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See Milk Thistle and BCM-95™ Turmeric for Liver Support

Herbs That May Assist

Milk thistle
Silybum marianum, seed dry
Globe artichoke
   Cyanara scolymus, leaf fres
Schisandra
   Schisandra chinensis, fruit dry
Turmeric
   Curcuma longa, root and rhizome dry, as BCM-95™ Turmeric
Broccoli
   Brassica oleracea var. italica, sprout powder

Actions

Increases bile production and secretion
Restores integrity of liver tissue
Hepatoprotective
Antioxidant
Anti-inflammatory

Clinical Applications

Detoxification
- Phase I, II and III transformation, conjugation and excretion
- Prevents deconjugation of toxins and hormones
Protects against elemental and synthetic toxin exposure
Supports liver tissue regeneration

Dosing Considerations*

Pregnancy

Breastfeeding

*Dosing regimens should be determined by appropriate assessment and monitoring.

One of the key functions performed by the hepatobillary system is the detoxification of natural and toxic compounds. Processes involved in detoxification are orchestrated by a cascade of homeostatic mechanisms that regulate the metabolism and elimination of toxins at a rate conducive to healthy cellular function. Further, these processes are paramount in chronic diseases that feature oxidative stress and inflammation, increasing net detoxification needs to maintain optimal cellular health.

Detoxification pathways may be supported through mitigating Phase I oxidative intermediates, promoting Phase II conjugation, and increasing Phase III elimination; collectively facilitating functional toxin elimination (Figure 1). Milk thistle is a particularly useful herb in all stages of detoxification promoting bile secretion, restoring hepatic damage, and offering antioxidant and anti-inflammatory actions. Similarly, globe artichoke promotes bile production alongside its hepatoprotective and antioxidant activity. Schisandra also has hepatoprotective and antioxidant activity as well as anti-inflammatory properties that further help to buffer oxidative damage. BCM-95™ Turmeric, a highly bioactive form of turmeric, provides additional anti-inflammatory action, while supporting the potent detoxifying qualities of broccoli extract. Compounds from these herbs demonstrate the ability to reduce toxic load and improve detoxification capacity overall.

Figure 1: The three phases of liver detoxification.

Background Technical Information

Detoxification

Detoxification describes the process of neutralisation, solubilisation and transformation of endogenous and exogenous compounds followed by appropriate excretion and elimination. Detoxification encompasses a network of biochemical activities that collectively manage the by-products of cellular metabolism, pharmaceutical compounds, pollutants, and chemical exposure. This biological response primarily occurs in the digestive tract and hepatobiliary systems, which involves the following phases:^[1]

Phase 0 is the uptake of a toxin into a cell;
Phase I reactions create a receptive site on the molecule to prepare it for the second phase;
Phase II involves conjugation reactions whereby activated molecules are combined with compounds to make them more water-soluble, thus easier to excrete; and
Phase III is the clearance (efflux) of these conjugated molecules from the cell and their excretion via the kidneys (in urine) and gut (in bile).

Hepatic biotransformation is well understood in relation to the toxicology of medical substances, and is widely variable across different populations and age groups. Detoxification capacity can therefore differ between individuals due to physiological variations in barrier integrity, enzyme activity, eliminative function and general quality of organ reserve.^[2]While these factors impact detoxification capacity, compromised detoxification is also associated with poor outcomes in several conditions including:

Alzheimer’s disease and dementia;^[3]
Autoimmune disease;^[4]
- Endocrine dysfunction including thyroid disorders,^[5] metabolic disease,^[6] and infertility;^[7],[8] and
- Autism spectrum disorder. ^[9]

Detoxification capacity is equal to the availability of resources and cofactors required to facilitate cellular detoxification. These resources include cellular energy, nutrients, antioxidants and functional tissue in balance with the net burden of endogenous and exogenous compounds. Suboptimal resources, or unmanageable toxin load can impair Phase II detoxification, leading to unbridled accumulation of harmful Phase I intermediates. This can result in amplified oxidative stress and inflammation leading to tissue damage, as illustrated in Figure 2. While some Phase I intermediates are considered to be of greater detriment than others; clinically, inadequate Phase II activity due to deficiency of substrates further compounds oxidative stress, leading to premature cellular apoptosis.

Furthermore, Phase III elimination may be disrupted by a variety of factors. An example of this is the bacterial enzyme β-glucuronidase that can disrupt the conjugation of bound toxin molecules, leading to their reabsorption via enterohepatic circulation; subsequently contributing to increased toxic load. As efficient detoxification is dependent on adaptation to changes in toxic burden, clinical management of any compromised detoxification pathway is significant in the management and prevention of chronic disease.

