Milk thistle

Milk thistle/Drug Interactions:

  • Alcohol (ethanol)Alcohol (ethanol): Milk thistle may reduce hepatotoxicity associated with ethanol ingestion. In rats, the flavonolignans silybin (silibinin), silydianin, and silychristin have been found to exert hepatocyte membrane-stabilizing and antioxidant effects (112).
  • AmiodaroneAmiodarone: Milk thistle ingredients have been shown to prevent amiodarone toxicity in studies conducted in animals. Research in humans is lacking.
  • Antidiabetic agentsAntidiabetic agents: Silymarin (e.g., Legalon?) has been reported to decrease fasting plasma glucose, hemoglobin A1c (HbA1c), and fasting insulin levels in patients with insulin-dependent diabetes (30; 31; 32; 33; 34; 35; 36; 37). Concomitant use with other hypoglycemic agents may require dose adjustments.
  • Anti-inflammatoriesAnti-inflammatories: In human research, silibinin has been shown to decrease production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) (5). Also, silymarin increased serum levels of immunoglobulin E (IgE) (58) and reduced levels of IL-1 alpha, IL-8, C3 proteins, and C4 proteins in humans (79).
  • AntilipemicsAntilipemics: Early animal experimentation with silybin demonstrated decreased cholesterol synthesis (113) and reduced biliary excretion of cholesterol salts by 60-70%, while leaving biliary flow rates unchanged (114). In perfused livers from rats fed a high-cholesterol diet, silymarin normalized the clearance of low-density lipoproteins (LDL) (115), providing significant protection against dietary-induced hypercholesterolemia (115). In human research, silymarin has been shown to lower levels of total cholesterol (TC), triglycerides (TG), and LDL cholesterol (33; 34; 35; 116; 37). Thus, milk thistle may have additive effects with hypocholesterolemic agents.
  • AntineoplasticsAntineoplastics: In animal and laboratory research, silymarin has demonstrated possible anticarcinogenic effects (117; 118; 119; 120; 121; 122; 41; 123; 124; 125; 126; 127; 128; 129; 130; 131; 19). There are preclinical data that silibinin increases the efficacy of platinum compounds (cisplatin, carboplatin) on human prostate cancer (PCA) cells (132); doxorubicin effects may also be increased (129).
  • AntiretroviralsAntiretrovirals: Animal and laboratory studies have suggested that milk thistle has an inhibitory effect on the cytochrome (CYP) system (particularly CYP2D6. 2C9, 3A4), which is responsible for metabolism of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (38; 39). Theoretically, concurrent use may increase levels of antiretroviral agents. However, in human research, the administration of milk thistle in common dosages lacked an effect on the metabolism of indinavir in healthy volunteers (133; 134) and darunavir in human immunodeficiency virus (HIV)-infected patients (135).
  • AntiviralsAntivirals: In cellular and human research, both oral and intravenous formulations of silibinin have demonstrated antiviral effects, including reduction of hepatitis C viral (HCV)-RNA, inhibition of progeny HCV particle production, and dose-dependent inhibition of HCV pseudoparticle fusion with fluorescent liposomes (136; 83; 84; 137).
  • AnxiolyticsAnxiolytics: In human research, milk thistle leaf extract was shown to reduce symptom severity scores in patients with obsessive-compulsive disorder but lacked obvious therapeutic benefit compared to conventional fluoxetine medication (92).
  • Cardiovascular agentsCardiovascular agents: An isolated case of pounding heart with dry, powdered milk thistle leaf has been reported, with similar frequency to that of an active fluoxetine control (92).
  • Cytochrome P450 metabolized agentsCytochrome P450 metabolized agents: There are equivocal data from animal studies, in vivo, and in vitro studies to suggest inhibition of the CYP P450 system by milk thistle, but effects in humans are unclear. There is some evidence of inhibition of CYP 3A4, 2C9, and 2D6 (38; 39; 40). Therefore, increased concentrations of concomitant medications (substrates) may occur. However, some reports disagree, and a lack of clinically relevant effect on CYP3A4, CYP2D6, CYP2E1, and CYP1A2 activity in vivo has also been observed (138; 139).
