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Metagenics

P-Lift

Relieves premenstrual symptoms, and improves fertility

Enhances Fertility and assists in the management and relief of PMS symptoms such as breast tenderness, tiredness, moodiness, headaches, bloating and fluid retention.

  • Assists in the management and relief of PMS symptoms
  • Enhances Fertility
  • Modulates female reproductive hormones

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BENEFITS

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CLINICALLY PROVEN;


FERTILITY

  • Enhances Fertility by increasing progesterone and reducting luteal phase defects

  • Modulates Female Reproductive Hormones

  • Stimulates ovulation

  • Enhance LH and FSH activity, supporting follicle growth and size

  • Positive effects on folliculogenesis and implantation

  • Increases anti-Mullerian hormone levels (indicating improved ovarian reserve)

  • Promotes menstrual cycle regularity


PMS

  • Allevates PMS symproms including irritability, tension, sleep problems, mood swings, food cravings, desire to be alone, depression, forgetfulness, anxiety, poor concentration, crying, suicidal thoughts, decreased libido, and fatigue

  • Reduces the elevated prolactin levels seen in PMS


OTHER

  • Modulates serum cortisol levels

  • Supports thyroid and adrenal hormone production

  • Supports stress adaptation

  • Supports the biosynthesis of serotonin and dopamine 

  • Anti-Inflammatory

  • Antioxidant


ABOUT PMS


PMS symptoms occur during the luteal phase of the menstrual cycle and resolve by the end of menstruation.[1] Whilst the exact aetiology and pathogenesis of PMS remains unknown, several mechanisms have been proposed to play a causative role.


Commencing after ovulation, the luteal phase is marked by formation of the corpus luteum from the ovarian follicle after it has released the egg, in preparation for fertilisation of the ovum and implantation of a zygote into the endometrium.[2] During this phase, the ovaries increase production of progesterone, promoting corpus luteum formation and increased endometrial proliferation (Figure 2).[3] Additionally, the corpus luteum itself produces increasing quantities of progesterone. In the absence of pregnancy, the corpus luteum persists for 14 to 16 days, until onset of menstruation.[4] 


However, if the corpus luteum fails to develop, lower levels of progesterone result, which contributes to PMS symptoms and adversely affects fertility.[5] A deficiency of progesterone or alterations in the oestrogen-to-progesterone ratio during this phase play a role in the symptoms of PMS, as evident by the rapid fluctuations and cyclical changes in progesterone and oestradiol levels that occur during the luteal phase.[6]


Evidence also suggests that high prolactin levels may contribute to some of the physical symptoms characteristic of PMS. The secretion of oestradiol promotes prolactin release by the pituitary gland, which naturally occurs during ovulation. 


Abnormally elevated prolactin levels have been shown to suppress the secretion of follicle stimulating hormone (FSH) and luteinising hormone (LH), involved in follicle maturation, and may consequentially inhibit ovulation, produce oligo- or amenorrhoea, and negatively impact fertility.[8] 


Furthermore, prolactin stimulates mammary tissue enlargement and is involved in osmoregulation, increasing water and salt absorption influencing fluid balance throughout the body.[9] Thus, elevated prolactin may contribute to symptoms of breast pain and tenderness, and fluid retention experienced during PMS.


Studies have also established an association between dopamine and prolactin, with dopamine shown to blunt prolactin release by binding to pituitary cell receptors.[10] In doing so, dopamine activity has the potential to normalise prolactin levels and reduce symptoms associated with elevated prolactin. This complex interaction between sex hormones and neurotransmitters leads to the mood and behavioural alterations associated with PMS.


Hormonal alterations can also affect neurotransmitter systems, as sex hormones are able to bind to serotonergic and gamma-aminobutyric acid (GABA) receptors, and can modulate synaptic neurotransmission.[11] 


Additionally, the brain represents an important target for oestrogen and progesterone, with receptors for these hormones highly expressed in the female brain in areas involving emotion and cognition, such as the amygdala and hippocampus.[12] Thus it has been proposed that women with PMS are more reactive to cyclical hormonal fluctuations, causing changes in neurotransmitter activity that result in mood alterations.[13],[14] 


This may also be a factor in premenstrual dysphoric disorder (PMDD), a debilitating form of PMS characterised by severe mood disturbances.


Further, the HPA axis is believed to play a pivotal role in the pathophysiology of PMS. Research has identified an association between PMS/PMDD and increased subjective stress, particularly during the late luteal phase of the menstrual cycle compared to all other cycle phases, and compared to healthy controls.[15] 


Despite extensive investigation, the exact nature of the relationship between HPA axis function and PMS remains controversial, with data supporting both hyper- and hypoactivity of the HPA axis during PMS. However, contemporary research has observed low cortisol levels during PMS/PMDD, which suggests a blunted stress response in line with hypoactivity of the HPA axis.[16]


The hypothalamic-pituitary-thyroid (HPT) axis also influences ovarian function, with thyroid hormones demonstrated to play a significant role in menstruation and fertility. Hypothyroidism is associated with increased prevalence of menstrual disturbances, including oligomenorrhoea and menorrhagia.[17] 