Figure 2: Physiological effects of hepatotoxic acetaminophen phase 1 intermediate, N-acetyl-p-benzoquinone-imine (NAPQ1) on hepatocytes.^[10]

High levels of Phase 1 intermediates damage hepatocytes and hepatic sinusoidal endothelial cells (SECs), resulting in inflammation and collateral tissue damage.^[11]

Actions

Increases Bile Production and Secretion

Traditionally, Silybum marianum (milk thistle) has been used as a liver and gall bladder tonic associated with enhancing the production of bile.^{^[12]}The role ofCyanara scolymus (globe artichoke) in detoxification is due to its prokinetic action on bile flow,^{^[13]} promoting Phase III elimination. A single dose of 2 g of globe artichoke has been shown to increase bile secretion at 120 and 150 minutes after ingestion. An increase in bile secretion two to three hours after a meal is considered clinically important as this promotes enzymatic digestion and stimulates intestinal motor function.^[14]

Restores Integrity of Liver Tissue

Herbal medicines that facilitate the restoration of liver tissue are regarded as hepatotrophorestoratives and have the ability to promote the recovery and integrity of hepatic tissue,^[15]reducing irreversible structural changes in the liver. Regenerative actions of milk thistle have been attributed to a group of flavonoid compounds collectively termed silymarin, which have been shown to reduce liver fibrosis^[16] and ameliorate hepatic steatosis.^[17]These benefits are thought to be due to milk thistle’s effect on stabilising hepatic membranes, promoting hepatic regeneration and inhibiting collagen deposition.^[18]

Further, Curcuma longa (turmeric) constituents have been shown to restore liver tissue integrity in humans diagnosed with non-alcoholic fatty liver disease (NAFLD) via inhibition of oxidative stress and the inflammatory mediator, nuclear factor-kappa B (NFκB), both associated with liver injury.^[19] The turmeric constituent, curcumin, has been shown to regulate hepatic lipogenesis through adenosine monophosphate-activated protein kinase (MAPK) resulting in the subsequent inhibition of hepatic lipid accumulation.^[20] Moreover, curcumin decreases serum levels of pro-inflammatory cytokines, tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6),^[21]which are involved in structural perpetuation of NAFLD pathogenesis involving hepatic inflammation, apoptosis and fibrosis.^[22]

Hepatoprotective

Milk thistle has a long history of traditional use for liver health.^[23]Mounting evidence supports the hepatoprotective effects of silymarin in various liver diseases including viral hepatitis,^[24]drug induced hepatitis,^[25]Amanita phalloides^[†]poisoning, alcoholic liver disease, and cirrhosis.^[26],[27]In a meta-analysis of these studies, reviewers concluded that silymarin had the following favourable effects:^[28]

Improvement of biochemical markers of liver function (e.g. transaminases, gamma-glutamyl-transferase (GGT), bilirubin, alkaline phosphatase (ALP), albumin and prothrombin time);
Amelioration of histological alterations;
Acceleration of recovery; and
Improvement of survival.

Globe artichoke has several studies demonstrating its hepatoprotective actions in models of hepatic inflammation,^{^[29]} paracetamol-induced toxicity,^{^[30]}lead toxicity,^{^[31]} Schistosoma mansoni-induced fibrosis[‡] and alcohol-induced liver damage.^{^[32]}This herb has been shown to increase antioxidant enzymes, super oxide dismutase (SOD)^{^[33]} and glutathione peroxidase (GPx)^{^[34]} alongside reducing biomarkers of hepatic inflammation.^{^[35]}Similarly, the traditional Korean herb, Schisandra chinensis (schisandra), has established hepatoprotective properties confirmed by rodent models of liver damage including fibrosis,^{^[36]} steatosis,^{^[37]} hepatoxicity,^{^[38]} NAFLD,^{^[39]}^{,^[40]} alcohol-induced liver injury,^{^[41]} paracetamol-induced toxicity,^{^[42]} and chemical-induced liver damage.^{^[43]}^{,^[44],^[45]}Positive results demonstrated by schisandra include reducing hepatic fat accumulation,^{^[46]} reducing hepatocyte swelling and necrosis,^{^[47]}and enhancing the cellular antioxidant, glutathione (GSH).^{^[48]}

Antioxidant

Antioxidants buffer and neutralise the effects of free radicals generated by toxins, which damage cell structure and accelerate cellular ageing. Milk thistle is a potent antioxidant, with multiple mechanisms to protect the body against oxidative stress, particularly in the liver (Figure 3). It is highly protective against lipid peroxidation with its constituent, silybin, a potent free radical scavenger, neutralising such radicals as hydroxyl (•OH), azide (N•3), dibromide (Br•2-), nitrite (NO•2), carbonate (CO•3-), and sulphate (SO•4-).^[49]Another constituent from milk thistle, silymarin, increases GSH content,^[50] and maintains an optimal cellular redox balance by activating a range of antioxidant enzymes, as well as non-enzymatic antioxidant effects via nuclear factor erythroid 2-related factor 2 (Nrf2) activation.^[51]

