The Potential for Dietary Supplements to Reduce Premenstrual Syndrome (PMS) Symptoms 2000

Review

The Potential for Dietary Supplements to ReducePremenstrual Syndrome (PMS) Symptoms

Adrianne Bendich, PhD, FACN

Associate Director, New Product Research, SmithKline Beecham Consumer Healthcare, Parsippany, New Jersey

Key words: calcium, magnesium, manganese, vitamin B6, vitamin E, gamma-linolenic acid

Many types of dietary supplements have been advocated for the reduction of certain symptoms of premen-strual syndrome (PMS). However, only one supplement—calcium—has been demonstrated to be of significantbenefit in a large, rigorous, double-blind, placebo-controlled trial. Limited evidence suggests that magnesium,vitamin E and carbohydrate supplements might also be useful, but additional research is needed to confirm thesefindings. Trials of vitamin B6 supplementation have had conflicting results, and high doses of this vitamin takenfor prolonged periods of time can cause neurological symptoms. Trials of evening primrose oil have also hadconflicting results; the two most rigorous studies showed no evidence of benefit. A variety of herbal productsare suggested to reduce symptoms of PMS. The efficacy of these products is uncertain because of a lack ofconsistent data from scientific studies. Health professionals should be aware of the possible use of thesesupplements and ask those with PMS about their use of such products and counsel them based upon the totalityof evidence.

Key teaching points:

• There is convincing evidence that calcium supplementation, at a dose of 1,000–1,200 mg/day, substantially decreases many of thesymptoms associated with PMS.

• Magnesium supplements, at a dose of 200–400 mg/day, may be helpful in relieving PMS symptoms. However, the evidence ofefficacy is less convincing than that for calcium, and some individuals may experience a mild laxative effect at the higher doserange.

• Trials of vitamin B6 supplementation in women with PMS have had conflicting results; the evidence of efficacy is not convincing.If vitamin B6 is used, doses should be limited to no more than 100 mg/day to avoid any risk of neuropathy.

• Carbohydrate supplements may provide some immediate relief of PMS symptoms, but the same effect can probably be achievedthrough simple dietary changes.

• Evening primrose oil has not been demonstrated to be consistently effective in reducing the symptoms of PMS.• Herbal supplements for PMS are currently of unproven efficacy. Some herbs (such as chaste tree fruit and dong quai) are considered

unsafe for women who may become pregnant. Others (such as St. John’s Wort and kava-kava) may interact with prescription drugsthat are used in the treatment of severe PMS.

INTRODUCTION

The term premenstrual syndrome (PMS) refers to a clusterof mood, physical and cognitive symptoms that occur duringthe luteal phase of the menstrual cycle and subside with theonset of menstruation. As many as 80% of women of repro-ductive age may experience premenstrual emotional and phys-ical changes [1]. Up to 40% of women of reproductive ageexperience premenstrual symptoms sufficient to affect their

daily lives to some degree, and 3% to 5% experience severeimpairment in a disease state known as premenstrual dysphoricdisorder [2]. Symptoms vary among individuals; the most com-mon symptoms include fatigue, irritability, abdominal bloating,breast tenderness, labile mood with alternating sadness andanger, and moodiness/depression [1].

A wide variety of strategies for PMS have been proposed.For women with mild symptoms, education, supportive coun-seling and general self-care measures such as increased

Address reprint requests to: Dr. Adrianne Bendich, SmithKline Beecham Consumer Healthcare, 1500 Littleton Road, Parsippany, NJ 07054-3884.

Journal of the American College of Nutrition, Vol. 19, No. 1, 3–12 (2000)Published by the American College of Nutrition

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exercise and adoption of a healthful diet are sometimes suffi-cient [3]. For those with severe symptoms, a variety of drugsmay be helpful. These include fluoxetine (Prozac) or otherselective serotonin reuptake inhibitors, the anxiolytic drug al-prazolam (Xanax), oral contraceptives, nonsteroidal anti-in-flammatory drugs, the diuretic spironolactone, and (in extremecases) gonadotropin-releasing hormone agonists that tempo-rarily obliterate the menstrual cycle [2,3].