This may be owing to the progesterone-stimulatory effects of thyroid hormone receptors present on the ovaries, where binding of thyroid hormones to this receptor stimulates progesterone production; thus, insufficient thyroid hormones adversely affect progesterone levels.[18] As such, the treatment of hypothyroidism has been shown to reverse menstrual abnormalities, increase luteal progesterone secretion and promote fertility.[19]


Inflammation may also play a role in PMS pathophysiology, with research demonstrating an association between symptomology and the acute phase inflammatory marker, high-sensitivity C-reactive protein (hs-CRP).[20] Many symptoms of PMS, such as premenstrual mood symptoms, abdominal cramping, back pain, appetite and cravings, weight gain, bloating, and breast pain, have been found to significantly correlate with elevated hs-CRP levels, an association that is further supported by the efficacy of anti-inflammatory agents in relieving PMS symptoms.[21]


Given these complex interactions, PMS/PMDD management requires a multifaceted treatment approach that targets multiple causative mechanisms, including hormone dysregulation, neurotransmitter alterations, HPA axis dysfunction, thyroid hormone insufficiency, and inflammation. Nutritional and herbal support that addresses these physiological drivers can provide a comprehensive treatment approach to PMS/PMDD.


ALLEVIATES PMS and PMDD


Chaste tree has been shown to alleviate symptoms associated with PMS/PMDD in a systematic review of eight randomised controlled trials involving 1,028 participants. At dosages ranging from 4 mg/d to 40 mg/d, chaste tree was evaluated as being both a safe and effective treatment for PMS and PMDD, particularly in alleviating somatic symptoms.[67]


Further to this, a systematic review and meta-analysis examining the efficacy of chaste tree for the treatment of PMS symptoms found similar results. Consisting of 14 studies and data from 1,786 participants, the review reported positive effects on total PMS symptoms when using dosages ranging between 8 mg/d and 41 mg/d. 


Additionally, a meta-analysis focussing on the depressive and anxiety symptoms of PMS showed considerable improvement in their severity.[68]


Chaste tree is recognised as being beneficial for the treatment of mastalgia, as evidenced by a randomised controlled trial involving 159 women aged 18 to 45 years with a history of cyclic mastalgia. Participants were assigned to receive 3.2 mg/d to 4.8 mg/d of chaste tree, 25 g/d of flax seed, or placebo for two months. Breast pain intensity and duration were significantly reduced after the first and second month of chaste tree intervention (p<0.001), indicating effective relief of mastalgia.[69]


Significant improvements in PMS symptoms have also been observed with vitamin B6 use. In a double-blind, randomised controlled trial, 76 women aged 20 to 30 years received either a combination of calcium (500 mg) and B6 (40 mg), or vitamin B6 (40 mg) alone, twice daily for two months. 


The vitamin B6 treatment group experienced a significant reduction in symptom scores including reduced irritability, tension, sleep problems, mood swings, food cravings, wish to be alone, depression, forgetfulness, anxiety, poor concentration, crying, suicidal thoughts, decreased libido, and fatigue (p<0.017).[70] Based on these findings, B6 treatment may be used to improve psychological and somatic symptoms of PMS.[71]


Zinc supplementation has been associated with improvement in PMS symptoms and quality of life scores. In a double-blind, randomised, placebo-controlled trial, 142 women aged 20 to 35 years were randomised to receive either 50 mg/d of elemental zinc or placebo for three consecutive menstrual cycles. 


Participants initially presented with at least one mood-related symptom, including anger or irritability, anxiety and tension, tearful, and depressed mood. Participants also displayed at least four additional symptoms, including decreased interest in work, home and/or social activities, difficulty concentrating, insomnia, hypersomnia, feeling overwhelmed, fatigue or lack of energy, overeating or food cravings. 


Compared to placebo, zinc treatment led to significant reductions in symptom scores throughout the study; a 9.5% decrease in the first cycle, 6% in the second, and 2.6% in the third cycle (p<0.001) [Figure 4], supporting the role of zinc in the management of PMS.[72]



INFERTILITY


Chaste tree was shown to enhance fertility in a clinical trial involving 61 patients aged 21 to 37 years with premature ovarian ageing (POA). All participants received 5 mg/d of letrozole[‡], from day three of the menstrual cycle for a total of four days. In addition to letrozole treatment, 32 patients received approximately 2 mL/d (40 drops/d) of chaste tree liquid extract (80 mg to 90 mg of fruit per mL) for four months throughout the follicular phase. 


Compared with women receiving letrozole alone, the chaste tree group demonstrated increased anti-Mullerian hormone levels (indicating improved ovarian reserve) (p<0.05), enhanced endometrial thickness (p<0.05), higher chemical pregnancy[§] rates (p<0.001), and higher clinical pregnancy rates (p<0.03).[74] 


The increase in pregnancy rates within the chaste tree group may be due to increased progesterone concentrations, which reduce luteal phase defects and enhance fertility. 


