Review

The Potential for Dietary Supplements to Reduce Premenstrual 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 premenstrual syndrome (PMS). However, only one supplement calcium has been demonstrated to be of significant benefit 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 these findings. Trials of vitamin B6 supplementation have had conflicting results, and high doses of this vitamin taken for prolonged periods of time can cause neurological symptoms. Trials of evening primrose oil have also had conflicting results; the two most rigorous studies showed no evidence of benefit. A variety of herbal products are suggested to reduce symptoms of PMS. The efficacy of these products is uncertain because of a lack of consistent data from scientific studies. Health professionals should be aware of the possible use of these supplements and ask those with PMS about their use of such products and counsel them based upon the totality of 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 the symptoms associated with PMS. Magnesium supplements, at a dose of 200 400 mg/day, may be helpful in relieving PMS symptoms. However, the evidence of efficacy is less convincing than that for calcium, and some individuals may experience a mild laxative effect at the higher dose range. 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 achieved through 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. Johns Wort and kava-kava) may interact with prescription drugs that are used in the treatment of severe PMS.

INTRODUCTION
The term premenstrual syndrome (PMS) refers to a cluster of mood, physical and cognitive symptoms that occur during the luteal phase of the menstrual cycle and subside with the onset of menstruation. As many as 80% of women of reproductive age may experience premenstrual emotional and physical changes [1]. Up to 40% of women of reproductive age experience premenstrual symptoms sufficient to affect their

daily lives to some degree, and 3% to 5% experience severe impairment in a disease state known as premenstrual dysphoric disorder [2]. Symptoms vary among individuals; the most common symptoms include fatigue, irritability, abdominal bloating, breast tenderness, labile mood with alternating sadness and anger, and moodiness/depression [1]. A wide variety of strategies for PMS have been proposed. For women with mild symptoms, education, supportive counseling 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.

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Dietary Supplements and PMS Symptom Reduction

exercise and adoption of a healthful diet are sometimes sufficient [3]. For those with severe symptoms, a variety of drugs may be helpful. These include fluoxetine (Prozac) or other selective serotonin reuptake inhibitors, the anxiolytic drug alprazolam (Xanax), oral contraceptives, nonsteroidal anti-inflammatory drugs, the diuretic spironolactone, and (in extreme cases) gonadotropin-releasing hormone agonists that temporarily obliterate the menstrual cycle [2,3]. For many women, however, neither lifestyle change nor the use of drugs is an entirely satisfactory approach to PMS. Some women with moderate symptoms may find lifestyle modifications insufficient to control their symptoms yet may be reluctant to consider the long-term use of prescription drugs, all of which have significant side effects. Others, with mild to moderate symptoms, may be reluctant to use medications that they perceive as unnatural in an effort to control symptoms associated with a natural biological function. Still others need to avoid the use of medications because they may become pregnant. The desire for safe and effective non-drug alternatives has prompted many women to consider the use of dietary supplements for PMS. Numerous supplements have been advocated for this purpose. Many women have found these to be helpful in relieving their symptoms and have shared their experiences with others. Such anecdotal reports, however, are not sufficient to establish objectively the benefit of a dietary supplement for PMS. Rigorous scientific studies, including double-blind, placebo-controlled trials, are needed. To date, only a few supplements have received this type of intense scientific scrutiny. This review summarizes the scientific evidence of the efficacy and safety of a variety of mineral, vitamin, herbal and other supplements that have been examined in women with PMS. preliminary studies served as the impetus for a large U.S.based, multicenter clinical trial [7]. In that trial, 466 women with rigorously diagnosed PMS received 1,200 mg/day of elemental calcium (as calcium carbonate) or placebo for three menstrual cycles. By the third treatment cycle, those receiving calcium showed an overall 48% reduction in total symptom scores of 17 criteria from baseline, as compared to a 30% reduction in the placebo group. All of four symptom factor scores (negative affect, water retention, food cravings, and pain) were significantly improved by calcium supplementation. For instance, the three criteria used to describe painaches and pains, low back pain and abdominal crampingwere all significantly reduced [Table 1]. The amounts of calcium administered in these trials are well within accepted safety limits. The Tolerable Upper Intake Level (UL) for calcium (that is, the maximum intake that is known to be safe) has been set at 2,500 mg/day [8]. Results from the USDAs 1994 Continuing Survey of Food Intakes by Individuals [9] show that among menstruating women (ages 12 to 50 years) the mean daily intake of calcium ranged from 607 to 809 mg, suggesting that most of the population at risk for PMS is not receiving the recommended intake levels. Therefore, since most women consume far less than 1,000 mg/day of calcium from food, they would not exceed the safety limit if they added 1,000 1,200 mg/day of supplemental calcium to their normal dietary intakes. Calcium, unlike some other supplements tested for PMS efficacy, is safe even for women who may become pregnant. It is also relatively inexpensive, especially in comparison with prescription medications. There is evidence that abnormalities in calcium and vitamin D regulation may contribute to the causation of PMS and that PMS may be linked to other disorders associated with inadequate calcium intake, such as osteoporosis. In a study that compared women with established vertebral osteoporosis to controls [10], it was found that the risk of osteoporosis was higher among those with a history of PMS. Another study found evidence of reduced bone mass in women with PMS as compared to asymptomatic controls [11]. Thus, PMS may serve as a clinical marker of low calcium status, perhaps reflecting an underlying abnormality in calcium metabolism, and it may serve as an early warning sign to young women of a possible increased risk of osteoporosis. The use of calcium supplements may therefore benefit women with PMS both by reducing their current symptoms and by promoting better bone health in later life.