For many women, however, neither lifestyle change nor theuse of drugs is an entirely satisfactory approach to PMS. Somewomen with moderate symptoms may find lifestyle modifica-tions insufficient to control their symptoms yet may be reluc-tant to consider the long-term use of prescription drugs, all ofwhich have significant side effects. Others, with mild to mod-erate symptoms, may be reluctant to use medications that theyperceive as “unnatural” in an effort to control symptoms asso-ciatedwith a natural biological function. Still others need to avoidthe use of medications because they may become pregnant.

The desire for safe and effective non-drug alternatives hasprompted many women to consider the use of dietary supple-ments for PMS. Numerous supplements have been advocatedfor this purpose. Many women have found these to be helpfulin relieving their symptoms and have shared their experienceswith others. Such anecdotal reports, however, are not sufficientto establish objectively the benefit of a dietary supplement forPMS. Rigorous scientific studies, including double-blind, pla-cebo-controlled trials, are needed. To date, only a few supple-ments have received this type of intense scientific scrutiny.

This review summarizes the scientific evidence of the efficacyand safety of a variety of mineral, vitamin, herbal and othersupplements that have been examined in women with PMS.

SCIENTIFIC EVIDENCE ON THEEFFICACY AND SAFETY OFSPECIFIC SUPPLEMENTS

Calcium

There is a long history of scientific examination of the linkbetween calcium status and the menstrual cycle. A 1930 study[4] showed that plasma calcium levels were lower in thepremenstrual period compared to those seen in the week fol-lowing menstruation. Thus, it is not surprising that calciumsupplementation might be considered of value in the treatmentof PMS. Several anecdotal reports indicate symptom relief;there is also a similarity between PMS symptoms and thoseoccurring during hypocalcemia. In 1989, a small (33 partici-pants) randomized crossover trial [5] demonstrated a signifi-cant reduction in premenstrual symptoms after supplementationwith 1,000 mg/day of elemental calcium (as calcium carbon-ate). In 1993, a controlled dietary study [6] demonstrateddecreased symptoms of premenstrual and menstrual distresswhen women received diets containing 1,336 mg/day of cal-cium, as opposed to 587 mg. The promising results of these two

preliminary studies served as the impetus for a large U.S.-based, multicenter clinical trial [7].

In that trial, 466 women with rigorously diagnosed PMSreceived 1,200 mg/day of elemental calcium (as calcium car-bonate) or placebo for three menstrual cycles. By the thirdtreatment cycle, those receiving calcium showed an overall48% reduction in total symptom scores of 17 criteria frombaseline, as compared to a 30% reduction in the placebo group.All of four symptom factor scores (negative affect, water re-tention, food cravings, and pain) were significantly improvedby calcium supplementation. For instance, the three criteriaused to describe pain—aches and pains, low back pain andabdominal cramping—were all significantly reduced [Table 1].

The amounts of calcium administered in these trials are wellwithin accepted safety limits. The Tolerable Upper IntakeLevel (UL) for calcium (that is, the maximum intake that isknown to be safe) has been set at 2,500 mg/day [8]. Resultsfrom the USDA’s 1994 Continuing Survey of Food Intakes byIndividuals [9] show that among menstruating women (ages 12to 50 years) the mean daily intake of calcium ranged from 607to 809 mg, suggesting that most of the population at risk forPMS is not receiving the recommended intake levels. There-fore, since most women consume far less than 1,000 mg/day ofcalcium from food, they would not exceed the safety limit ifthey added 1,000–1,200 mg/day of supplemental calcium totheir normal dietary intakes. Calcium, unlike some other sup-plements tested for PMS efficacy, is safe even for women whomay become pregnant. It is also relatively inexpensive, espe-cially in comparison with prescription medications.

There is evidence that abnormalities in calcium and vitaminD regulation may contribute to the causation of PMS and thatPMS may be linked to other disorders associated with inade-quate calcium intake, such as osteoporosis. In a study thatcompared women with established vertebral osteoporosis tocontrols [10], it was found that the risk of osteoporosis washigher among those with a history of PMS. Another studyfound evidence of reduced bone mass in women with PMS ascompared to asymptomatic controls [11]. Thus, PMS may serveas a clinical marker of low calcium status, perhaps reflecting anunderlying abnormality in calcium metabolism, and it mayserve as an early warning sign to young women of a possibleincreased risk of osteoporosis. The use of calcium supplementsmay therefore benefit women with PMS both by reducing theircurrent symptoms and by promoting better bone health in later life.