  • Dermatologic agentsDermatologic agents: In breast cancer patients undergoing radiotherapy, topical silymarin-based cream (Leviaderm?) was shown to reduce the number, severity, and manifestation time of radiotherapy-induced toxic skin reactions, compared to conventional panthenol-based cream (85). Various dermatological symptoms have been reported in several trials of milk thistle, with a similar incidence to control groups (91; 93; 94; 95; 44; 96; 97; 98; 99; 47).
  • Fertility agentsFertility agents: In women undergoing in vitro fertilization (IVF), adjunct silymarin to human gonadotropin (HCG) reduced the proportion of total and early granulosa cell apoptosis vs. placebo but lacked evidence of benefit with regard to oocyte retrieval and endometrial thickness (71).
  • GalactagoguesGalactagogues: As a purported galactagogue, milk thistle has been added to certain proprietary mixtures with the intent of increasing milk supply (15; 16). In one nonrandomized, single-blind study, Di Pierro et al. found that supplementation with 420mg of micronized silymarin (Pi?Latte? BIO-C? micronized silymarin, Milte S.p.A., Italy) daily for 63 days significantly increased milk production compared to placebo (85.94% vs. 32.09%, respectively; p<0.01), with good tolerability and a lack of between-group difference with respect to milk composition (109).
  • Gastrointestinal agentsGastrointestinal agents: According to a review, a combination formulation composed of milk thistle, bitter candy tuft, chamomile flower, peppermint leaves, caraway fruit, licorice root, lemon balm leaves, angelica root, and celandine herbs (STW 5, Iberogast) improved gastrointestinal symptoms of functional dyspepsia vs. placebo (140). Infrequent, mild gastrointestinal symptoms have been reported in several studies (101; 102; 27; 62; 96; 94; 73; 86; 103; 104; 74; 87; 66; 98; 53; 77; 95; 99; 54; 92).
  • Glucuronidated agentsGlucuronidated agents: Silymarin may inhibit beta-glucuronidase (41) and theoretically may decrease the clearance of glucuronidated agents, such as lorazepam (Ativan?), lamotrigine (Lamictal?), and entacapone (Comtan?) (39).
  • HematologicsHematologics: In patients with beta-thalassemia, adjunct administration of silymarin (Legalon?) to conventional desferrioxamine therapy decreased serum ferritin levels vs. baseline but lacked obvious treatment benefit vs. conventional therapy alone (47). Results from blood histological examination in a clinical trial demonstrated isolated alterations in various hematologic parameters, including decreased platelets, increased creatinine, increased glucose, increased lactate dehydrogenase level, increased indirect bilirubin, increased aspartate aminotransferase level, and increased alkaline phosphatase level (107). According to the investigators, all observed changes were small in magnitude and lacking in clinical relevance. In a study investigating the use of silybin-phytosome in prostate cancer patients, one grade 4 postprostatectomy thromboembolic episode was noted (87).
  • HepatotoxinsHepatotoxins: In human research, reductions in transaminase and gamma-glutamyltransferase activity (e.g., AST, ALT, serum glutamic pyruvic transaminase [SGPT], serum glutamic oxalacetic transaminase [SGOT]) have been observed following the administration of milk thistle (e.g., Legalon?) monotherapy or combination therapy (35; 141; 142; 54; 143; 34; 33; 37).
  • Hormonal agentsHormonal agents: Milk thistle may interact with hormonal agents. In theory, silymarin might increase the clearance of estrogen by inhibiting beta-glucuronidase (42).
  • Impotence agentsImpotence agents: A case of impotence in a pilot clinical trial of silymarin for alcoholic cirrhosis has been reported (106). Sexual dysfunction has also been reported, with similar frequency to that of an active control (92).
  • IrinotecanIrinotecan: In human research, milk thistle lacked evidence of an effect on irinotecan clearance (144). Given that irinotecan is a known substrate of CYP3A4 and glucuronosyltransferase isoform 1A1 (UGT1A1) metabolism, the investigators concluded that milk thistle is unlikely to affect CYP3A4 or UGT1A1 activity.
  • LosartanLosartan: Milk thistle has been shown to reduce the bioactivation of losartan (40) and inhibit its metabolism to E-3174 (145). The inhibition of CYP2C9 activity has been purported as a possible mechanism of action for milk thistle's inhibitory effect on losartan (40).