SCIENTIFIC EVIDENCE ON THE EFFICACY AND SAFETY OF SPECIFIC SUPPLEMENTS

Calcium
There is a long history of scientific examination of the link between calcium status and the menstrual cycle. A 1930 study [4] showed that plasma calcium levels were lower in the premenstrual period compared to those seen in the week following menstruation. Thus, it is not surprising that calcium supplementation might be considered of value in the treatment of PMS. Several anecdotal reports indicate symptom relief; there is also a similarity between PMS symptoms and those occurring during hypocalcemia. In 1989, a small (33 participants) randomized crossover trial [5] demonstrated a significant reduction in premenstrual symptoms after supplementation with 1,000 mg/day of elemental calcium (as calcium carbonate). In 1993, a controlled dietary study [6] demonstrated decreased symptoms of premenstrual and menstrual distress when women received diets containing 1,336 mg/day of calcium, as opposed to 587 mg. The promising results of these two

Manganese
Manganese levels have also been shown to vary with the menstrual or estrus cycle in humans and animals, and low manganese intakes are associated with disruption of reproduction in animals. Thus, there is good reason to suspect that

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Table 1. Effects of 1,200 mg/day of Calcium or Placebo Taken by 466 Women for Three Menstrual Cycles on PMS Symptom Scores
Core Symptoms Behavioral Negative affect Symptom Factors Mood swings, depression, tension, anxiety, anger, crying spells Increased/decreased appetite, cravings for sweets/salts Percent Improvement in Luteal Phase by 3rd Menstrual Cycle Negative affect reduced by 45% by calcium vs. 28% by placebo. Food cravings reduced by 54% by calcium vs. 35% by placebo. Percent Improvement in Global Symptoms by 3rd Menstrual Cycle 55% on calcium had greater than 50% improvement in global symptoms vs. 36% on placebo. Percent of Worsening of Baseline Symptoms Of the entire sample group, 8% on calcium vs. 24% on placebo. Of the negative improvement groups, 24% on calcium vs. 76% on placebo.

Food cravings

Physical

Pain

Water retention

Lower abdominal cramping, generalized aches and pains, low backache Swelling of extremities, tenderness of breasts, abdominal bloating, headache, fatigue.

Pain reduced by 54% by calcium vs. increase by 15% in placebo. Water retention reduced by 36% by calcium vs. 24% by placebo.

60% on calcium greater than 50% improvement in pain symptoms.

29% on calcium had greater than 75% improvement in global symptoms vs. 16% on placebo.

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

manganese might play a role in PMS or other menstrual cyclerelated disorders. In a metabolic ward study, healthy women were assigned to diets high and low in manganese (5.6 vs. 1.0 mg/day) for 39-day periods [6]. The lower dietary manganese intake was associated with increased mood and pain symptoms during the premenstrual phase of the cycle. It is unclear, however, whether the difference between the two conditions represents a benefit of manganese supplementation or an adverse effect of manganese depletion; the lower intake level tested in this study was about 50% of the typical manganese intake. No other studies of manganese and PMS have been reported.

