Chaste tree

Chaste Tree (Vitex agnus-castus L.): A Comprehensive Reference

1. Identity, Botany, and Natural Source

Botanical name: Vitex agnus-castus L. Family: The modern taxonomy of plants classifies it as a member of the Lamiaceae family, but it previously belonged to the Verbenaceae family. Common names: The most common names are "chaste tree," "vitex," and "monk's pepper." Additional synonyms include chasteberry, Abraham's balm, lilac chastetree, and hemptree. Vitex agnus-castus is a plant native of the Mediterranean region.

Nomenclature and etymology: Chaste tree is a small flowering tree native to Asia and the Mediterranean regions but which is now widely cultivated. In the past it was believed to decrease sexual desire, for which reason it was named "chaste tree," which is also the meaning of "agnus" (in Greek) and "castus" (in Latin).

Plant description: The chaste tree is a low tree or tall shrub that grows to a height of 3–6 m. It is widely cultivated in warm, temperate, and subtropical regions for its delicately textured, aromatic foliage and butterfly-attracting midsummer spikes of lavender flowers opening in late summer in cooler climates.

Parts used: Extracts of chaste tree are prepared from the leaves, tender stems, flowers, and seeds and provided as syrup, elixir, powder, or a component of a multi-ingredient dietary supplement. In medicinal and regulatory contexts, the fruit (berry) is the primary herbal substance of interest. Chaste tree is derived from fresh or dried, green, sterile shoots of the plant Vitex agnus-castus.

Pharmacopoeial identity: There is a monograph with the title "Agnus Castus Fruit (Agni casti fructus)" published in the European Pharmacopoeia (01/2015: 2147). The whole, ripe, dried fruit of Vitex agnus-castus L. must contain a minimum of 0.08% of casticin (C₁₉H₁₈O₈; Mr 374.3) (dried drug). The herbal preparations appear in liquid forms as an ethanol tincture, and in solid forms as dry extracts using solvents with different concentrations of ethanol (50–70% V/V). Dry extract produced from Agnus castus fruit must contain a minimum of 0.10% of casticin (dried extract). The extract is produced from the herbal drug by a suitable procedure using ethanol (40–80% V/V).

2. Traditional and Historical Use

Ancient Mediterranean Civilizations

Vitex agnus-castus has a very long history of medicinal use, which dates back to at least ancient Egyptian, Greek, and Roman times. Its fruit has been used for more than 2500 years as a phytotherapeutic agent.

In ancient Greece, the chaste tree played a significant role in the female agricultural festival of Thesmophoria, dedicated to honoring the goddesses Demeter and Persephone in Greek cities. In Archaic Sparta, in the 8th–6th centuries BCE, it was incorporated into the cult of the local agriculture goddess, Artemis Orthia. In ancient Greece, the tree was called agnos, meaning holy, pure, and chaste. They dedicated it to their mother goddess Demeter. At the festival of Thesmophoria held in her honour, Greek women, who aimed to remain chaste for the occasion, strewed their beds with branches of the tree, and wore garlands of it in the day, so that the aroma might subdue the ardour of any would-be suitor.

Theophrastus mentioned the shrub several times, as ágnos (ἄγνος) in Enquiry into Plants. The first-century physician Dioscorides documented various synonyms for the lilac chaste tree. Historical documents reference Vitex agnus-castus as early as the 1st century CE in Dioscorides' "De Materia Medica," where it was noted for promoting chastity among convent nuns (hence the common name "chaste tree").

Its macaronic specific name agnus-castus repeats "chaste" in both Greek and Latin; the small tree was considered to be sacred to the virginal goddess Hestia/Vesta. The ancient Romans dedicated the vitex tree to the goddess Hera, the protector of motherhood and marriage, who was said to have been born under one. Roman wives were also said to use the leaves to reduce the libido of their husbands.

Roman physicians, including Pliny the Elder, recommended it for menstrual irregularities and mastitis, and medieval herbalists in Europe kept the tradition going, calling it "monk's pepper" (Monkpepper). The ability of chaste tree fruit to stimulate menstrual flow was reported by Lonicerus in 1582.

