1.1. Origin and Composition
Vitex agnus-castus belongs to the Verbenaceae family of plants. The most well-known effect of this herb is the usage of its ripe berries for treatment of various various obstetric and gynecological disorders; there appears to be a history of usage in Greece for menstrual problems, pain, swelling, inflammation, headaches, rheumatism, and sexual dysfunction.
Traditional usage of Vitex Agnus in Turkish medicine includes its usage as a diuretic, digestive, antifungal, anti-anxiety, early birth and stomachache medication. It has been used in Greece, where it derived the name of Chastetree (and the berries Chasteberries), as it was believed consumption of the berries promoted Chastity. It was popular among clergymen wishing to be celibate.
Historical usage for a myriad of female-related symptoms and complications associated with PMS and Menopause, with some other usage related to fighting inflammation-related conditions
The berries of Vitex Agnus appear to contain:
Rotundifuran (1.04-2.23% dry weight) and 6β,7β-diacetoxy-13-hydroxy-labda-8,14-diene (B110, 0.17-0.8% dry weight), which may be bioactive and belong to a labdane class of diterpenoid structures with 3 others including vitexilactone (0.33-1% dry weight) and vitexin (0.06% content); these four are commonly referred to as the active components (Labdane-type Diterpenoids)
Vitexlactam A, another Labdane diterpenoid
Penduletin (0.1% of BN1095 extract)
8,13-dihydroxy-14-labden (B111; 2mg/g dry weight), X-hydroxy-Y-keto-15,16-epoxy-13(16),14-labdadien (B115; 0.8mg/g), and X-Acetonxy-13-hydroxylabda-y-14-dien (B116; 0.7mg/g)
Cleroda-x,14-dien-13-ols (up to 5) and Cleroda-x,y,14-trien-13-ol, the Clerodadienol series of structures
Viteagnuside A and C as well as Viteagnusins A-E, F, G, H, I and J
2alpha-hydroxyursolic acid, 3-epimaslinic acid and maslinic acid as well
Casticin, a flavonoid used as a biomarker of quality for the Ze110 extract at 0.5-1.2% dry weight
Viticosterone E, an Ecdysteroid compound
Apigenin at 0.06% as well as 3-methylkaempferol and luteolin
When looking at non-fruit parts:
The Leaves appear to have much higher polyphenolic content than the roots, reaching 3.15% dry weight (caffeic acid equivalents) and a higher o-diphenol content (1.24% dry weight caffeine acid equivalents); higher in the methanolic extract compared to ethanolic (2.05% and 0.74%, respectively) Most of these phenolic compounds were flavonoids (55.2–69.1%)
The roots appeared to be slightly better sources of anthocyanins than the leaves, both outperforming seeds
1.2. Variants and Formulations
A particular extract known as BNO-1095 is sometimes used due to standardization; it is a 70:30 ethanolic:water extract of the herb Vitex Agnus Castus and is the extract used for the brand name Agnucaston. 4mg of this extract appears to be bioequivalent to 40mg of the plants dry weight, and it is thus referred to as a 10:1 concentrated extract (pdf in German).
BNO 1095 is a 10:1 concentrated extract of Vitex, and is mostly an ethanolic extract which is under the brand name of Agnucaston
Ze 110 is another standardized extract that tends to be dosed around 10-20mg, with 20mg being derived from 120-240mg of the Vitex Agnus fruits, and has a drug:extract ratio of 6-12:1 while being standardized for casticin content. Ze 110 is a 60% ethanolic extract.
Ze 110 is an alternative extraction which has a more variable, but overall comparable, drug to plant ratio as BNO 1095 does
2.1. Phase I Enzyme Interactions
One study using Vitex Agnus Castus ethanolic liquid extract noted that VAC was able to inhibit CYP1A2 (IC50 of 3.8µg/mL), CYP2C19 (IC50 of 0.22µg/mL), CYP2D6 (IC50 of 2.9µg/mL), and CYP3A4 (IC50 of 0.3µg/mL).
