Herb-Drug Interactions: Saw palmetto

Serenoa repens (Bartram) J.K. Small (Arecaceae)

Synonym(s) and related species

American dwarf palm, Sabal, Serenoa.

Brahea serrulata H.Wendl., Sabal serrulata (Michx.) Schult f., Sabal serrulatum Schult f., Serenoa serrulata (Michx.) Hook. f. ex B.D. Jacks.

Pharmacopoeias

Powdered Saw Palmetto (US Ph 32); Saw Palmetto (US Ph 32); Saw Palmetto Capsules (US Ph 32); Saw Palmetto Fruit (British Ph 2009, European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4).

Constituents

The fruit of saw palmetto contains about 25% fatty acids (extracts are often standardised to a minimum of 11% total fatty acids) consisting of capric, caprylic, lauric, palmitic, oleic, linoleic and linolenic acids in the form of fixed oils. Sterols including campesterol, stig masterol and beta-sitosterol are also present, as are long-chain alcohols, carotenoids, various polysaccharides and some flavonoids, including rutin, isoquercetin and kaempferol.

Use and indications

The main contemporary use of saw palmetto fruit is to treat the urological symptoms of benign prostatic hyperplasia. It has also been used as a diuretic, a sedative, an endocrine agent, an antiseptic and for treating disorders involving the sex hormones.

Pharmacokinetics

Saw palmetto (ProstaPro 160 mg berry extract containing 85 to 95% fatty acids and sterols) was found to inhibit the cytochrome P450 isoenzymes CYP2D6, CYP2C9 and CYP3A4 in vitro.’ However, a clinical study in patients given debrisoquine, a probe substrate for CYP2D6, found that saw palmetto had no effect on this isoenzyme, and other clinical studies suggest that the in vitro effects reported for CYP3A4 and CYP2D6 may not be clinically relevant, see benzodiazepines5, and dextromethorphan6, for further information. Clinical studies with chlorzoxazone5, and caffeine5, also suggest that saw palmetto has no clinically relevant effect on CYP1E2 or CYP1A2, respectively. For information on the pharmacokinetics of individual flavonoids present in saw palmetto, see under flavonoids.

Interactions overview

There may be an increased response to anticoagulant treatment in patients who also take saw palmetto. Saw palmetto does not appear to have a clinically relevant effect on the majority of cytochrome P450 isoenzymes and no other interactions with saw palmetto have been found. For information on the interactions of individual flavonoids present in saw palmetto, see under flavonoids.

Saw palmetto + Anticoagulants

The INR of one patient taking warfarin modestly increased after he took Curbicin (saw palmetto, cucurbita and vitamin E). This product has also been associated with an increased INR in a patient not taking anticoagulants. Excessive bleeding during surgery has been reported in another patient who had been taking saw palmetto.

Clinical evidence

A 61-year-old man taking warfarin and simvastatin, with a stable INR of around 2.4, had an increase in his INR to 3.4 within 6 days of starting to take 5 tablets of Curbicin daily. Within a week of stopping the Curbicin, his INR had fallen to its previous value. Another elderly man who was not taking any anticoagulants and was taking 3 tablets of Curbicin daily was found to have an INR of 2.1 (normal 0.9 to 1.2). His INR decreased (to between 1.3 and 1.4) when he was given vitamin K, but did not normalise until a week after the Curbicin was stopped. Curbicin is a herbal remedy used for micturition problems, and contains extracts from the fruit of saw palmetto and the seed of Cucurbita pepoJ

In addition, saw palmetto has been attributed to excessive bleeding in a 53-year-old man undergoing a surgical procedure to remove a brain tumour. An estimated 2 litres of blood were lost during surgery and bleeding time did not return to normal for 5 days. The patient denied taking NSAIDs pre-operatively but admitted to taking saw palmetto for benign prostate hypertrophy.

Experimental evidence

Saw palmetto may inhibit the cytochrome P450 isoenzyme CYP2C9 in vitro (see Pharmacokinetics), but it is not known if this is clinically relevant.

Mechanism

The authors of the first report suggest that what happened was possibly due to the presence of vitamin E in the Curbicin preparation (each tablet contains 10 mg), but vitamin E does not normally affect INRs. Experimental evidence suggests that saw palmetto may inhibit the cytochrome P450 isoenzyme CYP2C9, which is an important route of warfarin metabolism.