Figure 3: Activities promoted by milk thistle in liver tissue.^[52]

Schisandra has also been found to attenuate oxidative stress via activation of Nrf2 signalling.^[53] Further to this, animal models have shown schisandra supplementation to effectively increase intracellular SOD levels in response to acute liver injury.^[54] Curcumin has demonstrated protective properties against the noxious effects of toxic metals, which have been attributed to its scavenging and chelating properties, and its ability to induce protective and detoxifying Nrf2, Kelch like-ECH-associated protein 1(Keap1), and antioxidant response element (ARE) pathways.^[55]Similarly, Nrf2-induced benefits have been associated with broccoli compounds, particularly, sulfur-containing glucosinolates in animal models of inflammatory colitis.^[56]

Moreover, globe artichoke has been shown to increase total plasma antioxidant capacity (TAC) in humans.^[57]Supplementation in a drug-induced diabetic rat model has also shown globe artichoke to effectively decrease oxidative stress markers and increased erythrocyte GSH levels.^[58]Synergistically, these herbs promote antioxidant activity through diverse mechanisms, supporting detoxification capacity.

Human studies reveal silymarin supplementation significantly decreases acute inflammatory marker, high sensitivity C-reactive protein (hs-CRP).

Anti-Inflammatory

Mitigating inflammation assists with improving cellular resilience to oxidative stress, which is critical in supporting the compounded effects of compromised detoxification. Silymarin from milk thistle has been shown to inhibit upstream inflammatory transcription factor NFκB in individuals with viral hepatitis.^[59] Human studies reveal silymarin supplementation significantly decreases acute inflammatory marker, high sensitivity C-reactive protein (hs-CRP).^[60] The anti-inflammatory qualities of silymarin have been associated with renal protection, anti-atherosclerotic activity, cardiovascular protection, prevention of cirrhosis-associated hyperinsulinemia, and prevention of Alzheimer’s.^[61]

Globe artichoke has demonstrated anti-inflammatory activity in animal models of alcoholic liver disease due to inhibition of inflammatory meditators NFκB and Toll-like receptor 4 (TLR4).^[62]Further, bioactive constituents of schisandra have been confirmed to stimulate anti-inflammatory mechanisms in animal models of lipopolysaccharide induced inflammation, including:

Suppression of inflammatory cytokines TNF-α, IL-1β, and IL-6;^[63]and
Suppression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) resulting in suppression of nitric oxide (NO) and prostaglandin E₂ (PGE₂).^[64]

The anti-inflammatory actions of turmeric are well known, inhibiting a myriad of inflammatory mediators including phospholipase, lipoxygenase (LOX), COX-2,^[65] leukotrienes, thromboxane, PGs, NO, collagenase, elastase, hyaluronidase, TNF-α, and IL-12.^[66]These mechanisms present an essential target to reduce the negative effects of chronic inflammation, particularly in context of chronic liver injury.^[67]Protective effects facilitated by amending chronic inflammatory processes improve detoxification by reducing immediate and downstream impacts of oxidative stress and supporting hepatobiliary function.

Clinical Applications

Detoxification

Phase I, II and III Transformation, Conjugation and Excretion

Phase I detoxification can be adjusted via modification of enzyme activity and up-regulation of antioxidant function to buffer reactive Phase I intermediates. Phase 1 enzymes include cytochrome P450 (CYP) enzymes that are responsible for the addition of a hydroxyl group to molecules, enhancing their solubility. Constituents within milk thistle,^[68] turmeric^[69]and schisandra^[70]have been shown to reduce the activity of various CYP enzymes, and in effect, dampen Phase I processes that may cause unfavourable oxidative stress.

Oxidative stress may also be mitigated by regenerating the redox antioxidants: SOD, catalase (CAT) and GSH. Human clinical data demonstrates the ability of silymarin to enhance serum antioxidant capacity of GSH and SOD.^[71]This is evidenced in a randomised, triple-blinded, placebo-controlled trial. Forty medicated type 2 diabetic patients were assigned either 140 mg of milk thistle extract three times daily or placebo for 45 days, and screened for antioxidant indices and hs-CRP. Results demonstrated positive increases in SOD, GSH and TAC by 12.85%, 30.32% and 8.43%, respectively (p<0.05).^{^[72]}

Further to this, animal studies have demonstrated schisandra up-regulates SOD and GSH, ^[73]while similar effects have also been observed in globe artichoke in the presence of acute oxidative injury.^[74],[75] In one study, professional rowing athletes received either 400 mg of globe artichoke three times daily, or placebo following strenuous exercise, measuring athlete antioxidant status before and after exercise. Results of the study revealed globe artichoke to enhance TAC and antioxidant activity.^[76]

During Phase II, enzymes conjugate and effectively neutralise intermediate metabolites. Expression of Phase II enzymes can be modified through activation of Nrf2 which, in addition to enhancing antioxidant pathways, regulates expression of detoxification genes. Several functional features of Nrf2 activation include:^[77]

Induces Phase II conjugation activity through activating ARE gene;
Up-regulates efflux transporters to facilitate excretion;
Cytoprotection against highly reactive compounds including quinones; and
Up-regulation of GSH biosynthesis.