Further, chaste tree’s dopaminergic action, which inhibits prolactin activity, may have also enhanced LH and FSH secretions required for follicle maturation.[75]


MODULATES FEMALE REPRODUCTIVE HORMONES


Withania has shown beneficial effects in the treatment of hormonal irregularities. Animal studies indicate phytochemicals contained in withania, including withanolides such as withaferin A, enhance LH and FSH activity, supporting follicle growth and size, and decrease oestrogen and prolactin levels by inhibiting aromatase activity.[22]


Chaste tree has also been shown to benefit reproductive function, with studies indicating it stimulates ovulation, stabilises sex hormones, and promotes menstrual cycle regularity by inhibiting prolactin production and increasing progesterone biosynthesis.[23],[24] These effects occur via dopaminergic activity of chaste tree’s bioactive constituents, clerodadienols, which bind to dopamine D2 receptors in the brain.[25],[26]


By interacting with dopamine receptors, chaste tree may up-regulate the dopamine-inhibited adenylate cyclase signalling pathway, which inhibits cyclic adenosine monophosphate (cAMP), a chemical messenger that mediates hormone release including pituitary prolactin.[27] Thus, chaste tree may reduce the elevated prolactin levels seen in PMS by down-regulating prolactin release.


Additionally, zinc is involved in progesterone binding, gonadal hormone secretion, regulation of the menstrual cycle,[28] ovulation and fertilisation.[29] Zinc deficiency is therefore likely to compromise these functions and contribute to hormonal imbalances.[30]


SUPPORTS THYROID HORMONE PRODUCTION


The regulation of thyroid hormones is essential for optimal reproductive function. The pharmacological properties of withania are known to exert beneficial effects at each point of the hypothalamic-pituitary-thyroid-adrenal-ovarian (HPTAO) axis.[31] 


Studies also show improvements in levels of thyroid, adrenal and sex hormones (LH and FSH). Additionally, human clinical trials have highlighted withania’s ability to improve thyroid function, mood and stress response, and libido.[32]


The pharmacological properties of withania are known to exert beneficial effects at each point of the hypothalamic-pituitary-thyroid-adrenal-ovarian (HPTAO) axis.


In the thyroid, withania appears to directly induce thyroid hormone release at the glandular level, enhance the conversion of thyroxine (T4) to active triiodothyronine (T3), and to modulate levels of glucocorticoids, somatostatin and inflammatory cytokines that are detrimental to thyroid function.[33] 


Additionally, the production of thyroid hormones is heme-dependant; therefore, the iron content of this herb and its capacity to increase haemoglobin and red blood cell levels[34] may provide additional support for thyroid hormone synthesis.


Iodine is an essential cofactor for the production of thyroid hormones. T4, the prohormone, has four iodine molecules, and is converted to the active T3 by the removal of one of these iodines by deiodinase enzymes.[35] Even a mild, transient iodine deficiency can cause an up-regulation of growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor 2 and angiopoetin-1, which enlarge the thyroid.[36] These changes occur to help the gland compensate for reduced iodine levels, but left unchecked, they can initiate the growth of goitres and nodular thyroid tissue, resulting in glandular dysfunction that ultimately reduces thyroid hormone production.[37]


Selenium also plays a crucial role in the metabolism of iodine and the production of thyroid hormones. Iodothyronine deiodinase enzymes are selenium-dependent (containing selenocysteine) and are responsible for the activation of thyroid hormones via the removal of one iodine molecule; for example, 5’-deiodinase converts T4 to T3.[38]


Low zinc levels are associated with altered thyroid hormone metabolism and basal metabolic rate. It is known that zinc affects both the synthesis and function of thyroid hormones.[39] While the exact mechanism remains unknown, zinc is required in the cysteine residues of thyroid transcription factors[*], and to facilitate the release of retinol-binding protein, which plays a central role in T4 to T3 conversion.[40] Interestingly, while low zinc levels seem to impair thyroid function, low thyroid function has also been shown to limit absorption of dietary zinc, which can have detrimental ramifications for reproductive function and menstrual disturbances.


STRESS ADAPTION


Research has established an association between reproductive dysfunction and chronic stress, with cortisol dysregulation correlating with gonadal and sexual dysfunction.[41] 


The adaptogenic actions of withania’s bioactive constituents appear to modulate serum cortisol levels, thereby improving resilience towards stress and reducing its contribution to PMS/PMDD pathogenesis.[42],[43]


Vitamin B6 also modifies the activity of steroid hormones involved in HPA axis activity via modulation of steroid hormone receptor proteins.[44] In doing so, vitamin B6 diminishes sympathetic nervous system output and acts peripherally to blunt the physiological impact of corticosteroids,[45] thus supporting stress adaptation.


Additionally, zinc facilitates optimal HPA axis activity.  As a component of the binding protein, metallothionein[†], which is synthesised in response to increases in endogenous corticosterone, serum zinc levels have been shown to decrease following exposure to acute stress and increased metallothionein activity.[46] 


As such, adequate zinc concentrations are required to support HPA axis activity, with deficiencies leading to dysfunction under severe stress circumstances.[47]


MOOD SUPPORT


Withania is reported to modulate GABA neurotransmission and provide neuroprotective benefits by inducing regeneration of axons, dendrites, and pre- and postsynaptic neurons.[48] 


It is proposed that these functions occur through antioxidant and GABAmimetic actions of key constituents, withanolide A, withanoside IV and withanoside VI, which act upon the inhibitory GABA-α receptor to modulate central nervous system activity.[49],[50]  


Such functions are particularly beneficial for attenuating the psychological symptoms that present with PMS/PMDD.