3.1. Dopaminergic Neurotransmission
There appears to be dopaminergic agonists (D2 receptor assays) in the ethanolic:water extract BNO-1095. When testing isolated molecules, B115 was the most potent at 1uM having similar binding affinity to 218nM dopamine but the two clerodadienol structures appeared to be more practically relevant due to a higher concentrations; with their aspect of the extract exerting 5.7-fold more dopaminergic action than B115 and accounting for over 50% of dopaminergic action of Vitex Agnus. The water, butanol, and chloroform extract do not actually appear to possess any significant dopaminergic activity as all activity is concentrated in hexane or ethanolic extracts.
Beyond the clerodadeinol compounds, others that may contribute to dopaminergic effects are linoleic acid (IC50 of 40+/-12ug/mL), Rotundifuran (45+/-7ug/mL), and 6β,7β-diacetoxy-13-hydroxy-labda-8,14-diene (IC50 of 79+/-12ug/mL).
3.2. Melatonergic Neurotransmission
In men, Vitex Agnus appears to have dose-dependent effects on inducing melatonin secretion. 120mg and 480mg of a 5:1 extract (0.6g and 2.4g dry extract equivalent) increased Melatonin AUC in serum approximately 20%, with more significance during sleep, in an open label trial.
3.3. Opioidergic Neurotransmission
A basic 90% methanolic extract of Vitex Agnus Castus (VAC) has an IC50 of 88.4+/-8.47µg/mL on the Gamma-Opioid receptor, and the potency of the chloroform subset appeared to be enhanced with an IC50 of 23.8+/-2.81µg/mL and the EtOAc with an IC50 of 62.2+/-18.5µg/mL; no affinity was found in the water extract for either Gamma or Delta receptors. IC50 of the methanolic, chloroform, and EtOAc extracts against the Delta-Opioid receptor were 43.0+/-7.78µg/mL, 21.4+/-3.84µg/mL, and 20.7+/-16.9µg/mL; respectively. Interaction with the Opioid receptors appears to be noncompetitive.
The flavonoids of apigenin, luteolin, 3-methylkaempferol, and casticin have been reported to have dose-dependent agonistic properties on Gamma and Delta opioid receptors with isokaempferide having no effect and the effects on the Delta opioid receptor possibly only coming from Casticin; the opioid activating ingredients appear to be present in chloroform or ethanolic extracts for the most part.
Casticin appears to be the most prominent player here (as defatted extracts do not have affinity, suggesting fatty acids play no role), binding to both receptors with IC50 values on Gamma-Opioid and Delta-Opioid being 2.84+/-0.707uM and 2.05+/-0.631uM while other flavonoids ranged in the 20-40uM range. It is unable to activate the Gamma-Opioid receptor, but activates the Delta-Opioid receptor with an EC50 value of 15.3+/-6.32uM and Emax of 74.6+/-18.2%.
Fat soluble compounds in Vitex Agnus appear to have efficacy in interacting with opioid receptors, and Casticin has been demonstrated to activate the opioid receptors
Opioid activity may play a role in Hot Flash symptoms due to a decrease of opioid activity preceding adrenergic instability (assessed by withdrawal from Opioid acting drugs) with is hypothesized to be normalized with opioid activity. Lower levels of B-endorphin (opioid peptide) has also been noted in menopause, and activation of Opioid receptor expressing neurons tends to release B-endorphin compounds.
Activation of Opioid receptors may release B-endorphin, which is inversely correlated with symptoms of menopause
3.4. Serotonergic Neurotransmission
In evaluating a variety of bioactives including flavonoids, no molecule appeared to have significant activity through serotonin receptors up to 40µg/mL.
One study has noted that binding directly to serotonin receptors failed to occur with Vitex in vitro, yet at least one study suggests a possible increase in anxiety at higher doses (100-300mg/kg rats) of Vitex Agnus via acting as an modulator of 5-HT1A receptors, increasing the anxiogenic effects of 5-HT1A antagonists while attenuating the anxiolytic effects of agonists.