Literature supports the advantageous nature of Nrf2 as an up-regulator of Phase II detoxification activity.^[78] Several animal studies looking at Nrf2 knockout mice demonstrated significant deficits and worsened responses to acute liver injury.^[79]In comparison to studies looking at the effects of healthy mice administered with Nrf2 activators, the healthy mice demonstrated significantly greater resilience against hepatotoxicity compared to the control mice,^[80]suggesting the importance of targeting Nrf2 pathways to enhance hepatic detoxification and protection.

Milk thistle constituent, silybin, has also been shown to up-regulate Nrf2 expression,^[81]increase levels of GSH^[82] and up-regulate buffering enzyme of oxidative intermediate, quinone via NAD(P)H:quinone oxidoreductase 1 (NQO1).^[83] Animal studies demonstrate Nrf2-inducing qualities of schisandra in models of induced hepatotoxicity, where schisandra supplementation accelerated the recovery of damaged liver tissue compared to controls.^[84]Experimental studies reveal sulphoraphane within broccoli also facilitates Nrf2 activation alongside human data demonstrating sulphoraphane-mediated induction of Phase II activity.^[85]

Similarly, curcumin has been shown to enhance the expression of several detoxification enzymes through Nrf2 activation, impacting both Phase I and Phase II detoxification pathways, as well as GPx and NQO1.^[86] Detoxification mechanisms of curcumin were investigated in an animal model using benzo[a]pyrene (B[a]P) as a model carcinogen. Dietary pretreatment with chemopreventive doses of curcumin showed significant inhibition of B[a]P-induced enzyme activity of CYP450 1A1/1A2, and increased detoxification of B[a]P.^[87] The researchers concluded that curcumin exhibits detoxifying effects via modulating the transcriptional regulators of Phase I and Phase II enzymes. The above discussed mechanisms work in synergy to reduce the impacts of unmitigated toxins and can serve to optimise detoxification pathways, ultimately leading to improved cellular health and function.

Prevents Deconjugation of Toxins and Hormones

Decongugation of Phase II compounds promotes the recirculation of bioactive metabolites, which can be the result of β-glucuronidase enzyme activity. β-glucuronidase opposes functional Phase III elimination through destabilising and deconjugating bound substrates.^[88]Silymarin has been shown to reduce β-glucuronidase when administered to rats at 30 mg/kg daily (equivalent to 2.1 g/day for a 70 kg human), inhibiting β-glucuronidase activity by 53% in hepatocytes.^[89]This inhibitory action can help prevent the deconjugation and reabsorption of glucuronidated toxins and hormones, allowing for more effective elimination.

Protects Against Elemental and Synthetic Toxin Exposure

Elemental and synthetic toxin exposure is endemic in modern society and is commonly undetected until toxicity upturns physical health. Silymarin provides cellular protection by mitigating toxic metal exposure including lead-induced hepatotoxicity,^[90]nephrotoxicity, genotoxicity,^[91] and arsenic-induced oxidative stress.^[92] Silymarin also ameliorates chemical induced oxidative stress observed in rodent models of acetaminophen toxicity, where silymarin countered behavioural changes, reversed biochemical indices of liver and kidney injury, improved antioxidant capacity and protected tissue histology.^[93]In addition, animals administered silymarin after carbon tetrachloride (CCl4) induced liver damage showed a significant reduction in inflammatory markers and liver fibrosis,^[94] demonstrating the versatility of silymarin actions in toxicity.