  • PenicillinPenicillin: Evidence of therapeutic effect was lacking following the coadministration of milk thistle, penicillin, and N-acetyl cysteine (146) or the sequential administration of penicillin then milk thistle (59), in a case report and case series of mushroom poisoning (Amanita smithiana, Amanita phalloides), respectively.
  • P-glycoprotein modulatorsP-glycoprotein modulators: The resulting isoprenoid dehydrosilybins from the flavonolignan silybin has been shown to display high in vitro affinity for direct binding to p-glycoprotein (147; 148).
  • Phenytoin (Dilantin?)Phenytoin (Dilantin?): Milk thistle may inhibit p-glycoprotein (148) and theoretically increase concentrations and risk of adverse effects associated with phenytoin.
  • RapamycinRapamycin: In vitro, silymarin has been shown to counteract the antiproliferative activity of rapamycin in endothelial progenitor cells by increasing proliferative activity up to 64%, augmenting telomerase activity threefold, and reducing the number of senescent cells (149). In hepatically impaired renal transplant patients, coadministration of silymarin was shown to decrease the apparent clearance of sirolimus (rapamycin) (150).
  • TalinololTalinolol: In healthy volunteers, the coadministration of silymarin has been shown to increase the plasma concentration of talinolol (151).

    • Milk thistle/Herb/Supplement Interactions:

  • Anti-inflammatoriesAnti-inflammatories: In human research, silibinin has been shown to decrease production of TNF-alpha and IL-1beta (5). Also, silymarin increased serum levels of IgE (58) and reduced levels of IL-1 alpha, IL-8, C3 proteins, and C4 proteins (79).
  • AntilipemicsAntilipemics: Early animal experimentation with silybin demonstrated decreased cholesterol synthesis (113) and reduced biliary excretion of cholesterol salts by 60-70%, while leaving biliary flow rates unchanged (114). In perfused livers from rats fed a high-cholesterol diet, silymarin normalized the clearance of LDL (115), providing significant protection against dietary-induced hypercholesterolemia (115). In human research, silymarin has been shown to lower levels of TC, TG, and LDL cholesterol (33; 34; 35; 116; 37). Thus, milk thistle may have additive effects with hypocholesterolemic agents.
  • AntineoplasticsAntineoplastics: In animal and laboratory research, silymarin has demonstrated possible anticarcinogenic effects (117; 118; 119; 120; 121; 122; 41; 123; 124; 125; 126; 127; 128; 129; 130; 131; 19).
  • AntioxidantsAntioxidants: Flavonoids present in milk thistle, such as silymarin and silybin, have been shown to act as antioxidants and free radical scavengers (152; 153; 154; 155; 156; 157; 158; 159; 160; 161). In animal and human research, silymarin demonstrated antioxidant properties, both alone and when coadministered with vitamin E (20; 162; 60).
  • AntiretroviralsAntiretrovirals: Animal and laboratory studies have suggested that milk thistle has an inhibitory effect on the cytochrome (CYP) system (particularly CYP2D6. 2C9, and 3A4), which is responsible for metabolism of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (38; 39). Theoretically, concurrent use may increase levels of antiretroviral agents. However, in human research, the administration of milk thistle in common dosages lacked an effect on the metabolism of indinavir in healthy volunteers (133; 134) and darunavir in human immunodeficiency virus (HIV)-infected patients (135).
  • AntiviralsAntivirals: In cellular and human research, both oral and intravenous formulations of silibinin have demonstrated antiviral effects, including reduction of HCV-RNA, inhibition of progeny HCV particle production, and dose-dependent inhibition of HCV pseudoparticle fusion with fluorescent liposomes (136; 83; 84; 137).
  • AnxiolyticsAnxiolytics: In human research, milk thistle leaf extract was shown to reduce symptom severity scores in patients with obsessive-compulsive disorder but lacked obvious therapeutic benefit compared to conventional fluoxetine medication (92).
  • CalciumCalcium: Studies suggest that silymarin and silybin protect against genomic injury, increase hepatocyte protein synthesis, decrease the activity of tumor promoters, stabilize mast cells, chelate iron, and slow calcium metabolism (22).