Manganese

Manganese levels have also been shown to vary with themenstrual or estrus cycle in humans and animals, and lowmanganese intakes are associated with disruption of reproduc-tion in animals. Thus, there is good reason to suspect that

Dietary Supplements and PMS Symptom Reduction

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manganese might play a role in PMS or other menstrual cycle-related disorders. In a metabolic ward study, healthy womenwere assigned to diets high and low in manganese (5.6vs.1.0mg/day) for 39-day periods [6]. The lower dietary manganeseintake was associated with increased mood and pain symptomsduring the premenstrual phase of the cycle. It is unclear, how-ever, whether the difference between the two conditions rep-resents a benefit of manganese supplementation or an adverseeffect of manganese depletion; the lower intake level tested inthis study was about 50% of the typical manganese intake. Noother studies of manganese and PMS have been reported.

Magnesium

Serum magnesium concentrations have been shown to varycyclically in women of reproductive age [12]. The levels ofmagnesium in erythrocytes and leukocytes of women withPMS have been found to be lower than those of women withoutPMS; plasma magnesium levels, however, do not show thispattern [13–19]. Since magnesium is found predominantlywithin cells, intracellular magnesium concentrations may be abetter biological indicator of body status than plasma values.

Since magnesium is involved in the activity of serotonin andother neurotransmitters, as well as in vascular contraction,neuromuscular function and cell membrane stability, there aremany possible pathways by which it might influence PMS.Three randomized, double-blind trials have evaluated the effectof magnesium supplementation on various premenstrual symp-toms. All of these studies have been small, but their resultshave been promising.

In a trial involving 38 subjects with relatively mild premen-strual symptoms [20], a daily supplement of 200 mg of mag-nesium reduced one out of six symptom categories. Fluidretention in the second, but not the first month of use, wassignificantly reduced; no significant effects on mood-relatedsymptoms were reported. In 32 women with PMS, supplemen-tation with 360 mg/day of magnesium (during the second halfof the menstrual cycle) significantly reduced total PMS symp-toms and specifically those symptoms related to mood changes.It should be noted that the experimental design resulted in theplacebo group’s receiving only two months of supplementationat crossover, whereas the magnesium group received the sup-plement for four months [21]. In 20 patients with premenstrualmigraine, prophylactic supplementation with magnesium (360mg/day or placebo during the second half of the menstrual cycle)significantly reduced the number of days with headache [22].

In addition, it is also possible that some of the favorableresults obtained in trials of combination vitamin/mineral sup-plements in patients with PMS may have been due to themagnesium content of the products. In particular, as noted in arecent review [3], the doses of the combination supplement“Optivite” that were used in several controlled trials wouldhave provided at least 250 mg/day of magnesium, in addition toother vitamins and minerals. A yeast-based supplement usedwith some success [23] was also high in magnesium, providing400 mg/day.

Magnesium supplementation, at the doses used in the trialsdescribed above, is usually well tolerated. One possible sideeffect, however, is mild osmotic diarrhea. In various studies ofmagnesium supplementation (not specifically focused on

Table 1. Effects of 1,200 mg/day of Calcium or Placebo Taken by 466 Women for Three Menstrual Cycles on PMSSymptom Scores

CoreSymptoms

Symptom FactorsPercent Improvement

in Luteal Phase by 3rdMenstrual Cycle

Percent Improvement inGlobal Symptoms by 3rd

Menstrual Cycle

Percent of Worseningof BaselineSymptoms

Behavioral Negativeaffect

Mood swings,depression, tension,anxiety, anger,crying spells

Negative affectreduced by 45% bycalciumvs.28% byplacebo.

55% on calcium had greaterthan 50% improvementin global symptomsvs.36% on placebo.

Of the entire samplegroup, 8% oncalciumvs.24%on placebo.

Foodcravings

Increased/decreasedappetite, cravings forsweets/salts

Food cravings reducedby 54% by calciumvs.35% by placebo.

Of the negativeimprovementgroups, 24% oncalciumvs.76%on placebo.

Physical Pain Lower abdominalcramping,generalized achesand pains, lowbackache

Pain reduced by 54%by calciumvs.increase by 15% inplacebo.

60% on calcium greaterthan 50% improvementin pain symptoms.

Waterretention

Swelling of extremities,tenderness of breasts,abdominal bloating,headache, fatigue.

Water retentionreduced by 36% bycalciumvs.24% byplacebo.