Additionally, vitamin B6 serves as a cofactor in the production and metabolism of neurotransmitters.[51] Specifically, it functions as a coenzyme in the biosynthesis of GABA, serotonin and dopamine (Figure 3); thus, use of this nutrient may ease mood-related PMS symptoms that correspond with neurotransmitter deficiencies.[52]


Vitamin B6 is required for biosynthesis of GABA, serotonin and dopamine.


Zinc is highly concentrated in the synaptic vesicles of specific neurons, and regulates the release of neurotransmitters. The neurons that contain zinc are known as zinc-enriched neurons (ZEN), with cerebellar ZEN primarily associated with GABA neurotransmission, which produces a calming effect by balancing over-excitability. In other regions, ZEN are found in glutamate-producing neurons.[53] 


Furthermore, zinc has been shown to increase synaptic dopamine levels, thereby allowing dopamine to stay and engage with receptors longer within the synapse, and is considered an important regulator of dopamine transporter function.[54]


ANTI-INFLAMMATORY


Vitamin E is an effective treatment for cyclic mastalgia experienced during PMS, due to its anti-inflammatory properties. Research has associated vitamin E intake with reduced expression of inflammatory markers, including interleukins (IL) (IL-6 and IL-1α) and tumour necrosis factor (TNF-α), which are considered possible drivers of breast pain.[55]


Ginger also exhibits broad anti-inflammatory actions mediated through the inhibition of 5-lipoxygenase (5-LOX) and modulation of cyclooxygenase-1(COX-1) and COX-2 by active constituents’, gingerol, gingerdione and shogaols.[56],[57] Additionally, ginger has also been shown to inhibit IL-12, TNF-α, IL-1-β, prostaglandin E2 (PGE2), thromboxane-A2 (TX-A2) and TX-B2, which perpetuate the inflammatory response.[58] As inflammation is also a major contributor to oxidative stress, its attenuation can help to reduce overall oxidative burden, thereby limiting the detrimental effect on the HPTAO axis.


ANTIOXIDANT


Low antioxidant status adversely affects reproductive function due to increased oxidative stress and tissue damage. An imbalance between antioxidants and reactive oxygen species (ROS) can compromise follicle maturation, ovulation, fertilisation, and corpus luteum formation, leading to menstrual dysfunction and possible infertility.[59] 


The antioxidant properties of gingerols present within ginger have been shown to attenuate this, with research demonstrating positive effects on folliculogenesis and implantation, in addition to increased antral follicle count, which is predictive of ovarian reserve.[60]


Further to this, studies indicate an association between reduced zinc levels and total antioxidant capacity in women with PMS, with studies revealing serum zinc levels to be significantly lower in the luteal phase than the follicular phase in PMS patients.[61]


Vitamin E has also been shown to protect the body’s cell membranes from free radical damage by functioning as an antioxidant electron donor in oxidation-reduction (redox) reactions.[62] This action helps to maintain cell membrane integrity during inflammation; ultimately protecting against tissue damage that may adversely affect reproductive function. 


Additionally, the active form of vitamin E, alpha tocopherol, functions as a fat-soluble antioxidant and has been shown to prevent the oxidation of unsaturated fatty acids.[63] This is pertinent given the susceptibility of the corpus luteum to damage from ROS, which are produced locally within the vascular endothelium.[64]


THYROID SUPPORT


Withania has a long history of use in the treatment of symptoms that are now associated with suboptimal thyroid function. 


In a randomised, double-blind, placebo-controlled trial, 50 participants with raised levels of thyroid-stimulating hormone (TSH) and reduced levels of free T3 and free T4 were randomised to receive either 600 mg/d of standardised withania extract or placebo. At the end of eight weeks those in the active treatment arm showed statistically significant improvements in TSH, T3 and T4 levels.[76]


Zinc has similarly been shown to improve thyroid hormone levels, as evidenced by a study that examined its effect on TSH, T3 and T4 in healthy soccer players. Results indicated that zinc helped combat changes in thyroid hormone levels caused by strenuous exercise.[77]


Further, low zinc levels are associated with altered thyroid hormone metabolism and metabolic rate, with zinc distributed and utilised at a variety of sites related to thyroid function. In a small study of six healthy young men, a reduction of zinc intake from 16.5 mg/d to 5.5 mg/d resulted in a 10% decrease in basal metabolic rate, in addition to a significant reduction in serum free T4 and TSH.[78]


Iodine supplementation is shown to improve thyroid hormone production, which is required for optimal reproductive hormone health. It can also enhance conventional thyroid hormone therapy; the combination of iodine and thyroxine appears more effective than taking thyroxine alone. 