Magnesium
Serum magnesium concentrations have been shown to vary cyclically in women of reproductive age [12]. The levels of magnesium in erythrocytes and leukocytes of women with PMS have been found to be lower than those of women without PMS; plasma magnesium levels, however, do not show this pattern [1319]. Since magnesium is found predominantly within cells, intracellular magnesium concentrations may be a better biological indicator of body status than plasma values. Since magnesium is involved in the activity of serotonin and other neurotransmitters, as well as in vascular contraction, neuromuscular function and cell membrane stability, there are many possible pathways by which it might influence PMS. Three randomized, double-blind trials have evaluated the effect of magnesium supplementation on various premenstrual symptoms. All of these studies have been small, but their results have been promising.

In a trial involving 38 subjects with relatively mild premenstrual symptoms [20], a daily supplement of 200 mg of magnesium reduced one out of six symptom categories. Fluid retention in the second, but not the first month of use, was significantly reduced; no significant effects on mood-related symptoms were reported. In 32 women with PMS, supplementation with 360 mg/day of magnesium (during the second half of the menstrual cycle) significantly reduced total PMS symptoms and specifically those symptoms related to mood changes. It should be noted that the experimental design resulted in the placebo groups receiving only two months of supplementation at crossover, whereas the magnesium group received the supplement for four months [21]. In 20 patients with premenstrual migraine, prophylactic supplementation with magnesium (360 mg/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 favorable results obtained in trials of combination vitamin/mineral supplements in patients with PMS may have been due to the magnesium content of the products. In particular, as noted in a recent review [3], the doses of the combination supplement Optivite that were used in several controlled trials would have provided at least 250 mg/day of magnesium, in addition to other vitamins and minerals. A yeast-based supplement used with some success [23] was also high in magnesium, providing 400 mg/day. Magnesium supplementation, at the doses used in the trials described above, is usually well tolerated. One possible side effect, however, is mild osmotic diarrhea. In various studies of magnesium supplementation (not specifically focused on

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PMS), some individuals have experienced diarrhea at magnesium doses of 350 400 mg/day [8]. Other individuals, however, appear to be able to tolerate substantially larger doses of magnesium without experiencing gastrointestinal symptoms [8]. In light of the safety of moderate doses of magnesium and the promising preliminary evidence on the efficacy of this mineral in PMS, additional, larger randomized trials of magnesium supplementation are warranted.

Vitamin E
A single double-blind trial evaluated the effects of vitamin E supplementation in PMS. In that trial, 41 women with PMS received 400 IU/day of vitamin E or placebo for three cycles; significant improvements in some affective and physical symptoms were observed in the vitamin E group. Unlike in most other studies, there was no effect seen in the placebo group [46]. No further trials have been reported. It would be of interest to investigate vitamin E again in a new trial with more rigorous, up-to-date methods of subject selection and symptom assessment. If vitamin E is effective in relieving PMS, it evidently acts by 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 of women who do not have PMS [18,47].

Vitamin B6
During the 1970s, the successful use of vitamin B6 in the treatment of depression caused by the use of oral contraceptives prompted interest in the possible value of this vitamin in the treatment of PMS [24]. Vitamin B6 supplementation was discussed in the popular press during the late 1970s and early 1980s for potentially decreasing PMS symptoms. Since vitamin B6 is a cofactor in the synthesis of neurotransmitters, there is a reasonable basis for its role in alleviating mood-related premenstrual symptoms. However, controlled trials of this supplement have had equivocal results. A 1990 review of 12 controlled trials [25] found three with positive results [26 28], five with ambiguous results [29 33] and four with negative results [34 37]. All of the studies had important methodological shortcomings, and all except one were small, with fewer than 50 subjects in each treatment group. A trial involving 53 women [38], which was not included in the review, also showed no significant differences [39,40]. Subsequent to the review, two additional trials have been published [41,42]. Neither found a significant PMS benefit of vitamin B6 supplementation. The most recent review, published in 1999 [43], included unpublished data from authors of several of the 25 published trials of vitamin B6 and PMS. These authors also conclude that the studies suffer from several methodological problems and only one included sufficient subjects. The authors suggest that the pooled data indicate the potential for B6 to reduce PMS symptoms and may beneficially affect depression associated with PMS; however, the studies are of insufficient quality to draw definitive conclusions. Women with PMS who choose to take vitamin B6 supplements despite the lack of clear evidence of efficacy need to be aware that high doses of this vitamin can cause sensory neuropathy. Most reported cases of neuropathy associated with vitamin B6 supplementation have involved intakes of at least 500 mg/day for two years or more (or larger doses for shorter periods of time) [44]. There have been a few reported cases of neuropathy in individuals taking lower doses of vitamin B6, but the validity of those reports has been disputed [45]. The Institute of Medicine of the National Academy of Sciences has set the UL of vitamin B6 at 100 mg/day [45].