Similarly, curcumin demonstrates antihepatotoxic effects against environmental and occupational toxins.^[95] Curcumin reduces the toxicity caused by arsenic (As),^[96] cadmium (Cd),^[97] chromium (Cr),^[98] copper (Cu),^[99]lead (Pb),^[100]iron (Fe),^[101] and mercury (Hg)^[102]exposure. Moreover, curcumin has also been shown to prevent histological injury,^[103]lipid peroxidation^[104] and GSH depletion.^[105] Further, curcumin maintains liver antioxidant enzyme status^[106](Figure 4) and protects against mitochondrial dysfunction.^[107]

Figure 4: Curcumin protects cells against heavy metal exposure via chelating oxidative elements, scavenging free radicals and inducing gene transcription of detoxifying enzymes via Nrf2/ARE.^[108][§]

Broccoli sprout extract has been shown to enhance toxin elimination in an experimental study of 291 residents in the heavily polluted Qidong province in China. Participants received either a broccoli sprout–derived beverage providing 7.2 mg of sulphoraphane a day or a placebo beverage for 12 weeks. The results found a significant increase in the urinary elimination of levels of carcinogenic and volatile compounds benzene (61%) and acrolein (23%), highlighting the potent detoxification ability of sulphoraphane.^[109]The combined responses elicited by these plant extracts provides protection against deleterious compounds and ameliorates consequential impacts upon cellular health.

Broccoli sprout extract has been shown to enhance toxin elimination in an experimental study…results found a significant increase in the urinary elimination of levels of carcinogenic and volatile compounds benzene (61%) and acrolein (23%).

Supports Liver Tissues Regeneration

Repairing hepatocellular damage and subsequent loss of hepatic function is critical to restore adequate detoxification capacity. Moreover, a loss of liver tissue predisposes individuals to greater inflammation and oxidative stress as a result of compromised detoxification.^[110]Antioxidant and anti-inflammatory mechanisms aid hepatic regeneration by reversing damage caused by chronic liver injury, and improving functional detoxification of metabolic and toxic waste. Left unaddressed, individuals subject to chronic hepatic injury are predisposed to hepatic fibrosis, cirrhosis and liver failure.^[111]

A meta-analysis on the use of silymarin in patients with hepatitis B revealed this milk thistle constituent to be equivalent to antiviral drugs in improving serum transaminases, viral load and hepatic fibrosis markers.^{^[112]}Similar outcomes have been observed in a prospective clinical trial where hepatitis C patients were administered 650 mg/day of silymarin for six months. Silymarin use was shown to reduce serum hepatitis C biomarkers, serum aminotransferases and hepatic fibrosis.^{^[113]}Furthermore,meta-analysis data from 602 patients with liver cirrhosis found that silymarin treatment significantly reduced liver-related mortality by 7.3%. (P<0.01).^[114]

Similarly, several clinical trials have demonstrated curcumin to be effective in NAFLD.^{[115],[116],[117]}Two studies demonstrated improvements in liver damage after eight weeks of curcumin supplementation in 75% and 78.9% of participants compared to 4.7% and 27.5% of the control group.^[118],[119]Moreover, 400 mg of curcumin extract over 12 months improved liver morphology by 56% in participants with moderate liver damage, and 84% in participants with severe liver damage.^[120]Curcumin appeared to inhibit the development of hepatic stellate cells, a hallmark of non-alcoholic steatohepatitis and hepatic fibrogenesis. This was achieved via increasing peroxisome proliferator-activated receptor gamma (PPARγ) and GSH synthesis.^[121] In addition, curcumin has been shown to inhibit development of liver cirrhosis through anti-inflammatory activity rather than via direct effects on fibrotic tissue.^[122]These studies collectively suggest that herbs which target regenerative mechanisms can offer protection and improve treatment outcomes in cases of moderate to severe liver damage.

Clinical focus/additional information

In vitro, silybin has been shown to have minor inhibitory effects on several cytochrome P450 (CYP) enzymes, uridine diphosphoglucuronosyl transferase enzyme (UGT- the major phase II enzyme that is responsible for glucuronidation), and has also been shown to reduce P-glycoprotein membrane transport. However, for unknown reasons, these effects do not seem to have significantly translated to in vivo effects.
Although CYP2E1, CYP2D6, CYP2C19, CYP1A2 and CYP2A6 effects of silymarin do not seem to be clinically relevant, the data is inconsistent over potential metabolic interactions with substrates metabolised by CYP3A4 or CYP2C9. As long-term scientific data is lacking, it may be appropriate to monitor patients taking such medications for potential silymarin-drug interactions,^{^[123]}^{,^[124]}particularly medications with narrow therapeutic windows (e.g. warfarin).
Antidepressant medications: BCM-95ä turmeric has been clinically trialled alongside pharmaceutical antidepressants (SSRIs) and was been found to be safe as an adjunctive treatment for depression in that research.^{^[125]}

Cautions and Contraindications

Contraindications

Allergies and Sensitivities: Avoid in individuals with known allergy or hypersensitivity to members of the Asteraceae/Compositae family,^{[126],[127],[128],[129],[130]} artichoke,^[131] turmeric and/or curcuminoids^[132]orhypersensitivity to broccoli or other members of the Brassica genus.^[133]Contact dermatitis has been reported, as has a single case of anaphylaxis from turmeric and/or curcuminoids,^[134]and allergic contact dermatitis has been seen from allergy to the Brassica genus.^[135]