  • Cardiovascular agentsCardiovascular agents: An isolated case of pounding heart with dry, powdered milk thistle leaf has been reported with similar frequency to that of an active fluoxetine control (92).
  • Cytochrome P450 metabolized herbs and supplementsCytochrome P450 metabolized herbs and supplements: There are equivocal data from animal studies, in vivo, and in vitro studies to suggest inhibition of the CYP P450 system by milk thistle, but effects in humans are unclear. There is some evidence of inhibition of CYP 3A4, 2C9, and 2D6 (38; 39; 40). Therefore, increased concentrations of concomitant medications (substrates) may occur. However, some reports disagree, and a lack of clinically relevant effect on CYP3A4, CYP2D6, CYP2E1, and CYP1A2 activity in vivo has also been observed (138; 139).
  • Dermatologic agentsDermatologic agents: In breast cancer patients undergoing radiotherapy, topical silymarin-based cream (Leviaderm?) was shown to reduce the number, severity, and manifestation time of radiotherapy-induced toxic skin reactions, compared to conventional panthenol-based cream (85). Various dermatological symptoms have been reported in several trials of milk thistle, with similar incidence to control groups (91; 93; 94; 95; 44; 96; 97; 98; 99; 47).
  • Fertility agentsFertility agents: In women undergoing in vitro fertilization (IVF), adjunct silymarin to human gonadotropin (HCG) reduced the proportion of total and early granulosa cell apoptosis vs. placebo but lacked evidence of benefit with regard to oocyte retrieval and endometrial thickness (71).
  • GalactagoguesGalactagogues: As a purported galactagogue, milk thistle has been added to certain proprietary mixtures with the intent of increasing milk supply (15; 16). In one nonrandomized, single-blind study, Di Pierro et al. found that supplementation with 420mg of micronized silymarin (Pi?Latte? BIO-C? micronized silymarin, Milte S.p.A., Italy) daily for 63 days significantly increased milk production compared to placebo (85.94% vs. 32.09%, respectively; p<0.01), with good tolerability and a lack of between-group difference with respect to milk composition (109).
  • Gastrointestinal agentsGastrointestinal agents: According to a review, a combination formulation composed of milk thistle, bitter candy tuft, chamomile flower, peppermint leaves, caraway fruit, licorice root, lemon balm leaves, angelica root, and celandine herbs (STW 5, Iberogast) improved gastrointestinal symptoms of functional dyspepsia vs. placebo (140). Infrequent, mild gastrointestinal symptoms have been reported in several studies (101; 102; 27; 62; 96; 94; 73; 86; 103; 104; 74; 87; 66; 98; 53; 77; 95; 99; 54; 92).
  • HematologicsHematologics: In patients with beta-thalassemia, adjunct administration of silymarin (Legalon?) to conventional desferrioxamine therapy decreased serum ferritin levels vs. baseline but lacked obvious treatment benefit vs. conventional therapy alone (47). Results from blood histological examination in a clinical trial demonstrated isolated alterations in various hematologic parameters, including decreased platelets, increased creatinine, increased glucose, increased lactate dehydrogenase level, increased indirect bilirubin, increased aspartate aminotransferase level, and increased alkaline phosphatase level (107). According to the investigators, all observed changes were small in magnitude and lacking in clinical relevance. In a study investigating the use of silybin-phytosome in prostate cancer patients, one grade 4 postprostatectomy thromboembolic episode was noted (87).
  • HepatotoxinsHepatotoxins: In human research, reductions in transaminase and gamma-glutamyltransferase activity (e.g., AST, ALT, SGPT, SGOT) have been observed following the administration of milk thistle (e.g., Legalon?) monotherapy or combination therapy (35; 141; 142; 54; 143; 34; 33; 37; 78).
  • Hormonal agentsHormonal agents: Milk thistle may interact with hormonal agents. In theory, silymarin might increase the clearance of estrogen by inhibiting beta-glucuronidase (42).
  • HypoglycemicsHypoglycemics: Silymarin (e.g., Legalon?) has been reported to decrease fasting plasma glucose, HbA1c, and fasting insulin levels in patients with insulin-dependent diabetes (30; 31; 32; 33; 34; 35; 36; 37). Concomitant use with other hypoglycemic agents may require dose adjustments.
