November 4, 2016
Magnesium fails to reduce hot flashes: well not exactly fails…. It fails to beat placebo
Jacob Schor, ND, FABNO
For the last half-decade we’ve been suggesting magnesium oxide or magnesium citrate to women with a breast cancer history who are suffering from hot flashes. It often seemed to help. This recommendation came from two pilot studies that suggested that magnesium oxide might reduce the number and intensity of hot flashes experienced in women taking either tamoxifen or aromatase inhibitors.
The first of these studies was presented at a 2010, ASCO meeting in Chicago. Herrada described a pilot study of 22 women who received 400 mg of magnesium oxide three times a day for a month. All the women were receiving adjuvant treatment for breast cancer. “Ten (45%) pts achieved a complete resolution of hot flashes. Ten (45%) pts experienced at least a 50% reduction in the number of hot flashes per day. In two (10%) patients, no changes in the number of hot flashes were noted.” 
Results of a second pilot study were reported in 2011. A group of 25 breast cancer patients, also receiving some form of adjuvant treatment, were given 400 mg of magnesium oxide per day for four weeks, escalating to 800 mg if needed. Hot flash scores were significantly reduced. “Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. Fatigue, sweating, and distress were all significantly reduced.” 
These studies in combination seemed clinically significant and we had Michael Murray ND reviewed the second 2011 paper for the Natural Medicine Journal:
But last year something confusing happened. A much larger placebo controlled randomized trial was published that called these early results into question. The lead author of this new, larger and far more comprehensive placebo controlled trial is Haeseong Park, who was also the lead investigator in the small 2011 pilot study.
This new study enrolled a total of 289 women between 12/2011 and 03/2013, of which 20 were excluded from the final analysis for various valid reasons. All were postmenopausal with a history of breast cancer and had bothersome hot flashes.
They were randomized into treatment groups of magnesium oxide 800 mg or 1,200 mg daily or corresponding placebo groups. Patients started with lower doses of magnesium and increased doses over a period of several weeks. Treatment lasted a total of 8 weeks.
Hot flash frequency and hot flash score (number × mean severity) were measured using a validated hot flash diary.
Mean hot flash scores, mean hot flash frequencies, and associated changes during the treatment period were similar for each group. Those taking magnesium had an increased incidence of diarrhea. Nor surprise there as this is a known side effectNo statistically significant difference in other toxicities or quality-of-life measures was observed.  The conclusion of the study was that magnesium didn’t do anything. The reality is more complicated. Hot flashes dropped during the study a lot. But they dropped in the placebo group as well
Magnesium oxide did not offer any more benefit than placebo. Both doses of magnesium and also the placebo were associated with similar improvements in hot flashes. They all seem to help equally.
***Check out this nice graphic summary in the paper and you’ll get the idea:***
It is not that magnesium wasn’t associated with improvement; it was that the placebo worked just as well. This would suggest that the benefit of taking magnesium oxide for hot flashes is a just placebo effect. Both of the earlier pilot studies were open label without placebo arms.
These studies leave us in something of an ethical quandary. There are two ways to act on these data. One interpretation is that magnesium does not work any better than placebo for hot flashes and so we should stop prescribing magnesium for this indication. On the other hand the other way to look at this is that indeed magnesium or placebo appear to be quite effective for hot flashes in this patient population and should be considered for treating this complaint. Because bottles of ‘placebo pills’ are not routinely available, magnesium oxide is an easy to obtain and a safe choice.
Some will note that magnesium oxide is typically not our first choice in magnesium as it is poorly absorbed and tends to have a laxative effect. The fact that magnesium oxide does have this side effect may enhance its placebo effect and we should think twice before switching to “better forms” of magnesium.
Hot flashes appear to be quite responsive to placebo intervention. A placebo benefit has been reported in several prior randomized studies. In Boekhout’s 2006 review about 25% of 1174 patients who received placebo or the intervention reported hot flashes reduced by at least 50% and 15% had greater than 75% reduction.  In Sloan’s 2001 review of 7 randomized trials, the 375 patients who received placebo had an average 25% decrease in hot flash frequency and intensity.  It seems that hot flashes may be particularly sensitive to placebo effect.
Women with a history of breast cancer who are treated using the commonly prescribed drugs, venlafaxine, gabapentin or clonidine, have a high risk for adverse events. A November 2016 Cochrane review of 12 studies with a total of 1467 participants, reports that 81% of those women in the treatment group and only 19 % in the control group had adverse reactions.  With this in mind trying magnesium, even if it is only a placebo, may be a safer first option.
Perhaps we should title this: “Magnesium: great placebo for hot flashes”?
1. Herrada J, Gupta A, Campos-Gines AF, et al. Oral magnesium oxide for treatment of hot flashes in women undergoing treatment for breast cancer: A pilot study. Chicago: 2010 ASCO Annual Meeting; 2010
2. Park H, Parker GL, Boardman CH, Morris MM, Smith TJ. A pilot phase II trial of magnesium supplements to reduce menopausal hot flashes in breast cancer patients. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2011;19(6):859–863
3. Park H, Qin R, Smith TJ, Atherton PJ, Barton DL, Sturtz K, Dakhil SR, et al. North Central Cancer Treatment Group N10C2 (Alliance): a double-blind placebo-controlled study of magnesium supplements to reduce menopausal hot flashes. Menopause. 2015 Jun;22(6):627-32.
4. Mahon SM, Kaplan M. Placebo effect in hot flush research.
Lancet Oncol. 2012 May;13(5):e188; author reply e190.
5. Boekhout AH, Beijnen JH, Schellens JHM. Symptoms and treatment in cancer therapy-induced early menopause. Oncologist 2006; 11: 641–54.
6. Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H. Methodologic lessons learned from hot flash studies. J Clin Oncol 2001; 19: 4280–90.
7. Hervik JB, Stub T. Adverse effects of non-hormonal pharmacological interventions in breast cancer survivors, suffering from hot flashes: A systematic review and meta-analysis. Breast Cancer Res Treat. 2016 Nov;160(2):223-236.