Four double-blind studies were published on the use of chaste tree for PMS. Two of these were placebo-controlled, a very important criterion for clinical studies examining PMS because the placebo effect can be significant. The best of these studies tested one tablet daily of a 20-mg dry extract product (known as Ze 440) (Zeller Herbal Medicinal Products, Romanshorn, Switzerland) or a matching placebo that was given to 170 women (86 on active treatment and 84 on placebo) over three consecutive menstrual cycles. Self-reported symptoms of irritability, mood alteration, anger, headache, and breast fullness significantly improved (P < 0.001) relative to the placebo, while bloating was unaffected by the treatment. The physicians’ evaluation of the clinical global impressions (CGI) scale also noted a significant improvement (P < 0.001) for the treatment group. In addition, the responder rate for the women taking chaste tree extract was higher than that for the women on placebo (52% versus 24%) (18). A second double-blind, placebo-controlled trial of chaste tree for the treatment of PMS involved 217 people using a dose of 1,800 mg per day for 3 months. Symptoms were assessed using the Moos Menstrual Distress Questionnaire (MMDQ) (19). Chaste tree was effective at reducing restlessness compared to placebo. Other symptoms also improved compared to placebo, but these improvements were not statistically significant. However, the choice of a soy-based placebo in this study was questionable because hormonal effects can be elicited by soy.

Two other studies used active controls, but no placebo controls. One of these studies compared Agnolyt with pyridoxine (vitamin B6) in 127 women and found both to be equally effective using the premenstrual tension syndrome scale (PMTS) and the CGI scale, collectively measuring breast tenderness, edema, inner tension, headache, constipation, and depression. However, although pyroxidine is often recommended for reducing PMS symptoms, its efficacy for this purpose has not been well established (20). One of the most recent clinical trials compared chaste tree (20 to 40 mg per day dry extract) with the selective serotonin reuptake inhibitor (SSRI) fluoxetine for 8 weeks in 41 patients with premenstrual dysphoric disorder (PMDD), the more severe form of PMS. Fluoxetine is often prescribed for depressive symptoms of PMS. This study found that both fluoxetine and chaste tree were effective; however, fluoxetine was more effective for psychologic symptoms, whereas chaste tree berry was more effective for physical symptoms (21). Numerous other studies, although flawed in design, have also claimed therapeutic effects of chaste tree on PMS (1,22).

Clinical studies have shown chaste tree to be effective in alleviating mastalgia (breast pain), which is often a principal symptom of PMS. Mastalgia is likely related to latent and slightly increased basal prolactin serum levels. One of the functions of prolactin is to stimulate mammary growth. Increased serum levels of the hormone prolactin stimulate lactation and lobular-alveolar growth of mammary tissue, causing mastalgia. Mastalgia can occur as a symptom of PMS or as a separate disorder.

Three randomized placebo-controlled studies showed favorable results in reducing breast pain. One double-blind study involving 104 participants compared either 30 drops or 1 tablet of Mastodynon (equivalent to 32 mg of extract a day) against placebo, given twice daily for three cycles. These patients were all diagnosed with cyclical mastalgia. By cycle three, breast pain decreased for both dosage forms, and basal prolactin levels decreased 4.35 ng per mL and 3.7 ng per mL for those taking the solution or tablet, respectively. Patients taking the liquid solution responded faster than those taking chaste tree in tablet form (23). A similar double-blind study of 97 women using a dose of 30 drops Mastodynon twice daily found a reduction in breast pain in women who had suffered from a minimum of 5 days of mastalgia during their last menstrual cycle (24). A third partially blinded study using the same dose of Mastodynon compared chaste tree to both the gestagen Lynestrenol and placebo in 160 women with mastalgia. Both chaste tree and Lynestrenol were equally effective in reducing mastalgia (25). Numerous open studies have also supported the use of chaste tree for the treatment of mastalgia (1).

Chaste tree has also been recommended to correct menstrual irregularities, such as secondary amenorrhea (no bleeding), oligomenorrhea (long cycles), and polymenorrhea (short cycles), which are often attributed to dysfunction of the corpus luteum. This condition is often caused by the altered secretion of the gonadotropins LH and follicle-stimulating hormone (FSH) from the pituitary gland, which prevents the corpus luteum from fully developing. As a result, serum progesterone levels are decreased and the luteal phase is shortened.