Combination Supplements Containing Essential Nutrients

Several supplements containing combinations of vitamins, minerals and/or other ingredients have been advocated for use in PMS. One formulation, a multivitamin/multimineral supplement high in magnesium and vitamin B6 (Optivite) was significantly more effective than placebo in relieving premenstrual symptoms in several clinical trials [48 50]. However, the formulation of this product is not consistent with current safety recommendations. The recommended dose (6 12 tablets per day) provides 300 600 mg of vitamin B6, which is well in excess 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 vitamin A as retinol, which is above the safety limit of 8,000 IU/day for women of childbearing potential that has been established by the Centers for Disease Control and Prevention and other authorities [51]. Of the components of Optivite, the one with the greatest evidence of efficacy is magnesium. A dose of 6 to 12 tablets per day of Optivite would provide 250 500 mg/day of this mineral, which is within the range associated with beneficial effects on PMS symptoms in studies of magnesium alone. A yeast-based, magnesium-containing combination supplement called Sillix Donna was shown to reduce premenstrual symptoms in a single double-blind study [23]. As is the case with Optivite, the most likely beneficial ingredient in Sillix Donna is magnesium; the recommended dose (2 tablets twice a day) provides 400 mg of this mineral. Unlike Optivite, Sillix Donna does not contain any components in quantities that exceed current safety limits. Several combination herbal/vitamin products are currently being marketed. No double-blind trials of these specific formulations have been reported in the scientific literature.

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Dietary Supplements and PMS Symptom Reduction Carbohydrate Supplements

Increased consumption of carbohydrates (carbohydrate craving) is one of the characteristic features of PMS in some women. It has been hypothesized that this change in food intake may lead to an increase in the serum ratio of tryptophan to other large neutral amino acids, which may in turn lead to a serotonin-mediated improvement in mood [52]. It is sometimes recommended that women with PMS eat small, frequent meals high in carbohydrates in an effort to improve symptoms such as tension and depression [53]. In a placebo-controlled study, a single dose of a drink mix containing the sugars dextrose and maltodextrin produced an increase in self-reported recognition memory in women with PMS three hours post-dosing; no data are available on the reproducibility of this effect [52]. It is also unclear whether the use of this drink, which contains 200 calories/dose, has any advantage over simple changes in eating patterns.

Herbal Products
In the U.S., herbal products with traditional medicinal uses are marketed as dietary supplements. In Europe and Asia, products containing these herbs are tested and then marketed as over-the-counter or prescription drugs. Evaluation of the safety and efficacy of some of these newer products produced in the U.S. is difficult because few of these specific products have been tested in double-blind, placebo-controlled trials. Nevertheless, the use of herbal remedies is widespread and increasing in the U.S. [58]. Herbs that have been suggested for the reduction of PMS symptoms include black cohosh, blue cohosh, wild yam root, chaste tree fruit (also called chasteberry) and dong quai. Black cohosh (Cimicifuga racemosa) is an herb which appears to affect estrogenic receptors [57]. In Germany (where herbal remedies can be officially approved if they are known to be safe and if there is reasonable certainty of benefit), black cohosh root is officially approved to be sold for the reduction of PMS [58]. Most of the scientific study of this herb, however, has focused on the treatment of menopausal symptoms rather than PMS. No controlled trials have demonstrated the efficacy of black cohosh in PMS. No serious toxicity has been reported for this herb, but experts recommend that it should not be used for more than six months because its long-term safety has not yet been demonstrated [58,59]. Blue cohosh (Caulophyllum thalictroides) is an entirely different herb from black cohosh. Unlike black cohosh, blue cohosh has significant toxicity, and experts recommend against its use for any type of medical self-treatment [57]. Wild yam root (Dioscorea villosa) contains diosgenin, a substance used in the laboratory synthesis of steroid hormones. The use of this herb in the treatment of PMS is based on the rationale that diosgenin will be converted in the body into progesterone, which may relieve premenstrual symptoms. However, the conversion of diosgenin to progesterone has been demonstrated only in vitro; it has not been shown to occur in the human body [57]. Little is known about the effects of wild yam root in women with PMS [53]. The rationale for the use of the chaste tree fruit (Vitex agnus-castus) in PMS is that this herb may inhibit the secretion of prolactin [57]. Chaste tree fruit is approved in Germany for the reduction of PMS symptoms [58]. A recent German study found chaste tree fruit extract to be at least as effective as vitamin B6 for PMS [60]; however, since no placebo control was included in this study and since the efficacy of vitamin B6 is uncertain, the results of this study are difficult to interpret. Chaste tree fruit is not safe for use during pregnancy [58] and should not be taken by women with PMS who are sexually active and who are not using a reliable form of contraception. Dong quai (Angelica polymorpha var sinensis) is a Chinese herb advocated for a variety of gynecological ailments, including PMS. Controlled scientific studies of this herb in PMS have not been conducted [57]. Since dong quai is not considered safe