29% on calcium had greaterthan 75% improvementin global symptomsvs.16% on placebo.

Source: S. Thys-Jacobs et al. Am J Obstet Gynecol 179:444–452 (1998) [7].


JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 5

PMS), some individuals have experienced diarrhea at magne-sium doses of 350–400 mg/day [8]. Other individuals, how-ever, appear to be able to tolerate substantially larger doses ofmagnesium without experiencing gastrointestinal symptoms [8].

In light of the safety of moderate doses of magnesium andthe promising preliminary evidence on the efficacy of thismineral in PMS, additional, larger randomized trials of mag-nesium supplementation are warranted.

Vitamin B6

During the 1970s, the successful use of vitamin B6 in thetreatment of depression caused by the use of oral contraceptivesprompted interest in the possible value of this vitamin in thetreatment of PMS [24]. Vitamin B6 supplementation was dis-cussed in the popular press during the late 1970s and early1980s for potentially decreasing PMS symptoms. Since vitaminB6 is a cofactor in the synthesis of neurotransmitters, there is areasonable basis for its role in alleviating mood-related pre-menstrual symptoms. However, controlled trials of this supple-ment have had equivocal results.

A 1990 review of 12 controlled trials [25] found three withpositive results [26–28], five with ambiguous results [29–33]and four with negative results [34–37]. All of the studies hadimportant methodological shortcomings, and all except onewere small, with fewer than 50 subjects in each treatmentgroup. A trial involving 53 women [38], which was not in-cluded in the review, also showed no significant differences[39,40]. Subsequent to the review, two additional trials havebeen published [41,42]. Neither found a significant PMS ben-efit of vitamin B6 supplementation.

The most recent review, published in 1999 [43], includedunpublished data from authors of several of the 25 publishedtrials of vitamin B6 and PMS. These authors also conclude thatthe studies suffer from several methodological problems andonly one included sufficient subjects. The authors suggest thatthe pooled data indicate the potential for B6 to reduce PMSsymptoms and may beneficially affect depression associatedwith PMS; however, the studies are of “insufficient quality todraw definitive conclusions.”

Women with PMS who choose to take vitamin B6 supple-ments despite the lack of clear evidence of efficacy need to beaware that high doses of this vitamin can cause sensory neu-ropathy. Most reported cases of neuropathy associated withvitamin B6 supplementation have involved intakes of at least500 mg/day for two years or more (or larger doses for shorterperiods of time) [44]. There have been a few reported cases ofneuropathy in individuals taking lower doses of vitamin B6, butthe validity of those reports has been disputed [45]. The Insti-tute of Medicine of the National Academy of Sciences has setthe UL of vitamin B6 at 100 mg/day [45].

Vitamin E

A single double-blind trial evaluated the effects of vitaminE supplementation in PMS. In that trial, 41 women with PMSreceived 400 IU/day of vitamin E or placebo for three cycles;significant improvements in some affective and physical symp-toms were observed in the vitamin E group. Unlike in mostother studies, there was no effect seen in the placebo group[46]. No further trials have been reported. It would be ofinterest to investigate vitamin E again in a new trial with morerigorous, up-to-date methods of subject selection and symptomassessment.

If vitamin E is effective in relieving PMS, it evidently actsby some mechanism other than the correction of a deficiency.Women with PMS are not biochemically deficient in vitamin E,and their plasma vitamin E levels are not lower than those ofwomen who do not have PMS [18,47].

Combination Supplements ContainingEssential Nutrients

Several supplements containing combinations of vitamins,minerals and/or other ingredients have been advocated for usein PMS. One formulation, a multivitamin/multimineral supple-ment high in magnesium and vitamin B6 (Optivite) was signif-icantly more effective than placebo in relieving premenstrualsymptoms in several clinical trials [48–50]. However, the for-mulation of this product is not consistent with current safetyrecommendations. The recommended dose (6–12 tablets perday) provides 300–600 mg of vitamin B6, which is well inexcess of the UL of 100 mg/day that was established in 1998[45]. Also, 6 to 12 tablets provide 12,500–25,000 IU of vitaminA as retinol, which is above the safety limit of 8,000 IU/day forwomen of childbearing potential that has been established bythe Centers for Disease Control and Prevention and otherauthorities [51].

Of the components of Optivite, the one with the greatestevidence of efficacy is magnesium. A dose of 6 to 12 tablets perday of Optivite would provide 250–500 mg/day of this mineral,which is within the range associated with beneficial effects onPMS symptoms in studies of magnesium alone.