May interact with serotonergic mechanisms, but no evidence supports direct agonist roles. Unknown significance for supplementation
3.5. Miscellaneous Mechanisms
When incubated in vitro with Prolactin cells, extracts from Vitex Agnus appear to suppress Prolactin secretion with the potency of one extract at 0.5mg/mL being as effective as 1uM Dopamine (reducing to 10% of control) and the other two at 5mg/mL reducing prolactin secretion to 60% of control. Diterpenoid structures present in these extracts appear to be rotundifuran and clerodadienols, with the latter outperfoming dopamine (1nM) when itself was at a slightly higher concentration of 86uM (underperforming at 43uM).
Histamine, which may influence prolactin, does not have its receptor (H1) affected with incubated Vitex Agnus. This release of prolactin appears to be a downstream effect of activation of Dopamine D2 receptors.
In vitro, reductions of prolactin appear to be apparent which may be mediated via D2 (dopamine) activation
The inhibition of prolactin release from isolated Casticin has been noted in vivo, where injections of 10, 20, and 40mg/kg for a week reduced prolactin levels by 33.9%, 54.3%, and 64.7%; 1mg/kg Bromocriptine used as a reference was approximately as effective as 15mg/kg (measuring at a 44.9% reduction). Another study in rats (800,1600mg/kg ethanolic extract) only noted this decrease of prolactin in rats undergoing experimental menopause (-30.44% and -37.83% at respective doses) and failed to find influence on otherwise normal female rats.
This reduction of prolactin may be mediated via the flavonoid Casticin, although due to other compounds exerting dopaminergic actions (Clerodane Diterpenoids) it may not be the only active ingredient
In otherwise healthy males an extract (BP1095E1) at 120, 240, and 480mg daily for 14 days was associated with an increase in prolactin (24 hour AUC and also in response to a TRH-stimulation test) was noted with 120mg but reductions were noted with 480mg.
3.6. Sedation and Sleep
Concentrations up to 1mg/mL (1000µg/mL) have failed to significantly bind to benzodiazepine receptors, suggesting that Vitex Agnus does not interact with this receptor subset.
4.1. Mastalgia (Breast Tenderness)
Mastalgia is a common symptom of pre-mentrual syndrome (PMS) that affects anywhere between 50-80% of women, while being benign in most cases (only 1% of cases are associated with breast cancer). It is a tenderness of breast tissue that, in most cases, associated with menstration and is highly associated with an increase in serum prolactin and sensitive to stressful situations. The current hypothesis regarding Vitex Agnus and breast tenderness is secondary to acting as a prolactin antagonist (secondary to activating dopaminergic receptors) and suppressing prolaction secretion which subsequently reduces the tenderness associated with higher serum prolactin. Either the suppression of prolactin or the reduction of prolactin is also associated with reduced hot flash symptoms, as evidenced by administration of Bromocriptine (a D2 agonist).
Breast tenderness during PMS is associated with high prolactin levels, which are reduced secondary to dopamine activation
One systemic review notes that the anti-estrogenic effects of Vitex Agnus may play a role in Mastalgia etiology, as anti-estrogenic compounds have shown efficacy in Mastalgia elsewhere. The review noted that although the possibility of diterpenoids acting as an selective estrogen receptor modulator (SERM) may exist, which would attenuate the levels of excess estrogen while inducing weak estrogenic effects, that this possibility was not fully elucidated.
Anti-estrogenic effects may also play a role, but evidence for this is currently subpar
4.2. PMS and Menopause
20mg of a Ze110 extract daily (seen as the lowest optimal dose) for three months spanning three menstrual cycles is associated with reduced general symptoms of PMS by 42.5% (as assessed by MMDQ) or 47.2% (VAS rating scale) which was reduced to 20-21.7% but not abolished after 3 months of cessation. Of this, 46.5% of persons were deemed 'responders' to treatment by having more than a 50% reduction of symptoms, and overall the average amount of days suffering from PMS was reduced from 7.5 to 6. Improvements on VAS have been noted elsewhere, and one blinded intervention (n=128) using the VAS rating scale used a liquid delivery systom (40 drops, 4.5mg; one morning dose in juice) noted that placebo was indeed effective in improving VAS Scores (to undermine the aforementioned unblinded study) but that Vitex Agnus was still associated with improvements on all parameters; headache (31%), nervousness (55%), restlessness (60%), depression (67.5%), breast swelling/pain (97.8%), and bloating/tympani (103%). Percentages are degree of improvement over placebo, which improved universally as well. These parameters as well as mood change were significantly reduced in another blinded study with a 52% response rate (greater than 50% reduction of symptoms), and the potency of Vitex Agnus appears to be similar to or slightly less (depending on paramater measured) than that of the SSRI drug Fluoxetine, and one trial noting similar efficacy to Vitamin B6.