Moderate Level Cautions

Anticoagulant/Antiplatelet drugs: The curcuminoids in turmeric have antiplatelet effects.^[136],[137]Concomitant use alongside anticoagulant or antiplatelet agents, such as aspirin and warfarin, might increase the risk of bleeding.^[138] Use with caution, and for patients taking warfarin, monitor international normalised ratio (INR).
Bleeding disorders: Due to the antiplatelet properties of turmeric, there have been safety concerns with regards to the risk of increased bleeding tendency in patients with bleeding disorders.^[139],[140]Studies are limited, however it still warrants caution in situations that carry a high risk of bleeding, such as haemorrhagic stroke and postoperative events. To minimise the risk of exacerbation of these serious bleeding events, it is recommended to discontinue use of turmeric during acute bleeding episodes.
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. However, it is still advisable to check with a patient’s oncologist before recommending a formula containing antioxidants.^[141],[142]
- Whilst curcumin has been shown to enhance chemotherapy in ovarian cancer,^[143]it may suppress chemotherapy-induced apoptosis in breast cancer: curcumin was found to inhibit chemotherapeutic effects by reducing camptothecin-, mechlorethamine- or doxorubicin-induced apoptosis in breast cancer cells, and reduce the effectiveness of cyclophosphamide in an in vivo mouse model.^[144]In contrast, curcumin has also been shown to augment the cytotoxic effects of other chemotherapeutic drugs, including doxorubicin, tamoxifen, cisplatin and camptothecin, 5-fluorouracil, paclitaxel, daunorubicin, vincristine, and melphalan, with no effect on the toxicity of etoposide, daunorubicin, and idarubicin.^[145]Use with caution and only under the supervision of a patient’s oncologist.
Gallstones and/or bile duct obstruction: Globe artichoke may worsen bile duct obstruction and/or increase the risk of gall bladder issues by increasing bile flow.^{[146],[147],[148]} Turmeric can benefit gallbladder health through promoting the flow of bile via stimulation of gallbladder contraction.^[149],[150]This stimulation of gallbladder contraction may cause problems in some patients.^[151],[152]Use with caution and only under medical supervision in these patients. Monitor patients with a history of gallbladder disease and adjust dosing or discontinue use if required.
Surgery: Due to the anticoagulant properties of turmeric, there have been safety concerns with regards to the risk of increased postoperative bleeding.^[153],[154]Studies are limited, however it would still warrant caution in postoperative events. To minimise the risk of exacerbation of these bleeding events, it is recommended to discontinue use of turmeric 4-7 days before elective procedures which have a high risk for bleeding complications.