A yeast-based, magnesium-containing combination supple-ment called Sillix Donna was shown to reduce premenstrualsymptoms in a single double-blind study [23]. As is the casewith Optivite, the most likely beneficial ingredient in SillixDonna is magnesium; the recommended dose (2 tablets twice aday) provides 400 mg of this mineral. Unlike Optivite, SillixDonna does not contain any components in quantities thatexceed current safety limits.

Several combination herbal/vitamin products are currentlybeing marketed. No double-blind trials of these specific formu-lations have been reported in the scientific literature.


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Carbohydrate Supplements

Increased consumption of carbohydrates (“carbohydratecraving”) is one of the characteristic features of PMS in somewomen. It has been hypothesized that this change in food intakemay lead to an increase in the serum ratio of tryptophan to otherlarge neutral amino acids, which may in turn lead to a seroto-nin-mediated improvement in mood [52].

It is sometimes recommended that women with PMS eatsmall, frequent meals high in carbohydrates in an effort toimprove symptoms such as tension and depression [53]. In aplacebo-controlled study, a single dose of a drink mix contain-ing the sugars dextrose and maltodextrin produced an increasein self-reported recognition memory in women with PMS threehours post-dosing; no data are available on the reproducibilityof this effect [52]. It is also unclear whether the use of thisdrink, which contains 200 calories/dose, has any advantageover simple changes in eating patterns.

Long Chain Fatty Acids

Supplements containing long-chain fatty acids such asevening primrose oil, black currant oil and borage seed oil havebeen suggested for reduction of PMS symptoms. Of these, onlyevening primrose oil has undergone formal scientific study inwomen with PMS.

Evening primrose oil is derived from the seeds of the nativeAmerican wildflower, evening primrose (Oenothera biennis). Itis a rich source of gamma-linolenic acid, a long chain fatty acidthat is a precursor in the synthesis of prostaglandins. The use ofevening primrose oil in the reduction of symptoms of PMS isbased on the hypothesis that women with PMS have a relativedeficiency of gamma-linolenic acid and that this may lead toabnormalities in prostaglandin synthesis, which may contributeto PMS symptoms [3]. A recent review [54] identified sevenplacebo-controlled trials of evening primrose oil in PMS, fiveof which were randomized. The results of these trials wereinconsistent, and the two trials with the most rigorous studydesign [55,56] showed no advantage of evening primrose oilover placebo. Because these trials were small, however, thepossibility of a modest beneficial effect cannot be excluded[54]. Evening primrose oil appears to be safe at the dosagesused in these studies [56,57].

Black currant oil (made from the seeds of the Europeanblack currant,Ribes nigrum) and borage seed oil (made fromthe seeds ofBorago officinalis) are sometimes used as alterna-tives to evening primrose oil. These oils are used because oftheir gamma-linolenic acid content, which is even greater thanthat of evening primrose oil [57]. As is the case with eveningprimrose oil, the efficacy of these oils for PMS has not beenproven. Concerns have been raised about the safety of borageseed oil, since the borage plant contains potentially toxic pyr-rolizidine alkaloids, and it may be possible for small amountsof these substances to contaminate the oil [57].

Herbal Products

In the U.S., herbal products with traditional medicinal usesare marketed as dietary supplements. In Europe and Asia,products containing these herbs are tested and then marketed asover-the-counter or prescription drugs. Evaluation of the safetyand efficacy of some of these newer products produced in theU.S. is difficult because few of these specific products havebeen tested in double-blind, placebo-controlled trials.

Nevertheless, the use of herbal remedies is widespread andincreasing in the U.S. [58]. Herbs that have been suggested forthe reduction of PMS symptoms include black cohosh, bluecohosh, wild yam root, chaste tree fruit (also calledchasteberry) and dong quai.

Black cohosh (Cimicifuga racemosa) is an herb which ap-pears to affect estrogenic receptors [57]. In Germany (whereherbal remedies can be officially approved if they are known tobe safe and if there is “reasonable certainty” of benefit), blackcohosh root is officially approved to be sold for the reductionof PMS [58]. Most of the scientific study of this herb, however,has focused on the treatment of menopausal symptoms ratherthan PMS. No controlled trials have demonstrated the efficacyof black cohosh in PMS. No serious toxicity has been reportedfor this herb, but experts recommend that it should not be usedfor more than six months because its long-term safety has notyet been demonstrated [58,59].

