Can Chaste Tree Berry Extract Help with PMS Symptoms?

Source: Schellenberg R. Treatment for the premenstrual syndrome with agnus-castus fruit extract: Prospective, randomized, placebo controlled study. BMJ 2001;322:134-137.

Abstract: This randomized, double-blind, placebo-controlled, parallel group comparison was conducted at general medicine clinics to compare the efficacy and tolerability of agnus-castus fruit (Vitex agnus-castus L extract Ze 440) with placebo in women with premenstrual syndrome (PMS) over three menstrual cycles. The study evaluated 170 women (active 86; placebo 84), with mean age of 36 years, mean cycle length of 28 days, and mean duration of menses of 4.5 days. Participants received one tablet daily of agnus-castus (dry extract tablets) or matching placebo, given for three consecutive cycles. The main efficacy variable was change from baseline to endpoint (end of third cycle) in women’s self-assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. Secondary efficacy variables included changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms). The researchers found that improvement in the main variable was greater in the active group compared with placebo group. Seven women reported mild adverse events (four active; three placebo), none of which caused discontinuation of treatment. The authors conclude that dry extract of agnus-castus fruit is an effective and well-tolerated treatment for the relief of PMS symptoms.

Source: Atmaca M, et al. Fluoxetine versus Vitex agnus- castus extract in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol 2003;18:191-195.

Abstract: Clinical trials have demonstrated that serotonin reuptake inhibitors and Vitex agnus-castus (AC) extract are effective for the treatment of premenstrual dysphoric disorder (PMDD). However, no study to date had compared the efficacy of the SRIs with AC extract. Therefore, the aim of the present study was to compare the efficacy of fluoxetine, a selective serotonin reuptake inhibitor, with that of the AC extract, a natural choice. After a period of two screening months to screen the patients for suitability, 41 patients with PMDD according to DSM-IV were recruited into the study. The patients were randomized to fluoxetine or AC for two months of single-blind, rater-blinded, and prospective treatment. The outcome measures included the Penn daily symptom report, the Hamilton depression rating scale, and the clinical global impression-severity of illness and -improvement scales. At endpoint, using the clinical criterion for improvement, a similar percentage of patients responded to fluoxetine (68.4%, n = 13) and AC (57.9%, n= 11). There was no statistically significant difference between the groups with respect to the rate of responders. This preliminary study suggests that patients with PMDD respond well to treatment with both fluoxetine and AC. However, fluoxetine was more effective for psychological symptoms while the extract diminished the physical symptoms.

Comments by Mary L. Hardy, MD

The symptoms of premenstrual syndrome (PMS) are all too familiar to the majority of women. Estimates of prevalence for PMS range from 30-80% with 5% of the menstruating population reporting severe symptoms.1,2 According to a recent telephone survey of a representative sample of childbearing-aged women, disturbance of mood is the most commonly reported severe symptom of PMS.1 Premenstrual dysphoric disorder (PMDD), a severe form of PMS defined in the DSM-IV, is mainly characterized by cyclical symptoms, such as depressed mood, anxiety, or irritability, which disrupt daily activity.3 Physical symptoms generally associated with PMS (bloating, cramps, etc.) often are present as well, and the disability experienced may be as high as that associated with major depression.

Conventional therapy for PMDD focuses on use of selective serotonin reuptake inhibitors (SSRI) to address the reported mood instability. 4 Despite the fact that this medication has been shown to be effective, the side effect profile of SSRIs has discouraged full compliance. In fact, women with PMS are very likely to use over-the-counter and alternative remedies for symptomatic relief, in part because this is largely a self-diagnosed illness and also to limit side effects of treatment. Estimates for lifetime use of complementary or alternative medicine (CAM) by PMS sufferers have been as high as 91%.2 CAM users with PMS are likely to be regular consumers of these therapies with the most popular choices being vitamin B6, evening primrose oil, Chinese or other herbs, homeopathy, and acupuncture.2 A growing body of clinical evidence supports the use of CAM therapies for PMS. A recent review of this subject cites positive studies for a number of therapies, including one for an herbal extract of the plant Vitex agnus-castus (VAC) or chaste tree berry.5 A plant native to the Mediterranean, VAC contains iridoids, flavinoids, progestin-like compounds, and essential oils, which are reported to have hormonal effects, such as promoting progesterone, opposing androgens, and decreasing prolactin.6 All of these are activities that could address the underlying mechanisms of PMS. In light of this, two recent trials that examined the efficacy of VAC for PMS and PMDD bear closer examination.

First, a double-blind, placebo-controlled trial examined the efficacy of VAC extract vs. placebo for the relief of PMS.7 In this trial, 170 women who met a diagnostic criteria for PMS were given either a standardized extract of VAC or placebo for three months. The VAC extract was a proprietary extract prepared from the berries using 60% ethanol and an extract ratio of 6-12:1 (a relatively concentrated product). Patients took one 20 mg tablet per day, which had been standardized to casticin, one of the major flavinoids in this plant. The principle outcome measured was the reduction in the score of self-rating visual analogue scales (VAS) for each of six major PMS symptoms (irritability, mood alteration, anger, headache, other physical symptoms, and breast fullness). Patients rated the severity of their PMS symptoms using these scales on entrance into the study retrospectively for their three previous cycles and prospectively at the end of three cycles of treatment. Response to treatment was defined as a 50% or greater reduction in the VAS symptoms scores. Physicians, who were blinded to the intervention, also independently rated the patient response to treatment using the global clinical impression (CGI) scale.

Results showed that more than twice as many patients responded to treatment in the treatment group as in the placebo group (52% vs. 24%). Significant improvements in five of the six symptoms scales was reported (P < 0.001), with the other physical symptoms scale not showing a significant decline. Physician evaluations of efficacy were significant and favored treatment. When the women who were taking oral contraceptive pills (OCPs) were removed from the analysis, there was no change in the significance of the outcomes. Few adverse events were reported and the authors believed the VAC extract was well-tolerated.