For instance, supplementing with 200 µg/d iodised salt, in addition to thyroxine (1.5 µg/kg/d) after surgery for benign nodular thyroid disease, has been shown to reduce the size of the thyroid remnant by 39.7%, compared with a 10.2% reduction in patients given thyroxine alone.[79]  


Additionally, taking iodine as 150 µg/d potassium iodide in combination with 50 µg/d to 100 µg/d thyroxine (in accordance with individual requirements) for 12 months appears to reduce nodule volume by 17.3%, versus 7.3% in the group using thyroxine alone.[80]


Herbs and nutrients that modulate ovarian hormones, support optimal HPA and HPT axis function, enhance neurotransmitter activity, and attenuate inflammation and oxidative stress can be of clinical utility in the management of hormonal conditions such as PMS/PMDD and infertility. 

INGREDIENTS

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DIRECTIONS

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Adults:
Take 1 tablet, once daily with food

EVIDENCE

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References

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[3] Plant TM, Zeleznik AJ. Physiology of Reproduction. 4th ed. San Diego (USA); Elsevier Science Publishing Co Inc.; 2015. p.1307-61.

[4] Plant TM, Zeleznik AJ. Physiology of Reproduction. 4th ed. San Diego (USA); Elsevier Science Publishing Co Inc.; 2015. p.1307-61.

[5] Trickey R. Women, hormones and the menstrual cycle. 3rd ed. Victoria (Aus): Trickey Enterprises Pty Ltd; 2011. p.64.

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[8] Capozzi A, Scambia G, Pontecorvi A, Lello S. Hyperprolactinemia: pathophysiology and therapeutic approach. Gynecol Endocrinol. 2015 Jul;31(7):506-10. doi: 10.3109/09513590.2015.1017810.

[9] Capozzi A, Scambia G, Pontecorvi A, Lello S. Hyperprolactinemia: pathophysiology and therapeutic approach. Gynecol Endocrinol. 2015 Jul;31(7):506-10. doi: 10.3109/09513590.2015.1017810.

[10] Capozzi A, Scambia G, Pontecorvi A, Lello S. Hyperprolactinemia: pathophysiology and therapeutic approach. Gynecol Endocrinol. 2015 Jul;31(7):506-10. doi: 10.3109/09513590.2015.1017810.

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[30] Fathizadeh S, Amani R, Haghighizadeh MH, Hormozi R. Comparison of serum zinc concentrations and body antioxidant status between young women with premenstrual syndrome and normal controls: A case-control study. Int J Reprod Biomed. 2016 Nov;14(11):699-704.

[31] Sharma AK, Basu I, Singh S. Efficacy and safety of ashwagandha root extract in subclinical hypothyroid patients: A double-blind, randomized placebo-controlled trial. Journal Altern Complement Med. 2018 Mar;24(3):243-248. doi: 10.1089/acm.2017.0183.

[32] Bhattacharya SK, Muruganandam AV. Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress. Pharmacol Biochem Behav. 2003;75(3):547-55.

[33] Cremaschi GA, Gorelik G, Klecha AJ, Lysionek AE, Genaro AM. Chronic stress influences the immune system through the thyroid axis. Life Sci. 2000;67(26):31719.

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[40] McGregor B. Extra-thyroidal factors impacting thyroid hormone homeosatsis: a review. JRM. 2015; 4(1):40-49. doi: http://dx.doi.org/10.14200/jrm.2015.4.0110.

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[170] Vitamin B6. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [cited 2018 Jan 8]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=934. subscription required to view.

[171] Stargrove MB, Treasure J, McKee DL. Herb, nutrient, and drug interactions. St Louis (MO): Mosby Elsevier; 2010. p. 312-313.

[172] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 1078-1091.

[173] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 1149-76.

[174] Vitamin E. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2018 July 27]. Available from: http://www.naturaldatabase.com. subscription required to view.

[175] Harkness R, Bratman S. Mosby’s handbook of drug-herb and drug-supplement interactions. St Louis (MO): Mosby Inc.; 2003. p. 22-4, 337-9.

[176] Stargrove MB, Treasure J, McKee DL. Herb, nutrient, and drug interactions. St Louis (MO): Mosby Elsevier; 2010. p. 422-46.

[177] Ibrahim ZO, Ali SH. Antiplatelet activity of vitamin E in relation to dose and duration of therapy. Iraqi J.Pharm.Sci. 2008; 17(1):25-30.

[178] Ginger. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [updated 2018 Mar 13; cited 2018 Aug 13]. Available from: http://www.naturaldatabase.com. subscription required to view.

[179] Mills S, Bone K. The essential guide to herbal safety. Philadelphia (PA): Elsevier/Churchill Livingstone; 2005. p. 420-4.

[180] Stargrove MB, Treasure J, McKee DL. Herb, nutrient, and drug interactions. St Louis (MO): Mosby Elsevier; 2010. p. 62-8.

[181] Wang CZ, Moss J, Yuan CS. Commonly used dietary supplements on coagulation function during surgery. Medicines. 2015;2(3):157-185. doi:10.3390/medicines2030157.

[182] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 400-15.