Blue cohosh (Caulophyllum thalictroides) is an entirelydifferent herb from black cohosh. Unlike black cohosh, bluecohosh has significant toxicity, and experts recommend againstits use for any type of medical self-treatment [57].

Wild yam root (Dioscorea villosa) contains diosgenin, asubstance used in the laboratory synthesis of steroid hormones.The use of this herb in the treatment of PMS is based on therationale that diosgenin will be converted in the body intoprogesterone, which may relieve premenstrual symptoms.However, the conversion of diosgenin to progesterone has beendemonstrated onlyin vitro; it has not been shown to occur inthe human body [57]. Little is known about the effects of wildyam root in women with PMS [53].

The rationale for the use of the chaste tree fruit (Vitexagnus-castus) in PMS is that this herb may inhibit the secretionof prolactin [57]. Chaste tree fruit is approved in Germany forthe reduction of PMS symptoms [58]. A recent German studyfound chaste tree fruit extract to be at least as effective asvitamin B6 for PMS [60]; however, since no placebo controlwas included in this study and since the efficacy of vitamin B6is uncertain, the results of this study are difficult to interpret.Chaste tree fruit is not safe for use during pregnancy [58] andshould not be taken by women with PMS who are sexuallyactive and who are not using a reliable form of contraception.

Dong quai (Angelica polymorpha var sinensis) is a Chineseherb advocated for a variety of gynecological ailments, includ-ing PMS. Controlled scientific studies of this herb in PMS havenot been conducted [57]. Since dong quai is not considered safe



for use during pregnancy [57], it should not be taken bysexually active women who are not using a reliable form ofcontraception.

Health care professionals should be aware that some women

may use other herbal products to treat specific premenstrualsymptoms. Clinicians should inquire about the use of all prod-ucts including herbals, since herb/herb interactions are possi-ble. Some herbal products may also interact adversely with

Table 2. Dietary Supplement Interventions in PMS: Double-Blind Placebo-Controlled Trials

Study Investigator(date, journal)

n5; duration in months5;intervention

Questionnaires Used/PMSInclusion Criteria

Findings

CALCIUM

Thys-Jacobs, 1989J Gen Int Med [5]

n533; duration58; 1,000 mg/dayelemental Ca (Os-Cal 500) forone menstrual cycle—baseline;3 cycles—Ca; 3 cycles—placebo;one cycle—offsupplement, in a randomized,cross-over study

Daily PMS symptoms/One cycle, 14symptoms, 4-point scale;comparing luteal & menstrualphase scores.

Significant reduction in pain, waterretention; negative affect in lutealphase & pain in menstrual phase; 50%decrease in Cavs.20% in placebo inluteal phase; 47% decrease in Cavs.30% in placebo in menstrual phase.

Alvir, Thys-Jacobs, 1991Psychopharmacol Bull [63]

*same cohort as Thys-Jacobs (1989)—verifyingsymptom scores

n533; duration58; same asabove

Same as above Four factors defined PMS and changedsignificantly with Ca supplementation:negative affect, water retention, pain,food.

Thys-Jacobs, 1998Am J Obstet Gynecol [7]

n5466; duration56; 1,200 mg/day elemental Ca (Tums), in arandomized, parallel study.

PMS diary, daily for 3 cycles/2menstrual cycles; NIMH PMScriteria; 17 symptoms; symptomintensity increase of 50% in lutealphase over intermenstrual.

48% symptom reduction in Ca groupvs.30% reduction in placebo group (seeTable 1 for details).

Penland, Johnson 1993Am J Obstet Gynecol [6]

n510; duration56; Baseline: 13days on controlled dietcontaining 800 mg Ca/day and2.97 mg Mn/day. Treatment:39 days on 587 mg Ca(calcium lactate)1either 1.0mg (manganese sulfate) or 5.6mg Mn, or 1,336 mgCa1either 1.0 mg or 5.6 mgMn.

Menstrual Distress Questionnaire(47 symptoms) at completion ofcycle.

Low Ca status increased negativeaffect1behavioral changes in all 3phases; greater pain, water retention,poorer concentration in premenstrualphase.