Medieval and Early Modern Europe

It was mentioned in ancient herbals for the treatment of reproductive pain. For unknown reasons, chaste tree is not found in many Western herbals until the middle of the 1900s. In nineteenth-century North America, the Eclectics, a leading group of doctors who had revived herbal approaches, recognized the complexity of this remedy and, as well as stabilising menstruation and encouraging lactation and "repressing sexual passions," applied it also to other purposes.

Other Traditions

In Chinese traditional medicine it is used as an anti-inflammatory agent. In a Philistine temple at Gath, an excavation uncovered around 100 chaste tree fruits, a find unparalleled in both quantity and context compared to other locations in Israel, indicating its ritual and/or medicinal significance in ancient Near Eastern cultures.

Traditional preparations varied widely: In ancient Greece, women chewed leaves or made wine infusions of the berries during festivals. In European herbal traditions, whole dried fruits, decoctions, tinctures, and powders were the principal forms. The German Commission E, in its 1992 monograph, codified the traditional use of the dried fruit for menstrual cycle disorders and PMS.

3. Key Constituents and Active Compounds

The fruits of Vitex agnus-castus contain a diverse and complex array of phytochemicals. According to current data, the presence of 20 flavonoids, 10 iridoids, 11 phenolic acids, three diterpene alkaloids, and 12 terpenes was confirmed in the extract of Vitex fruits.

Known phytoconstituents from the fruits include ten flavonoids, five terpenoids, three neolignans, and four phenolic compounds, as well as one glyceride.

Primary Compound Classes

• Flavonoids: The most pharmacologically studied include casticin (a polymethoxylated flavone that serves as a marker compound), vitexin, orientin, homoorientin, luteolin, apigenin, and penduletin. Biological evaluation identified apigenin, 3-methylkaempferol, luteolin, and casticin as weak ligands of delta and mu opioid receptors, exhibiting dose-dependent receptor binding.
• Labdane diterpenes: Diterpenes featuring a clerodadienol scaffold were identified as major active compounds in mediating dopaminergic activity. Key identified diterpenes include rotundifuran, vitexilactone, and viteagnusin I.
• Iridoid glycosides: Including aucubin and agnuside. Agnuside is an iridoid glycoside, used frequently as a standardization marker in commercial preparations.
• Essential oils: Major components of the essential oil from VAC were α-pinene (14.83%), limonene (10.29%), β-caryophyllene (6.9%), sabinene (5.27%), and β-farnesene (5.9%).
• Fatty acids: Linoleic acid, which has been studied for estrogenic activity. Linoleic acid present in the fruits of the plant possesses the ability to bind to estrogen receptors and cause some estrogen gene induction.
• Triterpenes: Triterpenes were also identified as pharmacologically active, with 3-epi-maslinic acid being the most active compound (EC₅₀: 5.1 µM).

4. Mechanisms of Action

VAC is rich in diverse bioactive constituents, including flavonoids, iridoids, diterpenes, and essential oils, which collectively contribute to its complex pharmacological profile. Emerging evidence from in vitro, in vivo, and clinical studies suggests that VAC may modulate key neuroendocrine pathways involved in menopause through dopaminergic, phytoestrogenic, opioidergic, and indirect serotonergic mechanisms.

Dopaminergic Mechanism

The best-established mechanism of action involves the dopamine system. Pre-clinical studies suggest that extracts prepared from the fruits of Vitex agnus castus interact with dopamine D2 receptors, leading to reduced prolactin secretion. It has been postulated that the diterpenes contained in VAC extract may interact with dopamine D2 receptors (D2R) and inhibit prolactin release via dopamine D2R activation in the anterior pituitary.

Research has identified specific compounds responsible: Viteagnusin I emerged as the most potent diterpene (EC₅₀: 6.6 µM), followed by rotundifuran (EC₅₀: 12.8 µM), whereas vitexilactone was inactive (EC₅₀: >50 µM). The dopaminergic activity of VAC diterpenes seems to depend on the configuration and on ring substitution in the side chain. This research also highlights for the first time the dopaminergic contribution of triterpenes such as 3-epi-maslinic acid.

The prolactin-inhibiting effect of chaste tree fruit (ACF) preparations, which is due to dopaminergic activities, has been shown in humans too and gives a pharmacological rationale for the clinical effects observed in the different indications.