[183] Ginger. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [updated 2018 Mar 13; cited 2018 Aug 13]. Available from: http://www.naturaldatabase.com. subscription required to view.

[184] Mills S, Bone K. Mills S, Bone K. The essential guide to herbal safety. Philadelphia (PA): Elsevier/Churchill Livingstone; 2005. p. 420-4.

[185] Fetrow CW, Avila JR. Professionals handbook of complementary and alternative medicines. 3rd ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2004. p. 352-8.

[186] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 400-15.

[187] Ashwagandha. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [updated 2017 Oct 31; cited 2018 Mar 7]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=953. subscription required to view.

[188] Ashwagandha. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [updated 2017 Oct 31; cited 2018 Mar 7]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=953. subscription required to view.

[189] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 1192-4.

[190] Harkness R, Bratman S. Mosby’s handbook of drug-herb and drug-supplement interactions. St Louis (MO): Mosby Inc.; 2003. p. 204-5.

[191] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 1149-76.

[192] Vitamin E. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2018 July 30]. Available from: http://www.naturaldatabase.com. subscription required to view.

[193] Ibrahim ZO, Ali SH. Antiplatelet activity of vitamin E in relation to dose and duration of therapy. Iraqi J Pharm Sci. 2008; 17(1):25-30.

[194] Dasgupta A, Peterson A, Wells A, Actor JK. Effect of Indian Ayurvedic medicine ashwagandha on measurement of serum digoxin and 11 commonly monitored drugs using immunoassays: study of protein binding and interaction with Digibind. Arch Pathol Lab Med. 2007 Aug;131(8):1298-303.

[195] Dasgupta A, Tso G, Wells A. Effect of Asian ginseng, Siberian ginseng, and Indian ayurvedic medicine ashwagandha on serum digoxin measurement by digoxin III, a new digoxin immunoassay. J Clin Lab Anal. 2008;22(4):295-301. doi:10.1002/jcla.20252.

[196] Vitamin B6. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2008 [cited 2017 Dec 19]. Available from: http://www.naturaldatabase.com. subscription required to view.

[197] Harkness R, Bratman S. Mosby’s handbook of drug-herb and drug-supplement interactions. St Louis (MO): Mosby Inc.; 2003. p. 270-1.

[198] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 1218.

[199] Stargrove MB, Treasure J, McKee DL. Herb, nutrient, and drug interactions. St Louis (MO): Mosby Elsevier; 2010. p. 618-652.

[200] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 400-15.

[201] Wang CZ, Moss J, Yuan CS. Commonly used dietary supplements on coagulation function during surgery. Medicines. 2015;2(3):157-185. doi:10.3390/medicines2030157.

[202] Ashwagandha. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [updated 2017 Oct 31; cited 2018 Mar 7]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=953. subscription required to view.

[203] Gardner Z, McGuffin M. Botanical safety handbook. 2nd ed. Boca Raton (FL): CRC Press; 2013. p 935-38.

[204] Gardner Z, McGuffin M. Botanical safety handbook. 2nd ed. Boca Raton (FL): CRC Press; 2013. p 935-38.

[205] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 1185-97.

[206] Vitex. In: Natural Medicines Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2019 [updated 2017 Oct 11th; cited 2019 May 7th]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=968. subscription required to view.

[207] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 159-66.

[208] Gardner Z, McGuffin M. Botanical safety handbook. 2nd ed. Boca Raton (FL): CRC Press; 2013. p 930-33.

[209] Mills S, Bone K. The essential guide to herbal safety. Philadelphia (PA): Elsevier/Churchill Livingstone; 2005. p. 333-36.

[210] Gardner Z, McGuffin M. Botanical safety handbook. 2nd ed. Boca Raton (FL): CRC Press; 2013. p 930-33.

[211] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney (AU): Elsevier/Churchill Livingstone; 2015. p. 159-66.

[212] Selenium. In: Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2018 [cited 2018 Jan 10]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1003. subscription required to view.

WARNINGS

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Contraindications


  • Allergies and Sensitivities: Avoid in people with allergies and sensitivities to soy and / or palm oil[91] (which are often the starting material for tocopherols and tocotrienols), the Solanaceae family of plants,[92],[93] iodine,[94] and carotenoids (from Lutein).[95]

  • Gallstones: Ginger can stimulate gall bladder contractions and is therefore contraindicated in patients with gallstones. It is recommended to only use after consultation with a physician if the patients has gallstones.[96],[97],[98],[99]

  • Hormone sensitive cancers: Chaste tree has hormonal effects and can alter hormone production. People with tumours sensitive to oestrogen or progesterone should avoid using chaste tree.[100],[101]


Moderate Level Cautions


  • Antithyroid drugs: These drugs are used to treat hyperthyroidism, and include propylthiouracil and carbimazole. The concomitant use of antithyroid drugs with iodine may alter a patient’s thyroid activity; therefore, monitor patient’s thyroid function if taking antithyroid medication.[102],[103]

  • Chemotherapy/Radiotherapy: It has generally been thought that antioxidants may interfere with chemotherapy and/or radiotherapy by decreasing the efficacy of the treatment, although recent studies have found that antioxidants are safe to use in conjunction with these treatments.[104],[105],[106] In particular, selenium has been shown to provide potentially beneficial effects alongside certain chemotherapy drugs.[107],[108],[109],[110],[111] However, it is still advisable to check with a patient’s oncologist before recommending a formula containing antioxidants.[112],[113],[114],[115],[116],[117]

  • Cyclophosphamide: Withania may decrease the effectiveness of immunosuppressant therapy because of its immunostimulating effects (withania stimulates stem-cell proliferation). There is preliminary evidence that withania might decrease immunosuppression caused by cyclophosphamide.[118],[119],[120],[121] Caution should be exercised with patients taking cyclophosphamide and withania concurrently.