Low Level Cautions

Amiodarone: This class III anti-arrhythmic drug is metabolised by cytochrome P450 3A4^[155],[156] and1A2,^[157],[158]and has a narrow therapeutic range.^[159],[160]Schisandra inhibits the activity of P450 3A4^[161],[162]and turmeric inhibits the activity of P450 1A2.^[163],[164]This could theoretically change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
Atazanavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[165],[166] Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[167],[168]Use cautiously in patients on this medication and monitor for symptom changes.
Carbamazepine: This anti-epileptic, neurotropic and psychotropic drug is metabolised by cytochrome P450 3A4,^[169],[170]and has a narrow therapeutic range.^[171],[172]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[173],[174]Use cautiously in patients on this medication and monitor for symptom changes.
Cyclosporine (ciclosporin): This potent immunosuppressant anti-rejection drug is metabolised by cytochrome P450 3A4,^[175],[176]and has a narrow therapeutic range.^[177],[178]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[179],[180]Use cautiously in patients on this medication and consult the patient’s specialist if prescribed to manage organ transplant.
Darunavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[181],[182]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[183],[184]Use cautiously in patients on this medication and monitor for symptom changes.
Delavirdine: This HIV antiretroviral non-nucleoside reverse transcriptase inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[185],[186]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[187],[188]Use cautiously in patients on this medication and monitor for symptom changes.
Digoxin: This cardiac glycoside drug is metabolised by cytochrome P450 3A4,^[189],[190] and has a narrow therapeutic range.^[191],[192]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[193],[194]Use cautiously in patients on this medication and only under medical supervision.
Disopyramide: This class IA anti-arrhythmic drug is metabolised by cytochrome P450 3A4,^[195],[196]and has a narrow therapeutic range.^{[197],[198],[199]}Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[200],[201]Use cautiously in patients on this medication and monitor for symptom changes.
Efavirenz: This HIV antiretroviral non-nucleoside reverse transcriptase inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[202],[203]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[204],[205] Use cautiously in patients on this medication and monitor for symptom changes.
Ethosuximide: This anticonvulsant drug is metabolised by cytochrome P450 3A4,^[206],[207]and has a narrow therapeutic range.^[208],[209]Schisandra inhibits the activity of this enzyme, which theoretically may affect the drug’s therapeutic effect.^[210],[211]Use cautiously in patients on this medication and monitor for symptom changes.
Etravirine: This HIV antiretroviral non-nucleoside reverse transcriptase inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[212],[213]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[214],[215]Use cautiously in patients on this medication and monitor for symptom changes.
Fosamprenavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[216],[217]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[218],[219]Use cautiously in patients on this medication and monitor for symptom changes.
Gastrointestinal Irritation: Turmeric benefits gastrointestinal health^[220], however in some people large doses of turmeric may cause gastrointestinal irritation (e.g. in people with history of peptic ulcers, reflux etc.).^[221],[222]Due to the potential benefits in these conditions, recommend use after food in these patients and monitor progress/adjust dosing down if required.
Indinavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[223],[224]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[225],[226]Use cautiously in patients on this medication and monitor for symptom changes.
Insulin and other hypoglycaemic medications: Milk thistle may modify glucose regulation and can reduce insulin requirements. Those with diabetes are advised to monitor their blood sugar levels.^[227],[228]
Levothyroxine: This thyroid hormone is transported by uridine 5’-diphospoo-glucuronosyltransferase (UGT),^[229],[230] is a substrate for cytochrome P450 3A4,^[231],[232]and has a narrow therapeutic range.^[233],[234]Milk thistle has the potential to affect the clearance of drugs that undergo glucuronidation^{[235],[236],[237]}and schisandra inhibits the activity of P450 3A4.^[238],[239]This couldtheoretically change the drug’s therapeutic effect.^[240],[241]Use cautiously in patients on this medication and monitor for symptom changes.
Lopinavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[242],[243]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[244],[245]Use cautiously in patients on this medication and monitor for symptom changes.
Nelfinavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[246],[247]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[248],[249]Use cautiously in patients on this medication and monitor for symptom changes.
Nevirapine: This HIV antiretroviral non-nucleoside reverse transcriptase inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[250],[251]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[252],[253]Use cautiously in patients on this medication and monitor for symptom changes.
Oestrogens: Animal model research shows that silymarin, a constituent of milk thistle, binds to oestrogen receptor beta. Theoretically, milk thistle might interfere with oestrogen therapy, due to competition for oestrogen receptors.^[254],[255]Use cautiously in patients on these medications and monitor for symptom changes.
Olanzapine: This antipsychotic medication is used for the treatment of schizophrenia and bipolar disorder. It is metabolised via glucoronidation,^[256],[257]and cytochrome P450 1A2^,[258],[259]and has a narrow therapeutic range.^[260],[261]Milk thistle has the potential to affect the clearance of drugs that undergo glucuronidation^{[262],[263],[264]}and turmeric^[265],[266] and broccoli^[267]inhibit the activity of P450 1A2. This could theoretically change the drug’s therapeutic effect. Use cautiously in patients on this medication and only under medical supervision.
Phenobarbital (phenobarbitone): This barbiturate is a widely used anti-seizure medication that is metabolised by cytochrome P450 3A4,^[268],[269]1A1 and 1A2,^[270],[271]and has a narrow therapeutic range.^[272],[273]Schisandra inhibits the activity of P450 3A4,^[274],[275]and turmeric^[276],[277]and broccoli^[278] inhibit the activity of P450 1A1 and 1A2. This could theoretically change the drug’s therapeutic effect, therefore use cautiously in patients on this medication and monitor for symptom changes.
Phenytoin: This anti-epileptic, anticonvulsant and anti-seizure drug is metabolised by cytochrome P450 3A4,^[279],[280]and cytochrome P450 1A2,^[281],[282] and has a narrow therapeutic range.^{[283],[284],[285]}Schisandra inhibits the activity of P450 3A4,^[286],[287]and turmeric^[288],[289]and broccoli^[290]inhibit the activity of P450 1A1 and 1A2. This could theoretically change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
Propafenone: This class IC anti-arrhythmic drug is metabolised by cytochrome P450 3A4^[291],[292]and 1A2,^[293],[294]and has a narrow therapeutic range.^[295],[296]Schisandra inhibits the activity of P450 3A4^[297],[298]and turmeric inhibits the activity of 1A2.^[299],[300]This could theoretically change the drug’s therapeutic effect. Use cautiously in patients on this medication and only under medical supervision.
Quinidine: This anti-malarial and class IA anti-arrhythmic drug is metabolised by cytochrome P450 3A4,^[301],[302]and has a narrow therapeutic range.^[303],[304]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[305],[306]Use cautiously in patients on this medication and monitor for symptom changes.
Rifampicin (rifampin): This antibiotic drug is metabolised by cytochrome P450 3A4^[307],[308]and 1A2,^[309],[310]and has a narrow therapeutic range.^[311],[312]Schisandra inhibits the activity of P450 3A4^[313],[314]and turmeric inhibits the activity of P450 1A2.^[315],[316]This could theoretically change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.
Ritonavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[317],[318] Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[319],[320]Use cautiously in patients on this medication and monitor for symptom changes.
Saquinavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[321],[322]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[323],[324]Use cautiously in patients on this medication and monitor for symptom changes.
Sirolimus (rapamycin): This immunosuppressant anti-rejection drug is metabolised by cytochrome P450 3A4,^[325],[326]and has a narrow therapeutic range.^[327],[328]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[329],[330]Use cautiously in patients on this medication and consult the patient’s specialist if prescribed to manage organ transplantation.
Tacrolimus: This potent immunosuppressant anti-rejection drug is metabolised by cytochrome P450 3A4,^[331],[332]and has a narrow therapeutic range.^[333],[334]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[335],[336]Use cautiously in patients on this medication and consult the patient’s specialist if prescribed to manage organ transplant.
Theophylline: This methylxanthine drug is used for acute relief in respiratory diseases such as COPD and asthma. This drug is metabolised by cytochrome P450 3A4^[337],[338]and 1A1 and 1A2,^{[339], [340]}and has a narrow therapeutic range.^[341],[342]Schisandra inhibits the activity of P450 3A4,^[343],[344]and turmeric^[345],[346]and broccoli^[347]inhibits the activity of 1A1 and 1A2.This could theoretically change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for any adverse effects.
Tipranavir: This HIV antiretroviral protease inhibitor is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range.^[348],[349]Schisandra inhibits the activity of this enzyme, which theoretically may change the drug’s therapeutic effect.^[350],[351]Use cautiously in patients on this medication and monitor for symptom changes.
Valproate (sodium valproate): This anti-epileptic, anticonvulsant and anti-seizure drug is metabolised by cytochrome P450 3A4,^[352],[353]is transported by uridine 5’-diphospoo-glucuronosyltransferase (UGT),^[354],[355]and has a narrow therapeutic range.^{^[356]} Schisandra inhibits the activity of P450 3A4^[357],[358]and milk thistle has the potential to affect the clearance of drugs that undergo glucuronidation.^{[359],[360],[361]}This could theoretically alter the drug’s therapeutic effect.^{[362],[363],[364]}Use cautiously in patients on this medication and monitor for symptom changes.
Warfarin: This anticoagulant medication has a narrow therapeutic range^{[365],[366],[367]}and is metabolised by cytochrome P450 3A4 and 2C9 enzymes,^[368],[369]and also 1A1 and 1A2.^[370],[371] Schisandra inhibits the activity of P450 3A4 and 2C9, ^[372],[373] turmeric inhibits the activity of P450 1A1 and 1A2, ^[374],[375]and broccoli inhibits the activity of 1A2.^[376]This could theoretically change the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor INR levels