The physiological relevance is direct: A decrease in dopamine secretion in females, such as under conditions of chronic stress, may lead to an increase in blood prolactin content, which in turn contributes to the occurrence of proliferative changes in the mammary gland and mastodynia. It also results in insufficiency of the luteal phase, thereby leading to infertility. Chaste tree compounds reduce the blood level of prolactin and decrease its negative manifestations by activating the dopamine receptors of the pituitary gland.

Opioidergic Mechanism

An extract of VAC was found to bind and activate μ- and δ-, but not κ-opioid receptor subtypes (MOR, DOR, and KOR respectively). Several flavonoids from VAC were found to bind to both MOR and DOR in a dose-dependent manner; however, only casticin, a marker compound for genus Vitex, was found to have agonist activity selective for DOR at high concentrations. These results suggest VAC may exert its therapeutic effects through the activation of MOR, DOR, but not KOR. Activation of opioid receptors is thought to contribute to the anxiolytic and mood-stabilizing properties observed clinically.

Phytoestrogenic / Estrogenic Mechanism

Estrogenic activities are mediated by means of estrogen receptors (ER). The flavonoid apigenin was identified as the most dynamically ERβ-selective phytoestrogen in VAC. Other isolated compounds were vitexin and penduletin. The outcome shows that the phytoestrogens in VAC are ERβ-specific.

Vitex has been shown to reduce levels of follicle-stimulating hormone (FSH) and increase luteinizing hormone (LH), thereby reducing estrogen and increasing progesterone levels. At higher doses, Vitex inhibits prolactin production.

Effects on the Hypothalamic-Pituitary-Gonadal Axis

The main described target of Vitex agnus-castus is female reproduction. It can up-regulate the ovarian cycle and fecundity via a wide spectrum of mediators from hypothalamic, pituitary, and ovarian hormones up to intracellular regulators of proliferation, apoptosis, oxidation, and dopamine receptors. These effects determine its potential action as a protector and medicine against a number of female reproductive disorders and reproduction-related health problems including menstrual disorders, premenstrual syndrome, cyclic mastalgia, corpus luteum insufficiency, abnormal production of progesterone and prolactin, low fertility and infertility, hyperandrogenism, and polycystic ovarian syndrome.

5. Regulatory Status: Official Monographs

The European Medicines Agency (EMA) and the German Commission E approved this herbal substance for use in the following complaints: disorders of the menstrual cycle, premenstrual syndrome, and mastalgia.

The EMA's Herbal Medicines Committee (HMPC) has published a Community herbal monograph on Vitex agnus-castus L., fructus. The EMA monograph identifies the following indications: Well-established use — "Herbal medicinal product for the treatment of premenstrual syndrome." Traditional use — "Traditional herbal medicinal product for the relief of minor symptoms in the days before menstruation (premenstrual syndrome)."

The HMPC concluded that one particular dry extract preparation of agnus castus fruit can be used continuously over 3 months for the treatment of premenstrual syndrome (symptoms that occur in the days before a woman's menstrual period).

The German Commission E monograph (1992) recognized the use of agnus castus fruit for menstrual cycle irregularities, PMS, and mastalgia. A routine consumption of 30–40 mg of dried herb in capsules or liquid preparation is recommended by the German Commission E monograph. This is normally taken once in the morning with liquid for several months.

6. Clinical Evidence by Area of Use

6.1 Premenstrual Syndrome (PMS)

PMS is the indication with the most accumulated clinical evidence for VAC. Apart from conventional drugs, like serotonin reuptake inhibitors and oral contraceptives, complementary and alternative medicines such as Vitex agnus castus are used by many women experiencing PMS.

Systematic reviews and meta-analyses:

A 2017 systematic review and meta-analysis found 17 randomized controlled trials of Vitex agnus castus in the treatment of premenstrual syndrome, and 14 of these could be included in the quantitative analysis. All trials, except one, found the Vitex agnus castus preparation to be more efficacious than placebo, pyridoxine, and magnesium for either total symptom score or individual symptoms or symptom clusters. However, although meta-analysis shows a large pooled effect of Vitex agnus castus in placebo-controlled trials, the high risk of bias, high heterogeneity, and risk of publication bias of the included studies preclude a definitive conclusion. The pooled treatment effects should be viewed as merely explorative and, at best, overestimating the real treatment effect of Vitex agnus castus for premenstrual syndrome symptoms. There is a clear need for high-quality trials of appropriate size examining the effect of standardized extracts of Vitex agnus castus in comparison to placebo, selective serotonin reuptake inhibitors, and oral contraceptives to establish relative efficacy.

