify this component.

A third arm of the study used a poorly justified multibotanical preparation also containing black cohosh (at a higher dose, but not from PureWorld):

The multibotanical delivered daily doses of the following: black cohosh, 200 mg; alfalfa (Medicago sativa), 400 mg; boron, 4 mg; chaste tree (Vitex agnus-castus), 200 mg; dong quai (Angelica sinensis), 400 mg; false unicorn (Chamaelirium luteum), 200 mg; licorice (Glycyrrhiza glabra), 200 mg; oats (Avena sativa), 400 mg; pomegranate (Punica granatum), 400 mg; Siberian ginseng (Eleutherococcus senticosus, standardized constituents 0.8% eleutherosides E and B), 400 mg.

Some of these herbs make sense mechanistically (such as Vitex, which potentially has central dopaminergic activity), but it seems that a second higher dose of the black cohosh-only supplement may have been more informative.

A fourth arm included the black cohosh supplement and soy diet counseling since soy isoflavones have estrogenic activity at higher doses. Finally, there was an active arm that included conjugated equine estrogen, 0.625 mg daily, with (for women with a uterus) or without (for women without a uterus) medroxyprogesterone acetate, 2.5 mg.

The bottom line is that only the active arm resulted in a reduction in hot flashes by more than 4 per day relative to placebo (or about 6 per day relative to baseline) at 3, 6, and 12 months of treatment.

However, Figure 2 of the paper reveals that placebo and all herbal approaches equally reduced hot flashed by about 2 per day relative to baseline (could not yet get permission from Annals to show figure here). As The Cheerful Oncologist pointed out, placebo had some modest activity.

But this fact illustrates a major reason why randomized trials include a placebo group - without it, one might assume that that herbal interventions had some effect. With the placebo group, we learn that some effect of enrolling in a clinical trial relieved women of about 30% of their daily hot flashes and/or night sweats.

I still have some issues with missed opportunities in the trial (like the lack of plasma measurements of any potentially active botanical constitutent), but the authors did as good a job as they could with the NIH funding that supported the trial. For example, the herbs were tested for heavy metals, pesticides, and even adulteration with steroids that may have given false positive efficacy - that's a major step forward in characterizing herbal materials used in clinical trials.

However, the results make me wonder how much longer the conventional medical community will continue to be interested in botanical medicines (relative to conventional drug discovery where single pure compounds are isolated from natural sources). The accumulation of negative efficacy trials also make the going difficult for the alternative/integrative medicine centers in academic medical centers that continue to proliferate here and abroad. Finally, the results of this trial showing that only HRT improved symptoms indicates that docs and patients are back were they were: having to weigh the benefits of HRT with the risks.