Importance and management

Evidence appears to be limited to case reports and an experimental study of unknown clinical relevance. Because of the many other factors influencing anticoagulant control, it is not possible to reliably ascribe a change in INR specifically to a drug interaction in a single case report without other supporting evidence. It may be better to advise patients to discuss the use of any herbal products that they wish to try, and to increase monitoring if this is thought advisable. Cases of uneventful use should be reported, as they are as useful as possible cases of adverse effects.

Saw palmetto + Benzodiazepines

No pharmacokinetic interaction appears to occur between saw palmetto and alprazolam or midazolam.

Clinical evidence

In a study in 12 healthy subjects, saw palmetto 320 mg daily for 16 days did not affect the pharmacokinetics of a single 2-mg dose of alprazolam given on day 14. In another study in 12 healthy subjects saw palmetto 160 mg twice daily for 28 days did not affect the metabolism of a single 8-mg dose of midazolam.

Experimental evidence

Experimental studies have suggested that saw palmetto may inhibit the cytochrome P450 isoenzyme CYP3A4, see Pharmacokinetics4.

Mechanism

Midazolam is metabolised by the cytochrome P450 isoenzyme CYP3A4. In vitro study suggested that saw palmetto inhibited this route or metabolism, but this does not appear to be clinically relevant.

Importance and management

The findings of these studies suggest that saw palmetto does not alter the metabolism of alprazolam or midazolam, and therefore no dosage adjustments of these benzodiazepines would be expected to be needed on concurrent use.

Midazolam is used as a probe drug for CYP3A4 activity, and therefore these results also suggest that a pharmacokinetic interaction between saw palmetto and other CYP3A4 substrates is unlikely.

Saw palmetto + Caffeine

Saw palmetto does not appear to affect the pharmacokinetics of caffeine.

Clinical evidence

In a randomised study, 12 healthy subjects were given saw palmetto 160 mg twice daily for 28 days, with a single 100-mg dose of caffeine at the end of treatment with saw palmetto. The pharmacokinetics of caffeine were unchanged by saw palmetto.

Experimental evidence

No relevant data found.

Mechanism

Caffeine is metabolised by the cytochrome P450 isoenzyme CYP1A2. Saw palmetto does not appear to inhibit this route of metabolism.

Importance and management

Evidence appears to be limited to the study cited, which suggests that in most patients saw palmetto is unlikely to raise caffeine levels. Caffeine is used as a probe drug for CYP1A2 activity, and therefore these results also suggest that a pharmacokinetic interaction between saw palmetto and other CYP1A2 substrates is unlikely.

Saw palmetto + Chlorzoxazone

Saw palmetto does not appear to affect the pharmacokinetics of chlorzoxazone.

Clinical evidence

In a study in 12 healthy subjects the metabolism of a single 250-mg dose of chlorzoxazone was not affected by saw palmetto 160 mg twice daily for 28 days.

Experimental evidence

No relevant data found.

Mechanism

Chlorzoxazone is used as a probe substrate of the cytochrome P450 isoenzyme CYP2E1. Saw palmetto does not appear to inhibit this route of metabolism.

Importance and management

Evidence appears to be limited to the study cited, which suggests that saw palmetto is unlikely to raise chlorzoxazone levels.

Chlorzoxazone is used as a probe drug for CYP2E1 activity, and therefore these results also suggest that a pharmacokinetic interaction between saw palmetto and other CYP2E1 substrates is unlikely.

Saw palmetto + Dextromethorphan

Saw palmetto does not appear to affect the metabolism of dextromethorphan.

Clinical evidence

In a study in 12 healthy subjects, saw palmetto 320mg daily for 16 days did not affect the metabolism of a single 30-mg dose of dextromethorphan given on day 14.

Experimental evidence

No relevant data found.

Mechanism

Dextromethorphan is used as a probe substrate of the cytochrome P450 isoenzyme CYP2D6. Saw palmetto does not appear to inhibit this route of metabolism.

Importance and management

Evidence appears to be limited to the study cited, which suggests that saw palmetto is unlikely to raise dextromethorphan levels.

Dextromethorphan is used as a probe drug for CYP2D6 activity, and therefore these results also suggest that a pharmacokinetic interaction between saw palmetto and other CYP2D6 substrates is unlikely.

This finding is confirmed by a study using debrisoquine, see Pharmacokinetics.

Saw palmetto + Food

No interactions found.

Saw palmetto + Herbal medicines

No interactions found.