The BNO 1095 (4mg of a 10:1 ethanolic extract, correlating to 40mg of the herb ethanolic extract once daily) extract also appears to be effective in women with moderate to severe PMS symptoms as assessed by Premenstrual Syndrome Diary (PMSD), although this particular study failed to find a benefit to lower abdominal cramping (with most benefit due to other pain symptoms and emotional instability). This particular study (duplicated in Medline) noted larger reductions in symptoms in both placebo and Vitex Agnus (due to worse symptoms at baseline), with placebo resulting in a reduction of 48.95-73.7% of symptom intensity and Vitex Agnus reduced symptom intensity by 80.1-92.46% yet a similar study design (cohort of Chinese women with moderate to severe PMS) noted 63% reductions in overall symptoms accompanied by a 46% reduction associated with placebo.
Null studies include one (cannot be found online, sourced in this study) noting that 600mg of basic Vitex Agnus extract daily (n=217) thrice a day had benefits to neurological symptoms of PMS but failed to influence bloating and edema.
Symptoms in general, assessed by total scores of self-reported rating scales (MMDQ or VAS) note global improvements of menopausal symptoms. Many studies are not blinded (which is important as placebo is active on PMS), but the blinded studies appear to show similar benefits that are both statistically significant and clinically relevant (with over half of users reporting over a 50% reduction in symptoms)
In regards to headaches specifically, one study assessing women who are prone to Migraines during menstrural cycles noted that 40mg/day of Vitex Agnus extract daily for 3 months was associated with a 66% response rate for 'dramatic' reductions in headaches (with 44% and 57% reporting over a 50% reduction in headaches per month and days each month suffering a headache; respectively) and an 8% nonresponse rate. This study was not blinded.
May reduce headaches associated with PMS
One review assessing studies on menopause (with variable stages of menopause, from 3-12 months after amenorrhea) notes that studies on Vitex Agnus Castus and menopause tend to be confounded with the inclusion of other herbs and botanicals (such as Black Cohosh or Soy Isoflavones or just St.John's Wort), although one study using the essential oils of Vitex Agnus (both leaves and fruit), where 2.5mL of a 1.5% cream, applied daily most days for 3 months, was associated with a 33% persons reporting significant reduction of symptoms (mostly mood and hot flushes) and 36% reporting mild reduction in symptoms (7.5% reporting no effects and 23.5% reporting worsened symptoms).|published=2003 Aug|authors=Chopin Lucks B|journal=Complement Ther Nurs Midwifery] This study is limited due to its lack of placebo, which limits conclusions on Menopausal symptoms (due to high placebo influence).
Interventions with Vitex Agnus Castus do not currently support its usage for menopausal symptoms despite its theoretical benefit
It appears one study (cited vicariously through a review) found benefits to symptoms of menorrhagia (heavy bleeding) in women given 15 drops of a tincture thrice daily (the product, Agnolyt®, appears to have a variable 20-240mg dry fruit equivalent). The aforementioned review also cites numerous studies using this brand name product finding benefits to oligomenorrhoea, polymenorrhoea, and secondary amenorrhoea although the primary studies (conducted throughout 1954-1982) are not located online.
Trials that report side-effect note infrequent side effects including intermenstrual bleeding and prolonged menstrual periods.
While there appear to be some early evidence for benefits to menstrual disorders, these studies do not appear to be indexed online and they appear to be all using the same brand name product; more evidence is required
4.4. Medication Interactions
One study (n=43) noted that 16 persons were concurrently using contraceptive medication, but failed to state the specific drugs used; there did not appear to be any interference.