A separate meta-analysis restricted to well-characterized, placebo-controlled, double-blind, randomized trials found: Out of 21 clinical trials, three studies (520 females) fulfilled the inclusion criteria, comparing the efficacy of special extracts Ze 440 and BNO 1095 to a placebo for the treatment of PMS. VAC preparations were confirmed to be effective in the reduction of PMS symptoms: women taking VAC were 2.57 (95% CI 1.52–4.35) times more likely to experience a remission in their symptoms compared to those taking the placebo. Despite this finding, several clinical trials cannot be used as evidence for efficacy due to incomplete reporting, especially concerning the description of the used medication. More trials following the CONSORT recommendations are needed to assess the efficacy of VAC extracts.

A 2013 systematic review of randomized controlled trials found that seven of eight trials evaluating the efficacy and safety of chaste tree for the treatment of premenstrual syndrome demonstrated the herb to be superior to placebo (5 out of 6 studies), pyridoxine (1 study), and magnesium oxide (1 study). The authors noted that the overall methodological quality of the trials was moderate to high; however, limitations of their review included some studies having small sample sizes, the range of the reference treatments, and the diversity of the symptoms being treated.

Specific symptoms showing benefit: Vitex agnus-castus has been shown clinically to be effective against PMS symptoms such as depression, irritability, anxiety, mastalgia, fatigue, and headache.

Evidence strength summary for PMS: Moderate. Multiple RCTs support benefit, particularly for specific extracts (Ze 440, BNO 1095), but study heterogeneity, variable preparation characterization, and risk of bias prevent definitive conclusions. The EMA has recognized well-established use for PMS based on the available evidence.

6.2 Cyclic Mastalgia (Breast Pain)

Since ancient times, the fruit of chastetree has been used in the therapy of disorders such as mastalgia and menstrual pain. Confirmation of efficacy in the treatment of mastalgia has been best endorsed by two recently published double-blind studies conducted according to the principles of GCP (Good Clinical Practice).

The fruit extract of Vitex Agnus castus L. is one treatment suggested for mastalgia. It is postulated that A. castus suppresses the stress-induced latent hyperprolactinemia which is a release of supra-physiological levels of prolactin in some patients in response to stressful stimuli, providing a plausible mechanism for its effect on breast pain.

The presence of dopaminergic properties was confirmed in a clinical study in patients with severe and mild mastalgia. The therapy involved daily administration of 40 mg of chaste tree fruit extract (Agnucaston®, Biomeks, Germany). The standard group was treated with 2.5 mg of bromocriptine, a dopamine receptor agonist, twice a day, a comparison that underscored the mechanistic rationale for VAC in this indication.

Evidence strength for mastalgia: Moderate. At least two placebo-controlled, double-blind RCTs support efficacy for cyclic mastalgia, and the German Commission E and EMA have both recognized this indication.

6.3 Luteal Phase Defect and Menstrual Cycle Irregularities

A randomized controlled trial of women with luteal-phase defect menstrual cycle irregularities attributable to elevated prolactin found that 20 mg of Vitex lowered prolactin levels and normalized menstrual cycles after 3 months.

Among the species, Vitex agnus-castus L. is the only one that has been reported to undergo clinical trials, mainly related to the use of the genus for the treatment of mastalgia, menstrual bleeding problems, amenorrhea, menorrhagia, luteal insufficiency, and premenstrual syndrome.

Studies have shown that the fruits of the chaste tree significantly reduce the symptoms of PMS, normalize the menstrual cycle, and lower prolactin levels.

Evidence strength: Preliminary to moderate. Limited RCT data specifically targeting luteal phase defect, though mechanistic plausibility is strong given the prolactin-lowering effect.

6.4 Hyperprolactinemia

VAC effects on hyperprolactinemia have been assessed in a small number of studies and in some patient series or single case reports. It has been postulated that the diterpenes contained in VAC extract may interact with dopamine D2 receptors (D2R) and inhibit prolactin release via dopamine D2R activation in the anterior pituitary.