Long Chain Fatty Acids

Supplements containing long-chain fatty acids such as evening primrose oil, black currant oil and borage seed oil have been suggested for reduction of PMS symptoms. Of these, only evening primrose oil has undergone formal scientific study in women with PMS. Evening primrose oil is derived from the seeds of the native American wildflower, evening primrose (Oenothera biennis). It is a rich source of gamma-linolenic acid, a long chain fatty acid that is a precursor in the synthesis of prostaglandins. The use of evening primrose oil in the reduction of symptoms of PMS is based on the hypothesis that women with PMS have a relative deficiency of gamma-linolenic acid and that this may lead to abnormalities in prostaglandin synthesis, which may contribute to PMS symptoms [3]. A recent review [54] identified seven placebo-controlled trials of evening primrose oil in PMS, five of which were randomized. The results of these trials were inconsistent, and the two trials with the most rigorous study design [55,56] showed no advantage of evening primrose oil over placebo. Because these trials were small, however, the possibility of a modest beneficial effect cannot be excluded [54]. Evening primrose oil appears to be safe at the dosages used in these studies [56,57]. Black currant oil (made from the seeds of the European black currant, Ribes nigrum) and borage seed oil (made from the seeds of Borago officinalis) are sometimes used as alternatives to evening primrose oil. These oils are used because of their gamma-linolenic acid content, which is even greater than that of evening primrose oil [57]. As is the case with evening primrose oil, the efficacy of these oils for PMS has not been proven. Concerns have been raised about the safety of borage seed oil, since the borage plant contains potentially toxic pyrrolizidine alkaloids, and it may be possible for small amounts of these substances to contaminate the oil [57].

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Table 2. Dietary Supplement Interventions in PMS: Double-Blind Placebo-Controlled Trials
Study Investigator (date, journal) CALCIUM Thys-Jacobs, 1989 J Gen Int Med [5] n ; duration in months ; intervention Questionnaires Used/PMS Inclusion Criteria Findings

n 33; duration 8; 1,000 mg/day Daily PMS symptoms/One cycle, 14 elemental Ca (Os-Cal 500) for symptoms, 4-point scale; one menstrual cyclebaseline; comparing luteal & menstrual 3 cyclesCa; 3 cycles phase scores. placebo;one cycleoff supplement, in a randomized, cross-over study Alvir, Thys-Jacobs, 1991 n 33; duration 8; same as Same as above Psychopharmacol Bull [63] above *same cohort as ThysJacobs (1989)verifying symptom scores Thys-Jacobs, 1998 n 466; duration 6; 1,200 mg/ PMS diary, daily for 3 cycles/2 Am J Obstet Gynecol [7] day elemental Ca (Tums), in a menstrual cycles; NIMH PMS randomized, parallel study. criteria; 17 symptoms; symptom intensity increase of 50% in luteal phase over intermenstrual. Penland, Johnson 1993 n 10; duration 6; Baseline: 13 Menstrual Distress Questionnaire Am J Obstet Gynecol [6] days on controlled diet (47 symptoms) at completion of containing 800 mg Ca/day and cycle. 2.97 mg Mn/day. Treatment: 39 days on 587 mg Ca (calcium lactate) either 1.0 mg (manganese sulfate) or 5.6 mg Mn, or 1,336 mg Ca either 1.0 mg or 5.6 mg Mn.