It has been noted that there are no current case studies of clinically relevant or letahl herb-drug interactions with Vitex Agnus supplementation. One review hypothesized that it may interfere with hormonal therapy or contraceptives acting via hormonal means (due to dopaminergic interactions) and these same dopaminergic actions are also a reason Vitex is currently contraindicted in persons undergoing medical therapy for Parkinson's disease (treated with dopaminergic drugs).
No known medication interactions exist, although there isn't a sufficient body of evidence to declare that there aren't any interactions
In general, studies in women for the purpose of controlling symptoms of PMS either report no adverse effects or adverse effects that are no different than placebo, statistically.
5Inflammation and Immunology
Casticin, a bioactive flavonoid in Vitex and standardized in the extracts, in concentrations of 0.78-25µg/mL shows efficacy in suppressing monocytic oxidative burst patterns ranged from 20-50%.
In regards to T-cells, Casticin was able to abolish (100% prevention) PHA-induced T-cell activation (as assessed by thymidine incorporation) at concentrations of 7.5µg/mL and above; outperforming Prednisolone on average (but not statistically significant due to high variability seen with Prednisolone). No toxicity was seen acutely up to 50µg/mL, but some was noted in an MDBK cell line after 5 days incubation with an IC50 of 0.7µg/mL.
Casticin may have immunosuppressive properties, relevance to oral consumption unknown
Cytotoxic effects have been observed with Casticin in three Leukemia cell lines with IC50 values varying from 5.95-15.56uM.
Casticin (as well as artemetin, a related flavonoid) can suppress lipoxygenase with IC50 values of 26+/-0.5uM and 54.6+/-3.3uM respectively.
Several compounds (Casticin, Artemetin, and benzoic acid derivatives) show some anti-inflammatory effects in activated neutrophils, but no compound surpassed the efficacy of Aspirin at the same concentrations.
May possess anti-inflammatory properties, significance unknown
6Interactions with Hormones
In vivo studies measuring serum levels of estrogen in female rats note increases in circulating estrogen (and progesterone), with 600mg/kg and 1200mg/kg of the ethanolic fruit extracts increasing estrogen by 332 and 432% as assessed by vaginal smears; estradiol (positive control) increased this number 625%. When measuring plasma estrogen in this same study, the increase was 24.3% and 115.5% (and progesterone changes being 32.14% and 76.79%, respectively). These increases in serum were attenuated to 11.99% and 23.62% in rats undergoing experimental menopause.
At least one study has noted increased serum estrogen (and progesterone) in female rats as a result of supplementation with Vitex Agnus
Vitex Agnus extract appears to have affinity for the estrogen receptor (ER; cytosolic prepared from human endometrium) and appears to have affinity for the beta-subunit of the ER with no affinity for the alpha subunit, which has been noted elsewhere. The binding affinity of BN1095 extract appears to have an EC50 value of 10µg/mL, and this may be mediated by penduletin (EC50 of 0.25µg/mL), vitexin (10µg/mL), or Apigenin (EC50 0.08µg/mL).
Due to this, administration of the Vitex Agnus extract for up to 3 months failed to significantly modify uterine weight in rats (no observable estrogenic effect) and has been noted in vitro that despite activation of the ERb and an induction of ERb mRNA that no increase of Estrogen-dependent Alkaline Phosphatase (indicative of estrogenicity via ERa) was noted.
Other studies note that a methanolic extract of Vitex Agnus can displace 50% of estrogen from the ERa and ERb receptors with IC50 values of 46+/-3µg/mL and 64+/-4µg/mL, respectively. Linoleic acid in isolation (found in the extract) was able to bind to both receptors with an IC50 of 27+/-2uM and 30+/-2uM (respectively) but this may be too high a concentration to be practically relevant for oral Vitex. Additionally, this studies that actually noted binding to ERa appear to stand alone against other studies that fail to find any binding to ERa at all concentrations tested, and even in one study noting ERa binding there was a failure to induce estrogenic effects as measured by Alkaline Phosphatase Induction (Ishikawa cells); one other study actually notes a decrease of ERa mRNA trancription levels that coexist with an increase in ERb mRNA content.