Due to its action on D2R, VAC could have a role in the treatment of mild hyperprolactinemia, including patients with idiopathic hyperprolactinemia, microprolactinoma, drug-induced hyperprolactinemia, or polycystic ovary syndrome.

Evidence strength: Weak to preliminary. Clinical evidence is limited to small studies and case series; this remains an investigational application.

6.5 Polycystic Ovary Syndrome (PCOS)

A randomized controlled trial investigated the efficacy of standardized Vitex agnus-castus extract in managing features of PCOS. The primary aim was to assess changes in oxidative stress markers; secondary outcomes included lipid profile, insulin resistance, and clinical signs such as hirsutism and menstrual frequency. Sixty women with PCOS were randomly assigned to a Vitex group (5.8 mg daily, standardized to 0.42–0.82 mg aucubin) or placebo for 12 weeks. Despite promising results, several limitations must be acknowledged. The short duration (12 weeks) limits the ability to assess long-term effects on fertility or metabolic outcomes.

There was evidence for an equivalent effect of two herbal medicines and the pharmaceutical agents bromocriptine (and Vitex agnus-castus) and clomiphene citrate in the context of managing PCOS-associated oligo/amenorrhea. Preclinical and clinical studies provide evidence that several herbal medicines may have beneficial effects for women with oligo/amenorrhea, hyperandrogenism, and PCOS. However, the quantity of pre-clinical data was limited, and the quality of clinical evidence was variable.

Evidence strength: Preliminary. A small number of clinical trials have been conducted; results are promising but insufficient for firm conclusions.

6.6 Infertility

One study used a preparation containing V. agnus castus as well as other botanicals. Ninety-six women with secondary amenorrhea, luteal insufficiency, or idiopathic infertility received either the Vitex combination or placebo over three menstrual cycles. Of these women, 15 went on to conceive (7 with amenorrhea, 4 with idiopathic infertility, and 4 with luteal insufficiency). This study used a combination product, limiting attribution to VAC alone.

Evidence strength: Preliminary and confounded by use of combination preparations. Insufficient standalone clinical evidence for infertility.

6.7 Menopausal Symptoms

Vitex agnus-castus alleviates menopausal symptoms, suggesting that more research may be appropriate. Emerging evidence from in vitro, in vivo, and clinical studies suggests that VAC may modulate key neuroendocrine pathways involved in menopause through dopaminergic, phytoestrogenic, opioidergic, and indirect serotonergic mechanisms.

Evidence strength: Weak to preliminary. Clinical trial data for menopause-specific outcomes is limited. The EMA has not recognized this as a well-established or traditional use indication in its current monograph.

6.8 Other Investigated Areas

According to a multitude of studies, Vitex agnus-castus can affect metabolism and impact obesity, insulin resistance, and lipid-metabolism dysfunctions. A crude extract and a butanolic fraction of Vitex reduced adiposity index and prevented liver steatosis and fibrosis in animal studies. Vitex secondary metabolites expressed anti-inflammatory activity in vitro. These findings are preclinical and have not been translated to human clinical trials.

The use of VAC in migrainous women with PMS proved to be safe and well tolerated, and decreased migraine attack frequency and duration in one study, though this remains a preliminary finding.

7. Dosage Forms and Reported Dosages

Chaste tree is commercially available in multiple forms. Extracts of chaste tree are prepared from the leaves, tender stems, flowers, and seeds and provided as syrup, elixir, powder, or a component of a multi-ingredient dietary supplement.

The EMA herbal monograph specifies, for well-established use: Female adults — Daily dose: Once daily 20 mg dry extract. For traditional use preparations, this monograph refers to preparations with liquid or dried extracts with ethanol as extraction solvent (50–70% V/V) and in a daily dosage of 30 to 40 mg herbal substance.

Dosages varied widely across studies. While some trials used a low dose (5.8 mg), other trials in PMS and mastalgia have employed doses between 20–40 mg, indicating that therapeutic efficacy may follow a non-linear dose-response pattern.

The product Mastodynon, studied in mastalgia and infertility trials, was used at a dose of 60 drops per day (32.4 mg of chasteberry extract).