VITAMIN B6Berman, 1990JADA [41]

n528; duration53; 250 mg B6/day and dietary advicevs.dietary advice (modifiedhypoglycemic diet—increaseprotein, decrease simplecarbohydrates); randomized,cross-over study.

Abraham & Hargrove adaptation ofMoos questionnaire; 4-point scale,6 symptoms, before & aftertreatment/PMS score of 8 in atleast one symptom cluster ofMenstrual Distress Questionnaire;30% decrease in symptomsbetween menstruation andovulation.

No major effect of B6 on PMSsymptoms.

Williams, 1985J Int Med Res [30]

n5434 (204 B6, 230 placebo);duration53; 100 mg B6/day ina randomized study; treatmentcould either be increased ordecreased (200 mg or 50 mg).

Daily diary card rating 11symptoms on a 4-point scale.Symptoms rated daily; only halfof the cards were filled outcompletely.

Overall, B6 showed a significant benefit.High placebo response: 70%improvement with placebovs.82%improvement with B6.

Malmgren, 1987Neuropsychobiology [36]

n519 PMS, 19 no PMS;duration53; 300 mg B6, dailyon day 15 to first day of nextcycle, in a crossover study.

Moos Menstrual DistressQuestionnaire (MDQ) &Spielberger’s State Anxiety Scale(days 5–7 & 25–27 of cycle);also, Karolinska Scales ofPersonality (KSP) & modifiedversion of Bem’s Sex RoleInventory during screening andassessment phases.

B6 did not significantly improve PMSsymptoms; there was no change inmean platelet count between pre- andpostmenstrual phase in the PMSpatient group, platelet count decreasedsignificantly in luteal phase incontrols.

(Table 2 continues next page)


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drugs used in the treatment of PMS. For example, St. John’sWort (an herb used to treat mild depression) may interact withselective serotonin reuptake inhibitors [61], and kava-kava (anherb used to relieve anxiety) may interact with alprazolam [62].

CONCLUSION

Dietary supplementation may be of value in reducing thesymptoms of PMS, especially in instances when the symptomsare not severe enough to warrant prescription drug therapy or

when drug therapy must be avoided because of the possibilityof pregnancy.

A conventional multivitamin supplement can be recom-mended to all women with PMS (and all other women ofchildbearing age), even though specific benefits in the treat-ment of PMS have not been demonstrated. It has been recom-mended that all women of childbearing potential consume 400mg/day of synthetic folate from fortified foods or supplementsin order to minimize their risk of bearing a child with a neuraltube birth defect [45]. The use of a multivitamin that contains400mg of folate (100% of the Daily Value) is the simplest and

Table 2. Continued

Study Investigator(date, journal)

n5; duration in months5;intervention

Questionnaires Used/PMSInclusion Criteria

Findings

VITAMIN ELondon, 1987J Reprod Med [46]

n541 (22 vitamin E, 19placebo); duration53; 400 IU/day, randomized study.

Daily PMS questionnaire,combining Abraham andSteiner’s/Minnesota MultiphasicPersonality Inventory (MMPI) infollicular phase prior to entry.

Vitamin E reduced PMS symptomsseverity in the range of 28%–42%between the pretreatment phase andthe treatment phases.

MULTIVITAMINS & O THER

SUPPLEMENTS

Facchinetti et al, 1997Gynecol Obstet Invest [23]

n540; duration56; 400 mg Mg1.56 mg B6, 12 mg vitamin E,0.2 mg folic acid, 20 mg iron,4 mg Cu, 1 g Saccharomycescerevisiae (Sillix Donna) intwo tablets, twice/day, in arandomized study.

Moos Menstrual DistressQuestionnaire (MDQ) at least30% increase in symptoms infollicular phase, at 2nd, 4th, &6th months of treatment.

Lowered MDQ scores to 18% ofbaseline with treatment,vs.73% ofbaseline with placebo.

London et al, 1991J Am Coll Nutr [49]

n544; duration53; 12 Optivitemultivitamin/mineral tablets (6tablets twice/day) in arandomized study. Six Optivitetablets in part of cohort forpart of the time.

Minnesota Multiphasic PersonalityInventory (MMPI) and London’smodification of Abraham’sMenstrual SymptomQuestionnaire (MSQ). Neededmoderate to severe scores onMSQ in luteal phase ofpretreatment cycle.

Optivite-12 tablets lowered symptoms.Significant reduction was seen in all 4symptom category scores withOptivite-12; in 3 categories withOptivite-6 and in 2 categories withplacebo.