  • Dopaminergic medications: Chaste tree has anti-dopaminergic (i.e. antagonistic) effects, therefore, use cautiously in patients taking dopamine receptor agonists or antagonists. Additionally, caution is advised in patients with Parkinson’s disease and other illnesses of the central nervous system where these medications (e.g. bromocriptine) are used. [122],[123],[124]

  • Gastric/ duodenal ulcers: Use with caution, inform patients of potential effect and cease use if required.

  • Because of ginger’s effect on the gastric mucosa, it may worsen discomfort in patients with gastric ulcers.[125],[126]

  • Withania may cause gastric irritation.[127],[128] If there is an increase in pain, patients could try taking a demulcent also, or taking the herb with food.

  • Hormone replacement therapies (HRT): Chaste tree can alter hormonal production and could adversely affect the therapeutic effects of HRT.[129],[130] Use cautiously, monitor patient symptoms and discontinue use if symptom exacerbation occurs.[131],[132]

  • Immunosuppressants: Withania may decrease the effectiveness of immunosuppressant therapy because of its immunostimulating effects (withania stimulates stem-cell proliferation).[133],[134],[135] Caution should be exercised when used concurrently in patients taking immunosuppressants.

  • In vitro fertilisation (IVF): Chaste tree alters hormonal production and may adversely affect IVF outcomes. Additionally, there have been reported cases of ovarian hyperstimulation syndrome in patients undergoing IVF and taking chaste tree concurrently. Use with extreme caution in patients undergoing IVF and only under medical supervision.[136],[137]

  • Oestrogens and oral contraceptive pills (OCPs): Coadministration of chaste tree alongside OCPs could adversely affect the contraceptive actions of OCPs. Use with extreme caution and recommend patients use barrier forms of contraception whilst taking this combination.[138],[139],[140]

  • Penicillamine: Zinc forms an insoluble complex with penicillamine, therefore interfering with absorption and activity, reducing the bioavailability of each other.[141],[142] Therefore, it is recommended to separate doses by 2 hours.

  • Phenobarbitone (phenobarbital): At doses above 200 mg/d, vitamin B6 can reduce plasma levels of this anticonvulsant. High doses of vitamin B6 should therefore be avoided in people on this medication.[143],[144] Consider the patient’s total daily intake.

  • Phenytoin: Vitamin B6 at doses above 200 mg/d can reduce plasma levels of this anticonvulsant. High doses of vitamin B6 should be avoided in people on this medication.[145],[146] Consider the patient’s total daily intake.

  • Quinolone antibiotics: These antibiotics may form complexes when taken with zinc and reduce the efficacy of one another, therefore it is recommended to separate doses by taking the medication 2 hours before, [147],[148],[149] or 4 to 6 hours after zinc.[150] Some quinolone antibiotics include ciprofloxacin (Cipro), levofloxacin (Levaquin), ofloxacin (Floxin), moxifloxacin (Avelox), gatifloxacin (Tequin), and others.

  • Tetracycline antibiotics: These antibiotics may form complexes when taken with zinc and reduce the efficacy of one another, therefore it is recommended to separate doses by taking the medication 2 hours before,[151],[152],[153] or 4 to 6 hours after zinc.[154],[155]

  • Thyroid dysfunction/disease:Prolonged use or excessive amounts of iodides (above the recommended daily intake) may cause or exacerbate thyroid gland disorders.[156],[157] In particular, prolonged high doses of iodine may cause or exacerbate thyroid gland hyperplasia, thyroid adenoma, goitre, and severe hypothyroidism.[158] Iodine-induced hyperthyroidism has been reported in euthyroid patients with previous thyroid diseases.[159] The current Australian RDI for iodine is 150 mg/d, with the upper level of intake for adult men and women recommended to be 1100 mg/d.[160] Evaluate total combined daily intake of iodine from all sources in patients with thyroid disease/dysfunction, and monitor thyroid hormone levels if altered thyroid function is suspected. Doses in excess of RDI should only be used under professional supervision.[161]

  • There is some evidence that withania can stimulate thyroid hormone synthesis or secretion. Theoretically, withania might exacerbate hyperthyroidism as it might increase thyroid hormone levels. Withania should be used cautiously in people with hyperthyroidism or in those being treated with thyroid hormones.[162]

  • Thyroxine/Levothyroxine: Withania may add to the effects of thyroid medication. An in vivo study reported that daily administration of withania enhanced serum thyroxine concentrations.[163],[164],[165] Monitor symptoms in patients taking thyroxine medications.