Use for at least 3 months is recommended to see beneficial effects, per ESCOP and other authoritative references.

The European Pharmacopoeia standardizes dry extract preparations to a minimum of 0.10% casticin content, with the tincture prepared at a 1:5 drug-to-solvent ratio using ethanol (58–70% V/V or 70% V/V).

The HMPC concluded that one particular dry extract preparation of agnus castus fruit can be used continuously over 3 months for the treatment of premenstrual syndrome.

8. Safety Considerations and Drug Interactions

General Tolerability

A systematic review of all clinical reports of adverse events in clinical trials, post-marketing surveillance studies, surveys, spontaneous reporting schemes, and to manufacturers and herbalist organizations has suggested that the adverse events are mild and reversible.

In one placebo-controlled trial, the occurrence of adverse events was comparable across treatment groups (4.7% in the VAC group and 4.8% in the placebo group). In trials with active controls, one study found a comparable adverse drug reaction rate between VAC and fluoxetine (40% and 42.8%, respectively); the other found a higher adverse drug reaction rate in the VAC treatment group (19.7%) compared with pyridoxine (7.7%). The most frequent adverse events recorded were nausea, acne, allergic reactions, headaches, and stomach disturbances.

Per the European Medicines Agency Community herbal monograph on Vitex, very rare side effects may include severe allergic reactions with face swelling, dyspnoea, and swallowing difficulties.

Pregnancy and Lactation

Vitex is presumed to be contraindicated in pregnancy and lactation, although evidence for its impact on lactation is contradictory. The EMA monograph does not recommend use during pregnancy or breastfeeding due to absence of safety data.

Pediatric Populations

The use in pubertal children and adolescents under 18 years of age is not recommended according to the EMA monograph, due to insufficient data.

Drug Interactions

Because VAC exerts dopaminergic activity, several pharmacodynamic interactions are of concern:

• Dopamine agonists (used in Parkinson's disease): Vitex agnus-castus contains chemicals that affect the brain similarly to some medications used for Parkinson's disease. Taking Vitex agnus-castus with these medications might increase the effects and side effects. Relevant drugs include bromocriptine (Parlodel), levodopa, pramipexole (Mirapex), and ropinirole (Requip).
• Antipsychotics and dopamine antagonists: Vitex agnus-castus affects a chemical in the brain called dopamine. Some medications for mental disorders help to decrease dopamine. Therefore, taking Vitex agnus-castus might affect therapy for certain mental disorders.
• Metoclopramide: Vitex agnus-castus seems to affect a certain brain chemical called dopamine. Metoclopramide (Reglan) also affects dopamine, creating a potential pharmacodynamic interaction.
• Hormonal contraceptives: Vitex agnus-castus seems to change hormone levels in the body. Birth control pills contain hormones. Taking Vitex agnus-castus along with birth control pills might decrease the effectiveness of birth control pills.
• Estrogen therapies: Vitex agnus-castus seems to change hormone levels in the body. Taking Vitex agnus-castus along with estrogen pills might decrease the effects of estrogen pills.

LiverTox Assessment

Oral forms of chaste tree have not been implicated in serum aminotransferase elevations or in instances of clinically apparent liver injury, according to the NIH LiverTox database.

9. Summary of Evidence and Research Gaps

In one review, special attention was paid to clinical trials because they are the most important and reliable studies of drug efficacy and safety. Nine clinical studies that examined the effect of preparations based on chaste tree fruit extract on the female reproductive system were reviewed. Studies showed that the fruits of the chaste tree significantly reduce the symptoms of PMS, normalize the menstrual cycle, and lower prolactin levels.

Nevertheless, further high-quality studies are needed to firmly establish the biological and clinical efficacy of this plant.

The strongest and best-supported clinical indications, recognized by regulatory bodies including the EMA and German Commission E, are PMS and cyclic mastalgia. In recent years, a favorable therapeutic profile in adjuvant treatment of gynecological diseases has been confirmed in numerous in vitro and in vivo tests on animal models and, above all, in clinical trials. Applications for menopause symptoms, PCOS, and infertility remain investigational, with promising but insufficient clinical data. Evidence for other conditions (bone fracture healing, liver protection) is at the preclinical stage only.

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