Two published randomized, double-blind, placebo-controlled studies have evaluated the ability of chaste tree to correct menstrual irregularities. Strotan (20 mg of 60% ethanol extract once daily) was tested in women with shortened luteal phases and found to increase the length of the luteal phase while shortening the follicular phase. The overall length of the menstrual intervals did not change (26). Mastodynon (30 drops twice daily for 2 months) was tested in 96 women with infertility problems caused by amenorrhea or luteal phase dysfunction. After treatment, pregnancy occurred more than twice as often in the treatment group than in the placebo group (27). Many open studies have also found that chaste tree corrected amenorrhea (28, 29, 30), oligomenorrhea (31), and polymenorrhea (32,33).

Chaste tree has been found to be effective alone, and in combination with other herbs, to treat menopause (2,22,34, 35, 36). Of 153 herbalists surveyed who use chaste tree in their practice, 86.3% use this herb for the treatment of perimenopausal symptoms, including hot flashes (2). Although good clinical trials have not been performed to test this effect, one long-term open study found that chaste tree was successful in relieving hot flashes and other perimenopausal symptoms (34). Topical application of chaste tree essential oil from fruit and leaves was found to improve emotional symptoms and reduce hot flashes (37). However, this study was not placebo-controlled or double-blinded. The use of chaste tree as a treatment for both PMS (hyperestrogen state) and menopause (hypoestrogen state) suggests a mechanism that works to regulate hormonal imbalances.

Chaste tree has also been found to be effective in treating acne. Two studies have found improvement of various forms of acne during treatment with chaste tree preparations. Patients with Acne vulgaris, A. follicularis, and A. excoriee were treated with either Agnolyt (20 drops twice daily for 4 to 6 weeks, the 15 drops for 1 to 2 years) or an unspecified conventional treatment. After 3 months, 70% of the patients who had failed to respond to prolonged conventional therapy prior to the trial showed complete healing (38). Another study that tested Agnolyt (15 drops three times daily) to treat abnormal menstrual cycles indicated improvement and healing of A. vulgaris in many of the patients (31). Other studies have also shown that chaste tree berry improves A. vulgaris and menstrual-related acne (39,40). However, none of these studies were placebo-controlled or well-designed.

A potential new application of chaste tree is for treatment and prevention of impulsive, compulsive, reward seeking, and other addictive behaviors, although this potential use is solely based on its ability to activate dopamine D2 receptors (D2R) and has not been tested in any experimental models or in humans. Two patents have been awarded for the use of Vitex agnus-castus entitled “Composition and method for modulating addictive behaviors” (41) and “Weight loss composition and method” (42). Chaste tree, in combination with other herbs, has also been proposed to treat heroin addiction (43).

Based on a number of studies, it is most likely that chaste tree modulates more than one physiologic system in order to elicit its effects. Most studies have focused on a dopaminergic-mediated mechanism on the anterior pituitary gland that reduces prolactin secretion. This notion began with studies that suggested that chaste tree decreased prolactin and lactation in rats (44). The effect was further mediated in vitro by activation of the D2R (45,46). In humans, activation of the D2R inhibits release of prolactin, resulting in a decrease of prolactin levels in the blood. The D2R also controls aspects of motor function, behavior, and melanocyte-stimulating hormone secretion from the pituitary, cardiovascular function, and the reward system. One study demonstrated the ability of chaste tree extracts to bind to the D2R, with activity residing in the lipophilic fraction (46). Compounds responsible for this activity have been found to be lipophilic clerodane diterpenes, which bind to the D2R and inhibit prolactin release in vitro (47,48). Similar to dopamine, these isolated compounds were able to inhibit production of cyclic adenosine monophosphate (cAMP) in dopaminergic cells (48). Two double-blind (23,26) and one open (49) human clinical studies have shown that chaste tree can reduce serum prolactin levels. Human studies with males found that the effect of chaste tree on prolactin may be dose-dependent (50). An increase in progesterone and estrogen was also seen in these studies (26,51).