Significant reduction in pain, water retention; negative affect in luteal phase & pain in menstrual phase; 50% decrease in Ca vs. 20% in placebo in luteal phase; 47% decrease in Ca vs. 30% in placebo in menstrual phase. Four factors defined PMS and changed significantly with Ca supplementation: negative affect, water retention, pain, food. 48% symptom reduction in Ca group vs. 30% reduction in placebo group (see Table 1 for details).

Low Ca status increased negative affect behavioral changes in all 3 phases; greater pain, water retention, poorer concentration in premenstrual phase.

VITAMIN B6 Berman, 1990 JADA [41]

n 28; duration 3; 250 mg B6/ day and dietary advice vs. dietary advice (modified hypoglycemic dietincrease protein, decrease simple carbohydrates); randomized, cross-over study.

Williams, 1985 J Int Med Res [30]

Malmgren, 1987 Neuropsychobiology [36]

Abraham & Hargrove adaptation of No major effect of B6 on PMS Moos questionnaire; 4-point scale, symptoms. 6 symptoms, before & after treatment/PMS score of 8 in at least one symptom cluster of Menstrual Distress Questionnaire; 30% decrease in symptoms between menstruation and ovulation. n 434 (204 B6, 230 placebo); Daily diary card rating 11 Overall, B6 showed a significant benefit. duration 3; 100 mg B6/day in symptoms on a 4-point scale. High placebo response: 70% a randomized study; treatment Symptoms rated daily; only half improvement with placebo vs. 82% could either be increased or of the cards were filled out improvement with B6. decreased (200 mg or 50 mg). completely. n 19 PMS, 19 no PMS; Moos Menstrual Distress B6 did not significantly improve PMS duration 3; 300 mg B6, daily Questionnaire (MDQ) & symptoms; there was no change in on day 15 to first day of next Spielbergers State Anxiety Scale mean platelet count between pre- and cycle, in a crossover study. (days 57 & 2527 of cycle); postmenstrual phase in the PMS also, Karolinska Scales of patient group, platelet count decreased Personality (KSP) & modified significantly in luteal phase in version of Bems Sex Role controls. Inventory during screening and assessment phases.
(Table 2 continues next page)

for use during pregnancy [57], it should not be taken by sexually active women who are not using a reliable form of contraception. Health care professionals should be aware that some women

may use other herbal products to treat specific premenstrual symptoms. Clinicians should inquire about the use of all products including herbals, since herb/herb interactions are possible. Some herbal products may also interact adversely with

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Table 2. Continued
Study Investigator (date, journal) VITAMIN E London, 1987 J Reprod Med [46] n ; duration in months ; intervention n 41 (22 vitamin E, 19 placebo); duration 3; 400 IU/ day, randomized study. Questionnaires Used/PMS Inclusion Criteria Daily PMS questionnaire, combining Abraham and Steiners/Minnesota Multiphasic Personality Inventory (MMPI) in follicular phase prior to entry. Findings

Vitamin E reduced PMS symptoms severity in the range of 28%42% between the pretreatment phase and the treatment phases.

MULTIVITAMINS & OTHER SUPPLEMENTS Facchinetti et al, 1997 n 40; duration 6; 400 mg Mg Moos Menstrual Distress Gynecol Obstet Invest [23] 1.56 mg B6, 12 mg vitamin E, Questionnaire (MDQ) at least 0.2 mg folic acid, 20 mg iron, 30% increase in symptoms in 4 mg Cu, 1 g Saccharomyces follicular phase, at 2nd, 4th, & cerevisiae (Sillix Donna) in 6th months of treatment. two tablets, twice/day, in a randomized study. London et al, 1991 n 44; duration 3; 12 Optivite Minnesota Multiphasic Personality J Am Coll Nutr [49] multivitamin/mineral tablets (6 Inventory (MMPI) and Londons tablets twice/day) in a modification of Abrahams randomized study. Six Optivite Menstrual Symptom tablets in part of cohort for Questionnaire (MSQ). Needed part of the time. moderate to severe scores on MSQ in luteal phase of pretreatment cycle. CARBOHYDRATES Sayegh et al, 1995 n 24; duration 6; Experimental Interactive Computer Telephone Obstet Gynecol [52] drink System, 90 & 180 minutes after A dextrose-maltodextrin; drink. NIMH PMS criteria and B protein & carbohydrates; late-luteal phase dysphoric C carbohydrates. Three-way disorder; 2 consecutive months of crossover; 1 drink/cycle, no prescreening needed; 30% repeats; no day to day repeats increase in symptoms postwithin luteal phase. ovulatory vs. menstrual. EVENING PRIMROSE OIL Collins et al, 1993 n 38; duration 10; 12 capsules/ DSM-IIIR criteria; 3 cyclic Obstet Gynecol (55) day evening primrose oil symptoms significantly increased (Efamol) or placebo (liquid in premenstrual phase; 16 PMS paraffin); 4 cycles with active, symptoms rated daily. 4 cycles with placebo in a randomized, cross-over study. Khoo et al, 1990 n 38; duration 6; 8 capsules/ 10 PMS symptoms worsened during Med J Aust [56] day evening primrose oil luteal phase and diminished during (Efamol) or placebo (liquid menstruation. paraffin), in a randomized, crossover study.