Vitex Agnus has the classification of containing phytoestrogens, but due to potent binding to the beta subunit of the Estrogen Receptors (ERb) and not the alpha subunit typically associated with 'estrogen-like effects', the overall actions of Vitex Agnus may be practically anti-estrogenic
One study conducted in male rats with injections of Vitex Agnus (fruit hydroalcoholic extract 80:20) at 65-465mg/kg daily for 30 days was associated with a reduction in testosterone and LH hormone levels at concentrations ranging from 165-365mg/kg, but with no significant effect at either extreme (65mg/kg or 465mg/kg). This effect was attenuated slightly with administration of a dopamine antagonist (Haloperidol) and the same research group has previously noted reductions in testosterone following the same injected doses.
The only human study in males investigating the effects of Vitex Agnus noted that 120-480mg of a BP1095E1 extract failed to influence testosterone levels after 20 days of supplementation, despite influencing prolactin.
Injections of Vitex Agnus appear to have anti-androgenic effects, but the dosage range showing reductions in testosterone (165-365mg/kg) equate to a human dose of 1.8-4g of an 80:20 hydroalcoholic extract (150lb male, significantly higher than that commonly supplemented)
One study that noted a large increase in estrogens in menopausal mice suggested that this was indicative of increased androgen synthesis being converted to estrogens (via aromatase); androgens were not measured in this study.
6.3. Luteinizing Hormone
Drops in Luteinizing hormone have been noted in a rat model of menopause following ingestion of 600-1200mg/kg ethanolic extract of the fruits and with relatively large dosed injections of hydroalcoholic Vitex Agnus in otherwise normal male mice; concurrent with drops in testosterone. In normal female mice, no abnormalities are noted with Luteinizing Hormone.
7.1. St.John's Wort
St.John's Wort and Vitex Agnus are commonly associated with each other due to being herbs with dopaminergic (acting on dopamine) actions.
The combination has been assessed in women going through menopause with PMS-like symptoms, and over 16 weeks in this double-blind trial with the daily dose of St.Johns Wort (5.4g dry plant extract conferring 990µg Hypericin and 9mg Hyperforin) and Vitex Agnus (1000mg dry herb equivalent) noted that while both placebo and treatment had significant reductions in overall symptoms at week 4 that placebo had partial attenuation of this improvement while treatment proceeded to exert slightly more benefit over 16 weeks, with significant differences at the time points of 8, 12, and 16 weeks between groups. When looking at subscales, it appeared to have more benefit for cravings and depression associated with PMS-like symptoms and less significant effects on hydration and anxiety (although a positive trend was noted, with hydration failing to be statistically significant).
The combination is used and both appear effective, but interventions do not currently support additive or synergistic effects of the two
One review assessing the evidence for the safety of Vitex Agnus in persons noted that despite a lack of case studies associated with Vitex consumption, that there is insufficient evidence to conclude whether or not Vitex is safe for consumption by pregnant or lactating women and it is uncertain if Vitex crosses into breast milk from the mother.
The LD50 of the ethanolic extract of vitex agnus castus in female rats appears to be 12.5g/kg, and while both a monograph and assessment report from European Medicines Agency (EMA) cite indications of liver damage associated with 26 weeks continued usage of unspecified doses of vitex agnus castus the claim was uncited (beyond "part of a national dossier").
Due to a current lack of evidence, the usage of vitex agnus castus during pregnancy is not advicsed and due to an influence on lactation (paired with a lack of safety data on this particular topic) it is not recommended during this period either; it is contraindicted during breast cancer therapy due to unknown effects on estrogen during this period.
8.2. Case studies
There is a report in existence of a case where a woman with a microadenoma tumor (which increaes prolactin levels in serum which is used as diagnosis) was falsely masked by consumption of Vitex Agnus Castus. It has intentionally been used in another case study where a lowering of prolactin levels in a 31 year old women with an adenoma tumor reached 80% of baseline levels, but no reduction in symptoms associated with high prolactin levels appeared to exist.
There appears to be case reports of pruritic exanthema associated with vitex agnus castus with other skin symptoms such as erythema and worsening of preexisting acne being sporadically associated with the supplement. It is possible that this is due to an allergic reaction, as at least one study has noted dermatitis after a single dose leading to cessation of the study medication.