Low Level Cautions


  • Amiloride: This thiazide and potassium-sparing diuretic has conflicting information regarding a potential interaction with zinc. Amiloride has been reported to lead to zinc deficiency, and also reduce zinc excretion, leading to zinc accumulation. Monitor zinc status.[166],[167]

  • Amiodarone:This class III anti-arrhythmic drug contains iodine and concomitant use with iodine may increase the risk of high iodine levels and altered thyroid function.[168],[169] Monitor patient’s thyroid function if combining.
    Conflicting information exists regarding potential interactions between amiodarone and vitamin B6. Preliminary research suggests that vitamin B6 can exacerbate amiodarone-induced photosensitivity. Other research suggests a protective effect.[170],[171] Monitor patients for signs of photosensitivity.[172]

  • Anticoagulant/Antiplatelet drugs: Use with caution in patients taking antiplatelet and/or anticoagulant medications (e.g. aspirin or warfarin) and monitor international normalised ratio (INR) as well as potential adverse bleeding experiences.

  • Vitamin E has antiplatelet effects and may alter blood clotting parameters and affect INR. Use doses above 800 IU/d  (536 mg/d) with caution.[173],[174],[175],[176],[177]

  • Ginger is thought to inhibit thromboxane synthetase and decrease platelet aggregation,[178],[179] affecting lipoxygenase and cyclooxygenase,[180],[181] particularly in doses that exceed 10 g/d.[182] Theoretically, excessive amounts of ginger might increase the risk of bleeding when used with anticoagulant/antiplatelet drugs.[183],[184],[185],[186] Consider combined supplemental and dietary ginger intake.

  • Autoimmune conditions: Withania may have immunostimulant effects, which theoretically might exacerbate autoimmune diseases by stimulating immune activity. Advise patients with autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or others to avoid, or use withania with caution.[187]

  • Benzodiazepines, barbiturates and CNS depressants: Withania has sedative effects and when taken with barbiturates, additive effects are theoretically possible, leading to increased sedation. A beneficial effect is possible under medical supervision. Observe patients taking withania and these types of medicines concurrently.[188],[189],[190]

  • Bleeding disorders: Due to the anticoagulant properties of vitamin E, there have been safety concerns in regards to the risk of increased bleeding tendency in patients with bleeding disorders and impaired coagulation. Although this theoretical possibility is not reflected functionally in human studies, it would still warrant caution in situations which carry a high risk of bleeding such as haemorrhagic stroke and postoperative events. To minimise the risk of exacerbation of these bleeding events it is recommended to discontinue use of high doses of vitamin E (i.e. doses above 800 IU/d or 536 mg/d) during acute bleeding episodes, such as during and immediately after a haemorrhagic stroke, or in patients who are at high risk for haemorrhagic stroke; or 1 week before major surgery.[191],[192],[193]

  • Digoxin: In vitro studies have found that withania may interfere with serum digoxin measurements by the fluorescent polarization immunoassay and other assays.[194],[195] Use caution and monitor if taking digoxin and withania concurrently.

  • Levodopa: Vitamin B6 at doses of 5 to 25 mg and above, may enhance the metabolism of levodopa, reducing its anti-parkinsonism effects. Monitor patients when combining.[196],[197]

  • Nonsteroidal anti-inflammatory drugs (NSAIDs): Zinc may form insoluble complexes with certain NSAIDs. Separate doses by at least 2 hours.[198],[199]

  • Surgery:

  • Due to the anticoagulant properties of ginger, there have been safety concerns in regards to the risk of increased bleeding tendency and postoperative bleeding. To minimise the risk of exacerbation of these bleeding events it is recommended to discontinue use 1-2 weeks before surgery.[200],[201]

  • Withania has CNS depressant effects. Theoretically, withania might cause additive CNS depression when combined with anesthesia and other medications during and after surgical procedures. Tell patients to discontinue withania at least two weeks before elective surgical procedures.[202]


Pregnancy and Breastfeeding


Pregnancy

  • Contraindicated. Generally not for use in pregnancy except under the supervision of a qualified health practitioner.[203]There are references to Withania as an ‘abortifacient’ and a ‘pregnancy tonic.’ The strength or accuracy of this information is difficult to assess given the lack of detail. It may be that low doses pose little danger; however clinicians should discuss the strength and limitations of the evidence when counselling about its use in pregnancy.[204] Western texts urge caution in pregnancy due to a reputed abortifacient activity and antifertility effects notes in early animal studies, despite there being no evidence of fetal damage. Note that withania is used to support pregnancy and lactation in the ayurvedic tradition.[205]
    The hormonal effects of chaste tree might adversely affect pregnancy.[206] 

Breastfeeding

  • Caution.Chaste tree has traditionally been used as a galactagogue. No recent human or animal studies on the safety of chaste tree during lactation were identified, although a review of human studies indicated that chaste tree may decrease prolactin secretion.[210],[211] Therefore, monitoring is advisable.

Children

  • N/A

MGXPL

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