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

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

Improved mood scores 180 minutes after drinking A (depression, tension, anger and confusion); no improvement at 30 or 90 minutes; A 90 minutes drink reduced decline in recognition memory score, but no effect in two other cognitive tests.

No significant difference in improvements between placebo (up to 50%) vs active. Significant positive effect of time on PMS symptoms.

No significant difference in improvements (38%) between placebo vs active.

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

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

when drug therapy must be avoided because of the possibility of pregnancy. A conventional multivitamin supplement can be recommended to all women with PMS (and all other women of childbearing age), even though specific benefits in the treatment of PMS have not been demonstrated. It has been recommended that all women of childbearing potential consume 400 g/day of synthetic folate from fortified foods or supplements in order to minimize their risk of bearing a child with a neural tube birth defect [45]. The use of a multivitamin that contains 400 g of folate (100% of the Daily Value) is the simplest and

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most reliable way to achieve this goal. In addition, many clinicians believe that improvement of diet and lifestyle is a useful first step in the reduction of PMS, even though rigorous evidence of efficacy is lacking; the use of a multivitamin can be one part of an overall strategy of dietary improvement. Of the various specific supplements that have been advocated for reducing the symptoms of PMS, the evidence of efficacy is most convincing for calcium (Tables 1 and 2). The controlled trial of calcium supplementation by Thys-Jacobs et al. [7] is by far the largest and most rigorous of all the trials of dietary supplementation for PMS that have been completed to date, and its results point to a clear benefit of calcium in relieving PMS symptoms. The overall risk-benefit ratio for calcium supplementation is also favorable; calcium offers longterm benefits for bone health in addition to its immediate benefit in relieving PMS symptoms, and the recommended doses are safe even for women who may become pregnant. A recommendation for the use of a calcium supplement can and should be incorporated into the general dietary and lifestyle suggestions that are usually offered as first-line treatment for patients with PMS. It should be mentioned that the usual multivitamin contains only 10% of the calcium associated with reducing symptoms of PMS. Preliminary studies have suggested that magnesium and vitamin E may also be of value in the relief of PMS symptoms. There is a need for additional research to confirm the findings of these trials in larger groups of women. Vitamin B6 has been widely advocated for PMS, but evidence of its efficacy is insufficient. Women who wish to try self-treatment with vitamin B6 should be cautioned not to exceed the accepted safety limit of 100 mg/day. Although there is some evidence that a carbohydrate-based drink may acutely affect PMS symptoms, it is unclear whether this high-calorie drink offers any benefit that could not be achieved through simple dietary changes. Supplements containing long chain fatty acids have been examined for the reduction of PMS. Evening primrose oil is the only such product tested for efficacy. Controlled studies of this supplement have had inconsistent results, with the most rigorous studies showing no evidence of a beneficial effect. The use of herbals is becoming increasingly popular in the U.S. Their efficacy for PMS is uncertain because of limited data from controlled trials. There are important safety concerns with some herbals, especially for women who are considering pregnancy or may become pregnant and for those who are taking prescription drugs (especially drugs used for PMS). Health professionals should ask women with PMS about their use of all products (prescription, OTC and dietary supplements) and counsel them about possible benefits, risks and drug interactions.

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Received August 1999; revision accepted September 1999.

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