There are two significant potential limitations of this study. First, it was sponsored by the company that makes the extract, thus raising the possibility of a bias in favor of a positive outcome. Second, asking the women to rate their initial symptoms retrospectively may have exaggerated the severity of their starting symptoms. If women had a bias in rating their symptoms higher in memory than they were in fact, this would tend to make the treatment appear more effective than it might otherwise. Finally, in support of this study, a relatively large number of women were enrolled from several different centers and they appeared to use an appropriate extract for a significant length of time with good clinical results after three months.

The second trial examined the efficacy of a VAC extract vs. fluoxetine, an accepted active therapy for the treatment of PMDD. Forty-two patients who met DSM-IV criteria for PMDD were enrolled in a single-blind, randomized, controlled trial.8 Their PMDD symptoms were rated using a standardized instrument, the Penn daily symptom reports (DSR) for the two cycles prior to entry into the trial and for the eight weeks of active therapy. Physicians also assessed the patients’ mood using the Hamilton Depression Rating Scale (HAM-D) and their response to therapy using the CGI scales. The prescribing physician knew the group assignment, but both the patient and the physician assessor were blinded. Patients were given 20-40 mg per day of either fluoxetine or a VAC extract. The dosing schedule was flexible and was allowed to increase based on symptom severity. Unfortunately, the VAC extract used was not described in any detail in this trial.

Results showed that the mean HAM-D scores at the start of therapy were 15.9 in the VAC group and 15.2 in the fluoxetine group, and were compatible with moderate depression. The mean DSR scores were high, twice the score needed to diagnose severe PMDD. The HAM-D scores and the DSR scores decreased for both groups by approximately 50% after eight weeks (HAM-D: VAC 7.4 and fluoxetine 7.2; DSR: VAC 82.8 and fluoxetine 85.6). The differences from baseline were significant in each group (P < 0.05), but the changes between groups were not significant, with the exception of the HAM-D score at one month. Treatment at that point favored fluoxetine, but the differences between the two groups were not significant at the end of the second month. Adverse effects were generally self-limited or not serious but somewhat greater for the fluoxetine group. Both medications were characterized by the authors as well-tolerated.

The limitations of this study are based on the lack of specificity of the VAC product used and the relatively small number of patients enrolled. Because the characteristics of the VAC extract used were not described, clinically it will be harder to apply the results of this trial to our populations. Thus, it cannot be replicated with certainty in our own practices. Further, it is possible that this study was under-powered and did not have sufficient numbers of patients to demonstrate differences between two active therapies. However, the within group comparisons do demonstrate a significant response to therapy (> 50% decrease in HAM-D and DSR scores) in both groups, thus bolstering the claim that the VAC extract tested was as effective as fluoxetine for PMDD after two months of treatment. Patients’ initial symptoms were assessed prospectively, thus limiting the possibility of recall bias, a definite strength in the design of this trial.

How can these trials and the other studies on VAC guide our clinical choices? VAC extracts do seem to be helpful for the symptoms of PMS and its more severe form, PMDD. These extracts appear to be well-tolerated, but need at least two to three months (two to three cycles) to be fully effective. They represent a reasonable intervention for mild PMS (first-line therapy) or for PMDD, especially for patients unwilling or unable to use the conventional SSRIs. In at least the first trial, positive benefit was similar in patients who used OCPs and those who did not. It has, however, been postulated that VAC extracts may improve fertility in patients with irregular menses and/or interfere with the mechanism of action of OCPs. This theoretical concern never has been demonstrated and the pregnancy rates in these trials did not confirm this, but they really weren’t designed to reveal this outcome, if present. Thus, caution should be exercised in counseling patients regarding barrier methods of birth control in addition to OCPs, if using a VAC extract.

It seems reasonable to recommend to our patients with PMS or PMDD to undertake a trial of a standardized extract of VAC for two months for the relief of symptoms associated with menstruation. The dose for these standardized extracts was 20-40 mg per day. This recommendation would work best in the context of a generalized intervention that includes recommendations for exercise, stress relief, dietary modifications, and perhaps additional supplements.

Dr. Hardy, Medical Director Cedars-Sinai Integrative Medicine Medical Group Los Angeles, CA, is on the Editorial Advisory Board of Alternative Therapiesin Women’s Health.


1. Singh B, et al. Incidence of premenstrual syndrome and remedy usage: A national probability sample study. Altern Ther Health Med 1998;4:75-79.

2. Domoney CL, et al. Premenstrual syndrome and the use of alternative therapies. Ann NY Acad Sci 2003; 997:330-340.

3. Freeman EW. Premenstrual syndrome and premenstrual dysphoric disorder: Definition and diagnosis. Psychneuroendocr 2003;28:25-37.

4. Mitweally MF, et al. Pharmacotherapy of premenstrual syndromes and premenstrual dysphoric disorder: Current practices. Expert Opin Pharmacother 2002;3:1577-1590.

5. Stevinson C, Ernst E. Complementary/alternative therapies for premenstrual syndrome: A systematic review of randomized controlled trials. Am J Obstet Gynecol 2001;185:227-235.

6. DerMarderosian A, Beutler JA, eds. The Review of Natural Products. 2nd ed. St. Louis, MO: Wolters Kluwer Company/Facts and Comparisons; 2003.

7. Schellenberg R. Treatment for the premenstrual syndrome with agnus-castus fruit extract: Prospective, randomized, placebo controlled study. BMJ 2001; 322:134-137.

8. Atmaca M, et al. Fluoxetine versus Vitex agnus-castus extract in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol 2003;18:191-195.