Pregnancy and Breastfeeding

Pregnancy: Contraindicated: Schisandra is traditionally contraindicated during pregnancy as it may have a uterine stimulant effect^.[377],[378]

Breastfeeding: Appropriate for use.^{[379],[380],[381],[382]}
- Note: Although no adverse effects from milk thistle^[383],[384]and schisandra^[385],[386]have been seen in breastfeeding if physiological changes occur that mobilize toxins stored in maternal tissues, these toxins may be harmful to the infant. Therefore, the use of herbal detoxification products during breastfeeding is not recommended. Use Practitioner discretion.
Children: Appropriate for use.^{[387],[388],[389],[390]}

Footnotes

[†] Amanita phalloides is a deadly poisonous basidiomycete fungus commonly known as the death cap mushroom.

[‡] Schistosoma mansoni is a virulent tropical parasite in humans associated with periportal fibrosis, granuloma formations and hepatosplenomegaly.

[§] Key antioxidants: NAD(P)H:quinone oxidoreductase 1 (NQ01), Glutathione-S-transferase (GST), heme-oxygenase-1 (HO-1).

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Milk Thistle and BCM-95™ Turmeric for Liver Support

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Herbs That May Assist

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Clinical Applications

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Background Technical Information

Detoxification

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Increases Bile Production and Secretion

Restores Integrity of Liver Tissue

Hepatoprotective

Antioxidant

Anti-Inflammatory

Clinical Applications

Detoxification

Phase I, II and III Transformation, Conjugation and Excretion

Prevents Deconjugation of Toxins and Hormones

Protects Against Elemental and Synthetic Toxin Exposure

Supports Liver Tissues Regeneration

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