  • Impotence agentsImpotence agents: A case of impotence in a pilot clinical trial of silymarin for alcoholic cirrhosis has been reported (106). Sexual dysfunction has also been reported, with similar frequency to that of an active control (92).
  • IronIron: Studies have suggested that milk thistle may protect against genomic injury, increase hepatocyte protein synthesis, decrease the activity of tumor promoters, stabilize mast cells, chelate iron, and slow calcium metabolism (22). Treatment with a standardized silybin and soy phosphatidylcholine complex (IdB 1016) was associated with reduced body iron stores among patients with advanced Batts-Ludwig fibrosis and hepatitis C; an apparent effect on serum iron or transferrin-iron saturation was lacking (163). A reduced postprandial rise in serum iron level following the consumption of silybin (Legalon? Forte) has been observed in hereditary hemochromatosis patients (12). In patients with beta-thalassemia, adjunct administration of silymarin (Legalon?) to conventional desferrioxamine therapy decreased serum ferritin levels vs. baseline but lacked obvious treatment benefit vs. conventional therapy alone (47).
  • N-acetyl cysteineN-acetyl cysteine: In a case report, combination milk thistle, N-acetyl cysteine, and penicillin for the treatment of acute Amanita smithiana mushroom poisoning lacked evidence of therapeutic effect (146).
  • P-glycoprotein modulatorsP-glycoprotein modulators: The resulting isoprenoid dehydrosilybins from the flavonolignan silybin has been shown to display high in vitro affinity for direct binding to p-glycoprotein (147).
  • Vitamin EVitamin E: Silymarin and vitamin E have been reported to prevent amiodarone toxicity in animal studies. Silymarin and its active constituent, silybin, have been reported to work as antioxidants, scavenging free radicals, and inhibiting lipid peroxidation (22).

    • Milk thistle/Food Interactions:

  • Insufficient available evidence.

    • Milk thistle/Lab Interactions:

  • Blood glucoseBlood glucose: Silymarin (e.g., Legalon?) has been reported to decrease fasting plasma glucose, HbA1c, and fasting insulin levels in patients with insulin-dependent diabetes (30; 31; 32; 33; 34; 35; 36; 37).
  • IronIron: Studies have suggested that milk thistle may chelate iron (22). Treatment with a standardized silybin and soy phosphatidylcholine complex (IdB 1016) was associated with reduced body iron stores among patients with advanced Batts-Ludwig fibrosis and hepatitis C; an apparent effect on serum iron or transferrin-iron saturation was lacking (163). A reduced postprandial rise in serum iron level following the consumption of silybin (Legalon? Forte) has been observed in hereditary hemochromatosis patients (12). In patients with beta-thalassemia, adjunct administration of silymarin (Legalon?) to conventional desferrioxamine therapy decreased serum ferritin levels vs. baseline but lacked obvious treatment benefit vs. conventional therapy alone (47).
  • Lipid profileLipid profile: Early animal experimentation with silybin demonstrated decreased cholesterol synthesis (113) and reduced biliary excretion of cholesterol salts by 60-70%, while leaving biliary flow rates unchanged (114). In perfused livers from rats fed a high-cholesterol diet, silymarin normalized the clearance of LDL (115), providing significant protection against dietary-induced hypercholesterolemia (115). In human research, silymarin has been shown to lower levels of TC, TG, and LDL cholesterol (33; 34; 35; 116; 37). Thus, milk thistle may decrease blood cholesterol.
  • Liver function testsLiver function tests: In one study, the most prominent adverse event was hyperbilirubinemia, with grade 1-2 bilirubin elevations in nine of the 13 patients (51). The only grade 3 toxicity observed was elevation of ALT in one patient; no grade 4 toxicity was noted. Silymarin in CCl4-induced liver-damaged rats decreased the elevation of AST, ALT, and alkaline phosphatase in serum, and also reversed the altered expressions of alpha-smooth muscle actin in liver tissue (164). Silymarin also reduced the AST levels in humans coinfected with HIV and hepatitis C (165). In human research, reductions in transaminase and gamma-glutamyltransferase activity (e.g., AST, ALT, SGPT, SGOT) have been observed following the administration of milk thistle (e.g., Legalon?) monotherapy or combination therapy (35; 141; 142; 54; 143; 34; 33; 37; 78).