CARBOHYDRATES

Sayegh et al, 1995Obstet Gynecol [52]

n524; duration56; ExperimentaldrinkA5dextrose-maltodextrin;B5protein & carbohydrates;C5carbohydrates. Three-waycrossover; 1 drink/cycle, norepeats; no day to day repeatswithin luteal phase.

Interactive Computer TelephoneSystem, 90 & 180 minutes afterdrink. NIMH PMS criteria andlate-luteal phase dysphoricdisorder; 2 consecutive months ofprescreening needed; 30%increase in symptoms post-ovulatoryvs.menstrual.

Improved mood scores 180 minutes afterdrinking A (depression, tension, angerand confusion); no improvement at 30or 90 minutes; A1 90 minutes drinkreduced decline in recognitionmemory score, but no effect in twoother cognitive tests.

EVENING PRIMROSE OIL

Collins et al, 1993Obstet Gynecol (55)

n538; duration510; 12 capsules/day evening primrose oil(Efamol) or placebo (liquidparaffin); 4 cycles with active,4 cycles with placebo in arandomized, cross-over study.

DSM-IIIR criteria; 3 cyclicsymptoms significantly increasedin premenstrual phase; 16 PMSsymptoms rated daily.

No significant difference inimprovements between placebo (up to50%) vs active. Significant positiveeffect of time on PMS symptoms.

Khoo et al, 1990Med J Aust [56]

n538; duration56; 8 capsules/day evening primrose oil(Efamol) or placebo (liquidparaffin), in a randomized, cross-over study.

10 PMS symptoms worsened duringluteal phase and diminished duringmenstruation.

No significant difference inimprovements (38%) between placebo vsactive.



most reliable way to achieve this goal. In addition, manyclinicians believe that improvement of diet and lifestyle is auseful first step in the reduction of PMS, even thoughrigorous evidence of efficacy is lacking; the use of a mul-tivitamin can be one part of an overall strategy of dietaryimprovement.

Of the various specific supplements that have been advo-cated for reducing the symptoms of PMS, the evidence ofefficacy is most convincing for calcium (Tables 1 and 2). Thecontrolled trial of calcium supplementation by Thys-Jacobset

al. [7] is by far the largest and most rigorous of all the trials ofdietary supplementation for PMS that have been completed todate, and its results point to a clear benefit of calcium inrelieving PMS symptoms. The overall risk-benefit ratio forcalcium supplementation is also favorable; calcium offers long-term benefits for bone health in addition to its immediatebenefit in relieving PMS symptoms, and the recommendeddoses are safe even for women who may become pregnant. Arecommendation for the use of a calcium supplement can andshould be incorporated into the general dietary and lifestylesuggestions that are usually offered as first-line treatment forpatients with PMS. It should be mentioned that the usualmultivitamin contains only 10% of the calcium associated withreducing symptoms of PMS.

Preliminary studies have suggested that magnesium andvitamin E may also be of value in the relief of PMS symptoms.There is a need for additional research to confirm the findingsof these trials in larger groups of women.

Vitamin B6 has been widely advocated for PMS, but evi-dence of its efficacy is insufficient. Women who wish to tryself-treatment with vitamin B6 should be cautioned not toexceed the accepted safety limit of 100 mg/day.

Although there is some evidence that a carbohydrate-baseddrink may acutely affect PMS symptoms, it is unclear whetherthis high-calorie drink offers any benefit that could not beachieved through simple dietary changes.

Supplements containing long chain fatty acids have beenexamined for the reduction of PMS. Evening primrose oil is theonly such product tested for efficacy. Controlled studies of thissupplement have had inconsistent results, with the most rigor-ous studies showing no evidence of a beneficial effect.

The use of herbals is becoming increasingly popular in theU.S. Their efficacy for PMS is uncertain because of limiteddata from controlled trials. There are important safety con-cerns with some herbals, especially for women who areconsidering pregnancy or may become pregnant and forthose who are taking prescription drugs (especially drugsused for PMS).

Health professionals should ask women with PMS abouttheir use of all products (prescription, OTC and dietary sup-plements) and counsel them about possible benefits, risks anddrug interactions.

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Received August 1999; revision accepted September 1999.


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The Potential for Dietary Supplements to Reduce Premenstrual Syndrome (PMS) Symptoms 2000